Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases [2 ed.] 0128138203, 9780128138205

Table of contents :
Cover
BIOACTIVE FOOD
AS DIETARY
INTERVENTIONS
FOR ARTHRITIS
AND RELATED
INFLAMMATORY
DISEASES
Copyright
Contributors
Acknowledgments
Section A: Overview and Background on Diet and Arthritis/Inflammation Modifications
1
Foods and Arthritis: An Overview
Arthritis
Prevalence of Arthritis
Foods and Arthritis
The Role of Diet in Arthritis
Foods That Avoid in Arthritis
High-Calorie Foods
Foods Cooked at High Temperature
Food Sensitivities
High-Purine Foods and Alcohol
Butter
Beef
Candy
Nightshade Vegetables
Food Ingredients That Can Cause Inflammation and Arthritis
Sugar
Saturated Fats
Transfats
Omega 6 Fatty Acids
Refined Carbohydrates
Monosodium Glutamate
Gluten and Casein
Aspartame
Alcohol
Best Foods for Arthritis
Fruits
Mango
Tart Cherries
Strawberries
Red Raspberries
Avocado
Watermelon
Grapes
Pomegranate
Vegetables
Dark Green Leafy Vegetables
Sweet Potatoes, Carrots, Red Peppers, and Squash
Red and Green Peppers
Onions, Garlic, Leeks and Shallots
Olives
Fish
Omega-3 Fatty Acid
Farm-Raised, or Wild-Caught?
Grains
Proinflammatory Grains
Better Grain Choices
Nuts and Seeds
Walnuts
Peanuts
Almonds
Pistachios
Flaxseed
Chia Seeds
Spices
Garlic
Turmeric
Ginger
Cinnamon
Chili
Oils
Olive Oil
Grapeseed Oil
Walnut Oil
Avocado Oil
Canola Oil
Soybean Oil
Beverages
Tea
Coffee
Milk
Juices
Smoothies
Alcohol
Water
References
2
Probiotics for the Management of Rheumatoid Arthritis
Introduction
Rheumatoid Arthritis
Probiotics
RA and Gut Bacteria
RA and Oral Bacteria
Probiotics as RA Therapy
Lactobacillus casei
Lactobacillus helveticus
Lactobacillus plantarum
Lactobacillus plantarum and Lactobacillus brevis
Lactobacillus rhamnosus
Bacillus coagulans
Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum
Lactobacillus rhamnosus and Lactobacillus reuteri
Limitations of Current Research
Conclusion
References
3
Integrative and Complementary Medicine Use in Adults With Chronic Lower Back Pain, Neck Pain, and Arthritis/Mu ...
Introduction
Costs, Quality of Life, and Patient Satisfaction With CAM
Trends in CAM Usage for Treating Lower Back Pain
Trends in CAM Usage for Treating Neck Pain
Trends in CAM Usage for Treating Musculoskeletal Diseases
Trends in CAM Usage for Treating Arthritis
Summary of Our Previous Research
Discussion
Summary and Future Directions
References
4
Antiinflammatory and Antiarthritic Activities of Some Foods and Spices
Introduction
Fenugreek (Trigonellafoenum-graecum Linn., Family: Fabaceae)
Turmeric (Curcumalonga L., Family: Zingiberaceae)
Ginger (Zingiber officinale Roscoe, Family: Zingiberacae)
References
5
Improvement of Standard Antirheumatic Therapy by Phytochemicals
Introduction
Inflammation in Rheumatoid Arthritis
Effect of Natural Polyphenols in Human and Experimental Rheumatoid Arthritis
Flavonoids and Polyphenols in Experimental Arthritis
Flavonoids and Polyphenols in Human Rheumatoid Arthritis
Innovative Combination Treatment of Methotrexate With Natural Compounds in the Adjuvant Arthritis
Pinosylvin and Methotrexate
N-Feruloylserotonin and Methotrexate
Ferulaldehyde and Methotrexate
Conclusion and Perspectives
References
Section B: Nutrients and Inflammation Modification During Arthritis
6
Nutrients and Dietary Supplements for Osteoarthritis
Introduction
Macronutrients
Antioxidant Vitamins
Ascorbic Acid (Vitamin C)
Alpha-Tocopherol (Vitamin E)
Beta-Carotene and Other Carotenoids
Nonantioxidant Vitamins
Vitamin D
Vitamin B Group
Vitamin K
Dairy Product
Fiber
Soy Milk and Soy Protein
Summary for Macronutrients
Dietary Supplements
Glucosamine
Chondroitin
Combination of Glucosamine and Chondroitin
Avocado Soybean Unsaponifiables
Polyunsaturated Fatty Acids and Marine Oil
Methylsulfonylmethane
S-Adenosylmethionine
Collagen Hydrolysates
Polyphenols
Turmeric (Curcuma longa)
Boswellia serrata
Zingiber officinale (Ginger)
Harpagophytum procumbens (Devil's Claw)
Other Dietary Supplements
Uncaria tomentosa and Uncaria guianensis (Cat's Claw)
Pomegranate
Camellia sinensis (Green Tea)
Summary for Dietary Supplements
Micronutrients (Trace Elements)
Magnesium
Boron
Selenium
Zinc and Copper
Summary for Micronutrients
Conclusion
References
7
Dietary Short Chain Fatty Acids: How the Gut Microbiota Fight Against Autoimmune and Inflammatory Diseases
The Host and the Gut Microbiota
Diet, Gut Microbiota, and SCFAs
A Leaky Gut: The Origin of Inflammatory Diseases
Microbial Metabolites and Mucosal Immunology
Mechanisms of Action in the Gut
SCFAs and HDAC Inhibition of Immune Function
Gut Microbiota and Their Metabolites as Therapeutics
Concluding Remarks
References
8
Vitamin K and Rheumatoid Arthritis
Introduction
Vitamin K
Rheumatoid Arthritis
Epidemiology of Rheumatoid Arthritis
Pathology of Rheumatoid Arthritis
Etiology of Rheumatoid Arthritis
Genetic Risk Factors
Environmental Risk Factors
Clinical Manifestations of Rheumatoid Arthritis
Treatment for Rheumatoid Arthritis
Rheumatoid Arthritis and Vitamin K
Vitamin K and Inflammation in Rheumatoid Arthritis
Vitamin K and Joint Destruction in Rheumatoid Arthritis
Vitamin K and Dyslipidemia in Rheumatoid Arthritis
Vitamin K and Clinical Status of Rheumatoid Arthritis
Vitamin K and Bone Health in Rheumatoid Arthritis
Vitamin K and Glucose Homeostasis in Rheumatoid Arthritis
Conclusion
References
9
Regulation of Immune Cell Function by Short Chain Fatty Acids and Their Impact on Arthritis
Introduction
SCFAs Production, Absorption, and Molecular Targets
Impact of the SCFAs on Components of the Innate Immune System
Impact of the SCFAs on the Adaptive Immune System
Impact of SCFAs on Osteoblasts and Osteoclasts
Impact of Short Chain Fatty Acids on Arthritis
Concluding Remarks and Perspectives in the Field
References
10
Effects of 25-Hydroxyvitamin D on Bone Mineral Density and Disease Activity in Patients With Rheum
Introduction
Effects of Vitamin D on Bone Mineral Density
Bone Mineral Density in Rheumatoid Arthritis
Vitamin D in Patients With Rheumatoid Arthritis
Effects of 25(OH)D on the Immune System in Rheumatoid Arthritis
25(OH)D Levels in Rheumatoid Arthritis Patients Compared to Healthy Individuals
25(OH)D Levels and Bone Mineral Density in Rheumatoid Arthritis Patients
Effect of 25(OH)D in Relationship to Rheumatoid Arthritis Disease Activity
Effect of Vitamin D Supplementation on Rheumatoid Arthritis
Effect of Vitamin D Supplementation on Rheumatoid Arthritis Disease Activity
Effect of Vitamin D Supplementation on Rheumatoid Arthritis Disease Flare
References
11
Vitamin D and Autoimmunity
Metabolism of Vitamin D and Its Regulation
Vitamin D Sufficiency, Insufficiency, and Deficiency
Safety of Supplementation
Calcemic and Noncalcemic Actions of Vitamin D
Immunomodulation and Vitamin D
Vitamin D and Autoimmune Diseases
Vitamin D and Multiple Sclerosis
Vitamin D and Diabetes Type I
Vitamin D and Rheumatoid Arthritis
Vitamin D and Crohn's Disease
Vitamin D and Systemic Lupus Erythematosus
Vitamin D and Systemic Sclerosis
Vitamin D and Sjögren's Syndrome
Vitamin D and Autoimmune Thyroid Disease
Vitamin D and Mixed Connective Tissue Disease
Vitamin D and Antiphospholipid Syndrome
Vitamin D and Primary Biliary Cirrhosis
Vitamin D Receptor and Autoimmune Diseases
Multiple Sclerosis
Systemic Lupus Erythematosus
Crohn's Disease
Rheumatoid Arthritis
Vitamin D Supplementation in Autoimmune Diseases
Multiple Sclerosis
Type 1 Diabetes
Systemic Lupus Erythematosus
Rheumatoid Arthritis
Crohn's Disease
Conclusion
References
Section C: Foods in Arthritis
12
Prebiotic Fibers and Their Potential Effects on Knee Osteoarthritis and Related Pain
References
13
Zingiber officinale: Antiinflammatory Actions and Potential Usage for Arthritic Conditions
Introduction
Inflammation
Acute Inflammation
Chronic Inflammation
Inflammatory Cells Involved in Pain-Inflammatory Disorders in Various Organs
Platelets (Thrombocytes)
Neutrophils/Macrophages/Monocytes
Mast Cells and Basophils
Lymphocytes (T and B Cells)
Arthritis
Zingiber officinale
Morphology
Traditional Use
Chemistry
Nutritional Importance
Potential Antiinflammatory Activity of Zingiber officinale
Conclusion
References
14
Garlic and Its Role in Arthritis Management
Introduction
Garlic-A Natural Remedy for Arthritis
Antiinflammatory Effects of Dietary Garlic
Inhibitory Role of Garlic-Derived Compounds in Arthritis Signaling Pathways
References
15
Cinnamon and Arthritic Care
Introduction
Cinnamon, Oxidative Stress, and Arthritis
Cinnamon, Inflammation, and Arthritis
Safety of Cinnamon
Conclusion
Implications for Practice
Implications for Research
References
16
Biochemistry and Biology of Avocado and Soy Unsaponifiables in Osteoarthritis
Clinical Studies Involving ASU in Osteoarthritis
References
17
Current Review on Mangosteen Usages in Antiinflammation and Other Related Disorders
Inflammation
Mangosteen Compounds as Nonsteroidal Antiinflammatory Drugs
Effects Against Neurological Disorders
Effects Against Arthritis
Effects Against Cancer Development
Effects Against Dental Problems
Effects Against Digestive Disorders
Effects on Dermal and Muscular Conditions
ACKNOWLEDGMENT
References
Section D: Nutraceuticals and Herbs in Modifications of Arthritis
18
Role of Flavonoids in Management of Inflammatory Disorders
Introduction
Flavonoids and Inflammation-Mediated Chronic Disorders
Flavonoids and Inflammatory Bowel Disease
Flavonoids and Cardiovascular Disease
Flavonoids and Neurological Diseases
Mechanism of Flavonoids in Inflammatory Disorders
Oxidative Stress and Inflammation
Flavonoids as Cytokine Modulators
Flavonoids as Potential Antiinflammatory Agents
Flavonoids as Anticytokine Agents
Membrane Transport and Flavonoids
Bioavailability of Flavonoids
Major Flavonoids Reported for Inflammatory Disorders
Apigenin
Astilbin
Astragalin
Baicalin and Baicalein
Butein
Chrysin
Epicatechin
Epigallocatechin Gallate
Eriodictyol
Fisetin
Hyperoside
Kaempferol
Luteolin
Myricetin
Naringin and Naringenin
Quercetin
Wogonin
Curcumin
Resveratrol
Conclusion and Perspectives
References
19 Nawarathne Kalka: Antiinflammatory Actions and Potential Usage for Arthritic Conditions
Introduction
Pathogenesis of Rheumatoid Arthritis
Role Played by the AA Metabolism Pathway on Inflammation
Specifications for Nawarathna Kalka (Table 19.1)8,22
Honey
Cedrus deodara (Devadara)
Cuminum cyminum (S. Suduru)
Eugenia caryophylla (S. Karabu)
Ferula asafetida (S. Perumkayam)
Glycyrrhiza glabra (S. walmi)
Myristica fragrans (S. Sadikka and S. Vasawasi)
Nigella sativa (S. Kaluduru)
Picrorhiza kurroa (S. Katukarosana)
Piper longum (S. Thippili)
Terminalia bellirica (S.Bulu) and Terminalia chebula (S. Aralu)
Trachyspermum roxburghianum (S. Asamodagum)
Vernonia anthelmintica (S. Sanninayam)
Zingiber officinale (S. Inguru)
Discussion
References
20
Naringenin: A Promising Flavonoid for Herbal Treatment of Rheumatoid Arthritis and Associated Inflammatory Di ...
Introduction
Effect of Naringenin on COX
Effect of Naringenin on LPS-stimulated nitric oxide (NO) production
Effect of Naringenin on TNF-α21,22
Effect of Naringenin on the NF-κB pathway23-26
Effect of Naringenin on dendritic cell maturation27-34
Conclusion
References
21
Endophytic Fungi as a New Source of Antirheumatoid Metabolites
Introduction
What is Meant by Inflammation and Cell Molecular Signaling?
Natural Products From Plants Against Rheumatoid Arthritis
Higher Fungi as Source of Antiinflammatory
Antiinflammatory Activity of Higher Fungi
Why Do We Study Endophytic Fungi?
Endophytic Fungi as a Tool for Conservation of Higher Plants
Antiinflammatory Activity of Endophytic Fungi
Antirheumatoid Activity of Endophytic Fungi
How to Study Antirheumatoid Activity of Endophytic Fungi?
Sampling
Surface Sterilization of Plant Samples
Media of Isolation
Identification of Isolated Taxa
Phenotypic Identification
Molecular Identification and Phylogenetic Analysis
Preparation of Fungal Fermentation Broth
Animals, Induction of Adjuvant Induced Arthritis (AIA) Rat Model, and Treatments
Assessing Swelling and Mobility Scoring
Histopathology Studies
Transmission Electron Microscope Examination
Egyptian Endophytic as a Promising Source of Antirheumatoid-Producing Taxa
Chaetomium globosum KC811080 as a Promising Antirheumatoid Producer
Conclusion
References
22
Herbal Formulations and Their Bioactive Components as Dietary Supplements for Treating Rheumatoid Arthritis
Introduction
Currently Prescribed Drugs for Treating RA
Herbal Formulations as Therapeutics for Rheumatoid Arthritis
Triphala
Majoon Ushba
Trikatu
Tea Extracts
Withania somnifera Extract
Barberry Extract
Tripterygium wilfordii Extract
Angelica sinensis
Rosa multiflora
Davallia bilabiata
Bioactive Components in Herbal Extracts With Antiinflammatory Action Against RA
Conclusions
Conflict of Interest
References
23
The Potential of Plants of the Genus Syzygium (Myrtaceae) for the Prevention and Treatment of Arthritic and A ...
Introduction
Autoimmune Inflammatory Disease Etiology and Progression
The Genus Syzygium as Natural Medicines
Antioxidant Content
Antimicrobial Activity
Antiinflammatory and Immunomodulatory Activity
Conclusions
References
24
Curcumin: An Antiinflammatory Compound From Turmeric and Its Role in Alleviating Arthritis
Introduction
Curcumin-A Boon for the Arthritis Patient
Curcumin From Laboratory to Clinical Trials
Curcumin as a Regulator of the Arthritis Signaling Pathway
Concomitant Effect of Arthritis Drugs With Curcumin
Arthritis Treatment With Curcumin Nanoparticles
Curcumin Analogs and Derivatives in Arthritis Treatment
References
25
Nuclear Factor Kappa B Inhibition as a Therapeutic Target of Nutraceuticals in Arthritis, Osteoarthritis, and ...
Introduction
Rheumatoid Arthritis
NF-κB Mediator in Rheumatoid Arthritis
NFKB in Models of RA
Herbals With Potential Antiarthritic Activities via NF-κB
Capsicum Genus
Curcuma Genus
Garlic
Ginger
Licorice
Pomegranate
Resveratrol
Sesamum Oil
Whitania somnifera
Nutraceuticals Target the NF-κB Pathway in Arthritis
Camel Milk
Glucosamine
Chondroitin and Glucosamine Combination
Omega 3 Fatty Acids
Conclusion
References
Section E: Plants Extracts and Compounds in Arthritis
26
The Beneficial Role of Rutin, A Naturally Occurring Flavonoid in Health Promotion and Disease Prevention:
Introduction
Biosynthesis of Flavonoidal Compounds
Pharmacological Importance of Flavonoidal Compounds
Metabolism of Flavonoids
Biological Sources of Rutin
Medicinal Importance of Rutin
General Usage of Rutin
Pharmacological Usage of Rutin
Pharmacological Activities of Rutin
Effect of Rutin on the Antioxidant System
Effect of Rutin on Bioavailability
Effect of Rutin on Blood Disorders
Effect of Rutin Against Cancer
The Effect of Rutin on Central Nervous System
The Effect of Rutin on Cardiovascular System
The Effect of Rutin Against Inflammation
The Effect of Rutin on Lipid System
The Effect of Rutin on Liver System
The Effect of Rutin on Metabolism
The Effect of Rutin on Bones System
The Effect of Rutin on the Reproductive System
The Effect of Rutin on the Urinary System
Toxicity Study of Rutin
Cytotoxicity of Rutin
Discussion
References
27
Ocimum basilicum L.: Antiinflammatory Actions and Potential Usage for Arthritic Conditions
Introduction
Basil (O. basilicum L.)
Isolated Compounds in Basil
Immunological and Antiinflammatory Activities
Biological Activity of Basil
Basil Toxicity Studies
Conclusions
References
28
Antiinflammatory Properties of Schinus terebinthifolius and Its Use in Arthritic Conditions
Introduction
Schinus terebinthifolius Raddi-Nomenclature, Folk Medicine, and Chemical Properties
Ethnopharmacological and Pharmacological Properties
Gallic Acid
Methyl Gallate
Quercetin
Pentagalloyl Glucose
Kaempferol
Conclusion
References
29
Hemidesmus indicus and Usage for Arthritic Conditions
Introduction
Importance of Herbal Medicines
Present-Day Scenario for Herbal Medicines
H. indicus
H. indicus Plant Description
Phytochemical Constituents of the Plant
Toxicity Studies of H. indicus
Therapeutic Evidence of H. indicus
Conventional Treatment: NSAIDs
Alternative Treatment: Natural Sources
Protective Effect of Tissue Necrosis
Conclusion
References
30
Phyllanthus spp. as a Potential Alternative Treatment for Arthritic Conditions
Introduction
Methods of Evaluating Antiarthritic Properties In Vitro and In Vivo
Antiarthritic Potential of Phyllanthus
P. amarus Schumach. & Thonn.
P. emblica L.
P. acidus (L.) Skeels
P. niruri L.
P. muellerianus (Kuntze) Exell.
P. polyphyllus Willd., P. urinaria L., P. debilis Klein ex Willd., and P. kozhikodianus Sivar. & Manilal
Conclusion
References
31
Purple Willow (Salix purpurea L.) and Its Potential Uses for the Treatment of Arthritis and Rheumatism
Introduction
General Description of Salix purpurea L.
Pharmacological Activity of Willow Bark
History
Medicinal Properties of Willow Bark
Metabolism of Salicylic Glycosides
The Potential of S. purpurea Bark for Rheumatism Treatment
Phytopharmaceuticals in the Treatment of Rheumatic Diseases
Willow Bark Medicines for Rheumatism Treatment
Composition of S. purpurea Bark
The Applicability of S. purpurea Bark for the Treatment of Arthritis and Rheumatism
Conclusions
References
32
Methylsulfonylmethane: Antiinflammatory Actions and Usage for Arthritic Conditions
Description of MSM
History
Common Applications and Use Statistics
MSM Synthesis
Bioavailability and Absorption
Safety Profile of MSM
Overview of Mechanisms of MSM Actions
Common Uses of MSM
Combating Inflammation and Arthritic Symptoms
Cell Culture Studies
Animal Studies
Human Studies
Summary of Evidence for Effect
Conclusion
References
33
Therapeutic Potential of Thymoquinone in Treatment of Rheumatoid Arthritis and Related Autoimmune Diseases
Introduction
Thymoquinone Against Rheumatoid and Autoimmune Diseases
References
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Y
Z
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Citation preview

BIOACTIVE FOOD AS DIETARY INTERVENTIONS FOR ARTHRITIS AND RELATED INFLAMMATORY DISEASES

BIOACTIVE FOOD AS DIETARY INTERVENTIONS FOR ARTHRITIS AND RELATED INFLAMMATORY DISEASES Second Edition Edited by

RONALD ROSS WATSON VICTOR R. PREEDY

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom © 2019 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-813820-5 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Acquisition Editor: Tari Broderick Editorial Project Manager: Carlos Rodriguez Production Project Manager: Punithavathy Govindaradjane Designer: Mark Rogers Typeset by SPi Global, India

Contributors Ahmed M. Abdel-Azeem Botany Department, Faculty of Science, University of Suez Canal, Ismailia, Egypt Mohamed A. Abdel-Azeem Faculty of Pharmacy and Pharmaceutical Industry, University of Sinai, North Sinai, Egypt Wan Mohd Aizat Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia (UKM), Bangi, Selangor, Malaysia Khokon Miah Akanda Department of Pharmacy, Varendra University, Rajshahi, Bangladesh Abdelwahab A. Alsenosy Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt Luana Barbosa Correa Laboratory of Applied Pharmacology, Farmanguinhos; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil Katarina Bauerova Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine, Slovak Academy of Sciences; Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic Rodney L. Benjamin Bergstrom Nutrition, Vancouver, WA, United States Prakash S. Bisen School of Life Sciences, Jaipur National University, Jaipur; Research and Development Division, Tropilite Foods Pvt Ltd, Gwalior, India Richard J. Bloomer The University of Memphis, Center for Nutraceutical and Dietary Supplement Research, School of Health Studies, Memphis, TN, United States Matthew Butawan The University of Memphis, Center for Nutraceutical and Dietary Supplement Research, School of Health Studies, Memphis, TN, United States

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Contributors

Matthew Cheesman School of Pharmacy and Pharmacology, Griffith University; Menzies Health Institute Queensland, Quality Use of Medicines Network, Southport, QLD, Australia Hymie Chera Division of Cardiology, SUNY Downstate Medical Center, Brooklyn, NY, United States Flavia M. Cicuttini Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia Ian Edwin Cock School of Natural Sciences; Environmental Futures Research Institute, Griffith University, Nathan, QLD, Australia Zhaoli Dai Boston University School of Medicine, Department of Medicine, Clinical Epidemiology Research and Training Unit, Boston, MA, United States; Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, NSW, Australia Jonathan Daich Montefiore Medical Center, Bronx, NY, United States Harman Dhanoa University of Arizona Undergraduate College of Public Health, Tucson, AZ, United States Palani Dinesh Immunopathology Lab, School of Bio Sciences and Technology, VIT University, Vellore, India Meenal Dixit School of Life Sciences, Jaipur National University, Jaipur, India David T. Felson Boston University School of Medicine, Department of Medicine, Clinical Epidemiology Research and Training Unit, Boston, MA, United States; NIHR Biomedical Research Centre, University of Manchester and Central Manchester Foundation Trust, Manchester, United Kingdom Neda Ghamarzad Shishavan Digestive Oncology Research Center, Digestive Diseases Research Institute (DDRI), Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran Reza Ghiasvand Department of Community Nutrition, School of Nutrition and Food Sciences, Isfahan University of Medical Sciences, Isfahan, Iran Sumit Govil School of Life Sciences, Jaipur National University, Jaipur, India

Contributors

Ramesh K. Goyal Department of Pharmacology and Toxicology, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, India Maria das Grac¸ as Henriques Laboratory of Applied Pharmacology, Farmanguinhos; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil Sultana Monira Hussain Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia Indrani Jadhav School of Life Sciences, Jaipur National University, Jaipur, India Rohini Karunakaran Unit of Biochemistry, Faculty of Medicine, AIMST University, Bedong, Malaysia Diyathi Tharindhi Karunaratne College of Chemical Sciences, Institute of Chemistry Ceylon, Rajagiriya, Sri Lanka Waleed F. Khalil Pharmacology Department, Faculty of Veterinary Medicine, University of Suez Canal, Ismailia, Egypt Viera Kuncirova Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovak Republic Yuan Z. Lim Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia Santram Lodhi Department of Pharmacognosy, Smt. Sharadchandrika Suresh Patil College of Pharmacy, Chopda, Jalgaon, Maharashtra, India Michel Mansur Machado Cellular Toxicology Research Group (ToxCel), Federal University of Pampa, Uruguaiana, Brazil Eliana Marin˜o Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia Ili Natasya Marzaimi Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia (UKM), Bangi, Selangor, Malaysia

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Contributors

Justice Mbizo Department of Public Health, University of West Florida, Pensacola, FL, United States Keiran H. McLeod Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia Maryam Miraghajani National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran Menachem Nagar Department of Neurology, Tulane University School of Medicine, New Orleans, LA, United States Mukesh Nandave Department of Pharmacology and Toxicology, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, India Shreesh Ojha Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates Anthony Okafor Department of Mathematics and Statistics, University of West Florida, Pensacola, FL, United States Siriwan Ongchai Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand Vikas Pandey Department of Pharmacy, Guru Ramdas Khalsa Institute of Science and Technology, Jabalpur, Madhya Pradesh, India Arzoo Pannu Department of Pharmacology and Toxicology, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, India Shalini Pareek School of Life Sciences, Jaipur National University, Jaipur, India Kanika Patel Department of Pharmaceutical Sciences, Faculty of Health Science, Shalom Institute of Health and Allied Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences (SHUATS), Allahabad, India

Contributors

Dinesh Kumar Patel Department of Pharmaceutical Sciences, Faculty of Health Science, Shalom Institute of Health and Allied Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences (SHUATS), Allahabad, India G.M. Masud Parvez Department of Pharmacy, Varendra University, Rajshahi, Bangladesh Brian A. Pedersen Department of Medicine, Division of Rheumatology, Allergy and Immunology, University of California, San Diego, La Jolla, CA, United States Pathirage Kamal Perera Institute of Indigenous Medicine, University of Colombo, Colombo, Sri Lanka Silvester Ponist Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovak Republic Bahram Pourghassem Gargari Nutrition Research Center, Department of Biochemistry and Diet Therapy, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran Jerzy A. Przyborowski Department of Plant Breeding and Seed Production, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland Kilambi Pundarikakshudu Department of Pharmacognosy, L.J. Institute of Pharmacy, L.J. Campus, Ahmedabad, India Mahaboobkhan Rasool Immunopathology Lab, School of Bio Sciences and Technology, VIT University, Vellore, India James L. Richards Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia Elaine Cruz Rosas Laboratory of Applied Pharmacology, Farmanguinhos; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil Yitzhak Rosen Division of Cardiology, SUNY Downstate Medical Center, Brooklyn, NY, United States Srikumar Padmalayam Sadanandan Unit of Psychiatry, Faculty of Medicine, AIMST University, Bedong, Malaysia

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Contributors

Hazem M. Shaheen Department of Pharmacology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt Divya Shrivastava School of Life Sciences, Jaipur National University, Jaipur, India Rajesh Shukla Department of Pharmacy, Guru Ramdas Khalsa Institute of Science and Technology, Jabalpur, Madhya Pradesh, India Lukas Slovak Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovak Republic Luı´s Fla´vio Souza de Oliveira Cellular Toxicology Research Group (ToxCel), Federal University of Pampa, Uruguaiana, Brazil Leauna M. Stone Department of Public Health, University of West Florida, Pensacola, FL, United States Vetriselvan Subramaniyan Department of Pharmacology, Faculty of Medicine, MAHSA University, Bandar Saujana Putra, Malaysia Paweł Sulima Department of Plant Breeding and Seed Production, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland Melanie A. Sutton Department of Public Health, University of West Florida, Pensacola, FL, United States Jared F. Taylor Systomic Health, Los Angeles, CA, United States Angelica Thomaz Vieira Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil Gautam P. Vadnere Department of Pharmacognosy, Smt. Sharadchandrika Suresh Patil College of Pharmacy, Chopda, Jalgaon, Maharashtra, India Maryam Vahedi Department of Horticultural Science, Faculty of Agricultural Science and Engineering, University of Tehran, Tehran, Iran

Contributors

Marie van der Merwe The University of Memphis, Center for Nutraceutical and Dietary Supplement Research, School of Health Studies, Memphis, TN, United States Marco Aurelio Ramirez Vinolo Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology and Immunology—Institute of Biology, University of Campinas, Campinas, Brazil Yuanyuan Wang Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia Yu Anne Yap Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia Puya G. Yazdi Systomic Health, Los Angeles, CA, United States Swan Sim Yeap Department of Medicine, Subang Jaya Medical Centre, Subang Jaya, Malaysia Luı´sa Zuravski Cellular Toxicology Research Group (ToxCel), Federal University of Pampa, Uruguaiana, Brazil

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ACKNOWLEDGMENTS

The work of Dr. Watson’s editorial assistant, Bethany L. Stevens, in communicating with authors and working on the manuscripts was critical to the successful completion of the book. The support of Carlos Rodriguez and Nancy Maragioglio was very helpful. These are very much appreciated. Support for Ms. Stevens’ and Dr. Watson’s work was graciously provided by Natural Health Research Institute (www.naturalhealthresearch. org). It is an independent, nonprofit organization that supports science-based research on natural health and wellness, set up by Elwood Richard and managed by Dr. Richard Sharpe and Antonella Matuszewski. It is committed to informing about scientific evidence on the usefulness and cost-effectiveness of diet, supplements, and a healthy lifestyle to improve health and wellness and reduce disease.

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CHAPTER 1

Foods and Arthritis: An Overview G.M. Masud Parvez, Khokon Miah Akanda

Department of Pharmacy, Varendra University, Rajshahi, Bangladesh

ABBREVIATIONS AGE AGEs ALA CRP DHA EGCG EPA ESR FDA IL LDL MMP MSG NSAIDs PCBs PG PUFA RA TNF

advanced glycation end advanced glycation end-products alpha linoleic acid C-reactive protein docosahexaenoic acid epigallocatechin-3-gallate eicosapentaenoic acid erythrocyte sedimentation rate Food and Drug Administration interleukin low-density lipoprotein matrix metalloproteinase monosodium glutamate nonsteroidal antiinflammatory drugs polychlorinated biphenyls prostaglandin polyunsaturated fatty acid rheumatoid arthritis tumor necrosis factor

1. ARTHRITIS The word arthritis is derived from the Greek words arthron for “joint” and itis for “inflammation.” Today, the term is used for hundreds of different varieties of joint problems that have specific symptoms, such as pain, swelling, and stiffness. Arthritis refers to a range of musculoskeletal conditions where a person’s joints become inflamed, which may result in pain, stiffness, disability, and deformity. These symptoms can often have a significant impact on a person’s everyday functioning life.1 There are more than 100 types of arthritis.2

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases https://doi.org/10.1016/B978-0-12-813820-5.00001-5

© 2019 Elsevier Inc. All rights reserved.

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Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

2. PREVALENCE OF ARTHRITIS In developed nations, osteoarthritis is considered to be one of the 10 most common disabilities in older individuals, especially those who remain active in the workforce.3 From 2013 to 2015, an estimated 54.4 million US adults (22.7%) had doctor-diagnosed arthritis, with significantly higher age-adjusted prevalence in women (23.5%) than in men (18.1%). Today, an estimated 30.8 million adults have osteoarthritis.4 Osteoarthritis ranks fifth among all forms of disability worldwide.5 In US adults, osteoarthritis is considered to be the most common form of arthritis and the most common cause of disability. Arthritis prevalence increases with age.6 By 2040, an estimated 78 million (26%) US adults aged 18 or older are projected to have doctor-diagnosed arthritis.7 In 2014–15, 15.3% of Australians (3.5 million people) had arthritis, with prevalence higher among women than men (18.3% compared with 12.3%). Of persons with arthritis, more than half (58.9%) had osteoarthritis (deterioration of cartilage inside a joint), 11.5% had rheumatoid arthritis (an autoimmune disease in which the body is attacked by bacteria or viruses), and 34.8% had an unspecified type of arthritis.1 Men are nearly three times more likely to develop gout compared with women, and black males are most commonly affected.8

3. FOODS AND ARTHRITIS Millions of people suffer from painful and swollen joints associated with arthritis. In the past, many doctors told arthritis patients that dietary changes would not help them. However, this conclusion was based on older research with diets that included dairy products, oil, poultry, or meat.9,10 New research shows that foods may be a more frequent contributor to arthritis than is commonly recognized.

4. THE ROLE OF DIET IN ARTHRITIS For years, people have suspected that foods are an important factor in the development of rheumatoid arthritis. Many notice an improvement in their condition when they avoid dairy products, tomatoes, eggplant, and certain other foods. At present, 69% of patients with OA take some form of dietary supplements for their condition.11 The spinaciaoleracea vegetable can mitigate OA effects by increasing bone volume to tissue volume, which results in a decrease of the trabecular pattern factor by more than 200%.12 After a survey of more than 1000 arthritis patients, it was concluded that foods most commonly believed to worsen the condition were red meat, sugar, fats, salt, caffeine, and nightshade plants (e.g., tomatoes, eggplant).13 Once the offending food is eliminated

Foods and Arthritis: An Overview

completely, improvement usually comes within a few weeks. Dairy foods are one of the principle offenders, and the problem is the dairy protein, rather than the fat, so skin products are as much a problem as whole milk.14 An increasing volume of research shows that certain dietary changes do, in fact, help. For example, polyunsaturated oils and omega-3 supplements have a mild beneficial effect, and researchers have found that vegan diets are beneficial.15 One study in 2002 looked at the influence of a very low-fat vegan diet on subjects with moderate to severe RA. After only 4 weeks on the diet, almost all measures of RA symptoms decreased significantly.16 The journal Rheumatology published a study that found that a gluten-free vegan diet improved the signs and symptoms of RA.17 An uncooked vegan diet rich in antioxidants and fiber was shown in another study to decrease joint stiffness and pain in patients with RA.18 Some research studies have looked at fasting followed by a vegetarian or vegan diet. A review of multiple research studies concluded that this dietary treatment might be useful in the treatment of RA.19 Vegan diets dramatically reduce the overall amount of fat in the diet and alter the composition of fats. This, in turn, can affect the immune processes that influence arthritis. The omega-3 fatty acids in vegetables may be a key factor as well as the presence of saturated fat in negligible amounts. In addition, vegetables are rich in antioxidants, which can neutralize free radicals. Oxygen free radicals attack many parts of the body and contribute to heart disease and cancer; they also generally intensify the aging processes, including the joints. Iron acts as a catalyst, encouraging the production of these dangerous molecules. Vitamins C and E, which are plentiful in a diet made of vegetables and grains, help neutralize free radicals. Meats supply an overload of iron, no vitamin C, and very little vitamin E, whereas vegetables contain more controlled amounts of iron and generous quantities of antioxidant vitamins. As well as being helpful in preventing arthritis, antioxidants may also have a role in reducing its symptoms. Some arthritis treatments, including nonsteroidal antiinflammatory drugs, work at least in part by neutralizing free radicals. For the most part, however, vitamins and other antioxidants will be of more use in preventing damage before it occurs, rather than in treating an inflamed joint.20 A diet drawn from fruits, vegetables, grains, and beans therefore appears to be helpful in preventing and, in some cases, ameliorating arthritis.

5. FOODS THAT AVOID IN ARTHRITIS Common forms of arthritis include osteoarthritis, caused by wear and tear on the joints; rheumatoid arthritis, an autoimmune disease in which the body attacks its own joints; and gout, caused by a buildup of uric acid in the body. Regardless of the type of arthritis you

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have, cutting back or eliminating foods that can aggravate inflammation may help alleviate the pain and swelling.

5.1 High-Calorie Foods Obesity is directly related to osteoarthritis, especially of the knees. Each pound of extra weight puts four pounds of extra stress on knees. Fat itself generates chemicals that can exacerbate inflammation, which describes why overweight people are also at greater risk of arthritis in the hands. It is clear that obesity is connected to rheumatoid arthritis and gout as well. Cutting back on foods that are full with fats and sugars, especially empty calories such as soda or foods that trigger overeating, can help peel off pounds.

5.2 Foods Cooked at High Temperature Advanced glycation end products, or AGEs, are substances present in high-fat foods, processed foods, and foods that are fried, grilled, microwaved, or baked. Although foods overburdened with AGEs have not been linked directly to arthritis, avoiding them can help to mitigate inflammation. By eating more fish, vegetables, fruits, grains, and low-fat dairy products and fewer meats and high-fat dairy foods, AGE can be uptaken to a lesser extent. Foods should be cooked at lower temperatures or by moist-heat methods or meats should be steeped in an acid-based marinade before grilling, baking, or frying.

5.3 Food Sensitivities The sensitivity of a person in regard to gluten can cause a variety of symptoms, including joint pain. People with rheumatoid arthritis have reported that dairy foods, citrus fruits, or plants in the nightshade family such as potatoes or chili peppers aggravated arthritis symptoms. It is thought that food sensitivities might aggravate the autoimmune responses in rheumatoid arthritis.

5.4 High-Purine Foods and Alcohol Purine-rich foods cause an increase in uric acid, so they should be used in lesser amounts. These types of foods include anchovies, asparagus, organ meats, herring, mackerel, sardines, scallops, and dried beans and peas. Alcohol can also increase uric acid.

5.5 Butter Many people grew up with the habit of taking butter with biscuits or potatoes, but people with arthritis may benefit by limiting butter intake. Obesity worsens arthritis because the extra weight puts pressure on the joints. Foods that are rich in fat are often high in calories and can lead to weight gain if eaten excessively. Butter not only contains high fat, but also

Foods and Arthritis: An Overview

saturated fat, which can increase swelling and pain in the body. Therefore, it is better that butter should be avoided by people with arthritis.

5.6 Beef Meats such as beef, and mutton have been linked to increased inflammation and joint pain from arthritis. People with arthritis generally experience less pain when they go on a vegetarian diet. Beef also contains saturated fat, which can increase pain. Ecological studies have shown that the prevalence of RA is also higher in countries with higher consumption of red meat..21

5.7 Candy Sugary foods such as candy and chocolate should be eaten sparingly by arthritis patients. Because candy contains calories but no fiber or nutrients, it can lead to weight gain. Gaining too much weight can worsen the pain for an arthritic person.

5.8 Nightshade Vegetables Eggplants, peppers, tomatoes, and potatoes are all members of the nightshade family. These vegetables contain the chemical solanine, which aggravates arthritis pain and inflammation.

6. FOOD INGREDIENTS THAT CAN CAUSE INFLAMMATION AND ARTHRITIS When someone has arthritis, their body is in an inflammatory state. What they eat may not only increase inflammation, but it may also set you up for other chronic conditions such as obesity, heart disease, and diabetes. Activated white adipose tissue increases the synthesis of proinflammatory cytokines such as IL-6, IL-1, IL-8, TNFα, and IL-18 while regulatory cytokines such as IL-10 are decreased to increase body fat. In addition, exercise disrupts the clustering of cytokine expression and improves glucose tolerance without reducing body fat or cytokine levels.22–25 A few recent studies show enhanced pain responses in peripheral inflammation models in rodents with diet-induced obesity.26–29 The following are some food ingredients that may trigger more inflammation in the body.

6.1 Sugar It may be hard to resist desserts, pastries, chocolate bars, sodas, and even fruit juices. However, processed sugars trigger the release of inflammatory messengers called cytokines. Sugar goes by many names so look out for any word ending in “ose,” for example, fructose or sucrose on ingredient labels.

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6.2 Saturated Fats Several studies have shown that saturated fats trigger adipose (fat tissue) inflammation, which is not only an indicator for heart disease but also worsens arthritis inflammation. Pizza and cheese are the biggest sources of saturated fats in the average American diet. Other culprits include meat products (especially red meat), full-fat dairy products, pasta dishes, and grain-based desserts.

6.3 Transfats Known to trigger systemic inflammation, transfat can be found in fast foods and other fried products, processed snack foods, frozen breakfast products, cookies, donuts, crackers, and most stick margarines. Avoid foods with partially hydrogenated oils in the ingredient labels.16

6.4 Omega 6 Fatty Acids Omega 6 fatty acids are an essential fatty acid that the body needs for normal growth and development. The body needs a healthy balance of omega-6 and omega-3 fatty acids. Excess consumption of omega-6 s can trigger the body to produce proinflammatory chemicals. These fatty acids are found in oils such as corn, safflower, sunflower, grapeseed, soy, peanut, and vegetable as well as mayonnaise and many salad dressings.30,31

6.5 Refined Carbohydrates White flour products (breads, rolls, crackers), white rice, white potatoes (instant mashed potatoes or french fries) and many cereals are refined carbohydrates. Processed carbohydrates may trump fats as the main driver of escalating rates of obesity and other chronic conditions. These high-glycemic index foods fuel the production of advanced glycation end (AGE) products that stimulate inflammation.

6.6 Monosodium Glutamate Monosodium glutamate (MSG) is a flavor-enhancing food additive most commonly found in prepared Asian food and soy sauce, but it can also be added to fast foods, prepared soups and soup mixes, salad dressings and daily meats. This chemical can trigger pathways of chronic inflammation and affect liver health.

6.7 Gluten and Casein People who have joint pain and are sensitive to gluten, found in wheat, barley, and rye, or casein, found in dairy products, may find relief by avoiding them. And those diagnosed with celiac disease, in which gluten sets off an autoimmune response that damages the small intestine and sometimes causes joint pain, may find relief when they adopt a

Foods and Arthritis: An Overview

gluten-free diet. There may be an overlap in which some people with arthritis also have gluten sensitivity or celiac disease.

6.8 Aspartame Trying to go sugar-free? Aspartame is a nonnutritive, intense artificial sweetener found in more than 4000 products worldwide. While aspartame is approved by the FDA, studies on its effects are mixed, and the impact on people with autoimmune disease is unknown. If someone is sensitive to this chemical, their immune system may react to the “foreign substance” by attacking the chemical, which, in turn, will trigger an inflammatory response.

6.9 Alcohol Alcohol is a burden to the liver. Excessive use weakens liver function, disrupts other multiorgan interactions, and can cause inflammation. It is best eliminated or used in moderation. Long-term consumption of alcohol in moderate amounts may affect immune function and could downregulate production of proinflammatory molecules involved in the development of RA.32–36 Cutting back on foods that promote inflammation, increasing the proportion of fruits and vegetables in the diet, making fish the main protein, and getting more omega-3 s can make a big difference in arthritis symptoms.

7. BEST FOODS FOR ARTHRITIS Although there is no diet cure for arthritis, certain foods have been shown to fight inflammation, strengthen bones, and boost the immune system. Adding these foods to your balanced diet may help ease the symptoms of your arthritis.

7.1 Fruits Fruits are naturally sweet and many offer a substantial dose of antioxidants, fiber, vitamins, minerals, and other nutrients. Some have components that may help lower the inflammation that often affects people with arthritis and is linked to other serious conditions, such as heart disease and stroke. The plasma levels of vitamin C, retinol, and uric acid are inversely correlated to variables related to rheumatoid arthritis disease activity.37 The vast variety of fruits means that there are lots of great options for a healthful boost. Many berries, for example, are loaded with antioxidants, such ascorbic acid (a form of vitamin C) and anthocyanins and carotenoids, which give soft berries their deep colors. These compounds help rid the body of free radicals that promote inflammation as well as help prevent heart disease and certain cancers.

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Whatever your favorite fruit, we should try to choose seasonal, locally grown fruits as they are fresh, readily available, and cheap. Although frozen fruits retain some of their nutrients, buy fresh for the best taste and highest concentration of beneficial compounds. 7.1.1 Mango Mangoes are cultivated throughout the tropical and subtropical world for commercial fruit production. Their main constituents are polyphenols, flavonoids, triterpenoids, mangiferin, isomangiferin, tannin, and gallic acid derivatives. The possible health benefits of mangoes are being antidiabetic, antioxidant, antifungal, antimicrobal, antiinflamatory, antiviral, hepatoprotective, hypoglycemic, antiallergic, and anticancer.38–41 7.1.2 Tart Cherries Tart cherries get their rich red color and many of their powerful antiinflammatory and antioxidant benefits from the flavonoid anthocyanin. These properties make tart cherries a popular research subject, and some investigators compare the effects to nonsteroidal antiinflammatory drugs (NSAIDs). Studies that often use the concentrated juice of Montmorency cherries have found that tart cherries may relieve joint pain in people with osteoarthritis and lower the risk of flares in those with gout.42 7.1.3 Strawberries Dietary strawberries may significantly decrease inflammation and cartilage degradation, interleukin (IL)-6, IL-1β, and matrix metalloproteinase (MMP)-3 in obese adults with established knee OA.43 Strawberries are naturally low in sugar and have more vitamin C per serving than an orange. Vitamin C can lower the risk for gout, high blood pressure, and cholesterol problems. Research has also shown that women who ate 16 or more strawberries a week had lower C-reactive protein (CRP), a measure of body-wide inflammation linked to arthritis flares and heart disease. Scientists suspect that anthocyanin, along with other phytochemicals, gives strawberries their antiinflammatory and antioxidant health benefits, as with cherries. These berries are also a good source of folic acid, which the arthritis medication methotrexate can deplete. People taking the drug often need folic acid supplements to help prevent side effects. 7.1.4 Red Raspberries Like strawberries, these berries are among the highest in vitamin C and anthocyanin. Animal studies have shown that extracts from the fruit reduce inflammation and osteoarthritis symptoms. Other research shows that the fruit’s bioactive compounds lower systemwide inflammation and, when a regular part of the diet, help prevent a number of chronic conditions, such as heart disease, stroke, and type-2 diabetes.

Foods and Arthritis: An Overview

7.1.5 Avocado The rich, creamy texture of this fruit comes in part from its high content of antiinflammatory monounsaturated fat. Avocados are also rich in the carotenoid lutein. Unlike most fruits, avocados are a good source of vitamin E, a micronutrient with antiinflammatory effects. Diets high in these compounds are linked to decreased risk of the joint damage seen in early osteoarthritis. 7.1.6 Watermelon Watermelon is another fruit with antiinflammatory action; studies show it reduces CRP. It’s high in the carotenoid beta-cryptoxanthin, which can reduce the risk of rheumatoid arthritis, according to studies that followed people’s dietary habits over time. It leads the fruit pack in lycopene, an antioxidant that may help protect against certain cancers and lower heart attack risk. 7.1.7 Grapes Grapes, both white and darker-colored varieties, are a great source of beneficial antioxidants and other polyphenols. Fresh red and black grapes also contain resveratrol, which is a potent antiinflammatory. Studies show that this bioactive compound acts on the same cellular targets as NSAIDs. 7.1.8 Pomegranate Pomegranate juice is rich in polyphenolic compounds that possess antioxidant and antiinflammatory activities, which can help with swollen and tender joints, pain intensity, and ESR levels.44

7.2 Vegetables Vegetables are rich in antioxidants and other nutrients that protect against cell damage and lower inflammation throughout the body, including joints. 7.2.1 Dark Green Leafy Vegetables Energy production and other metabolic processes in the body produce harmful byproducts called free radicals, which damage cells. Free radicals have been implicated in the development of rheumatoid arthritis (RA), and in the inflammation that attacks joints. Green, leafy vegetables such as broccoli, spinach, Brussels sprouts, kale, Swiss chard, and bok choy are packed with antioxidants such as vitamins A, C, and K, which protect cells from free-radical damage. These foods are also high in bone-preserving calcium. Broccoli and other cruciferous vegetables (Brussels sprouts, cabbage, bok choy, and cauliflower) offer another benefit, a natural compound called sulforaphane. Research shows sulforaphane blocks the inflammatory process and might slow cartilage damage

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in osteoarthritis. And there’s some evidence that diets high in this vegetable family could prevent RA from developing in the first place. 7.2.2 Sweet Potatoes, Carrots, Red Peppers, and Squash These brightly orange- and red-hued vegetables get their distinctive color from carotenoids such as beta-cryptoxanthin. Plant pigments also supply sweet potatoes, carrots, squash, and red peppers with antioxidants. Some research suggests eating more foods rich in beta-cryptoxanthin could reduce the risk of developing RA and other inflammatory conditions. 7.2.3 Red and Green Peppers Peppers-no matter what their color or whether they’re mild or hot-are an abundant source of vitamin C, which preserves bone and may protect cells in cartilage. Getting less than the recommended 75 mg for women and 90 mg for men daily may increase risk for OA of the knee. 7.2.4 Onions, Garlic, Leeks and Shallots These pungent vegetables are all members of the allium family, which are rich in a type of antioxidant called quercetin. Researchers are investigating quercetin’s potential ability to relieve inflammation in diseases such as RA. Alliums also contain a compound called diallyl disulfine, which may reduce the enzymes that damage cartilage. 7.2.5 Olives Though technically a fruit and not found in the produce aisle, olives and olive oil can be potent inflammation fighters. Extra-virgin olive oil contains the compound oleocanthal, a natural antiinflammatory agent that has properties similar to the NSAID drug ibuprofen.

7.3 Fish Essential fatty acids called omega-3 s are among the most potent edible inflammation fighters, particularly the kinds of fatty acids found in fish. Marine n-3 polyunsaturated fatty acid (PUFA) is found in oily fish. Fish oils can slow the development of arthritis by decreasing the arachidonic acid content of cells involved in immune responses and decrease the production of inflammatory eicosanoids from arachidonic acid.45 It is found that peoples who adequately take vitamin D and calcium supplements are at decreased fracture risk.46 7.3.1 Omega-3 Fatty Acid Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are called marine fatty acids because they come from fish. What makes these omega-3 sources worthwhile menu

Foods and Arthritis: An Overview

additions for people with arthritis is their ability to inhibit inflammation. Omega-3 s interfere with immune cells called leukocytes and enzymes known as cytokines, which are both key players in the body’s inflammatory response. Research finds that people who regularly eat fish high in omega-3 s are less likely to develop rheumatoid arthritis (RA). And in those who already have the disease, marine omega-3 s may help reduce joint swelling and pain. The best sources of marine omega-3 s are fatty fish, such as salmon, tuna, sardines, and mackerel. Eating a 3- to 6-oz serving of these fish two to four times a week is recommended for lowering inflammation and protecting the heart. Many fish that are rich in omega-3 s are also high in mercury, which can cause brain and nervous system damage when eaten in large enough quantities. It’s important to choose the smaller fish that have less mercury. Smaller fish are lower in mercury simply by virtue of their position near the bottom of the food chain. When larger fish such as swordfish, king mackerel, tuna, and shark feed on large numbers of small fish, mercury from all those fish accumulates in their bodies. 7.3.1.1 Farm-Raised, or Wild-Caught?

The next question many fish eaters want to know is whether it’s better to buy farm-raised or wild-caught fish. Some research has found that farm-raised fish contain higher levels of polychlorinated biphenyls (PCBs) and other contaminants that have been linked to cancer. These chemicals come from the diet of farm-raised fish, which is primarily made up of smaller fish. Another concern is that farm-raised fish might contain fewer omega-3 fatty acids than wild. On this issue, the research is conflicting, but both wild-caught and farm-raised fish are considered good sources of omega-3 s.

7.4 Grains Choosing which type of pasta to cook for dinner or what bread or cereal to have with breakfast doesn’t seem like a big decision, until someone consider the effect certain grains can have on their body. Eating the wrong types can aggravate inflammation, potentially making joints hurt more than they already do. 7.4.1 Proinflammatory Grains When contemplating options in the bread, cereal, and pasta aisles, you should avoid refined grains. Not only are these highly processed grains limited in nutrition, but they can also worsen inflammation throughout the body. Grains are made up of three parts: The bran is the outer skin of the grain kernel, the germ is the innermost part that grows into a new plant, and the endosperm is the center part that provides food for the plant. Whole grains contain all three parts. Refined grains

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have removed the bran and germ, where most of the vitamins, minerals, and protein are centered. Examples of food made with refined grains are white bread, white rice, cookies, and cakes. Because of their simple structure, these carbs break down in the body rapidly. The body turns them into sugar more quickly and sugar is highly inflammatory. Refined grains have been linked to higher levels of inflammatory markers in the blood. Inflammation throughout the body is not only bad for arthritis, but it can also increase the risk for other inflammatory conditions such as heart disease and diabetes. 7.4.2 Better Grain Choices To maximize nutrition while minimizing inflammation, stick to whole grains. Many of these grains are also gluten-free (labeled with a GF below), if someone has celiac disease or a gluten intolerance. • Amaranth-GF: Although amaranth isn’t officially a grain, its nutrient composition makes it similar to cereal grains. Amaranth is high in protein, has a nutty flavor, and you can pop it like popcorn or turn it into porridge by boiling it in water. • Barley: An ideal addition to soups, stews, and risotto dishes, barley is loaded with 6 g of fiber per cup. • Brown rice-GF: Because it has not had its bran and germ stripped away during processing, brown rice is nutrient-rich. Use it as a replacement in any recipe that calls for white rice, but you’ll need to use more water and adjust cooking times. • Buckwheat-GF: Another pseudocereal like amaranth, buckwheat is technically a fruit. It may be used in noodles, crepes, pancakes, and muffins. • Bulgur: This nutty-tasting grain comes from whole wheat that’s been partly cracked. Use it in recipes, just as you would rice or couscous. • Millet-GF: Millet is a grass that’s similar to corn. It can be used as an alternative to rice, or added to bread and muffin recipes. • Quinoa-GF: This versatile, high-protein seed is an ideal grain substitute. Research is finding that quinoa might suppress the release of immune substances called cytokines, which could be helpful for both preventing and treating inflammation. • Sorghum-GF: This cereal grain is rich in protein. Use sorghum flour instead of white flour in breads, cookies, and other recipes. • Rye: Often used to make rye bread, whole rye has been shown in research to suppress hunger, which might make it a useful weight-loss tool. • Whole oats-GF: Steel-cut and other whole oats are high in protein and are naturally gluten free (although most commercially available oats are contaminated with wheat). Have them for breakfast or use them in recipes. • Whole wheat: Swapping whole-wheat flour for white in recipes will increase nutrient intake and potentially lower inflammation.

Foods and Arthritis: An Overview

7.5 Nuts and Seeds Many nuts and seeds are a good source of polyunsaturated and monounsaturated fats, which lower cholesterol and reduce the risks for heart disease that are high in people with certain types of arthritis. They also are a good source of protein and antioxidant vitamins and minerals. In addition, some nuts and seeds are high in alpha linoleic acid (ALA), a type of antiinflammatory omega-3 fatty acid. Some nuts are rich in magnesium, l-arginine, and vitamin E, which may play a role in keeping inflammation under control. Studies have shown that people who eat a diet high in these nutrients tend to have lower levels of some inflammation-causing molecules that circulate in the bloodstream and higher levels of the antiinflammatory protein adiponectin compared with those who consumed less. 7.5.1 Walnuts With their high ALA content, walnuts head the nut pack in omega-3 content, and researchers studying their effects have found that they lower C-reactive protein (CRP), a marker of inflammation linked to increased risk of cardiovascular disease and arthritis. Eating walnuts regularly can lower cholesterol, relax blood vessels to lessen stress on the heart, and reduce blood pressure. 7.5.2 Peanuts Technically a legume, peanuts are the “nut” with the most protein (about 7 g per 1-oz serving). Peanuts are also a good source of monounsaturated and polyunsaturated fats, and research shows adding them to the diet can help lower “bad” low-density lipoprotein (LDL) cholesterol and reduce heart disease risk. Peanuts deliver about 12% of the daily magnesium requirement and may help keep blood sugar under control. 7.5.3 Almonds Almonds contain more fiber than most nuts; they’re a good choice for weight management. They are also a good source of antioxidant vitamin E. Research suggests that the monounsaturated fats from an almond-rich diet lower some markers of inflammation, including CRP. 7.5.4 Pistachios Snack on pistachios to help with weight loss. Dealing with the shell slows down consumption, which is good for people with arthritis trying to lose a few pounds to take pressure off joints. Pistachios can also help lower LDL cholesterol and are high in potassium and antioxidants, including vitamins A and E and lutein.

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7.5.5 Flaxseed Flaxseed is one of the richest plant-based sources of the antiinflammatory omega-3 fatty acid ALA. Studies show it may help lower overall and LDL cholesterol and reduce the complications of diabetes and heart disease risk. 7.5.6 Chia Seeds Chia seeds are also an excellent source of antiinflammatory ALA, but their biggest benefit is their high fiber content. The fiber fills people up, which can help control weight.

7.6 Spices Often when prepping a meal, food is the primary focus and spices are, at best, an afterthought. But when following an antiinflammatory diet to help reduce the pain and joint inflammation of arthritis, the potential benefits of the spices should be considered. The more antiinflammatory the foods and spices, the more they will tamp down the chronic inflammation. It is well known that increased levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were found in the joint tissues of patients suffering from RA.47 Lipid extract from hard-shelled mussels (mytiluscoruscus) improves the clinical conditions of patients with rheumatoid arthritis by decreasing TNF-α (tumor necrosis factor α), interleukin (IL)-1β, and PGE2 (prostaglandin E2) and increasing IL-10.48 7.6.1 Garlic Garlic is a tasty addition to just about any savory dish. Like onions and leeks, it contains diallyl disulfide, an antiinflammatory compound that limits the effects of proinflammatory cytokines. Therefore, garlic can help fight the pain, inflammation, and cartilage damage of arthritis. 7.6.2 Turmeric Curcumin is the active chemical in turmeric root; it blocks inflammatory cytokines and enzymes in two inflammatory pathways. Several human trials have shown an antiinflammatory benefit, which can translate to reduced joint pain and swelling.49–51 7.6.3 Ginger Gingerol and shogaol are the chemicals in ginger that block inflammation pathways in the body. Along with ginger’s antiinflammatory properties, some studies have shown that it can also reduce osteoarthritis symptoms.52–54 7.6.4 Cinnamon Cinnamon contains cinnamaldehyde and cinnamic acid, both of which have antioxidant properties that help inhibit cell damage caused by free radicals. Cinnamon is delicious mixed with oatmeal or added to smoothies, but it’s not strong enough on its own to offer

Foods and Arthritis: An Overview

a therapeutic effect. Used in combination with other foods and spices, it may offer a cumulative antiinflammatory effect over the course of the day. 7.6.5 Chili Chili peppers contain natural compounds called capsaicinoids, which have antiinflammatory properties. It reduces cytokines and ESR levels and heals joint pain.55

7.7 Oils Some oils offer antiinflammatory action and other health perks for people with arthritis. When part of a diet that emphasizes vegetables, fruits, whole grains, and lean proteins, certain oils can help stave off heart disease, stroke, and diabetes, for which many people with arthritis have an increased risk. Some may also help prevent inflammatory conditions such as rheumatoid arthritis as well as certain cancers. All oils are a mixture of fatty acids-monounsaturated, polyunsaturated, and saturatedand it’s the ratio of these acids that determines whether an oil or fat is healthful or harmful. Healthy oils and fats have a higher amount of unsaturated fatty acids and a lower amount of saturated fatty acids than their less-healthy counterparts. Unsaturated fats-mono and poly-have unique health benefits. Monounsaturated fats can help lower blood LDL [bad cholesterol] level and raise HDL [good] cholesterol, which in turn can help prevent cardiovascular disease. Polyunsaturated fats may lower total blood cholesterol, which also helps prevent heart disease. Squeeze the most health benefits out of your oils by understanding their best uses, which often depend on their smoke point. This is the temperature at which different oils begin to smoke and break down, which destroys the compounds that give them their health benefits. 7.7.1 Olive Oil High in monounsaturated fats and antiinflammatory and antioxidant compounds, olive oils are among the best-studied fats, with many known health benefits. Extra-virgin olive oil, the least refined type, is pressed mechanically rather than processed with heat or chemicals that change its chemical properties. It contains biologically active compounds such as the polyphenols oleocanthal, oleuropein, hydroxytyrosol, and lignans that have been linked to reduced joint damage in rheumatoid arthritis. 7.7.2 Grapeseed Oil This winemaking byproduct, which is pressed from the seeds of grapes, is high in polyunsaturated fatty acids and is a good source of vitamin E.

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7.7.3 Walnut Oil This oil is high in polyunsaturated fatty acids, including alpha-linoleic acid, that have cardiovascular and cholesterol-lowering benefits. These fatty acids can also lower levels of C-reactive protein (CRP), a measure of body-wide inflammation. 7.7.4 Avocado Oil This pale green oil is rich in monounsaturated fats, which can lower heart disease and stroke risks. Research also suggests avocado oil has an antiinflammatory effect, reducing CRP. It’s also a good source of the antioxidant vitamin E. 7.7.5 Canola Oil This oil is low in saturated fatty acids and is a good source of monounsaturated and polyunsaturated fats. Research shows it helps lower cholesterol and heart disease risk. 7.7.6 Soybean Oil Soy protein decreases the rheumatoid arthritis by reducing the serum concentrations of TNF-α and IL-6.56 The beans contain significant amounts of phytic acid, dietary minerals, and B vitamins.

7.8 Beverages 7.8.1 Tea Tea is one of the most-studied drinks when it comes to its benefits for arthritis patients. Green, black, and white teas are all rich in polyphenols-compounds from plants that have strong antiinflammatory effects. Green tea contain polyphenols, which reduce inflammation and slow cartilage destruction. Studies also show that an antioxidant in green tea called epigallocatechin-3-gallate (EGCG) blocks the production of molecules that cause joint damage in people with RA.57–62 7.8.2 Coffee Research shows that coffee also has antioxidant polyphenols. That means coffee can help fight free radicals in the body, which cause cell damage. Other research suggests coffee may have a protective effect against gout as well. 7.8.3 Milk Drinking milk may help prevent gout and fight the progression of osteoarthritis, but one should use low-fat milk to avoid consuming extra calories and saturated fat. 7.8.4 Juices Orange, tomato, pineapple, and carrot juices are all high in vitamin C, which means they have antioxidant properties that can neutralize free radicals that lead to inflammation.

Foods and Arthritis: An Overview

Tart cherry juice has been shown to protect against gout flares and reduce osteoarthritis symptoms. But be sensible when drinking juice: it’s delicious but also high in sugar and calories. 7.8.5 Smoothies Colorful fruits and vegetables are also high in antioxidants. Adding berries or leafy greens such as spinach or kale can give big doses of vitamins and nutrients. Smoothies containing yogurt are full of good bacteria known as probiotics as well as lots of vitamins. Also consider exploring a fermented beverage such as kefir as an alternative. It too is full of probiotics that can decrease inflammation in the body. 7.8.6 Alcohol Red wine has a compound in it called resveratrol, which has well-established antiinflammatory effects. Studies have shown that wine consumption is associated with a reduced risk of knee OA, and moderate drinking is also associated with a reduced risk of RA. 7.8.7 Water If there’s a magical elixir to drink, it’s water. Hydration is vital for flushing toxins out of the body, which can help fight inflammation. Adequate water can help keep joints well lubricated and can help prevent gout attacks. Drinking water before a meal can also help you eat less, promoting weight loss.

REFERENCES 1. Arthritis Australia. What is arthritis? http://www.arthritisaustralia.com.au/index.php/arthritisinformation/what-is-arthritis.html. Accessed 1 December 2015. 2. Centers for Disease Control and Prevention (CDC). Arthritis in General. Updated June 1, 2016. Retrieved from, http://www.cdc.gov/arthritis/basics/general.htm; 2006. Accessed 12 December 2016. 3. Palmer KT, Goodson N. Ageing, musculoskeletal health and work. Best Pract Res Clin Rheumatol. 2015;29(3):391–404. 4. Cisternas MG, Murphy L, Sacks JJ, Solomon DH, Pasta DJ, Helmick CG. Alternative methods for defining osteoarthritis and the impact on estimating prevalence in a U.S. population-based survey. Arthritis Care Res. 2016;68(5):574–580. 5. Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases andInjuries in 21 regions, 1990-2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2012;380 (9859):2197–2223. 6. Barbour KE, Helmick CG, Boring MA, Brady TJ. Vital signs: prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation—United States, 2013–2015. Morb Mortal Wkly Rep. 2017;66:246–253. 7. Hootman JM, Helmick CG, Barbour KE, Theis KA, Boring MA. Updated projected prevalence of selfreported doctor-diagnosed arthritis and arthritis-attributable activity limitation among US adults, 20152040. Arthritis Rheum. 2016;68(7):1582–1587. 8. Wilson L, Saseen JJ. Gouty arthritis: a review of acute management and prevention. Pharmacotherapy. 2016;36(8):906–922.

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9. Panush RS, Carter RL, Katz P, Kowsari B, Longley S, Finnie S. Diet therapy for rheumatoid arthritis. Arthritis Rheum. 1983;26:462–471. 10. Lithell H, Bruce A, Gustafsson IB, et al. A fasting and vegetarian diet treatment trial on chronic inflammatory disorders. Acta Derm Venereol. 1983;63:397–403. 11. Basedow M, Runciman WB, March L, Esterman A. Australians with osteoarthritis: the use of and beliefs about complementary and alternative medicines. Complement Ther Clin Pract. 2014;20:237–242. 12. Choudhary D, Kothari P, Tripathi AK, et al. Spinaciaoleracea extract attenuates disease progression and sub-chondral bone changes in monosodium iodoacetate-induced osteoarthritis in rats. BMC Complement Altern Med. 2018;18:69. 13. Sobel D, Klein AC. Arthritis: What Works. New York: St. Martin’s Press; 1989, ISBN: 9780312032890. 14. Skoldstam L, Larsson L, Lindstrom FD. Effects of fasting and lactovegetarian diet on rheumatoid arthritis. Scand J Rheumatol. 1979;8:249–255. 15. Skoldstam L. Fasting and vegan diet in rheumatoid arthritis. Scand J Rheumatol. 1986;15:219–223. 16. McDougall J, Bruce B, Spiller G, Westerdahl J, McDougall M. Effects of a very low-fat, vegan diet in subjects with rheumatoid arthritis. J Altern Complement Med. 2002;8(1):71–75. 17. Hafstrom I, Ringertz B, Spangberg A, von Zweigbergk L, Brannemark S, al NIE. A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens. Rheumatology (Oxford). 2001;40(10):1175–1179. 18. Hanninen KK, Rauma AL, Nenonen M, et al. Antioxidants in vegan diet and rheumatic disorders. Toxicology. 2000;155(1–3):45–53. 19. Muller H, de Toledo FW, Resch KL. Fasting followed by vegetarian diet in patients with rheumatoid arthritis: a systematic review. Scand J Rheumatol. 2001;30(1):1–10. 20. Merry P, Grootveld M, Lunec J, Blake DR. Oxidative damage to lipids within the inflamed human joint provides evidence of radical-mediated hypoxic-reperfusion injury. Am J Clin Nutr. 1991;53:362–369. 21. Grant WB. The role of meat in the expression of rheumatoid arthritis. Br J Nutr. 2000;84(5):589–595. 22. Fang H, Beier F. Mouse models of osteoarthritis: modelling risk factors and assessing outcomes. Nat Rev Rheumatol. 2014;10:413–421. 23. Griffin TM, Huebner JL, Kraus VB, Yan Z, Guilak F. Induction of osteoarthritis and metabolic inflammation by a very high-fat diet in mice: effects of short-term exercise. Arthritis Rheum. 2012;64:443–453. 24. Jhun JY, Yoon BY, Park MK, et al. Obesity aggravates the joint inflammation in a collagen-induced arthritis model through deviation to Th17 differentiation. Exp Mol Med. 2012;44:424–431. 25. Iannone F, Lapadula G. Obesity and inflammation–targets for OA therapy. Curr Drug Targets. 2010;11:586–598. 26. Loredo-Perez AA, Montalvo-Blanco CE, Herna´ndez-Gonza´lez LI, et al. High-fat diet exacerbates painlike behaviors and periarticular bone loss in mice with CFA-induced knee arthritis. Obesity (Silver Spring). 2016;24:1106–1115. 27. Wang J, Zhang Q, Zhao L, Li D, Fu Z, Liang L. Down-regulation of PPAR alpha in the spinal cord contributes to augmented peripheral inflammation and inflammatory hyperalgesia in diet-induced obese rats. Neuroscience. 2014;278:165–178. 28. Croci T, Zarini E. Effect of the cannabinoid C B1 receptor antagonist rimonabant on nociceptive responses and adjuvant-induced arthritis in obese and lean rats. Br J Pharmacol. 2007;150:559–566. 29. Totsch SK, Waite ME, Tomkovich A, Quinn TL, Gower BA, Sorge RE. Total Western diet alters mechanical and thermal sensitivity and prolongs hypersensitivity following complete Freund’s adjuvant in mice. J Pain. 2016;17:119–125. 30. Goldberg RJ, Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain. 2007;129(1–2):210–223. 31. Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother. 2002;56(8):365–379. 32. Mandrekar P, Catalano D, White B, Szabo G. Moderate alcohol intake in humans attenuates monocyte inflammatory responses: inhibition of nuclear regulatory factor kappa B and induction of interleukin 10. Alcohol Clin Exp Res. 2006;30(1):135–139. 33. Lu B, Solomon DH, Costenbader KH, Keenan BT, Chibnik LB, Karlson EW. Alcohol consumption and markers of inflammation in women with preclinical rheumatoid arthritis. Arthritis Rheum. 2010; 62(12):3554–3559.

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34. Waldschmidt TJ, Cook RT, Kovacs EJ. Alcohol and inflammation and immune responses: summary of the 2005 alcohol and immunology research interest group (AIRIG) meeting. Alcohol. 2006; 38(2):121–125. 35. Bhole V, de Vera M, Rahman MM, Krishnan E, Choi H. Epidemiology of gout in women: Fifty–two– year followup of a prospective cohort. Arthritis Rheum. 2010;62(4):1069–1076. 36. Singh JA, Reddy SG, Kundukulam J. Risk factors for gout and prevention: a systematic review of the literature. Curr Opin Rheumatol. 2011;23(2):192–202. 37. Hagfors L, Leanderson P, Sk€ oldstam L, Andersson J, Johansson G. Antioxidant intake, plasma antioxidants and oxidative stress in a randomized, controlled, parallel, Mediterranean dietary intervention study on patients with rheumatoid arthritis. Nutr J. 2003;2(5). https://doi.org/10.1186/1475-2891-2-5. 38. Ba´rbara BG, Garrido G, Delgado R, Bosch F, Rabi MD. A Mangifera indica L. extract could be used to treat neuropathic pain and implication of Mangiferin. Molecules. 2010;15(12):9035–9045. 39. Gonza´lez G, Backhouse D, Nunez-Selles AJ. Analgesic and anti-inflammatory effects of Mangifera indica L. extract (Vimang). Molecules. 2001;15(1):18–21. 40. Gonzalez G, Garcia L, Lodeiro H, Quintero G. In vivo and in vitro antiinflammatory activity of Mangifera indica L. extract. Molecules. 2004;50(2):143–149. 41. Parvez M. Pharmacological activities of mango (Mangifera Indica): a review. J Pharm Phytochem. 2016; 5(3):01–07. 42. He YH, Zhou J, Wang YS, et al. Anti-inflammatory and anti-oxidative effects of cherries on Freund’s adjuvant-induced arthritis in rats. Scand J Rheumatol. 2006;35:356–358. 43. Schell J, Scofield RH, Barrett JR, et al. Strawberries improve pain and inflammation in obese adults with radiographic evidence of knee osteoarthritis. Nutrients. 2017;9(9):49. 44. Ghavipour M, Sotoudeh G, Tavakoli E, Mowla K, Hasanzadeh J, Mazloom Z. Pomegranate extract alleviates disease activity and some blood biomarkers of inflammation and oxidative stress in rheumatoid arthritis patients. Eur J Clin Nutr. 2017;71(1):92–96. 45. Miles EA, Calder PC. Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis. Br J Nutr. 2002;107(Suppl 2):171–184. 46. Sunyecz JA. The use of calcium and vitamin D in the management of osteoporosis. Thera Clin Risk Manage. 2008;4(4):827–836. 47. Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Investig. 2008;118:3537–3545. 48. Yuanqing F, Li G, Zhang X, et al. Lipid extract from hard-shelled mussel (Mytilus coruscus) improves clinical conditions of patients with rheumatoid arthritis: a randomized controlled trial. Nutrients. 2015;7:625–645. 49. Kohli K, Ali J, Ansari MJ, Raheman Z. Curcumin. A natural antiinflammatory agent. Indian J Pharm. 2005;37(3):141–147. 50. Funk JL, Oyarzo JN, Frye JB, et al. Turmeric extracts containing curcuminoids prevents experimental rheumatoid arthritis. NIH Public Access. 2006;69(3):351–355. 51. Vaidya ADB. Reverse pharmacological correlates of ayurvedic drug action. Indian J Pharm. 2006; 38(5):311–315. 52. Rehman R, Akram M, Akhtar N, et al. Zingiber officinale roscoe (pharmacological activity). J Med Plant Res. 2011;5(3):344–348. 53. Zakeri Z, Izadi S, Bari Z, Soltani F, Narouie B, Rad MG. Evaluating the effects of ginger extract on knee pain, stiffness and difficulty in patients with knee osteoarthritis. J Med Plant Res. 2011;5(15):3375–3379. 54. Feng T, Su J, Ding ZH, et al. Chemical constituents and their bioactivities of “Tongling white ginger” (Zingiber officinale). J Agric Food Chem. 2011;9(21):11690–11695. 55. Parvez M. Current advances in pharmacological activity and toxic effetcs of various capsicum species. Int J Pharm Sci Res. 2017;8(5):1900–1912. 56. Mohammad-Shahi M, Haidari F, Rashidi B, Saei AA, Mahboob S, Rashidi MM. Comparison of the effects of Genistein and Daidzein with dexamethasone and soy protein on rheumatoid arthritis in rats. Bioimpacts. 2011;1(3):161–170.

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57. Comblain F, Sanchez C, Lesponne I, Balligand M, Serisier S, Henrotin Y. Curcuminoids extract, hydrolyzed collagen and green tea extract Synergically inhibit inflammatory and catabolic Mediator’s synthesis by normal bovine and osteoarthritic human chondrocytes in monolayer. PLoS One. 2015;10(3):e0121654. 58. Henrotin Y, Lambert C, Couchourel D, Ripoll C, Chiotelli E. Nutraceuticals: do they represent a new era in the management of osteoarthritis? a narrative review from the lessons taken with five products. Osteoarthritis Cartilage. 2011;19(1):1–21. 59. Ahmed S. Green tea polyphenol epigallocatechin 3-gallate in arthritis: progress and promise. Arthritis Res Ther. 2010;12(2):1–9. 60. Akroum S, Satta D, Antimicrobial LK. Antioxidant, cytotoxic activities and phytochemical screening of some Algerian plants. Eur J Sci Res. 2009;31(2):289–295. 61. Chopade VV, Phatak AA, Upaganlawar AB, Tankar AA. Green tea (Camellia sinensis), chemistry, traditional, medicinal uses and its pharmacological activities- a review. Pharm Rev. 2008;2(3):157–162. 62. Manocha N, Samanta KC, Sharma V. Evaluation of antirheumatic activity of extract of stem bark of Ficus bengalensis. J Global Pharm Technol. 2011;3(3):31–37.

CHAPTER 2

Probiotics for the Management of Rheumatoid Arthritis Harman Dhanoa

University of Arizona Undergraduate College of Public Health, Tucson, AZ, United States

1. INTRODUCTION There are millions of commensal and symbiotic microorganisms within the human body. There are roughly as many bacteria as human cells in the body.1 The sites of colonization are the skin, oral cavity, upper respiratory tract, female genital tract, and intestinal tract. The process of colonization begins right at birth when the baby is exposed to bacteria in the vaginal canal of the mother.2 In-depth analyses of the microbiome have found that the gut is the most prevalent site of colonization and contains the greatest bacterial diversity.3 Individual gut microbiome composition is influenced by factors such as age, drug use, nutrition, stress, and infection.2 The human microbiome has a significant role in the development and maintenance of the immune system.4 Thus, it is essential that the commensal bacteria maintain local homeostasis with the host’s intestinal immune system; otherwise, the immune response may be disrupted. The gut normally provides protection against antigens from many microorganisms. While healthy microbiota can be beneficial in preventing disease, the host immune system utilizes multiple methods to protect itself against the gut microbiome and other pathogens, including a mucus layer, tight junctions between epithelial cells, and responses from the innate immune system.2 The initial innate response in RA is a nonantigen-specific site and involves macrophages, dendritic cells, natural killer cells, cytokines, and γ/δ T cells.5 Macrophages and dendritic cells first stimulate the innate immune system for a rapid effector response. The adaptive immune response that causes RA is antigen-specific, and the response follows the activation of T cells. The proinflammatory cytokines GM-CSF, IL-1, TNFα, IL-12, IL-15, and IL-18 are known to contribute to the articular destruction in RA patients.6 One focus of diet therapy for RA is to heal the microbiome and restore a healthy immune system.

2. RHEUMATOID ARTHRITIS Arthritis affects 54.4 million men and women in the United States.7 It includes >100 disorders of the joints, tissue that surrounds the joint, and connective tissue. RA is a Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases https://doi.org/10.1016/B978-0-12-813820-5.00002-7

© 2019 Elsevier Inc. All rights reserved.

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specific type of arthritis that has a prevalence between 0.5% and 1% among adults worldwide, with greater prevalence among women.8 It is an inflammatory autoimmune disease in which the immune system attacks healthy cells of the body to cause inflammation, pain, and eventually joint deformities. RA generally inflicts joints of the hands, wrists, and knees. Current treatment options for RA include disease-modifying antirheumatic drugs (DMARDs), nonsteroidal antiinflammatory agents (NSAIDs), corticosteroids, biological response modifiers, and self-management strategies.7 Such treatment options simply manage the disease. This is because the exact etiology of the disease is still unknown. It is understood that genetic factors are involved in the development of RA.4 However, research has shown that there must be an environmental factor that triggers autoimmunity in genetically predisposed individuals.3 Several studies conducted on monozygotic and dizygotic twins found a low percentage of concordance for the development of RA.4 There is no definitive proof that bacteria cause RA. Yet, RA has become one of the most carefully studied autoimmune disorders with respect to microbial dysbiosis. There is knowledge that RA development is at least related to abnormal immune function, excess production of autoantibodies, and proinflammatory T lymphocytes.2 The microbiome begins to explain gaps in the search for a causative agent for RA.

3. PROBIOTICS As early as 1907, Russian scientist Elie Metchnikoff published The Prolongation of Life: Optimistic Studies to provide a rationale for the health benefits of regular consumption of fermented milk.9 This observation ushered in a wave of research on what we now call modern probiotics. Probiotics are defined as live microorganisms (bacteria or yeasts) that provide a health benefit to the host when consumed in adequate amounts.10 Metchnikoff had hypothesized that some microorganisms present within the body are toxic by nature and that the harmful microbes can be modified by beneficial microbes through diet.9 It is now understood that the bacteria in the human host can be classified as either harmful, beneficial, or a type that exhibits an intermediate property. The harmful bacteria include Clostridium, Enterobacteriaceae, Veillonella, and Proteus.10 The beneficial bacteria of the Bifidobacterium and the Lactobacillus genera will be discussed in this chapter as potential forms of probiotic diet therapy, both of which are Gram-positive and nonspore-forming rods.10 One type of health benefit related to the consumption of beneficial bacteria is regulation of the immune system. Probiotics yield an immunomodulatory effect, either by stimulation or inhibition of natural immune responses. In relation to RA, probiotics are believed to affect the imbalance of cytokine production that is known to cause inflammation in RA patients. Cytokines are the main group of immune response mediators that provide cell-to-cell communication during innate and acquired immune responses.10 RA patients suffer from an overproduction of proinflammatory cytokines and insufficient

Probiotics for the Management of Rheumatoid Arthritis

production of antiinflammatory cytokines. Probiotics are known to induce the production of certain cytokines, namely of the Interleukin gene cluster.10 Thus, probiotics may have a balancing effect on the immune system and could offer a simple intervention to treat RA. The health outcomes for probiotic diet therapy differ among population groups, depending on the specific strain of bacteria, the dose, and the frequency of treatment. The general estimate for a probiotic dose is at least 109 colony forming units (CFUs) each day; however, the optimum dose for each strain remains to be determined.10 Across species, probiotics generally have a wide safety margin and minimal side effects such as nausea, bloating, and thirst.8

4. RA AND GUT BACTERIA The gut mucosa is the primary mucosal site attributed to the onset of RA. When functioning properly, the complex interactions in this region between the human host and 30–400 trillion microorganisms allow for gut homeostasis to be maintained in a symbiotic relationship.11 The microbiota digest and ferment carbohydrates, synthesize vitamins, and prevent colonization by harmful pathobionts that are associated with chronic inflammatory conditions. In return, the host provides a healthy environment for the microbiota to survive. The health of the host is compromised when dysbiosis upsets normal immune system functions. Research has found that patients with early RA exhibit an altered gut microbiome when compared to non-RA controls, as evidenced by significantly different fecal samples between the two groups.12 In addition, it was found that almost 20% of inflammatory bowel disease (IBD) patients have episodes of arthritis.2 Thus, the hypothesis is that intestinal bacteria influence RA. Other biomarkers of dysbiosis within the gut include increased inflammation, defective gut barrier function, and changes in the differentiation of naive CD4+ T-cells into effector T cells or Tregs.2 Tregs are regulatory T cells that supply self-tolerance to the body by suppressing immune responses against autoantigens, and the cells are crucial for the prevention of RA.13 Bacterial dysbiosis may cause Tregs to be defective in their ability to regulate other types of cells that release proinflammatory cytokines. Several studies have identified an important relationship between Tregs and pathogenic T-helper 17 (Th17) cells that also contribute to autoimmunity.14 The decline of Treg cells creates a Treg/Th17 imbalance that results in a chronic, proinflammatory state. A decline in Treg cells also leads to the production of autoantibodies such as rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies that lead to RA.14 Finally, dysbiosis of the intestinal mucosa affects the ability of toll-like receptors (TLRs) to function as innate immune response sensors.15 There are 10 types of TLRs in humans that induce signal pathways for the production of cytokines in the presence of an infection. TLRs are highly expressed within the joints of RA patients, and studies

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suggest that abnormal TLR ligands contribute largely to the chronic inflammation that is present in RA.16 Gut bacteria significantly impact local homeostasis within the host.

5. RA AND ORAL BACTERIA The production of RA-related antibodies also occurs at the oral cavity mucosal site. There are >700 species of microorganisms colonizing this cavity, yet the periodontal pockets are the most significant sites as they may contain up to 108 bacteria.17 There is a relationship between RA and periodontopathic bacteria, which may allow RA-related antibodies to be identified in periodontal disease patients prior to the onset of RA symptoms.17 RA patients also have a considerably increased comorbidity with periodontal disease and patients with periodontal disease are more likely to have RA. An epidemiological relationship may exist between the two diseases because of their similar risk factors, mechanisms for disease progression, and the fact that treatment of periodontal disease positively impacts RA severity in patients.18 Periodontal diseases such as periodontitis and gingivitis are dysbiotic and polymicrobial conditions. Inflammation and tissue damage occur when the host’s innate and adaptive immune functions fail. The pathogens Porphyromonas gingavalis and Aggregatibacter actinomycetemcomitans may cause the development of RA-related antibodies, known as anticitrullinated protein antibodies (ACPAs), through the production of citrullinated proteins.17 The critical Th17 cells that are present in diseased gut mucosa also appear in the sites of periodontal disease where chronic inflammation exists.2 A murine model by Chukkapalli et al.18 found that oral bacteria exacerbate RA by infecting mice with three oral pathogens (P. gingavalis, T. denticola, and T. forsythia). These strains are common in human periodontal disease as well. The infection occurred 24 weeks before inducing collagen-induced arthritis (CIA). The infected mice showed increased inflammation and more severe destruction of cartilage while suffering from active arthritis. The injected bacteria were present within the synovial joints of the mice, thus supporting the hypothesis that the bacteria of the oral cavity have an important role in RA. The study suggests that pathogenesis of RA follows in two steps: harmful subgingival bacteria first attack the host immune system in the form of periodontal disease and the resulting inflammatory conditions cause tissue damage in the form of RA.18 These findings provide knowledge about the human microbiome and autoimmune disease that could lead to more effective treatment for both periodontal disease and RA in the future.

6. PROBIOTICS AS RA THERAPY RA patients are often required to undergo long-term therapy. Though primarily efficacious, the treatment options of pharmaceutical drugs can yield unpleasant side effects.

Probiotics for the Management of Rheumatoid Arthritis

Some 30%–60% of RA patients utilize complementary and alternative medicine (CAM) for relief of pain and overall well-being.19 Probiotics are one of several available nutritional supplements that may provide adjuvant therapy for RA. A limited number of highquality studies with murine models and human subjects have found a positive relationship between oral administration of certain probiotic strains and decreased RA disease activity. These studies differ by probiotic strain and dose. They highlight the most favorable observations for each strain.

6.1 Lactobacillus casei The supplementation of Lactobacillus casei (L. casei) improved RA symptoms and inflammatory biomarkers among study subjects.20,21 In the human RCT by Alipour et al.,20 female patients with inactive to moderate levels of RA were studied. All participants had been under treatment with DMARDs. The study examined several measurements of RA in patients: tender and swollen joint counts, global health score, disease activity score, serum high-sensitivity C-reactive protein (hs-CRP), and serum levels of proinflammatory cytokines IL-1b, IL-6, IL-12, and TNF-α and the regulatory cytokine IL-10. Patients in the probiotic group (n ¼ 22) received a daily capsule of at least 108 colony-forming units of L. casei 01 and maltodextrin while the placebo group (n ¼ 24) received maltodextrin only. At the end of the study, significant differences were observed between the study group and the placebo group.20 Compared to baseline measurements, patients in the L. casei group had reduced serum hs-CRP levels, less swollen and tender joints, and reduced disease activity.20 There was also a significant improvement in the IL-10, IL-12, and TNF-α levels of patients in the L. casei group. The study reported no adverse effects for probiotic supplementation. The study also contributed to the current understanding of the dose-dependent effects of probiotics. The researchers found their intervention to be more efficacious than previous studies that had much larger doses of probiotics. There is some evidence that low doses of live microorganisms can be ideal for treatment because high doses have sometimes shown opposite effects to those beneficial effects seen at low doses.22 The Alipour et al.20 study did not fully explore the mechanisms by which probiotics improved RA symptoms in their subjects. It was briefly explained that probiotics can regulate the immune system in RA patients by increasing the strength of Treg cells, limiting Treg apoptosis, and preventing the production of harmful Th17 cells. The researchers suggest taking a daily capsule of 108 CFU of L. casei 01 to improve disease activity at a chemical level and alleviate physical symptoms of swollen joints in patients. So et al.21 observed similar beneficial effects of L. casei supplementation in a murine model; however, this study further investigated the effector functions of CD4 + T cells to explain the underlying mechanisms of L. casei treatment for RA. In their study, female Lewis rats were given experimental CIA. Rats in the experimental L. casei group were fed

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5  109 CFU/dose and compared to a placebo group. L. casei inhibited the production of several proinflammatory molecules: IL-1β, IL-2, IL-6, IL-12, IL-17, IFN-γ, TNF-α, and Cox-2 by CD4 + T cells. Probiotic supplementation also increased antiinflammatory IL-10 levels. The treatment group exhibited reduced swelling in the paws. To explain the underlying mechanism of L. casei in arthritis, the researchers hypothesize that L. casei downregulates the production of Th1-type cytokines while upregulating the Th2-type cytokines.21 Data from quantitative real-time PCR analysis show that the changes in cytokine expression were related to CD4+ T cells. Th1 cells are a type of T cell that produces the proinflammatory cytokines known to exacerbate synovial inflammation while Th2 cells secrete antiinflammatory cytokines needed to suppress autoimmunity. The researchers found that L. casei reduced the type II collagen-reactive effector function of Th1 cells, thereby inhibiting the release of proinflammatory cytokines. These findings suggest that L. casei can regulate the immune response in a manner that would benefit patients of RA and similar immune disorders.

6.2 Lactobacillus helveticus Lactobacillus helveticus (L. helveticus) can also reduce RA disease activity by mechanisms similar to those identified by Alipour et al.20 and So et al.21 The Kim et al.23 study is significant because it utilized an ex vivo screening system prior to testing the in vivo model in mine. The screening system was used to determine which strain of probiotic would provide the best candidate for treatment in experimental CIA. This was completed by culturing lymphocytes from the lymph nodes with probiotics. L. helveticus HY7801 was selected based on its IL-10^high/IL-12p^low expression profile. This balance of antiinflammatory/inflammatory cytokines was selected for its implications in RA development. The researchers believe this could make an important selection marker when choosing a probiotic. More research on ex vivo screening for probiotics is needed. The study found that supplementation of probiotics 3 weeks prior to induction of CIA had a preventative effect on the development of CIA.23 First, the researchers tested three strains as pretreatment options: Bifidobacterium longum (B. longum), L. helveticus, and Lactobacillus johnsonii (L. johnsonii). The mice were given a dose of 5  108 CFU/day. All three probiotics reduced the development of CIA; however, L. helveticus HY7801 most effectively reduced CII-reactive immunoglobulin antibodies. Thus, this strain was selected to treat ongoing arthritis in the second phase of the experiment. The study later found that L. helveticus HY7801 delayed the onset of experimental RA and reduced symptoms of paw swelling. It is believed that L. heleveticus improved disease activity by reducing proinflammatory cytokines TNF-α, IFN-γ, and IL-17A and enhancing IL-10 expression by CD4 T cells.23 These findings are consistent with the So et al.21 study. Their findings demonstrate the ability of probiotics to treat experimental RA, which may translate to beneficial effects in

Probiotics for the Management of Rheumatoid Arthritis

humans. The study contributes to the literature by providing a strategy to select probiotic strains ex vivo prior to in vivo intervention.

6.3 Lactobacillus plantarum A recent study of complete Freund’s adjuvant (CFA)-induced arthritis in rats found that the cell wall content of L. plantarus can reduce the progression of inflammation in arthritis. Gohil et al.24 created a model of chronic polyarthritis by testing six groups of female Wistar rats. In the treatment groups, rats received standard dexamethasone or one of three dosages for cell wall content of L. plantarum: 105, 107, or 109 CFU/animal. The arthritis development was physically measured by body weight, paw volume, lesions, joint inflammation, gait, and mobility. The biochemical measurements were erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and serum TNF-alpha. CFA-injected rats receiving treatment with L. plantarum displayed improvements in all parameters, suggesting antiarthritic activity for the probiotic.24 The beneficial effects of the treatment in improving joint health, gait, and mobility were only observed with the highest dose of 109 CFU/animal L. plantarum. Though this study utilized a murine model, its results are significant for understanding human RA. CFA has features that resemble RA in humans, and CFA includes cellmediated autoimmunity. The results illustrate that the cell wall content of L. plantarum can relieve painful symptoms of arthritis while decreasing the presence of inflammatory molecules in the joints. This study did not identify the mechanism by which L. plantarum causes changes in disease activity. Future studies should include quantitative real-time PCR as a measurement tool.

6.4 Lactobacillus plantarum and Lactobacillus brevis In addition to probiotic supplementation, the symptoms of RA patients can also be treated with functional foods. Nenonen et al.25 demonstrated the therapeutic effects of an uncooked, lactobacilli-rich, vegan diet in RA patients. The diet provided large of amounts of probiotics, chlorophyll, and fiber. Compared to the control group that ate an omnivorous diet, the “living food” diet decreased subjective symptoms of rheumatic pain, joint swelling, and morning stiffness in RA patients. Furthermore, a return to an omnivorous diet caused RA patients to experience aggravated symptoms.25 There were no observed statistically significant changes in the objective measures of the disease, which included the number of swollen and tender joints, DAS 28, HAQ, CRP, and ESR. The decrease in RA disease activity is linked to fermented wheat drink, wheat grass drink, fiber, and iron. Of these, fermented wheat drink is the rich source of lactobacilli. Patients in the experimental group received fermented wheat drink containing 2.4–4.5  1010/day of L. plantarum and Lactobacillus brevis (L. brevis). Analysis of the fecal

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microbiota of this group showed an increase in fecal lactobacilli. Thus, Nenonen et al.25 associate the decreased RA activity in the experimental group with diet-induced changes in a patient’s intestinal microflora. Unfortunately, half the patients in the diet group experienced adverse effects that caused them to stop the treatment prematurely. The nausea and diarrhea associated with this diet suggest that extreme diet therapy may not be advisable for all patients. It remains possible that a vegan diet, rich in lactobacilli, may have therapeutic effects on objective measures of RA.

6.5 Lactobacillus rhamnosus Probiotic therapy with Lactobacillus rhamnosus GG (LGG) did not yield clinically significant benefits related to RA activity; however, more patients in the LGG group (71%) reported better subjective well-being.26 No seriously adverse effects of LGG were reported. The research subjects were separated into the LGG that group received >5  109 CFU/capsule twice and a placebo group that did not receive any treatment. At a length of 12 months, this study is considered to be long term and is unlike most probiotic interventions that have been tested for RA. All patients were examined by the same physician at 0, 1, 4, 8 and 12 months from the start. The researchers were primarily interested in evaluating the number of swollen and tender joints on the body and changes in the Health Assessment Questionnaire (HAQ). The LGG was associated with a reduced number of swollen and tender joints, yet the sample size was too small to detect statistically significant differences between the treatment and placebo groups. The study observed negligible changes in the HAQ index after the study. In an effort to better understand the mechanisms of LGG by which LGG affects RA activity, researchers also analyzed secondary outcome variables: cytokines, fecal urease activity, and changes in medication. Again, there were no major changes in these variables. There was a small increase in the IL-1B cytokine, but conclusions could not be made because baseline levels had been low. There were no significant changes in other proinflammatory cytokines (IL-6 and TNF-a), antiinflammatory cytokines (IL-10 or IL-12), or serum levels of myeloperoxidase (MPO). The lack of results from a biochemical perspective may partially be explained by the fact that patients in the study were in a stable phase of the disease, meaning their disease parameters were not likely to reduce to a great extent.26 The improvement in self-reports of subjective well-being by patients is beneficial to their personal wellness but does not suggest clinical implications for LGG therapy in RA.

6.6 Bacillus coagulans In separate studies of humans and rats, the oral intake of Bacillus coagulans (B. coagulans) improved the disease activity of RA.27,28 Mandel et al.27 created an intervention for humans by means of a randomized, double-blind, placebo-controlled, parallel-design

Probiotics for the Management of Rheumatoid Arthritis

study. They provided adjunctive treatment to adult RA patients with oral administration of B. coagulans GBI-30, 6086 at a daily dose of 2  1010 CFU, and the placebo group received microcrystalline cellulose. Both groups continued the use of their standard arthritis medications. The researchers measured arthritis activity by clinical criteria, the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI), and biomarkers for ESR and CRP. No seriously adverse effects of B. coagulans were reported. There were statistically significant improvements in the treatment group.27 At the end of the study, the clinical criteria established by the American College of Rheumatology were used to evaluate physical improvements in research subjects. Patients in the probiotic group showed statistically significant improvement in Pain Scale and borderline statistically significant improvement in their own Pain Assessment. Some patients also reported better self-assessed disability, consistent with their ability to walk 2 miles and carry out daily activities at the end of the study. Biochemical analysis showed a total reduction in CRP levels, thus indicating a reduction in RA disease activity. The suggested mechanism of action for this probiotic is related to the antiinflammatory properties of the bacteria. B. coagulans produces proteins known as bacteriocins and lactic acid that lowers local pH levels. This process may eliminate some of the microbes that contribute to an inflammatory response in the host. B. coagulans also produces a butyric acid, a short-chain fatty acid, that aids in the healing process of cells in the small and large intestines.27 These immunomodulating and antiinflammatory properties may explain the ability of B. coagulans to alleviate RA. The sample size of the present study was low (n ¼ 45); however, the favorable results suggest that supplementation of B. coagulans is a safe and effective addition to RA treatment. B. coagulans has also shown improvement in the RA activity of rats. Abhari et al.28 created an in vivo model of CFA in male Wistar rats. They investigated the effects of prebiotic, probiotic, and synbiotic diets on several inflammatory markers of arthritis. These results were compared to a treatment control group that received indomethacin as a reference nonsteroidal antiinflammatory drug (NSAID). In the probiotic treatment group, rats received B. coagulans at a dose of 109 spores/day. The arthritis was measured by paw thickness, fibrinogen (Fn), serum amyloid A (SAA), and TNF-α and alpha-1-acid glycoprotein (α1AGp). Fn is a critical autoantigen in RA. SAA is known to activate proinflammatory Th1 cells and regulate the behavior of leukocytes, angiogenesis, and matrix degradation. Fn, SAA, and TNF-α have important roles in RA joint damage. There were statistically significant improvements in the treatment group.28 The B. coagulans group had a significant decrease in the production of SAA, Fn, and TNF-α proinflammatory cytokines. This group also demonstrated a significant reduction in paw thickness. The proposed mechanism of action for B. coagulans in relation to paw thickness is explained by the properties of the Indomethacin reference drug.28 Indomethacin is thought to reduce paw thickness and other RA-related inflammation by inhibiting enzymes that produce prostaglandins. Prostaglandins are downregulated by

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antiinflammatory cytokines. Abhari et al. believe that B. coagulans may act in a similar way by lowering prostaglandin production to activate antiinflammatory cytokines. These results support the supplementation of B. coagulans in RA treatment.

6.7 Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum A combined probiotic treatment with Lactobacillus acidophilus (L. acidophilus), L. casei, and Bifidobacterium bifidum demonstrated beneficial effects for RA patients. Zamani et al.29 designed a short-term RCT to test the effects of a multispecies probiotic at a total dose of 6  109 CFU/g. Each individual bacterial strain was measured at 2  109 CFU/g. Patients in the treatment and placebo groups continued the use of their standard arthritis medications. The arthritis of patients was measured primarily by the Disease Activity Score of 28 joints (DAS28) and inflammatory factors. The secondary outcome measurements were of insulin resistance, lipid concentrations, biomarkers, and oxidative stress. The results show that the mixed probiotic improved DAS-28.29 It reduced serum insulin levels, homeostatic model assessment-B cell function (HOMA-B), and (hsCRP) concentrations. There was also a borderline statistically significant improvement in the cholesterol levels of the probiotic group. They found no relationship between the probiotic treatment and glucose homeostasis parameters, lipid profiles, or biomarkers of oxidative stress. Zamani et al. explained the mechanism of action for the mixed probiotic in a manner similar to Mandel et al.27 by referencing the ability of probiotics to produce bacteriocins and butyric acid that downregulate inflammation in arthritis.

6.8 Lactobacillus rhamnosus and Lactobacillus reuteri Oral administration of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 did not significantly improve clinical criteria for RA; however, the experimental group displayed functional improvements that the control group did not.30 Pineda et al.30 conducted a pilot study on RA patients with chronic synovitis. Patients in the probiotic group received a dose of 2  1010 CFU twice daily. The primary outcome was the ability of probiotic patients to achieve an ACR20 response versus the placebo group. Arthritis activity was also physically measured by swollen and tender joints, Physician Global Assessment, HAQ, Patient Assessment of Pain, and morning stiffness. The biochemical parameters included ESR, CRP, and 15 inflammatory cytokines (IL-1α, IL-1β, IL-6, IL-8, TNF-α, IL-12p70, IL-15, IL-10, GM-CSF, G-CSF, IL-17, sCD40 ligand, MIP-1α, MIP-1β, and MCP-1). Based on the primary outcome variable, there was no statistically significant difference between the treatment and placebo groups. Interestingly, patients within the probiotic group showed statistically significant improvement in their HAQ scores from baseline to end of study.30 This bears resemblance to the Hatakka et al.26 study in which patients reported better subjective

Probiotics for the Management of Rheumatoid Arthritis

well-being despite insignificant clinical improvements. There is some reason to believe that HAQ accurately assesses the ability of RA patients to function with their illness better than other clinical evaluations. This remains unclear, so it is difficult to conclude the efficacy of Lactobacillus rhamnosus and Lactobacillus reuteri as an adjunctive treatment for RA. Still, the sample size of the present study was small (n ¼ 29) with just 15 patients in the probiotic treatment group. This may partially explain why the number of patients who received an ACR20 response was too low to demonstrate statistical significance. Further research is needed to determine if probiotics can improve functionality in the long term.

7. LIMITATIONS OF CURRENT RESEARCH The experiments described in this paper have individually demonstrated a beneficial link between probiotic supplementation and RA. Mohammed et al.8 conducted a systematic review and metaanalysis to determine the overall efficacy of probiotics in various RCTs. After conducting a comprehensive search of the existing literature, they compared nine studies involving 361 patients. The studies include those by Hatakka et al.26, Mandel et al.27, Alipour et al.20, Pineda et al.30, Nenonen et al.25, and Zamani et al.29. The metaanalysis investigated the following outcome variables: DAS 28, CRP, ESR, HAQ, swollen and tender joints, and cytokines (IL1β,IL6, IL10, IL12, and TNF-α). It was determined that probiotics significantly lowered proinflammatory cytokine IL-6.8 There was no difference of DAS 28 between the probiotic and placebo groups. The remaining outcome variables did not show a statistically significant difference. The change in IL-6 is of relevance to joint destruction in RA patients; however, the lack of additional clinical improvements shows only a small therapeutic effect for probiotics in RA treatment. Mohammed et al.8 attributed the absence of significance in the outcome variables with the large variability between RCTs. First, separate studies used different strains of probiotics at varying dosages. It is suggested that future RCTs investigating RA follow careful guidelines. RA patients should be grouped by severity of disease. There were also major differences in sample size among the studies. The sample size should be calculated with 5% type I error rate and 20% type II error rate. The therapy should continue for at least 12 weeks to accurately assess changes in outcome variables, which should include those metaanalyzed variables in Mohammed et al. Furthers RCTs of suitable statistical power are needed to determine the effects of probiotics on RA.

8. CONCLUSION RA is an inflammatory autoimmune disease without a known cause. New findings have shown that the host-microbe equilibrium has a critical role in the pathogenesis of the disease. Probiotics provide an immunomodulatory benefit to the host with minimal

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reported complications. There is some evidence that inflammation in RA can be reduced by adjunctive probiotic therapy. The likely mechanism of action is related to the release of proinflammatory cytokines, such as IL-6; however, the current state of evidence remains too low to make definitive conclusions. The data suggest that future RCTs are needed to prove the efficacy of probiotics in treating RA symptoms and biochemical activity.

REFERENCES 1. Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016;14:e36103. 2. Jethwa H, Abraham S. The evidence for microbiome manipulation in inflammatory arthritis. Rheumatology. 2017;56:1452–1460. 3. Sandhya P, Danda D, Sharma D, Scaria V. Does the buck stop with the bugs?: An overview of microbial dysbiosis in rheumatoid arthritis. Int J Rheum Dis. 2016;19:8–20. 4. Bedaiwi MK, Inman RD. Microbiome and probiotics: link to arthritis. Curr Opin Rheumatol. 2014;26:410–415. 5. Arend WP. The innate immune system in rheumatoid arthritis. Arthritis Rheumatol. 2001;44:2224–2234. 6. Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest. 2008;118:3537–3545. 7. Centers for Disease Control and Prevention. 2017 Rheumatoid Arthritis (RA)jArthritis Basics jArthritis Types j Arthritis jCDC. https://www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html. Updated July, 07 2017. Accessed 17 January 2018. 8. Mohammed AT, Khattab M, Ahmed AM, et al. The therapeutic effect of probiotics on rheumatoid arthritis: a systematic review and meta-analysis of randomized control trials. Clin Rheumatol. 2017;36:2697–2707. 9. Anukam KC, Reid G. Probiotics: 100 years (1907-2007) after Elie Metchnikoff’s Observations. In: Mendez-Vilas A, ed. Communicating Current Research and Educational Topics and Trends in Applied Microbiology. Bajadoz: Formatex; 2007:466–474. 10. Gill H, Prasad J. Probiotics, immunomodulation, and health benefits. Adv Exp Med Biol. 2008;606:423–454. 11. de Oliveira GLV, Leite AZ, Higuchi BS, Gonzaga MI, Mariano VS. Intestinal dysbiosis and probiotic applications in autoimmune diseases. Immunology. 2017;152:1–12. 12. Eerola E, M€ ott€ onen T, Hannonen P, et al. Intestinal flora in early rheumatoid arthritis. Br J Rheumatol. 1994;33:1030–1038. 13. Cooles FAH, Isaacs JD, Anderson AE. Treg cells in rheumatoid arthritis: an update. Curr Rheumatol Rep. 2013;15:352. 14. Alunno A, Manetti M, Caterbi S, et al. Altered immunoregulation in rheumatoid arthritis: the role of regulatory T cells and proinflammatory Th17 cells and therapeutic implications. Mediators Inflamm. 2015;2015:751793. 15. Frosali S, Pagliari D, Gambassi G, Landolfi R, Pandolfi F, Cianci R. How the intricate interaction among toll-like receptors, microbiota, and intestinal immunity can influence gastrointestinal pathology. J Immunol Res. 2015;2015:489821. 16. Huang Q, Pope R. The role of toll-like receptors in rheumatoid arthritis. Curr Rheumatol Rep. 2009;11:357–364. 17. Cheng Z, Meade J, Mankia K, Emery P, Devine DA. Periodontal disease and periodontal bacteria as triggers for rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2017;31:19–30. 18. Chukkapalli S, Rivera-Kweh M, Gehlot P, et al. Periodontal bacterial colonization in synovial tissues exacerbates collagen- induced arthritis in B10.RIII mice. Arthritis Res Ther. 2016;18:161. 19. Ferna´ndez-Llanio Comella N, Ferna´ndez Matilla M, Castellano Cuesta JA. Have complementary therapies demonstrated effectiveness in rheumatoid arthritis? Reumatol Clı´n. 2016;12:151–157.

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20. Alipour B, Homayouni-Rad A, Vaghef-Mehrabany E, et al. Effects of Lactobacillus casei supplementation on disease activity and inflammatory cytokines in rheumatoid arthritis patients: a randomized double-blind clinical trial. Int J Rheum Dis. 2014;17:519–527. 21. So J-S, Kwon H-K, Lee C-G, et al. Lactobacillus casei suppresses experimental arthritis by downregulating T helper 1 effector functions. Mol Immunol. 2008;45:2690–2699. 22. Borchers A, Selmi C, Meyers F, Keen C, Gershwin M. Probiotics and immunity. J Gastroenterol. 2009;44:26–46. 23. Kim J, Chae C, Kim G, et al. Lactobacillus helveticus suppresses experimental rheumatoid arthritis by reducing inflammatory T cell responses. J Funct Foods. 2015;13:350–362. 24. Gohil P, Vimal Patel B, Shrikalp Deshpande B, Mehul Chorawala B, Gaurang Shah B. Anti-arthritic activity of cell wall content of Lactobacillus plantarum in freund’s adjuvant-induced arthritic rats: involvement of cellular inflammatory mediators and other biomarkers. Inflammopharmacology. 2017;26:171–181. 25. Nenoen M, Elorinne AL, Helve TA, H€anninen O. Uncooked, lactobacilli-rich, vegan food and rheumatoid arthritis. Br J Rheumatol. 1998;37:274–281. 26. Hatakka K, Martio J, Herranen M, et al. Effects of probiotic therapy on the activity and activation of mild rheumatoid arthritis—a pilot study. Scand J Rheumatol. 2003;211–215. 27. Mandel DR, Eichas K, Holmes J. Bacillus coagulans: a viable adjunct therapy for relieving symptoms of rheumatoid arthritis according to a randomized, controlled trial. BMC Complement Altern Med. 2010;10(1). 28. Abhari K, Shekarforoush SS, Hosseinzadeh S, Nazifi S, Sajedianfard J, Eskandari MH. The effects of orally administered Bacillus coagulans and inulin on prevention and progression of rheumatoid arthritis in rats. Food Nutr Res. 2016;6030876. 29. Zamani B, Golkar HR, Farshbaf S, et al. Clinical and metabolic response to probiotic supplementation in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled trial. Int J Rheum Dis. 2016;19:869–879. 30. Pineda M, Thompson SF, Summers K, de Leon F, Reid G. A randomized, double-blinded, placebocontrolled pilot study of probiotics in active rheumatoid arthritis. Med Sci Monit. 2011;16:347–354.

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CHAPTER 3

Integrative and Complementary Medicine Use in Adults With Chronic Lower Back Pain, Neck Pain, and Arthritis/Musculoskeletal Diseases Justice Mbizo*, Anthony Okafor†, Melanie A. Sutton*, Leauna M. Stone* * Department of Public Health, University of West Florida, Pensacola, FL, United States Department of Mathematics and Statistics, University of West Florida, Pensacola, FL, United States

†

1. INTRODUCTION This chapter provides an overview of the distribution and factors that influence complementary and alternative medicine (CAM) use worldwide for chronic diseases, with an emphasis on musculoskeletal diseases and chronic arthritis/rheumatoid arthritis as well as symptoms commonly associated with these conditions (e.g., chronic neck and back pain). We additionally provide a summary of our recent research on the role of body mass index (BMI) on CAM use among normal weight, overweight, and obese adults in the United States with these conditions. In the United States, four nationally administered surveys since 1990 have demonstrated that a third of American adults turned to CAM therapies for acute and chronic issues, with total expenditures for CAM therapies most recently estimated at $34 billion in 2007.1 Early trends suggested CAM usage for back pain was the highest commonly reported reason,2 and a number of studies to examine the perceived benefits of various CAM modalities for patients who suffer from back pain followed.3 Yoga evolved as one of the more common CAM activities used to help reduce chronic low back pain,2 with additional studies examining the benefits of yoga for overweight or obese persons with comorbid conditions.4 CAM use for pain management in patients with chronic musculoskeletal pain has been studied in the United Kingdom, with glucosamine and fish oil being the most commonly used treatments.5 Adult patients in this study remained active users of conventional medicine, but supplemented their care with CAM as a healing therapy for persistent pain. Studies of healthy individuals have sought to investigate how attitudes of healthcare recipients impact CAM use beyond justifications based on dissatisfaction with conventional medicine. For example, McFadden and colleagues reported that among healthy

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individuals, having a mindset congruent with CAM philosophies was the sole predictor of past CAM use, agreement with holistic balance (more narrowly focused as the mind-body relationship) was the sole predictor for current CAM use, and future CAM use was predicted by CAM philosophical congruence and influence from powerful others (e.g., doctors, family, friends).6 Alternatively, for chronic pain populations, factors such as having more control of their treatment plan have been reported at a higher rate compared to dissatisfaction with conventional medicine.7 A CAM adherence study examining perceptions of arthritis patients to the use of provider-based CAM found that viewing oneself as having a healthy lifestyle predicted CAM use.8 Results from additional surveys, such as the Canadian Community Health Survey, allowed researchers to begin reporting on the use of CAM with chronic diseases such as asthma, migraines, diabetes, and epilepsy.9 Nationwide observational studies in France on patients with musculoskeletal disorders noted patients with chronic musculoskeletal conditions (i.e., a duration of >12 weeks with their current episode) tended to seek care more often with practitioners offering alternatives to conventional medicine (e.g., homeopaths or regular prescribers of CAM).10 In Lagos, Nigeria, studies on childhood use of CAM for treating chronic health conditions (epilepsy, sickle cell anemia, and asthma) noted the high use of biological products as well as the influence of relatives, friends, and neighbors in making choices regarding CAM use.11 Research on factors associated with pediatric use of CAM in Germany has been ongoing within the German Infant Study on the Influence of Nutrition Intervention birth cohort established in 1995, with 14% of 15 year olds contacted in 2011–13 reporting the use of at least one type of medicinal CAM in the preceding month.12

2. COSTS, QUALITY OF LIFE, AND PATIENT SATISFACTION WITH CAM Studies addressing the cost of annual sick days due to back pain have been conducted for decades in countries such as Sweden and the United Kingdom.13 As CAM use has increased, a number of researchers have examined the overall impact to cost expenditures within healthcare systems for CAM users versus non-CAM users. For example, annual out-of-pocket expenses for vitamins/minerals and/or at least one form of CAM for cancer survivors and cancer-free adults in the US have been estimated at $6.7 and $52 billion, respectively.14 A 2012 study on US patients with back or neck problems showed that the spine-related medical expenditures were lower among CAM users compared to non-CAM users.15 Researchers have also quantified the higher costs associated with lost productivity due to lower back pain compared to the costs of different doses of CAM, such as number of sessions of spinal manipulative therapy.16 Comparison studies of private health plans have similarly shown the reduced cost of chiropractic care compared to costs associated with conventional treatments.17

Integrative and Complementary Medicine Use

Quality of life and patient satisfaction studies related to CAM use are difficult to evaluate in terms of direct cost savings, but can help healthcare providers understand both stressors and dissatisfaction points in various patient populations as related to the utilization of various CAM modalities. For example, Malaysian researchers within outpatient chemotherapy centers noted that CAM users reported higher financial burdens.18 In a systematic review comparing the costs of chiropractic care to other interventions for spine pain, Dagenais and colleagues noted that several studies noted high patient satisfaction with chiropractic care compared to receiving care from a medical physician or receiving an educational booklet about lower back pain.17

3. TRENDS IN CAM USAGE FOR TREATING LOWER BACK PAIN Using data from the 2012 National Health Interview Survey, Ghildayal and colleagues reported that individuals suffering from lower back pain most commonly used herbal therapies compared to other CAM options.19 Additional studies have noted the efficacy outcomes with this condition when CAM treatments were applied immediately or at short-term follow-up.20 The relevance of long-term use of CAM in this population is critical, given that estimates range from 10% to 62% for the percentage of this population that will develop chronic pain,21 and back pain or back problems rank within the top five medical conditions for which CAM was most used across multiple studies.22 In addition, the mean pain duration for patients with chronic pain has been reported as high as 9.8 years.7 Healthcare utilization costs for lower back pain have been estimated at $100 billion a year, and these patients have been reported with rates of psychological distress at four times the rate of those without back pain.19 Due to the longevity and debilitating chronic nature of their medical conditions, this patient population has been reported to have significant concerns about permanent conventional drug intake, with some studies noting concerns about drugs at a rate four times more frequent than concerns resulting from bad experiences with conventional medical practitioners.23 When comparing insured patients with back pain that do and do not use CAM providers, cost savings were noted in studies among CAM users, with reduced expenditures attributed to less inpatient care and reduced use of high-tech imaging.24 Gender-based studies of back pain populations have noted that females tend to seek out CAM as a supplement, rather than a replacement, for conventional care.25

4. TRENDS IN CAM USAGE FOR TREATING NECK PAIN Among US adults, national surveys suggest the 38% utilizing some form of CAM therapy most commonly use it to relieve back or neck pain.26 In 2007, neck and back pain together ranked as the most frequent reason for CAM therapies among children.27 In

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Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

a recent study on pregnant women and CAM usage, patients reported consultations for neck pain were most often done with CAM practitioners only.28 In a cohort study including patients with neck pain, Saha and colleagues found that a 2-week integrative medicine inpatient treatment including CAM demonstrated improved health outcomes related to improved pain intensity/disability, health-related quality of life, and mental health.29

5. TRENDS IN CAM USAGE FOR TREATING MUSCULOSKELETAL DISEASES For individuals with musculoskeletal conditions, CAM is most often cited for its use to improve pain and functional limitations.30 Studies have additionally examined the use of CAM in patient populations using opioid therapy for chronic pain syndromes as a way to help guide physicians seeking information on the use of CAM therapies as initial or adjunctive treatments alongside the lowest-effective opioid dosing strategy.31 Given the economic burden of these conditions on healthcare systems, assessing the medical expenditures associated with musculoskeletal conditions often focuses on understanding the direct and indirect costs for specific CAM modalities. For example, studies on the use of neural therapy in this population compared to conventional medicine have suggested that direct costs may be higher due to longer consultations, but improved health outcomes in terms of fewer work incapacity attestations can lower indirect costs.32

6. TRENDS IN CAM USAGE FOR TREATING ARTHRITIS Given the high disability burden of arthritis in the United States33 (approximately 22% of adults are diagnosed with this condition34), researchers have sought to identify specific populations with comorbidities (e.g., cancer35) as well as underserved populations34 that may benefit from CAM-specific therapies. The use of CAM to treat stress in autoimmune diseases36 has important implications for this population, particularly those with a family history of rheumatoid arthritis and especially because of the serious side effects of conventional therapy.37 A study on CAM use among African Americans with rheumatoid arthritis found that, on average, patients tried three treatments, five activities, and consulted at least one CAM provider.38 Additional studies examining the use of CAM in women across urban, suburban, and rural areas showed that supplements were commonly used across all locations.39

7. SUMMARY OF OUR PREVIOUS RESEARCH We have previously examined CAM use trends by normal weight, overweight, and obese persons with arthritis or other musculoskeletal diseases,40 using data from

Integrative and Complementary Medicine Use

participants completing the 2007 National Health Interview Survey (NHIS)41 and the supplemental Adult Alternative Medicine module. Respondents completing this survey reported CAM use within the following domains defined by the National Center for Complementary and Alternative Medicine:42 (1) manipulative, including chiropractic approaches and massage; (2) mind-body, including meditation, prayer, and yoga; (3) biologically based, including herbs and diets; (4) energy therapies, including Reiki and magnet therapy; and (5) alternative/whole medical systems, including Ayurveda, homeopathy, and naturopathy. A dataset consisting of 9724 adult Americans (
18 years) provided the means to examine self-reported cases of chronic musculoskeletal diseases and chronic rheumatoid arthritis, stratified by BMI, along with the ability to include cases of self-reported chronic neck or lower back pain or limitation due to chronic disease (common symptoms of many forms of musculoskeletal diseases). As summarized in Table 3.1, in addition to the variables noted above, the characteristics of the study population included age, gender, race/ethnicity, education, marital status, family income, insurance status, whether the participant had a regular source of care, and region of residence. A complete description of the descriptive, bivariate, and multivariate logistic regression results is provided in Mbizo et al.40 with an overview provided here. Key findings from this research based on demographic characteristics and health conditions included the following: • CAM use was high (>70%) for all groups with nonmissing data based on:  Age ( χ 2 ¼ 4.7, P < .01)  Gender ( χ 2 ¼ 77.1, P < .001)  Race/ethnicity ( χ 2 ¼ 13.1, P < .001)  Education ( χ 2 ¼ 4.3, P < .01)  Marital status ( χ 2 ¼ 10.6, P < .001)  Family income ( χ 2 ¼ 75.0, P < .001)  BMI status ( χ 2 ¼ 44.1, P < .001)  Insurance status ( χ 2 ¼ 34.8, P < .001)  Region of residence ( χ 2 ¼ 2.7, P < .05)  With and without chronic neck pain ( χ 2 ¼ 22.6, P < .001)  With and without chronic lower back pain ( χ 2 ¼ 21.9, P < .001)  With and without limitation due to chronic disease ( χ 2 ¼ 152.1, P < .001)  With and without chronic/rheumatoid arthritis ( χ 2 ¼ 73.3, P < .001). • Participants with a usual source of care had higher CAM use at 83% compared to those without a usual source of care, reporting CAM usage at 52% ( χ 2 ¼ 622.8, P < .001). • For those with self-reported chronic musculoskeletal diseases, CAM use was 50% compared to those without this condition reporting 80% usage, ( χ 2 ¼ 349.5, P < .001). Figure 3.1 provides a summary of significant results in terms of those characteristics of the study population from Table 3.1 with increasing odds ratio of CAM use (see Table 3.1 for

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Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

Table 3.1 Characteristics of study participants Independent variables

Sample characteristics (n 5 9724) Count

Weighted (%)

Male (ref ) Female

3816 5908

39.5 60.5

Race/ethnicity White (ref ) Black/African American Hispanic Others Missing

7751 1466 123 338 46

79.6 15.1 1.2 3.6 0.5

Normal/underweight (ref ) Overweight Obese

3689 3063 2972

37.9 31.5 30.6

Age 64 Missing

1737 1495 1901 3193 1398

17.8 15.5 19.4 32.8 14.5

5293 2830 1565 36

54.4 29.1 16.1 0.4

1760 5585 2105 274

18.2 57.3 21.7 2.8

4273 1229 1300 1816 1106

44.0 12.5 13.4 18.9 11.2

1668 2297 3499 2260

17.1 23.5 35.9 23.5

Gender

Body mass index

Marital status Married (ref ) Widowed/divorced Single/never married Missing Education Incomplete high school (ref ) High school graduate College graduate Missing Family income Less than $35,000 (ref ) $35,000–49,999 $50,000–74,999 $75,000 or more Other (including missing) Region Northeast (ref ) Midwest South West

Integrative and Complementary Medicine Use

Table 3.1 Characteristics of study participants—cont’d Independent variables

Sample characteristics (n 5 9724)

Count

Weighted (%)

8216 1508

84.5 15.5

8342 1382

86.0 14.0

Yes No (ref )

768 8956

7.9 92.1

Chronic/rheumatoid arthritis Yes No (ref )

5100 4624

52.5 47.5

Chronic neck pain Yes No (ref )

3105 6619

32.2 67.8

6067 3657

62.3 37.7

5399 4325

55.8 44.2

Have a usual source of care Yes No (ref ) Insurance Yes No (ref ) Chronic musculoskeletal disease

Chronic lower back pain Yes No (ref ) Limitation due to chronic disease Yes No (ref )

the reference characteristics). For example, patients reporting chronic/rheumatoid arthritis were 27% more likely to use CAM compared to those not reporting this condition (95% confidence interval, 1.10–1.45; P < .01). For the educational levels reported in Table 3.1, those with high school education and those college graduates were 25% (95% confidence interval, 1.07–1.46; P < .01) and 49% (95% confidence interval, 1.21–1.83; P < .001) more likely to use CAM, respectively, compared to those with an incomplete high school education. Of additional note is that persons with a usual source of care were approximately three times more likely to use CAM compared to those without a usual source of care (95% confidence interval, 2.54–3.45; P < .001). For additional details on confidence intervals for the remaining items in Figure 3.1 (and also in Figure 3.2), see Mbizo et al.40 Alternatively, Figure 3.2 summarizes significant results in terms of those characteristics where a decreased odds ratio of CAM use was observed. Notably, a 23% reduction in the odds of CAM use was found for those aged 50–64 (95% confidence interval, 0.64–0.92; P < .01), and those with a chronic musculoskeletal disease were 56% less likely

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Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases 2.96***

1.25**

1.24**

1.27**

1.27*

1.49*** 1.57*** 1.30*** 1.35*** 1.37*** 1.37***

1.68*

1.74***

Figure 3.1 Significance levels: *P < .05, **P < .01, ***P < .001. 0.77** 0.44***

Age 50–64 years

Chronic musculoskeletal disease (yes)

Figure 3.2 Significance levels: **P < .01, ***P < .001.

to use CAM (95% confidence interval, 0.37–0.52; P < .001), compared to the respective reference characteristics in Table 3.1. Marital status and having insurance were not significantly associated with CAM use (P
.05). CAM use by BMI stratification provided additional insights into the proportion of CAM use by chronic disease status, as shown in Figure 3.3. BMI categories were defined as normal/underweight (BMI < 25 kg/m2), overweight (25  BMI < 30 kg/m2), and obese (BMI
30kg/m2). Across all weight groups, 50% of persons with chronic musculoskeletal disease reported using CAM (P < .001). However, when stratified by BMI, for those persons Yes 80%***

79%***

92%** 82%**

83% 80%

No 82%*** 73%***

80%*** 67%***

85%*** 79%***

82%*

78%*

50%*** 25%***

Across all weights

Normal/ underweight

Overweight

Chronic musculoskeletal disease

Obese

Across all weights

Normal/ underweight

Overweight

Chronic/rheumatoid arthritis

Figure 3.3 Significance levels: *P < .05, **P < .01, ***P < .001; BMI ¼ body mass index.

Obese

Integrative and Complementary Medicine Use 2.13*

1.32*

1.27**

1.16

1.06

0.98

0.44*** 0.27***

Across all weights

Normal/ underweight

Overweight

Obese

Across all weights

Normal/ underweight

Chronic musculoskeletal disease

Overweight

Obese

Chronic/rheumatoid arthritis

Figure 3.4 Significance levels: *P < .05, **P < .01, ***P < .001; BMI ¼ body mass index.

with chronic musculoskeletal disease, CAM use was highest among those overweight (92%, P < .01) and lowest in those underweight or with normal weight (25%, P < .001). The proportion of CAM use for obese chronic musculoskeletal disease patients was not statistically significant (P
.05). Alternately, CAM use was very high (
80%) across all weight groups and at each level of BMI for those with chronic/rheumatoid arthritis (P < .05). The associated odds ratios of CAM use by chronic disease status, stratified by BMI, are summarized in Figure 3.4. Of note here is that for persons with chronic musculoskeletal disease, those overweight were more than two times more likely to use CAM compared to those overweight patients without chronic musculoskeletal disease (P < .05). Similarly, overweight patients with chronic/rheumatoid arthritis were 32% more likely to report CAM use compared to those overweight but not reporting having chronic/rheumatoid arthritis (P < .05). The odds ratios of CAM use by race/ethnicity, overall and stratified by BMI, are summarized in Figure 3.5. Blacks/African Americans and Hispanics showed statistically significant increased odds of CAM use when compared to whites across all weight groups (P < .05). Increased odds of CAM use were also observed for these two races in the normal/underweight group after BMI stratification; however, these odds were not statistically significant (P
.05). Furthermore, blacks/African Americans who were overweight White (ref)

Black/African American

Hispanic

Other

Missing

2.46*** 2.03 1.74*** 1.68* 1.00

1.28

1.14

1.00 0.71

Across all weights

1.94*** 1.81

1.44

1.40 1.00

0.89

1.00

0.68

Normal/underweight

0.98

0.57

Overweight

Figure 3.5 Significance levels: *P < .05, ***P < .001; BMI ¼ body mass index.

0.51

Obese

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46

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases Northeast (ref)

1.00

1.37*** 1.27* 1.14

Across all weights

1.20 1.28 1.00 1.10

Normal/underweight

South

Midwest

West 1.35*

1.00

1.14

Overweight

1.57**

1.43*

1.21

1.24

1.00

Obese

Figure 3.6 Significance levels: *P < .05, **P < .01, ***P < .001; BMI ¼ body mass index.

were 2.46 times more likely to report CAM use compared to white participants (P < .001). Obese blacks/African Americans were 94% more likely to report CAM use compared to whites (P < .001). Across all weight groups, Figure 3.6 summarizes how individuals from the South and West demonstrated the highest odds of CAM use at 37% and 27% increased likelihood compared to those from the Northeast, respectively (P < .05). However, when region of residence was stratified by BMI, it was observed that region of residence was not a significant indicator of CAM use for normal and underweight participants. Alternatively, those overweight participants from the South and West were 35% and 43%, respectively, more likely to report CAM use compared to Northeast residents (P < .05). For obese individuals only from the South, this likelihood increased to 57% (P < .01). Additional results from BMI stratification in Mbizo et al.40 included: • Female gender was a statistically significant predictor of CAM use at all levels of BMI (P < .001). • For educational levels, increased odds of CAM use were statistically significant for high school graduates at both the normal/underweight and overweight BMI levels, increasing from 1.32 to 1.65 (P < .05). • Increased odds of CAM use were also statistically significant for college graduates at both the normal/underweight and overweight BMI levels, increasing from 1.57 to 2.25 (P < .01).

8. DISCUSSION Studies comparing consumer motivations toward CAM noted a shift in 2005 where consumers were weighing the positive aspects of CAM more so than the negative aspects of conventional medicine.43 Following these trends in 2007, consumers were spending nearly twice as much on self-care purchases of CAM products, classes, and materials ($22 billion) compared to practitioner visits ($12 billion).44 Examining behavioral indicators,45 demographic46 and sociocultural factors,47 and religious beliefs48 for impact on CAM use will continue to be critical as future economic evaluations of CAM1, 15 attempt to identify specific clinical populations that may be best suited for educational

Integrative and Complementary Medicine Use

outreach. Equally important to these outreach efforts will be the consideration of ongoing studies identifying how the structure of healthcare systems impacts CAM utilization, particularly when there are delays in seeking conventional care49 or cost considerations.50

9. SUMMARY AND FUTURE DIRECTIONS CAM use has gained popularity in the United States and the western hemisphere. Its growing acceptance both among native-born Americans and immigrants importing health practices from their lands of origin provides unique opportunities for systematic examinations of usage trends. Our work and those of others have provided observational yet convincing evidence of the prevalence of the use of numerous types of CAM modalities. The time has now come for more basic science studies to understand the biochemical processes by which these modalities work to improve health and wellness among users. Such studies should also address safety and toxicity effects so healthcare providers can be better informed regarding the relevance of patients sharing CAM usage information.

REFERENCES 1. Herman PM, Poindexter BL, Witt CM, Eisenberg DM. Are complementary therapies and integrative care cost-effective? A systematic review of economic evaluations. BMJ Open. 2012;2(5):e001046. 2. Williams K, Abildso C, Steinberg L, et al. Evaluation of the effectiveness and efficacy of Iyengar yoga therapy on chronic low back pain. Spine. 2009;34(19):2066–2076. 3. Kanodia AK, Legedza AT, Davis RB, Eisenberg DM, Phillips RS. Perceived benefit of complementary and alternative medicine (CAM) for back pain: a national survey. J Am Board Fam Med. 2010;23 (3):354–362. 4. Bernstein A, Bar J, Pernotto Ehrman J, Golubic M, Roizen M. Yoga in the management of overweight and obesity. Am J Lifestyle Med. 2014;8(1):33–41. 5. Artus M, Croft P, Lewis M. The use of CAM and conventional treatments among primary care consulters with chronic musculoskeletal pain. BMC Fam Pract. 2007;8:26. 6. McFadden KL, Herna´ndez TD, Ito TA. Attitudes towards complementary and alternative medicine influence Its Use. Explore. 2010;6(6):380–388. 7. Ho KY, Jones L, Gan TJ. The effect of cultural background on the usage of complementary and alternative medicine for chronic pain management. Pain Physician. 2009;12(3):685–688. 8. Sirois FM. Health-related self-perceptions over time and provider-based complementary and alternative medicine (CAM) use in people with inflammatory bowel disease or arthritis. Complement Ther Med. 2014;22(4):701–709. 9. Metcalfe A, Williams J, McChesney J, Patten SB, Jett
e N. Use of complementary and alternative medicine by those with a chronic disease and the general population—results of a national population based survey. BMC Complement Altern Med. 2010;10:58. 10. Rossignol M, B
egaud B, Avouac B, et al. Who seeks primary care for musculoskeletal disorders (MSDs) with physicians prescribing homeopathic and other complementary medicine? Results from the EPI3LASER survey in France. BMC Musculoskelet Disord. 2011;12:21. 11. Oshikoya KA, Senbanjo IO, Njokanma OF, Soipe A. Use of complementary and alternative medicines for children with chronic health conditions in Lagos, Nigeria. BMC Complement Altern Med. 2008;8:66.

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12. Italia S, Brand H, Heinrich J, Berdel D, von Berg A, Wolfenstetter SB. Utilization of complementary and alternative medicine (CAM) among children from a German birth cohort (GINIplus): patterns, costs, and trends of use. BMC Complement Altern Med. 2015;15:49. 13. Andersson GB. Epidemiological features of chronic low-back pain. The Lancet. 1999;354 (9178):581–585. 14. John GM, Hershman DL, Falci L, Shi Z, Tsai WY, Greenlee H. Complementary and alternative medicine use among US cancer survivors. J Cancer Surv Res Pract. 2016;10(5):850–864. 15. Martin BI, Gerkovich MM, Deyo RA, et al. The association of complementary and alternative medicine use and health care expenditures for back and neck problems. Med Care. 2012;50(12):1029–1036. 16. Vavrek DA, Sharma R, Haas M. Cost analysis related to dose-response of spinal manipulative therapy for chronic low back pain: outcomes from a randomized controlled trial. J Manipulative Physiol Ther. 2014;37(5):300–311. 17. Dagenais S, Brady O, Haldeman S, Manga P. A systematic review comparing the costs of chiropractic care to other interventions for spine pain in the United States. BMC Health Serv Res. 2015;15:474. 18. Chui PL, Abdullah KL, Wong LP, Taib NA. Quality of life in CAM and non-CAM users among breast cancer patients during chemotherapy in Malaysia. PLoS One. 2015;10(10):e0139952. 19. Ghildayal N, Johnson PJ, Evans RL, Kreitzer MJ. Complementary and alternative medicine use in the US adult low back pain population. Global Adv Health Med. 2016;5(1):69–78. 20. Furlan AD, Yazdi F, Tsertsvadze A, et al. Complementary and alternative therapies for back pain II. Evid Rep Technol Assess. 2010;(194):1–764. 21. Kumar S, Beaton K, Hughes T. The effectiveness of massage therapy for the treatment of nonspecific low back pain: a systematic review of systematic reviews. Int J Gen Med. 2013;6:733–741. 22. Frass M, Strassl RP, Friehs H, M€ ullner M, Kundi M, Kaye AD. Use and acceptance of complementary and alternative medicine among the general population and medical personnel: a systematic review. Ochsner J. 2012;12(1):45–56. 23. Gaul C, Schmidt T, Czaja E, Eismann R, Zierz S. Attitudes towards complementary and alternative medicine in chronic pain syndromes: a questionnaire-based comparison between primary headache and low back pain. BMC Complement Altern Med. 2011;11:89. 24. Lind BK, Lafferty WE, Tyree PT, Diehr PK. Comparison of health care expenditures among insured users and nonusers of complementary and alternative medicine in Washington State: a cost minimization analysis. J Altern Complement Med. 2010;16(4):411–417. 25. Broom AF, Kirby ER, Sibbritt DW, Adams J, Refshauge KM. Use of complementary and alternative medicine by mid-age women with back pain: a national cross-sectional survey. BMC Complement Altern Med. 2012;12:98. 26. DeBar LL, Elder C, Ritenbaugh C, et al. Acupuncture and chiropractic care for chronic pain in an integrated health plan: a mixed methods study. BMC Complement Altern Med. 2011;11:118. 27. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Rep. 2008;12:1–23. 28. Steel A, Adams J, Sibbritt D, Broom A, Gallois C, Frawley J. Utilisation of complementary and alternative medicine (CAM) practitioners within maternity care provision: results from a nationally representative cohort study of 1,835 pregnant women. BMC Pregnancy Childbirth. 2012;12:146. 29. Saha FJ, Br€ uning A, Barcelona C, et al. Integrative medicine for chronic pain: a cohort study using a process-outcome design in the context of a department for internal and integrative medicine. Medicine. 2016;95(27):e4152. 30. Ward L, Stebbings S, Cherkin D, Baxter GD. Yoga for functional ability, pain and psychosocial outcomes in musculoskeletal conditions: a systematic review and meta-analysis. Musculoskeletal Care. 2013;11(4):203–217. 31. Fleming S, Rabago DP, Mundt MP, Fleming MF. CAM therapies among primary care patients using opioid therapy for chronic pain. BMC Complement Altern Med. 2007;7:15. 32. Mermod J, Fischer L, Staub L, Busato A. Patient satisfaction of primary care for musculoskeletal diseases: a comparison between neural therapy and conventional medicine. BMC Complement Altern Med. 2008;8:33.

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33. Enyinnaya EI, Anderson JG, Merwin EI, Taylor AG. Chiropractic use, healthcare expenditures, and rural and non-rural health outcomes for individuals with arthritis. J Manipulative Physiol Ther. 2012;35(7):515–524. 34. Hoerster KD, Butler DA, Mayer JA, Finlayson T, Gallo LC. Use of conventional care and complementary/alternative medicine among US adults with arthritis. Prev Med. 2012;54:13–17. 35. Lafferty WE, Tyree PT, Devlin SM, Andersen MR, Diehr PK. CAM provider use and expenditures by cancer treatment phase. Am J Manag Care. 2008;14(5):326–334. 36. Hui K, Johnston MF, Brodsky M, Tafur J, Ho MK. Scleroderma, stress and CAM utilization. Evid Based Complement Alternat Med. 2009;6(4):503–506. 37. Khan MU, Jamshed SQ, Ahmad A, Bidin MABA, Siddiqui MJ, Al-Shami AK. Use of complementary and alternative medicine among osteoarthritic patients: a review. J Clin Diagn Res. 2016;10(2): JE01–JE06. 38. Tamhane A, McGwin G, Redden DT, et al. Complementary and alternative medicine use in African Americans with rheumatoid arthritis. Arthritis Care Res. 2014;66(2):180–189. 39. Cheung C, Geisler C, Sunneberg J. Complementary/alternative medicine use for arthritis by older women of urban–rural settings. J Am Assoc Nurse Pract. 2014;26(5):273–280. 40. Mbizo J, Okafor A, Sutton MA, Burkhart EN, Stone LM. Complementary and alternative medicine use by normal weight, overweight, and obese patients with arthritis or other musculoskeletal diseases. J Altern Complement Med. 2016 Mar 1;22(3):227–236. 41. Parsons VL, Moriarity C, Jonas K, Moore TF, Davis KE, Tompkins L. Design and estimation for the National Health Interview Survey, 2006-2015. Vital Health Stat. 2014;2(165):1–53. 42. National Center for Complementary and Alternative Medicine (US). Expanding Horizons of Healthcare: Five-year Strategic Plan 2001–2005. US Department of Health and Human Services, Public Health Service, National Institutes of Health; 2000. [Online document]. https://nccih.nih.gov/sites/nccam.nih.gov/ files/about/plans/fiveyear/fiveyear.pdf. 43. Sirois FM. Motivations for consulting complementary and alternative medicine practitioners: a comparison of consumers from 1997–8 and 2005. BMC Complement Altern Med. 2008;8:16. 44. Nahin RL, Barnes PM, Stussman BJ, Bloom B. Costs of complementary and alternative medicine (CAM) and frequency of visits to CAM practitioners: United States, 2007. Natl Health Stat Rep. 2009;18. 45. Sirois FM, Salamonsen A, Kristoffersen AE. Reasons for continuing use of complementary and alternative medicine (CAM) in students: a consumer commitment model. BMC Complement Altern Med. 2016;16:75. 46. Bishop FL, Lewith GT. Who uses CAM? A narrative review of demographic characteristics and health factors associated with CAM use. Evid Based Complement Alternat Med. 2010;7(1):11–28. 47. Harris PE, Cooper KL, Relton C, Thomas KJ. Prevalence of complementary and alternative medicine (CAM) use by the general population: a systematic review and update. Int J Clin Pract. 2012;66 (10):924–939. ˘ LU M, Gemalmaz A, Ozc € ¸akir A, Ozt€ € urk A. What influences herbal 48. Aydin S, Bozkaya AO, MAZICIOG medicine use? Prevalence and related factors. Turk J Med Sci. 2008;38(5):455–463. 49. Ayers SL, Kronenfeld JJ. Delays in seeking conventional medical care and complementary and alternative medicine utilization. Health Serv Res. 2012;47(5):2081–2096. 50. Purohit MP, Wells RE, Zafonte RD, Davis RB, Phillips RS. Neuropsychiatric symptoms and the use of complementary and alternative medicine. PM R. 2013;5(1):24–31.

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CHAPTER 4

Antiinflammatory and Antiarthritic Activities of Some Foods and Spices Kilambi Pundarikakshudu

Department of Pharmacognosy, L.J. Institute of Pharmacy, L.J. Campus, Ahmedabad, India

1. INTRODUCTION Rheumatoid and osteoarthritis are debilitating, progressive autoimmune diseases afflicting approximately 1% of the world population. The disease is degenerative and causes the destruction of bone and cartilage leading to pain, stiffness of joints, and nonsynchronization of movement.1 Genetic and environmental factors trigger autoimmune responses directing macrophages, T cells, and B cells to invade the connective and synovial tissues of the joints. Macrophages, T cells, and B cells induce overexpression of the tumor necrosis factor -α (TNF-α), Interleukins (IL-1, -2, - 4, -6, -8, -10, -12, -13, -15, -18, -23), nuclear factor kappa B (NF-κB), etc. These mediators are responsible for the proliferation of fibroblast-like synoviocytes that produce cytokines, matrix metalloproteinases (MMPs), and cyclooxygenase-2 (COX-2), all of which contribute to the destruction of bones and the degradation of cartilage.2–6 Osteoarthritis is a degenerative joint disease characterized by progressive loss of articular cartilage, which is made up of type-II collagen. MMP-1, -8, -13 are the constituents of collagenases. MMPs are prime candidates involved in the degradation of the extracellular matrix (ECM) and thus are implicated in tumor invasion and metastasis.7 Pain and fever are other common features encountered in arthritis and inflammation conditions. The central and peripheral neuronal systems are also associated with these disorders. Hence, in most of the antiinflammatory and antiarthritis screening experiments, the analgesic and antipyretic effects of the test drugs are also investigated. A broad array of well-defined and reliable in vivo and in vitro experimental models are available for testing the effects of synthetic and herbal medical agents on inflammation, arthritis, pain, and fever. In in vivo experiments, mostly rats and mice are employed. In in vitro experiments, RAW 264.7 cells, J774.1 cells derived from synovial macrophages, the human melanocyte cell line THP-1, human umbilical vein endothelial cells (HUVEc), the ML-1 cell line, primary microglial cells, etc., are employed to study the levels of various cytokines, their expressions, and other related molecular mechanisms. Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases https://doi.org/10.1016/B978-0-12-813820-5.00004-0

© 2019 Elsevier Inc. All rights reserved.

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Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

Conventionally, nonsteroidal antiinflammatory drugs (NSAIDS), steroids, immunosuppressants, and disease-modifying rheumatoid arthritis drugs (DMRADs) are used for the treatment of inflammation and arthritis. These medications sometimes cause ulceration, gastrointestinal (GI) perforation, hepatic failure, anemia, osteoporosis, etc. Plants and plant-derived drugs have been in use in different traditions and cultures throughout the world for thousands of years. Some reviews are available on medicinal plants effective in treating arthritis and pain.2,8–10 Certain plants regularly used as foods or spices have positive effects on inflammation and arthritis without adverse effects. In this review, we present our research as well as work from other researchers on fenugreek (Trigonellafoenum-graecum L. Family: Fabaceae), turmeric (Curcumalonga L.; Family: Zingiberaceae), and ginger (ZingiberofficinaleRoscoe; Family: Zingiberaceae).

2. FENUGREEK (TRIGONELLAFOENUM-GRAECUM LINN., FAMILY: FABACEAE) Fenugreek is a small seasonal herb cultivated in India and widely used as a vegetable and spice to prepare curries, pickles, and salads. In India, it is known as “Methi” and is used to reduce blood glucose and regulate lipid profiles as well as an antioxidant, antibacterial, antiinflammatory, and antiarthritic agent. Fenugreek has been used for the treatment of various inflammatory disorders in Iranian traditional medicine.11,12 The seeds were reported to contain galactomannans, proteins, fixed oils (lipids), alkaloids (mainly trigonelline), flavonoids, free amino acids (especially 5-hydroxy isoleucine),13 and 0.2%–0.9% w/w of diosgenin14,15 (Figure 4.1). Both green herbs and seeds of fenugreek have been investigated for their effectiveness in the treatment of pain, fever, inflammation, lipid disorders, diabetes, etc. Ethanolic, methanolic, and hydroalcoholic extracts of the seeds reduced carrageenaninduced paw edema in rats when given orally or applied as a topical cream.16–18 Steroid glycosides in the water extract of the seeds showed significant analgesic activity at 40 mg/ CH3 N+ O O

O

Trigonelline

–

O H

OH H3C

H H H

CH3 NH2

H H

H OH

Diosgenin

OH O

4-Hydroxy isoleucine

Figure 4.1 Some chemicals with antiinflammatory and anti-arthritic activities from fenugreek.

Antiinflammatory and Antiarthritic Activities of Some Foods and Spices

kg dose. The extract significantly inhibited carrageenan-induced rat paw edema at 10 and 20 mg/kg.19 In bleomycin (4 mg/kg intratracheal)-induced experimental pulmonary fibrosis, fenugreek powder and its polyphenol fraction showed significant antiinflammatory and antioxidant activities.20 Liu et al.21 found that flavonoid glycosides from water extracts showed the strongest antioxidant potential. Flavone-8-C-glycoside isolated from the water extract showed more COX-2 enzyme inhibition. The highly polar mucilage from the seeds was shown to have strong antioxidant activity; it also exhibited potent antiarthritic activity. It was postulated that the mucilage might be acting through the inhibition of leukotriene (LT) synthesis, inducible nitric oxide synthase (iNOS), and the release of IL-1, IL-6, TNF-α, and TNF-β.22 The hydroalcoholic extract of the seeds also exhibited significant antinociceptive action in neuropathic pain caused by partial sciatic nerve ligation or sciatic nerve crush injury in rats23 or in the first and second phases of the formalin-induced hyperalgesia that is indicative of their central and peripheral action.24 Flavonoids and alkaloids present in the seeds are considered to be responsible for these actions.25 The trigonelline-rich seed fraction of fenugreek showed strong action in peripheral neuropathy when administered to rats for 30 days after partial sciatic nerve ligation or partial sciatic nerve crush injury.23 The water extract of leaves exhibited significant antiinflammatory, antiarthritic, and antipyretic effects in NMRI rats.26 The leaf extract was also found to have a significant analgesic effect with the partial involvement of purine receptors and 5-HT systems.27–29 The leaf extract prevented ADP-induced platelet aggregation, inhibited α-β-Me-ATP (a P2 purinergic receptor agonist)-induced isometric contraction of vas deferens, and prevented α-β-Me-ATP-induced hyperalgesia. It also inhibited COX-enzymes. The leaf extract alleviated formalin-induced pain in both the first and second phases, suggesting the involvement of central and peripheral mechanisms.29 Treatment of adjuvant-induced arthritic rats with ethanol extract of fenugreek seeds significantly reduced paw edema in 21 days while restoring all blood parameters and antioxidant enzyme levels to near normal. The elevated levels of synovial IL-1 α, IL-1β, IL-2, IL-6, and TNF-α due to complete Freund’s adjuvant (CFA)-induced arthritis were significantly reduced with a 40 mg/kg dose.30 We analyzed cold petroleum ether extract of fenugreek seeds by gas liquid chromatography and found it to contain linoleic (40.37% v/v), oleic (33.61% v/v), and linolenic (12.51%v/v) acids. This fraction showed significant antiinflammatory activity in carrageenan-induced acute and formaldehyde-induced chronic inflammations in rat paws. At 0.5 mL/kg dose, the extract exhibited 37% and 85% inhibition in these two animal models, respectively. In cotton pellet-induced granuloma in rats, the extract inhibited the formation of granuloma as evidenced by a 42.5% reduction in the dry weight of the cotton pellets (Table 4.1). We further noted a significant reduction in polyarthritis induced by CFA. The elevated liver peroxide enzymes in the cotton pelletinduced granuloma in rats were brought down by petroleum ether extract

53

54

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

Table 4.1 Antiinflammatory and antiarthritic potential of fenugreek seed petroleum ether (P.E.) extract in rats % Reduction in % Reduction of % Reduction of cotton pelletformaldehyde-induced carrageenan-induced induced arthritis paw edema after 48 h paw edema after 3 h Treatment

Vehicle control (0.5 mL ground nut oil p.o.) n ¼ 5 0.5 mL/kg P.E. extract (p.o.) n ¼5 100 mg/kg phenylbutazone (p.o.) n ¼ 5

–

–

–

37.23*

85*

42.5*

71.21*

90*

56.25*

Results are presented as mean SEM. As compared with controls: *P < .05. Data from: Pundarikakshudu K, Shah DH, Panchal AH, Bhavsar GC. Antiinflammatory activity of fenugreek (Trigonella foenum-graecum Linn) seed petroleum ether extract. Indian J Pharmacol 2016; 48:441–4.

Table 4.2 Effect of oral administration of fenugreek seed PE extract on liver enzymes in rats with cotton pellet-indced arthritis Treatment SGPT (U/mL) SGOT (U/mL) ALP (U/mL)

Vehicle control 0.5 mL/kg ground nut oil (p.o.) n ¼ 5 0.5 mL/kg P.E. Extract (p.o.) n ¼ 5 100 mg/kg phenylbutazone (p.o.) n ¼ 5

154.5  11.03

325.84  20.81

602.50  73.2

63.50  6.66** 81.1  6.75**

300.60  8.83 260.15  4.73*

473.75  102.6* 545.00  10.1*

Results are presented as mean  SEM. As compared with control: **P < .01; *P < .05. ALP, alkaline phosphtase; SGOT, serum glutamate oxaloacetate transaminase; SGPT, serum glutamate pyruvate transaminase. Data from: Pundarikakshudu K, Shah DH, Panchal AH, Bhavsar GC. Antiinflammatory activity of fenugreek (Trigonella foenum-graecum Linn) seed petroleum ether extract. Indian J Pharmacol 2016; 48:441–4.

(Table 4.2). It is possible that the observed effects might be mediated through the antioxidant properties of the unsaturated fatty acids in the extract.31 Diosgenin, the steroidal sapogenin in fenugreek, was shown to decrease cell proliferation by inhibiting TNF-α activated transcription factors such as NF-kB.32 Fenugreek methanol extract and its saponin fraction inhibited the production of inflammatory cytokines such as IL-1, IL-6, and TNF-α.33 Diosgenin showed a 76% inhibition in the proliferation of fibroblast-like synoviocytes.34 Highly purified compounds such as GII35, 36 and a mixture containing trogonelline and 4-hydroxy isoleucine37 were reported to have good antidiabetic activity. Defatted fenugreek seed exhibited lipid-lowering activity in humans.38 Thus, both the leaves and seeds of fenugreek are very useful for the treatment of pain, fever, and arthritis. The preliminary experiments in our studies and the molecular mechanisms studied by different groups of researchers confirm the beneficial effects of this

Antiinflammatory and Antiarthritic Activities of Some Foods and Spices

vegetable and spice in the treatment of inflammation and arthritis. Because the seed and its different groups of compounds have also shown very good effects in the treatment of diabetes and cancer, it has a holistic effect on the general health of the body. Even though fenugreek has been used as a regular dietary food, its prolonged use in rats at 1000 mg/kg dose caused liver toxicity and male antifertility.39, 40 This observation warrants further in-depth study into the toxic effects of fenugreek.

3. TURMERIC (CURCUMALONGA L., FAMILY: ZINGIBERACEAE) Turmeric is a herbaceous plant and its rhizomes that are yellow in color are used as a spice and for coloring/flavoring. In Ayurveda, turmeric has been used for various medicinal conditions including rhinitis, wound healing, the common cold, skin infections, liver and urinary tract diseases, etc. Turmeric contains volatile oils known as turmerones and about 3%–4% curcuminoids. Curcumin (diferuloylmethane) constitutes 90% of the total curcuminoids.41 (Figure 4.2). Curcumin was found to block the expression of NF-kB, TNF-α, IL-1β, and IL-6 in both synovial fluid and blood serum, reduce oxidative stress, and inhibit prostaglandin E-2 (PGE-2).42, 43 It was found to improve skeletal muscle atrophy.44 Curcumin inhibited the TNF-α-induced intercellular adhesion molecule-1(ICAM-1), the vascular cell adhesion molecule-1(VCAM-1), and the E-selectin expression in human umbilical vein endothelial cells (HUVECs).45 It was found to inhibit the activation of NF-kB in human ML-1A cells induced by TNF-α, phorbol 12-myristate 13-acetate (PMA), and hydrogen peroxide. Curcumin was also found to inhibit the DNA binding of the C-Jun/AP1 transcription factor.46 Curcumin formulation in full fat milk with ghee showed higher

O

OH

HO

O

OCH3

CH3O O

HO

O

OH OCH3

Curcumin

Curcumin I

Curcumin II CH3

O

O

CH3 CH3

O

H3C HO

OH

Curcumin III

Figure 4.2 Some important phytoconstituents in turmeric.

a-Turmerone

55

56

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

inhibitory effects on carrageenan and CFA-induced arthritis compared to aqueous suspension. IL-6 and TNF-α levels were reduced.47 Curcumin produced a dose-dependent antinociceptive response by reducing facial grooming behavior in acute and chronic phases of pain.48 It inhibited action on the Janus Kinase (JAK-STAT) signaling pathway in brain microglial cells.49 Oral bioavailability of curcumin was found to be poor.50 Turmeric and ginger powders reduced the arthritis-induced rise in spleen weight and bone marrow cellularity. Decreased thymic weight due to arthritis was increased. Increased serum IL-6 was completely modulated while increased TNF-α and IL-1α were partially alleviated.51 Funk et al.52 suggested that turmeric essential oils inhibit the release of histamine, bradykinin, 5-hydroxy tryptamine, and prostaglandins (PGs) in various acute and chronic inflammatory models. Curcumin was found to inhibit/modulate the upstream pathways of arachidonic acid cascades COX-2 and lipoxygenase, MMP-3, and MMP-13 gene expression by inhibiting the c-Jun-N-terminal Kinase (JNK), activation protein-1 (AP-1), and NF-kB pathways in human chondrocytes.53 Curcumin also inhibits effects on the production of IL-8, monocyte inflammatory protein-1 (MIP-1 a), monocyte chemotactic protein-1 (MCP-1) in IL-1β, TNF-α, 4-β-Phorbol-12-β myristate-13-α acetate (PMA), or lipopolysaccharide (LPS)-stimulated monocytes and macrophages.54 An antioxidant activity mediated protective effect of curcumin on experimentally induced inflammation, heptotoxicity, and cardiotoxicity was reported in rats. These studies strongly indicated the ability of curcumin to reduce oxidative stress during inflammatory conditions.55 Total curcuminoids reduced bovine type II collagen-induced arthritis in rats.56 Curcumin reduced the expression of angiogenesis linked genes, vascular endothelial growth factor (VEGF), and MMP-9.57, 58 It prevented angiogenesis and inhibited neutrophil activation in synoviocyte proliferation.59, 60 Balasubramanyam et al.61 found that curcumin abolished both PMA and thaspigargin-induced ROS generation in cells from control and diabetic patients in a dose-dependent manner, suggesting that curcumin mechanistically interferes with protein kinase C (PKc) and calcium regulation. Curcumin, given along with a subtherapeutic dose of methotrexate, showed synergistic activity with methotrexate in reducing arthritis and preventing the hepatotoxicity of methotrexate.62 An oil-free aqueous extract devoid of turmerones and curcuminoids also exhibited significant antiinflammatory activity in cotton pellet-induced granuloma.63 Turmeric oil showed activity comparable with curcumins. The activity of the crude extract exceeded that of individual fractions in blocking COX-mediated PGE production.60

Antiinflammatory and Antiarthritic Activities of Some Foods and Spices

Curcumin was shown to be a potent scavenger of superoxide radicals. It was also found to act as a hydroxyl radical scavenger at higher concentrations, and at lower concentrations, it activated the Fenton reaction, leading to higher hydroxyl radical generation.64 Employing rat primary microglia and murine BV2 microglial cells, Kim et al.65 found that curcumin effectively suppressed ganglioside LPS or IFN-γ-stimulated induction of COX-2 and inducible NO synthase. In Phase I clinical studies, curcumin was not detected in plasma if given in doses below 3.6 g for 4 months. Glucuronide and sulfate metabolites of curcumin were detected in all patients of the high dose group at all measurement points of the study.66 In humans, 20 mg piperine given concomitantly with 2.0 g of curcumin increased the serum curcumin level 20-fold, which was attributed to piperine’s inhibition of hepatic glucuronidation and the intestinal metabolism.67 Satoskar et al.68 studied the effects of curcumin (400 mg) and phenylbutazone three times daily for 6 days on spermiatic cord edema after surgery for an inguinal hernia or hydrocele. Curcumin proved to be superior in reducing spermiatic cord edema, spermatic cord tenderness, operative site pain, and operative site tenderness in postoperative patients. In a double-blind, randomized, controlled clinical trial, curcumin at 1200 mg given daily showed improvement in joint swelling, morning stiffness, and walking time.69 The US Food and Drug Administration (FDA) classified turmeric among substances generally regarded as safe. Oral administration of curcumin to rats decreased the levels of inflammatory glycoprotein GPA 72, with a reduction in paw inflammation.70 Thus, the traditional beliefs and claims have been substantiated by a number of studies elucidating the molecular mechanisms underlying the turmeric effects. We studied in rats the antiinflammatory and antiarthritic activities of a proprietary formulation (Vanpain) that is a combination of fenugreek seed petroleum ether extract, Boswellia serrata oleo gum resin ethanol extract, and turmeric ethanol extract in a proportion of 2:2:1. This combination was dissolved in groundnut oil (1.5 mL) plus tween-80 (two drops) and administered orally at a dose of 0.5 g/kg in all the experiments. Phenylbutazone was dissolved in 1% normal saline with two drops of tween-80 and was given at a dose of 0.1 g/kg as a standard. The formulation showed significant activity in carrageenan and formaldehydeinduced rat paw edema and in cotton pellet-induced granuloma in rats (Table 4.3). The synergistic effect of the formulation at 0.5 g/kg was more than the activities of the fenugreek petroleum ether extract (Pundarikakshudu et al., unpublished work).

57

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Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

Table 4.3 Antiinflammatory and antiarthritic effects of Vanpain % Reduction of % Reduction of carrageenan induced formaldehyde induced Treatment paw edema after 3 h paw edema after 48 h

Vehicle control (0.5 mL ground nut oil p.o.) n ¼ 5 0.5 g/kg combined extracts (p.o.) n ¼ 5 100 mg/kg phenylbutazone (p.o.) n ¼ 5

% Reduction in the dry weight of cotton pellet

–

–

–

93.9**

55.0**

53.57%**

76.3**

88.25*

53.15**

Results are presented as mean  SEM. As compared with controls: **P < .01; *P < .05.

4. GINGER (ZINGIBER OFFICINALE ROSCOE, FAMILY: ZINGIBERACAE) Ginger is a herbaceous plant cultivated in many parts of the world. The underground rhizome of the plant has been an important ingredient in Chinese, Ayurvedic, and Tibb-Unani herbal medicines for the treatment of inflammation, rheumatism, fevers, nervous diseases, gingivitis, toothaches, asthma, strokes, constipation, dyspepsia, nausea, vomiting, pain, the common cold, motion sickness, and diabetes for thousands of years.71–74 The pungency of fresh ginger is because of gingerols, a homologous series of phenols. The pungency of dry ginger is due to shogaols, the dehydrated forms of gingerols formed during thermal processing.75 [6]-Gingerols and [6]-shogoals are biologically active and are the main components in fresh and dry ginger, respectively.76 Ginger oil contains a high proportion of sesquiterpene hydrocarbons, predominantly zingiberene77 (Figure 4.3). Gingerols and shogoals mimicked dual-acting nonsteroidal antiinflammatory drugs (NSAIDs) in intact human leukocytes in vitro.78 Ginger extract was effective against cytokines synthesized and secreted at sites of inflammation and has antiinflammatory, antithrombotic, and analgesic effects by inhibiting the production of nitric oxide O

O

OH

H

HO

HO

O

OCH3 [6]-Gingerol

[6]-Shogaol

Zingiberene

Figure 4.3 Some important secondary metabolites of ginger with antiinflammatory and antiarthritic activities.

Antiinflammatory and Antiarthritic Activities of Some Foods and Spices

(NO), inflammatory cytokines, cyclo-oxygenase (COX), and lipoxygenase (LOX).79, 80 It was found to inhibit beta-amyloid peptide-induced cytokine and chemokine expression in cultured THP-1 monocytes and suppressed their production by synoviocytes, chondrocytes, and leukocytes.81 It showed antiinflammatory and antipyretic activities through inhibition of lipoxygenase and cyclooxygenase activities and production of TNF-α, but it did not show analgesic activity.82, 83 It prevented denaturation of fresh egg albumin proteins.84 High doses of ginger extracts were significantly effective in lowering serum PGE-2 when given either orally or i.p. However, TXB2 levels were significantly lower in rats given 500 mg/kg ginger orally, but not i.p.80 The extract given either by p.o.or i.p. decreased cholesterol but not triglycerides. Ginger extracts, as a whole, were found to be more effective than individual compounds and inhibited TNG-α expression.85, 86 Ethanol-insoluble squeezed ginger extract increased the production of TNF-α, IL-6, and monocyte chemotactic protein-1(MCP-1) when added to RAW 264 cells. Oral administration of the squeezed ginger extract or its ethanol-insoluble fraction once or the whole extract or its fraction given twice to mice increased the TNF-α production in peritoneal cells. But on repeated administration, the serum corticosterone level increased and arachidonic acid-induced ear inflammation was inhibited in mice, indicating a negative feedback of the endogenous corticosterone production by the extract.87 Ojewole88 reported significant analgesic, antiinflammatory, and hypoglycemic activity of the ethanol extract of dried ginger. Methanolic extract of dried ginger produced a significant reduction in fructoseinduced hyperlipidemia associated with insulin resistance.89 Ginger extract decreased the TNF-α-induced production of macrophage chemotactic factor (MCF-α) and interferon activated protein (IP-10) as well as their respective m-RNA.85, 90, 91 The extract inhibited PGE-2 and TNF-α while 6-Shogaol inhibited only PGE-2 production. A standardized fraction of the ginger extract containing gingerols suppressed LPS-induced COX-2 expression in differentiated human leukemia U937 cells while a shogaol-rich fraction failed to inhibit COX-2 expression.92 Toll-like receptors (TLR) with their ligands lead to the activation of macrophages and in turn initiate an inflammatory reaction.93 Whole ginger extract effectively inhibited the production of proinflammatory lymphokins in macrophages activated through their TLRs by lipopolysaccharide (LPS) and reduced the upregulation of MHC class II and costimulatory molecules in these macrophages. These effects led to the inhibition of macrophage-mediated antigen presentation to T-cells.94 It was found that in contrast to the profound and global effect of whole ginger, [6]-gingerol inhibited cytokine and lymphokine production in macrophages but had no effect on the upregulation of either MHC class II costimulatory molecules or macrophage antigen presentation.94

59

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Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

Dedovet al.95 reported gingerols to act as agonists at vanilloid (VR1) receptors. The VR1 receptor has been suggested to integrate chemical and thermal nociceptive stimuli.96, 97 Gingerols evoked [Ca++] transients in capsaicin-sensitive neurons. They induced a rapid rise in intracellular calcium similar to that produced by capsaicin. Gingerols exhibited agonist activity toward the VR 1 (Vanillyl 1) receptor in rat DRG neurons similar to that of capsaicin. The activity of gingerols was proportional to the size of the side chain. [8]-Gingerol has 10-fold more potency in inducing plasma membrane currents than 6-gingerol.95 Shogaol appears to be a preferential inhibitor of 5-Hydroxyeicosatetraenoic acid (5-HETE) formation and gingerol and dehydro-paradol favored the inhibition of cyclooxygenase.78 S-[6]-gingerol markedly suppressed IL-6, IL-8, and SAAI and inhibited COX2 m-RNA and NF-kB activation in HuH7 cells.98 Pretreatment of HuH7 cells with [6]-gingerol for 6 h significantly inhibited IL-1β induced NF-kB activity, suggesting that the protective effect of [6]-gingerol against IL-1β induced inflammation is, at least in part, associated with inhibition of NF-kB activation in HuH-7 cells. Gingerols inhibit COX-2 directly.99 Gingerol analogues reduced nitric oxide production via the attenuation of NF-kB-mediated iNOS gene expression, providing another pathway for antiinflammatory activity associated with insulin.100 6-Shogaol significantly reduced knee swelling due to edema production in CF-induced arthritis. It blocked protein and m-RNA expression of iNOS and COX-2 in murine RAW264.7 cells activated with LPS.101 The downregulation of inflammatory iNOS and COX-2 gene expression was mediated by inhibition of the NF-kB activation.102 6-Shogaol suppressed COX-2 and iNOS proteins while 6-gingerol did not suppress COX-2 proteins but only suppressed iNOS proteins. Both 6-shogoal and 6-gingerol strongly inhibited LPS-induced NF-kB transcriptional activity. TP-induced iNOS and COX-2 were also significantly inhibited by 6-shogaol. 6-Shogaol was found to be a stronger inhibitor of iNOS and COX-2 than 6-gingerol and appears to be a promising novel chemopreventive agent.103 [6]-Gingerol inhibited acetic acid-induced writhes and the late phase of formalininduced pain in male ICR mice. It also reduced λ carrageenan-induced paw edema in rats.104 A topical application of [6]-gingerol or [6]-paradol significantly attenuated TPAinduced mouse ear edema and epidermal vascular permeability. [6]-gingerol suppressed the expression of COX-2 by inactivating NF-kB.105 [6]-Gingerol diminished the expression of COX-2 protein and its m-RNA transcript as well as NF-kB activation in mouse skin in vivo and in HaCaT keratocytes in culture.106 Ippoushi107 found that [6]-gingerol inhibited NO production by LPS-activated J774.1 macrophages. It also reduced iNOS protein levels but did not alter α-tubulin levels in these cells. [6]-Gingerol prevented peroxynitrile mediated strand breaks in DNA of

Antiinflammatory and Antiarthritic Activities of Some Foods and Spices

pTZ18U plasmid DNA. [6]-Shogaol, 1-dehydro-10-gingerdione, and 10-gingerdione significantly reduced NO production in RAW264.7 cells.108 In a gouty arthritic model developed by monosodium urate crystal-induced inflammation, [6]-gingerol significantly reduced the lysosomal enzymes level as well as inhibited lactate dehydrogenase and acid phosphatase.109 6-Shogaol reduced the chronic inflammation induced by CPF in the knees of rats.101 In a clinical study, Srivastava and Mustafa110 reported that ginger was effective in relieving pain and swelling in the joints of seven RA patients. Drozdov et al.111 tested the effect of standardized ginger extract EV. Ext. 35 (100 mg) plus 500 mg glucosamine as glucosamine sulfate on patients with osteoarthritis of the knee or hip and compared the results with the treatment of diclofenac (100 mg) as diclofenac sodium and 1000 mg glucosamine as glucosamine sulfate for 4 weeks. The major cause of NSAID-induced gastropathy is considered to be a cyclo-oxygenase-1 blockade leading to impaired gastrointestinal mucosa. Patients in the ginger group had less visual analogue score (VAS) pain after treatment. In patients of the diclofenac treatment, PGs were decreased in the mucosa while in patients of the ginger treatment group, PGE-1, PGF-2 α, and PG12 were found to be increased at the end of day 28. In a double-blind, randomized, placebo-controlled clinical trial on 120 osteoarthritis patients, 95% ethanol extract of ginger (30 mg  2) showed pain relief similar to ibuprofen (400 mg x3) as indicated by the VAS, gelling regressive pain after a rising score, joint swelling scores, and joint motion slope scores.112 Altman and Marcussen113 carried out randomized, double-blind, placebo-controlled, multicenter parallel group clinical studies on osteoarthritis patients. The ginger extract (225 mg of EV.Ext77) has shown a significant reduction in knee pain. Gastrointestinal (GI) adverse events were noted in 45% of patients, although none of the events were serious. Thus, both fresh and dry ginger showed prominent antiinflammatory activities that are, by and large, mediated by inhibition of iNOS, TNF-α, and NF-kB. We investigated the antiinflammatory and antiarthritic effects of a classical Ayurvedic formulation Patyadhyachurna containing fine powders of dry ginger, dried pericarp of Haritaki (Terminalia chebula Retz., F.-Combretaceae), and dried fruits of Ajwain (Trachyspermum ammi Linn., F.-Umbelliferae) in equal quantities.114 It is recommended for treating rheumatism, inflammation, indigestion, and heart diseases.115 Treatment with the ethanol extract of Patyadhyachurna (PCE) reduced paw swelling in arthritis caused by formaldehyde and CFA. Significant improvements in various hematological and lipid parameters were observed with treatment of the extract (Table 4.4). Treatment with PCE minimized injury to the cells in the ankle joints. The effect was very prominent with a dose of 540 mg/kg. There was a greater increase in synocyte number and a decrease in the number of inflammatory cells as compared to even standard indomethacin treatment. The effect was found to be moderate with a lower dose of 135 mg/kg (Figure 4.4).

61

Table 4.4 Amelioration of hematological parameters and lipid profile by ginger containing Ayurvedic formulation Pathyadya Churna in arthritic rats Normal Arthritic Indomethacina PCEa 270 PCEa 540 PCEa 135 a a Parameters control control mg/kg mg/kg mg/kg 10 mg/kg Lipid profile (mg/dl)

TC TG HDL LDL VLDL

96.85  1.33 71.69  1.06 29.40  0.33 53.11  1.73 14.34  0.37

145.05  0.88 96.60  1.20 16.13  0.58 109.60  1.16 19.32  0.87

113.85  1.53* 78.02  0.88* 24.67  0.58* 73.57  1.20* 15.6  0.48*

124.34  1.81* 90.67  0.86* 23.18  0.87* 83.03  1.27* 18.13  0.72*

115.89  1.73* 84.51  1.16* 27.41  1.53* 71.57  1.73* 16.9  0.72*

111.64  1.59* 81.87  1.21* 27.91  0.37* 67.36  1.19* 16.37  0.68*

13.92  1.27 7.32  0.87 8.22  0.67 2.46  0.23 44.04  1.21 3.76  0.31

9.97  1.03 6.58  0.74 11.42  0.79 4.15  0.41 30.56  1.43 8.03  0.42

13.23  1.43* 7.31  0.91 8.89  0.74* 2.86  0.33* 36.5  1.50* 3.95  0.47*

11.13  1.18* 7.10  0.88 9.08  0.89* 3.12  0.41* 31.67  1.76* 6.32  0.54*

12.64  1.33* 7.24  0.88* 8.80  0.73 2.87  0.17* 36.29  1.67* 4.84  0.53*

13.28  1.27* 7.31  0.78 8.42  0.84* 2.67  0.32* 38.42  1.86* 4.12  0.66*

7.17  0.13

26.77  1.46

10.78  0.77*

13.35  0.67*

11.55  0.91*

11.20  1.01*

Hematological parameters

Hb (gm/dl) RBC (millions/mm3) WBC (thousands/mm3) Platelet (lakhs/mL) PCV (%) ESR (60 min) Rheumatoid factor (IU/mL)

RF

*P12.8 million years lived with disability in 2015, an increase of 34.8% since 2005.3 OA is a heterogeneous disease of the whole joint with multifactorial etiology, characterized by loss of articular cartilage, remodeling of the underlying subchondral bone, and a state of chronic low-grade inflammation. Management of OA is primarily focused on the relief of symptoms. Strategies to relieve OA pain and improve joint function are necessary to improve the quality of life in patients with OA. Multiple approaches have been applied to manage the symptoms of OA, including lifestyle modifications, exercise, medications, and surgery. However, effective management options for pain are limited.4 With the chronic nature of OA, pharmacological approaches must be safe for long-term use. Acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs) are the mainstay of management for OA pain recommended by several international societies, but they cause serious gastrointestinal and cardiovascular adverse events and have no beneficial effect on joint structures.5 There is currently no disease-modifying OA drug. Although several drugs and nutraceuticals have been examined for their ability to slow structural progression, none have shown a consistent benefit in order to be approved by regulatory authorities for clinical application.6 With the lack of effective therapies for OA, many patients are eventually faced with costly total joint replacement as the only option to improve pain, function, and quality of life. Identifying agents capable of slowing or reversing the symptomatic and structural progression in patients suffering from OA is an important research and clinical objective for which there is emerging evidence for a role of nutritional factors. It is known that many dietary nutrients and supplements have antioxidant, antiinflammatory, or Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases https://doi.org/10.1016/B978-0-12-813820-5.00006-4

© 2019 Elsevier Inc. All rights reserved.

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Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

chondroprotective effects that can modulate chronic pain and disease course. Dietary supplements or nutraceuticals have shown potential in relieving OA symptoms in human clinical trials.7,8 Moreover, the safety profile of nutraceuticals makes them attractive for the treatment of chronic diseases and disorders such as OA. This chapter reviews the available literature on the efficacy and safety of dietary nutrients and supplements for the management of OA.

2. MACRONUTRIENTS 2.1 Antioxidant Vitamins A variety of reactive oxygen species are continuously formed in tissues by endogenous and exogenous mechanisms.9 There is emerging evidence that reactive oxygen species have a role in the pathogenesis of OA.10,11 The antioxidant vitamins, ascorbic acid, alpha-tocopherol, and beta-carotene, are free radical scavenging nutrients that protect cells from damage by prooxidants.12,13 Data for the effects of antioxidant vitamins on joint symptoms and structures are presented in Table 6.1. 2.1.1 Ascorbic Acid (Vitamin C) Ascorbate is a highly effective antioxidant as it not only completely protects lipids from detectable peroxidative damage, but also spares alpha-tocopherol, urate, and bilirubin.26 Data have been conflicting for the association between dietary vitamin C intake and knee symptoms, showing a higher intake of vitamin C being associated with a reduced risk of development of knee pain,11 not associated with knee pain severity14,15 and physical function,14 or associated with worse knee function.15 In a randomized, placebocontrolled trial, calcium ascorbate reduced pain significantly compared with a placebo in patients with hip and/or knee OA over 2 weeks, with the effect less than half as pronounced as commonly reported for NSAIDs.16 There has been inconsistent evidence for the relationship between dietary vitamin C intake and knee structural outcomes. While one cohort study showed higher vitamin C intake was associated with reduced risk of OA progression but not the incidence of knee OA,11 another cohort study showed the opposite.17 Two studies reported that higher vitamin C intake was associated with reduced presence of knee OA18 and reduced joint space narrowing.19 In contrast, one study reported higher vitamin C intake was associated greater prevalence of knee OA,20 and another study found no association between vitamin C intake and knee cartilage loss in knee OA.15 Summary: The evidence from observational studies for an association between vitamin C intake and symptoms and progression of OA is conflicting. Well-designed randomized controlled trials with longer duration are needed to determine whether vitamin C has a role in improving the clinical and structural outcomes of OA.

Table 6.1 Summary for effects of antioxidant vitamins on joint symptoms and structures Effects of vitamins on Study Study design symptoms

Effects of vitamins on structures

Vitamin C McAlindon (1996), United States11

Cohort study

Hung (2017), United States14

Cross-sectional study

Wang (2006), Australia15

Cohort study

Jensen (2003), Denmark16

Multicenter, double-blind, randomized, placebocontrolled, crossover trial

Higher vitamin C intake reduced the risk of development of knee pain Vitamin C intake was not associated with knee pain severity and physical function in patients with knee OA There was no association of vitamin C intake with knee pain or stiffness in patients with knee OA, but higher vitamin C intake was associated with worse knee function Calcium ascorbate (containing 898 mg vitamin C, for 2 weeks) reduced pain significantly compared with a placebo, with similar superiority found for function and patient preference. The demonstrated effect was less than half as pronounced as commonly reported for NSAIDs Continued

Table 6.1 Summary for effects of antioxidant vitamins on joint symptoms and structures—cont’d Effects of vitamins on Study Study design symptoms

McAlindon (1996), United States11

Cohort study

Peregoy (2011), United States17

Cohort study

Sanghi (2015), India18

Case-control study

Muraki (2014), Japan19

Cross-sectional study

Li (2016), China20

Cross-sectional study

Wang (2006), Australia15

Cohort study

Effects of vitamins on structures

A moderate intake of vitamin C (120–200 mg/day) resulted in a threefold lower risk of OA progression, with no significant association observed for the incidence of knee OA There was no protective role of self-reported vitamin C supplementation in the progression of knee OA, but vitamin C supplement usage was associated with a reduced risk of developing knee OA Higher vitamin C intake was associated with reduced presence of knee OA Higher vitamin C intake was associated with reduced joint space narrowing in women but not in men Higher vitamin C intake was associated greater prevalence of knee OA There was no association of dietary vitamin C intake with knee cartilage volume or rate of cartilage volume loss over 2 years in patients with knee OA

Table 6.1 Summary for effects of antioxidant vitamins on joint symptoms and structures—cont’d Effects of vitamins on Study Study design symptoms

Effects of vitamins on structures

Vitamin E Machtey (1978), Israel21

Simple-blind crossover trial

Blankenhorn (1986), Germany22

Multicenter, placebocontrolled, double-blind trial

Scherak (1990), Germany23

Randomized double-blind controlled trial

Brand (2001), Australia24

Randomized, double-blind, placebo-controlled trial

Vitamin E supplementation (600 mg/day for 10 days) was significantly more effective than a placebo in relieving pain in patients with OA Vitamin E (400 IU/day for six weeks) was significantly superior to a placebo for reduction of pain and requirement for additional analgesic medication in patients with OA There were no significant differences in the efficacy of vitamin E (400 mg, 3 times/day for 3 weeks) compared with diclofenac in reducing pain at rest/on pressure/on movement, knee circumference, walking time, or increasing joint mobility in patients with hip or knee OA Neither vitamin E (500 IU/ day for 6 months) nor a placebo showed a significant improvement in pain, stiffness, or physical function in patients with knee OA Continued

Table 6.1 Summary for effects of antioxidant vitamins on joint symptoms and structures—cont’d Effects of vitamins on Study Study design symptoms

Wluka (2002), Australia25

Randomized, double-blind, placebo-controlled trial

McAlindon (1996), United States11

Cohort study

Muraki (2014), Japan19

Cross-sectional study

Li (2016), China20

Cross-sectional study

Wluka (2002), Australia25

Randomized, double-blind, placebo-controlled trial

Effects of vitamins on structures

Neither vitamin E (500 IU/ day for 2 years) nor a placebo resulted in a significant improvement in pain, stiffness, function, or quality of life in patients with knee OA Higher dietary intake of vitamin E reduced the risk of OA progression in men only while vitamin E had no significant association with the incidence of knee OA Higher vitamin E intake was associated with reduced osteophytosis in women but not in men There was no association between dietary vitamin E intake and prevalence of radiographic knee OA There was no significant effect of vitamin E supplementation (500 IU/day for 2 years) on the rate of tibial cartilage loss compared with a placebo in patients with knee OA

Table 6.1 Summary for effects of antioxidant vitamins on joint symptoms and structures—cont’d Effects of vitamins on Study Study design symptoms

Effects of vitamins on structures

Beta-carotene and other carotenoids Wang (2006), Australia15

Cohort study

McAlindon (1996), United States11

Cohort study

Li (2016), China20

Cross-sectional study

Wang (2006), Australia15

Cohort study

There was no association of dietary beta-carotene intake with knee pain, stiffness, or function in patients with knee OA Higher beta-carotene intake reduced the risk of progression of knee OA, but only after adjustment for vitamin C intake. It had no significant association with the incidence of knee OA There was no association between dietary carotenoid intake and prevalence of radiographic knee OA There was no association of dietary beta-carotene intake with knee cartilage volume or rate of cartilage volume loss over 2 years in patients with knee OA

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2.1.2 Alpha-Tocopherol (Vitamin E) Alpha-tocopherol is the only significant lipid-soluble, chain-breaking antioxidant present in plasma and red blood cells.27 It has been shown that OA patients have dietary intakes of vitamin E lower than the recommended dietary allowance.28 Short-term clinical trials with a small number of patients suggested vitamin E treatment may be more effective than a placebo in relieving pain,21,22 and may have similar efficacy to diclofenac.23 Larger clinical trials performed over a longer period showed no effect of vitamin E supplementation compared with a placebo in improving pain, stiffness, or physical function in patients with knee OA over 6 months24 or 2 years.25 While two studies showed a higher dietary intake of vitamin E was associated with reduced risk of knee OA progression in men11 or reduced osteophytosis in women,19 another study reported no association between vitamin E intake and radiographic knee OA.20 A randomized, double-blind, placebo-controlled trial found no effect of vitamin E supplementation on tibial cartilage loss compared with a placebo in patients with knee OA.25 Summary: The beneficial effect of vitamin E on pain relief in OA demonstrated in short-term studies has not been supported by results from well-conducted clinical trials over longer durations. Larger studies of longer duration are warranted. Further research is required to investigate the structural effect of vitamin E supplementation in OA. 2.1.3 Beta-Carotene and Other Carotenoids Beta-carotene, an unusual type of lipid antioxidant, is neither a peroxide-decomposing preventive antioxidant nor a conventional chain-breaking antioxidant. Beta-carotene can behave as a radical-trapping antioxidant only at low oxygen pressures significantly 6 months. It showed no pain-reduction benefits after 6 months of therapy. Glucosamine hydrochloride is ineffective for pain reduction in patients with knee OA

Table 6.3 Systematic reviews for effects of glucosamine and chondroitin on joint symptoms and structures—cont’d Test statistics (95% Systematic review Number of studies confidence interval) Conclusions

Lequesne index Glucosamine sulfate

Wandel (2010)70

6 randomized controlled trials

Overall: SMD 0.47 ( 0.82 to 0.12) 24 weeks: SMD 0.36 ( 0.56 to 0.17) VAS pain 0.4 cm ( 0.7 cm to 0.1 cm) ES:

Glucosamine was not superior to a placebo in reducing OA pain

0.17 ( 0.28 to 0.05)

Structure Zeng (2015)67

7 randomized controlled trials

Kongtharvonskul (2015)68

31 randomized controlled trials

Wandel (2010)70

6 randomized controlled trials

Joint space narrowing MD 0.18 mm (0.03 mm to 0.34 mm) Joint space width UMD 0.008 ( 0.232 to 0.248) Joint space narrowing 0.2 mm ( 0.3 mm to 0.0 mm) ES 0.16 ( 0.25 to 0.0)

The structure-modifying effect of glucosamine remained uncertain The structure-modifying effect of glucosamine remained uncertain Glucosamine was not superior to placebo in reducing joint space narrowing

Continued

Table 6.3 Systematic reviews for effects of glucosamine and chondroitin on joint symptoms and structures—cont’d Test statistics (95% Systematic review Number of studies confidence interval) Conclusions

Chondroitin Symptoms Liu (2018)7

14 randomized controlled trials

Zeng (2015)67

19 randomized controlled trials

Singh (2015)71

43 randomized controlled trials

Pain Short term: SMD 0.34 ( 0.49 to 0.19) Medium term: SMD 0.26 ( 0.47 to 0.05) Long term: SMD 0.18 ( 0.41 to 0.05) Physical function Short term: SMD 0.36 ( 0.58 to 0.13) Medium term: SMD 0.22 ( 0.42 to 0.01) Long term: SMD 0.34 ( 1.06 to 0.39) Pain relief SMD 0.45 cm ( 0.85 cm to 0.08 cm) Pain 6 months: absolute risk difference 9% lower than placebo (18%–0%) WOMAC Absolute risk reduction 6% (1%–11%) Lequesne’s index Absolute risk difference 8% (12%–5%)

Chondroitin revealed statistically significant improvements on pain at short-term, but were unclear of clinical importance. Chondroitin cannot be recommended for the treatment of OA

Chondroitin was effective in pain relief. However, it was of minimal effect Chondroitin (alone or in combination with glucosamine) was better than placebo in improving pain in participants with OA in short-term studies. The benefit was small to moderate with an eight-point greater improvement in pain (range 0–100) and twopoint greater improvement in Lequesne’s index (range 0–24), likely to be clinically meaningful

Table 6.3 Systematic reviews for effects of glucosamine and chondroitin on joint symptoms and structures—cont’d Test statistics (95% Systematic review Number of studies confidence interval) Conclusions

Wandel (2010)70

3 randomized controlled trials

Reichenbach (2007)72

20 randomized controlled trials

VAS pain 0.3 cm ( 0.7 cm to 0.0 cm) ES 0.13 ( 0.27 to 0.00) Pain ES 0.75 ( 0.99 to 0.50), 20 studies of any quality ES

Chondroitin was not superior to a placebo in reducing OA pain

Symptomatic benefit of chondroitin is minimal or nonexistent

0.03 ( 0.13 to 0.07), 3 studies with good quality

Structure Liu (2018)7

14 randomized controlled trials

Zeng (2015)67

7 randomized controlled trials

Wandel (2010)70

3 randomized controlled trials

Lee (2010)73

4 randomized controlled trials

Structural improvement SMD 0.30 ( 0.42 to 0.17) Joint space narrowing MD 0.15 mm (0.02 mm to 0.30 mm) Joint space narrowing 0.1 mm ( 0.3 mm to 0.1 mm) ES 0.08 ( 0.25 to 0.08) Joint space narrowing After 1 year treatment: SMD 0.295 (0.000 to 0.590) At 2 years: SMD 0.261 (0.131 to 0.392)

Chondroitin revealed structural improvement, but were unclear of clinical importance The structure-modifying effect of chondroitin remained uncertain Chondroitin was not superior in reducing joint space narrowing

Chondroitin may delay radiological progression of knee OA after daily administration for over 2 years

Continued

Table 6.3 Systematic reviews for effects of glucosamine and chondroitin on joint symptoms and structures—cont’d Test statistics (95% Systematic review Number of studies confidence interval) Conclusions

Hochberg (2010)74

7 randomized controlled trials

Reichenbach (2007)72

20 randomized controlled trials

Joint space width 0.13 mm (0.06 mm to 0.19 mm) ES 0.23 (0.11 to 0.35) Joint space width ES 0.12  SD 0.18

Chondroitin is effective for reducing the rate of decline in joint space width in patients with knee OA

Pain relief SMD 0.68 cm ( 1.18 cm to 0.15 cm)

Glucosamine plus chondroitin was more effective than placebo in pain relief and function improvement

Chondroitin is not effective for structural changes

Glucosamine + chondroitin Symptoms Zeng (2015)67

7 randomized controlled trials

Function improvement SMD 0.48 units ( 0.80 units to 17 units) Structure Zeng (2015)67

7 randomized controlled trials

Joint space narrowing SMD 0.30 ( 0.09 to 0.63)

The structure-modifying effect of glucosamine and chondroitin combination remained uncertain

ES, effect size; MD, mean difference; SMD, standardized mean difference; UMD, unstandardized mean difference; VAS, visual analogue scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Nutrients and Dietary Supplements for Osteoarthritis

differentiating the treatment duration also exhibited contradictory results. While some showed improved pain relief,66–68 others showed no effect of glucosamine on pain relief.69,70 Similarly, the effect of glucosamine on function improvement remained inconsistent. While one metaanalysis showed short-term but not long-term effect of glucosamine on function improvement,7 another metaanalysis showed long-term but not short-term effect.69 Metaanalyses not differentiating the duration of glucosamine use showed varied effects. While most metaanalyses showed effects of glucosamine on function improvement,67,68 another one showed no effect.66 None of the three metaanalyses suggested a structure-modifying effect of glucosamine.67,68,70 This may be due to the heterogeneity of included studies, insensitive outcome measures, and/or inadequate duration of follow-up. It should be noted that many of the clinical trials have been sponsored by pharmaceutical companies producing glucosamine, possibly leading to bias toward positive outcomes and publication or industry bias. Most clinical trials have tested glucosamine sulfate, with pooled findings suggesting that this formulation reduces OA pain. Findings from trials using different formulations, including glucosamine hydrochloride, suggest no significant improvement.75 Glucosamine has been safely used in long-term clinical trials. Side effects from glucosamine occurred at a rate similar to that of a placebo and less than that of NSAIDs.75 There are theoretical concerns that glucosamine increases insulin resistance and affects glycemic control in patients with diabetes. However, the clinical studies have not shown an increase in blood glucose or hemoglobin A1c levels in patients with type 2 diabetes on glucosamine.76 Summary: The evidence supports a minimal effect of glucosamine sulfate, but not other glucosamine preparations, on improving pain and function in patients with OA. There is no evidence for an effect of glucosamine on slowing disease progression. Glucosamine sulfate might provide a potential option for patients with OA who are interested in trying a dietary supplement to improve symptoms.

3.2 Chondroitin Chondroitin sulfate belongs to the group of glycosaminoglycans and is a major component of articular cartilage.77 Chondroitin sulfate is believed to help draw water and nutrients into the cartilage to keep it spongy and healthy, maintain viscosity in joints, reduce apoptosis of chondrocytes, stimulate cartilage repair mechanisms, and inhibit enzymes that break down cartilage.78,79 Chondroitin sulfate also exerts antiinflammatory activity.80 Chondroitin sulfate supplements are made from bovine or shark cartilage. Chondroitin is almost always combined with other ingredients in commercial products. Seven systematic reviews and metaanalyses have examined the effect of chondroitin on OA in the past 10 years (Table 6.3). The effect of chondroitin on pain relief remained inconsistent. Some metaanalyses showed a short-term effect but not a long-term one of

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chondroitin on pain relief; however, it was unclear whether this minimal effect was of any clinical importance.7,71 The metaanalyses not differentiating treatment duration reported conflicting results; one showed a minimal effect in pain relief67 while others showed no effect.70,72 Only one metaanalysis evaluated the effect of chondroitin on function improvement and reported no effect.7 Six metaanalyses evaluated the effect of chondroitin on joint structure with conflicting results. Some reported structural improvement with unclear clinical importance,7,73,74 while others reported uncertain structure-modifying effects.67,70,72 Chondroitin has been safely used and well tolerated in clinical trials. Summary: Overall, the evidence for a therapeutic effect of chondroitin in OA from metaanalyses is inconsistent. Although there is some evidence for a short-term effect of chondroitin on improving pain slightly and a possible delay in structural progression, the benefit is little and may not be of any clinical significance.

3.3 Combination of Glucosamine and Chondroitin One systematic review and metaanalysis were found in this area, which included seven randomized controlled trials (Table 6.3). This metaanalysis showed that the combination of glucosamine and chondroitin was more effective than a placebo in pain relief and function improvement, with an uncertain effect on structural progression. Summary: A combination of glucosamine and chondroitin may be effective in reducing pain in OA. However, chondroitin does not appear to offer an advantage over glucosamine sulfate, and there is no evidence that combining chondroitin with any formulation of glucosamine is more effective than glucosamine sulfate alone.

3.4 Avocado Soybean Unsaponifiables Avocado soybean unsaponifiables (ASUs) are made up of unsaponifiable fractions of onethird avocado oil and two-third soybean oil. Considering the multiple elements of ASU, the active ingredients are still unknown. ASUs have chondroprotective, anabolic, and antiinflammatory effects. In a randomized, double-blind, placebo-controlled, parallel-group, a multicenter trial of 300 mg ASU in patients with knee or hip OA with a 6-month treatment period and a 2-month posttreatment follow-up, the ASU group had decreased Lequesne’s functional index, visual analog scale (VAS) pain, and functional disability scores compared with the placebo group. The beneficial effects of ASU were shown between the second and fourth months, persisting up to month eight with good to excellent tolerance.81 A 3-month, randomized, double-blind, placebo-controlled, parallel-group trial showed 300 mg ASU reduced NSAID use in patients with knee or hip OA after 6 weeks. The ASU group showed greater improvement in functional index than the placebo group. Safety was good in both groups.82 A multicenter double-blind placebo-controlled study over

Nutrients and Dietary Supplements for Osteoarthritis

3 months in patients with knee OA showed ASU at a dosage of 300 and 600 mg/day reduced NSAID and analgesic intake and knee symptoms, with no differences between the two doses.83 In a large prospective cohort study of patients with symptomatic knee OA, receiving 300 mg ASU per day over 6 months was associated with improved knee pain and function and reduced use of analgesics and NSAIDs.84 Only one clinical trial examined the structural effect of 300 mg ASU in the treatment of OA. A multicenter, randomized, parallel-group, double-blind, placebo-controlled trial was conducted in patients with symptomatic hip OA over 2 years. There was no significant difference in the change in joint space width between the ASU and placebo groups. In the subgroup of patients with more severe hip OA, joint space loss was greater in the placebo group than the ASU group. Pain, function, and NSAID use did not differ between the two groups. The findings suggest a potential structural effect of ASU in severe hip OA.85 A systematic review and metaanalysis of four randomized controlled trials81–83,85 showed the combined pain reduction and function improvement favored ASU. The number of responders following ASU corresponded to a number needed to treat six patients.86 Summary: Metaanalysis of the available high-quality randomized controlled trials indicate that 300 mg ASU per day appear to be beneficial for modestly improving OA symptoms in patients with hip or knee OA over 3–6 months.86,87 Whether ASU slows the structural progression of OA needs to be investigated in larger randomized controlled trials.

3.5 Polyunsaturated Fatty Acids and Marine Oil Marine oil (oil from fish, seals, and mussels) is thought to have an analgesic effect in arthritis due to its high content of docosahexaenoic acid (DHA; 22:6 n-3) and eicosapentaenoic acid (EPA; 20:5 n-3). Supplementation with EPA- and DHA-rich oil could exert antiinflammatory effect,88 making it a possible treatment for arthritis pain. In an 8-week trial of knee OA patients, fish oil at 1000 mg (EPA 400 mg and DHA 200 mg) and 2000 mg doses both reduced the VAS pain score and increased the walking speed compared with the placebo, but the higher dose did not show higher efficacy over the lower dose.89 A randomized, double-blind, multicenter trial in patients with symptomatic knee OA showed that the low-dose fish oil supplementation (0.45 g omega-3 fatty acids) group had greater improvement in pain and function assessed by the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) at 2 years compared with the high-dose (4.5 g omega-3 fatty acids) group.90 There was no difference between the two groups in cartilage volume loss, bone marrow lesions, quality of life, and analgesic and NSAID use at 2 years.90 A 26-week, two-center, randomized, double-blind trial of patients with hip or knee OA found no superiority of a combination of glucosamine

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sulfate and omega-3 polyunsaturated fatty acids versus glucosamine sulfate alone in improving pain, stiffness, and function.91 A double-blind, placebo-controlled trial assessed the efficacy of cod liver oil as an adjunct treatment to NSAIDs in OA patients for 24 weeks. There was no benefit for taking cod liver oil compared with taking a placebo in joint pain, inflammation, overall interference with daily activities, or unwanted treatment effects.92 The clinical efficacy and safety of Lyprinol (a patented extract from the New Zealand green-lipped mussel (Perna Canaliculus)) were assessed in a multicenter trial of patients with knee or hip OA. Lyprinol led to significant improvement in VAS, Lequesne functional index, and global assessment by patients and physicians.93 Similar results were found in another clinical trial of patients with knee OA over 6 months where greater improvements in perception of pain, patients’ global assessment of arthritis, physical function, and psychological status were observed in the Lyprinol group compared with controls.94 A randomized double-blind placebo-controlled trial found no significant differences in pain or quality of life between BioLex (a novel green-lipped mussel extract) and placebo groups in patients with hip or knee OA over 12 weeks while there was a significant improvement in stiffness and reduction in paracetamol use in the BioLex group compared with the placebo group.95 A recent systematic review and metaanalysis of five clinical trials showed no effect of marine oil on joint pain in people with OA, and the evidence for using marine oil to alleviate pain in OA patients was overall of low quality.96 Summary: Based on limited research, there is no evidence supporting the use of polyunsaturated fatty acids or marine oil for the management of OA symptoms, and larger randomized controlled trials are warranted.

3.6 Methylsulfonylmethane Methylsulfonylmethane (MSM) occurs naturally in small amounts in some green plants, fruits, and vegetables. It is usually found in combination supplements containing glucosamine and/or chondroitin. MSM is promoted as having antiinflammatory and analgesic effects. In a randomized, double-blind, placebo-controlled trial, MSM resulted in significant improvement in WOMAC pain and physical function and SF-36 activities of daily living in knee OA patients over 12 weeks.97 In another randomized, double-blind, placebocontrolled clinical trial of patients with knee OA over 12 weeks, MSM treatment produced significant improvement in WOMAC physical function and total score, and VAS pain, with no difference in WOMAC pain/stiffness or SF-36 total score between the groups.98 Two clinical trials examined the efficacy of MSM combined with glucosaminechondroitin or glucosamine.99,100 A double-blind, randomized controlled clinical trial

Nutrients and Dietary Supplements for Osteoarthritis

showed that a combination of glucosamine-chondroitin-MSM provided clinical benefits in improving WOMAC and VAS scores compared with glucosamine-chondroitin and a placebo in patients with knee OA over 12 weeks.99 Similarly, another randomized, double-blind, parallel, placebo-controlled trial in knee OA patients for 12 weeks reported that MSM decreased the pain index and swelling index, and that a combination of MSM with glucosamine provided greater and more rapid improvement in pain, swelling, and functional ability. All treatments were well tolerated.100 Summary: Data from randomized controlled trials have consistently shown the efficacy of MSM in improving pain and function in people with knee OA over a short time period (12 weeks) with no major adverse events. Because these trials have been of a short term and there is no reliable evidence for long-term efficacy and safety, MSM should not be recommended for the treatment of OA. The effect of MSM on symptoms over longer time and whether its effect achieves clinical significance need to be investigated in large clinical trials.

3.7 S-Adenosylmethionine S-adenosylmethionine (SAMe) is produced in the liver from methionine. SAMe may reduce inflammation and have direct analgesic effects at central or peripheral levels, potentially mediated through inhibition of cyclooxygenase (COX). An 8-week, multicenter, randomized, double-blind trial in patients with knee OA found no significant difference between the SAMe group and control group (receiving nabumetone) in reduction of pain intensity, patient’s global assessment of disease status, physician’s global assessment of response to therapy, WOMAC scores, use of acetaminophen as rescue medication, or adverse events.101 Another randomized double-blind crossover study compared the effectiveness of SAMe with celecoxib for 16 weeks in patients with knee OA. SAMe had a slower onset of action but was as effective as celecoxib in the management of OA symptoms.102 A long-term multicenter open trial studied the efficacy and tolerance of SAMe for 2 years in patients with OA of the knee, hip, and spine. SAMe showed good clinical effectiveness and was well tolerated. The improvement of clinical symptoms was evident after the first weeks of treatment and continued until the end of the 24th month. SAMe improved the depressive feelings associated with OA.103 A metaanalysis of 11 randomized controlled trials assessed the efficacy of SAMe in the treatment of OA. SAMe was more effective than a placebo in reducing functional limitation, but not in reducing pain. SAMe was as effective as NSAIDs in reducing pain and improving functional limitation, but without the adverse effects often associated with NSAIDs.104 A Cochrane systematic review with four trials compared SAMe with a placebo for efficacy and safety. The analysis indicated a small difference for pain and function, with no significant increase in adverse event and withdrawals or drop-outs due to adverse events.105

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Summary: The effect of SAMe on pain and function in OA is inconclusive. The effect sizes are small and may not be clinically relevant. Larger randomized controlled trials with longer duration are needed to evaluate the long-term efficacy and safety of SAMe and the optimal dose to be used. Because SAMe is an unstable compound, product quality is another concern; products on store shelves may contain little or none of the active ingredient. Until these concerns have been resolved, SAMe may not be a reliable alternative treatment option.

3.8 Collagen Hydrolysates Collagen hydrolysates are manufactured from animal bones and hides. Collagen hydrolysates may have a direct analgesic effect or provide a pool of amino acids in the body that improves matrix structure. A double-blind, placebo-controlled, randomized trial showed a significant reduction in WOMAC and VAS scores and the quality of life score in the collagen peptide group compared with the placebo group in patients with knee OA over 13 weeks.106 In a randomized, double-blind, placebo-controlled multicenter trial of patients with knee OA over 6 months, there was a significant improvement in VAS pain and WOMAC pain in the collagen hydrolysate group.107 In a randomized, double-blind, placebo-controlled trial of patients with knee OA performed in the United States, United Kingdom, and Germany over 32 weeks, there were no significant differences in pain score for the total study group. Increased efficacy of collagen hydrolysate versus a placebo was observed in German sites, and in the overall study population among patients with more severe symptoms.108 In a 13-week multicenter, randomized, parallel, double-blind study of patients with knee OA, enzymatic hydrolyzed collagen resulted in greater improvement than glucosamine sulfate in the WOMAC index, the total score index for painful joints, the patient’s global assessment of efficacy, and the SF-36 physical health index. Both treatments were well tolerated with similar incidence of adverse events.109 Only one study examined the effect of collagen hydrolysate on structural outcomes. In a randomized, placebo-controlled, double-blind, pilot trial in patients with mild knee OA, at 24 weeks, the delayed gadolinium-enhanced magnetic resonance imaging of the cartilage score in the tibia increased in patients assigned to collagen hydrolysate but decreased in the placebo arm. There was no significant differences between the two groups in T2 values, symptom and functional measures, or overall analgesic use. There may be a change in proteoglycan content in the knee cartilage in individuals taking collagen hydrolysate after 24 weeks.110 The pooled analysis in a systematic review showed no significant difference for WOMAC pain or disability between collagen hydrolysate and a placebo. There were significant differences in pain measured with VAS or other instruments, or when collagen

Nutrients and Dietary Supplements for Osteoarthritis

hydrolysate was compared with glucosamine sulfate. The most reported adverse events of collagen derivatives were mild to moderate gastrointestinal complaints.111 Summary: There is insufficient evidence to recommend the use of collagen hydrolysates for the management of OA. High-quality randomized controlled trials are needed to confirm the therapeutic effects of collagen hydrolysates on OA complaints.

3.9 Polyphenols Pycnogenol is a special standardized extract from the bark of the French maritime pine (Pinus pinaster), representing a concentrate of polyphenols. Only Pycnogenol has been tested in clinical trials. In a double-blind, placebo-controlled study of patients with knee OA over 3 months, the Pycnogenol arm had greater improvement in the global WOMAC score and walking distance in the treadmill test, reduced NSAID use, and decreased gastrointestinal complications and foot edema.112 Similar findings were observed in a 3-month randomized, double-blind, parallel-group, placebo-controlled trial of knee OA patients, showing significant improvement in WOMAC pain, physical function and total scores, and reduced dosage and frequency of NSAIDs or selective COX-2 inhibitors in the Pycnogenol group compared with the placebo group.113 In another randomized, double-blind, placebo-controlled trial of patients with mild to moderate knee OA over 3 months, the Pycnogenol group reported significant improvement in WOMAC index and VAS pain and reduction in NSAID use compared with the placebo arm. Treatment with Pycnogenol was well tolerated.114 Summary: These studies demonstrate that Pycnogenol treatment alleviates OA symptoms and is effective in reducing NSAID or COX-2 inhibitor medication over 3 months, suggesting that Pycnogenol could be used as an effective adjuvant treatment for OA symptoms.

3.10 Turmeric (Curcuma longa) Turmeric (C. longa) is a yellow spice commonly used in curry powders. The pharmacologically active constituent is curcumin. Curcumin appears to have antiinflammatory effects due to inhibition of COX-2, prostaglandins, and leukotrienes.115 A randomized, double-blind, placebo-controlled trial in patients with knee OA showed greater improvement in VAS and WOMAC scores in the C. longa extract group compared with the controls at 4 months.116 In a randomized, double-blind, placebocontrolled trial in patients with knee OA over 8 weeks, the Theracurmin (a form of curcumin) group had reduced VAS pain score and celecoxib dependence than the placebo group, with no major side effects.117 In a pilot randomized double-blind placebo-control parallel-group trial in patients with knee OA for 6 weeks, curcuminoids resulted in greater reduction in WOMAC, VAS, and Lequesne’s index scores compared with a

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placebo, with no considerable adverse effect.118 Another randomized, single-blind, placebo-controlled trial in patients with knee OA for 6 weeks found C. longa Linn resulted in decreased VAS and WOMAC scores and use of rescue medication compared with a placebo, with a better tolerability and acceptability profile.119 Two randomized controlled trials demonstrated that C. domestica extracts were as effective as ibuprofen for the treatment of knee OA with similar or fewer adverse events.120,121 In one trial, WOMAC total, pain, and function scores of the C. domestica extracts group were noninferior to those for the ibuprofen group at week four, with no difference in adverse events.120 Another trial showed no differences between the groups over 6 weeks for improvement in pain on level walking, knee functions, or adverse events.121 A double-blind randomized controlled trial in knee OA over 3 months showed no potential beneficial effect of the adjuvant therapy of curcumin with diclofenac versus diclofenac alone.122 A systematic review and metaanalysis of randomized clinical trials evaluated the efficacy of turmeric extracts and curcumin for alleviating symptoms. Metaanalyses reported a significant reduction in VAS pain and WOMAC with turmeric/curcumin compared with a placebo, with no significant difference in VAS pain between turmeric/curcumin and pain medicine.123 Summary: Although clinical trials have consistently shown the efficacy of C. longa extract in improving pain and function in knee OA over a short period (4 weeks to 4 months), the current data are not sufficient to draw definitive conclusions due to the number of randomized clinical trials, the total sample size, and the methodological quality of the primary studies. More rigorous and larger trials are needed to confirm the therapeutic efficacy of turmeric for OA. Until there is reliable clinical evidence for the long-term efficacy and safety, turmeric cannot be recommended for the management of OA.

3.11 Boswellia serrata Boswellia is a moderate-sized flowering plant native to tropical regions of Africa and Asia. There are several known boswellia species; B. serrata or Indian frankincense is mostly used for medicinal purposes. B. serrata, via its active boswellic acids, appears to exhibit potential antiinflammatory properties by inhibiting the 5-lipoxygenase enzyme. In a randomized, double-blind, placebo-controlled crossover study of patients with knee OA for 8 weeks, there were statistically significant and clinically relevant differences between the B. serrata extract and control groups in terms of reduced pain and joint swelling and increased knee flexion and walking distance. B. serrata extract was well tolerated except for minor gastrointestinal adverse drug reactions.124 A 90-day, double-blind, randomized, placebo-controlled trial showed patients in the 5-Loxin (a novel B. serrata extract) group experienced clinically and statistically significant improvements in pain

Nutrients and Dietary Supplements for Osteoarthritis

and physical function in patients with knee OA. The safety parameters were comparable between the groups.125 Aflapin is a novel synergistic composition derived from B. serrata gum resin. A 30-day, double-blind, randomized, placebo-controlled study in patients with knee OA reported that Aflapin conferred clinically and statistically significant improvements in pain and physical function, showing an effect in as early as 5 days of treatment.126 A 90-day, double-blind, randomized, placebo-controlled study evaluated the comparative efficacy and tolerability of 5-Loxin and Aflapin in patients with knee OA. Both 5-Loxin and Aflapin conferred clinically and statistically significant improvements in pain and physical function. Significant improvements were shown as early as 7 days after initiation of Aflapin treatment. The safety parameters were comparable in both groups.127 A three-arm, parallel-group, randomized, double-blinded, placebo-controlled trial assessed the efficacy and safety of curcuminoid complex extract (CuraMed) and its combination with boswellic acid extract (Curamin) versus a placebo in patients with knee OA for 12 weeks. There was a significant effect of Curamin versus a placebo in physical performance tests and WOMAC pain index, and superior efficacy of CuraMed versus a placebo in physical performance tests. Curamin was more effective than CuraMed. Both treatments were well tolerated.128 Summary: Previous clinical trials have shown the effect of B. serrata on improving pain and function in knee OA. Larger studies with a longer follow-up period are needed to confirm the therapeutic efficacy and safety of B. serrata before it can be recommended for the management of OA.

3.12 Zingiber officinale (Ginger) Ginger may have antiinflammatory effects by inhibiting COX and lipoxygenase. It may also affect the tumor necrosis factor and decrease the synthesis of inflammatory prostaglandins.115 In a double-blind, placebo-controlled, crossover study of patients with knee OA, Zintona EC (a ginger extract) was as effective as a placebo in reducing pain during the first 3 months, but showed a significant superiority over the placebo at the end of 6 months, 3 months after crossover.129 The efficacy and safety of Z. officinale and Alpinia galanga (both highly concentrated extracts of ginger species) were assessed in a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 6-week trial of patients with knee OA. The ginger extract group had a greater percentage of responders experiencing a reduction in knee pain on standing, a greater reduction in knee pain on standing and knee pain after walking 50 ft, a greater change in global status and reduction in rescue medication intake, and more gastrointestinally adverse events that were mostly mild.130 Ginger extract was compared with a placebo and ibuprofen in patients with hip or knee OA in a controlled, double-blind, double-dummy crossover study. A significant

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effect of ginger extract on joint pain was demonstrated in the first period of treatment before crossover while no significant difference was observed in the study as a whole.131 A 12-week randomized open label study in patients with knee OA evaluated the safety and efficacy of diclofenac with a placebo, ginger with a placebo, and ginger with diclofenac. Ginger with diclofenac resulted in a greater improvement in WOMAC and VAS scores than the individual treatments. There was no difference in adverse events among three groups.132 The clinical efficacy and safety of ginger for symptomatic treatment of OA were assessed in a systematic review and metaanalyses of five randomized controlled trials. A significant reduction in pain and disability was in favor of ginger. Patients given ginger were more than twice as likely to discontinue treatment compared to a placebo. There was moderate evidence suggesting that ginger was modestly efficacious and reasonably safe for treatment of OA.133 Another systematic review evaluated the safety and effectiveness of ginger in adults with OA with five randomized controlled trials. There was no clear evidence to suggest that ginger extract was superior to a placebo or active control in reducing joint pain or improving function. Ginger was well tolerated compared with ibuprofen, with infrequent reports of mild, and predominantly gastrointestinal, adverse effects.134 Summary: Ginger is safe and well tolerated in clinical trials. However, there is not enough evidence to support recommending ginger for the treatment of OA.

3.13 Harpagophytum procumbens (Devil’s Claw) Devil’s claw is an African plant that gets its name from the “claws” found on the fruit. It is thought to have antiinflammatory effects, possibly due to inhibition of COX and lipoxygenase. In a multicenter, double-blind, randomized clinical study, the efficacy and tolerance of Harpadol (containing cryoground powder H. procumbens) was compared with diacerhein in patients with knee or hip OA for 4 months. The improvement in pain and function was not different between the two groups. The Harpadol group used less NSAIDs and antalgic drugs, had a lower frequency of adverse events, and better global tolerance. The most frequent event was diarrhea.135 A postmarketing surveillance estimated the effectiveness and safety of an 8-week course of Harpagophytum extract Doloteffin in patients suffering from low back pain or OA pain in the knee or hip. Pain and function improved by week 4 and further by week 8. About 10% of the patients suffered from minor adverse events.136 A multicenter drug surveillance study assessed the efficacy and safety of an aqueous Harpagophytum extract (Doloteffin) in patients with hip or knee OA for 12 weeks. There was a reduction in WOMAC subscales and total index and VAS pain score, improvement in physician-reported clinical findings, and few cases of adverse drug reactions.137

Nutrients and Dietary Supplements for Osteoarthritis

A systematic review examined the effectiveness of H. procumbens preparations in the treatment of OA pain or low back pain. Six trials investigated OA. There is moderate evidence of effectiveness for use of a Harpagophytum powder at 60 mg harpagoside in the treatment of hip and knee OA.138 Another systematic review assessed the efficacy and safety of Devil’s claw in OA with 14 studies. The data from higher-quality studies suggest that Devil’s claw appeared to be effective in reducing the main clinical symptom of pain and was associated with minor risk relative to NSAIDs.139 Summary: Although Devil’s claw seems promising, the clinical evidence to date cannot provide a definitive comment on the efficacy and safety of Devil’s claw. More evidence from high-quality clinical trials is needed before it can be recommended for the treatment of OA.

3.14 Other Dietary Supplements 3.14.1 Uncaria tomentosa and Uncaria guianensis (Cat’s Claw) Cat’s claw is a vine from the basin of the Amazon River. Two species, U. tomentosa and U. guianensis, are traditionally used in South America for their antiinflammatory properties.115 The efficacy and safety of freeze-dried U. guianensis was evaluated in patients with knee OA. Pain with activities was reduced, but pain at rest or at night was not reduced during the 4-week trial period. U. guianensis was well tolerated.140 In another randomized study of patients with knee OA, a combination of a natural mineral supplement (Sierrasil) with a cat’s claw extract (U. guianensis) improved WOMAC and VAS scores and reduced rescue medication use after 8 weeks compared with a placebo.141 In a multicenter, randomized, double-blind trial of patients with OA over 8 weeks, Reparagen (a mixture of U. guianensis and Lepidium meyenii) and glucosamine sulfate produced similar improvements in pain, stiffness, and function, with rescue medication use significantly lower in the Reparagen group. Tolerability was excellent; no serious adverse events were noted.142 3.14.2 Pomegranate Pomegranate is the predominant member of the Punicaceae family. Pomegranate is a good antioxidant source and has antiinflammatory properties. In a randomized placebo-controlled study of patients with knee OA over 6 weeks, the pomegranate juice group had significant decreases in WOMAC total score, stiffness score, and physical function score compared with the control group.143 3.14.3 Camellia sinensis (Green Tea) Green tea contains proteins, amino acids, fiber, other carbohydrates, lipids, pigments, minerals, and phenolic compounds. Epigallocatechin-3-gallate, a green tea polyphenol, may exert chondroprotective and antiinflammatory effects.115 The efficacy and safety of green tea extract were assessed in a randomized, open-label, active-controlled trial with

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patients with knee OA for 4 weeks. VAS pain as well as WOMAC total and physical function scores significantly reduced in the green tea extract plus the diclofenac group compared with the diclofenac alone group.144 Summary: There is not enough evidence to support the use of cat’s claw, pomegranate, or green tea in the management of OA symptoms. Further randomized controlled trials of longer duration and larger sample size are needed.

3.15 Summary for Dietary Supplements Data from randomized controlled trials suggest ASU, glucosamine sulfate, B. serrata extract, pycnogenol, C. longa extract, and MSM may improve OA symptoms over short to medium periods. However, the effect sizes are small to moderate. The evidence is limited and conflicting for the effect of dietary supplements on OA structural outcomes.

4. MICRONUTRIENTS (TRACE ELEMENTS) 4.1 Magnesium Magnesium acts as a calcium channel antagonist, plays an important role in activities regulated by intracellular calcium concentration fluxes,145 and has the ability to alter the levels of inflammatory cytokines and neurotransmitters.146 A higher serum magnesium concentration was associated with a lower prevalence of radiographic knee OA.147 Three observational studies have evaluated the association between dietary magnesium intake and radiographic OA148,149 and pain and function in knee OA.150 In a cross-sectional study, a higher magnesium intake was associated with a lower prevalence of radiographic knee OA and joint space narrowing.148 Another cross-sectional study conducted in the United States found a modest inverse threshold association between magnesium intake and prevalence of knee OA in whites but not in African Americans.149 The Osteoarthritis Initiative study showed that a lower magnesium intake was associated with worse pain and function throughout 4 years in knee OA, especially among individuals with low fiber intake.150 Summary: The findings from these studies suggest that higher dietary magnesium might have some beneficial effect in knee OA.

4.2 Boron The estimated incidence of arthritis was higher in areas of the world where boron intake is 1 mg or less daily compared with that of areas of the world where boron intake is 3–10 mg daily (20%–70% versus 0%–10%).151 In a double-blind pilot trial conducted for 8 weeks in patients with OA, 50% of patients receiving a boron supplement (6 mg boron/day) improved compared with 10% on a placebo, with no side effects observed.152 The result suggested that boron might be safe and beneficial in the treatment of OA.

Nutrients and Dietary Supplements for Osteoarthritis

However, problems with this study included the very small number of patients, short duration, high proportion of dropout, low response rate, and slightly worse initial condition of the placebo patients. Summary: Only one clinical trial has been conducted. Further research is needed to confirm this preliminary study.

4.3 Selenium Selenium is a component of glutathione peroxidase that protects macromolecules from oxidation stress.153 Selenium, taken for a period of months, may help decrease pain and inflammation associated with joint problems.154 However, a cross-sectional study among community-dwelling adults found no association between dietary selenium and radiographic knee OA.20 A placebo-controlled, double-blind trial of selenium-ACE (a formulation containing selenium and vitamins A, C, and E) in OA failed to demonstrate any significant efficacy in improving pain and stiffness over a placebo at 3 or 6 months.155 Summary: There is no clear evidence for an association between selenium and OA outcomes. Further clinical trials are needed to evaluate the relationships.

4.4 Zinc and Copper Low zinc levels have been found in OA.28,50,156 There is some evidence that zinc may play a role in OA due to its antiinflammatory and antioxidant activity.156 As early as 1938, it was suggested that copper may help symptoms of arthritis.157 Synovial fluid copper concentrations were higher in OA patients compared with healthy subjects.158 Summary: To date no clinical trials have been conducted to evaluate the effect of zinc and copper intake on OA outcomes.

4.5 Summary for Micronutrients There have been a limited number of observational studies and a lack of randomized controlled trials examining the effect of micronutrients on OA. There is no evidence to support the use of micronutrients for the management of OA.

5. CONCLUSION Given the modest benefits of the nonsurgical treatments for OA and the adverse effects associated with NSAIDs and surgical interventions, the use of dietary supplements has been rapidly increasing. This chapter reviews a number of promising dietary nutrients and supplements that might have a role in treating OA in humans. Nutritional factors may influence the course of OA through a wide variety of mechanisms. There is preliminary evidence that deficiency of vitamins, such as vitamin D, may be found in patients with OA, for which nutritional supplementation may have impact on relieving

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symptoms in OA. People with vitamin deficiency may be the group to be targeted for nutritional supplementation. The available data suggest nutritional supplementation of ASUs, glucosamine sulfate, B. serrata extract, pycnogenol, C. longa extract, and MSM might have a role in symptomatic relief of OA over a short to medium term (50 nmol/L (20 ng/mL) were associated with better hip BMD.24 In a communitydwelling population in Shanghai, China, the 25(OH)D concentrations corresponding to the highest BMD at the LS and TH were 53 nmol/L (21 ng/mL) and 75 nmol/L (30 ng/mL), respectively.27 Thus, it would seem that for better bone health, 25(OH) D levels should be
50 nmol/L (20 ng/mL).16 So, although subjects with low 25(OH)D levels tend to have lower BMD, does supplementation with vitamin D help to improve bone health? A metaanalysis on the effects of vitamin D supplements on BMD published in 2013 concluded that vitamin D supplementation resulted in a small BMD benefit at the FN (weighted mean difference 0.8%, 95% confidence interval [CI] 0.2–1.4) with significant heterogeneity among the trials, but no effect at the LS or TH.28 After this metaanalysis, a few individual studies have been published with varying results. Macdonald and colleagues studied healthy postmenopausal women given vitamin D 400 or 1000 IU or a placebo for 1 year. They found that mean BMD loss at the hip was significantly less for the 1000 IU vitamin D group (0.05%  1.46%) compared with the 400 IU vitamin D or placebo groups.29 Reid and colleagues supplemented community-dwelling adults with monthly doses of 100,000 IU vitamin D compared to a placebo for 2 years. There was no difference in LS BMD at the end of 2 years, but bone loss at the hip was reduced by 0.5% in those on vitamin D supplements. However, for those who had very low 25(OH)D levels, below 30 nmol/L (12 ng/mL), supplementation did reduce BMD loss at the LS and FN by 2%.30 In contrast, Hansen and colleagues found no difference in LS, FN, TH, or total body BMD in postmenopausal women supplemented for 1 year with either daily or monthly vitamin D compared with a placebo.31 Therefore, it would be useful to supplement people with low 25(OH)D levels to prevent bone loss, especially at the hip.29, 30 The threshold to start supplementation for bone health would definitely be when the 25(OH)D concentration is below 30 nmol/L (12 ng/mL), a state of vitamin D deficiency that puts individuals at risk of nutritional rickets/osteomalacia,32 but can be considered at higher 25(OH)D levels in patients at risk of osteoporosis.

2.1 Bone Mineral Density in Rheumatoid Arthritis Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation that leads to joint deformities due to bone and cartilage destruction. Skeletal changes in RA include local bone erosions, periarticular bone loss, and systemic osteoporosis. This results in a twofold increase in the risk of both vertebral and hip fractures in RA patients compared to a control population.33–36 Cross-sectional studies have

Effects of 25-Hydroxyvitamin D in Rheumatoid Arthritis

generally shown a lower BMD in Caucasian RA patients compared to controls,37–39 with an increased prevalence of osteoporosis.40 In Asian populations, studies in Chinese41, 42 and Korean43 RA patients have shown that the proportion of subjects with osteoporosis as defined by a dual-energy X-ray absorptiometry (DXA) T-score of 2.5 was significantly higher compared to healthy controls, but this was not found in a study with Malaysian RA patients.44 However, it must be remembered that other factors such as disease duration, disease activity, and corticosteroid usage45 are also important influences on BMD in RA patients.

3. VITAMIN D IN PATIENTS WITH RHEUMATOID ARTHRITIS Similar to healthy individuals, bone health in RA patients can be affected by vitamin D levels. In addition, as RA is an autoimmune disease, vitamin D can influence the inflammatory pathways via modulation of the immune system, and thus play a role in RA disease activity. Both genetic and environmental factors contribute to the development of RA and the subsequent articular and systemic inflammation. In a genetically susceptible individual, environmental stimuli such as smoking and chronic inflammation of the oral mucosa, particularly periodontitis, can lead to the posttranslational modification of peptides, for example citrullination, which causes it to be more effectively bound to the HLADRB1 alleles that are linked to RA susceptibility.46 Antigen-presenting cells (APCs) then present these altered peptides as antigens to activate T cells, with subsequent activation of B cells as well. Dendritic cells (DC) are important APCs in RA, expressing high levels of major histocompatibility complex (MHC) proteins.47 They have been shown to induce T cell differentiation into pro- and antiinflammatory populations. If an activated DC presents an autoantigen to an aberrant peripheral T cell able to recognize it, this DC-T cell interaction can lead to inappropriate immune activation and a loss of tolerance, resulting in autoimmunity.48 In the RA synovium, DCs are found in higher numbers compared to patients with osteoarthritis,48 contributing to the synovial inflammation found in RA. In addition, T cells constitute about 50% or more of cells in most RA synovia; most of these are CD4+ with a memory phenotype.49 The link between vitamin D and RA inflammation is from the fact that VDRs have been identified in mononuclear cells (MNCs), DCs, and APCs as well as activated B lymphocytes and CD4+ T cells,50 all of which are involved in the pathophysiology of RA.

3.1 Effects of 25(OH)D on the Immune System in Rheumatoid Arthritis In contrast to the endocrine regulation of calcium homeostasis, the immunomodulatory actions of vitamin D seem to be dependent on localized intracrine or paracrine conversion of 25(OH)D to 1,25(OH)2D, an effect mainly involving DCs and macrophages

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expressing 1α-hydroxylase.51 In addition, unlike the endocrine effects of vitamin D on the skeleton that are tightly regulated by negative feedback loops, the immunomodulatory actions of vitamin D seem to be far more dependent on the availability of precursor 25(OH)D for conversion to 1,25(OH)2D.52 Thus, 25(OH)D deficiency can have a direct effect on the immune system. Adequate levels of 1,25(OH)2D will inhibit T-lymphocyte proliferation and cytokine production in the Th1 and Th17 cells and shift the T cell response toward a Th2 predominance that is antiinflammatory.50 The cellular effects of 1,25(OH)2D have been reviewed in detail recently.51 In short, adequate levels of 1,25(OH)2D will inhibit antigen presentation by DCs and reduce T cell activation. It will act on DCs to suppress Th1inducing interleukin (IL)-12 and pro-Th17 IL-23 while promoting expression of tolerogenic IL-10. In peripheral blood MNCs and macrophages from patients with RA, 1,25 (OH)2D has been shown to suppress the tumor necrosis factor (TNF), IL-17, IL-1, and IL-6 production. It will also decrease Th17-induced osteoclast activity and RA-associated bone resorption by inducing expression of the receptor activator of the NFκB (RANK) ligand on fibroblast-like synoviocytes and osteoblasts.51 Further articular damage is prevented by vitamin D because it inhibits IL-1A-mediated production of matrix metalloproteinases,53 responsible for degradation of the collagen that is the major component of bone and cartilage. Moreover, vitamin D also increases regulatory T cells (Treg) cells that are important in the maintenance of tolerance to selfantigens, the function of which is impaired in RA.51 At a clinical level, 25(OH)D has been found to be significantly negatively correlated with IL-17 and IL-23 in Chinese RA patients with established disease.54 In a group of newly diagnosed RA patients from India, the inflammatory cytokines TNFα, IL-1β, IL-6, and IL-17 were found to be significantly negatively correlated with 25(OH) D.55 A significant positive correlation between 25(OH)D and IL-6 was observed in Polish RA patients with established disease.56 In addition, RA patients can be on corticosteroids, which can accelerate the catabolism of 25(OH)D and 1,25(OH)2D via activation of the pregnane X receptor (PXR). The PXR plays an important role in detoxifying xenobiotics and drugs. It is an intracellular receptor that is expressed in the cells of the gastrointestinal tract, kidneys, and liver, showing 60% homology with the VDR in the DNA-binding domains. The PXR can thereby bind to vitamin D-responsive elements (VDRE) in the DNA and, as a transcription factor, affect the expression of genes whose expression is normally regulated by vitamin D. Through activation of the PXR, expression of the 24-hydroxylases is upregulated, leading to increased degradation of 25(OH)D and 1,25(OH)2D.57 Thus, RA patients on corticosteroids will be prone to low 25(OH)D levels. At a clinical level, a metaanalysis showed that serum 25(OH)D in corticosteroid users was on average 0.5 (95% CI, 1.0, 0.1) ng/mL lower than in

Effects of 25-Hydroxyvitamin D in Rheumatoid Arthritis

healthy controls with a weighted mean level of 22.4 ng/mL (56 nmol/L).58 So, although the effect of corticosteroids on 25(OH)D levels is small clinically, it can add onto the already less-than-optimal vitamin D concentrations in RA patients (further discussed in Section 3.2). Whether supplementation with vitamin D can reverse some of these changes in vivo is not clear. In healthy volunteers, a 12-week high-dose oral cholecalciferol supplementation (140,000 IU/month) led to significantly increased numbers of peripheral Tregs in vivo.59 In contrast, a study of 39 early RA patients with a disease duration of 10.8 mmol/L), which was easily corrected by a dose reduction of 0.25 μg daily.72 Subsequent studies used oral vitamin D in various regimes. One study randomized patients with early RA (disease duration of