Advances in the Management of Psoriatic Arthritis [1 ed.] 9781780842615, 9781780842639

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The Management of Psoriatic Arthritis

Editor Douglas J Veale University College Dublin, Dublin, Ireland

Published Published by by Future Future Medicine Medicine Ltd Ltd Future Future Medicine Medicine Ltd, Ltd, Unitec Unitec House, House, 2 2 Albert Albert Place, Place, London London N3 N3 1QB, 1QB, UK UK www.futuremedicine.com www.futuremedicine.com ISSN: ISSN: 2047-332X 2047-332X ISBN: 978-1-78084-263-9 (print) ISBN: XXX (print) ISBN: 978-1-78084-262-2 (epub) ISBN: XXX (epub) ISBN: (pdf) ISBN: 978-1-78084-261-5 XXX (pdf) © Future Medicine Medicine Ltd Ltd © 2013 2012 Future All All rights rights reserved. reserved. No No part part of of this this publication publication may may be be reproduced, reproduced, stored stored in in aa retrieval retrieval system system or or transmitted transmitted in in any any form form or or by by any any means means electronic, electronic, mechanical, mechanical, photocopying, photocopying, recording recording or or otherwise otherwise without without prior prior written written permission permission of of the the copyright copyright holder. holder. British British Library Library Cataloguing-in-Publication Cataloguing-in-Publication Data. Data. A A catalogue catalogue record record for for this this book book is is available available from from the the British British Library. Library. Although Although the the author author and and publisher publisher have have made made every every effort effort to to ensure ensure accuracy accuracy of of published published drug drug doses doses and and other other medical medical information, information, they they take take no no responsibility responsibility for for errors, errors, omissions, omissions, or or for for any any outcomes outcomes related related to to the the book book contents contents and and take take no no responsibility responsibility for for the the use use of of any any products products described described within within the the book. book. No No claims claims or or endorsements endorsements are are made made for for any any marketed marketed drug drug or or putative putative therapeutic therapeutic agent agent under under clinical clinical investigation. investigation. Any Any product product mentioned mentioned in in the the book book should should be be used used in in accordance accordance with with the the prescribing prescribing information information prepared prepared by by the the manufacturers, manufacturers, and and ultimate ultimate responsibility responsibility rests rests with with the the prescribing prescribing physician. physician. Content Content Development Development Editor: Editor: Duc Duc Hong Hong Le Le Senior Senior Manager, Manager, Production Production & & Design: Design: Karen Karen Rowland Rowland Head Head of of Production: Production: Philip Philip Chapman Chapman Managing Managing Production Production Editor: Editor: Harriet Harriet Penny Penny Production Editor: Georgia Patey Production Editor: Georgia Patey Assistant Baxter Assistant Production Production Editors: Editors: Samantha Samantha Whitham, Whitham &Abigail Gemma King & Kirsty Brown Editorial Ben Kempson Graphics Assistant: & Design Manager: Hannah Morton Graphics & Design Manager: Hannah Morton

Contents Psoriatic arthritis: recognizing and managing disease in the 21st century Douglas J Veale Symptoms and diagnosis of psoriatic arthritis Deepak Jadon & Neil J McHugh Classification and monitoring of disease activity Oliver Fitzgerald Psoriatic arthritis pathogenesis Rodolfo Perez Alamino & Luis R Espinoza Imaging features in psoriatic arthritis Wilson Bautista-Molano & Désirée van der Heijde Treatment options: NSAIDs and DMARDs Raffaele Scarpa, Luisa Costa, Mariangela Atteno, Francesco Caso & Ennio Lubrano Treatment options: biologicals Douglas J Veale Prognosis and treatment guidelines Renata Baronaite Hansen & Arthur Kavanaugh Index

3 7 25 37 49 63 73 79 94

About the Editor Douglas J Veale Douglas J Veale is Director of Translational Research at the Dublin Academic Medical Center, Adjunct Professor of Medicine at University College Dublin and Consultant Rheumatologist at St Vincent’s University Hospital (Dublin, Ireland). He heads an active translational research group in inflammatory arthritis, biopharma­ ceutical therapies and biomarkers. He was elected as a fellow of the Royal College of Physicians in Ireland (1997) and the Royal College of Physicians in London, UK (1999).

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Foreword Psoriatic arthritis: recognizing and managing disease in the 21st century Douglas J Veale Psoriatic arthritis (PsA) was first described by Moll and Wright as a distinct clinical entity as recently as 1973 is a common condition (3.5–7/100,000 individuals) [1]. Inflammation of the skin and the joints may be an independent process as 90% of psoriasis patients never develop an associated arthritis and the skin and joint manifestations are usually not contiguous. Cutaneous lesions precede joint disease in 60% of subjects; however, cutaneous lesions may occur simultaneously (20%) or develop after joint manifestations (20%) [2]. PsA was initially considered to be a benign condition; however, the evidence over the last 20 years suggests that if it is undertreated, serious morbidity and increased mortality may occur in the long term. In one pivotal observational cohort study, over 10% of PsA subjects were classified as having severe functional limitation (American Rheumatology Association – class III or IV) as a result of their arthritis [3]. Increased mortality has been increasingly recognized in PsA patients, mainly from associated cardiovascular disease including atherosclerosis, peripheral vascular disease, congestive heart failure, cerebrovascular disease, Type 2 diabetes mellitus, hyperlipidemia and hypertension [4] compared with age- and sex-matched controls. PsA, while similar in many clinical features to rheumatoid arthritis, is characterized by a younger population (peak incidence 35–45 years of age), a preponderance of male subjects rather than females and by definition it is seronegative for rheumatoid factor. However, it has recently been described doi:10.2217/EBO.12.486

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Veale that PsA patients may show a greater overall response, including a faster rate to achieve remission following treatment with TNF inhibitor therapy [5]. Psoriasis demonstrates a familial association with a third of patients having a history of a family member with the disease, and PsA, although the familial association is not as strong, clearly demonstrates a role for a genetic etiological factor. The key features of PsA are highlighted in this book. Initially, the most common symptoms and signs of this complex disorder are summarized and the goal of Chapter 1 is to highlight the clinical features of PsA to facilitate the correct diagnosis at an earlier stage. Following this, the book updates the reader on the latest classification and monitoring of the disease, again the advances in standardization of a classification (the CASPAR criteria) has lead to a reduction in delays of recognizing PsA in subjects and earlier diagnosis. The monitoring of disease activity and response to drug therapy is also covered in Chapter 2. There have been considerable developments in our understanding of the pathogenesis and imaging of PsA that are extensively covered in Chapters 3 & 4. One of the most striking advances in PsA has been the introduction of novel therapies, namely TNF inhibitors, in combination with traditional disease-modifying antirheumatic drugs, which has lead to remission rates of 60% in one report [5]. In the final chapter, the recent treatment guidelines for PsA and the literature on prognosis are reviewed. In conclusion, this book brings the very latest advances in diagnosis, pathogenesis, management and prognosis of PsA into perspective, to enable the reader to appreciate how to recognize this complex disease at an early stage, choose appropriate investigations and introduce a relevant management program. Financial & competing interests disclosure DJ Veale was supported by unrestricted educational grants or research funding from Abbott, Immunoqure, MSD, Opsona, Pfizer and Roche. He has worked on clinical trials that were supported by Actelion, MSD, Pfizer, Roche and UCB. He has been a Consultant/Advisor for MSD, Pfizer and Roche, and has been on the speakers bureau for Abbott, MSD, Pfizer, Roche and UCB. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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Psoriatic arthritis: recognizing & managing disease in the 21st century References 1

Shbeeb M, Uramoto KM, Gibson LE, O’Fallon WM, Gabriel SE. The epidemiology of psoriatic arthritis in Olmsted County, Minnesota, USA, 1982–1991. J. Rheumatol. 27(5), 1247–1250 (2000).

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Veale D, Rogers S, Fitzgerald O. Classification of clinical subsets in psoriatic arthritis. Br. J. Rheumatol. 33(2), 133–138 (1994).

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Gladman DD, Stafford-Brady F, Chang CH, Lewandowski K, Russell ML. Longitudinal study of clinical and radiological progression in psoriatic arthritis. J. Rheumatol. 17(6), 809–812 (1990). Han C, Robinson DW Jr, Hackett MV, Paramore LC, Fraeman KH, Bala MV. Cardiovascular disease and

risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosingspondylitis. J. Rheumatol. 33(11), 2167–2172 (2006). 5

Saber TP, Ng CT, Renard G et al. Remission in psoriatic arthritis: is it possible and how can it be predicted? Arthritis Res. Ther. 12(3), R94 (2010).

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About the Authors Deepak Jadon Deepak Jadon is a Specialist Registrar in rheumatology and general medicine at the Royal National Hospital for Rheumatics Diseases (Bath, UK). He is currently undertaking a PhD investigating the characteristics of axial disease in psoriatic arthritis. His research interests include genetic, serum biomarker and radiographic profiling of psoriatic arthritis, ankylosing spondylitis and the spondyloarthropathies.

Neil J McHugh Neil J McHugh graduated from Otago University (New Zealand) in 1978. He completed a research fellowship at Walter and Eliza Hall (Melbourne, Australia) in 1985 and he was also Registrar at the Royal National Hospital for Rheumatic Diseases until 1990. He became a postdoctoral fellow at Yale University (CT, USA), in 1991 and Consultant Rheumatologist at the Royal National Hospital for Rheumatic Diseases in 1992. Current fields of interest are psoriatic arthritis (including treatment guidelines, outcome measures, genetics and clinical trials) and autoimmune mechanisms in connective tissue disease (including genetics, autoantibodies, proteomics and clinical trials).

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1

Chapter

Symptoms and diagnosis of psoriatic arthritis

Epidemiology

8

Clinical presentation

8

Presenting symptoms

9

Patterns of clinical disease at presentation

9

Other manifestations of PsA

11

Clinical examination

16

Differential diagnosis16 Laboratory investigation 18

Deepak Jadon & Neil J McHugh Psoriatic arthritis is a distinctive inflammatory musculoskeletal disorder with clinical, radiological and immunopathogenic features that set it apart from other forms of arthritis. In this chapter, the clinical manifestations of psoriatic arthritis will be described, including patterns of disease, symptoms and signs. Useful laboratory investigations and differential diagnoses will also be highlighted.

doi:10.2217/EBO.13.20

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Jadon & McHugh Epidemiology Psoriatic arthritis (PsA) affects women and men equally [1]. Studies from northern Europe and the USA estimate that PsA has an annual incidence of approximately six per 100,000 of the population [2,3] and a prevalence of 0.1–0.25% in the general population [2–5]. Less is known for both parameters in other parts of the world due to differing definitions of PsA and the scarcity of longitudinal epidemiological data. PsA may be less prevalent in certain ethnic groups; Afro–Caribbean and Native American populations [6]. PsA tends to occur between the ages of 20–50 years, but can also present in childhood. Studies from the UK and North America indicate that between 5 and 42% of psoriasis patients will develop PsA [7–9]. The establishment of the Classification of Psoriatic Arthritis (CASPAR) criteria [10] has improved researchers’ ability to define clinical disease for the purpose of clinical trials and longitudinal studies. Using the CASPAR criteria, the prevalence of PsA among psoriasis cases in two large primary care cohorts in the UK was 13.8% [11]. Similarly, using the CASPAR criteria, the incidence of PsA in psoriasis patients was found to be 2% per year [12]. Psoriasis has long been known to occur frequently within families, with 40% of psoriasis cases having a family history of psoriasis [13]. Similarly, PsA is up to 55-fold more frequent if a first-degree relative is affected by PsA [14]. There is some research suggesting that environmental factors can trigger the first presentation, possibly in genetically susceptible individuals. Streptococcal infection, HIV and trauma have been implicated [15]. PsA carries a significant burden of morbidity, mortality and economic cost that is comparable to rheumatoid arthritis (RA) [16,17]. Prospective studies have shown deteriorating functional status and progressive joint damage over time [18–20].

Clinical presentation PsA presents as a heterogenous pattern of joint inflammation and extraarticular manifestations that can include enthesitis, dactylitis, uveitis, spondylitis and usually psoriatic skin, nail disease and metabolic syndrome. In order to understand these diverse manifestations, one must appreciate that there is significant clinical and genetic overlap between PsA, psoriasis, RA and Psoriatic arthritis (PsA) carries a significant ankylosing spondylitis (AS). Some authors burden of morbidity, mortality and economic propose that PsA is part of the broad cost that is comparable with rheumatoid continuum of ‘spondyloarthritis’ (SpA) that arthritis [16,17].

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Symptoms & diagnosis comprises AS, reactive arthritis, arthritis associated with inflammatory bowel disease, juvenile SpA and undifferentiated SpA (Figure 1.1). For example, PsA and AS share a broad clinical phenotype that includes an asymmetrical peripheral oligoarthritis with involvement of the sacroiliac joints and entheses.

Presenting symptoms PsA patients characteristically describe inflammatory early morning musculoskeletal stiffness lasting for at least 30 min (documented in ≥50% of patients) [21], pain affecting peripheral joints, enthesitis and spinal pain (termed spondylitis). Often these symptoms affect joints in an asymmetric pattern [22]. Patterns of clinical disease at presentation In 1973, a review article by Moll and Wright described the clinical, serological and radiological characteristics of PsA, and identified five distinct patterns of presentation [23]: Figure 1.1. The overlapping clinical phenotype of psoriatic arthritis.

PsV

ReA

jSpA RA

PsA

AS

IBD uSpA

AS: Ankylosing spondylitis; IBD: Inflammatory bowel disease; jSpA: Juvenile spondylo­ arthritis; PsA: Psoriatic arthritis; PsV: Psoriasis vulgaris; RA: Rheumatoid arthritis; ReA: Reactive arthritis; uSpA: Undifferentiated spondyloarthritis.

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Jadon & McHugh Polyarthritis

n

Oligoarthritis

n

Distal interphalangeal joint (DIPJ)

n

Arthritis mutilans

n

Psoriatic spondyloarthropathy (PsSpA)

n

It has been observed that although a patient may initially present with the attributes of one particular subset, over the course of their disease, it is not unusual to migrate between the subsets or have two subsets occurring concomitantly [20]. Oligoarthritis was described by Moll and Wright as the most common subset; however, subsequent studies indicate that prevalence varies according to the population studied, with polyarthritis being the most common in some populations [24]. DIPJ and arthritis mutilans patterns appear to be the most specific for PsA. Polyarthritis Polyarthritis in PsA is defined as arthritis affecting five or more joints. It often symmetrically affects the proximal interphalangeal joints (PIPJs), DIPJs, wrists, knees and ankles. It can be indistinguishable from RA until radiological or extra-articular features are considered. Oligoarthritis Oligoarthritis in PsA is defined as arthritis affecting two to four small and/or large joints, usually in an asymmetric manner. The most frequently affected joints include the PIPJs, wrists, knees and ankles. The asymmetry may simply be a reflection of the limited number of joints affected. Distal interphalangeal joint This pattern of PsA affects the DIPJs, with relative sparing of other joints. It is usually symmetrical and polyarthritic giving a bulbous drumstick appearance to the distal finger. DIPJ involvement alone occurs in male

Symptom onset

Insidious

Insidious

Symmetry of joint involvement

Asymmetrical

Symmetrical

Small joint distribution

Distal and proximal interphalangeal joints

Metacarpophalangeal and proximal interphalangeal joints

Erythema over affected joint Common

Rare

Nail lesions

Common

Rare

Psoriatic skin lesion

Common

Rare

Enthesopathy

Common

Rare

Dactylitis

Common

Rare

Inflammatory back pain

Common

Rare

Rheumatoid nodules

Absent

Common

of asymmetrical oligoarthritis, urethritis and 10% have skin lesions affecting the palms/soles. Just as in PsA, they are prone to dactylitis and inflammatory back pain. Psoriatic nail disease is very rare in reactive arthritis. Gonococcal arthritis Gonococcal arthritis characteristically affects young women with an abrupt onset of asymmetrical mono-/oligo-arthritis and gonococcal urethritis. There is usually no dactylitis or inflammatory back pain. Skin lesions are usually pustular/vesicular rather than plaques. Inflammatory osteoarthritis Inflammatory osteoarthritis of DIPJs can mimic the DIPJ subset of PsA. It presents in middle-aged women with a family history of bony swelling affecting the DIPJs and PIPJs. Inflammatory episodes can occur whereby the joint becomes red, tender and with some superimposed soft-tissue swelling. Calcium pyrophosphate disease may further complicate the picture.

Laboratory investigation There are no specific laboratory tests diagnostic of PsA. Unlike in RA, the majority (70%) of patients with PsA present with normal acute phase reactants, erythrocyte sedimentation rate and C-reactive protein.

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Symptoms & diagnosis Anemia has been reported in 14% of PsA cases at presentation, with a higher prevalence at follow-up [21]. Hyperuricemia occurred in 21% of cases in one prospective 6-year follow-up study [64]. In total, 5% of PsA patients are rheumatoid factor positive and 8–16% are anti-CCP positive [62,63]. It is not known if anti-CCP antibodies occur in early disease, thereby holding a prognostic value, or if they develop in established PsA simply as an epiphenomenon. Antinuclear antibody is present in low titer (1/40) in 50% of cases, and at a high titer in 14% of cases (≥1/80). Some of theses antinuclear antibodies are directed against stratum corneum antigens [24]. Up to 3% of cases can carry antibodies to dsDNA. Synovial fluid aspiration in PsA is similar to that in RA; with a high white-cell count and neutrophil predominance. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Summary. ƒƒ Psoriatic arthritis (PsA) is an inflammatory musculoskeletal disorder associated with psoriasis. ƒƒ PsA is a heterogenous disease that has both features in common and features that set it apart from rheumatoid arthritis, ankylosing spondylitis and other forms of spondyloarthropathy. ƒƒ Although PsA has five distinct patterns of presentation, a patient may migrate between them. ƒƒ PsA has many facets of clinical presentation, many of which are extra-articular. ƒƒ There is no robust diagnostic criteria for PsA, only classification systems. Therefore, one must consider several differential diagnoses. ƒƒ There are no specific laboratory tests diagnostic of PsA.

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C et al. Association of functional variants of PTPN22 and tp53 in psoriatic arthritis: a case–control study. Arthritis Res. Ther. 8, R27 (2006).

60 Ho PY, Barton A, Worthington

comparison with psoriasis and undifferentiated inflammatory arthritis. Ann. Rheum. Dis. 67, 677–682 (2008).

R et al. Antibodies to cyclic citrullinated peptides in psoriatic arthritis. J. Rheumatol. 32, 511–515 (2005).

64 Bruce IN, Schentag C,

Gladman DD. Hyperuricaemia in psoriatic arthritis does not reflect the extent of skin involvment. J. Clin. Rheumatol. 6, 6–9 (2000).

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About the Author Oliver Fitzgerald Oliver Fitzgerald is Consultant Rheumatologist and Newman Clinical Research Professor at St Vincent’s University Hospital and the Conway Institute, University College Dublin, Ireland. His main research interests in psoriatic arthritis include clinical and therapeutic studies; the development of novel imaging techniques for measuring synovial or entheseal inflammation, including ultrasound and MRI; analysis of synovial and skin cellular and cytokine profiles; and, more recently, studies of gene and protein expression in diseased tissue.

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Chapter

2 Classification and monitoring of disease activity

Diagnostic & classification criteria

Oliver Fitzgerald 26

Earlier classification criteria26 CASPAR criteria

27

Remaining challenges

28

Measuring disease

29

New composite measures31

Psoriatic arthritis is a complex multisystem disease with autoimmune and autoinflammatory features. The development and validation of the classification criteria for psoriatic arthritis has been a significant advancement and these criteria should be used when enrolling patients in studies including randomized controlled clinical trials. Some additional clarification regarding the definition of inflammatory musculoskeletal disease is required. With classification criteria agreed, the development and validation of composite disease activity and response measures is the new challenge for clinicians.

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Fitzgerald The diagnosis of prehistoric arthritis is usually made by a rheumatologist on the basis of the appropriate clinical, radiographic features in the absence of rheumatoid factor. There are no diagnostic criteria.

Diagnostic & classification criteria Historically, the development of rheumatoid factor was important in separating out those patients who had coincidental rheumatoid arthritis and psoriasis from those who had psoriatic arthritis (PsA). The association of PsA with the absence of rheumatoid factor and the recognition by Moll and Wright of some of the unique clinical features that occur in patients with PsA, such as distal interphalangeal joint disease, sacroiliitis and arthritis mutilans were key to establishing PsA as a distinct clinical entity [1].

As of yet, there are no pathognomic clinical features or ‘gold-standard’ diagnostic tests for PsA and thus diagnostic criteria have not been developed. The diagnosis is usually made by a rheumatologist and is based on the clinical presentation together with other laboratory and radiographic features. The case definition can vary depending on the experience and expertise of the rheumatologist involved. One study has shown that expert clinicians do have different thresholds for making a diagnosis of PsA in patients with nonclassical disease presentations [2]. Using a statistical technique of latent class analysis and diagnostic simulations of a variety of paper patients, it was possible to identify three classes of patients: definite disease, definite nondisease and a class of possible disease. Furthermore, it was possible to classify the 15 rheumatologist participants as ‘high diagnosers’ or ‘low diagnosers’ depending on their behavior with respect to the ‘possible disease’ class of patient. In order to overcome some of these difficulties, classification criteria have been developed; such criteria can be used when trying to ensure uniformity of recruitment of patients to clinical studies including randomized trials. Such criteria should be highly specific for the disease and while high sensitivity would also be desirable, somewhat lower sensitivity might nonetheless be acceptable. The development and validation of the Classification Criteria for Psoriatic Arthritis (CASPAR) represents a considerable advance in the study of this complex rheumatic disease [3]. Diagnostic criteria: are usually a group of symptoms, physical findings and investigation results used by clinicians to make a disease diagnosis. Classification criteria: are usually a group of symptoms, physical findings and investigation results used in order to standardize recruitment to clinical studies, including clinical trials.

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Earlier classification criteria Prior to 2006 a number of classification criteria had been proposed [4–9]. All were largely developed based on clinical or other features but none were developed using rigorous methods. The original Moll and

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Classification & monitoring of disease activity The CASPAR criteria have been endorsed as Wright criteria were the most widely used those appropriate to use in clinical studies, but it was unclear which classification including clinical trials. criteria set best represented ‘true PsA’. While all of the criteria included clinical features, the individual features included were quite variable. Most but not all criteria required negative rheumatoid factor, some included x-ray features and Fournier’s criteria definition also included HLA typing. The appropriateness or otherwise of the classification criteria was much discussed and with different criteria used in different studies, it proved difficult to compare and contrast study findings.

CASPAR criteria For the development of the CASPAR criteria, data were collected prospectively from consecutive clinic attendees with PsA and other inflammatory arthropathies. Based on data from 588 cases and 536 controls, the CASPAR criteria were proposed (Box 2.1). The CASPAR criteria are simple to apply Box 2.1. Classification Criteria for Psoriatic Arthritis. To meet the CASPAR criteria†, a patient must have inflammatory articular disease (joint, spine or entheseal) with at least three points from the following five categories: ƒƒ Evidence of current psoriasis, a personal history of psoriasis or a family history of psoriasis −− Current psoriasis is defined as psoriatic skin or scalp disease present today as judged by a rheumatologist or dermatologist‡ −− A personal history of psoriasis is defined as a history of psoriasis that may be obtained from a patient, family physician, dermatologist, rheumatologist or other qualified healthcare provider −− A family history of psoriasis is defined as a history of psoriasis in a first- or second-degree relative according to patient report ƒƒ Typical psoriatic nail dystrophy including onycholysis, pitting and hyperkeratosis observed on current physical examination ƒƒ A negative test result for the presence of rheumatoid factor by any method except latex but preferably by ELISA or nephelometry, according the the local laboratory reference range ƒƒ Either current dactylitis, defined as swelling of an entire digit, or history of dactylitis recorded by a rheumatologist ƒƒ Radiographic evidence of juxtaarticular new bone formation, appears as ill-defined ossification near joint margins (but excluding osteophyte formation) on plain radiographs of the hand or foot The CASPAR criteria have specificity of 98.7% and sensitivity of 91.4%. Current psoriasis is assigned a score of 2; all other features are assigned a score of 1. CASPAR: Classification Criteria for Psoriatic Arthritis. Adapted with permission from Wiley [5].

† ‡

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Fitzgerald and highly specific (0.987). Sensitivity was found to be somewhat lower than the Vasey and Espinoza criteria (0.914 vs 0.972); however, one attraction of the CASPAR criteria is that they permit the diagnosis of PsA despite rheumatoid factor positivity or in the absence of psoriasis as long as other typical features of PsA are present. The CASPAR criteria have now become the standard for case definition in clinical studies, especially intervention studies, of PsA. Since their publication, some additional challenges have been addressed in particular the question as to whether the criteria might prove useful in early disease. In the original CASPAR data set, the average disease duration was 12.5 years with only small numbers of patients recruited with disease duration of less than 12 months. Initial studies of early PsA did not include a control group with other inflammatory arthropathies and therefore specificity could not be estimated. Coates and colleagues have recently addressed the issue of early disease and included 111 early PsA patients and 111 early arthritis controls [10]. They found that the sensitivity and specificity of the CASPAR criteria in classifying early PsA was 87.4 and 99.1%, respectively. They concluded that the CASPAR criteria are valid inclusion criteria to be used for clinical trials in early PsA. While sensitivities are not quite as good as in established disease, this study of early PsA is certainly reassuring.

Remaining challenges The Assessment of Spondyloarthritis International Society (ASAS) have recently proposed new classification criteria for peripheral spondyloarthritis (SpA) in patients with SpA and peripheral manifestations only [11]. These criteria are applicable to patients with peripheral arthritis (usually predominantly of the lower limbs and asymmetric), and/or enthesitis and/or dactylitis. To meet the criteria patients must also have at least one of six additional features, one of which may be psoriasis. Thus, patients with arthritis and/or dactylitis and/or enthesitis plus psoriasis will meet these ASAS peripheral SpA criteria. When tested, these criteria had a sensitivity of 77.8% and a specificity of 82.2%. The issue with these new peripheral SpA criteria is whether they provide any clarity to patient recruitment efforts or do they serve more to blur our understanding as to what type of patient is being studied? Carefully defining a patient’s clinical phenotype is likely to be very important, with previous data suggesting that there may be important clinical differences between categories of patients with peripheral SpA [12]. Comparing peripheral SpA patients who present with psoriasis with those who present following infection as in reactive arthritis and with those with an undifferentiated SpA phenotype, patients with psoriasis present subacutely compared with

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Classification & monitoring of disease activity Composite measures of disease activity have reactive arthritis patients who present been developed and are now ready for testing acutely and are often very unwell with high in clinical trials. inflammatory markers. The presentation features of the undifferentiated group fall somewhat in between. On follow-up, most reactive arthritis patients were in remission at 1 and 2 years but those with psoriasis continued to have ongoing active disease. Again the undifferentiated group were intermediate in position. Importantly, in regression analysis the presence of psoriasis was a predictor for chronic disease at 2 years of follow-up.

It is certainly possible that an individual’s genotype may determine clinical disease expression. Recent data have shown that the time interval between development of psoriasis and development of PsA is significantly influenced and shortened by the presence of HLA B27 [13]. Other clinical features, including sacroileiitis and the presence of erosive disease may also be determined by genotype. Therefore, using the ASAS criteria for peripheral SpA, which serves to combine all peripheral SpA cases into the one cohort, is not likely to be a significant advance when recruiting for studies or for clinical trials and will inhibit our understanding of differential treatment responses. The second challenge, which is currently being examined by the Group for Research in Psoriasis and Psoriatic Arthritis (GRAPPA), is how we best define the term inflammatory articular disease (joint, spine or entheseal) which is part of the stem of the CASPAR criteria. This issue is perhaps not a particular concern for rheumatologists; however, other specialists, such as dermatologists or ophthalmologists, when attempting to identify and study cases with PsA have difficulty with this concept. A study has been initiated by GRAPPA, which will attempt to precisely define what is meant by the term inflammatory joint, spine or entheseal disease. It may be that the CASPAR classification criteria will need to be further evaluated following agreement of these definitions.

Measuring disease With the agreement that the CASPAR criteria should be used as inclusion criteria in future PsA studies including randomized control trials (RCTs), the next key challenge is to agree how best to monitor disease activity. This is not an easy task given the diverse nature of psoriatic disease, which includes joint involvement but also includes involvement of the skin and nail, the enthesis, dactylitis and the spine. Other extra-articular involvement, such as uveitis, may occur and data would also suggest that features of the metabolic syndrome are not uncommon. To date, the primary outcome measure in clinical trials in PsA has related to joint involvement. A variety of secondary

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Fitzgerald outcomes have been included in PsA RCTs, such as psoriatic skin disease as measured by the Psoriasis Area and Severity Index (PASI), dactylitis, which is usually measured as a simple digit count, or enthesitis, measured at just a few sites such as at the plantar fascia or Achilles insertion. The joint counts used are frequently limited with fewer joints assessed than the 66 swollen and 68 tender joints that are recommended by GRAPPA. Clinical trials have used composite outcome measures and these have largely been shown to be able to discriminate between responders and nonresponders. The composite measures used such as the ACR response measure or the DAS28 and EULAR response measure are predominantly joint-related and were originally developed for use in rheumatoid arthritis. Clegg and colleagues developed the Psoriatic Arthritis Response Criteria (PsARC) in a study of sulfasalazine [14]. PsARC is a dichotomous measure that appears to poorly discriminate between treatment groups giving a high placebo response. Figure 2.1. Domains of involvement in psoriatic arthritis.

Participation

Tissue analysis

Enthesitis Dactylitis

Nails

Peripheral joint activity Skin activity Patient global Pain Physical function Health-related quality of life

MRI

PGA

Fatigue Inner circle Spinal US

CT

Radiology Outer circle

Research agenda Inner circle lists the core domains that should be included in clinical trials. CT: Computed tomography; PGA: Patient Global Assessment; US: Ultrasound. With permission from [15].

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Classification & monitoring of disease activity Working with Outcome Measures in Rheumatology Clinical Trials (OMERACT), GRAPPA agreed a core set of outcome measures that should be included in RCTs (Figure 2.1) [15]. A further set of optional measures were also identified, as well as some that are still part of the research agenda. In the 6 years since the core set was agreed, additional progress has been made with greater validation of appropriate instruments and it is likely that some of the optional domains such as dactylitis or enthesitis, may be ready to join the core set. In general, the instruments that are shown in Table 2.1 are easily applied in the clinical setting and should be included in RCTs. With responsiveness of features such as dactylitis or enthesitis to biologic agents often lacking in RCTs to date, the inclusion of validated instruments to measure such features in future studies will provide important clinical information. As mentioned above and despite their limitations, the composite measures that have been used to date in PsA clinical trials have proven to be responsive to change. The measures do discriminate between study drug and comparator but confining observations to 28 joints as in the DAS 28 score probably limits our capacity to determine treatment response. Previous studies have also shown that you will significantly reduce patient recruitment to clinical trials if the joints evaluated are limited to those included in the 28 joint count [16].

New composite measures Reflecting the need to develop a composite score which might reflect all of the ways in which a patient with PsA might be affected, three new composite measures have recently been proposed. Based on the GRAPPA treatment Table 2.1. Instruments used to measure psoriatic arthritis disease features. Disease feature

Instrument

Range

Peripheral arthritis

66 SJC; 68 TJC

66/68

Skin disease

PASI; DLQI

0–72; 0–30

Enthesitis

Leeds Enthesitis Score

0–6

Dactylitis

Digit count

0–20

Spinal disease

BASDAI

0–10

Patient global health

PsA global heath; skin only; joint only

VAS 0–10

BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; DLQI: Dermatology Life Quality Index; PASI: Psoriasis Area and Severity Index; SJC: Swollen joint count; TJC: Tender joint count; VAS: Visual Analog Scale.

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Fitzgerald grid, the Composite Psoriatic Disease Activity Index (CPDAI) records disease activity in five domains (Table 2.2) with each domain scored both by an instrument which reflects the extent or severity of domain involvement and by an instrument which will reflect the effect on function or quality of life [17]. Involvement is then scored on a ‘none’ to severe involvement scale (0–3) which allows for individual domain assessment as well as for a composite assessment to be calculated (0–15). CPDAI has been validated in a small clinical study but it was also compared with the Disease Activity in Psoriatic Arthritis (DAPsA) response criteria, a joint-related composite measure recently proposed, in the PRESTA clinical trial data set [18]. Both composite measures were able to identify responders but only CPDAI successfully separated twice weekly versus once weekly treatment groups. Most recently GRAPPA has completed an additional study which aimed to develop and agree the most appropriate composite score for PsA [19]. Table 2.2. Composite Psoriatic Disease Activity Index. Disease

None (0)

Mild (1)

Moderate (2)

Severe (3)

Peripheral arthritis

≤4 joints; normal function (HAQ ≤0.5)

≤4 joints but function >4 joints and impaired; or >4 joints, function normal function impaired

Skin disease

PASI ≤10 and DLQI ≤ 10

PASI ≤ 10 but DLQI >10; or PASI >10 but DLQI ≤ 10

PASI >10 and DLQI >10

Enthesitis

≤3 sites; normal function (HAQ ≤0.5)

≤3 sites but function impaired; or >3 sites but normal function

>3 sites and function impaired

Dactylitis

≤ 3 digits; normal function (HAQ ≤0.5)

≤3 digits but function >3 digits and impaired; or >3 digits has function but normal function impaired

Spinal disease

BASDAI ≤4; normal function (ASQol ≤ 6)

BASDAI >4 but normal function; BASDAI ≤4 but function impaired

BASDAI >4 and function impaired

ASQol: Ankylosing Spondylitis Quality of Life; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; DLQI: Dermatology Life Quality Index; HAQ: Health Assessment Questionnaire; PASI: Psoriasis Area and Severity Index.

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Classification & monitoring of disease activity Multiple centers contributed baseline and follow-up information in a systematic manner on 503 PsA patients establishing the GRACE data set. New indices were developed by multiple linear regression (psoriatic arthritis disease activity score [PASDAS] and empirically utilizing physician defined cut-offs for disease activity (Arithmetic mean of desirability functions: AMDF). Both new measures provide a single composite measure of disease activity. Although all measures performed well, compared with existing indices PASDAS was better able to discriminate between high and low disease activity. Following the recent OMERACT meeting it has been agreed that these two new measures together with the CPDAI should be tested in other data sets in order to validate further and to agree which instrument should be included in future RCTs. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Summary. ƒƒ The classification criteria for psoriatic arthritis have been validated and should be used for inclusion in clinical studies and in randomized control trials. ƒƒ The classification criteria for psoriatic arthritis has now been validated in early psoriatic studies. ƒƒ Domains of involvement other than skin and joint disease should be routinely measured in patients with psoriatic arthritis. ƒƒ A number of new composite measures of disease activity have been proposed and it is likely that one of these measures will be accepted as an essential component of future randomized control trials.

References 1

Moll JM, Wright V. Psoriatic arthritis. Semin. Arthritis Rheum. 3(1), 55–78 (1973).

2

Symmons D, Lunt M, Watkins G et al. Developing classification criteria for peripheral joint psoriatic arthritis. Step I. Establishing whether the rheumatologist’s opinion on the diagnosis can be used as the ‘gold

standard’. J. Rheumatol. 33(3), 552–557 (2006). 3

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Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H, CASPAR Study Group. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 54(8), 2665–2673 (2006).

4

Bennett RM. Psoriatic arthritis. In: Arthritis Related Conditions (9th Edition). McCarty DJ (Ed.). Lea & Febiger, PA, USA, 645 (1979).

5

Vasey F, Espinoza LR. Psoriatic arthropathy. In: Spondyloarthropathies. Calin A (Ed.). Grune & Stratton, Orlando, FL, USA, 151–185 (1984).

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Fitzgerald 6

7

8

9

Gladman DD, Shuckett R, Russell ML, Thorne JC, Schachter RK. Psoriatic arthritis – an analysis of 220 patients. Q. J. Med. 62(238), 127–141 (1987). Dougados M, van der Linden S, Juhlin R et al. The European Spondyloarthropathy Study Group preliminary criteria for the classification of spondyloarthropathy. Arthritis Rheum. 34(10), 1218–1227 (1991). McGonagle D, Conaghan PG, Emery P. Psoriatic arthritis: a unified concept twenty years on. Arthritis Rheum. 42(6), 1080–1086 (1999). Fournie B, Crognier L, Arnaud C et al. Proposed classification criteria of psoriatic arthritis. A preliminary study in 260 patients. Rev. Rhum. Engl. Ed. 66(10), 446–456 (1999).

10 Coates LC, Conaghan PG,

Emery P et al. Investigating the use of the CASPAR criteria in early psoriatic arthritis. Arthritis Rheum. 64(10), 3150–3155 (2012).

34

11 Rudwaleit M, van der Heijde

set of domains for psoriatic arthritis. J. Rheumatol. 34(5), 1167–1170 (2007).

D, Landewé R et al. The Assessment of Spondylo Arthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann. Rheum. Dis. 70(1), 25–31 (2011).

16 Leeb BF, Andel I, Sautner J,

12 Stafford L, Kane D, Murphy E

et al. Psoriasis predicts a poor short-term outcome in patients with spondylarthropathy. Arthritis Rheum. 45(6), 485–493 (2001).

13 Winchester R, Minevich G,

Steshenko V et al. HLA associations reveal genetic heterogeneity in psoriatic arthritis and in the psoriasis phenotype. Arthritis Rheum. 64(4), 1134–1144 (2012).

17 Mumtaz A, Gallagher P, Kirby B

et al. Development of a preliminary composite disease activity index in psoriatic arthritis. Ann. Rheum. Dis. 70(2), 272–277 (2011).

18 Fitzgerald O, Helliwell P,

Mease P et al. Application of composite disease activity scores in psoriatic arthritis to the PRESTA data set. Ann. Rheum. Dis. 71(3), 358–362 (2012).

14 Clegg DO, Reda DJ, Mejias E

et al. Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A department of veterans affairs cooperative study. Arthritis Rheum. 39(12), 2013–2020 (1996).

19 Helliwell PS, Fitzgerald O,

15 Gladman DD, Mease PJ, Strand

V et al. Consensus on a core

Fassl C, Nothnagl T, Rintelen B. The disease activity score in 28 joints in rheumatoid arthritis and psoriatic arthritis patients. Arthritis Rheum. 57(2), 256–260 (2007).

Fransen J et al. The development of candidate composite disease activity and responder indices for psoriatic arthritis (GRACE project). Ann. Rheum. Dis. 72(6), 986–991 (2013).

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About the Authors Rodolfo Perez Alamino Rodolfo Perez Alamino is a post-doctoral research fellow from Tucuman, Argentina. His main interest is spondyloarthropathy, particularly concerning the role of the inflammasome on psoriatic arthritis pathogenesis and disease activity.

Luis R Espinoza Luis R Espinoza is Professor and Chief of the Department of Rheumatology at the Louisiana State University Health Sciences Center – New Orleans (LA, USA). He has a long-standing interest in the role of growth factors and cytokines in psoriatic arthritis pathogenesis.

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Chapter

3 Psoriatic arthritis pathogenesis

Genetic factors

38

Environmental factors

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Immune mechanisms

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Vascular immunology

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Tissue destruction & bone signaling

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Rodolfo Perez Alamino & Luis R Espinoza Psoriatic arthritis (PsA) is an inflammatory articular disorder associated with psoriasis (Ps), and associated with a wide spectrum of clinical manifestations. Depending on the method of assessment and on the population, 5–40% of patients with Ps develop PsA [1]. Both are considered as systemic disorders with a complex etiopathogenesis that involves the interplay of environmental, genetic and innate and adaptive immune system factors. In addition, nonimmune mechanisms, such as inflammasome activation, hypoxia and autophagy, may also contribute to the associated comorbidities seen in these disorders. In this chapter, we will explore the relationship between Ps and PsA as a potentially single disease entity with similarities and differences with respect to genetics features, inflammatory mediators and cellular and molecular pathways.

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Perez Alamino & Espinoza The precise relationship between skin involvement and joint manifestations in psoriasis (Ps) and psoriatic arthritis (PsA) patients remains controversial, and despite the considerable progress that has occurred in recent years, immunogenetic factors and pathogenic pathways are still being elucidated. Currently, an interesting debate has emerged as to whether it is the same disease or different entities. While some consider that PsA is an extracutaneous manifestation of Ps, others put forward the notion that it is a distinct inflammatory articular disorder occurring more frequently in the setting of Ps [2]. Although PsA is preceded by Ps in 75% of cases, in 10–15% of cases arthritis precedes the Ps, suggesting that the two diseases may be regulated by different mechanisms or that a common etiology, if it exists, remains dormant for a longer period in the synovial compartment [3].

Genetic factors The wide clinical spectrum observed in PsA, including a variable response to different treatments, is probably a reflection of underlying genetic heterogeneity. Since the prevalence of PsA is less than Ps, the study of its genetic background is more difficult to ascertain. In recent years, however, the role of genetic factors in the pathogenesis of autoimmune disorders has been a topic of great interest and investigation, and has led to the discovery of an association of many genes with the pathogenesis of both disorders. Genome-wide association studies (GWAS) conducted in cohorts of patients with Ps and PsA have identified different genetic variants, particularly in Ps, and numerous genes have been associated with the skin barrier function, as well as innate and adaptive immunity. Evidence gathered from population-based family studies, candidate gene studies, as well as genome-wide linkage analysis and GWAS have shown greater heritability of PsA than Ps, at least three- to five-times higher than Ps. Data have shown a strong association between Ps and the MHC region, within this region the strongest and most consistently reported association is with HLA-C*06, thereby emphasizing an important role for adaptive immune responses. While HLA-C*06 is also increased in PsA patients compared with the general population, this association is stronger with Ps than with PsA [4]. Recently, several investigators have described other class I HLA antigens associated with PsA, which includes HLA-B13, HLA-B27, HLA-B38, HLAG e n o m e - w i d e a s s o c i a t i o n s t u d i e s: B39, HLA-B 57 and HLA-C*12. Among a hypothesis-free method of identifying subtypes of PsA, HLA-B38 and HLA-B39 are disease-susceptibility genes in complex diseases. Up most strongly associated with peripheral to a million markers, such as single-nucleotide arthritis, while HLA-B27 is associated with polymorphisms, are investigated and allele frequencies are compared between cases and healthy spondylitis. MHC class I molecules could controls.

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Psoriatic arthritis pathogenesis promote PsA by presenting arthritogenic peptides to CD8⁺ T lymphocytes or by selection of a T-cell repertoire that is autoreactive in skin and joints (Table 3.1) [5–7]. In general, GWAS studies have been carried out more widely in Ps than in PsA patients, with data generated providing more robust evidence in Ps than in PsA. As a consequence, GWAS studies in Ps have allowed more genes to achieve a genome-wide significance. Some genes have reached this level in both diseases: HLA-C, IL12B, IL23, TNIP1 and TRAF3IP2. Of these, IL12B and the IL23 receptor are linked to Th17 cell population. TRAF3IP2 is also associated with the IL-17 signaling network and TNIP1 is part of the NF-kB pathway. Regarding HLA class II molecules, HLA-DRB1*04 and HLA-DRB1*07 have been associated with PsA and worse radiological damage; however, these associations have not been consistently replicated. Furthermore, the finding that relevant HLA class I MHC alleles occur in less than 50% of PsA patients may reflect involvement of non-HLA genes in the causal pathway. Table 3.1. Psoriasis- and psoriatic arthritis-associated genes. Gene

Chromosomal region

Disease association

ERAP1

5q15

Ps

HLA-C

6p21

Ps/PsA

IFIH1

2q24

Ps

IL2 and IL21

4q26–27

PsA

IL12B†

5q31–33

Ps/PsA

IL13

5q31

PsA

IL23A

12q13

Ps/PsA

IL23R

1p31

Ps/PsA

IL28RA

1p36

Ps

LCE3B/3C

1q21

Ps

NFKBIA

14q13

Ps/PsA

TNFAIP3

6q23

Ps/PsA

5q32–33

Ps/PsA

TRAF3IP2

6q21

Ps/PsA

TYK2

19p13

Ps

ZNF313

20q13

Ps/PsA

†

†

TNIP1

† †

Genes with genome-wide significance in both diseases. Ps: Psoriasis; PsA: Psoriatic arthritis. Data from [5]. †

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Perez Alamino & Espinoza Clearly, these data highlight the fact that the genetic etiology for both diseases is multifactorial and have been demonstrated that the association of various susceptibility genes and HLA antigens with Ps or PsA is difficult to interpret, particularly if the association is primary to PsA or secondary to an association with Ps.

The strongest genetic association signal for psoriasis and psoriatic arthritis is with HLA-C, within the MHC region.

Environmental factors The exact triggering mechanisms of Ps and PsA are unknown, but compelling evidence suggests that an array of environmental factors, such as trauma and infection play a role in the etiologic pathway in genetically susceptible individuals. Early studies by Moll and Wright reported an association between trauma and the subsequent evolution of PsA in the same digit [8]. This was termed as a ´deep Koebner response´ and coined on the basis of the well-recognized Koebner response in Ps [9]. Furthermore, some studies suggest involvement of Gram-positive bacteria agents in Ps and possibly PsA. For example, post-streptococcal Ps, which can evolve into chronic Ps in approximately 40% of cases, often has a short incubation phase following the inciting infection and is associated with carriage of the HLA-Cw*0602 antigen [10]. Streptococcal and staphylococcal superantigens promote inflammation and upregulation of keratinocytes TNF-a in signaling psoriatic skin, but not in other inflammatory dermatoses, stressing the potential importance of this novel immune pathway in Ps. Immune mechanisms There is evidence of dysregulation of the innate and adaptive immune system in the pathogenesis of Ps and PsA. Genomic signatures in psoriatic lesions point to dendritic cells (DCs) and T cells (in particular the Th1 and Th17 populations) as key cell types, and type I IFN, IFN-g and TNF-a as key cytokines (Figure 3.1 & Table 3.2). Innate immune system & the role of keratinocytes Plasmacytoid DCs (pDCs) are increased and activated in early psoriatic lesions by trauma, infection or other signals. This activation occurs through complexes of the antimicrobial peptide LL-37 cathelicidin and DNA in a Toll-like receptor (TLR)9-dependent manner. pDCs have an important role as an inducer of Ps by release of IFN-a [11]. On the other hand, psoriatic keratinocytes have been implicated in the regulation of skin immune response, due to the fact that in response to skin infections or injury, they are able to release antimicrobial peptides, including LL-37, b-defensins and S100A7 (psoriasin). In addition, they respond to activated DC- and

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Psoriatic arthritis pathogenesis Figure 3.1. Key cells and mediators in the pathogenesis of psoriasis and psoriatic arthritis.

NK cell

IFN-γ TNF-α IL-1β

Keratinocyte

IL-12

IFN-α

Triggers

pDC TNF-α IL-1β

mDC

Mast cells

Triggers

Th1 cell Keratinocyte

IL-23

IL-17 Macrophages

IFN-γ TNF-α

Cytokines Chemokines Epidermal hyperplasia

Th17 cell

TNF-α IL-1β IL-6

IL-17 A–F IL-22 Synovitis Enthesitis Dactylitis Sacroiliitis

mDC: Myeloid dendritic cell; NK: Natural killer; pDC: Plasmacytoid dendritic cell.

T-cell-derived mediators, including TNF-a, IFN-a, IFN-g, IL-17 and IL-22. Once activated, keratinocytes induce the production of antimicrobial peptides and different proinflammatory cytokines (mainly IL-1b, IL-6 and TNF-a), chemokines (CXCL8–11, CCL-20) and S100 proteins. These soluble mediators feed back into the proinflammatory disease cycle and modulate the psoriatic inflammatory infiltrate [12]. DCs, macrophages & natural killer cells Both immature and mature DCs, as well as macrophages and natural killer (NK) cells, are present in inflammatory infiltrates of skin and synovium of patients with Ps and PsA. The proinflammatory milieu present appears to activate another population of DCs, myeloid dermal DCs, which migrate to the skin-draining lymph nodes. In these adaptive immunity centers, myeloid dermal DCs present antigen and secrete mediators such as IL-12 and IL-23, leading to the differentiation of Th1 and Th17 cells. Homing of these cells, in particular the Th17 cells, to the skin plays a key role in the perpetuation and amplification of the inflammatory reaction [13]. Wenink et al. have studied the characteristics of myeloid (DC) in PsA, and have described a lower production of DC-derived proinflammatory cytokines after in vitro stimulation. In vivo implications of these data remain unknown, however, since the impairment activation was present only in PsA and not Ps patients, this defective function of myeloid (DC) in PsA suggest important pathogenetic differences between the two disorders [14].

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Perez Alamino & Espinoza Table 3.2. Shared mechanisms between psoriasis and psoriatic arthritis. Attributes

Ps

PsA

Mode of inheritance

Multifactorial

Multifactorial

Trigger/initiation

Unknown (infection–trauma)

Unknown (infection–trauma)

Innate immune activation

Yes

Yes

Main cells involved

pDCs, mDCs, macrophages, NK cells, mast cells, keratinocytes

DCs, macrophages, NK cells, mast cells

Main inducer cytokines

IFN-a/IFN-g/TNF-a

TNF-a/IL-1/IL-6/IL-8

Adaptive immune activation

Yes

Yes

Main cells involved

Th1, Th17 cells

Th1, Th17 cells

Main inducer cytokines

IL-12/TNF-a/IFN-g/IL-1/IL-23/ IL-17A-F/IL-22

IL-12/TNF-a/IFN-g/IL-1/IL-23/ IL-17A-F

Outcome main effectors

Angiogenesis, TGF-b/PDGF/ VEGF/VCAM Epidermal hyperplasia, IL-22/ EGF

Angiogenesis, TGF-b/PDGF/ VEGF/VCAM Cartilage-bone destruction, MMPs/ADAMTs/OC/RANKL

mDC: Myeloid dendritic cell; MMP: Matrix metalloproteinase; NK: Natural killer; OC: Osteoclast; pDC: Plasmacytoid dendritic cell; Ps: Psoriasis; PsA: Psoriatic arthritis; VCAM: Vascular cell adhesion molecule.

The presence of lymphocytes expressing different NK surface markers and g/d TCR antigen, involved in non-MHC-restricted cytotoxicity have been shown in synovial fluid (SF) and peripheral blood of PsA patients, suggesting that this component of the cell-mediated immune response seems to play a role in the development of PsA [15]. B cells B cells may be present in the skin and joints, occasionally forming primitive germinal centers; however, no convincing evidence for the presence of autoantigens exists and the factors that subsequently redirect the auto­ immune process toward the synovial joint remain unknown. In PsA patients, the absence of antibodies directed against specific auto-antigens, such as rheumatoid factor, does not allow us to apply a paradigm similar to rheumatoid arthritis (RA). However, there is a subset of PsA patients with positive cyclic citrullinated peptide (CCP) antibodies, which seems to be associated with a more erosive disease [16]. Spadaro et al., however, have shown lower levels of IgG anti-CCP antibodies in SF (p