Psoriatic Arthritis: Current Topics David McCarey, MRCP, MD, and Iain B. McInnes, FRCP, PhD
Corresponding author Iain B. McInnes, FRCP, PhD Centre for Rheumatic Diseases, University of Glasgow, 10 Alexandra Parade, Glasgow, Scotland, G31 2ER, UK. E-mail:
[email protected] Current Rheumatology Reports 2007, 9:442–448 Current Medicine Group LLC ISSN 1523-3774 Copyright © 2007 by Current Medicine Group LLC
Psoriatic arthritis is a common inflammatory arthropathy that occurs in approximately 25% of psoriasis patients. Due to significant advances in therapeutics—mainly the advent of biologic therapy—the disease has been subject to intense investigation recently. This review summarizes recent investigations of disease pathogenesis and clinical treatment. Clinical responses to tumor necrosis factor– blocking agents appear robust and superior to traditional disease-modifying drug responses, whereas other interventions, such as costimulation blockade, require more investigation. The pathogenesis of the disease appears related to T helper 17–polarized immune responses that target skin, joints, and the enthesial compartment. Finally, new insights into the disorder’s genetic antecedents are emerging as more cohorts of patients undergo advanced genetic screening methods.
Introduction Psoriatic arthritis (PsA) is a common inflammatory arthropathy that occurs in approximately 20% to 25% of patients with psoriasis. The precise relationship between psoriasis and PsA is disputed. It may represent a disease with a spectrum of tissue targeting and hence pathology, but the clinical syndrome could represent two disorders sharing significant common genetic and environmental triggers. Investigations regarding the treatment and pathogenesis of PsA have increased exponentially recently, for several reasons. Well-organized, well-characterized cohorts of patients are being examined systematically using sophisticated molecular genetic and proteomic methodologies. The advent of biologic therapeutics, mainly those blocking tumor necrosis factor (TNF)-B, has stimulated a large number of placebo-controlled studies to provide a much-needed evidence base for therapeutic decision making. Paradoxically, the evidence base for biologic agents considerably exceeds that supporting the use of traditional immune modulator agents such as methotrexate (MTX)
and sulfasalazine, and at present, the optimal treatment algorithm for the disease is uncertain. In general, clinicians are moving to earlier introduction of biologic agents analogous to the treatment of rheumatoid arthritis (RA). However, the evidence base to support such is sparse, because few studies have addressed specifically the issue of early intervention and its potential for improved outcomes. The analogy with RA is discrepant, because earlier interventions for RA have now been shown to clearly confer therapeutic advantage and perhaps even improved remission rates. Approximately 80% of PsA patients develop articular disease after skin disease onset; therefore, PsA patients represent an intriguing population for potential preventive strategies. Psoriasis patients could be screened, followed for subsequent development of articular disease, and administered preventive therapeutics. This trial activity has also provoked renewed interest in optimizing outcome measures to best represent clinical function and progress and usefully discriminate active from placebo agents. An important corollary to such studies has been the effort to derive an internationally acceptable disease definition. This goal is reflected in the development of the ClASsification for Psoriatic ARthritis (CASPAR) criteria (outlined later), which will considerably enhance the consistency and reproducibility of clinical trials in years to come. This short report considers recently published papers that inform and advance our understanding of therapeutics and pathogenesis. Though necessarily selective, they offer the promise of improved prediction, clinical categorization, and ultimately therapeutics.
Diagnosis and Classification The diagnosis of PsA encompasses a number of overlapping clinical entities. Most clinicians refer back to the classical study by Moll and Wright [1], which described a large cohort of patients with PsA and characterized five main subgroups of disease: polyarticular symmetric (RA-like), oligoarticular asymmetric (< 5 joints), distal interphalangeal predominant, spondylitis predominant, and arthritis mutilans. This classification is a useful framework for considering PsA in its various forms in day-to-day practice. However, these and other classification criteria have been used in distinct studies with no clear evidence of which was most sensitive or specific. This lack of standardization makes outcome comparison among different studies very difficult.
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The CASPAR group sought to address this problem by comparing the performance of various available classification criteria in 1124 patients (588 PsA patients and 536 controls with other diagnoses, mostly RA and ankylosing spondylitis) recruited from 13 countries [2•]. They derived sensitivity and specificity for the most commonly used criteria using conditional logistic regression analysis. They used classification and regression trees methodology and logistic regression to identify items for new criteria, which were then constructed using a receiver operating characteristic curve. The CASPAR criteria consisted of established inflammatory articular disease with at least three points from the following features: current psoriasis (assigned a score of 2; all other features were assigned a score of 1), a history of psoriasis (unless current psoriasis was present), a family history of psoriasis (unless current psoriasis or a history of psoriasis was present), dactylitis, juxta-articular new bone formation, rheumatoid factor negativity, and nail dystrophy. These criteria were more specific (0.987 vs 0.960) but less sensitive (0.914 vs 0.972) than those of Vasey and Espinoza, which are generally thought to be the optimal existing set of criteria. These new, scrupulously derived criteria are certainly worthy of further evaluation in wider populations and comparison with the established classification sets. However, these new criteria were derived from populations with established PsA and are therefore unvalidated for diagnostic purposes.
Cardiovascular Risk RA is associated with premature mortality and, most notably, an increased risk of vascular disease. Undoubtedly, RA patients have a greater burden of traditional and novel vascular risk factors, but it is also increasingly clear that systemic inflammation per se is directly damaging to the vasculature [3]. Emerging literature now supports a similar link between PsA and accelerated atherosclerosis. Peters et al. [4] recently presented an excellent overview of the sparse data concerning cardiovascular risk profiles in the spondyloarthropathies. They found inconsistent literature on mortality in PsA. Some PsA cohorts did not differ from the general population, whereas others were at increased risk of early death. This difference likely represents inconsistency between centers in diagnostic classification, further underscoring the need for standardization in this area. Most recently, Ali et al. [5] reported that survival in PsA seems to be improving over time, but their cohort overall was estimated to have lost an average of 2.99 life years. They argued that this improvement is due to a trend toward less severe disease at presentation, earlier diagnosis, and more aggressive treatment. To date, mortality studies in PsA have been disappointingly small; hence, no reliable data are available to confirm definitively an increased likelihood of cardiovascular disease–related death in PsA patients. However, the
available small studies consistently report cardiovascular disease as the leading cause of death in PsA patients [4]. In keeping with the RA literature, erythrocyte sedimentation rate seems to be a good predictor of premature mortality in PsA [6], which is congruent with the theory that chronic, systemic inflammation drives accelerated atherosclerosis, contributing to premature mortality. More recent publications from Gonzalez-Juanatey et al. [7,8] provide clear evidence of higher prevalence of endothelial dysfunction and indeed subclinical atherosclerosis in PsA patients compared with normal controls. Recent interesting data from our own group describe the effects of TNF-B blockade on cardiovascular risk factors in PsA [9•]. Beneficial effects including decreases in lipoprotein (a) and homocysteine were observed; however, unexpected deleterious effects including increases in triglyceride levels were also found. Clearly, careful prospective evaluation of the impact of biologic agents will be required to assess any positive or negative effects on cardiovascular comorbidity and mortality in PsA.
Treatment Disease-modifying antirheumatic drugs As with all other aspects of the diseases, the literature on PsA poorly describes the effects of disease-modifying antirheumatic drugs (DMARDs) as compared with the RA literature. Neither efficacy nor toxicity data may be extrapolated reliably from one disease to the other. Moreover, the management of PsA is arguably more complex, because consideration must be given to multiple disease manifestations including peripheral and axial arthritis, enthesitis, and cutaneous disease. MTX remains most rheumatologists’ DMARD of choice in PsA by virtue of its beneficial effects on arthritis and skin disease [10,11]. In contrast to the very sparse clinical trial data concerning MTX in PsA treatment, we now have an increasing understanding of the effects of MTX at the tissue level. In a study by Kane et al. [12], PsA patients underwent knee arthroscopies before and after commencement of MTX therapy (median interval 11.5 months). This elegant study demonstrated in detail the diminution of the inflammatory cell infiltrate and reduction in proinflammatory cytokines, notably interleukin (IL)-8, and matrix metalloproteinase-3 levels. Nonetheless, despite a decent median dose of 13.75 mg/week, MTX failed to abolish the inflammatory infiltrate and had no impact on the characteristic hypervascularity of the synovium. Another established drug with efficacy in skin and joint disease is cyclosporine. This drug appears to have an impact on skin and joint disease similar to that observed with MTX, although it does not reduce erythrocyte sedimentation rate levels to the same extent [13]. The critical difference is that cyclosporine is not as well tolerated as MTX, especially with respect to hypertension and nephrotoxicity [14].
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Sulfasalazine has been shown to benefit peripheral arthritis but has no effect on axial or cutaneous disease [15]. Antimalarials have been demonstrated to have modest beneficial effects in PsA [16], but a number of case reports suggest that hydroxychloroquine may precipitate or exacerbate psoriatic skin disease. Leflunomide is the most recent addition to the armamentarium of conventional DMARDs, and a recent study suggested that it has utility in both articular and cutaneous psoriatic disease [17]. Fifty-nine percent of leflunomide-treated patients compared with only 30% of placebo-treated patients achieved the PsA response criteria. Modest but statistically significant improvements were observed in functional status as assessed by health assessment questionnaire (HAQ) and in skin disease as assessed by the psoriasis area and severity index (PASI).
Biologic agents The development of targeted biologic therapies has been the single greatest advance in rheumatologic practice in the last decade. In particular, the TNF-B antagonists have become a cornerstone of therapy in RA. We now have more evidence for the efficacy of these therapies in the spondyloarthropathies. The Induction and Maintenance Psoriatic Arthritis Clinical Trial (IMPACT) and IMPACT2 provide us with a great deal of information regarding the efficacy of infliximab, a chimeric monoclonal antibody to TNF-B, in PsA. The original IMPACT study was a double-blind, randomized, placebo-controlled crossover study of 104 patients conducted in Europe and North America [18•]. Patients received infliximab, 5 mg/kg, or placebo (1:1 ratio) at weeks 0, 2, 6, and 14, after which placebo patients crossed over to infliximab therapy. Concomitant use of DMARDs at stable doses was allowed. Infliximab demonstrated significant superiority over placebo in articular disease: American College of Rheumatology (ACR) 20 (65% vs 10%), ACR50 (46% vs 0%), and ACR70 (29% vs 0%) at 16-week evaluation. Significant improvement was also noted in enthesitis and dactylitis in the infliximabtreated group. Of the patients with a baseline PASI of 2.5 or greater, 68% of infliximab-treated patients achieved a reduction in PASI of 75% or more, compared with none of the placebo-treated patients. IMPACT2 was a larger study of infliximab in 200 PsA patients and had a broadly similar design [19]. This study also allowed escalation of infliximab dose to 10 mg/kg in nonresponders, although such a small number of patients proceeded to this phase of the study that interpretation is difficult. The ACR scores achieved with infliximab in this study were less impressive, and more than 30% of patients failed to achieve ACR20. The “major clinical response” of ACR70 sustained for 24 weeks was assessed for the first time in PsA, but only a disappointing 12.1% of infliximab-treated patients achieved it. On the other hand, the degree of improvement in cutaneous disease was
impressive: 42% of infliximab-treated patients achieved a PASI90 response. Infliximab was shown to have a significant effect in inhibiting radiographic progression at both 24 and 54 weeks [20]. Interestingly, coadministration of MTX made no significant difference in any of the outcome measures. Adalimumab is a fully humanized monoclonal antibody to TNF-B that has the additional benefit of subcutaneous administration. The ADalimumab Effectiveness in Psoriatic arthritis Trial (ADEPT) was a randomized, double-blind, placebo-controlled study in 313 patients. Adalimumab was administered at the standard dosage of 40 mg subcutaneously every other week. The 48-week follow-up data from this study have now been published [21•]. Results were rather mixed, with only a 56% ACR20 response rate but an impressive 30% ACR70 response. Skin responses were more uniformly impressive, with a 33% PASI100 response being the most notable finding. A separate paper reports compelling data from the same study illustrating the impact of adalimumab on function and quality of life with respect to both joint and skin disease [22]. The HAQ disability index showed highly significant changes at both 12 and 24 weeks (-0.4 vs -0.1). Improvements in Short Form–36 domains of physical functioning, role-physical, bodily pain, general health, vitality, and social functioning, as well as the physical component summary score, were observed for adalimumab versus placebo (P < 0.01) at 24 weeks. Significantly more adalimumab-treated patients had complete resolution of functional loss (HAQ disability index = 0) and skin-related functional impairment (dermatology life quality index = 0) at weeks 12 and 24 (P c 0.001). Similar improvements were observed in measures of fatigue. Etanercept is a soluble TNF receptor (p75)-immunoglobulin G1 fusion protein administered subcutaneously either once or twice weekly. The initial phase 3 study confirmed beneficial effects on joint and skin disease using a standard dosing schedule of etanercept 25 mg subcutaneously twice weekly [23]. Concomitant use of MTX (but not other DMARDs) was allowed, and after 24 weeks all patients were eligible for the 48-week open-label extension on etanercept. At 24 weeks, 59% of etanercepttreated patients achieved the ACR20 prespecified primary outcome compared with only 15% of placebo-treated patients (P < 0.0001). The mean improvement in PASI in etanercept-treated patients was 42% compared with 8% worsening in placebo recipients. A more recent report provides longer term radiographic data from the same study [24]. Of the original 205 randomized patients, 169 subsequently continued into the open-label part of the study. At 2 years, radiographic data were available for 141 of those 169 patients (71 randomized to receive placebo/etanercept and 70 randomized to receive etanercept/etanercept). Radiographic progression was inhibited in the etanercept/ etanercept patients (mean adjusted change in total Sharp score of -0.38 from baseline to 2 years). In the placebo/
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etanercept patients, disease progression was inhibited once etanercept therapy was initiated (mean adjusted change of -0.22 from 1 year to 2 years). Alefacept was the first biologic agent used in the treatment of chronic plaque psoriasis. It is thought to act by inhibiting T-cell activation, blocking CD2-leukocyte function–associated antigen-3 interactions. Researchers recently reported a double-blind, randomized, placebocontrolled study of alefacept in PsA patients with active disease despite MTX therapy [25]. Of 185 patients, 123 were randomized to receive alefacept and MTX and 62 were randomized to receive placebo and MTX. Alefacept was administered at a dosage of 15 mg intramuscularly weekly for 12 weeks, followed by 12 weeks of observation on MTX alone. The primary end point at 24 weeks was ACR20, which was achieved by 54% of the alefacept group and 23% of the placebo group (P < 0.001). A significant difference in skin disease was also observed: 53% of alefacept patients and 17% of placebo patients achieved PASI50 at 14 weeks. Safety data from the study were reassuring. Clearly, these results are rather disappointing compared with those of the TNF antagonists; however, it is crucial that novel therapeutic approaches are developed for the considerable proportion of patients with severe disease who fail to respond to TNF blockade.
Pathogenesis Advances Cytokine biology The foregoing discussion clearly elucidates advances in therapeutics; however, there is a notable lack of evidence of remission induction or consistent predictable responses in most patients. Biologic agent retention rates are falling over time in the RA population, and a similar trend should be anticipated in PsA patients as sufficient numbers of them are accrued into registries. Therefore, considerable interest remains in better defining the pathogenesis of PsA in the hope that such understanding will lead to improved therapies. Recently, particular interest has focused on the biology of cytokines in PsA. TNF has primacy based on therapeutic studies, but interest has increased in the possibility that other cytokines promote local articular and cutaneous inflammation. The IL-10 superfamily members (including IL-19, IL-20, IL-24, IL-26, and the T helper [Th] 17–derived cytokine IL-22), share homology with IL-10 but exhibit a distinct function with biologic plausibility in PsA. IL-10 is a predominantly anti-inflammatory cytokine, produced by Th2 cells, B cells, and monocytes that can suppress monokine production [26] and interfere with T-cell activation via downregulation of costimulatory molecules [27,28] and induction of regulatory T-cell subsets [29]. Psoriatic plaques contain IL-10 at low levels, but administration of IL-10 leads to reduction in plaque area and severity [30]. The IL-19/IL-20 subfamily is characterized by structural similarity and binding to the same receptor chains
IL-20R1/2 [31]. Their expression in psoriatic and normal skin and their emerging functional profile have rendered these moieties candidate proinflammatory cytokines in psoriasis pathology [32,33,34•]. Monocytes treated with IL-19 produce elevated levels of IL-6 and TNF-B [35,36]. Overexpression of IL-20 in transgenic mice is associated with neonatal death but also with aberrant epidermal differentiation similar to psoriasis. IL-22 and IL-26 are expressed by T cells. IL-22 increases proinflammatory gene expression and regulates proliferation of keratinocytes. IL-22 is a Th17derived cytokine and may have a potential role in psoriasis initiation [37••]. IL-26 is expressed as a homodimer in epithelial cells, but its role in a normal or pathological environment is unclear [38].
Cytokines and T-cell subsets in psoriasis and PsA Functional polarization of effector T cells is considered fundamentally important in PsA pathogenesis. CD4+ and CD8+ T-cell subsets of memory phenotype are present in the psoriatic skin lesion and synovium, express activation makers, and exhibit oligoclonal distribution, suggesting the presence of a local inciting antigen [39,40]. The clinical efficacy of various therapies directed at T cells (eg, cyclosporine, CTLA4 immunoglobulin, and alefacept) suggests a crucial role for T cells in the development and maintenance of disease. Until recently, PsA was considered a dominant Th1 lesion with dysfunction of Th2 cell and regulatory TH cell responses. Cytokine expression of IL-2, interferon-H, and TNF-B B in involved skin and the presence of the IL-12 subunits (IL-12p40 and IL-12p35) are consistent with this hypothesis [41]. However, IL-23 is also expressed in psoriatic skin and induces psoriatic phenomena after local injection. A recent double-blind, placebo-controlled randomized trial with a human IL-12/23 monoclonal antibody (CNTO1275), targeting the common IL-12/23p40 subunit, demonstrated a significant improvement of PASI [42••]. IL-23 is implicated in the development and maintenance of Th17 cell phenotype. IL-17A, a product of Th17 cells, is highly expressed in psoriatic skin lesions. Further, in a murine model, IL-23 can induce epidermal hyperplasia via TNF- and IL-20R2– dependent mechanisms [43]. By targeting IL-12/IL-23p40, this clinically therapeutic antibody interferes not only with Th1 cytokines but also with direct effects of IL-23 on the development of Th17 cells. Interestingly, IL-23 acts downstream not only via IL-17 but also via IL-22 produced by Th17 cells. IL-22 from Th17 cells is induced by IL-23 or IL-6 and can lead to dermal inflammation and acanthosis depicting a psoriasiform lesion [37••]. Thus data suggest a role for the Th17 lineage in cutaneous inflammation. Matters are less clear in the synovial compartment. IL-17, IL-23, and IL22 expression has been described in RA synovial membrane where these cytokines seem to play a proinflammatory role by inducing proliferation and chemokine production. So far, no data exist concerning the role of IL-22, IL-23, and IL-17 on the psoriatic synovial environment.
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Genetics Recently, researchers have made many interesting observations using advances in techniques to interrogate the genetics of well-characterized clinical cohorts. They have reported on a variety of questions about the genetics of PsA—both shared with and distinct from psoriasis—and related inflammatory disorders, particularly Crohn’s disease. Considerable interest resides in defining polymorphisms in the TNF F gene that might be related to susceptibility or severity, and contrasting data on this subject have emerged recently. Canadian investigators detected an association with the TNF*-238A allele in Newfoundland and Toronto cohorts. In a subsequent German cohort containing matched psoriasis, PsA, and control patients, this association was confirmed for psoriasis but was found to be dependent on carriage of the PSORS1 risk allele. A strong association was detected for TNF*-857T T and PsA in PSORS1-negative patients [44,45]. Parallel studies in the Canadian cohort have similarly identified two independently associated loci in the extended IL-1 family gene cluster, one in the IL-1A region and a second extending from IL-1B through IL-1F7, IL-1F8, to IL-1F10 [46]. Several other candidate genes including IL-4 filaggrin were not found to have significant associations in these cohorts. Studies in the United Kingdom have addressed the potential interaction between HLA class I and II alleles in predicting PsA disease course. Thus, the presence of HLACw6 and HLA-DRB1*07 7 conferred a protective effect as determined by functional progression, damaged joints, and involved joints. Neither allele alone mediated this protective effect, suggesting that a protective allele may reside within these loci. This study also failed to show an effect for the shared epitope alleles (HLADRB1*03 and *04) upon disease severity [47]. Finally, the pathogenetic involvement of angiogenetic factors is well established in PsA. A search for polymorphisms in the vascular endothelial growth factor (VEGF), fibroblast growth factor 1, fibroblast growth factor 2, and epidermal growth factor genes revealed an increased frequency in VEGF+936T in controls, suggesting that this may confer some protective effect [48]. In all these studies, confirmatory data will be essential in independent cohorts, in particular to unravel the complexities of risk in the PSORS1 region, which contains a variety of plausible candidate genes. High-density mapping to address this issue is under way.
Conclusions The combination of formal characterization of PsA cohorts in the genomic age together with increased nearpatient translational research will shortly offer significant advances in prognosis and therapeutic options in PsA. Major challenges remain, including defining the best strategy to induce disease remission. Defining and under-
standing dichotomous clinical responses between the skin and joint compartments pose both a clinical conundrum and a pathogenetic opportunity. Moreover, definition of the relationship between skin, the synovial compartment, and the enthesis organ remains a major challenge of considerable importance as we move from detecting established disease to early evaluation, imaging, and therapeutic intervention.
Acknowledgments Dr. McCarey has no potential conflicts of interest, financial or otherwise. Dr. McInnes has received honoraria for speaking and research grants from Schering-Plough Corp. (Kenilworth, NJ), Wyeth (Madison, NJ), and Abbott Laboratories (Abbott Park, IL), all of which have products in the field of biologics.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
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