Current concepts and new developments in the treatment of psoriatic arthritis

Transcription

1 Rheumatology 2003;42: doi: /rheumatology/keg363, available online at Advance Access publication 16 June 2003 Review Current concepts and new developments in the treatment of psoriatic arthritis N. Pipitone 1, G. H. Kingsley 2, A. Manzo 3, D. L. Scott 1 and C. Pitzalis Objectives. Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis with psoriasis. Many agents have been proposed for the treatment of PsA, but their use is based more on clinical experience than on sound scientific evidence. Methods. We reviewed MedLine up to November 2002, searching for psoriatic arthritis, drug therapy, controlled trials and outcomes and all possible acronyms for these terms. All relevant papers were then examined in detail. Results. PsA is a condition that runs a variable clinical course. Mild forms can usually be controlled by non-steroidal anti-inflammatory drugs (NSAIDs). Intraarticular glucocorticoid injections are indicated in patients with persistent monoor oligoarthritis. Patients with severe and progressive articular disease not responsive to NSAIDs should be treated with disease-modifying anti-rheumatic drugs (DMARDs) to prevent joint damage and disability. Currently, methotrexate and sulphasalazine are considered the DMARDs of choice, but the evidence for the use of methotrexate in PsA is still largely empirical, while the clinical benefit induced by sulphasalazine appears to be modest. Other DMARDs proposed for the treatment of PsA include cyclosporin, gold salts and, more recently, leflunomide. However, none of the DMARDs available to date are effective in the treatment of psoriatic pelvispondylitis; in addition, a number of patients with severe peripheral arthritis fail to respond to standard DMARDs. Recently, tumour necrosis factor a inhibitors have proved effective in many PsA patients with pelvispondylitis or recalcitrant peripheral synovitis. Conclusions. None of the current treatments for PsA is curative, but significant clinical amelioration can be achieved in the vast majority of patients. Identification and prompt treatment of patients with severe articular disease is crucial for the achievement of a satisfactory clinical response and the improvement of the longterm outcome. KEY WORDS: Psoriatic arthritis, Drug therapy, Non-steroidal anti-inflammatory drugs, Diseasemodifying agents, Glucocorticoids, TNF- blockers. Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis and psoriasis, and was recognized as a clinical entity distinct from rheumatoid arthritis (RA) in 1964 [1]. Subsequent studies have revealed that PsA shares a number of genetic, pathogenic and clinical features Rheumatology Unit, Thomas Guy House, GKT School of Medicine, Guy s Campus, London SE1 9RT, 1 Clinical and Academic Rheumatology, King s College Hospital, London SE5 9RS, 2 Rheumatology Department, Lewisham Hospital, London SE13 6LH, UK and 3 U.O. di Reumatologia, Policlinico S. Matteo, P. le Golgi, Pavia, Italy. Submitted 15 November 2002; revised version accepted 5 March Correspondence to: C. Pitzalis, Rheumatology Unit, Thomas Guy House, GKT School of Medicine, Guy s Campus, London SE1 9RT, UK. costantino.pitzalis@kcl.ac.uk 1138 ß 2003 British Society for Rheumatology

2 New developments and treatment of psoriatic arthritis 1139 with the so-called spondyloarthropathies (SpAs), a group of diseases that comprise ankylosing spondylitis, reactive arthritis and enteropathic arthritis [2]. The notion that PsA belongs to the SpA group has recently gained further support from imaging studies demonstrating widespread enthesitis in the SpAs, including PsA but not RA [3, 4]. More specifically, enthesitis has been postulated to be one of the earliest events occurring in the SpAs, leading to bone remodelling and ankylosis in the spine, as well as to articular synovitis when the inflamed entheses are close to peripheral joints. However, the link between enthesitis and the clinical manifestations in PsA remains largely unclear, as PsA can present with fairly heterogeneous patterns of joint involvement with variable degrees of severity [5 8]. Thus, other factors must be posited to account for the multifarious features of PsA, only a few of which (such as the expression of the HLA-B27 molecule, which is strongly associated with axial disease) have been identified. As a consequence, it remains difficult to map the disease manifestations to specific pathogenic mechanisms, which means that the treatment of this condition remains largely empirical. Furthermore, the mechanisms of action of the medications currently employed to treat PsA are often only incompletely documented. Although some of the therapeutic modalities used in PsA are based on its putative pathogenic factors [9], in the majority of cases the rationale for their use comes simply from extrapolation of their efficacy in RA [10]. For this reason, in this review we will focus chiefly on the evidence of efficacy of the different regimens used to treat joint disease in PsA that is derived from clinical studies. However, interference with pathogenic pathways will be highlighted, particularly in discussing the new targeted therapies using biological agents. Symptomatic treatment of PsA PsA is a chronic inflammatory arthropathy that runs a variable course, from mild synovitis to severe progressive erosive arthropathy [10]. Mild arthritis can usually be controlled by non-steroidal antiinflammatory drugs (NSAIDs) taken as required [11]. Because NSAIDs can potentially shunt products of the inflammatory arachidonic acid cascade from the cyclooxygenase (COX) to the lipooxygenase pathway, concerns have been raised that the increased leukotriene load might provoke a flare of skin lesions [12]. However, a recent randomized controlled trial (RCT) showed no worsening of cutaneous psoriasis in the patients treated with the NSAID nimesulide, which suggests that such a side-effect is to a large extent clinically irrelevant [13]. Most NSAIDs can cause gastrointestinal toxicity, especially during prolonged therapy. Elderly subjects and those with a history of peptic ulcer appear to be particularly at risk and should be treated with those NSAIDs that are least toxic in this regard, such as nabumetone [14] and etodolac [15] (if necessary in association with a proton pump inhibitor). Alternative options are the combination therapy misoprostol diclofenac or a COX-2-selective inhibitor, such as celecoxib [16]. At the same time, because there is evidence that even the new COX-2-selective inhibitors may affect renal function adversely, patients with decreased glomerular filtration rate (including most elderly subjects) should be treated with particular caution at appropriately reduced doses, and should be monitored carefully to avoid acute renal failure [17]. NSAIDs are not recommended in patients with severe chronic renal failure. Systemic glucocorticoids (GC) are recommended for protracted use in PsA for many reasons [18]. First, chronic GC administration can produce resistance to control of psoriasis by other effective therapies, such as methotrexate (MTX) [12]. Secondly, it may cause a number of side-effects, including osteoporosis, reduced glucose tolerance and lowered resistance to infections. Finally, cessation of GC treatment has been linked to rebound worsening of psoriasis, sometimes with a generalized pustular form [12, 19]. However, intraarticular GC injections may be given judiciously to treat persistent mono- or oligoarthritis, often with good clinical results [20]. Monoarthritis recalcitrant to intraarticular GC therapy has been reported to respond to arthroscopic [21] or radiation [22] synovectomy, with success rates of 86 and 50% respectively. Disease-modifying anti-rheumatic drugs in PsA Treatment with the so-called disease-modifying antirheumatic drugs (DMARDs) should be considered in severe and progressive cases of articular disease not responsive to NSAIDs [23], particularly the polyarticular subgroup [11]. Unfortunately, to date there are no welldefined criteria to dictate the use of DMARDs in PsA synovitis for a number of reasons. First, there is a lack of validated classification criteria for PsA [24], which impedes efforts to provide a proper evidence base for therapy. Secondly, there is insufficient knowledge of disease mechanisms and of the mode of action of most DMARDs, which precludes truly targeted treatment. In fact, management is often extrapolated from trials in RA, although significant differences between RA and PsA, in terms of the responses to DMARDs and their side-effects, have been documented [25, 26]. Thirdly, although the high placebo response observed in PsA (three times as high as the placebo arm in RA) strongly suggests that results of uncontrolled trials should not be used to guide management decisions in this condition, not all DMARDs used in PsA have been evaluated in proper, adequately sized RCTs [27]. Fourthly, the difficulty in defining clear disease subgroups and the possible maldistribution of arthritis subtypes between placebo and treatment arms does not usually allow the extrapolation of results to specific disease subsets [27]. One exception is the gross distinction between pre-

3 1140 N. Pipitone et al. dominantly axial vs peripheral joint involvement, axial involvement showing a stronger association with HLA-B27 and a poor response to treatment with conventional DMARDs [28, 29]. Fifthly, there is no consensus on the appropriate end-points to be chosen in PsA RCT. In practice, common outcome measures of therapy include a combination of clinical and biochemical assessments of disease activity and both clinical and radiological assessments of joint damage. However, the correlation between these measures and disability is usually low, with the possible exception of the number of actively inflamed joints [30]. Similarly, imaging techniques such as dynamic gadolinium-enhanced magnetic resonance imaging and positron emission tomography have shown good sensitivity in detecting synovitis, but poor correlation with treatment outcomes [31, 32]. Finally, clinical measures of functional status, such as the Health Assessment Questionnaire (HAQ) and its derivative, the HAQ for SpA (HAQ-S), have proved less reliable in outcome prediction in PsA compared with RA [30]. As a consequence, the long-term effects of DMARDs on the functional status of patients with PsA are often unclear, while comparisons across different trials are hampered by the lack of common outcome measures. In addition to the need for a better characterization of the efficacy and safety of DMARDs in PsA, an equally important challenge is to determine the risk factors associated with disease progression in individual patients. This is all the more important because an aggressive therapeutic regimen starting in the early stages of progressive disease, particularly in subjects with poor prognostic indicators, in a manner not much different from that advocated for the treatment of RA, is now being advocated [33]. Recently, a prospective study conducted over a period of 14 yr has identified a large number of effusions and of past medications as predictors of progression of disease damage, especially in association with the HLA antigens B27, B39 and DQw3 [34, 35]. In a similar vein, other studies have demonstrated that the prior use of medications and radiological changes, as well as an elevated erythrocyte sedimentation rate (ESR) at presentation, are prognostic indicators for death [36]. Other indicators of poor prognosis include younger age at onset, extensive skin involvement, polyarticular synovitis and association with HIV infection [18]. However, a limitation of this approach is that a number of the prognostic factors that have been identified, such as the development of radiological changes or prior use of medications, cannot be evaluated in the initial stages of the PsA, when aggressive therapy is more likely to be most beneficial in preventing deterioration of function. Furthermore, some factors, such as the extent of psoriasis, correlate only loosely with a poor prognosis. Therefore, it would be important to determine reliable outcome predictors that could be evaluated at disease onset. In this regard, cytokines could be ideal candidates, because proinflammatory cytokines, such as tumour necrosis factor (TNF-) and interleukin (IL) 1, have been shown to be associated with articular erosions, and our group has provided evidence that patients with non-erosive arthropathies, including PsA, have greater amounts of synovial mrna for the anti-inflammatory cytokine IL-10 compared with those with erosive disease [37]. Thus, it is conceivable that, in the future, the assessment of the cytokine profile, or of the genes which control cytokine synthesis, could help identify those patients who are at risk of developing joint erosions and therefore require more aggressive treatment. Currently, the most widely used DMARDs for PsA synovitis are MTX, sulphasalazine (SSZ) and cyclosporin, employed alone or in combination [33, 38]. However, the efficacy and side-effects of these and other DMARDs used in clinical practice in PsA have been evaluated only in a few adequately sized RCTs. In particular, a MedLine search up to June 2002 identified only 13 RCTs of standard DMARDs (Table 1), some of which included a limited number of subjects. Therefore, in the majority of cases the evidence of efficacy for these medications cannot be regarded as conclusive. Methotrexate Among the DMARDs, MTX is considered by many rheumatologists the agent of choice because of its remarkable efficacy in ameliorating both skin and joint disease, because of its rapid onset of action, and because of its good safety profile [27, 39]. Not surprisingly, MTX treatment is less likely to be discontinued than most other DMARD therapies; this is similar to what has been reported in RA [39]. A further advantage of MTX is that it can be easily combined with a number of DMARDs, such as SSZ or cyclosporin, with increased clinical efficacy but apparently without more toxicity. In particular, combination therapy with MTX and cyclosporin has been shown to achieve positive results for efficacy in a retrospective, multicentre study conducted in patients with severe psoriasis mostly associated with arthritis [40]. However, the evidence for the use of MTX in PsA is empirical rather than being based on proper RCTs. To date there have been only two proper RCT with MTX, involving a total 58 patients. The first [41] used three intravenous MTX pulses given at a dose of 1 3 mg/kg body weight, a high and unacceptably toxic dose that would not be used today. Although joint counts and the ESR improved with MTX therapy, one patient died during treatment from marrow aplasia and haematemesis and there were many other substantial adverse events. The second study [42] showed that low-dose oral MTX ( mg weekly) reduced the physician s global assessment compared with placebo therapy. However, this study enrolled a total of only 37 patients (half the calculated sample size) due to a low recruitment rate, and was therefore substantially underpowered to show a significant difference in joint swelling and tenderness between MTX and placebo. Therefore, while the data in the literature suggest that MTX may be beneficial in ameliorating synovitis in PsA, conclusive proof of its

4 New developments and treatment of psoriatic arthritis 1141 TABLE 1. Randomized controlled trials of DMARDs and TNF- blockers in psoriatic arthritis found in a MedLine search up to June 2002 Study (first author) Year Disease duration (months) Drugs No. of cases Design Main conclusion Black [41] MTX (i.v.) 21 Crossover MTX reduced joint count, ESR and range of movement compared with placebo (P 0.01 in all cases) Levy [97] AZA 6 Crossover Intra-group improvement with AZA (P < 0.01) but no improvement with placebo Willkens [42] MTX (oral) 37 Inter-group MTX reduced physician s global assessment compared with placebo (P < 0.001) but no effect on joint counts Price [98] D-pen 11 Inter-group No significant effect with D-pen Carette [65] AUR 238 Inter-group AUR reduced physician s global assessment compared with placebo (P ¼ 0.031) and occupational activity scale (P ¼ 0.005) but not joint counts Palit [64] AUR or gold 82 Intra-group Intra-group improvement with i.m. gold in pain score, Ritchie index and ESR (P < 0.05 in all cases) but no improvement with placebo or AUR Farr [54] SSZ 30 Intra-group Intra-group improvement with SSZ in morning stiffness, pain, ESR and articular index (P < 0.05) but no improvement with placebo Fraser [49] SSZ 39 Intra-group Intra-group improvement with SSZ and placebo in pain score (P > 0.03) and articular index (P > 0.002) but ESR improvement only significant with SSZ (P ¼ 0.004) Gupta [51] SSZ 24 Inter-group SSZ reduced duration of morning stiffness, patient s global assessment and physician s global assessments compared with placebo (P < 0.01) Dougados [52] SSZ 136 Inter-group SSZ reduced pain score in psoriatic arthritis subset compared with placebo (P < 0.001) Clegg [47] SSZ 221 Inter-group There were more responders with SSZ than with placebo using a composite responder index (P ¼ 0.05); individual variables showed no significant differences Combe [50] SSZ 117 Inter-group SSZ reduced pain compared with placebo (P ¼ 0.01) but no other variables showed a difference Salvarani [59] CSA, SSZ 99 Inter-group CSA superior to SSZ and placebo (P < 0.05) in decreasing pain after 6 months AUR, auranofin; AZA, azathioprine; D-pen, D-penicillamine; i.v., intravenous; i.m. intramuscular. efficacy is still lacking. By contrast, there is no evidence that MTX is effective in treating axial disease, and it is also doubtful whether it can confer advantage with respect to long-term damage [43]. In addition, patients with psoriasis are more likely than patients with RA to develop histological liver changes and progression, the risk increasing with the total cumulative dose of MTX and with heavy consumption of alcohol [25]. Therefore, heavy users of alcohol should not receive long-term MTX therapy. Similarly, co-administration of sulpha drugs or ketoconazole with MTX is best avoided because of the increased risk of toxicity, while the hypothesized interaction of MTX with NSAIDs has been shown not to be clinically significant in patients in whom renal function is preserved. If renal function is impaired, however, the dosage of MTX should be decreased depending on the degree of renal failure, because the elimination half-life of MTX has been shown to correlate with the severity of renal impairment, being 11.5, 12, 13.7 and 22.7 h for creatinine clearance values of >80, 61 80, and <45 ml/min respectively [44]. On the basis of these results, it has been suggested that MTX could be used at a dose reduced by about 50% in patients with a creatinine clearance of <45 ml/min [44], but the high interindividual variability of the pharmacokinetics of MTX raises some concerns about the safety of this approach. Thus, the current recommendation of the British Medical Association is that MTX should not be used when renal function is severely impaired (glomerular filtration rate <20 ml/min, corresponding approximately to serum creatinine values of mol/l), while it may be used at a low dose (approximately 7.5 mg weekly) when the glomerular filtration rate lies between 20 and 50 ml/min (corresponding approximately to serum creatinine values of mol/l) [45]. Finally, particular caution should be adopted when

5 1142 N. Pipitone et al. MTX is used in patients with documented HIV infection because of the potential increased risk of opportunistic infections [46]. Sulphasalazine Results similar to those shown for MTX have been provided by several studies that have investigated the role of SSZ in PsA. Although the interpretation of the results of these trials is complicated by the heterogeneity of study designs and of the outcome measures chosen as end-points, there is converging evidence that SSZ therapy can induce a decline in ESR [47 49] as well as decrease pain [50], duration of morning stiffness [49, 51] and peripheral joint tenderness and swelling [48, 52]. Furthermore, SSZ also appears to ameliorate cutaneous psoriasis to some extent [52], although it may not halt radiographic progression of the arthritis [53]. However, closer scrutiny of the six published RCTs reveals that the degree of clinical benefit induced by SSZ is less impressive than open studies would suggest. More specifically, in the largest RCT, by Clegg et al. and involving 221 PsA cases, the difference in a composite index of disease activity (which included patient selfassessment, physician assessment, tender joint score and swollen joint score) between patients treated with SSZ and those receiving placebo was at a low level of significance (P ¼ 0.05) and not substantial (57.8% responded to SSZ, 44.6% to placebo) [47]; furthermore, none of the above outcome measures taken separately showed a significant benefit from SSZ. Two other large clinical studies, by Dougados et al. [52] and Combe et al. [50], showed that pain improved significantly with SSZ therapy compared with placebo therapy, which is especially relevant as pain was not measured by Clegg et al. [47]. However, Combe et al. [50] did not find any difference in other variables, including joint counts. In the report from Dougados et al. [52] it is impossible to dissect out the specific benefits of SSZ in PsA as the cases are grouped together with other seronegative arthropathies; however, taking the group as a whole there were no effects on any measure except patient s global assessment, which showed a small benefit. Two other studies [49, 54], both enrolling fewer than 40 patients, showed intragroup improvement from baseline with SSZ. However, in one study [49], significant improvement was also seen with placebo. The study by Gupta et al. [51] differs from all the others in showing significant benefits of SSZ for patient s and physician s global assessments and morning stiffness compared with placebo, but the study lasted only 8 weeks and could be explained by regression towards the mean. Thus, taken together, the results of these studies demonstrate that SSZ has a small beneficial effect on peripheral synovitis in PsA patients, although it is unclear whether the dosage of SSZ is important in determining clinical efficacy, i.e. if higher doses (in the range of 3 mg/day) are more effective in disease control [55]. By contrast, SSZ does not appear to exert any beneficial effect on spinal disease, even though a comparable decrease in the ESR has been observed in patients with axial involvement and in patients with peripheral joint involvement [48]. In terms of side-effects, there has been a trend in most studies towards higher withdrawal rates in the SSZ group compared with the placebo group [48], mostly related to the occurrence of adverse events such as gastrointestinal intolerance, dizziness and liver toxicity, which have been observed in up one-third of the patients receiving SSZ [52]. Cyclosporin Cyclosporin has been proposed for the treatment of PsA by virtue of its beneficial effects on both articular and cutaneous manifestations [56], but its use is mainly based on open studies and case reports rather than evidence from proper, adequately sized RCTs [27]. In an open 18- week study, administration of an average daily dose of cyclosporin A of 4.8 mg/kg improved skin symptoms by 65% as early as 2 weeks after onset of therapy, and the most intense effect on the activity of arthritis was observed after 18 weeks [57]. These positive results have been confirmed by a small study comparing cyclosporin (at a dose of 3 5 mg/kg/day) with MTX (given at the maximum dose of 15 mg/week) [58]. In this trial, the number of painful and swollen joints, the Ritchie index, the duration of morning stiffness, grip strength, C- reactive protein (CRP) concentration, the patient s and physician s assessments of PsA activity, and the psoriasis activity and severity index improved significantly in both treatment groups. This clinical amelioration remained at 6 and 12 months, although after 1 yr of therapy cyclosporin and MTX had to be withdrawn in 41.2 and 27.8% of the patients respectively [58]. Unfortunately, because of the lack of a placebo arm in this study, it is not possible to distinguish any beneficial effects of these medications from the spontaneous improvement that occurs in a relapsing remitting disorder like PsA. More recently, the efficacy of cyclosporin in PsA has been confirmed by an Italian multicentre trial comparing cyclosporin with SSZ and placebo therapy [59]. In particular, this study showed a statistically significant difference in favour of cyclosporin A (CSA) in terms of the mean change in the pain score (P < 0.05), which was considered the primary response variable. A significant decrease in favour of CSA vs placebo alone was also observed for the swollen joint count (P ¼ 0.05), tender joint count (P ¼ 0.01), joint/pain tenderness score (P ¼ 0.002), patient s and physician s global assessments (by at least 1 point; P ¼ 0.04 and 0.01 respectively), total Arthritis Impact Measurement Scale score (P ¼ 0.002) and spondylitis functional index (P ¼ 0.002). Finally, there is some evidence from a 2-yr open study that cyclosporin may control the progression of radiological damage in the peripheral joints in PsA patients [60], but no RCT has yet been conducted to confirm these data. In terms of side-effects, cyclosporin has significant renal toxicity even at the recommended low dose (3 mg/kg/ day); of particular concern, in some cases, is that the renal damage has not improved following discontinuation of therapy [61]. For this reason, the use of

6 New developments and treatment of psoriatic arthritis 1143 cyclosporin should only be considered in patients with severe PsA that is not responsive to MTX or SSZ. Antimalarials Patients who are refractory or intolerant to MTX or SSZ may be considered for other therapeutic modalities that have proved beneficial in RA, such as antimalarials, gold salts and leflunomide. Again, a careful reappraisal of the benefit safety profile of these treatments is indicated when extrapolating the results of the studies done in RA to PsA. In particular, the use of antimalarials in PsA is poorly documented, as no data from RCTs are available [27]; however a small case control study suggested that chloroquine may be of limited benefit in the treatment of PsA synovitis without exacerbating psoriasis [62]. Gold salts Chrysotherapy given either intramuscularly (sodium thiomalate) or orally (auranofin), has been shown in two clinical trials to ameliorate arthritis in PsA, the degree of improvement of arthritis being higher in the cohort of patients receiving sodium thiomalate [63, 64]. On the other hand, the benefit of auranofin vs placebo therapy has been shown to be very limited [65], while a head-to-head study comparing sodium thiomalate with MTX demonstrated that the former was significantly less effective than MTX in the treatment of PsA synovitis, the likelihood of a clinical response being estimated to be 8.9 times greater with MTX than with intramuscular gold [39]. In addition, chrysotherapy can potentially exacerbate psoriasis [26], and it has been questioned whether it can slow down radiological disease progression in PsA [66]. Therefore, gold therapy should ideally be restricted to PsA patients with mild cutaneous psoriasis and active synovitis not responsive to MTX or SSZ. There is some evidence that PsA patients presenting with polyarticular, RAlike joint involvement may be those most responsive to chrysotherapy; it is still unclear whether this subset represents a true disease subgroup of PsA or whether it simply describes patients with RA who have skin psoriasis coincidentally [67]. Leflunomide Another DMARD initially employed in RA which has subsequently been proposed for use in patients with polyarticular PsA is leflunomide. Leflunomide is a selective pyrimidine synthesis inhibitor that interferes with T-cell activation, and it has recently been shown to have remarkable clinical and radiological efficacy in patients with RA and possibly patients with other chronic inflammatory disorders. Preliminary data from a small pilot, open-label study of six patients with psoriatic polyarthritis showed a significant decrease in the CRP level as well as in the tender and swollen joint count, although not in the extent of psoriasis, after 3 months of therapy [68]. Another study conducted in 12 patients with polyarticular PsA who had failed at least one DMARD confirmed the clinical efficacy of leflunomide in the eight patients available for follow-up, not only in the short term but also after nearly 2 yr [69]. Of note, in this longer-term study skin psoriasis improved in twothirds of the patients, which may suggest that amelioration of skin disease may require more prolonged therapy than that of arthritis. Radiographic disease progression was not evaluated in these studies, and the small number of patients enrolled did not permit confident assessment of adverse reactions. Overall, these data suggest that leflunomide could have a role in the treatment of polyarticular PsA, which should be further investigated by proper RCTs. At present, however, leflunomide is not licensed for the treatment of PsA. Other DMARDs An array of other medications have been claimed to be of benefit in PsA, but the data available are insufficient or too controversial for confident conclusions to be drawn. Mofetil mycophenolate has shown some efficacy and good tolerability in one small study and one case report [70, 71]. Colchicine has been found to be highly beneficial in one RCT and of no benefit in another [72, 73]. In a case report, successful treatment with colchicine of renal amyloidosis secondary to protracted PsA has been documented [74]. A number of clinical studies (with one RCTs of acceptable quality) are available for etretinate, showing overall a significant beneficial effect of treatment vs placebo [27, 75]. In particular, etretinate has been shown to improve several treatment outcome variables, including ESR, tender joint count, and duration of morning stiffness. However, owing to high toxicity it was withdrawn from the US market in 1998 and replaced with acitretin. Azathioprine demonstrated a clear benefit over placebo in an RCT, but the data are difficult to interpret due to the small number of patients enrolled and because of the paucity of outcome measures reported [76]. Systemic therapy with 1,25-dihydroxyvitamin D3, which is successfully used to treat cutaneous psoriasis, has not been evaluated in a proper RCT; however, a 6- month open-label trial in 10 patients with active PsA demonstrated statistically significant improvement in the tender joint count and physician s global impression [77]. The inhibitor of prolactin synthesis bromocriptine was shown to improve the skin and joint manifestations of hyperprolactinaemic patients who had PsA concomitantly [78, 79]; however, because a similar improvement has been observed in patients without hyperprolactinaemia [80], it may be that bromocriptine has an intrinsic direct anti-inflammatory action. 2- Chlorodeoxyadenosine at weekly doses of mg/ kg for 12 weeks has been demonstrated in a small study to mitigate joint disease and psoriasis in two-thirds and five-sixths of DMARD-refractory PsA patients respectively [81], while somatostatin, an inhibitor of growth hormone, has been successfully used to treat both psoriasis and PsA [82, 83]. A clinical response was observed in 50% of patients, better results being achieved in those with extensive skin psoriasis and polyarticular

7 1144 N. Pipitone et al. synovitis. Interferon has been evaluated in 24 PsA patients in an RCT of 1 month s duration and in 56 patients in an open study of 9 months duration. In the double-blind study, the interferon arm was superior to the placebo arm, but no further improvement was observed after the third month of treatment [84]. A review of therapies used specifically for the management of cutaneous psoriasis is beyond the scope of this article, but it is interesting to note that in a large open study on heliotherapy the improvement in skin psoriasis was paralleled by a significant amelioration of the joint manifestations [85]. Similarly, photochemotherapy with psoralen ultraviolet A irradiation was reported as improving peripheral joint arthritis in 49% of treated patients, whereas no improvement was observed in the group of patients with axial disease [18, 86]. Thus, these data support the concept of a link between cutaneous and articular disease, at least in a subset of PsA patients, while confirming the poor response to therapy of the pelvispondylitic subset. Biological agents in the treatment of PsA The recognition that a subset of PsA patients respond inadequately to treatment with NSAIDs, DMARDs or both and the dubious capacity of existent DMARDs to control joint damage and disease progression have prompted a search for newer, more effective therapeutic agents in PsA. In this regard, the discovery of the key role in arthritis played by some cytokines, such as TNF- and IL-1, has paved the way for the development of agents specifically targeted at neutralizing the biological action of such cytokines. Among the treatments tested so far, anti-tnf- agents have demonstrated remarkable efficacy in the treatment of DMARD-refractory RA, with a rapid and profound benefit for virtually all response variables measured. Anti-TNF- has been investigated less extensively in the SpAs, including PsA, TABLE 2. Biological agents used in or proposed for the treatment of PsA Agent Mechanism of action Main results but a number of research and clinical studies suggest a role for this therapy in PsA patients. More specifically, research studies have identified by in situ hybridization techniques the presence of TNF- not only in the psoriatic skin [87] and in the synovium [88] of affected joints, but also in the inflamed entheses [89], i.e. in those sites which are thought to be precociously involved in the disease process. Because enthesitis, or inflammation of the enthesis, is thought to be the initial pathogenic process underlying spinal disease, leading to bone remodelling and ultimately spinal ankylosis, anti-tnf- therapy seems to be particularly promising in offering control of both peripheral joint synovitis and axial disease. The potential efficacy of this therapy has been confirmed by a number of open trials and RCTs conducted in North America and Europe in patients with various SpAs, including PsA. The two commonest anti-tnf- drugs available at present are infliximab (Remicade Õ, Centocor, Malvern, PA, USA), a chimeric human murine anti-tnf- IgG1 antibody, and etanercept (Enbrel Õ, Immunex Corporation, Seattle, VA, USA), a dimeric fusion protein consisting of the extracellular portion of the human p75 TNF- receptor linked to the Fc portion of a human IgG1. Both agents can exert powerful antiinflammatory effects by binding and inactivating soluble and cell-bound TNF- [90]. So far, infliximab therapy in PsA has been shown in an open-label study to improve joint and skin symptoms significantly in eight patients with active PsA and psoriasis after 7 and 14 days respectively [91], while in another study conducted in six patients with severe PsA insufficiently controlled by MTX (average dose mg/week) both joint and skin manifestations improved rapidly after infliximab was added to the MTX [92]. In fact, concomitant therapy with MTX (and possibly azathioprine) is now being advocated by some authors, not only because of its greater clinical and radiological efficacy but also because it can reduce Etanercept TNF- blocker One RCT conducted in 60 patients with PsA showed that 87% of etanercept-treated patients and 23% of placebo controls met the PsA response criteria (PsARC). The improvement in median psoriasis area and severity index (PASI) a was 46% in etanercept-treated patients vs 9% of the placebo controls [93] Infliximab TNF- blocker No RCT available. One open-label study showed amelioration of synovitis and cutaneous psoriasis [91], while another open study showed a beneficial effect when infliximab was added to MTX in PsA patients with incomplete clinical response [92] Anakinra IL-1 receptor antagonist No studies available in PsA, but data from RA patients suggest that anakinra may ameliorate synovitis in PsA [94] huokt31 Anti-CD3 antibody No RCT available. One open study showed improvement of joint inflammation in 6 out of 7 subjects [95] Alefacept Interference with the CD2/LFA-3 pathway One open study showed improvement of arthritis in 64% and amelioration of skin disease in 50% of patients [96] *The psoriasis area and severity index (PASI) is a measure of the overall severity and extent of psoriasis [99]. For the PASI, the body is divided into four parts (legs, arms, head and trunk), and the amount of skin involved in each part is quantified using a score ranging from 0 to 6. For each body section, severity is measured with four parameters (pruritus, erythema, desquamation and thickness) on a scale of 0 4. A total score is calculated per body part by summing the four severity scores, multiplying the total by the area score, and multiplying the result by the percentage of skin in that section. The PASI is obtained by summing the total scores obtained for each body section.

8 New developments and treatment of psoriatic arthritis 1145 the risk of developing anti-infliximab antibodies, which in turn may potentially influence the therapeutic response and perhaps also the frequency of particular side-effects [91]. Finally, a single-centre pilot study of 21 patients with different SpAs, including nine patients with PsA, showed a rapid improvement in virtually all outcome measures considered, including ESR, CRP, patient s and physician s global assessments, and tender and swollen joint count [91]. Importantly, in this trial infliximab was also able to reduce significantly the functional and disease activity indices in the subset of patients (11 of 21) with axial disease, while the psoriasis activity and severity index decreased in the eight patients with skin involvement. Similar encouraging results have been reported in a 12-week RCT assessing the efficacy of etanercept (given at the standard dose of 25 mg subcutaneously twice weekly) in 60 patients with active PsA and psoriasis [93]. In particular, 87% of the etanercept-treated patients but only 23% of the placebo control patients met the psoriatic arthritis response criteria (PsARC), a composite measure that requires improvement in two factors (at least one being a joint score) and worsening in none of the physician s and patient s global assessments and the tender and swollen joint count. Of the 19 patients in each treatment group who could be assessed for psoriasis (3% body surface area), five (26%) of the etanercept-treated patients achieved a 75% improvement in the psoriasis activity and severity index, compared with none of the placebo-treated patients (P ¼ 0.015). The median improvement in the psoriasis activity and severity index was 46% in etanercept-treated patients vs 9% in placebo-treated patients [93]. No data on axial involvement were reported in this trial, but a more recent longitudinal study of 10 SpA patients (with active inflammatory spinal pain and peripheral arthritis) treated with etanercept 25 mg subcutaneously twice weekly demonstrated a significant improvement in clinical enthesitis as well as in all clinical and functional parameters, including Schober s test for lumbar spine flexion, and a visual analogue scale score for pain [89]. The observed clinical efficacy of etanercept was highly correlated with the resolution of entheseal (Romanus lesions, end-plate oedema, spinous process oedema) and articular lesions detected on magnetic resonance imaging. Thus, this study suggests that the superior efficacy of etanercept in SpA compared with conventional DMARDs may be indeed related to its capacity to decrease inflammation, not only in the synovium but also in the peripheral and spinal entheses. On these grounds, anti-tnf- therapy may be indicated both in DMARD-resistant polyarticular synovitis and in pelvispondylitic disease, although more data from RCTs are required before proper inclusion criteria for these expensive regimens are defined. In all these trials, both infliximab and etanercept showed a relatively good safety profile. The commonest adverse reactions reported included local reactions at injection sites (2 5%), development of an abnormal autoimmune profile of blood tests (10 16%), and upper respiratory tract infections (20 30%), without significant differences between the treated and placebocontrolled arms, whereas no increased incidence of any cancer type has been reported [91]. At the same time, because in the overwhelming majority of clinical trials the study populations are not powered adequately to predict the safety of the drugs confidently, reference to post-marketing surveillance reports is strongly recommended. In addition to TNF-, IL-1 has also been implicated as a key cytokine in the pathogenesis of joint inflammation on the basis of experimental studies in arthritis and clinical trials in RA. In RA, a large RCT of the IL-1 receptor antagonist (IL-1RA) anakinra Õ (Amgen, Thousand Oaks, CA, USA), a specific competitive inhibitor of IL-1, demonstrated a significant improvement in several clinical response variables in the arm treated with the active drug, while the rate of radiological progression measured using the Larsen score and the erosive joint count was reduced by 41% compared with the placebo control group [94]. There are no published trials on the use of IL-1RA in PsA, but it is conceivable that this therapy may be considered in the future to treat erosive polyarthritis in PsA in view of its clinical efficacy and of its remarkable anti-erosive properties. Other biological therapies proposed for use in PsA aim to interfere with T cells, which are part of the inflammatory infiltrate found in PsA-affected skin and synovium, although their exact role in disease pathogenesis remains to be defined. A modified anti- CD3 therapy using the non-fc receptor-binding humanized derivative of the murine anti-cd3 antibody huokt31 was recently demonstrated in an open-label trial to improve joint inflammation considerably within 1 month in six of the seven subjects included in the study [95]. Interestingly, the only non-responder later developed classical seropositive erosive RA, raising the possibility that anti-cd3 therapy may have different effects on PsA and RA polyarthritis. A second recent study evaluated the clinical impact on 11 patients with active PsA of alefacept Õ (Biogen, Cambridge, MA, USA), a leukocyte function-associated 3 (LFA-3) IgG1 fusion protein interfering with the CD2/LFA-3 pathway, which mediates both T-cell activation and recruitment to inflammation sites. After 12 weeks of treatment with alefacept, some degree of improvement in arthritis was observed in 64% of patients, and a similar proportion of patients achieved 50% amelioration of skin disease [96]. Analysis of synovial samples before and after therapy showed a significant decrease in the number of infiltrating CD4 þ and CD8 þ T cells, but also of CD68 þ cells (macrophages), which may indicate that T cells can also act by orchestrating macrophage activation. Furthermore, the fact that both anti-cytokine and anti-t-cell therapies appear to ameliorate disease manifestations in PsA suggests that the pathogenic loop in PsA can

9 1146 N. Pipitone et al. be blocked at different levels, even though the cause and early pathogenic process remains unclear. Conclusions Despite our incomplete knowledge of the aetiology and pathogenesis of PsA, there is now a large panoply of medications available for its treatment. None of the current treatments is curative, but significant clinical amelioration can be achieved in the majority of patients. Biological agents such as anti-tnf- therapies have shown promising results in patients with axial and/or polyarticular joint involvement refractory to DMARDs. At present, etanercept has been approved for use in PsA. However, properly conducted RCTs are needed to measure treatment efficacy in different disease subsets and to identify prognostic factors of disease progression. Today s challenge is not only to produce more effective medications, but also to identify those patients who should be treated more aggressively and to monitor the response to treatment adequately. This should lead to better allocation of health resources and future management planning. Conflict of interest The authors declare that they have no conflicts of interest. References 1. Blumberg BS, Bunim JJ, Calkins E, Pirani CL, Zvaifler NJ. ARA nomenclature and classification of arthritis and rheumatism (tentative). Arthritis Rheum 1964;7: Wright V. A unifying concept for the spondyloarthropathies. Clin Orthop Related Res 1979;143: McGonagle D, Khan MA, Marzo-Ortega H, O Connor P, Gibbon W, Emery P. Enthesitis in spondyloarthropathy. Curr Opin Rheumatol 1999;11: McGonagle D, Gibbon W, O Connor P, Green M, Pease C, Emery P. Characteristic magnetic resonance imaging entheseal changes of knee synovitis in spondylarthropathy. Arthritis Rheum 1998;41: Marsal S, Armadans-Gil L, Martinez M, Gallardo D, Ribera A, Lience E. Clinical, radiographic and HLA associations as markers for different patterns of psoriatic arthritis. Rheumatology 1999;38: Salvarani C, Cantini F, Olivieri I et al. Isolated peripheral enthesitis and/or dactylitis: a subset of psoriatic arthritis. J Rheumatol 1997;24: Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 1973;3: Salvarani C, Olivieri I, Cantini F, Macchioni L, Boiardi L. Psoriatic arthritis. Curr Opin Rheumatol 1998;10: Gladman DD. Psoriatic arthritis: recent advances in pathogenesis and treatment. Rheum Dis Clin North Am 1992;18: Gladman DD, Brockbank J. Psoriatic arthritis. Expert Opin Investig Drugs 2000;9: Cuellar ML, Citera G, Espinoza LR. Treatment of psoriatic arthritis. Bailliere s Clin Rheumatol 1994;8: Griffiths CE. Therapy for psoriatic arthritis: sometimes a conflict for psoriasis. Br J Rheumatol 1997;36: Sarzi-Puttini P, Santandrea S, Boccassini L, Panni B, Caruso I. The role of NSAIDs in psoriatic arthritis: evidence from a controlled study with nimesulide. Clin Exp Rheumatol 2001;19:S17 S Scott DL, Palmer RH. Safety and efficacy of nabumetone in osteoarthritis: emphasis on gastrointestinal safety. Aliment Pharmacol Ther 2000;14: Bennett A, Tavares IA. COX-2 inhibitors compared and contrasted. Expert Opin Pharmacother 2001;2: Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. Br Med J 2002;325: Ahmad SR, Kortepeter C, Brinker A, Chen M, Beitz J. Renal failure associated with the use of celecoxib and rofecoxib. Drug Saf 2002;25: Espinoza LR, Cuellar ML. Psoriatic arthritis: management. In: Klippel JH, Dieppe PA (eds). Rheumatology. London: Mosby, 1998: Baker H, Ryan TJ. Generalized pustular psoriasis. A clinical and epidemiological study of 104 cases. Br J Dermatol 1968;80: Wright V. Psoriatic arthritis. In: Kelley WN, Harris ED, Ruddy S, Sledge CB (eds). Textbook of rheumatology. Philadelphia: Saunders, 1989: Fiocco U, Cozzi L, Rigon C et al. Arthroscopic synovectomy in rheumatoid and psoriatic knee joint synovitis: long-term outcome. Br J Rheumatol 1996;35: Stucki G, Bozzone P, Treuer E, Wassmer P, Felder M. Efficacy and safety of radiation synovectomy with yttrium-90: a retrospective long-term analysis of 164 applications in 82 patients. Br J Rheumatol 1993;32: Bulbul R, Williams WV, Schumacher HR Jr. Psoriatic arthritis. Diverse and sometimes highly destructive. Postgrad Med 1995;97:97 6, Fournie B, Crognier L, Arnaud C et al. Proposed classification criteria of psoriatic arthritis. A preliminary study in 260 patients. Rev Rhum Engl Ed 1999;66: Whiting-O Keefe QE, Fye KH, Sack KD. Methotrexate and histologic hepatic abnormalities: a meta-analysis. Am J Med 1991;90: Smith DL, Wernick R. Exacerbation of psoriasis by chrysotherapy. Arch Dermatol 1991;127: Jones G, Crotty M, Brooks P. Psoriatic arthritis: a quantitative overview of therapeutic options. The Psoriatic Arthritis Meta-Analysis Study Group. Br J Rheumatol 1997;36: Taccari E, Spadaro A, Riccieri V. Correlations between peripheral and axial radiological changes in patients with psoriatic polyarthritis. Rev Rhum Engl Ed 1996;63: Scarpa R. Psoriatic arthritis. Is something changing? Adv Exp Med Biol 1999;455: Blackmore MG, Gladman DD, Husted J, Long JA, Farewell VT. Measuring health status in psoriatic arthritis: the Health Assessment Questionnaire and its modification. J Rheumatol 1995;22:

10 New developments and treatment of psoriatic arthritis Ostergaard M, Stoltenberg M, Henriksen O, Lorenzen I. Quantitative assessment of synovial inflammation by dynamic gadolinium-enhanced magnetic resonance imaging. A study of the effect of intra-articular methylprednisolone on the rate of early synovial enhancement. Br J Rheumatol 1996;35: Palmer WE, Rosenthal DI, Schoenberg OI et al. Quantification of inflammation in the wrist with gadolinium-enhanced MR imaging and PET with 2-[F-18]-fluoro-2-deoxy-D-glucose. Radiology 1995;196: Cuellar ML, Espinoza LR. Management of spondyloarthropathies. Curr Opin Rheumatol 1996;8: Gladman DD, Farewell VT. The role of HLA antigens as indicators of disease progression in psoriatic arthritis. Multivariate relative risk model. Arthritis Rheum 1995;38: Gladman DD, Farewell VT, Nadeau C. Clinical indicators of progression in psoriatic arthritis: multivariate relative risk model. J Rheumatol 1995;22: Gladman DD, Farewell VT, Wong K, Husted J. Mortality studies in psoriatic arthritis: results from a single outpatient center. II. Prognostic indicators for death. Arthritis Rheum 1998;41: Huizinga TW, Keijsers V, Yanni G et al. Are differences in interleukin 10 production associated with joint damage? Rheumatology 2000;39: Salvarani C, Olivieri I, Cantini F, Macchioni L, Boiardi L. Psoriatic arthritis. Curr Opin Rheumatol 1998;10: Lacaille D, Stein HB, Raboud J, Klinkhoff AV. Longterm therapy of psoriatic arthritis: intramuscular gold or methotrexate? J Rheumatol 2000;27: Clark CM, Kirby B, Morris AD et al. Combination treatment with methotrexate and cyclosporin for severe recalcitrant psoriasis. Br J Dermatol 1999;141: Black RL, O Brien WM, Van Scott EJ, Auerbach R, Eisen AZ, Bunim JJ. Methotrexate therapy in psoriatic arthritis. Double-blind study on 21 patients. J Am Med Assoc 1964;189: Willkens RF, Williams HJ, Ward JR et al. Randomized, double-blind, placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritis. Arthritis Rheum 1984;27: Abu-Shakra M, Gladman DD, Thorne JC, Long J, Gough J, Farewell VT. Longterm methotrexate therapy in psoriatic arthritis: clinical and radiological outcome. J Rheumatol 1995;22: Bressolle F, Bologna C, Kinowski JM, Sany J, Combe B. Effects of moderate renal insufficiency on pharmacokinetics of methotrexate in rheumatoid arthritis patients. Ann Rheum Dis 1998;57: British Medical Association, Royal Pharmaceutical Society of Great Britain. British National Formulary. London: British Medical Association, Maurer TA, Zackheim HS, Tuffanelli L, Berger TG. The use of methotrexate for treatment of psoriasis in patients with HIV infection. J Am Acad Dermatol 1994;31: 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 1996;39: Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: a Department of Veterans Affairs cooperative study. Arthritis Rheum 1999;42: Fraser SM, Hopkins R, Hunter JA, Neumann V, Capell HA, Bird HA. Sulphasalazine in the management of psoriatic arthritis. Br J Rheumatol 1993;32: Combe B, Goupille P, Kuntz JL, Tebib J, Liote F, Bregeon C. Sulphasalazine in psoriatic arthritis: a randomized, multicentre, placebo-controlled study. Br J Rheumatol 1996;35: Gupta AK, Grober JS, Hamilton TA, Ellis CN, Siegel MT, Voorhees JJ, McCune WJ. Sulfasalazine therapy for psoriatic arthritis: a double blind, placebo controlled trial. J Rheumatol 1995;22: Dougados M, van der Linden S, Leirisalo-Repo M et al. Sulfasalazine in the treatment of spondylarthropathy. A randomized, multicenter, double-blind, placebocontrolled study. Arthritis Rheum 1995;38: Rahman P, Gladman DD, Cook RJ, Zhou Y, Young G. The use of sulfasalazine in psoriatic arthritis: a clinic experience. J Rheumatol 1998;25: Farr M, Kitas GD, Waterhouse L, Jubb R, Felix-Davies D, Bacon PA. Sulphasalazine in psoriatic arthritis: a double-blind placebo-controlled study. Br J Rheumatol 1990;29: Pitzalis C, Pipitone N. Psoriatic arthritis. J R Soc Med 2000;93: Mahrle G, Schulze HJ, Farber L, Weidinger G, Steigleder GK. Low-dose short-term cyclosporine versus etretinate in psoriasis: improvement of skin, nail, and joint involvement. J Am Acad Dermatol 1995;32: Raffayova H, Rovensky J, Malis F. Treatment with cyclosporin in patients with psoriatic arthritis: results of clinical assessment. Int J Clin Pharmacol Res 2000;20: Spadaro A, Riccieri V, Sili-Scavalli A, Sensi F, Taccari E, Zoppini A. Comparison of cyclosporin A and methotrexate in the treatment of psoriatic arthritis: a one-year prospective study. Clin Exp Rheumatol 1995;13: Salvarani C, Macchioni P, Olivieri I et al. A comparison of cyclosporine, sulfasalazine, and symptomatic therapy in the treatment of psoriatic arthritis. J Rheumatol 2001;28: Macchioni P, Boiardi L, Cremonesi T et al. The relationship between serum-soluble interleukin-2 receptor and radiological evolution in psoriatic arthritis patients treated with cyclosporin-a. Rheumatol Int 1998;18: Korstanje MJ, Bilo HJ, Stoof TJ. Sustained renal function loss in psoriasis patients after withdrawal of low-dose cyclosporin therapy. Br J Dermatol 1992;127: Gladman DD, Blake R, Brubacher B, Farewell VT. Chloroquine therapy in psoriatic arthritis. J Rheumatol 1992;19: Bruckle W, Dexel T, Grasedyck K, Schattenkirchner M. Treatment of psoriatic arthritis with auranofin and gold sodium thiomalate. Clin Rheumatol 1994;13: Palit J, Hill J, Capell HA et al. A multicentre doubleblind comparison of auranofin, intramuscular gold thiomalate and placebo in patients with psoriatic arthritis. Br J Rheumatol 1990;29: Carette S, Calin A, McCafferty JP, Wallin BA. A doubleblind placebo-controlled study of auranofin in patients with psoriatic arthritis. Arthritis Rheum 1989;32: Mader R, Gladman DD, Long J, Gough J, Farewell VT. Does injectable gold retard radiologic evidence of joint