Current treatment of psoriatic arthritis

Rheum Dis Clin N Am 29 (2003) 495 511 Current treatment of psoriatic arthritis Philip J. Mease, MD a,b,c, * a Seattle Rheumatology Associates, Swedish Hospital Medical Center campus, Seattle, WA, USA b Division of Clinical Research, Swedish Hospital Medical Center, Seattle, WA, USA c University of Washington School of Medicine, Seattle, WA, USA Psoriatic arthritis (PsA) is a progressive, chronic, inflammatory arthritis seen in 7% to 42% of psoriasis patients [1 4]. It is generally accepted that psoriasis occurs in 2% to 3% of the population [5]. PsA is classified as one of the subtypes of spondyloarthropathy, sharing clinical features such as asymmetry of joint involvement, a frequent tendency to present in an oligoarticular fashion, similar frequency in men and women, enthesial inflammation, extra-articular manifestations such as iritis, and infrequency of rheumatoid factor, all features that help distinguish the disease from rheumatoid arthritis (RA) [3,6 8]. Although a clinical association between psoriasis and PsA has long been described, the immunologic links between the diseases are only now being explained, in part through new treatments that target molecules involved in the immune response. Psoriatic arthritis has been associated with joint damage, functional impairment, and potential for early mortality [9 13]; therefore, treatments that slow disease progression are desirable. Enthesopathy is being increasingly recognized as a prominent feature of PsA. McGonagle has postulated that it a key inflammatory lesion in PsA [14]. Supporting this concept is a recently reported study in HLA-B27 transgenic rats, all of which develop a spondyloarthropathy with psoriaform skin lesions and arthritis by approximately 52 weeks. Enthesitis was detected by contrastenhanced MRI well before synovitis developed [15]. Various studies have demonstrated the utility of MRI and ultrasound in detecting the location and severity of disease activity (in joints and enthesium) and structural damage. As diagnostic assessment tools such as contrast-enhanced MRI [15 17] and ultrasound improve [18 20], the ability to determine the magnitude of the effect of new therapies on progression of joint damage should also improve. Traditionally, PsA has been treated with agents originally tested in, and indicated for, RA. There have been few controlled studies in PsA, and these * Seattle Rheumatology Associates, Swedish Hospital Medical Center campus, 1101 Madison Street, Seattle, WA 98104. E-mail address: pmease@nwlink.com 0889-857X/03/$ see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/s0889-857x(03)00047-4

496 P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 few have demonstrated lackluster efficacy of older agents. Studies of newer medications, however, have shown significant efficacy and improved safety in PsA and have shown that radiologic progression of PsA might be significantly slowed with disease-modifying therapy. Conventional therapies Disease severity is the primary determinant of therapy choice for PsA. Mild PsA (ie, with minimal inflammation, functional impairment, and number of joints involved) is often treated first with physiotherapy and nonsteroidal anti-inflammatory drugs (NSAIDs). The development of selective COX-2 inhibitors (celecoxib, rofecoxib, valdecoxib, and etoricoxib) and the relatively selective COX-2 inhibitors (meloxicam) might help alleviate pain and restore function in some patients while protecting the gastrointestinal tract from the toxicity common to many NSAIDs. Recent trials of two of these medications, celecoxib and etoricoxib, have demonstrated efficacy in PsA [21,22]. More severe disease typically requires the use of corticosteroids or diseasemodifying antirheumatic drugs (DMARDs) to adequately control disease symptoms and diminish disease progression. Key predictors of disease severity have included number of involved joints, elevation of acute phase reactants, presence of radiographic change, and degree of functional impairment [23]. Corticosteroids have traditionally been used to treat many forms of arthritis, but they must be used with caution in patients who have PsA because their withdrawal might trigger flares of psoriasis [24,25]. Long-term immunomodulatory treatments for RA that are also used to treat PsA include methotrexate (MTX), cyclosporine, gold, sulfasalazine, azathioprine, and antimalarial medications. Trials of these therapies in PsA have been generally small and few in number. For most of these trials, the placebo group has also responded, and improvement in PsA symptoms has rarely been dramatically different between treatment groups. Jones et al conducted a meta-analysis of randomized, placebo-controlled trials with results reported in English-language publications. The researchers concluded that only high-dose MTX (at doses currently considered toxic) and sulfasalazine were associated with significant improvements in PsA symptoms [26]. MTX is commonly used to treat PsA even though most published safety and efficacy data on the drug pertain to the treatment of RA rather than PsA. Willkens and colleagues conducted a 12-week, prospective, double-blind trial in which 37 patients who had PsA received either 7.5 mg or 15 mg of MTX per week, or placebo. MTX decreased the psoriasis skin surface area to a greater extent than placebo and was rated better than placebo on the physician s global assessment; however, MTX was no different from placebo in terms of joint pain/tenderness and swelling, duration of morning stiffness, or skin induration or scaling [27]. Similarly, an open-label study designed to examine the disease-modifying effects of MTX found no radiologic difference between patients treated with MTX (n = 38) and matched controls [28]. In a retrospective analysis, however,

P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 497 when clinical response was defined as at least a 50% reduction in inflamed joint count for 6 months or from first to last visit, MTX was found to be more likely to be associated with a clinical response and less likely to be discontinued than gold. Lacaille and colleagues reviewed records of 87 PsA patients treated with gold or MTX during a 24-year period at their clinic. The likelihood of a clinical response was 8.9 times greater with MTX than intramuscular gold. Patients were five times more likely to discontinue therapy with intramuscular gold than with MTX. No major toxicity occurred, and frequency of side effects was similar for both treatments [29]. A prospective, randomized study by Spadaro and colleagues concluded that MTX was as effective as cyclosporine in treating PsA. In 35 patients treated for 1 year, cyclosporine dosages of 3 to 5 mg/kg/d and MTX at 7.5 to 15 mg/wk were associated with numerous clinical improvements such as fewer painful or swollen joints, decreased Ritchie index score, shorter duration of morning stiffness, improved grip strength, improvement in Psoriasis Activity Severity Index (PASI), and improved patient and physician global assessments. MTX therapy yielded significantly greater improvements in the erythrocyte sedimentation rate (ESR) than cyclosporine. Cyclosporine was not associated with elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes, as was MTX. Fewer patients given MTX withdrew from the study despite issues with hepatotoxicity [30]. Cyclosporine was compared with sulfasalazine and to symptomatic therapy (eg, analgesics, NSAIDs) in a 24-week, open-label study of 99 patients who had PsA. The primary endpoint of this study was decreased pain. After 6 months, patients receiving cyclosporine experienced improvements in pain that were significantly greater than those in the other two groups ( P < 0.05). Cyclosporine also resulted in significantly greater improvement in 6-month PASI scores and was better than symptomatic therapy alone in terms of joint pain ( P = 0.002) and swelling ( P = 0.05), joint count ( P = 0.01), patient and physician global assessment improvements (by at least one point [ P = 0.04 and P = 0.01, respectively]), total Arthritis Impact Measurement Scales (AIMS, P = 0.002) score, and American College of Rheumatology (ACR) ACR50 and ACR70 scores ( P = 0.02, P = 0.05). Cyclosporine was also associated with a reduction in C-reactive protein (CRP). Sulfasalazine was superior to symptomatic therapy in terms of ESR [31]. In the absence of placebo-controlled trials, cyclosporine appears to be at least as efficacious as sulfasalazine in the treatment of PsA, and it might be more efficacious than sulfasalazine with regard to pain relief. Sulfasalazine has been used in more published PsA trials than most conventional therapies. Clegg and colleagues treated 221 PsA patients whose disease was resistant to NSAIDs with either 2 g/d sulfasalazine or placebo for 36 weeks. An overall response to therapy was calculated based on joint pain and tenderness, joint swelling, and physician and patient global assessments. Response to sulfasalazine was better than response to placebo at a level that was statistically significant (58% versus 45%, P = 0.05), although individual response criteria did not show a significant benefit for sulfasalazine [32]. This study employed a unique

498 P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 outcome assessment tool, which was subsequently called the Psoriatic Arthritis Response Criteria (PsARC). The elements of this criteria set include at least 30% improvement in tender or swollen joint score and a physician and patient global assessment on a five-point Likert scale. To be a responder, at least two of these elements must improve, including at least one joint score, and no element can worsen. Clegg and associates also performed a retrospective reanalysis of data from various studies on treatment of spondyloarthropathies; 221 PsA patients were included in this reanalysis. When this larger group (n = 619) was considered, sulfasalazine provided more benefit than placebo in terms of an overall response to therapy, but its effectiveness was limited to the treatment of peripheral articular symptoms, not axial manifestations [33]. In a 24-week trial of 2 g/d sulfasalazine for PsA, Combe and colleagues found sulfasalazine superior to placebo in terms of decreased pain but not in terms of patients overall assessment of joint and skin improvement, morning stiffness, Ritchie articular index, ESR, or CRP [34]. A 12-month trial that compared PsA patients receiving sulfasalazine to matched controls found no clinical differences as judged by swollen joint count (> 50% reduction) or radiographic scores. This study also reported tolerability problems with sulfasalazine in many patients [11]. Sulfasalazine was superior to placebo only in terms of the patient s overall assessment in a 6-month trial of high-dose (3 g/d) sulfasalazine or placebo in 351 patients who had spondyloarthropathy. When the subgroup of PsA patients was analyzed, however, Dougados and colleagues found significant benefits for sulfasalazine in the patient s and physician s global assessments, overall pain, joint pain and swelling, and the duration of morning stiffness [11,35]. These results are supported by those of a smaller (n = 24), shorter (8-week) crossover study using 3 g/day sulfasalazine. Improvements in patient and physician global assessments, duration of morning stiffness, and cutaneous involvement were reported [36]. Two additional studies have also shown sulfasalazine to offer greater benefit than placebo in the treatment of PsA [37,38]. Numerous other agents have been examined for the treatment of PsA. Retinoids, traditionally used for psoriasis, might benefit PsA patients, as demonstrated in a study of etretinate, in which both etretinate and ibuprofen patients showed improved articular indices. Etretinate also improved the ESR and CRP levels [39]. Gold has also been traditionally used for arthritic relief. A study of 82 PsA patients found that intramuscular administration provided superior relief to oral administration in terms of overall pain and improvement in the Ritchie index [40]. Adding somatostatin to a regimen of gold salts has also been found to be beneficial in terms of decreased pain and joint tenderness [41]. Antimalarials might offer some benefit in the treatment of PsA [42,43], although their use is somewhat controversial because of reports of flares of psoriasis associated with the use of these drugs [44]. A review of 18 English-language publications performed in 1999 revealed that up to 18% of patients who had psoriasis would develop an exacerbation of their disease following antimalarial therapy [45].

P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 499 Biologic agents The agents described thus far have been used because they have generalized immunomodulatory effects that might benefit PsA patients. In contrast, biologic agents are designed with specific, targeted effects on the immune system that affect immunologic disease processes, including the PsA disease process. Numerous biologic agents are in development for the treatment of PsA and psoriasis. Table 1 lists biologic agents that have reached at least Phase II trials. Tumor necrosis factor inhibitors Of all current biologic agents, the tumor necrosis factor (TNF) inhibitors etanercept and infliximab have generated the most clinical data on the treatment of PsA. These agents impede inflammatory processes and have been shown to have disease-modifying effects in RA that prevent joint damage and preserve function [46 48]. Etanercept, a fully human, soluble TNF receptor protein, binds to circulating TNF and prevents it from interacting with its cell surface receptor and inducing inflammation. Etanercept is the first U.S. Food and Drug Administration (FDA)- approved biologic drug for treatment of PsA. The potential for its use in the treatment of other spondyloarthropathies such as ankylosing spondylitis (AS), is currently being investigated. Additional indications for etanercept include treatment of RA and polyarticular-course juvenile rheumatoid arthritis (JRA) Table 1 Biologic agents in clinical trials for the treatment of psoriatic arthritis Mechanism of action Agent Description Comments TNF inhibitors Etanercept Soluble TNF receptor fusion protein Infliximab Chimeric anti-tnf mab Onercept Recombinant human TNF binding protein-1 (r-htbp-1) Anti-inflammatory cytokines Blockade of T-cell interactions FDA approved for PsA Recombinant IL-10 Recombinant IL-10 Might be more effective on skin versus joint symptoms Alefacept Efalizumab huokt3g1(ala ala) Recombinant LFA-3 fusion protein Humanized anti-cd11a mab Humanized anti-cd3 mab This table covers some of the more notable compounds that have reached at least Phase II trials for PsA, but because of the rapidly evolving nature of this field, some agents might have been inadvertently omitted. Abbreviations: FDA, U.S. Food and Drug Administration; IL, interleukin; LFA, leukocyte functionassociated antigen; mab, monoclonal antibody; TNF, tumor necrosis factor. Adapted from Mease P. Psoriatic arthritis/psoriasis. In: Smolen JS, Lipsky PE, editors. Targeted therapies in rheumatology. London: Martin Dunitz Ltd; 2003. p. 525 48; with permission.

500 P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 [46,49 51]. Consistent efficacy in clearing of chronic plaque psoriasis has been observed in both PsA and psoriasis trials of etanercept [52 55]. Etanercept is currently in Phase III trials for the treatment of psoriasis. FDA approval of etanercept for the treatment of PsA was based on two controlled, randomized trials [52,53]. In a 12-week, randomized, double-blind trial, 60 patients received either 25 mg twice-weekly subcutaneous injections of etanercept or placebo. Patients who were previously receiving some benefit from MTX (47% of the study population) were allowed to continue its use during the trial. These patients were randomly assigned separately to ensure similar groups. Although NSAID or prednisone ( 10 mg/d) use was allowed during the trial, other systemic and topical medications for arthritis and psoriasis were discontinued. Patients ranged in age from 24 to 70 years, with a median PsA duration of 9 to 9.5 years. PsARC, first named as such in this study and previously developed in the Clegg sulfasalazine study [56], was the primary efficacy criterion. Overall pain was also assessed and disability was scored on the Health Assessment Questionnaire (HAQ). Additionally, ESR and serum concentration of CRP were recorded. When psoriasis covered 3% or more of a patient s body surface area, target lesions were monitored and PASI was used [52]. The PASI score derives from a publication by Fredriksson and Pettersson in 1978 [57] and considers the localization, extent, and severity of the findings. This composite measure assesses severity of scale, erythema, and induration weighted by lesional surface area and body region. The PsARC response rates for patients receiving etanercept or placebo are shown in Fig. 1. As early as 4 weeks, the response to etanercept was highly statistically significant compared with the response to placebo ( P < 0.0001). This result was sustained through the 12-week endpoint. At 12 weeks, 26 of 30 (87%) Fig. 1. Percentage of patients who have PsARC responses over time. Open bars represent placebo while filled bars represent etanercept. * P < 0.0001. (From Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomized trial. Lancet 2000;356(9227):385 90; with permission.)

P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 501 of etanercept patients had shown a response, compared with only seven of 30 (23%) placebo patients. ACR response rates were also significantly higher in the etanercept group (Fig. 2). At 12 weeks, ACR20 was achieved by 22 of 30 (73%) of etanercept patients but only 4 of 30 (13%) patients receiving placebo (P < 0.0001). All measures of efficacy showed improvement with etanercept treatment. Median percentage improvements occurred in 75% of tender and 72% of swollen joint counts during etanercept treatment, compared with 5% worsening of tender, and 19% improvement of swollen joint counts in placebo-treated patients. Disability, as measured by responses to the HAQ, decreased in 83% of etanercept patients but only 3% of placebo patients (P < 0.0001). Thirty-four percent of patients given etanercept had no disability after 12 weeks, compared with 3% of placebo patients. Improvements also occurred in morning stiffness (39% of etanercept patients, 3% of placebo patients), ESR (82% versus 48%), and CRP (75% versus 32%). Concomitant use of MTX did not seem to affect patient response rates [52]. Among patients in this study with significant psoriasis ( 3% body surface area involvement, n = 38), the median improvement in PASI score was 46% for the etanercept group and 9% for the placebo group. Target lesions improved significantly more in the etanercept group, with median response of a target lesion being 50% in the etanercept group and 0% in the placebo group [52]. Injection site reactions were the most common adverse event in the etanercept group, and they resolved as the study progressed. No patients in the etanercept group withdrew, compared with four in the placebo group. No serious adverse events were associated with etanercept. Respiratory infections occurred in both Fig. 2. Percentage of patients who have ACR20, ACR50, and ACR70 responses at 12 weeks. Open bars represent placebo while filled bars represent etanercept. * and y P < 0.0001 (placebo versus etanercept). (From Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomized trial. Lancet 2000;356(9227):385 90; with permission.)

502 P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 etanercept (n = 8) and placebo patients (n = 4); intravenous antibiotics or hospitalization were not required. Etanercept was well tolerated and demonstrated significant clinical benefit in this trial [52]. Patients completing this study were allowed to receive etanercept in an openlabel extension of the trial [58,59]. Patients originally assigned to the placebo group responded rapidly to etanercept treatment. At 36 weeks, PsARC responses were achieved by 81%, and 74% and 55% of these patients achieved ACR20 and ACR50 responses, respectively. Patients in this group who also had psoriasis (n = 37) achieved median improvements of 62% and 50% in the PASI and target lesions scores, respectively. Patients receiving etanercept in the original study experienced further improvements. ACR20 responses increased from 73% after the original 3 months of etanercept treatment to 87% at the end of the extension study. ACR70 responses increased from 13% to 33%, and PASI scores improved to a median of 62%. Of the patients taking concomitant MTX, 12 of 28 (43%) decreased their dosage and seven of 28 (25%) discontinued MTX therapy altogether. Similarly, eight of 18 patients receiving prednisone at baseline discontinued corticosteroid therapy. Etanercept was well tolerated over this longer-term study [58,59]. A double-blind, placebo-controlled Phase III trial involving 205 patients who had PsA confirmed and extended earlier findings. Patients receiving 25 mg of subcutaneous etanercept twice weekly had significant ACR20 (the study s primary endpoint) and PsARC responses at 12 weeks compared with patients receiving placebo (ACR20: 59% versus 15%, P < 0.001; PsARC: 72% versus 31%, P < 0.001) [53]. Responses were maintained throughout the next 12 weeks, with ACR20 scores at 24 weeks being 50% for the etanercept group and 13% in the placebo group (P < 0.001). PASI scores were evaluated in a subgroup of patients who had plaque psoriasis involving 3% or more of body surface. PASI scores improved in the etanercept group (median, 42%, P < 0.001) but not in the placebo group. Similarly, target lesions improved in the etanercept group (median 30%, P < 0.001) but not in the placebo group. This larger study reported etanercept to be well tolerated, with a safety profile similar to that observed in patients who had RA [53]. Quality of life was assessed in this Phase III trial at baseline and at 6 months using the HAQ, the Medical Outcomes Study Short Form 36 (SF-36), and the EuroQOL Feeling Thermometer. Baseline HAQ scores were 1.1 units in both treatment groups, indicating a moderate degree of functional disability (with 3 being greatest disability). After 6 months of treatment, patient HAQ scores had improved by 0.6 units in the etanercept group and 0.1 units in the placebo group, which was highly statistically significant ( P < 0.0001). On the SF-36 Physical Component Summary, baselines scores were 36 (versus a norm of 50) in both treatment groups. Etanercept patients had a mean improvement of 9.3 units after 6 months of treatment, compared with 0.7 units in the placebo group (P < 0.0001). Improvement of at least 10 units on this scale was observed in 43% of etanercept patients but only 9% of placebo patients (P < 0.0001). Similarly, baseline scores on the Mean Feeling Thermometer scores were substantially lower than the norm of 80 units in the etanercept (64.7 units) and placebo

P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 503 (62 units) groups. At 6 months, etanercept patients had a significantly greater mean improvement than did placebo patients (14.3 versus 2.1 units, respectively, P < 0.0001). As indicated by all three measures, etanercept improved healthrelated quality of life for PsA patients [60]. Patients completing the 24-week trial were eligible to enroll in an open-label extension examining long-term effects of treatment on joint disease and patient safety. Radiographs of the hands and feet were taken at baseline of the original study, after 24 weeks of treatment (ie, at the end of the blinded trial), at the start of the open-label treatment phase, and after 1 year of open-label treatment (or at study withdrawal, whichever applied). Pairs of independent readers, blinded to study treatment and chronology of the radiographs, read digitized radiographs and rated them on a modified Sharp s scale for erosions and joint space narrowing. The modified scale included ratings of distal intraphalangeal joints and other radiologic features. There was significantly less progression of joint damage as judged radiographically in patients who received etanercept for the entire study. After 1 year, the mean rate of change in the total Sharp score of joint damage was 0.02 units in the etanercept group and +1.03 units in the placebo group (P < 0.0001). Mean rates of change in erosion scores were 0.08 units/year in etanercept patients versus +0.69 units/year in placebo patients (P < 0.0001). Mean rates of change in joint space narrowing were +0.06 and +0.35 units/year in etanercept and placebo patients, respectively (P = 0.04). Treatment of PsA with etanercept appears to inhibit structural damage [61]. This was the first trial to demonstrate radiologic evidence that joint damage associated with PsA could be prevented. Infliximab, a chimeric human mouse monoclonal antibody to TNF, has been studied in the treatment of Crohn s disease [62,63], RA [64,65], and, most recently, for spondyloarthropathies [66 68] and psoriasis [69,70]. An open-label trial in 21 patients who had spondyloarthropathies (nine with PsA) found that treatment with infliximab 5 mg/kg intravenously at weeks 0, 2, and 6 significantly reduced axial and peripheral arthritis symptoms [67], and that continuation of the drug with 5 mg/kg administered every 14 weeks thereafter maintained patients condition for more than 1 year, although symptoms tended increasingly to recur before retreatment [68]. In a double-blind trial, 40 patients who had active spondyloarthropathies were randomly assigned to receive either 5 mg/kg infliximab or placebo intravenously at weeks 0, 2, and 6. Primary endpoints were patient and physician global assessment on a visual analog scale. The infliximab group significantly improved after 2 weeks and maintained that therapeutic benefit until study s end at 12 weeks. One serious adverse event occurred (a patient developed disseminated tuberculosis), but otherwise the drug was well tolerated [71]. In a study involving patients who had progressive PsA and psoriasis, patients whose disease was resistant to MTX often responded well to infliximab. In a 54-week, open-label, compassionate use study, 10 patients received initial doses of infliximab, 5 mg/kg, at weeks 0, 2, and 6, with subsequent individualized dosing thereafter (typically infliximab, 3 to 5 mg/kg, at intervals of 8 weeks or greater). All patients achieved an ACR20 response by week 2. By week 10, eight

504 P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 of 10 patients had achieved an ACR70 response, which was maintained in six patients beyond the 54-week trial endpoint. MRI assessment of inflammation at week 10 demonstrated a mean reduction of 82.5% from baseline. PASI scores were also reduced by 71.3% ± 16.7%. No significant adverse events, severe infections, or infusion reactions occurred [72]. Based on the results observed in these small trials, a large-scale trial was conducted in 102 patients who had active PsA with five or more affected joints. Patients in this randomized, double-blind trial received infliximab, 5 mg/kg, or placebo at baseline and at weeks 2, 6, and 14. Concomitant administration with other disease-modifying drugs was allowed as long as the dosage was stable. Use of NSAIDs and prednisone less than or equal to 10 mg was also allowed. Two patients in each group discontinued therapy before the end of the study period. An ACR20 response was achieved in 51 of 71 (70.6%) infliximab-treated patients and five of 51 (9.8%) patients receiving placebo. ACR50 responses were achieved in 27 (52.9%), and ACR70 in 13 (25.5%) of the 51 patients receiving infliximab at 16 weeks. Twenty patients in the infliximab group with a baseline PASI score of 2.5 (the a priori definition for evaluating skin involvement) were also assessed for improvement. The mean baseline PASI score of those patients was 8.59 (range 2.8 26.1). The mean reduction in the PASI score in the infliximab group was 80.9%, and 70% of patients had an improvement of at least 75%. Treatment was well tolerated overall [73]. TNF inhibitors such as etanercept and infliximab are generally well tolerated. The most common adverse events (injection site or infusion reactions) are generally mild and self-limiting. Unfortunately, agents that alter the immune response, even though they are quite targeted, might ultimately be associated with rare but serious adverse events. The use of TNF inhibitors has been reported to predispose some patients to bacterial infections, tuberculosis or other atypical infections, and, rarely, to demyelinating disorders and drug-induced lupus [71,74 83]. Appropriate patient monitoring is needed to ensure timely treatment of any infection. Etanercept and infliximab set a standard for treatment of PsA, and newer TNF inhibitors are in development. Adalimumab is a fully human anti TNF-a monoclonal antibody that shows significant efficacy in RA when administered subcutaneously every other week, although some patients might experience superior effects when it is used weekly. It has shown ability similar to the current TNF inhibitors in inhibiting the radiologic progression of RA [84], and trials in PsA are being initiated. Onercept is a recombinant human p55 TNF-binding protein that is currently being tested in RA, psoriasis, and PsA. Other types of biological agents Future research might allow treatment of PsA through suppression of other proinflammatory cytokines, use of anti-inflammatory cytokines, inhibition of interleukin (IL)-2 receptor binding, or by blockade of T-cell interactions. For

P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 505 example, IL-10 typically maintains immune homeostasis, inhibiting TNFa and IL-1. Although it has not yet been shown to affect articular disease [85], one recombinant IL-10 compound has demonstrated some initial clinical benefits in the treatment of psoriasis [85 87]. Further research might determine if IL-10 has any effect on joints. There are a number of agents that block T-cell interactions. Alefacept is a lymphocyte function-associated (LFA) antigen-3 fusion protein that prevents interaction between T cells and antigen-presenting cells, thereby preventing T-cell activation. A small, open-label study treated PsA patients (n = 11) with alefacept for 12 weeks. More than half of the patients (6/11; 55%) responded as indicated by Disease Activity Score at treatment s end, and most (9/11; 81%) responded at some time during the study [88]. Alefacept would ideally target pathogenic T cells without impairing primary or secondary immune responses, but transient CD4 cell depletion might still occur [89]. LFA antigen 1 (LFA-1), consisting of CD11a and CD18 subunits, plays an important role in T cell activation and leukocyte migration. Efalizumab is a humanized antibody to the CD11 subunit of LFA-1. It inhibits interaction between LFA-1 and ICAM-1 and has demonstrated significant clinical and histologic improvements in patients who had moderate to severe psoriasis [90]. A trial to determine the therapeutic potential of efalizumab for PsA is beginning. Leflunomide, an inhibitor of pyrimidine synthesis that is taken orally daily, has been shown to be effective in PsA and psoriasis in a multinational, placebocontrolled trial in 190 patients (of which 186 were evaluable). PsARC, the primary endpoint, was achieved by 57.9% of the leflunomide-treated patients, compared with 31.9% of the placebo patients. Significantly more patients in the leflunomide treatment group achieved an ACR20 response than in the placebo group (38.5% versus 20.0%, respectively; P < 0.0067). Patients in the leflunomide treatment group also had highly significant improvement in the median PASI score from baseline compared with the placebo group (23.8% versus 0.0%, respectively; P < 0.0030). Changes from baseline in the median target lesion score were also significantly higher in the leflunomide-treated group compared with the placebo group (48.4% versus 25.6%, respectively; P < 0.0048) [91]. LFT abnormalities were seen more often in leflunomide-treated patients. All LFT changes were self-limited. Subreum, a fractionated, lyophilized extract containing immunoactive peptides from Escherichia coli, has shown efficacy in the treatment of RA [92] and might also provide benefit to some patients who have undifferentiated spondyloarthropathies [93]. A non-fcr binding monoclonal antibody to CD3 (a component of the T-cell receptor complex), huokt3g1(ala ala), has also demonstrated some therapeutic value in the treatment of PsA. In a Phase I/II, open-label, dose-escalating trial involving seven patients who had PsA who received huokt3g1 (ala ala) for 12 to 14 days, six patients had an ACR70 or greater response at day 30. There was a transient depletion of T cells noted in this trial, and one patient developed symptoms of a mild cytokine release syndrome.

506 P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 There are numerous other therapies emerging that will require adequate, controlled trials to determine their safety and efficacy in PsA. Summary The definition of PsA is still being refined, as is the understanding of the genetic and immunologic contributors to the pathophysiology of this disease. As knowledge of the underlying immunologic causes of PsA evolves, so too do treatment choices. Conventional therapies with broadly immunosuppressive effects have been the standard of therapy, but the clinical benefits of these agents are often unpredictable and might be limited by their side effects. Newer agents with mechanisms of action targeted toward specific components of the immune cascade are expected to provide more reliable responses with fewer efficacylimiting side effects than the more conventional agents borrowed from the RA armamentarium. Anti-TNF medicines such as etanercept, the first agent approved specifically for treatment of PsA, are an advance in the treatment of PsA, and other biological agents are on the horizon that might continue to help define the immunopathogenesis of PsA and treat the disease effectively. 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 2000;27(5):1247 50. [2] Brockbank J, Schentag CT, Rosen C, Gladman DD. Psoriatic arthritis (PsA) is common among patients with psoriasis and family medicine clinic attendees [abstract 249]. Arthritis Rheum 2001; 44(Suppl 9):S94. [3] Gladman DD. Psoriatic arthritis. In: Maddison PJ, Isenberg DA, Glass DN, editors. Oxford textbook of rheumatology. Oxford: Oxford University Press; 1998. p. 1071 84. [4] Salvarani C, Lo SG, Macchioni P, Cremonesi T, Rossi F, Mantovani W, et al. Prevalence of psoriatic arthritis in Italian psoriatic patients. J Rheumatol 1995;22(8):1499 503. [5] Adams PF, Hendershot GE, Marano MA. Current estimates from the National Health Interview Survey, 1996. National Center for Health Statistics. Vital Health Statistics 1999;10(200):1 212. [6] Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 1973;3(1):55 78. [7] Sege-Peterson K, Winchester R. Psoriatic arthritis. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, et al, editors. Fitzpatrick s dermatology in general medicine. New York: McGraw-Hill; 1999. p. 522 33. [8] Gladman DD, Brockbank J. Psoriatic arthritis. Expert Opin Investig Drugs 2000;9(7):1511 22. [9] Gladman DD, Stafford-Brady F, Chang C-H, Lewandowski K, Russell ML. Longitudinal study of clinical and radiological progression in psoriatic arthritis. J Rheumatol 1990;17(6):809 12. [10] Torre Alonso JC, Rodriguez PA, Arribas Castrillo JM, Ballina GJ, Riestra Noriega JL, Lopez LC. Psoriatic arthritis (PA): a clinical, immunological and radiological study of 180 patients. Br J Rheumatol 1991;30(4):245 50. [11] Rahman P, Gladman DD, Cook RJ, Zhou Y, Young G, Salonen D. Radiological assessment in psoriatic arthritis. Br J Rheumatol 1998;37(7):760 5. [12] 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(6): 1103 10.

P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 507 [13] Wong K, Gladman DD, Husted J, Long JA, Farewell VT. Mortality studies in psoriatic arthritis: results from a single outpatient clinic. I. Causes and risk of death. Arthritis Rheum 1997;40(10): 1868 72. [14] McGonagle D, Gibbon W, Emery P. Classification of inflammatory arthritis by enthesitis. Lancet 1998;352(9134):1137 40. [15] Bukulmez H, Dunn RS, Pratt RG, Dardzinski BJ, Colbert RA. Magnetic resonance imaging (MRI) in HLA-B27 transgenic rat model of spondyloarthropathy: image findings prior to clinically detectable arthritis [abstract 982]. Arthritis Rheum 2002;46(Suppl 9):S380. [16] Braun J, Barakiakos X, Golder W, Listing J, Brandt J, Bollow M, et al. Ankylosing spondylitis (AS) development and evaluation of a spinal scoring system (ASspiMRI) using magnetic resonance imaging (MRI) in patients with active disease [abstract 114]. Arthritis Rheum 2002; 46(Suppl 9):S426. [17] Braun J, Barakiakos X, Golder W, Listing J, Brandt J, Bollow M, et al. Improvement of spinal inflammation in ankylosing spondylitis (AS) by infliximab therapy as assessed by a magnetic resonance imaging (MRI) using a novel evaluated spinal scoring system results of a doubleblind, placebo-controlled trial [abstract 115]. Arthritis Rheum 2002;46(Suppl 9):S426 7. [18] Klauser A, Springer P, Frauscher F, Schirmer M. Comparison between magnetic resonance imaging, unenhanced and contrast-enhanced ultrasound in the diagnosis of active sacroiliitis [abstract 113]. Arthritis Rheum 2002;46(Suppl 9):S426. [19] Kamel M, Mansour R, Eid H, Fernandez I. Ultrasound detection of patellar enthesitis: a comparison with MRI [abstract 177]. Arthritis Rheum 2002;46(Suppl 9):S104. [20] Alcalde M, Cruz M, Bordoy C, González L, Acebes C, Sánchez-Pernaute O, et al. Assessment of entheseal injury in ankylosing spondylitis by ultrasound [abstract 1117]. Arthritis Rheum 2002;46(Suppl 9):S427. [21] Dougados M, Behier JM, Jolchine I, Calin A, van der Heijde D, Olivieri I, et al. Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: a six-week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug. Arthritis Rheum 2001;38:618 27. [22] Melian A, Van der Heijde D, James MK, Calin A, Giallella KM, Reicin AS, et al. Etoricoxib in the treatment of ankylosing spondylitis (AS) [abstract 1131]. Arthritis Rheum 2002; 46(Suppl 9):S432. [23] Gladman DD, Farewell VT, Nadeau C. Clinical indicators of progression in psoriatic arthritis: multivariate relative risk model. J Rheumatol 1995;22(4):675 9. [24] Christophers E, Mrowietz U. Psoriasis. In: Freedberg IM, Eisen AZ, Wolff K, et al, editors. Fitzpatrick s dermatology in general medicine. 5th edition. New York: McGraw Hill; 1999. p. 495 521. [25] Witman PM. Topical therapies for localized psoriasis. Mayo Clin Proc 2001;76:943 9. [26] Jones G, Crotty M, Brooks P. Interventions for treating psoriatic arthritis (Cochrane Review). Oxford: The Cochrane Library; 2001. [27] Willkens RF, Williams HJ, Ward JR, Egger MJ, Reading JC, Clements PJ, et al. Randomized, double-blind, placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritis. Arthritis Rheum 1984;27(4):376 81. [28] 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;22:241 55. [29] Lacaille D, Stein HB, Raboud J, Klinkhoff AV. Longterm therapy of psoriatic arthritis: intramuscular gold or methotrexate? J Rheumatol 2000;27(8):1922 7. [30] 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(5):589 93. [31] Salvarani C, Macchioni P, Olivieri I, Marchesoni A, Cutolo M, Ferraccioli G, et al. A comparison of cyclosporine, sulfasalazine, and symptomatic therapy in the treatment of psoriatic arthritis. J Rheumatol 2001;28(10):2274 82. [32] Clegg DO, Reda DJ, Mejias E, Cannon GW, Weisman MH, Taylor T, et al. Comparison of

508 P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 sulfasalazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affairs Cooperative Study. Arthritis Rheum 1996;39(12):2013 20. [33] Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondyloarthropathies: a Department of Veterans Affairs cooperative study. Arthritis Rheum 1999;42(11):2325 9. [34] Combe B, Goupille P, Kuntz JL, Tebib J, Liota F, Bregeon C. Sulfasalazine in psoriatic arthritis: a randomized, multicentre, placebo-controlled study. Br J Rheumatol 1996;35(7):664 8. [35] Dougados M, vam der Linden S, Leirisalo-Repo M, Huitfeldt B, Juhlin R, Veys E, et al. Sulfasalazine in the treatment of spondyloarthropathy. A randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum 1995;38(5):618 27. [36] Gupta AK, Grober JS, Hamilton TA, Ellis CN, Siegel MT, Voorhees JJ, et al. Sulfasalazine therapy for psoriatic arthritis: a double blind, placebo controlled trial. J Rheumatol 1995;22(5): 894 8. [37] Fraser SM, Hopkins R, Hunter JA, Neumann V, Capell HA, Bird HA. Sulfasalazine in the management of psoriatic arthritis. Br J Rheumatol 1993;32(10):923 5. [38] 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;29:46 9. [39] Hopkins R, Bird HA, Jones H, Hill J, Surrall KE, Astbury C, et al. A double-blind controlled trial of etretinate (Tigason) and ibuprofen in psoriatic arthritis. Ann Rheum Dis 1985;44(3):189 93. [40] Palit J, Hill J, Capell HA, Carey J, Daunt SO, Cawley MI, et al. A multicentre double-blind comparison of auranofin, intramuscular gold thiomalate and placebo in patients with psoriatic arthritis. Br J Rheumatol 1990;29(4):280 3. [41] Matucci-Cerinic M, Pignone A, Lotti T, Partsch G, Livi R, Cagnoni M. Gold salts and somatostatin: a new combined analgesic treatment for psoriatic arthritis. Drugs Exp Clin Res 1992;18(2): 53 61. [42] Gladman DD, Blake R, Brubacher B, Farewell VT. Chloroquine therapy in psoriatic arthritis. J Rheumatol 1992;19(11):1724 6. [43] Sayers ME, Mazanec DJ. Use of antimalarial drugs for the treatment of psoriatic arthritis. Am J Med 1992;93(4):474 5. [44] Vine JE, Hymes SR, Warner NB, Cohen PR. Pustular psoriasis induced by hydroxychloroquine: a case report and review of the literature. J Dermatol 1996;23(5):357 61. [45] Wolf R, Ruocco V. Triggered psoriasis. Adv Exp Med Biol 1999;455:221 5. [46] Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343(22):1586 93. [47] Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum 2002;46(6):1443 50. [48] Bondeson J, Maini RN. Tumour necrosis factor as a therapeutic target in rheumatoid arthritis and other chronic inflammatory diseases: the clinical experience with infliximab (REMICADE). Int J Clin Pract 2001;55(3):211 6. [49] Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 1999;130(6):478 86. [50] Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340(4):253 9. [51] Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton JJ, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 2000;342(11):763 9. [52] Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000;356(9227):385 90. [53] Mease P, Kivitz A, Burch F, Siegel E, Cohen S, Burge D. Improvement in disease activity in

P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 509 patients with psoriatic arthritis receiving etanercept (ENBREL): results of a phase 3 multicenter clinical trial [abstract 226]. Arthritis Rheum 2001;44(Suppl 9):S90. [54] Gottlieb AB, Lowe NJ, Matheson RT, Lebsack ME. Efficacy of etanercept in patients with psoriasis [abstract]. Presented at the American Association of Dermatology. New York, August, 2002. [55] Gottlieb AB, Matheson RT, Lowe NJ, Zitnik RJ. Efficacy of Enbrel in patients with psoriasis. J Invest Dermatol 2003; in press. [56] Clegg DO, Reda DJ, Weisman MH, Blackburn WD, Cush JJ, Cannon GW. Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. A Department of Veterans Affairs Cooperative Study. Arthritis Rheum 1996;39(12):2004 12. [57] Fredriksson T, Pettersson U. Severe psoriasis oral therapy with a new retinoid. Dermatologica 1978;157(4):238 44. [58] Mease PJ, Goffe BS, Metz J, VanderStoep A, Burge DJ. Enbrel (etanercept) in patients with psoriatic arthritis and psoriasis [abstract 2019]. Arthritis Rheum 2000;43(Suppl 9):S403. [59] Mease PJ, Goffe BS, Metz J, VanderStoep A, Burge DJ. ENBREL (etanercept) in patients with psoriatic arthritis and psoriasis [abstract THU0237]. Ann Rheum Dis 2001;60(Suppl 1):146. [60] Wanke LA, Gottlieb AB, Mease PJ, Kivitz AJ, Cohen SB, Burge DJ. Etanercept improves healthrelated quality of life in patients with psoriatic arthritis [abstract 97]. Arthritis Rheum 2002; 46(Suppl 9):S76. [61] Ory P, Sharp JT, Salonen D, Rubenstein J, Mease PJ, Kivitz AJ, et al. Etanercept (ENBRELâ) inhibits radiographic progression in patients with psoriatic arthritis [abstract 442]. Arthritis Rheum 2002;46(Suppl 9):S196. [62] Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, et al. A short-term study of chimeric monoclonal antibody ca2 to tumor necrosis factor alpha for Crohn s disease. Crohn s Disease ca2 Study Group. N Engl J Med 1997;337(15):1029 35. [63] Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogez RA, et al. Infliximab for the treatment of fistulas in patients with Crohn s disease. N Engl J Med 1999;340(18):1398 405. [64] Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999;354:1932 9. [65] Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, et al. Randomised doubleblind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (ca2) versus placebo in rheumatoid arthritis. Lancet 1994;344(8930):1105 10. [66] Van den Bosch F, Kruithof E, Baeten D, De Keyser F, Mielants H, Beys EM. Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) versus placebo in active spondyloarthropathy [abstract 603]. Arthritis Rheum 2001; 44(Suppl 9):S153. [67] Van den Bosch F, Kruithof E, Baeten D, De Keyser F, Mielants H, Veys EM. Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor alpha (infliximab) in spondyloarthropathy: an open pilot study. Ann Rheum Dis 2000;59(6):428 33. [68] Kruithof E, Van den Bosch F, Baeten D, Herssens A, De Keyser F, Mielants H, et al. Repeated infusions of infliximab, a chimeric anti-tnfalpha monoclonal antibody, in patients with active spondyloarthropathy: one year follow up. Ann Rheum Dis 2002;61(3):207 12. [69] Schopf RE, Aust H, Knop J. Treatment of psoriasis with the chimeric monoclonal antibody against tumor necrosis factor alpha, infliximab. J Am Acad Dermatol 2002;46(6):886 91. [70] Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001;357(9271): 1842 7. [71] Van den Bosch F, Kruithof E, Baeten D, Herssens A, De Keyser F, Mielants H, et al. Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) versus placebo in active spondyloarthropathy. Arthritis Rheum 2002;46(3): 755 65.

510 P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 [72] Antoni C, Dechant C, Hanns-Martin Lorenz PD, Wendler J, Ogilvie A, et al. Open-label study of infliximab treatment for psoriatic arthritis: clinical and magnetic resonance imaging measurements of reduction of inflammation. Arthritis Rheum 2002;47(5):506 12. [73] Antoni C, Kavanaugh A, Kirkham B, Burmeister G-R, Weisman M, Keystone E, et al. The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) [abstract 985]. Arthritis Rheum 2002;46(Suppl 9):S381. [74] Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002;359(9313): 1187 93. [75] Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345(15):1098 104. [76] Robinson WH, Genovese MC, Moreland LW. Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism: by what mechanisms could tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? Arthritis Rheum 2001;44(9):1977 83. [77] Mohan N, Edwards ET, Cupps TR, Oliverio PJ, Sandberg G, Crayton H, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001;44(12):2862 9. [78] Lee JH, Slifman NR, Gershon SK, Edwards ET, Schwieterman WD, Siegel JN, et al. Lifethreatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum 2002;46(10):2565 70. [79] Cairns AP, Duncan MK, Hinder AE, Taggart AJ. New onset systemic lupus erythematosus in a patient receiving etanercept for rheumatoid arthritis. Ann Rheum Dis 2002;61(11):1031 2. [80] Ali Y, Shah S. Infliximab-induced systemic lupus erythematosus. Ann Intern Med 2002;137(7): 625 6. [81] Mohan AK, Edwards ET, Cote TR, Siegel JN, Braun MM. Drug-induced systemic lupus erythematosus and TNF-alpha blockers. Lancet 2002;360(9333):646. [82] Ferraccioli GF, Assaloni R, Perin A. Drug-induced systemic lupus erythematosus and TNF-alpha blockers. Lancet 2002;360(9333):645. [83] Shakoor N, Michalska M, Harris CA, Block JA. Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet 2002;359(9306):579 80. [84] Keystone E, Kavanaugh AF, Sharp J, Hua Y, Teoh L, Fischkoff S, et al. Adalimumab (D2E7), a fully human anti-tnf-a monoclonal antibody, inhibits the progression of structural joint damage in patients with active RA despite concomitant methotrexate therapy [abstract 468]. Arthritis Rheum 2002;46(Suppl 9):S205. [85] McInnes IB, Illei GG, Danning CL, Yarboro CH, Crane M, Kuroiwa T, et al. IL-10 improves skin disease and modulates endothelial activation and leukocyte effector function in patients with psoriatic arthritis. J Immunol 2001;167:4075 82. [86] Reich K, Garbe C, Blaschke V, Maurer C, Middel P, Westphal G, et al. Response of psoriasis to interleukin-10 is associated with suppression of cutaneous type 1 inflammation, downregulation of the epidermal interleukin-8/cxcr2 pathway, and normalization of keratinocyte maturation. J Invest Dermatol 2001;116:319 29. [87] Asadullah K, Friedrich M, Hanneken S, Rohrbach C, Audring H, Vergopoulos AS, et al. Effects of systemic interleukin-10 therapy on psoriatic skin lesions: histologic, immunohistologic, and molecular biology findings. J Invest Dermatol 2001;116:721 7. [88] Kraan MC, Van Kuijk AW, Dinant HJ, Goedkoop AY, Smeets TJ, De Rie MA, et al. Alefacept treatment in psoriatic arthritis: reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis. Arthritis Rheum 2002; 46(10):2776 84. [89] Gottlieb AB, Vaishnaw AK. Alefacept (Amevive) does not blunt primary or secondary immune responses [abstract 232]. Arthritis Rheum 2001;44(Suppl):S91. [90] Gottlieb AB, Krueger JG, Wittkowski K, Dedrick R, Walicke PA, Garovoy M. Psoriasis as a

P.J. Mease / Rheum Dis Clin N Am 29 (2003) 495 511 511 model for T-cell-mediated disease: immunobiologic and clinical effects of treatment with multiple doses of efalizumab, an anti-cd11a antibody. Arch Dermatol 2002;138(5):591 600. [91] Kaltwasser P, Nash P, Gladman D, Mease PJ. Efficacy and safety of leflunomide in the treatment of psoriatic arthritis: results from the TOPAS study [abstract LB04]. Presented at the 66th Annual Scientific Meeting of the American College of Rheumatology. New Orleans, 2002. [92] Bloemendal A, Van der Zee R, Rutten VP, van Kooten PJ, Farine JC, van Eden W. Experimental immunization with anti-rheumatic bacterial extract OM-89 induced T cell responses to heat shock protein (hsp) 60 and hsp 70; modulation of peripheral immunological tolerance as its possible mode of action in the treatment of rheumatoid arthritis (RA). Clin Exp Immunol 1997;110:72 8. [93] Granfors K, Marker-Hermann E, de Keyser F, Khan MA, Veys EM, Yu DT. The cutting edge of spondyloarthropathy research in the millennium. Arthritis Rheum 2002;46:606 13.