LOCALLY AVAILABLE BIOLOGIC AGENTS IN THE TREATMENT OF PSORIATIC ARTHRITIS

Locally Available Biologic Agents in the Treatment of Psoriatic Arthritis 253 Phil. J. Internal Medicine, 47: 253-259, Nov.-Dec., 2009 LOCALLY AVAILABLE BIOLOGIC AGENTS IN THE TREATMENT OF PSORIATIC ARTHRITIS Sidney Erwin T. Manahan, M.D. and Bernadette Heizel D. Reyes, M.D. ABSTRACT Introduction: Traditional studies on psoriatic arthritis have evaluated the response to treatment in terms of the rheumatic condition excluding the dermatologic condition. Treatment of the disease with biologic agents has been demonstrated to be effective in the control of both the arthritis and skin condition. Objective: To systematically review the efficacy of locally available biologic agents (etanercept and infliximab) in the treatment of rheumatic and dermatologic manifestations of psoriatic arthritis. Search Strategy: A MEDLINE search (from 1966 to June 2007) was performed using the following search terms: biologic agents, infliximab, etanercept, psoriasis, psoriatic arthritis and randomized clinical trials. Likewise, the Cochrane Database was also searched for existing studies on psoriatic arthritis. This was supplemented by citation tracking of published bibliographies and conference proceedings. Selection Criteria: All randomized clinical trials evaluating the efficacy of etanercept and infliximab in Adult patients with active Psoriatic arthritis were included. Outcome assessments should include evaluation of both arthritic and dermatologic manifestations of the disease. These could be in the form of Psoriatic Arthritis Response Criteria (PsARC), American College of Rheumatology (ACR) Response Criteria (20, 50, and 70) and the Psoriatic Arthritis Severity Index (PASI) 75. Main Results: Nine studies were identified using the search strategy previously outlined. Of these, the four main clinical trials involving 569 patients were included in the quantitative analysis. Studies publishing the results of post hoc analysis were excluded if they did not assess for joint and dermatologic efficacy. Reprint request to: Sidney Erwin T. Manahan, M.D., Section of Rheumatology, Department of Medicine, UP-PGH Medical Center, Taft Ave., Manila, Philippines Quantitative analysis showed that patients treated with biologic agents were more likely to experience improvement in arthritic complaints compared to placebo [PsARC RR 0.32 favoring treatment 95% CI (0.25-0.40) P<0.0001] [ACR 20 RR 0.20 favoring treatment 95%CI (0.15-0.29) P<0.00001] and were more likely to experience improvement in skin lesions [PASI 75 RR 0.06 favoring treatment 95% CI (0.03-0.13) P<0.00001]. However, adverse events tended to occur more frequently in the biologics-treated patients mostly in the form of infusion/injection-related reactions [RR 0.82 95% CI (0.61-1.09) P 0.17] AuthorÊs Conclusion: Infliximab and Etanercept are both effective in treating psoriasis and psoriatic arthritis. INTRODUCTION Psoriatic arthritis is a chronic inflammatory condition that occurs among patients with psoriasis. Prevalence data varies depending on the population studied and the criteria used and is estimated to be 0.04 1.4 percent in the general population. Among patients with arthritis, prevalence of psoriasis ranges from 2.6 to 7.0 percent. Prevalence increases among psoriasis patients, ranging from 7 to 42 percent. Despite various arguments against psoriatic arthritis being a distinct clinical entity, its clinical features differentiate it from the other arthritides. Unlike osteoarthritis, it is inflammatory in nature and tends to affect both proximal and distal joints of the hands. As opposed to rheumatoid arthritis, there is the lack of gender preference, absence of rheumatoid factor and the presence of spondyloarthropathy and a tendency for asymmetry. Furthermore, radiographic findings in psoriatic arthritis such as pencil-incup deformity, osteolysis, joint space widening, juxtaarticular periostitis and tuft resorption make it unique among the inflammatory joint diseases. Treatment of psoriatic arthritis is directed at controlling the inflammatory process. While no clear pathogenic relationship exists between the joint and skin inflammation, articular and dermatologic manifestations need to be treated simultaneously. Initial therapy consists of anti-inflammatory agents for the articular complaints and topical therapies 253

254 Manahan SE T and Reyes BH D for psoriasis. Patients who do not improve or worsen following initial therapy are candidates for disease modifiying anti-rheumatic drugs (DMARDs). Available agents include gold salts, anti-malarial agents, azathioprine, sulfasalazine and methotrexate. Of these, methotrexate is the standard drug treatment due to its efficacy for both articular and dermatologic manifestations of psoriatic arthritis. The meta-analysis by Jones, Crotty and Brooks (Cochrane 2000) concluded that intravenous methotrexate and sulfasalazine are effective therapies for psoriatic arthritis and based on articular assessments- joint counts, acute phase reactants, pain and global assessment of disease activity, with no reference to effects on skin psoriasis. Traditional studies have monitored patient response in terms of the rheumatic condition mainly clinical assessment of joint inflammation and damage as well as radiographic evaluations. Composite indices used to monitor patients for treatment response, such as the Psoriatic Arthritis Response Criteria (PsARC) and the American College of Rheumatology Response Criteria (ACR-N) are primarily based on joint parameters. Responses to DMARDs are extrapolated from trials involving patients with psoriasis, not necessarily manifesting with joint problems. With the entry of biologic response modifiers, also known as biologic agents or biologics, into the treatment of psoriatic arthritis, both skin and joint manifestations are measured simultaneously in clinical trials. Their use in the management of psoriatic arthritis has been the focus of much interest in the recent years. OBJECTIVE The systematic review aims to evaluate the safety and efficacy of the locally available biologic agents - infliximab (INF) and etanercept (ETN) in the treatment of articular and dermatologic manifestations of psoriatic arthritis. Criteria for Considering Studies for this Review Types of Studies For inclusion in the meta-analysis, randomized clinical trials with at least two treatment groups were included. Concomitant therapy with methotrexate, the standard drug used in the treatment of psoriatic arthritis, should be permitted in the treatment groups. Types of Patients Trials were included if patients enrolled were clinically diagnosed with active psoriatic arthritis and at least 18 years of age. Types of Interventions Studies comparing infliximab and etanercept were included in the meta-analysis. Types of Outcomes Measured Included trials assessed outcome measures for both psoriasis and psoriatic arthritis. Assessment of the rheumatic condition were in the form of any of the composite outcome measures used in previous psoriatic arthritis studies Psoriatic Arthritis Response Criteria (PsARC), American College of Rheumatology Response Criteria (ACR 20, ACR 50 or ACR 70). The Psoriatic Arthritis Response Criteria (PsARC), developed as an outcome measure for research includes four measurements of the articular component of the disease the swollen joint count (SJC), the tender joint count (TJC), physician global assessment of disease activity and patient global assessment of disease activity. The American College of Rheumatology Response Criteria (ACR- N) which was originally developed for trials on Rheumatoid Arthritis but its use has been extended to evaluation of other inflammatory arthritides consists of improvement in the SJC, the TJC, pain, disability as evaluated by health assessment questionnaires, acute phase reactants, physician global assessment of disease activity and patient global assessment of disease activity. Measurements for psoriasis were in the form of the Psoriasis Area and Severity Index (PASI 75) - which is the proportion of patients achieving a 75 percent improvement in psoriasis activity from baseline and assessments of prospectively identified skin lesions (target lesion evaluation, dermatologistês static global assessment of target lesions -percent clear or almost clear). Search Method for Identification of Studies A MEDLINE Search was performed to identify randomized placebo controlled clinical trials or systematic reviews on the efficacy of infliximab and etanercept in the treatment of psoriatic arthritis from 1966-2006. This was supplemented by citation tracking in published bibliographies and conference proceedings. The Cochrane Database of Systematic

Locally Available Biologic Agents in the Treatment of Psoriatic Arthritis 255 Reviews was likewise searched for existing studies on biologic agents and psoriatic arthritis. The following terms were used in the literature search: biologic agents, etanercept, infliximab, psoriasis, psoriatic arthritis, randomized controlled trials. RESULTS Nine journal articles were identified. Of these, five were excluded: four published results of post-hoc analysis of the main studies presenting outcomes measures other than arthritis response criteria and dermatologic improvement and one study by Ritchlin, C (2006) could not be retrieved. [Table 1] The studies included in the meta-analysis were 4 randomized controlled clinical trials IMPACT 1, IMPACT 2, Mease 2000 and Mease 2004 which had a total of 569 patients randomized to receive either placebo or biologic agents. Table I. Characteristics of Included Trials Methods Participants Intervention Outcomes IMPACT 1 Randomized 104 patients Infliximab 1. ACR 20, 50 Double Blind with active PsA 5mg/kg IV vs and 70 at Placebo who had failed Placebo at week 16 Controlled at least weeks 2. PASI75 at Trial 1 DMARD O, 2, 6, 14 week 16 3. PsARC at week 16 4. DAS28 IMPACT 2 Randomized 200 adult Infliximab 1. ACR 20, 50 Double Blind patients with 5mg/kg IV vs and 70 at Placebo active PsA Placebo at week 24 Controlled weeks 2. PsARC at Trial O, 2, 6, 22 week 24 3. PASI75 at week 24 Mease 2000 Randomized 60 adult Etanercept 1. PsARC at Double Blind patients with 25mg sc week 12 Placebo active PsA 2x/week vs 2. ACR 20, 50 Controlled Placebo sc and 70 at Trial for 12 weeks week 12 3. PASI75 at week 12 Mease 2004 Randomized 205 adult Etanercept 1. ACR 20, 50 Double Blind patients with 25mg sc and 70 at Placebo active PsA 2x/week vs week 24 Controlled Placebo sc 2. PsARC at Trial for 24 weeks week 24 3. PASI75 at week 24 The quality of the studies were evaluated independently by three assessors (SETM, BHMR and JOG) using the Quality Scale for Meta-analytic reviews provided by the UP-PGH Department of Medicine. IMPACT1 and IMPACT2 were evaluated to be good-quality studies by all three assessors. While the two trials by Mease, et al were assessed to be studies of fair quality (Table 2). Table II. Quality Assessment of Included Trials Selection Performance Exclusion Detection Over-all IMPACT 1 A A A A A IMPACT 2 A A A A A Mease 2000 B A A A B Mease 2004 B A A A B Table III. Summary of Comparisons Between Treatment and Placebo Groups Comparisons Studies Participants Statistical method Effect size or outcome 01 PsARC 4 519 RR (fixed), 95% CI 3.06[2.44, 3.85] 02 PASI75 4 504 RR (fixed), 95% CI 17.69[7.88,39.70] 03 ACR 20 4 565 RR (fixed), 95% CI 4.96[3.59,6.86] 04 ACR 50 3 364 RR (fixed), 95% CI 16.78[6.62,42.49] 05 ACR 70 3 364 RR (fixed), 95% CI 17.50[4.27,71.73] 06 Serious AE 4 610 RR (fixed), 95% CI 0.84[0.43,1.65] 07 Adverse 12 1658 RR (fixed), 95% CI 1.37[1.07,1.76] Events All studies recruited adult patients (Aged 18-70 years) who were clinically diagnosed with Psoriatic Arthritis and assessed to have active disease. For the studies by Mease, disease activity was determined by the presence of > 3 swollen and > 3 tender joints at the time of study enrolment. While IMPACT used a different set of criteria - at least five swollen and five tender joints and at least one of the following parameters: CRP > 15 mg/l, ESR > 28 mm/hr or morning stiffness lasting at least 45 minutes before maximal improvement. Among the patients included by the above criteria, only patients with at least a baseline PASI score of 2.5 were included in the evaluation of dermatologic response to biologic agents. Methotrexate was allowed as concomitant disease modifying anti-rheumatic drug (DMARD) in all four trials. Other DMARDs were discontinued at least four weeks before the start of the study in the studies by Mease. DMARDs other than methotrexate such as leflunomide, sulfasalazine, hydroxychloroquine, penicillamine and azathioprine

256 Manahan SE T and Reyes BH D were allowed in IMPACT 1 and IMPACT 2. Stable doses of corticosteroids were allowed in all four trials. Treatments for psoriasis (oral retinoids, topical vitamin A or D analog preparations and anthralin) were not allowed. However, topical therapies were permitted on the scalp, axillae and groin only as this did not affect PASI evaluation. Both studies by Mease involved the administration of ETN 25 mg subcutaneously twice weekly given for 12 or 24 weeks. INF was given at a dose of 5 mg/kg body weight at weeks 0, 2, 6 and every 8 weeks thereafter for 16 or 24 weeks. Efficacy of Biologic Agents on the Rheumatic Disease For all outcome measures, treatment with biologic agents was more effective than placebo in treating psoriatic arthritis. Patients receiving biologic agents were three times more likely to achieve the Psoriatic Arthritis Response Criteria [RR 3.06 95% CI (2.44, 3.85) p-value <0.00001] which was developed specifically for evaluation of treatment response among psoriatic arthritis patients. (Comparison 01 Outcome 01). This resulted in a number needed to treat (NNT) of 2. The proportion of patients achieving the PsARC in the studies for INF and ETN were comparable (Figure 1). More patients receiving biologic treatment achieved ACR 20 (Figure 2) at the end of the study period [RR 4.96% CI (3.59, 6.86) p-value<0.00001]. (Comparison 01 Outcome 03) Similarly, more patients in treatment groups for infliximab and etanercept achieved ACR 50 and ACR 70 (Figure 3) responses [ACR 50 RR 16.78 95% CI (6.62, 42.49) p-value<0.00001] [ACR 70 RR 17.50 95% CI (4.27, 71.73) p-value<0.00001] (Outcomes 04 and 05). The trend favoring treatment with biologics was seen in both groups receiving INF and ETN. These translated to number needed to treat (NNT) of 2 (95% CI 2,2) to achieve an ACR 20 response, 3 (95% CI 2,3) to achieve an ACR 50 response, and 6 (95% CI 4,8) to achieve an ACR 70 response. Efficacy of Biologic Agents on Psoriasis Only the PASI 75 was consistently reported in all four clinical trials. The proportion of patients achieving a 75 percent improvement in skin lesions was 17 times more likely to be treated with biologic agents compared to placebo [PASI 75 RR 17.69 95% CI (7.88, 39.70) p-value <0.00001]. (Comparison 01 Outcome 02). This translated to a number needed to treat (NNT) of 2 (95% CI 2,3). Adverse Events Patients treated with the biologic agents experienced 37 percent more adverse events compared to the placebo groups [RR 1.44 95% CI (1.08, 1.93) p-value 0.01][Number needed to harm NNH 27 (95% CI 14,200)]. Serious adverse events tended to occur more in the biologics-treated patients. However, the difference did not reach statistical significance [RR 0.84 95% CI (0.43, 1.65) p-value 0.61][Number needed to harm NNH 74 (95% CI 20, 45). Contrary to what was expected, infections were more common in the placebo groups but was not significantly greater than the biologics group. The only significant adverse event reported among biologic treated patients was the occurrence of infusion and injection-related reactions. Other events such as flu-like syndrome and ecchymosis did not show any significant differences in the study groups. Fig. 1. Outcome of Treatment Measured by PsARC

Locally Available Biologic Agents in the Treatment of Psoriatic Arthritis 257 Fig. 2. Outcome of Treatment Measured by ACR 20 Fig. 2. Outcome of Treatment Measured by ACR 20

258 Manahan SE T and Reyes BH D Fig. 4. Adverse Events

Locally Available Biologic Agents in the Treatment of Psoriatic Arthritis 259 CONCLUSIONS Locally available biologic agents are effective in the treatment of both psoriasis and psoriatic arthritis. Articular and cutaneous manifestations improved similarly among patients treated with INF and ETN. Adverse events occurred more frequently among biologics-treated patients, mostly related to the drug administration. The difference in the frequency of serious adverse events between groups did not reach statistical significance. REFERENCES 1. Gladman DG, Rahman P: Psoriatic Arthritis in KelleyÊs Textbook of Rheumatology, 6 th ed. Volume II: pp 1071-1079. Ruddy S, Harris ED and Sledge CB-eds. W.B. Saunders Company, Philadelphia, 2001. 2. Cuellar ML, Espinoza LR: Psoriatic Arthritis: Management in Rheumatology, 3 rd ed. Volume II; pp. 1259-1266. Hochberg MC, et al-eds. Elsevier Science, Spain, 2003. 3. Bruce IN: Psoriatic Arthritis: Clinical features in Rheumatology, 3 rd ed. Volume II; pp. 1241-1252. Hochberg MC, et al-eds. Elsevier Science, Spain, 2003. 4. Antoni C: Psoriatic Arthritis: Etiology and Pathogenesis in Rheumatology, 3 rd ed. Volume II; pp. 1253-8. Hochberg MC, et al-eds. Elsevier Science, Spain, 2003. 5. Jones G, Crotty M, Brooks P: Interventions for Treating Psoriatic Arthritis. Cochrane Database of Systematic Reviews 2000, Issue 3. Art. No.: CD000212. DOI: 10.1002/14651858. CD000212. 6. Antoni CE, Kavanaugh A, et al.: Sustained Benefits of Infliximab Therapy for Dermatologic and Articular Manifestations of Psoriatic Arthritis: Results from the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT). Arthritis and Rheum; 52(4):1227, April 2005. 7. Kavanaugh A, Krueger GG, et al.: Infliximab Maintains A High Degree of Clinical Response in Patients with Active Psoriatic Arthritis Through 1 yr of Treatment: Results from the IMPACT 2 Trial. Ann Rheum Dis; 66:498, 2007. 8. Mease PJ, Goffe BS, et al.: Etanercept in the Treatment of Psoriatic Arthritis and Psoriasis: A Randomized Trial. Lancet; 356:385. 2000. 9. Mease PJ, Kivitz AJ, et al.: Etanercept treatment of psoriatic arthritis: safety, efficacy and effect on disease progression. Arthritis and Rheum July 2004; 50(7): 2264-72.