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- PATIENTS AND METHODS
Psoriatic arthritis (PsA) is a spondylarthropathy that occurs in approximately 6–20% of patients with psoriasis (1). There is evidence that tumor necrosis factor α (TNFα) is linked to the pathogenesis of PsA and psoriasis. This proinflammatory cytokine upregulates adhesion molecules and triggers an inflammatory cytokine cascade (2–4), resulting in inflammation and arthritis. Evidence of the involvement of TNFα in the pathophysiology of PsA is based on several findings. First, circulating T lymphocytes and macrophages isolated from PsA patients produce increased TNFα compared with healthy controls (5). The levels of TNFα are elevated in patient synovium, (6, 7) as well as in the skin lesions of PsA patients, (8–10) and TNFα levels correlate with disease activity in psoriasis (11–14). Second, TNF receptors are elevated in synovial fluid and their level of expression correlates with clinical disease severity (15). Finally, a mutation in the promoter region of TNFα is associated with juvenile-onset PsA (16).
The current therapeutic approaches for PsA, similar to those for rheumatoid arthritis (RA), include nonsteroidal antiinflammatory drugs and disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (17), sulfasalazine (18), and cyclosporin A (19). Although the exact mechanism of action of these agents is unknown, they may directly or indirectly downregulate TNFα or other immune mechanisms associated with PsA and RA. Of the current therapeutic options, methotrexate and sulfasalazine are the only 2 agents with well-documented efficacy (20). However, these agents are associated with significant adverse events, and many patients do not respond to these treatments (17, 21).
Because anti−TNFα antibodies (22–24) and fusion proteins (25) have demonstrated efficacy and safety in the treatment of RA, another TNFα–mediated inflammatory arthritis, it was reasoned that they may have efficacy for the treatment of PsA as well. Infliximab is a novel chimeric murine-human monoclonal antibody (cA2, Remicade; Centocor, Malvern, PA) that blocks TNFα, neutralizing both the soluble and membrane-bound forms of the cytokine. In RA patients, it has been demonstrated that, following infliximab therapy, adhesion molecules and inflammatory cytokines known to potentiate inflammation, such as interleukin-6, are downregulated (26). In a recent clinical trial evaluating the efficacy and safety of infliximab and methotrexate combination therapy in RA, 50% of treated patients achieved a 20% or greater improvement according to the American College of Rheumatology (ACR) criteria (ACR20) (27) as early as 2 weeks after treatment, with most patients maintaining an ACR20 response at week 30 (24). Based on clinical trials in RA, infliximab was considered safe and well tolerated. Infliximab has US Food and Drug Administration and European Agency for the Evaluation of Medicinal Products approval for use in RA as well as for the treatment of Crohn's disease (28). However, the potential of infliximab as a treatment for PsA has been previously evaluated in only 9 patients with a rather short observation period of 12 weeks (29).
The objective of the current study was to determine the efficacy and safety of infliximab inhibition of TNFα in PsA patients unresponsive to DMARD therapy. Patient responses to therapy were monitored by magnetic resonance imaging (MRI), an objective measure of inflammation, as well as by standard assessments of arthritis and psoriasis.
- Top of page
- PATIENTS AND METHODS
There are few treatment alternatives for patients with progressive PsA who fail to respond to methotrexate. Of the world's population, 1–3% is afflicted with psoriasis (1) and 6–20% of those patients develop PsA (1, 33). In the present study, infliximab, a chimeric antibody that binds to and inactivates TNFα, thereby downregulating inflammatory cytokines and adhesion molecules (26), was administered to PsA patients who had failed to respond to the standard treatment options. Infliximab treatment resulted in an improvement in all global and peripheral assessments of arthritis in all treated patients. Furthermore, applying the stringent response criteria established by the ACR to evaluate RA patient responses to therapy revealed that by week 6 every patient had achieved a 50% improvement in arthritis severity (ACR50)—a response that was sustained by all patients out to week 54 despite lowering the dose or discontinuing infliximab treatment due to remission in some patients. Response criteria defined by Clegg et al (21) also demonstrated that all patients responded to infliximab treatment. Improvements in both arthritis measures were achieved as early as week 2 following the administration of the antibody, and 6 patients continued to meet ACR70 criteria at week 54 after the initiation of infliximab therapy. The MRI analysis provided objective confirmation of the patients' reduced inflammation with a mean reduction in gadolinium-DTPA uptake of 82.5%. Lastly, infliximab appeared to also resolve other manifestations of psoriasis with improvements in PASI indices in addition to a visual reduction in psoriatic plaque size that was confirmed by histopathologic analysis. Within this small cohort we have seen only 1 infusion reaction and no serious adverse events.
The present study was open-label and involved only a small number of patients and no control group. The conclusions that can be drawn from the results are limited. However, our observation that the arthritis measures correlated with MRI data (an objective measure of inflammation) suggests that the responses were due to a true therapeutic effect. The rapid response of clinical parameters, as well as the marked reduction of ESR and CRP, makes a spontaneous reduction of inflammation due to selection criteria unlikely. MRI can be used to visualize the soft tissue abnormalities prior to any further inflammatory damage and is, therefore, a powerful technique for monitoring patients who may be predisposed to arthritis, such as psoriasis patients, as well as for monitoring patient responses to antiinflammatory therapy (34). In the present study MRI was used to document the decrease in inflammation in the joints of infliximab-treated PsA patients. These data, and a previous study using MRI to quantitate the effects of infliximab therapy (32), confirm that MRI, in addition to its current use in diagnosing inflammatory arthritis, is a powerful tool for monitoring antiinflammatory therapy responses.
Data from this study are consistent with those of Van den Bosch et al (29), in which infliximab was used to treat 21 patients with various spondylarthropathies, including 9 patients with PsA. The dose (5 mg/kg infliximab) and treatment regimens were similar between the 2 studies and were modeled after the treatment regimens that have proven efficacious for RA (23). Similar to the current study, Van den Bosch et al documented significant improvements following the first infliximab infusion, with treatment responses maintained through 84 days posttreatment. In addition to the global and peripheral assessments, ESR, CRP, and PASI score measurements presented by Van den Bosch et al, the current study includes ACR and Clegg response data that are more stringent measurements of a drug effect than the individual measures. Additionally, the MRI data objectively quantify the improvement of PsA in response to infliximab. Furthermore, in the present study, patient improvements in psoriasis plaques were observed and examined by histopathologic techniques, confirming the concurrent improvements in skin and joint psoriasis. During a recent double-blind, monocenter study of PsA treatment with etanercept (a TNFα receptor fusion protein), patient improvements according to ACR and Clegg response criteria were also documented (35). In this study 73% of etanercept-treated patients achieved an ACR20 response by week 12 of treatment compared with 13% of patients in the placebo group. The ACR50 and ACR70 responses were 50% and 13%, respectively, for the etanercept-treatment group compared with 3% and 0% in the placebo group. Interpreted together, the present study and the 2 previously published studies highlight the pathophysiologic role of TNFα in PsA and suggest that, similar to RA patients, PsA patients may benefit from infliximab therapy.
In the present study, in the Van den Bosch study (29), and in the etanercept study (35), improvements in PsA were accompanied by improvements in psoriatic plaques. These data suggest that, irrespective of the antigens and cell types driving disease in the skin and joints, both manifestations of psoriasis are dependent to some extent upon TNFα. Therefore, inhibition of TNFα may effectively treat both aspects of the disease.
In conclusion, based on our analysis of this small study, infliximab is effective and safe for the treatment of PsA in patients unresponsive to DMARD therapy. Furthermore, patients also benefited by an improvement in psoriatic plaques. Taken together, the improvement in ACR and Clegg arthritis criteria and the reduction in inflammation detected by MRI, an objective measure of inflammation, suggest that infliximab warrants further investigation for the treatment of psoriatic arthritis.