Open-label study of infliximab treatment for psoriatic arthritisClinical and magnetic resonance imaging measurements of reduction of inflammation.код для вставкиСкачать
Arthritis & Rheumatism (Arthritis Care & Research) Vol. 47, No. 5, October 15, 2002, pp 506 –512 DOI 10.1002/art.10671 © 2002, American College of Rheumatology ORIGINAL ARTICLE Open-Label Study of Infliximab Treatment for Psoriatic Arthritis: Clinical and Magnetic Resonance Imaging Measurements of Reduction of Inflammation CHRISTIAN ANTONI, CLAUDIA DECHANT, P. D. HANNS-MARTIN LORENZ, JOERG WENDLER, ALEXANDRA OGILVIE, MATHIAS LUEFTL, DOLORES KALDEN-NEMETH, JOACHIM R. KALDEN, AND BERNHARD MANGER Objective. To evaluate infliximab efficacy and safety in disease-modifying antirheumatic drug– unresponsive psoriatic arthritis (PsA). Methods. In a 54-week, open-label, compassionate-use study, 10 patients received intravenous infliximab (5 mg/kg; weeks 0, 2, 6; individualized dosing after week 10). Patients continued their current therapy (stable dose) until week 10. Assessments were performed at weeks 2, 6, 10, and 54. Magnetic resonance imaging (MRI) objectively measured joint inflammation at weeks 0 and 10. Results. Patients achieved a 20% improvement according to the American College of Rheumatology (ACR) criteria (ACR20) in all patients by week 2; 8 patients improved 70% (ACR70) at week 10; 6 patients maintained ACR70 after week 54. Week 10 MRI revealed an 82.5% mean reduction in inflammation from baseline, and psoriasis area and severity index scores were reduced by 71.3% ⴞ 16.7%. There were no significant adverse events, severe infections, or infusion reactions. Conclusion. Infliximab was effective, safe, and well tolerated in PsA. Arthritis and psoriasis improved in all patients during the 54-week evaluation. Further investigation of the use of infliximab for PsA and psoriasis is warranted. KEY WORDS. Infliximab, Magnetic Resonance Imaging, Psoriasis, Psoriatic arthritis, Remicade, Tumor Necrosis Factor ␣ INTRODUCTION Psoriatic arthritis (PsA) is a spondylarthropathy that occurs in approximately 6 –20% of patients with psoriasis (1). There is evidence that tumor necrosis factor ␣ (TNF␣) 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 TNF␣ in the pathophysiology of PsA is Christian Antoni, MD, Claudia Dechant, MD, P. D. HannsMartin Lorenz, MD, Joerg Wendler, MD, Alexandra Ogilvie, MD, Mathias Lueftl, MD, Dolores Kalden-Nemeth, MD, Prof. Dr. H. C. Joachim R. Kalden, MD, Prof. Bernhard Manger, MD: Friedrich-Alexander-University, Erlangen, Germany. Address correspondence and reprint requests to Christian Antoni, MD, Friedrich-Alexander-University, Department of Medicine III, Krankenhausstrasse 12 91056 Erlangen, Germany. E-mail: firstname.lastname@example.org. de. Submitted for publication October 20, 2001; accepted in revised form March 11, 2002. 506 based on several findings. First, circulating T lymphocytes and macrophages isolated from PsA patients produce increased TNF␣ compared with healthy controls (5). The levels of TNF␣ are elevated in patient synovium, (6,7) as well as in the skin lesions of PsA patients, (8 –10) and TNF␣ 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 TNF␣ 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 TNF␣ 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 ad- Infliximab Treatment of Psoriatic Arthritis 507 Table 1. DMARD and infliximab treatment history for weeks 10 –50* ACR score Treatment after week 10 Patient Week 10 Week 54 DMARD Infliximab 1 2 70 70 50 70 3 4 5 6 7 8 9 10 70 70 70 50 70 70 70 50 50 50 70 70 70 70 70 50 MTX No DMARD, discontinued MTX after week 10 due to side effects MTX MTX No DMARD MTX No DMARD MTX MTX No DMARD 5 mg/kg every 8 weeks 3 mg/kg every 8 weeks 3 mg/kg every 8 weeks 3 mg/kg every 8 weeks Discontinued month 8; infusion reaction and pregnancy Discontinued month 5, remission Discontinued month 8, remission Discontinued month 7, remission Discontinued week 10, remission 3 mg/kg every 8 weeks DMARD ⫽ Disease-modifying antirheumatic drug; ACR score ⫽ American College of Rheumatology criteria; MTX ⫽ Methotrexate. verse events, and many patients do not respond to these treatments (17,21). Because anti⫺TNF␣ antibodies (22–24) and fusion proteins (25) have demonstrated efficacy and safety in the treatment of RA, another TNF␣–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 TNF␣, 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 TNF␣ 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. PATIENTS AND METHODS Patients. Ten patients with a diagnosis of polyarticular disease with persistent clinical and serologic activity despite DMARD therapy were eligible for study inclusion. Seven patients were taking methotrexate, 1 patient was taking sulfasalazine, and 2 patients were not taking DMARDs at the time of inclusion. All patients had psoriatic skin lesions, joint involvement, and x-ray lesions characteristic of PsA. Patients with ⱖ 6 tender joints and ⱖ 6 swollen joints as well as 1 of 3 baseline criteria (erythrocyte sedimentation rate [ESR] ⱖ 25 mm, C-reactive protein [CRP] ⱖ 15 mg/L, or morning stiffness ⱖ 45 minutes) were included. Patients with a prior history of malignancy, ongoing or recent history of severe infection, pregnancy, or any unstable medical condition were excluded. All patients provided written informed consent. Patients had not previously received infliximab and had no known sensitivity to its components. Study design. The study was designed as a single-center, open-label, compassionate-use trial of infliximab. Patients were recruited from the outpatient department of the Department of Medicine III of the University of ErlangenNurnberg or after referral from a rheumatologist. Patients were treated within the study center on an outpatient basis. Infliximab (5 mg/kg) was infused intravenously with normal saline over a 2-hour period. Infliximab treatments were administered at the initial visit (week 0 or baseline) and at weeks 2 and 6, with additional followup evaluation at weeks 10 and 54. Between weeks 10 and 54, patients were treated with infliximab (3 mg/kg) every 8 weeks (with some exceptions; Table 1) on an individual basis determined by their response to infliximab and adverse events reported. Patients were allowed to continue stable-dose DMARD (methotrexate [15 to 25 mg/week] or sulfasalazine), steroid (ⱕ 10 mg/day prednisolone equivalent, stable dose), and nonsteroidal antiinflammatory drug therapy through week 10. After week 10, doses of concurrent medications were adjusted (decreased as appropriate), but no new DMARD or steroid therapy was started. Patients did not receive topical treatment for their psoriasis lesions between weeks 0 and 10. Patient evaluation. At weeks 2, 6, 10, and 54, the following assessments were made by the physician: tender joint count (the number of tender joints of 68 possible), 508 Antoni et al swollen joint count (the number of swollen joints of 66 possible), Physician Global Visual Analogue Scale (VAS) of disease severity (0 –100 mm VAS, with increasing numbers indicating increasing disease severity). Patients also assessed their pain and disease severity by recording the Patient Global VAS (0 –100 mm VAS) of disease severity and the Patient VAS Assessment of Pain (0 –100 mm VAS), as well as by completing the Stanford Health Assessment Questionnaire (HAQ, a measure of patient functional disability). Laboratory measurements included CRP and ESR, both of which increase in proportion to disease severity. Based on the arthritis measures, the stringent response criteria established by the ACR (27) and by Clegg et al (30) were calculated. The ACR criteria for arthritis improvement from baseline are defined as a 20%, 50%, or 70% improvement (ACR20, ACR50, or ACR70, respectively) in the number of swollen and tender joints, with a corresponding improvement in 3 of 5 additional categories (Patient Global VAS, Physician Global VAS, HAQ, ESR, or CRP, and Patient VAS of Pain). Clegg et al (30) defined response to treatment as improvements in 2 of 4 criteria with 1 improvement being joint tenderness or swelling. The 4 criteria are as follows: a 30% improvement in the tender joint count, a 30% improvement in the swollen joint count, an improvement in Physician Global VAS, and an improvement in Patient Global VAS. When applying the Clegg PsA response criteria, no categories may deteriorate. MRI of gadolinium-diethylenetriaminepentaacetic acid (DTPA) uptake (described in detail below) was determined at baseline and week 10 following infliximab treatment to document changes in joint inflammation. Psoriasis skin disease was monitored by calculating the psoriasis area and severity index (PASI) (31) for 6 out of 10 patients at weeks 0 and 10. The remaining 4 patients had only very mild skin involvement at baseline and were not evaluated. The PASI scores measure the extent of psoriasis disease as well as the morphology and thickness of psoriasis plaques. The PASI is calculated as follows: PASI⫽0, 1(Eh⫹Ich⫹Dh)Ah⫹0,3(Et⫹It⫹Dt)At⫹ 0,2(Eu⫹Iu⫹Du)Au⫹0,4(El⫹Il⫹Dl)Al. H, t, u, and l represent head, trunk, upper extremities and lower extremities, respectively. Erythema (E), infiltration (I) and desquamation (D) are measured on a scale of 0 to 4 according to the severity of the skin changes. The area (A) is recorded as 0 to 6 according to the percentage of the skin involved. Skin biopsies were obtained from 3 patients at baseline (before treatment) and at week 10. Biopsies were subject to routine histopathologic sectioning, staining, and analysis. Magnetic resonance imaging. Because both the Physician and Patient Global VAS are subjective measures of disease severity and because placebo effects occur during DMARD trials for PsA (20), MRI detection of gadoliniumDTPA was employed as an objective measure of inflammation. The amount of gadolinium-DTPA uptake by joints directly correlates with the severity of inflammatory arthritis (32). MRI of gadolinium-DTPA uptake by inflamed joints at baseline (week 0) and week 10 was performed on 8 patients who gave consent to the examination. The patient’s inflamed joints were imaged with a 1.5 Tesla magnet (Magneton/Siemens, Erlangen, Germany) as previously described (32). A dynamic flash 2D gradient echo was employed in addition to special superficial coils for optimal resolution. Time-dependent signal intensity changes were measured in 4 defined, enhancing regions of interest after a bolus injection of 0.1 mg/kg gadolinium-DTPA (Magnevist/Schering, Berlin, Germany) following 1 prior unenhanced series. The relative signal intensity (SI) increase (percentage per minute) was calculated at baseline and at week 10 by the following formula: [SImax ⫺ SIpre-contrast] ⫻ 100 SIpre-contrast ⫻ Tmax Safety. Vital signs including blood pressure, pulse, and temperature were measured every 30 minutes until 1 hour after the end of the infliximab infusion. Vital sign parameters and laboratory tests (including a blood count with differential, and biochemical tests including electrolytes, urea, creatinine, total protein, and liver enzymes [serum glutamic-pyruvic transaminase, serum glutamic-oxaloacetic transaminase, gamma-glutamyltransferase]) were performed during and after each infusion and again at followup (week 54). Patient-reported adverse events were monitored at each visit and noted by the study evaluator in addition to any adverse events occurring during infliximab infusion. Statistical analysis. All data are depicted graphically or in tabular format. Means and standard deviations were calculated for global and peripheral arthritis measures. Two-tailed Mann-Whitney Test (P ⬍ 0.05 considered significant) was applied to determine the significance of changes in gadolinium-DTPA uptake. RESULTS Patients. A total of 10 patients (6 male and 4 female) with a mean age of 34.8 years (range 23– 43 years) and a disease duration of 6.6 years (range 1–22 years) were enrolled in the study. All patients exhibited polyarticular disease with stable clinical and serologic activity despite DMARD therapy. All patients presented with elevated CRP and ESR values and experienced morning stiffness for ⬃30 to 120 minutes (with the exception of 1 patient who did not experience any morning stiffness). All patients completed infusions at weeks 0, 2, and 6, and were included in the data analysis. Patient treatment was individualized between weeks 10 and 54, based on patient response to infliximab and adverse events. After week 10, treatment with infliximab was continued or discontinued in 5 patients. Reasons for discontinuation were infusion reaction and detected pregnancy (1 patient), and clinical remission (4 patients). Remission was defined as absence of any active joint inflammation and/or serologic activity (Table 1). Infliximab Treatment of Psoriatic Arthritis 509 Table 2. Arthritis assessments* Response parameter Week 0 Week 2 Week 6 Week 10 Week 54 Physician Global VAS assessment, mm Patient Global VAS assessment, mm HAQ VAS Pain, mm CRP, mg/L ESR, mm Tender joint count (68) Swollen joint count (66) Morning stiffness, minutes 69.2 (19.0) 72.8 (21.0) 1.05 (0.53) 67.7 (19.6) 37.9 (24.4) 35.2 (16.4) 20.6 (15.7) 14.1 (9.8) 58.5 (45.0) 11.6 (11.4) 19.3 (18.4) 0.5 (0.6) 16.9 (16.2) 2.7 (2.5) 10.7 (8.1) 4.5 (5.9) 2.6 (2.8) 16.5 (37.7) 4.4 (6.9) 17.0 (15.9) 0.28 (0.38) 14.3 (11.6) 3.4 (3.7) 8.6 (6.1) 3.6 (6.6) 2.1 (4.9) 15.5 (37.9) 3.5 (6.9) 12.1 (13.5) 0.28 (0.39) 11.8 (10.1) 1.7 (2.1) 10.7 (12.4) 2.1 (4.3) 1.6 (3.7) 12.0 (14.6) 9.0 (16.5) 20.8 (16.0) 0.39 (0.53) 20.2 (21.4) 9.9 (12.4) 15.0 (14.3) 3.6 (7.5) 2.0 (4.7) 18.1 (24.3) * Values are mean (SD). VAS ⫽ visual analogue scale; HAQ ⫽ Health assessment questionnaire; CRP ⫽ C-reactive protein; ESR ⫽ erythrocyte sedimentation rate. Efficacy. Measures of arthritis severity. Two weeks following infliximab therapy, improvements were seen in the mean global and peripheral assessments of arthritis severity (Table 2) compared with baseline (week 0). Improvements were noted in Physician Global VAS, Patient Global VAS, HAQ, Patient VAS Assessment of Pain, ESR, and CRP. The number of tender and swollen joints decreased, as did the duration of morning stiffness. Maximum improvements for all global and peripheral assessments were seen at week 10 following infliximab treatment, with improvements maintained in all categories at week 54 compared with baseline. The ACR20, ACR50, and ACR70 responses are summarized in Table 3. By week 2 after infliximab treatment, 10 of 10 patients achieved an ACR20 response, with 8 patients achieving ACR50 and 6 patients achieving ACR70 responses. Additionally, all 10 patients demonstrated ACR50 responses by 6 weeks after the initiation of infliximab therapy. Finally, 8 patients attained ACR70 responses by week 10, with 6 of 10 patients maintaining an ACR70 response at the 54-week followup. Patient responses calculated according to the PsA response criteria established by Clegg et al (21) showed similar patient improvements at week 2 with all patients remaining stable at week 54 after the initiation of infliximab therapy (Table 3). At week 54, 8 of 10 patients still had no tender or swollen joints. Inflammation measures. Prior to infliximab treatment, the peripheral joints of 8 patients demonstrated marked inflammation as revealed by MRI detection of gadoliniumDTPA uptake (Figure 1A). The mean gadolinium-DTPA uptake at week 0 was 114%/min (SD ⫾ 73.0% per minute; Figure 2). By the week 10 MRI (Figure 1B) the inflammaTable 3. American College of Rheumatology (ACR) Criteria and Clegg Criteria responses of 10 patients to infliximab treatment Response, no. patients ACR20 ACR50 ACR70 Clegg response Week 2 Week 6 Week 10 Week 54 10 8 6 10 10 10 6 10 10 10 8 10 10 10 6 10 tion was substantially reduced as evidenced by decreased gadolinium-DTPA within the joints (mean, 16.4%/min ⫾ 10.4% per minute; Figure 2). Upon quantitation of the percent reduction in gadolinium-DTPA uptake, it was determined that all patients achieved a reduction in inflammation, with a mean reduction of 82.5% ⫾ 10.3% (P ⫽ 0.0071; Table 4). Psoriasis measures. As summarized in Table 5, PASI scores improved significantly at week 10 for all 6 evaluated patients, with a mean percent reduction from baseline of 71.3% ⫾ 16.7% (P ⫽ 0.0321). Prior to infliximab therapy, 6 PsA patients exhibited characteristic sharply circumscribed erythematous psoriasis plaques covered by silvery scales. By week 10 after infliximab treatment the plaque was almostly completely clear, a response that was typical for all of the 6 patients who had significant skin manifestation at baseline. Upon histopathologic analysis of psoriasis plaques from patient skin, demonstrated a reduction in epidermal hyperplasia and inflammation coinciding with the decrease in plaque size by week 10 of infliximab treatment, as evidenced by the near-normal epidermal structure. Safety. Infliximab treatment was well tolerated by all patients, with no significant adverse events, severe infections, or infusion reactions. Nine of 10 patients completed the 54-week study, with no patient discontinuations due to adverse events. One patient discontinued infliximab at month 8 because of a mild infusion reaction (facial flushing and myalgia in the extremities) and a detected pregnancy. The infusion reaction was successfully resolved by antihistamine treatment. At term, the patient gave birth to a healthy child. One patient stopped methotrexate therapy because of combined hyperlipidemia. Infliximab treatment was continued in this patient and the abnormal values improved. One patient paused infliximab treatment between months 5 and 12 because of an elective spine operation. There were no reports of dyspnea, urticaria, or headache. DISCUSSION There are few treatment alternatives for patients with progressive PsA who fail to respond to methotrexate. Of the 510 Antoni et al Figure 1. Magnetic resonance imaging of gadolinium-diethylenetriaminepentaacetic acid uptake. A, Representative patient foot before and B, 10 weeks after infliximab treatment. 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 TNF␣, 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 Table 4. Reduction of magnetic resonance imaging Gadolinium uptake at week 10 Figure 2. Gadolinium-diethylenetriaminepentaacetic acid (DTPA) uptake at baseline (week 0) and week 10 after infliximab treatment. Gadolinium-DTPA uptake based on magnetic resonance imaging, expressed as percentage per minute, was calculated as described in the Methods section. Patient Week 0* Week 10* % Reduction 2 3 4 5 6 7 8 9 110 230 130 43 32 50 200 120 10 29 8 10 11 8 20 35 91 87 94 78 65 84 90 71 * Values are % per minute. Infliximab Treatment of Psoriatic Arthritis 511 Table 5. Psoriasis Activity and Severity Index (PASI)* Patient Week 0 Week 10 Reduction at Week 10 (%) 1 2 3 4 5 6 8.8 6.6 24.9 2.1 7.2 31.7 4.9 1.0 5.4 0.2 2.4 11.2 44 85 78 91 67 65 * PASI score described in Methods section. 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 TNF␣ 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 TNF␣ 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 TNF␣. Therefore, inhibition of TNF␣ 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. ACKNOWLEDGMENT The authors would like to thank Bettina Raddatz, RN for her excellent assistance during this study. REFERENCES 1. Smiley JD. Psoriatic arthritis. Bull Rheum Dis 1995;44:1–2. 2. Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 1989;2:244 –7. 3. Haworth C, Brennan FM, Chantry D, Turner M, Maini RN, Feldmann M. Expression of granulocyte-macrophage colonystimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-alpha. Eur J Immunol 1991;21:2575–9. 4. Butler DM, Maini RN, Feldmann M, Brennan FM. Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures: comparison of monoclonal anti TNFalpha antibody with the interleukin-1 receptor antagonist. Eur Cytokine Netw 1995;6:225–30. 5. Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG. The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 1999;113:752–9. 512 6. Ritchlin C, Haas-Smith SA, Hicks D, Cappuccio J, Osterland CK, Looney RJ. Patterns of cytokine production in psoriatic synovium. J Rheumatol 1998;25:1544 –52. 7. Danning CL, Illei GG, Hitchon C, Greer MR, Boumpas DT, McInnes IB. Macrophage-derived cytokine and nuclear factor B p65 expression in synovial membrane and skin of patients with psoriatic arthritis. Arthritis Rheum 2000;43:1244 –56. 8. Ettehadi P, Greaves MW, Wallach D, Aderka D, Camp RD. Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions. Clin Exp Immunol 1994;96: 146 –51. 9. Uyemura K, Yamamura M, Fivenson DF, Modlin RL, Nickoloff BJ. The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol 1993;101:701–5. 10. Olaniran AK, Baker BS, Paige DG, Garioch JJ, Powles AV, Fry L. Cytokine expression in psoriatic skin lesions during PUVA therapy. Arch Dermatol Res 1996;288:421–5. 11. Shiohara T, Imanishi K, Sagawa Y, Nagashima M. Differential effects of cyclosporine and etretinate on serum cytokine levels in patients with psoriasis. J Am Acad Dermatol 1992;27: 568 –74. 12. Bonifati C, Carducci M, Cordiali Fei P, Trento E, Sacerdoti G, Fazio M, et al. Correlated increases of tumour necrosis factoralpha, interleukin-6 and granulocyte monocyte-colony stimulating factor levels in suction blister fluids and sera of psoriatic patients—relationships with disease severity. Clin Exp Dermatol 1994;19:383–7. 13. Mussi A, Bonifati C, Carducci M, D’Agosto G, Pimpinelli F, D’Urso D, et al. Serum TNF-alpha levels correlate with disease severity and are reduced by effective therapy in plaquetype psoriasis. J Biol Regul Homeost Agents 1997;11:115– 8. 14. Chodorowska G. Plasma concentrations of IFN-gamma and TNF-alpha in psoriatic patients before and after local treatment with dithranol ointment. J Eur Acad Dermatol Venereol 1998;10:147–51. 15. Partsch G, Wagner E, Leeb BF, Dunky A, Steiner G, Smolen JS. Upregulation of cytokine receptors sTNF-R55, sTNF-R75, and sIL-2R in psoriatic arthritis synovial fluid. J Rheumatol 1998; 25:105–10. 16. Hohler T, Kruger A, Schneider PM, Schopf RE, Knop J, Rittner C, et al. A TNF-␣ promoter polymorphism is associated with juvenile onset psoriasis and psoriatic arthritis. J Invest Dermatol 1997;109:562–5. 17. 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;27:376 – 81. 18. Clegg DO, Reda DJ, Weisman MH, Cush JJ, Vasey FB, Schumacher HR Jr, et al. Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter’s syndrome): a Department of Veterans Affairs Cooperative Study. Arthritis Rheum 1996;39:2021–7. 19. Olivieri I, Salvarani C, Cantini F, Macchioni L, Padula A, Niccoli L, et al. Therapy with cyclosporine in psoriatic arthritis. Semin Arthritis Rheum 1997;27:36 – 43. 20. Jones G, Crotty M, Brooks P. Interventions for psoriatic arthritis. Cochrane Database Syst Rev 2000:CD000212. 21. 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 Antoni et al 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. Department of Veterans Affairs Cooperative Study. Arthritis Rheum 1999;42:2325–9. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994;344:1105–10. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti–tumor necrosis factor ␣ monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552– 63. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al., ATTRACT Study Group. Infliximab (chimeric anti-tumour necrosis factor ␣ monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999; 354:1932–9. Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997;337: 141–7. Maini RN, Taylor PC, Paleolog E, Charles P, Ballara S, Brennan FM, et al. Anti-tumor necrosis factor specific antibody (infliximab) treatment provides insights into the pathophysiology of rheumatoid arthritis. Ann Rheum Dis 1999;58 Suppl 1:156 – 60. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al, American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727–35. Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, et al, Crohn’s Disease cA2 Study Group. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. N Engl J Med 1997;337:1029 –35. 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 ␣ (infliximab) in spondyloarthropathy: an open pilot study. Ann Rheum Dis 2000;59:428 –33. Clegg DO, Reda DJ, Mejias E, Cannon GW, Weisman MH, Taylor T, et al. Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis: a Department of Veterans Affairs Cooperative Study. Arthritis Rheum 1996;39:2013–20. Fredriksson T, Pettersson U. Severe psoriasis: oral therapy with a new retinoid. Dermatologica 1978;157:238 – 44. Kalden-Nemeth D, Grebmeier J, Antoni C, Manger B, Wolf F, Kalden JR. NMR monitoring of rheumatoid arthritis patients receiving anti-TNF-␣ monoclonal antibody therapy. Rheumatol Int 1997;16:249 –55. Gladman DD, Shuckett R, Russell ML, Thorne JC, Schachter RK. Psoriatic arthritis (PSA): an analysis of 220 patients. Q J Med 1987;62:127– 41. Beltran J, Caudill JL, Herman LA, Kantor SM, Hudson PN, Noto AM, et al. Rheumatoid arthritis: MR imaging manifestations. Radiology 1987;165:153–7. 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;356:385–90.