Rheumatol Int (2002) 22: 227–232 DOI 10.1007/s00296-002-0246-3
O R I GI N A L A R T IC L E
Edmund Cauza Æ Marita Spak Æ Karla Cauza Ursula Hanusch-Enserer Æ Attila Dunky Æ Ernst Wagner
Treatment of psoriatic arthritis and psoriasis vulgaris with the tumor necrosis factor inhibitor infliximab Received: 2 February 2002 / Accepted: 14 August 2002 / Published online: 4 September 2002 Ó Springer-Verlag 2002
Abstract Objective The aim was to evaluate the efficacy and safety of multiple infusions with achimeric, antitumor necrosis factor (TNF)a monoclonal antibody (infliximab) in patients with psoriatic arthritis (PsA) and psoriasis vulgaris. Methods Over 22 weeks, nine patients with both active psoriasis and PsA received five infusions of 3 mg/kg infliximab. The endpoints included changes in the swollen and tender joints counts, American College of Rheumatology (ACR) preliminary criteria for improvement response rates 20, 50, and 70, and improvement in the psoriasis area and severity index (PASI). Results The swollen count (SJC) and tender joint count (TJC) fell from means of 5.33±2.22 and 17.80±4.21 to 1.44±1.09 and 9.77±0.92, respectively, by week 2 (P=0.02, P=0.02). This benefit was sustained through week 22 (2.00±1.12/7.77±3.68, P=0.05/ P=0.002). The ACR 20/50/70 response was achieved in 89%/56%/22% of cases. The mean PASI score improved from 19.04±5.41 to 4.91±2.51 (P=0.002). Conclusion Multiple infusions of infliximab were effective and well tolerated in patients with active psoriasis and PsA. Keywords Infliximab Æ Psoriatic arthritis Æ Psoriasis vulgaris Æ Tumor necrosis factor
E. Cauza (&) Æ M. Spak Æ U. Hanusch-Enserer A. Dunky Æ E. Wagner Department of Internal Medicine V, Department of Rheumatology, Wilhelminenspital, Montleartstrasse 37, 1160 Vienna, Austria E-mail:
[email protected] Tel.: +43-1-491502508 Fax: +43-1-491502509 K. Cauza Department of Dermatology, University of Vienna, Vienna, Austria
Introduction A new era in the treatment of rheumatoid arthritis (RA) started with the development of anti-tumor necrosis factor a (TNFa) agents. This TNFa is a key cytokine in the activation of the inflammatory cascade within the rheumatoid synovium and is therefore a useful target for specific biological therapy in RA [1, 2, 3]. Dramatic and sustained responses following administration of TNFablocking agents have been reported in RA [4, 5]. Infliximab is a human-mouse chimeric monoclonal antibody that binds and inhibits the activity of TNFa [6]. It has proven efficacious in patients with RA who are unresponsive to conventional disease-modifying antirheumatic drug (DMARD) therapy [7]. Intravenous infliximab administration has been shown to reduce expression of interleukins, chemokines, and adhesion molecules in patients with RA [8] and produced sustained clinical response by ACR response criteria in 45– 80% of patients with treatment-resistant, active RA [4, 5, 9, 10]. Psoriatic arthritis (PsA) is one of the spondylarthropathy group of inflammatory joint diseases in which a somewhat different set of genetic factors, trauma, and infections may play a role. Recent studies demonstrate that the disease may be as severe as RA [11, 12]. Conventional antirheumatic DMARDs and nonsteroidal anti-inflammatory drugs (NSAIDs) serve as a first line of therapy for controlling inflammation [13], however, DMARD therapy alone or in combination with NSAIDs sometimes fails [14, 15] or is associated with toxicity and intolerance [16, 17, 18]. To date, only limited experience on the treatment of psoriasis and PsA with antiTNFa agents exists. Dechant [19] observed dramatic responses in clinical activity evaluation of patients with severe PsA after treatment with infliximab, and three out of ten were able to discontinue therapy due to remission of the disease. Furthermore, in a pilot study, van den Bosch treated patients suffering from different types of spondylarthropathies, including PsA, with infliximab
228
and observed a marked decrease in the activity of arthritis and skin involvement (assessed by the psoriasis area severity index, or PASI, score), as early as 2 weeks after treatment initiation [20]. Ogilvie [21] observed a rapid clearing of psoriatic skin lesions resistant to methotrexate after anti-TNFa treatment of patients with PsA. The first open trials of anti-TNFa agents in patients with spondylarthropathies including PsA give rise to justified hopes in the treatment of otherwise resistant forms [22, 23, 24, 25]. Etanercept, another anti-TNFa agent that has been successful in the treatment of resistant RA, was studied in a placebo-controlled trial in 60 patients with PsA for 6 months [26]. It proved efficacious in ameliorating arthritic signs and symptoms as well as skin lesions. The role of TNFa in psoriatic lesions and in the synovium of joints in patients with PsA has been described by several authors [27, 28, 29, 30]. In this study, the objective was to assess the effects of long-term administration of infliximab, a TNFa-blocking agent, in patients with active psoriasis and PsA.
Materials and methods Study design and patients Over a period of 22 weeks, nine consecutive patients (five men, four women, mean age 57.3 years, mean duration of PsA and psoriasis 17.2 years and 18.1 years, respectively) who had both active psoriasis and PsA were included in this study. Six patients (66%) had failed standard DMARD therapy including methotrexate, other cytotoxic drugs, retinoids, and psoralen-ultraviolet A irradiation (PUVA). All patients with PsA fulfilled the currently accepted criteria for psoriatic arthritis [12, 31]. Rheumatologists of our division diagnosed PsA, and one or more dermatologists additionally examined each individual. To minimize interobserver variation, the same persons assessed each patient’s disease activity throughout the study. The percent change from baseline to week 22 in SJC and TJC was the primary measure of efficacy for PsA. Another primary endpoint for the assessment of psoriatic arthritis was the proportion of patients meeting the American College of Rheumatology (ACR) preliminary criteria for improvement (score of 20) designed for assessment of RA [32] at week 22. This definition requires that the patient improve by at least 20% in both tender and swollen counts and also by at least 20% in three of five other core set parameters (patient global assessment, physician global assessment, self-reported physical disability, acute phase reactant, and patient pain assessment). The scores ACR 50 and ACR 70 were also assessed (defined in a similar manner as ACR 20, but the patient must have improved at least 50% or 70% in the individual measures). The coprimary endpoint was the change in psoriatic plaques of the skin as assessed by the PASI. Methods Treatment-resistant patients with active disease who fulfilled the diagnostic criteria received infusions of 3 mg/kg infliximab at weeks 0, 2, 6, 14, and 22. At baseline and weeks 2, 6, 14, and 22, the following variables were evaluated: patient assessment of pain using the 100-mm visual analog scale (VAS), duration of morning stiffness (MGST), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) count. All blood samples were collected in the morning. For ESR, the Westergren method was used (normal range 0–10 mm/h). C-reactive protein was determined by
nephelometry (normal level 0–12mg/l). Evaluation of the duration of MGST (in min) was made by the patients, and SJC (0–66) and TJC (0–68) were assessed by a rheumatologist. All patients had plaque-type psoriasis and had not been treated topically or systemically for at least 1 month before enrollment. The evaluation of psoriasis activity included the PASI [33]. Statistical analysis Paired Student’s t-tests were used to evaluate significant differences in all main parameters (PASI, MGST, SJC, TJC, ESR, VAS, and CRP) at baseline and after 2 and 22 weeks. P values below 0.05 were considered statistically significant. All continuous variables are expressed as means ± standard deviation (SD).
Results The demographic data of patients before treatment are summarized in Table 1. Eight of the nine patients enrolled completed the study. Only one patient withdrew (after receiving four infusions) due to a mild injection site reaction (erythema plus discomfort) potentially related to anti-TNFa therapy. No side effects were observed in any other patients and no major abnormalities in hematology values were noted during or after the study. Vital signs remained within normal ranges during and 2 h after infusions. Infliximab proved efficacious as judged by all the criteria used. In all patients, the response was rapid: 90% of the patients achieved a 50% or more decrease from baseline in SJC, TJC, and PASI score at the first evaluation point of 2 weeks and all eight patients at the 6-week evaluation point. Thereafter, following a small increase in TJC and PASI, total response rates were sustained up to the 22-week endpoint at levels of 50–70% improvement in SJC and TJC. All efficacy parameters are summarized in Table 2. One patient was maintained on infliximab for the duration of 1 year (given an infusion every 8 weeks from week 22). In this patient, all significant improvements in clinical and laboratory parameters were sustained throughout the entire treatment period. Efficacy of infliximab in psoriasis Evaluation of skin lesions as judged by objective criteria (PASI) demonstrates a significant response to infliximab therapy. The mean index of all patients was 19.04±5.41 (range 1.8–56.2) at baseline. After a single infusion with infliximab, the index decreased significantly to 7.41±2.51 (range 0.9–24.7) at week 2 (P=0.007). At study end (week 22), the mean PASI value had further
Table 1. Demographics of all patients receiving infliximab N patients Male/female Mean age (years) Duration of psoriasis (years) Duration of arthritis (years)
9 5/4 57 (range 46–76) 18.1 17.2
229 Table 2. Values (mean±SD) of the main parameters in the nine patients before treatment (T0), after 2 weeks (T2), after 6 weeks (T6), after 14 weeks (T14), and after 22 weeks (T22) and statistical significance (P values) as determined by paired Student’s t-test of the change from baseline (P
