Treatment of psoriatic arthritis and psoriasis vulgaris with the tumor necrosis factor inhibitor infliximab

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1 Rheumatol Int (2002) 22: DOI /s ORIGINAL ARTICLE 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 edmund.cauza@akh-wien.ac.at Tel.: Fax: 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 NSA- IDs 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 anti- TNFa 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

2 228 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 ) at baseline. After a single infusion with infliximab, the index decreased significantly to 7.41±2.51 (range ) 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 9 Male/female 5/4 Mean age (years) 57 (range 46 76) Duration of psoriasis (years) 18.1 Duration of arthritis (years) 17.2

3 229 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<0.05). PASI psoriasis area and severity index, MGST morning stiffness in min, SJC swollen joint count 0 66, TJC tender joint count 0 68, CRP C-reactive protein <10 mg/l, ESR erythrocyte sedimentation rate <10 mm/h, VAS visual analog scale pain assessment 0 10 cm T0 T2 T6 T14 T22 P value PASI 19.04± ± ± ± ± MGST 52.77± ± ± ± ± SJC. 5.33± ± ± ± ± TJC 17.8± ± ± ± ± CRP 16.04± ± ± ± ± ESR 34.44± ± ± ± ± VAS 5.88± ± ± ± ± decreased to 4.91±2.51 (range ) and remained significantly lower than baseline (P=0.002) (Fig. 1). Improvements in joints Mean joint activity at baseline for all patients was 18 tender joints and five swollen joints. The results show that infliximab therapy has a favorable effect on articular signs directly after the first infusion. The joint activity after 2 weeks of treatment reduced to ten tender joints (P=0.02) and one swollen joint (P=0.02) and was maintained up to week 22 for eight tender (P=0.002) and two swollen joints (P=0.05)). In addition, 6/9 patients (67%) at 2 weeks and 5/9 (56%) at 22 weeks had no swollen joints, while 2/9 (22%) at 2 weeks and 3/9 (33%) at 22 weeks had no tender joints (Fig. 2). after five infusions: mean CRP dropped to 3.53±1.00 (P=0.04) and mean ESR decreased to 11.55±3.86 (P=0.01) (Fig. 3). Response of visual analog scale and morning stiffness Consistent with the previous clinical parameters (SJC and TJC), significant improvements in MGST and VAS values were observed after 22 weeks of therapy: MGST changed from a mean of 52.77±17.0 at baseline to 24.44±11.06 at the end of the study (P=0.01), while VAS improved from a mean 5.88±0.63 at baseline to 3.33±0.66 at week 22 (P=0.01) (Fig. 4, Fig. 5). Effect of infliximab on ESR and CRP The patients presented with slightly increased CRP levels (16.04±5.43) and elevated ESR (34.44±6.34) at the beginning of the study. There was a significant correlation between drops in CRP and ESR levels over the duration of therapy with infliximab. Two weeks after the first infusion, the mean CRP value dropped to 7.8±4.09 (P=0.024), while mean ESR decreased to 14.66±3.96 (P=0.01). Similar results were achieved at the study end Fig. 2. Effects on the mean SJC (dotted line) and mean TJC before, during, and after 22 weeks of infliximab treatment Fig. 1. Effect of infliximab on skin lesions. Mean PASI Fig. 3. Measurement of mean CRP (dotted line) and ESR before, during, and after 22 weeks of treatment with infliximab

4 230 Fig. 4. Effect of infliximab on mean MGST (in min) before and after treatment Fig. 5. Values for the patients assessments of pain on the mean VAS before, during, and after treatment Improvements in ACR 20, 50, and 70 from baseline to week 22 The results at 22 weeks demonstrated big improvements in the ACR response rate, and in eight patients (89%), ACR 20 was achieved. The percentage of patients at the ACR 50 levels who improved was 56% (five patients), and this dropped to 22% (two patients) using the ACR 70 definition. Discussion The hypothesis that TNFa inhibition could result in efficacious treatment of PsA was generated after several studies reporting increased expression of monocyte-derived cytokines (including TNFa) in synovial fluid (SF) and synovial tissue (ST) of patients with PsA. Histologic studies [34] on multiple biopsy samples obtained from patients with PsA found infiltration of T cells and macrophages and increased vascularity in ST. The same authors demonstrated the presence of the cytokines TNF-a, IL-1b, IL-1a, IL-10, and IL-15 in ST. In addition, the expression of the p65 subunit of the transcription factor nuclear factor jb was localized and immunohistochemically quantified in ST. In 1998, Ritchlin [29] observed the release of elevated levels of the cytokines IL-1b, IL-2, IL-10, IFN-c, and TNF-a in supernatants from synovial and dermal explant cultures, while Nishibu [35] later described an increased production of proinflammatory cytokines, namely IL-1b, IL-6, and IL-8, by freshly isolated peripheral blood mononuclear cells. Similarly, Elkayam [36] found higher serum levels of the cytokines IL-10, IL-6, IL-1ra, and sil-2r than in healthy volunteers. Interestingly, sil-2r correlated with PASI score but not with clinical parameters of joint severity, while IL-1ra correlated with the numbers of tender and swollen joints. Furthermore, Partsch [27] found increased levels of TNF-a, IL-1, IL-6, and IL-8 in SF of patients with PsA. Lastly, inflammatory markers, namely the soluble TNF receptors p55 and p75 as well as sil-2r, are increased in SF of patients with PsA [37]. All these findings support the assumption that, similar to RA, macrophage-derived cytokines drive joint inflammation and cutaneous lesions of PsA. Like RA, PsA is suspected to be an immunologically mediated disease, in that several immunogenetic studies link PsA to certain HLA class I and class II types. Familial clustering confirms the genetic background of PsA [38]. Although the question of whether PsA is an antigendriven disease remains to be answered, substantial insight into the pathophysiologic process of the disease was achieved recently. T lymphocytes and increased vascularity are predominant in synovial tissue of individuals affected by PsA, and T lymphocytes have been identified to be important for T cell extravasation in the skin [39]. Summarizing the immunological findings, it has been confirmed that several proinflammatory cytokines are locally and systemically upregulated in psoriasis and PsA and that TNFa plays a major role. This resembles exactly the situation in RA. These findings gave rise to the application of a novel, therapeutic modality, namely anti-tnfa agents, in the treatment of PsA. Few publications have highlighted the effects of anti- TNFa treatment in PsA. Mease [26] reported dramatic effects on joint symptoms and PASI score in a double blind study of etanercept in PsA. Dechant [19] found remission-inducing properties of infliximab in patients with PsA, and Bosch [20] treated patients with various spondylarthropathies including PsA with a loading dose of infliximab and arrived at similar results, reductions in the number of active joints and PASI scores. Clearing of psoriatic lesions by infliximab was observed by Ogilvie [21] and Oh [40]. Therefore infliximab was employed, a chimeric monoclonal antibody to TNFa proven to be efficacious in active and fistulizing Crohn s disease [41] and RA [1]. Therapy with infliximab produced significant improvements in all measures of articular disease activity. The swollen joint count decreased in five out of six patients with swollen joints at the start of the observation period. This improvement was apparent by the end of

5 231 week 2 and most pronounced at the end of treatment (at 22 weeks). Infliximab not only proved effective in treatment of the signs and symptoms of PsA but also in diminishing psoriatic skin lesions. All treated patients experienced significant decreases in PASI scores. The therapeutic method used in our study was identical to the treatment dosage and time schedule approved for RA. Duration of treatment was originally scheduled for 22 weeks, with extension beyond this time in case of good response. Five patients have now been treated for 1 year and included in the results. Overall, five patients remaining on infliximab were successfully treated over 1 year, with no cutaneous flare reported. Here we report the interim data of a treatment period of 22 weeks. Our objective is to assess the effect of long-term treatment with infliximab. At present we do not consider discontinuation of treatment or a change in treatment regimen (dosage and administration intervals), even for patients with very good response, also taking into consideration that one patient on maintenance treatment for 1 year has sustained remission. Our observations concerning articular disease activity and cutaneous involvement confirm those reported by van den Bosch [20] and Dechant [19], who reported 3/9 patients to be in remission after 5, 7, and 8 months of treatment, respectively, leading to discontinuation of treatment with infliximab. The clinical response of the arthritic component to infliximab occurred within 2 weeks from treatment start, reaching a maximum level of improvement at week 6 and remaining stable through week 22. This trial showed that infliximab provides a clinically high benefit to patients with PsA. Of infliximab patients, nearly 90% achieved ACR 20, more than 50% ACR 50, and 22% ACR 70 response rates after week 22. These findings were superior to the beneficial effects found by Mease et al. using etanercept in the treatment of PsA [26]. Our results in joint counts are similar to those observed in RA, suggesting similar pathogenetic mechanisms. Both cutaneous and articular remissions imply a substantial involvement of TNFa in the pathogenesis of skin lesions and articular inflammation in psoriasis. The response to infliximab was not dependent on concomitant treatment with a DMARD. Patients who had stopped DMARD treatment due to intolerable side effects or inefficacy more than 3 months before starting infliximab responded to monotherapy with infliximab. Cutaneous lesions healed in eight patients, whereby remission occurred rapidly and led to a nearly complete normalization of the skin in all but one case. An interesting finding was the cutaneous flare of one patient after 22 weeks of continuous treatment and following a viral infection that occurred in the early autumn, perhaps seasonally triggered. The recurrence was presented by an exanthematous-type psoriasis. This incidence points toward the necessity of carefully controlled, regular clinical investigations in psoriasis patients treated with infliximab. Since TNFa is found in SF of PsA as well as in cutaneous lesions of psoriasis patients, the hypothesis that an anti-tnfa agent would ameliorate the signs and symptoms of both psoriasis and PsA has been proposed. The results of our observational trial verified this concept and indicated that infliximab may be the treatment of choice in moderate-to-severe, treatment-resistant PsA. However, larger, controlled studies are needed for establishing the treatment of PsA with infliximab. 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