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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Objective

To investigate the efficacy and tolerability of infliximab therapy for the articular and dermatologic manifestations of active psoriatic arthritis (PsA).

Methods

One hundred four patients with PsA in whom prior therapy with at least 1 disease-modifying antirheumatic drug (DMARD) had failed were recruited into this investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical trial. During the initial blinded portion of the study, patients received infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, and 14. After week 16, patients initially assigned to receive placebo crossed over to receive infliximab 5 mg/kg every 8 weeks through week 50, while patients initially randomized to infliximab continued to receive active treatment at the same dose through week 50. The primary efficacy outcome was achievement of the American College of Rheumatology 20% criteria for improvement in rheumatoid arthritis (ACR20) at week 16. Additional predefined clinical efficacy assessments included the Psoriasis Area and Severity Index (PASI) score, the ACR50 and ACR70 criteria, the Disease Activity Score in 28 joints, the Health Assessment Questionnaire, ratings of enthesitis and dactylitis, and the Psoriatic Arthritis Response Criteria score.

Results

The proportion of infliximab-treated patients who achieved an ACR20 response at week 16 (65%) was significantly higher than the proportion of placebo-treated patients who achieved this response (10%). In addition, 46% of infliximab-treated patients achieved an ACR50 response, and 29% achieved an ACR70 response; no placebo-treated patient achieved these end points. Among patients who had PASI scores of ≥2.5 at baseline, 68% of infliximab-treated patients achieved improvement of ≥75% in the PASI score at week 16 compared with none of the placebo-treated patients. Continued therapy with infliximab resulted in sustained improvement in articular and dermatologic manifestations of PsA through week 50. The incidence of adverse events was similar between the treatment groups.

Conclusion

Therapy with infliximab at a dose of 5 mg/kg significantly improved the signs and symptoms of arthritis, psoriasis, dactylitis, and enthesitis in patients with active PsA that had been resistant to DMARD therapy. With continued infliximab treatment, benefits were sustained through 50 weeks. The benefit-to-risk ratio appeared favorable in this study population.

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy that occurs in association with psoriasis. Among articular disorders, PsA was once considered to have a relatively benign course; however, a growing body of data suggest that PsA is often progressive and refractory to therapy. Moreover, patients with PsA may experience substantial morbidity and unfavorable outcomes (1, 2). Although the disease course can be variable, factors such as polyarticular inflammation have been associated with the development of deformities, radiographic joint damage, and impaired functional status (3, 4). Despite the recent data on leflunomide (5), responses to traditional disease-modifying antirheumatic drugs (DMARDs) have been suboptimal, leaving an unmet therapeutic need (4, 6–10).

Recent advances in the understanding of the immunopathogenesis of psoriasis and PsA, combined with developments in biotechnology, have led to the introduction of novel therapeutic options (11). Several studies have suggested that proinflammatory cytokines, in particular tumor necrosis factor α (TNFα), serve a key role in potentiating inflammatory responses associated with both psoriasis and PsA (12–17). Increased levels of TNFα have been observed in skin, synovial fluid, and synovial tissue from affected patients (14–16), and allelic polymorphisms in the promoter region for TNFα have been shown to correlate with certain aspects of the disease (13). More recently, evidence from trials of biologic agents targeting TNF have highlighted the key role of TNF in these conditions. Etanercept, a dimeric p75–TNF receptor/Ig Fc fusion construct, has been shown to be effective in PsA (18, 19) and psoriasis (20). Infliximab, a chimeric monoclonal antibody specific for TNFα, has also been shown to be effective in psoriasis (21). In an open-label study of infliximab in PsA, clinical benefits were accompanied by objective improvements in inflammatory synovitis as measured using magnetic resonance imaging (22). On the basis of these results, we conducted a controlled trial to evaluate the efficacy and safety of infliximab, using multiple assessments of skin and joint disease activity in patients with active PsA in whom treatment with at least 1 DMARD had failed.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patients.

The study group comprised 104 patients (ages 18 years and older) with an established diagnosis of PsA of 6 months duration or longer. Eligibility criteria included previous failure of treatment with ≥1 DMARDs. At enrollment, patients were required to have active peripheral polyarticular arthritis, defined as the presence of ≥5 swollen and tender joints (based on joint counts of 66 and 68, respectively) in conjunction with at least 1 of the following criteria: erythrocyte sedimentation rate (ESR) ≥28 mm/hour, C-reactive protein (CRP) level ≥15 mg/liter, and/or morning stiffness lasting 45 minutes or longer. Patients also were required to have negative results of serum tests for rheumatoid factor and negative results for active or latent tuberculosis by purified protein derivative skin test and chest radiography.

This study was conducted at 9 centers in Europe, the US, and Canada, and the protocol was approved by the institutional review boards at each of the participating sites. All patients provided written informed consent prior to participating in any study-related activities.

Study design.

The study was conducted in 2 phases. In phase 1, patients were randomly assigned to receive placebo (n = 52) or infliximab 5 mg/kg (n = 52) at weeks 0, 2, 6, and 14. At the start of phase 2, in order to preserve the blinding and allow for a treatment introduction course for the placebo group, patients in the infliximab group received placebo infusions at weeks 16 and 18, followed by infliximab 5 mg/kg at weeks 22, 30, 38, and 46; patients in the placebo group received infliximab 5 mg/kg at weeks 16, 18, 22, 30, 38, and 46. Patients, investigators, and study personnel other than the pharmacist were unaware of the initial assignments throughout the 50-week study period.

Study agent.

Infliximab (Remicade; Centocor, Malvern, PA) was supplied in 20-ml vials containing 100 mg of the lyophilized concentrate; placebo was identically formulated but did not contain infliximab. Infusions were administered over 2 hours by blinded personnel using an infusion set with an in-line, sterile, nonpyrogenic, low protein-binding filter (pore size 1.2 μm) through a peripheral venous access site.

Concomitant medications.

Patients were allowed to receive concomitant therapy with 1 of the following DMARDs: methotrexate (MTX; dosage of 15 mg/week or more, with folic acid supplementation), leflunomide, sulfasalazine, hydroxychloroquine, intramuscular gold, penicillamine, or azathioprine. For patients who were receiving a DMARD at the time of enrollment, the dosage was required to have been stable for at least 4 weeks prior to randomization and to remain stable throughout the study. Concomitant therapy with oral corticosteroids (dosage of 10 mg prednisone equivalent/day or less) and nonsteroidal antiinflammatory drugs (NSAIDs) was permitted, provided that dosages had been stable for at least 2 weeks prior to screening. Dosages of corticosteroids and NSAIDs were required to remain stable throughout the study. Use of intramuscular or intravenous corticosteroids, cyclosporine, or tacrolimus was prohibited within 4 weeks of screening and throughout the study. One injection of intraarticular corticosteroids was permitted in phase 2 of the study, and the injected joint would be excluded from subsequent efficacy assessment. Standard topical treatments for psoriatic lesions (e.g., topical steroids) were permitted, provided they remained stable throughout the study. Therapy with psoralen ultraviolet A was not permitted. Eligible patients could not have received any investigational drug within 3 months of screening or any previous treatment with a monoclonal antibody or fusion protein.

Study procedures and evaluations.

The primary efficacy assessment was the achievement at week 16 of the American College of Rheumatology 20% criteria for improvement (ACR20) in rheumatoid arthritis (RA) (23). Assessment of skin involvement was made using the Psoriasis Area and Severity Index (PASI) at the time of screening and at weeks 16 and 50 (24). For the PASI, lesional erythema, scaling, and thickness were rated for 4 anatomic regions (head, trunk, upper extremities, and lower extremities). The area of each anatomic region was factored into the overall score. The maximum possible PASI score is 72. Patients with a baseline PASI score of ≥2.5 were included in the efficacy evaluation of the skin.

Additional response evaluations made at weeks 2, 6, 10, 14, 16, 18, 22, 30, 38, 46, and 50 included graded assessments of pain and swelling in 68 and 66 joints, respectively (0–3 scale); the number of digits with dactylitis (maximum 20 digits; 0–3 scale); the Psoriatic Arthritis Response Criteria (PsARC) (25); the Disease Activity Score in 28 joints (DAS28) (26, 27); the presence of enthesitis (at bilateral Achilles tendons and calcaneal insertions); patient's and physician's assessments of pain and overall disease activity (0–10-cm visual analog scale); responses to the 20-question Health Assessment Questionnaires (HAQ) (28); measurement of serum CRP levels; and determination of the ESR. Joints that had undergone surgical replacement or fusion operations were excluded from evaluation. Joints that had undergone synovectomy within 12 months prior to screening or radiosynovectomy within the months prior to screening were also excluded from evaluation.

Statistical analysis.

The sample size calculation for this trial was based on the assumption that 50% of infliximab-treated patients and 20% of placebo-treated patients would achieve an ACR20 response. A sample size of 45 patients per group provided power of 0.8 and a 2-sided alpha value of 0.05.

The predefined primary efficacy end point was the proportion of patients achieving an ACR20 response at week 16 in the intent-to-treat analysis. The secondary end points were compared between treatment groups.

Chi-square testing with Yates' correction for contingency tables was used to compare the primary efficacy end point between the 2 treatment groups. To assess the onset of clinical effect, the ACR20 response rates were assessed at weeks 2, 6, 10, and 14. The Mantel-Haenszel test was conducted to estimate the common odds ratio of the 2 treatment groups. In secondary efficacy analyses, the chi-square test was used for end points with discrete data, and a one-way analysis of variance with treatment group as a factor was used for end points with continuous data.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Baseline characteristics, patient disposition, and concomitant therapy.

Of the 104 enrolled patients, 99 (95%) completed the study through week 16 (Figure 1). A summary of baseline characteristics of the patients is provided in Table 1. The baseline characteristics for the 2 treatment groups were generally similar, with a few exceptions. The mean CRP value was 31.1 mg/liter in the placebo group and 21.7 mg/liter in the infliximab group, with medians of 14.0 mg/liter and 9.9 mg/liter, respectively (P = 0.15). Patients in both treatment groups had active and severe psoriatic arthritis.

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Figure 1. Study design and patient disposition. Broken line indicates period during which patients were receiving placebo. Solid boldface line indicates period during which patients were receiving infliximab 5 mg/kg. Patients initially assigned to the infliximab group received infusions of placebo at weeks 16 and 18 in order to maintain blinding.

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Table 1. Baseline characteristics of the study population*
CharacteristicPlacebo (n = 52)Infliximab, 5 mg/kg (n = 52)
  • *

    Except where indicated otherwise, values are the mean ± SD. PsA = psoriatic arthritis; ACR20 = American College of Rheumatology 20% criteria for improvement; VAS = visual analog scale; PASI = Psoriasis Area and Severity Index.

  • Forty patients in the placebo group and 42 patients in the infliximab group were evaluated.

Women, no. (%)22 (42.3)22 (42.3)
Age, years45.2 ± 9.745.7 ± 11.1
Disease duration, years  
 Patients with PsA11.0 ± 6.611.7 ± 9.8
 Patients with psoriasis19.4 ± 11.616.9 ± 10.9
ACR20 components  
 No. of swollen joints (0–66 count)14.7 ± 8.214.6 ± 7.5
 No. of tender joints (0–68 count)20.4 ± 12.123.7 ± 13.7
 C-reactive protein, mg/liter31.1 ± 38.121.7 ± 27.0
Global assessment of disease activity (0–10-cm VAS)  
 Patient's56.0 ± 22.752.4 ± 23.5
 Physician's52.4 ± 18.753.6 ± 18.5
Patient's assessment of pain (0–10-cm VAS)56.0 ± 20.853.4 ± 21.3
Health Assessment Questionnaire (0–3 scale)1.2 ± 0.71.2 ± 0.7
Digits with dactylitis, no. (%)  
 026 (50.0)27 (51.9)
 1–213 (25.0)11 (21.2)
 ≥313 (25.0)14 (26.9)
Dactylitis score (0–60 scale)2.0 ± 2.82.3 ± 3.5
Enthesopathy, no. (%)13 (25.0)13 (25.0)
Disease Activity Score5.4 ± 1.05.5 ± 1.1
Psoriasis evaluation  
 PASI score (0–72 scale)4.2 ± 5.85.1 ± 5.9
 Patients with PASI score ≥2.5, no. (%)17 (32.7)22 (42.3)

Five patients discontinued study treatment during phase 1 (Figure 1). In the placebo group, 1 patient was withdrawn before the first infusion due to suspected atypical mycobacterial infection, and 1 patient withdrew after the third infusion, at her request. In the infliximab group, 1 patient discontinued at week 16 due to a suspected joint infection after a steroid injection into the wrist, 1 patient was lost to followup after 2 infusions, and 1 patient withdrew at week 14 after experiencing a lower respiratory tract infection and worsening of asthma. During phase 2 of the study, when all patients were receiving infliximab, 12 additional patients discontinued treatment for the following reasons: adverse events (n = 4), patient request (n = 3), treatment failure/lack of benefit (n = 3), and noncompliance and lost to followup (n = 1 each). Data for all 104 patients were included in the statistical analysis.

Efficacy.

Articular manifestations.

The proportion of infliximab-treated patients who achieved the primary end point of an ACR20 response at week 16 (34 of 52 [65%]) was significantly higher than the proportion of placebo-treated patients (5 of 52 [10%]) who achieved this end point (P < 0.001). In addition, at week 16, 24 of 52 infliximab-treated patients (46%) achieved an ACR50 response, and 15 of 52 infliximab-treated patients (29%) achieved an ACR70 response; no placebo-treated patient achieved these end points (P < 0.001) (Table 2). As shown in Figure 2, the response to infliximab therapy was evident as early as week 2, and improvement continued through the week 50 evaluation in patients initially randomized to infliximab. Following initiation of infliximab therapy, patients initially randomized to placebo who received infliximab therapy at weeks 16, 18, 22, 30, 38, and 46 exhibited a pattern of clinical response similar to that of patients initially randomized to infliximab (Table 2 and Figure 2).

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Figure 2. Percentages of patients achieving improvement by the American College of Rheumatology 20% criteria for improvement in rheumatoid arthritis (ACR20) through week 50. Arrows indicate weeks at which infusions were administered: open arrows denote placebo (Pbo) infusions, and solid arrows denote infusions of infliximab (Ifn) 5 mg/kg.

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Table 2. Summary of clinical efficacy parameters at weeks 16 and 50*
Efficacy parameterWeek 16Week 50
PlaceboInfliximabPlacebo/infliximabInfliximab/infliximab
  • *

    For the American College of Rheumatology (ACR) parameters, values are the proportion (%) of patients meeting the criteria for 20%, 50%, and 70% improvement. Except where indicated otherwise, all other values are the mean ± SD percent improvement (a negative value indicates worsening). CRP = C-reactive protein; HAQ = Health Assessment Questionnaire; DAS28 = Disease Activity Score in 28 joints.

  • P < 0.001 versus placebo, for all comparisons.

  • Week 16 results show number of patients with enthesitis at any time from baseline to week 16. Week 50 results show number of patients with enthesopathies at week 50.

ACR205/52 (9.6)34/52 (65.4)34/50 (68.0)34/49 (69.4)
ACR500/52 (0.0)24/52 (46.2)21/50 (42.0)26/49 (53.1)
ACR700/52 (0.0)15/52 (28.8)17/50 (34.0)19/49 (38.8)
Tender joint count−23.6 ± 9.855.2 ± 9.762.3 ± 5.966.9 ± 5.9
Swollen joint count−1.8 ± 9.259.9 ± 9.176.8 ± 5.172.5 ± 5.1
Patient's pain assessment−8.7 ± 7.853.7 ± 7.754.1 ± 6.154.1 ± 6.1
Global disease assessment    
 Patient's−13.9 ± 7.547.5 ± 7.449.5 ± 7.350.0 ± 7.3
 Physician's−4.7 ± 6.058.4 ± 6.067.4 ± 4.370.3 ± 4.4
CRP, mg/dl3.6 ± 9.557.1 ± 9.548.2 ± 17.225.7 ± 17.2
HAQ score−1.6 ± 8.349.8 ± 8.249.2 ± 8.842.5 ± 8.8
DAS28 score, mean ± SD2.8 ± 3.245.5 ± 3.247.8 ± 3.648.2 ± 3.6
Enthesitis, no. (%)16 (31.4)7 (13.5)3 (6.1)4 (8.2)
Dactylitis score (0–60 scale)29.2 ± 10.184.5 ± 10.181.5 ± 6.491.0 ± 6.4

Among infliximab-treated patients, significant improvement from baseline to week 16 was also observed in the individual components of the ACR20 (Table 2). In particular, the mean HAQ score improved significantly from 1.2 at baseline to 0.6 at week 16 in infliximab-treated patients, while the mean HAQ scores in placebo-treated patients showed no improvement (1.2 at baseline and week 16) (P < 0.001). By week 50, mean HAQ scores were 0.7 and 0.5 in patients initially randomized to placebo and infliximab, respectively. Despite slightly higher CRP values among placebo patients at baseline, the median CRP values were similarly improved at week 50 in both groups (9.9 mg/liter and 7.5 mg/liter for the infliximab/infliximab and placebo/infliximab groups, respectively).

At the 16-week evaluation, 39 of 52 infliximab-treated patients (75%) were improved according to the PsARC, compared with 11 of 52 placebo-treated patients (21%) (P < 0.001). By week 50, the treatment groups showed similar PsARC response rates (76% and 74% of patients in the placebo/infliximab and infliximab/infliximab groups, respectively). Infliximab-treated patients also showed a significantly greater mean percent improvement from baseline to week 16 in the dactylitis score (85%) when compared with placebo-treated patients (29%) (P < 0.001). Of note, 72% of infliximab-treated patients had a dactylitis score of 0 at week 16, compared with 31% of placebo-treated patients. At baseline, 25% of patients in each group had enthesitis; at week 16, the proportion of infliximab-treated patients with enthesitis (14%) was significantly lower than the proportion of placebo-treated patients (31%; P = 0.021).

The mean baseline DAS28 scores (5.4 and 5.5 for the placebo and infliximab groups, respectively) indicate that the study population comprised patients with a high level of articular disease activity. At week 16, patients in the infliximab group showed a mean improvement in the DAS28 score of 46%, compared with an improvement of 2.8% among patients in the placebo group (P < 0.001). Furthermore, at week 16, 89% of patients in the infliximab group were DAS responders (i.e., had a good or moderate response according to the DAS28 criteria) compared with 25% of patients in the placebo group (P < 0.001). The treatment groups showed similar levels of improvement at week 50 (Table 2), with 82% of patients in the infliximab/infliximab group and 84% of patients in the placebo/infliximab group achieving a DAS28 response. Moreover, the mean DAS28 value in both groups after initiation of infliximab therapy was below the threshold defining low disease activity (Figure 3).

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Figure 3. Values (mean ± SD) for the Disease Activity Score in 28 joints (DAS28) during the 50-week treatment period. Broken lines indicate the thresholds defining low disease activity (<3.2) and high disease activity (>5.1).

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Dermatologic response.

Baseline PASI scores were similar between the 2 treatment groups (Table 1). Thirty-nine patients (22 in the infliximab group and 17 in the placebo group) had PASI scores of ≥2.5 at baseline and were therefore eligible for evaluation of changes in skin scores during treatment. At week 16, patients in the infliximab group had a mean improvement from baseline in their PASI score of 86%; this compared with a 12% worsening in the PASI score for patients in the placebo group (P < 0.001). Among patients with baseline PASI scores of ≥2.5, 68% of infliximab-treated patients achieved improvement of ≥75% in the PASI score at week 16 compared with none of the placebo-treated patients (P < 0.001).

For patients initially assigned to infliximab treatment, the response to infliximab therapy was sustained through the week 50 evaluation. Patients initially randomized to placebo, who received infliximab therapy after week 16, exhibited a similar pattern of PASI response following initiation of infliximab therapy (Figure 4). At week 50 PASI scores were 2.4 and 1.7, respectively, in the placebo/infliximab and infliximab/infliximab groups. Looking at dermatologic responses in another way, 100% (22 of 22), 68% (15 of 22), and 36% (8 of 22) of infliximab-treated patients experienced at least 50%, 75%, and 90% improvement in the PASI score from baseline to week 16. None of the placebo-treated patients achieved any of these end points at week 16. At week 50, 50%, 75%, and 90% improvement in the PASI score was sustained in 86% (19 of 22 patients), 59% (13 of 22 patients), and 41% (9 of 22 patients) of patients in the infliximab/infliximab group, respectively. By week 50, 69% (11 of 16), 50% (8 of 16), and 38% (6 of 16) of patients in the placebo/infliximab group achieved these end points.

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Figure 4. Psoriasis Area and Severity Index (PASI) scores (mean and SD) at baseline, week 16, and week 50 in patients who had a PASI score of ≥2.5 at baseline.

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Effect of concomitant DMARD use.

Overall, 74 of 104 patients (71%) were receiving a concomitant DMARD at baseline, including 41 of 52 patients in the placebo group (79%) and 33 of 52 patients in the infliximab group (63%) (P = 0.08). The most commonly used DMARD was MTX; 34 patients in the placebo group were receiving a mean MTX dosage of 16.2 mg/week, and 24 patients in the infliximab group were receiving a mean MTX dosage of 15.9 mg/week. The concomitant use of DMARDs appeared to have little effect on ACR20 response rates at week 16. Thus, 62.5% of infliximab patients also receiving MTX achieved an ACR20 response at week 16, as did 68% of infliximab patients not receiving MTX and 74% of those not receiving any DMARDs (P not significant).

Adverse events.

A summary of adverse events by treatment group is provided in Table 3. The treatment groups were similar with regard to the incidence of all adverse events, treatment-related adverse events, infusion-associated adverse events, severe adverse events, and serious adverse events during both phase 1 (double-blind phase; weeks 0–16) and phase 2 (crossover phase; weeks 16–50) of the study.

Table 3. Summary of adverse events*
Adverse eventWeeks 0–16Weeks 16–50
Placebo (n = 51)Infliximab, 5 mg/kg (n = 52)Placebo/infliximab (n = 50)Infliximab/infliximab (n = 49)
  • *

    Values are the number (%).

  • One patient was randomly assigned to the placebo group but did not receive any infusions. This patient was included in the efficacy analysis but was excluded from the safety analysis.

All events33 (65)38 (73)44 (88)41 (84)
Treatment-related events24 (47)29 (56)34 (68)34 (69)
Infusion-associated adverse events    
 All events5 (10)4 (8)7 (14)4 (8)
 Treatment-related events4 (8)2 (4)6 (12)4 (8)
Severe adverse events    
 All events2 (4)3 (6)6 (12)6 (12)
 Treatment-related events1 (2)2 (4)3 (6)3 (6)
Serious adverse events    
 All events1 (2)1 (2)6 (12)8 (16)
 Treatment-related events0 (0)1 (2)2 (4)3 (6)

The most frequently reported treatment-related adverse events (i.e., those reported by ≥4 patients overall) during phase 1 of the study were as follows: headache (3 patients assigned to placebo and 4 patients assigned to infliximab), bronchitis (4 placebo patients and 3 infliximab patients), upper respiratory tract infection (5 placebo patients and 1 infliximab patient), influenza-like symptoms (4 placebo patients and 1 infliximab patient), rhinitis (2 placebo patients and 3 infliximab patients), and rash (2 placebo patients and 3 infliximab patients). During phase 2 of the study, the most frequently occurring treatment-related adverse events were upper respiratory tract infection (23 patients), headache (7 patients), dizziness (6 patients), influenza-like symptoms (5 patients), nonproductive cough (5 patients), rhinitis (4 patients), hypertension (4 patients), and sinusitis (4 patients). Most treatment-related adverse events were mild to moderate in intensity. Severe treatment-related events were reported by 3 patients through week 16 (1 in the placebo group and 2 in the infliximab group) and by 6 patients between week 16 and week 50.

Two patients reported serious adverse events during phase 1. One patient in the placebo group had rectal bleeding due to diverticulitis, and 1 patient in the infliximab group had synovitis suspected to be infectious that was culture negative. Serious adverse events reported during phase 2 included unrelated events of inguinal hernia, surgical procedure (4 patients), angina pectoris, atrial fibrillation, urinary retention, chest pain, and cerebrovascular event, as well as the following events with a possible or probable relationship to the study drug: fever, acute Salmonella gastroenteritis, pyelonephritis, and leg weakness. The incidence of infusion reactions between groups was comparable in both phases of the study (Table 3). One patient who received placebo in phase 1 followed by infliximab in phase 2 had dyspnea and urticaria at week 38, resulting in the only infusion-related study discontinuation.

No patients experienced an opportunistic infection, including tuberculosis, during the study. There were no reports of autoimmune, cytopenic, or neurologic events.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Although at one time PsA was considered to be a relatively benign condition, it is now known that PsA can be associated with substantial morbidity, comparable with that of RA, especially in patients with active polyarticular and oligoarticular PsA involving the large joints (3). Patients with PsA may also experience accelerated mortality and a significantly impaired quality of life (2). However, in contrast to studies of RA, the use of traditional DMARDs has not uniformly been shown to be associated with notable efficacy in randomized controlled trials of PsA, particularly with regard to treating cutaneous symptoms (25, 29–31). Thus, patients with PsA, particularly those with severe disease, have an unmet therapeutic need.

Patients in the Infliximab Multinational Psoriatic Arthritis Controlled Trial, all but 1 of whom were negative for serum rheumatoid factor at baseline, had severe refractory disease, as shown by their polyarticular involvement, high global disease severity ratings, elevated HAQ scores, high DAS28 scores, and their lack of response to DMARD therapy. In addition, the majority of patients had skin involvement, approximately half had dactylitis, and a quarter had enthesitis.

Assessments of improvement in the arthritis symptoms of PsA in recent randomized controlled trials of DMARDs and biologic agents have focused primarily on the ACR and PsARC criteria. Patients in this trial responded very well to infliximab treatment according to these assessments. The primary end point of the trial was clearly met, with 65% of patients in the infliximab group achieving an ACR20 response at week 16, compared with 10% of patients in the placebo group; the response for infliximab-treated patients was maintained through week 50. The rapidity of response was noteworthy, with many patients improving at the initial assessment (week 2). Furthermore, patients in the placebo group who crossed over to active treatment achieved a response that was similar in magnitude, rapidity, and sustainability to that of patients originally assigned to infliximab.

In addition to the response shown with traditional assessments of improvement in patients with PsA, to our knowledge this is the first published randomized, controlled study that has also incorporated DAS28, enthesitis, and dactylitis assessments. The results showed that the study population consisted mostly of patients with high disease activity at baseline according to the DAS28. It is noteworthy that the PsARC, ACR, and DAS28 criteria have not been validated for PsA. However, in published trials, both the PsARC and the ACR criteria have been used and have appeared to be helpful. After treatment with infliximab, disease activity was significantly reduced at week 16, and the response was maintained until week 50. The average DAS28 response achieved was below the threshold defining low disease activity. Enthesitis and dactylitis are common and clinically meaningful manifestations of PsA (32, 33). However, they have not received significant attention in therapeutic trials. In the infliximab group in this study, significant reductions from baseline were observed in mean dactylitis scores and the number of patients with enthesitis at week 16, and these responses were maintained until week 50.

In addition to experiencing improvements in joint symptoms, patients in the infliximab group showed rapid and sustained improvement in skin psoriasis. At week 16, the mean PASI score for patients with notable psoriasis involvement at baseline (i.e., baseline PASI score of ≥2.5) was reduced in the infliximab group, whereas the placebo group showed a slight worsening in the mean PASI score. At week 16, a 50% improvement, a 75% improvement, and a 90% improvement in the PASI score was reached by 100%, 68%, and 36% of patients, respectively, in the infliximab treatment group and by none of the patients in the placebo group. After crossing over to active treatment, patients in the placebo/infliximab group had skin response that mirrored those of patients in the infliximab group, and both groups were able to maintain the skin responses until week 50. Because of the relatively small number of patients with substantial skin involvement, these results will have to be confirmed in a larger trial.

Although it is potentially tenuous to compare results across trials, the articular responses noted in this study of infliximab were quite comparable with those noted in 2 previous studies of etanercept in PsA (18, 19). However, dermatologic responses in these studies of etanercept appeared to be somewhat lesser than those observed in this current trial of infliximab. Thus, at 12 weeks a 75% improvement in the PASI score was achieved by 26% of etanercept-treated patients in one study (18) and by 23% of etanercept-treated patients in another study (19), with no placebo-treated patients in either study achieving this end point. The reasons for the comparability of articular responses and the potential differentiation in dermatologic responses remain to be fully delineated. Interestingly, whereas clinical efficacy appears to be quite comparable among the various TNF inhibitors in RA, differential efficacy has been noted in Crohn's disease, another systemic inflammatory autoimmune condition.

The improvement in HAQ scores observed among infliximab-treated patients in this trial is particularly noteworthy for this patient population; that is, relatively young patients with the potential for many additional years of productive work. HAQ scores in patients initially treated with infliximab improved from 1.2 at baseline to 0.6 at week 16, while the HAQ scores in patients receiving placebo showed no improvement (1.2 at both baseline and week 16). By week 50, HAQ scores were 0.7 and 0.5 in patients initially assigned to placebo and infliximab, respectively. These HAQ scores represent a level of function that approaches what is considered to be normal (28).

Infliximab was generally well tolerated by all study participants, and the safety profile observed in this study was similar to previously reported findings (21, 34, 35). The incidence of adverse events, treatment-related adverse events, infusion-associated adverse events, severe events, serious adverse events, and adverse events leading to discontinuation was similar between placebo- and infliximab-treated patients.

In this trial, infliximab or placebo was added to the DMARD regimen that the patient was receiving at baseline. Overall, 56% of patients were receiving MTX at baseline, while 22% were receiving other DMARDs. Of note, the concomitant use of MTX or other DMARDs seemed to have little effect on the clinical efficacy of infliximab. Whether there might be synergy in clinical efficacy, alterations in dose response, or other interactions between infliximab and MTX or other DMARDs, as has been suggested in RA (36), remains to be determined in PsA.

In conclusion, infliximab was effective and generally well tolerated in patients with PsA who were unresponsive to DMARD therapy. Infliximab at a dose of 5 mg/kg rapidly improved the signs and symptoms of arthritis and significantly improved dermatologic manifestations, as shown by multiple assessments including the ACR criteria, the DAS28, enthesitis, dactylitis, the PsARC, and the PASI. The treatment effect was maintained throughout 1 year of therapy. Infliximab was generally well tolerated, and the benefit-versus-risk profile appeared to be favorable in this study population.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We thank the patients and study site personnel who made this trial possible and Scott Newcomer from Centocor for his input in editing the paper.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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