PREGNANCY AND LACTATION: DYNAFIL is not indicated for use in women. dynafil 25 mg DYNAFIL was not found to be carcinogenic, teratogenic, embryotoxic or fetotoxic in animal studies. Single 100 mg oral doses of sildenafil did not impair sperm motility or morphology. dynafil 50 mg DOSAGE AND DIRECTIONS FOR USE: dynafil 100 mg The recommended oral dose is 50 mg, taken if nee
Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (impact)Vol. 52, No. 4, April 2005, pp 1227–1236 2005, American College of Rheumatology Sustained Benefits of Infliximab Therapy for Dermatologic and Articular Manifestations of Psoriatic Arthritis Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) Christian E. Antoni,1 Arthur Kavanaugh,2 Bruce Kirkham,3 Zuhre Tutuncu,2 Gerd R. Burmester,4 Udo Schneider,4 Daniel E. Furst,5 Jerry Molitor,6 Edward Keystone,7 Dafna Gladman,7 Bernhard Manger,1 Siegfried Wassenberg,8 Ralf Weier,8 Daniel J. Wallace,9 Michael H. Weisman,9 Joachim R. Kalden,1 and Josef Smolen10 Objective. To investigate the efficacy and tolera-
receive active treatment at the same dose through week
bility of infliximab therapy for the articular and derma-
50. The primary efficacy outcome was achievement of
tologic manifestations of active psoriatic arthritis (PsA).
the American College of Rheumatology 20% criteria for
Methods. One hundred four patients with PsA in
improvement in rheumatoid arthritis (ACR20) at week
whom prior therapy with at least 1 disease-modifying
16. Additional predefined clinical efficacy assessments
antirheumatic drug (DMARD) had failed were recruited
included the Psoriasis Area and Severity Index (PASI)
into this investigator-initiated, multicenter, random-
score, the ACR50 and ACR70 criteria, the Disease
ized, double-blind, placebo-controlled clinical trial.
Activity Score in 28 joints, the Health Assessment
During the initial blinded portion of the study, patients
Questionnaire, ratings of enthesitis and dactylitis, and
received infusions of infliximab (5 mg/kg) or placebo at
the Psoriatic Arthritis Response Criteria score.
weeks 0, 2, 6, and 14. After week 16, patients initially
Results. The proportion of infliximab-treated pa-
assigned to receive placebo crossed over to receive
tients who achieved an ACR20 response at week 16
infliximab 5 mg/kg every 8 weeks through week 50, while
(65%) was significantly higher than the proportion of
patients initially randomized to infliximab continued to
Dr. Antoni has received consulting fees of less than $10,000 Supported in part by the NIH (grant M01-RR-00827 to the from Centocor and more than $10,000 from Schering-Plough. Dr.
University of California, San Diego), an unrestricted grant from Kavanaugh has received consulting fees of less than $10,000 from Centocor, Inc., to the University of Erlangen, Erlangen, Germany, and Centocor. Dr. Kirkham has received consulting fees of less than by the Schering-Plough Research Institute. Dr. Burmester’s work was $10,000 from Schering-Plough, Wyeth, and Abbott. Dr. Burmester has supported by the Competence Network “Inflammatory Rheumatic received consulting fees of less than $10,000 from Schering-Plough.
Diseases” of the German Federal Ministry of Education and Science.
Dr. Furst has received consulting fees of less than $10,000 from 1Christian E. Antoni, MD (current address: Schering-Plough Centocor. Dr. Molitor has received consulting fees of less than $10,000 Research Institute, Kenilworth, NJ), Bernhard Manger, MD, Joachim from Bristol-Myers Squibb and Abbott. Dr. Keystone has received R. Kalden, MD: Friedrich-Alexander University, Erlangen- consulting fees of less than $10,000 from Centocor. Dr. Gladman has Nuremberg, Germany; 2Arthur Kavanaugh, MD, Zuhre Tutuncu, MD: received consulting fees of less than $10,000 from Centocor, Schering- Center for Innovative Therapy, University of California, San Diego; Plough, Amgen, and Wyeth. Dr. Manger has received honoraria of less 3Bruce Kirkham, MD: Guy’s Hospital, London, UK; 4Gerd R. Burm- than $10,000 from Essex, Wyeth, Abbott, and Novartis. Dr. Weisman has received consulting fees of less than $10,000 from Bristol-Myers Germany; 5Daniel E. Furst, MD: University of California, Los Ange- Squibb, Amgen, ISIS Pharmaceutical, Centocor, and Regeneron, and les; 6Jerry Molitor, MD, PhD: Virginia Mason Clinic, Seattle, Wash- has received consulting fees of more than $10,000 from Abbott and ington; 7Edward Keystone, MD, Dafna Gladman, MD, FRCPC: TAP Pharmaceutical Products. Dr. Smolen has received consulting University of Toronto, Toronto, Ontario, Canada; 8Siegfried Wassen- fees of less than $10,000 from Schering-Plough and Centocor.
berg, MD, Ralf Weier, MD: Evangelisches Fachkrankenhaus, Ratin- Address correspondence and reprint requests to Christian E.
gen, Germany; 9Daniel J. Wallace, MD, Michael H. Weisman, MD: Antoni, MD, 2015 Galloping Hill Road, Kenilworth, NJ 07033. E-mail: Cedars-Sinai Medical Center, Los Angeles, California; 10Josef Smolen, MD: Medical University of Vienna and Lainz Hospital, Vienna, Submitted for publication July 30, 2004; accepted in revised placebo-treated patients who achieved this response
role of TNF in these conditions. Etanercept, a dimeric (10%). In addition, 46% of infliximab-treated patients
p75–TNF receptor/Ig Fc fusion construct, has been achieved an ACR50 response, and 29% achieved an
shown to be effective in PsA (18,19) and psoriasis (20).
ACR70 response; no placebo-treated patient achieved
Infliximab, a chimeric monoclonal antibody specific for these end points. Among patients who had PASI scores
TNF␣, has also been shown to be effective in psoriasis of >2.5 at baseline, 68% of infliximab-treated patients
(21). In an open-label study of infliximab in PsA, clinical achieved improvement of >75% in the PASI score at
benefits were accompanied by objective improvements week 16 compared with none of the placebo-treated
in inflammatory synovitis as measured using magnetic patients. Continued therapy with infliximab resulted in
resonance imaging (22). On the basis of these results, we sustained improvement in articular and dermatologic
conducted a controlled trial to evaluate the efficacy and manifestations of PsA through week 50. The incidence of
safety of infliximab, using multiple assessments of skin adverse events was similar between the treatment
and joint disease activity in patients with active PsA in whom treatment with at least 1 DMARD had failed.
Conclusion. Therapy with infliximab at a dose of
5 mg/kg significantly improved the signs and symptoms
PATIENTS AND METHODS
of arthritis, psoriasis, dactylitis, and enthesitis in pa-
tients with active PsA that had been resistant to
Patients. The study group comprised 104 patients
DMARD therapy. With continued infliximab treatment,
(ages 18 years and older) with an established diagnosis of PsAof 6 months duration or longer. Eligibility criteria included benefits were sustained through 50 weeks. The benefit-
previous failure of treatment with Ն1 DMARDs. At enroll- to-risk ratio appeared favorable in this study popula-
ment, patients were required to have active peripheral polyar- ticular arthritis, defined as the presence of Ն5 swollen andtender joints (based on joint counts of 66 and 68, respectively) Psoriatic arthritis (PsA) is a chronic inflamma- in conjunction with at least 1 of the following criteria: eryth-rocyte sedimentation rate (ESR) Ն28 mm/hour, C-reactive tory arthropathy that occurs in association with psoriasis.
protein (CRP) level Ն15 mg/liter, and/or morning stiffness Among articular disorders, PsA was once considered to lasting 45 minutes or longer. Patients also were required to have a relatively benign course; however, a growing body have negative results of serum tests for rheumatoid factor and of data suggest that PsA is often progressive and refrac- negative results for active or latent tuberculosis by purified tory to therapy. Moreover, patients with PsA may expe- protein derivative skin test and chest radiography.
This study was conducted at 9 centers in Europe, the rience substantial morbidity and unfavorable outcomes US, and Canada, and the protocol was approved by the (1,2). Although the disease course can be variable, institutional review boards at each of the participating sites. All factors such as polyarticular inflammation have been patients provided written informed consent prior to participat- associated with the development of deformities, radio- ing in any study-related activities.
graphic joint damage, and impaired functional status Study design. The study was conducted in 2 phases. In
phase 1, patients were randomly assigned to receive placebo (3,4). Despite the recent data on leflunomide (5), re- (n ϭ 52) or infliximab 5 mg/kg (n ϭ 52) at weeks 0, 2, 6, and sponses to traditional disease-modifying antirheumatic 14. At the start of phase 2, in order to preserve the blinding drugs (DMARDs) have been suboptimal, leaving an and allow for a treatment introduction course for the placebo group, patients in the infliximab group received placebo infu- Recent advances in the understanding of the sions at weeks 16 and 18, followed by infliximab 5 mg/kg atweeks 22, 30, 38, and 46; patients in the placebo group received immunopathogenesis of psoriasis and PsA, combined infliximab 5 mg/kg at weeks 16, 18, 22, 30, 38, and 46. Patients, with developments in biotechnology, have led to the investigators, and study personnel other than the pharmacist introduction of novel therapeutic options (11). Several were unaware of the initial assignments throughout the 50- studies have suggested that proinflammatory cytokines, in particular tumor necrosis factor ␣ (TNF␣), serve a key Study agent. Infliximab (Remicade; Centocor,
Malvern, PA) was supplied in 20-ml vials containing 100 mg of role in potentiating inflammatory responses associated the lyophilized concentrate; placebo was identically formulated with both psoriasis and PsA (12–17). Increased levels of but did not contain infliximab. Infusions were administered TNF␣ have been observed in skin, synovial fluid, and over 2 hours by blinded personnel using an infusion set with an synovial tissue from affected patients (14–16), and allelic in-line, sterile, nonpyrogenic, low protein-binding filter (pore polymorphisms in the promoter region for TNF␣ have size 1.2 m) through a peripheral venous access site.
Concomitant medications. Patients were allowed to
been shown to correlate with certain aspects of the receive concomitant therapy with 1 of the following DMARDs: disease (13). More recently, evidence from trials of methotrexate (MTX; dosage of 15 mg/week or more, with folic biologic agents targeting TNF have highlighted the key acid supplementation), leflunomide, sulfasalazine, hydroxy- chloroquine, intramuscular gold, penicillamine, or azathio-prine. For patients who were receiving a DMARD at the timeof enrollment, the dosage was required to have been stable forat least 4 weeks prior to randomization and to remain stablethroughout the study. Concomitant therapy with oral cortico-steroids (dosage of 10 mg prednisone equivalent/day or less)and nonsteroidal antiinflammatory drugs (NSAIDs) was per-mitted, provided that dosages had been stable for at least 2weeks prior to screening. Dosages of corticosteroids andNSAIDs were required to remain stable throughout the study.
Use of intramuscular or intravenous corticosteroids, cyclo-sporine, or tacrolimus was prohibited within 4 weeks ofscreening and throughout the study. One injection of intraar-ticular corticosteroids was permitted in phase 2 of the study,and the injected joint would be excluded from subsequentefficacy assessment. Standard topical treatments for psoriaticlesions (e.g., topical steroids) were permitted, provided theyremained stable throughout the study. Therapy with psoralenultraviolet A was not permitted. Eligible patients could nothave received any investigational drug within 3 months ofscreening or any previous treatment with a monoclonal anti-body or fusion protein.
Study procedures and evaluations. The primary effi-
cacy assessment was the achievement at week 16 of theAmerican College of Rheumatology 20% criteria for improve-ment (ACR20) in rheumatoid arthritis (RA) (23). Assessmentof skin involvement was made using the Psoriasis Area andSeverity Index (PASI) at the time of screening and at weeks 16and 50 (24). For the PASI, lesional erythema, scaling, andthickness were rated for 4 anatomic regions (head, trunk,upper extremities, and lower extremities). The area of eachanatomic region was factored into the overall score. The Figure 1. Study design and patient disposition. Broken line indicates
maximum possible PASI score is 72. Patients with a baseline period during which patients were receiving placebo. Solid boldface PASI score of Ն2.5 were included in the efficacy evaluation of line indicates period during which patients were receiving infliximab 5 mg/kg. Patients initially assigned to the infliximab group received Additional response evaluations made at weeks 2, 6, infusions of placebo at weeks 16 and 18 in order to maintain blinding.
10, 14, 16, 18, 22, 30, 38, 46, and 50 included graded assess-ments of pain and swelling in 68 and 66 joints, respectively (0–3scale); the number of digits with dactylitis (maximum 20 digits; Chi-square testing with Yates’ correction for contin- 0–3 scale); the Psoriatic Arthritis Response Criteria (PsARC) gency tables was used to compare the primary efficacy end (25); the Disease Activity Score in 28 joints (DAS28) (26,27); point between the 2 treatment groups. To assess the onset of the presence of enthesitis (at bilateral Achilles tendons and clinical effect, the ACR20 response rates were assessed at calcaneal insertions); patient’s and physician’s assessments of weeks 2, 6, 10, and 14. The Mantel-Haenszel test was con- pain and overall disease activity (0–10-cm visual analog scale); ducted to estimate the common odds ratio of the 2 treatment responses to the 20-question Health Assessment Question- groups. In secondary efficacy analyses, the chi-square test was naires (HAQ) (28); measurement of serum CRP levels; and used for end points with discrete data, and a one-way analysis determination of the ESR. Joints that had undergone surgical of variance with treatment group as a factor was used for end replacement or fusion operations were excluded from evalua- tion. Joints that had undergone synovectomy within 12 monthsprior to screening or radiosynovectomy within the monthsprior 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- Baseline characteristics, patient disposition, and
treated patients and 20% of placebo-treated patients would concomitant therapy. Of the 104 enrolled patients, 99
achieve an ACR20 response. A sample size of 45 patients per (95%) completed the study through week 16 (Figure 1).
group provided power of 0.8 and a 2-sided alpha value of 0.05.
A summary of baseline characteristics of the patients is The predefined primary efficacy end point was the provided in Table 1. The baseline characteristics for the proportion of patients achieving an ACR20 response at week16 in the intent-to-treat analysis. The secondary end points 2 treatment groups were generally similar, with a few were compared between treatment groups.
exceptions. The mean CRP value was 31.1 mg/liter in the Baseline characteristics of the study population* Global assessment of disease activity (0–10-cm VAS) Patient’s assessment of pain (0–10-cm VAS) Health Assessment Questionnaire (0–3 scale) * Except where indicated otherwise, values are the mean Ϯ SD. PsA ϭ psoriatic arthritis; ACR20 ϭAmerican College of Rheumatology 20% criteria for improvement; VAS ϭ visual analog scale; PASI ϭPsoriasis Area and Severity Index.
† Forty patients in the placebo group and 42 patients in the infliximab group were evaluated.
placebo group and 21.7 mg/liter in the infliximab group, [65%]) was significantly higher than the proportion of with medians of 14.0 mg/liter and 9.9 mg/liter, respec- placebo-treated patients (5 of 52 [10%]) who achieved tively (P ϭ 0.15). Patients in both treatment groups had this end point (P Ͻ 0.001). In addition, at week 16, 24 of active and severe psoriatic arthritis.
52 infliximab-treated patients (46%) achieved an Five patients discontinued study treatment dur- ACR50 response, and 15 of 52 infliximab-treated pa- ing phase 1 (Figure 1). In the placebo group, 1 patient tients (29%) achieved an ACR70 response; no placebo- was withdrawn before the first infusion due to suspected treated patient achieved these end points (P Ͻ 0.001) atypical mycobacterial infection, and 1 patient withdrew (Table 2). As shown in Figure 2, the response to after the third infusion, at her request. In the infliximab infliximab therapy was evident as early as week 2, and group, 1 patient discontinued at week 16 due to a improvement continued through the week 50 evaluation suspected joint infection after a steroid injection into the in patients initially randomized to infliximab. Following wrist, 1 patient was lost to followup after 2 infusions, and initiation of infliximab therapy, patients initially ran- 1 patient withdrew at week 14 after experiencing a lower domized to placebo who received infliximab therapy at respiratory tract infection and worsening of asthma.
weeks 16, 18, 22, 30, 38, and 46 exhibited a pattern of During phase 2 of the study, when all patients were clinical response similar to that of patients initially receiving infliximab, 12 additional patients discontinued randomized to infliximab (Table 2 and Figure 2).
treatment for the following reasons: adverse events (n ϭ Among infliximab-treated patients, significant 4), patient request (n ϭ 3), treatment failure/lack of improvement from baseline to week 16 was also ob- benefit (n ϭ 3), and noncompliance and lost to followup served in the individual components of the ACR20 (n ϭ 1 each). Data for all 104 patients were included in (Table 2). In particular, the mean HAQ score improved significantly from 1.2 at baseline to 0.6 at week 16 in Efficacy. Articular manifestations. The proportion
infliximab-treated patients, while the mean HAQ scores of infliximab-treated patients who achieved the primary in placebo-treated patients showed no improvement (1.2 end point of an ACR20 response at week 16 (34 of 52 at baseline and week 16) (P Ͻ 0.001). By week 50, mean 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 thePsARC, compared with 11 of 52 placebo-treated pa-tients (21%) (P Ͻ 0.001). By week 50, the treatmentgroups showed similar PsARC response rates (76% and74% of patients in the placebo/infliximab and infliximab/infliximab groups, respectively). Infliximab-treated pa-tients also showed a significantly greater mean percentimprovement from baseline to week 16 in the dactylitisscore (85%) when compared with placebo-treated pa-tients (29%) (P Ͻ 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. Atbaseline, 25% of patients in each group had enthesitis; at Figure 2. Percentages of patients achieving improvement by the
week 16, the proportion of infliximab-treated patients American College of Rheumatology 20% criteria for improvement in with enthesitis (14%) was significantly lower than the rheumatoid arthritis (ACR20) through week 50. Arrows indicateweeks at which infusions were administered: open arrows denote proportion of placebo-treated patients (31%; P ϭ placebo (Pbo) infusions, and solid arrows denote infusions of inflix- The mean baseline DAS28 scores (5.4 and 5.5 for the placebo and infliximab groups, respectively) indicatethat the study population comprised patients with a high HAQ scores were 0.7 and 0.5 in patients initially ran- level of articular disease activity. At week 16, patients in domized to placebo and infliximab, respectively. Despite the infliximab group showed a mean improvement in the slightly higher CRP values among placebo patients at DAS28 score of 46%, compared with an improvement of baseline, the median CRP values were similarly im- 2.8% among patients in the placebo group (P Ͻ 0.001).
proved at week 50 in both groups (9.9 mg/liter and 7.5 Furthermore, at week 16, 89% of patients in the inflix- Summary of clinical efficacy parameters at weeks 16 and 50* * For the American College of Rheumatology (ACR) parameters, values are the proportion (%) of patients meeting thecriteria for 20%, 50%, and 70% improvement. Except where indicated otherwise, all other values are the mean Ϯ SDpercent improvement (a negative value indicates worsening). CRP ϭ C-reactive protein; HAQ ϭ Health AssessmentQuestionnaire; DAS28 ϭ Disease Activity Score in 28 joints.
† P Ͻ 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 shownumber of patients with enthesopathies at week 50.
response following initiation of infliximab therapy (Fig-ure 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 inanother way, 100% (22 of 22), 68% (15 of 22), and 36%(8 of 22) of infliximab-treated patients experienced atleast 50%, 75%, and 90% improvement in the PASIscore from baseline to week 16. None of the placebo-treated patients achieved any of these end points at week16. At week 50, 50%, 75%, and 90% improvement in thePASI score was sustained in 86% (19 of 22 patients),59% (13 of 22 patients), and 41% (9 of 22 patients) ofpatients in the infliximab/infliximab group, respectively.
By week 50, 69% (11 of 16), 50% (8 of 16), and 38% (6of 16) of patients in the placebo/infliximab groupachieved these end points.
Figure 3. Values (mean Ϯ SD) for the Disease Activity Score in 28
joints (DAS28) during the 50-week treatment period. Broken lines
Effect of concomitant DMARD use. Overall, 74 of indicate the thresholds defining low disease activity (Ͻ3.2) and high 104 patients (71%) were receiving a concomitant DMARD at baseline, including 41 of 52 patients in theplacebo group (79%) and 33 of 52 patients in theinfliximab group (63%) (P ϭ 0.08). The most commonly imab group were DAS responders (i.e., had a good or used DMARD was MTX; 34 patients in the placebo moderate response according to the DAS28 criteria) group were receiving a mean MTX dosage of 16.2 compared with 25% of patients in the placebo group mg/week, and 24 patients in the infliximab group were (P Ͻ 0.001). The treatment groups showed similar levels receiving a mean MTX dosage of 15.9 mg/week. The of improvement at week 50 (Table 2), with 82% of concomitant use of DMARDs appeared to have little patients in the infliximab/infliximab group and 84% of effect on ACR20 response rates at week 16. Thus, 62.5% patients in the placebo/infliximab group achieving a of infliximab patients also receiving MTX achieved an DAS28 response. Moreover, the mean DAS28 value ACR20 response at week 16, as did 68% of infliximab in both groups after initiation of infliximab therapy patients not receiving MTX and 74% of those not was below the threshold defining low disease activity receiving any DMARDs (P not significant).
Adverse events. A summary of adverse events by
Dermatologic response. Baseline PASI scores treatment group is provided in Table 3. The treatment were similar between the 2 treatment groups (Table 1).
Thirty-nine patients (22 in the infliximab group and 17 inthe placebo group) had PASI scores of Ն2.5 at baselineand were therefore eligible for evaluation of changes inskin scores during treatment. At week 16, patients in theinfliximab group had a mean improvement from base-line in their PASI score of 86%; this compared with a12% worsening in the PASI score for patients in theplacebo group (P Ͻ 0.001). Among patients with base-line PASI scores of Ն2.5, 68% of infliximab-treatedpatients achieved improvement of Ն75% in the PASIscore at week 16 compared with none of the placebo-treated patients (P Ͻ 0.001).
For patients initially assigned to infliximab treat- ment, the response to infliximab therapy was sustainedthrough the week 50 evaluation. Patients initially ran- Figure 4. Psoriasis Area and Severity Index (PASI) scores (mean and
domized to placebo, who received infliximab therapy SD) at baseline, week 16, and week 50 in patients who had a PASI after week 16, exhibited a similar pattern of PASI * Values are the number (%).
† One patient was randomly assigned to the placebo group but did not receive any infusions. This patient was included in theefficacy analysis but was excluded from the safety analysis.
groups were similar with regard to the incidence of all ported during phase 2 included unrelated events of adverse events, treatment-related adverse events, inguinal hernia, surgical procedure (4 patients), angina infusion-associated adverse events, severe adverse pectoris, atrial fibrillation, urinary retention, chest pain, events, and serious adverse events during both phase 1 and cerebrovascular event, as well as the following (double-blind phase; weeks 0–16) and phase 2 (cross- events with a possible or probable relationship to the over phase; weeks 16–50) of the study.
study drug: fever, acute Salmonella gastroenteritis, pye- The most frequently reported treatment-related lonephritis, and leg weakness. The incidence of infusion adverse events (i.e., those reported by Ն4 patients reactions between groups was comparable in both overall) during phase 1 of the study were as follows: phases of the study (Table 3). One patient who received headache (3 patients assigned to placebo and 4 patients placebo in phase 1 followed by infliximab in phase 2 had assigned to infliximab), bronchitis (4 placebo patients dyspnea and urticaria at week 38, resulting in the only and 3 infliximab patients), upper respiratory tract infec- infusion-related study discontinuation.
tion (5 placebo patients and 1 infliximab patient), No patients experienced an opportunistic infec- influenza-like symptoms (4 placebo patients and 1 inflix- tion, including tuberculosis, during the study. There imab patient), rhinitis (2 placebo patients and 3 inflix- were no reports of autoimmune, cytopenic, or neuro- imab patients), and rash (2 placebo patients and 3 infliximab patients). During phase 2 of the study, themost frequently occurring treatment-related adverse DISCUSSION
events were upper respiratory tract infection (23 pa-tients), headache (7 patients), dizziness (6 patients), Although at one time PsA was considered to be a influenza-like symptoms (5 patients), nonproductive relatively benign condition, it is now known that PsA can cough (5 patients), rhinitis (4 patients), hypertension (4 be associated with substantial morbidity, comparable patients), and sinusitis (4 patients). Most treatment- with that of RA, especially in patients with active related adverse events were mild to moderate in inten- polyarticular and oligoarticular PsA involving the large sity. Severe treatment-related events were reported by 3 joints (3). Patients with PsA may also experience accel- patients through week 16 (1 in the placebo group and 2 erated mortality and a significantly impaired quality of in the infliximab group) and by 6 patients between week life (2). However, in contrast to studies of RA, the use of traditional DMARDs has not uniformly been shown to Two patients reported serious adverse events be associated with notable efficacy in randomized con- during phase 1. One patient in the placebo group had trolled trials of PsA, particularly with regard to treating rectal bleeding due to diverticulitis, and 1 patient in the cutaneous symptoms (25,29–31). Thus, patients with infliximab group had synovitis suspected to be infectious PsA, particularly those with severe disease, have an that was culture negative. Serious adverse events re- Patients in the Infliximab Multinational Psoriatic and sustained improvement in skin psoriasis. At week Arthritis Controlled Trial, all but 1 of whom were 16, the mean PASI score for patients with notable negative for serum rheumatoid factor at baseline, had psoriasis involvement at baseline (i.e., baseline PASI severe refractory disease, as shown by their polyarticular score of Ն2.5) was reduced in the infliximab group, involvement, high global disease severity ratings, ele- whereas the placebo group showed a slight worsening in vated HAQ scores, high DAS28 scores, and their lack of the mean PASI score. At week 16, a 50% improvement, response to DMARD therapy. In addition, the majority a 75% improvement, and a 90% improvement in the of patients had skin involvement, approximately half had PASI score was reached by 100%, 68%, and 36% of dactylitis, and a quarter had enthesitis.
patients, respectively, in the infliximab treatment group Assessments of improvement in the arthritis and by none of the patients in the placebo group. After symptoms of PsA in recent randomized controlled trials crossing over to active treatment, patients in the of DMARDs and biologic agents have focused primarily placebo/infliximab group had skin response that mir- on the ACR and PsARC criteria. Patients in this trial rored those of patients in the infliximab group, and both responded very well to infliximab treatment according to groups were able to maintain the skin responses until these assessments. The primary end point of the trial week 50. Because of the relatively small number of was clearly met, with 65% of patients in the infliximab patients with substantial skin involvement, these results group achieving an ACR20 response at week 16, com- will have to be confirmed in a larger trial.
pared with 10% of patients in the placebo group; the Although it is potentially tenuous to compare response for infliximab-treated patients was maintained results across trials, the articular responses noted in this through week 50. The rapidity of response was notewor- study of infliximab were quite comparable with those thy, with many patients improving at the initial assess- noted in 2 previous studies of etanercept in PsA (18,19).
ment (week 2). Furthermore, patients in the placebo However, dermatologic responses in these studies of group who crossed over to active treatment achieved a etanercept appeared to be somewhat lesser than those response that was similar in magnitude, rapidity, and observed in this current trial of infliximab. Thus, at 12 sustainability to that of patients originally assigned to weeks a 75% improvement in the PASI score was achieved by 26% of etanercept-treated patients in one In addition to the response shown with tradi- study (18) and by 23% of etanercept-treated patients in tional assessments of improvement in patients with PsA, another study (19), with no placebo-treated patients in to our knowledge this is the first published randomized, either study achieving this end point. The reasons for the controlled study that has also incorporated DAS28, comparability of articular responses and the potential enthesitis, and dactylitis assessments. The results differentiation in dermatologic responses remain to be showed that the study population consisted mostly of fully delineated. Interestingly, whereas clinical efficacy patients with high disease activity at baseline according appears to be quite comparable among the various TNF to the DAS28. It is noteworthy that the PsARC, ACR, inhibitors in RA, differential efficacy has been noted in and DAS28 criteria have not been validated for PsA.
Crohn’s disease, another systemic inflammatory auto- 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 among infliximab-treated patients in this trial is partic- was significantly reduced at week 16, and the response ularly noteworthy for this patient population; that is, was maintained until week 50. The average DAS28 relatively young patients with the potential for many response achieved was below the threshold defining low additional years of productive work. HAQ scores in disease activity. Enthesitis and dactylitis are common patients initially treated with infliximab improved from and clinically meaningful manifestations of PsA (32,33).
1.2 at baseline to 0.6 at week 16, while the HAQ scores However, they have not received significant attention in in patients receiving placebo showed no improvement therapeutic trials. In the infliximab group in this study, (1.2 at both baseline and week 16). By week 50, HAQ significant reductions from baseline were observed in scores were 0.7 and 0.5 in patients initially assigned to mean dactylitis scores and the number of patients with placebo and infliximab, respectively. These HAQ scores enthesitis at week 16, and these responses were main- represent a level of function that approaches what is In addition to experiencing improvements in joint Infliximab was generally well tolerated by all symptoms, patients in the infliximab group showed rapid study participants, and the safety profile observed in this study was similar to previously reported findings 6. Veale DJ, FitzGerald O. Psoriatic arthritis: pathogenesis and (21,34,35). The incidence of adverse events, treatment- epidemiology. Clin Exp Rheumatol 2002;20 Suppl 28:S27–33.
7. Rahman P, Nguyen E, Cheung C, Schentag CT, Gladman DD.
related adverse events, infusion-associated adverse Comparison of radiological severity in psoriatic arthritis and events, severe events, serious adverse events, and ad- rheumatoid arthritis. J Rheumatol 2001;28:1041–4.
verse events leading to discontinuation was similar be- 8. Gladman DD, Hing EN, Schentag CT, Cook RJ. Remission in psoriatic arthritis. J Rheumatol 2001;28:1045–8.
tween placebo- and infliximab-treated patients.
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Material Safety Data Sheet Revision Date 29-Mar-2011 Revision Number 1 Product Name Remel Prepared Culture Media Containing Nalidixic acid R01064, 01065, 01318, 01320, 01321, 01322, 01323, 01359, 01478, 01590, 01802, 01952, 02060, 02065, 02066, 02077, 02482, 064810, 064812, 08520, 08522, 10102, 10103, 112850, 112870 Synonyms Recommended Use Emergency Telephone N