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a A > 50% reduction from baseline in the number of open fistulas observed for two consecutive evaluation visits (i.e., at least 1 month). b Absence of any draining fistulas for at least two consecutive evaluation visits.

a A > 50% reduction from baseline in the number of open fistulas observed for two consecutive evaluation visits (i.e., at least 1 month). b Absence of any draining fistulas for at least two consecutive evaluation visits.

nificantly greater than the placebo response rate (12.9%, P = .001). The best clinical benefit was observed with the 5-mg/kg dose (>50% reduction in a number of open fistulas in 68% of patients; complete response in 55% of patients) (50).

Treatment with infliximab was associated with a rapid onset of response. The majority of patients responding to infliximab treatment demonstrated the response by 2 weeks following infusion (median number of days to onset of response was 14 days for infliximab-treated patients compared to 42 days for the few responding placebo-treated patients). Through 18 weeks of follow-up, the median duration of benefit was approximately 3 months (50).

In summary, treatment of patients with enterocutaneous fistulas with infliximab produced a rapid and profound benefit in the closure and healing of these fistulas. These findings represent the first time that a therapeutic agent has demonstrated a statistically significant clinical benefit (closure of fistulas) in a controlled clinical trial setting. The onset of benefit was rapid, with the majority of responding patients demonstrating fistula closure by the first evaluation at 2 weeks. The benefit of treatment lasted at least 12 weeks in the majority of patients who responded to treatment. A regimen dose of 5 mg/kg given at 0, 2, and 6 weeks was approved by the FDA for the treatment of patients with fistulizing Crohn's disease for the reduction in the number of draining enterocutaneous fistulas.

Treatment of RA with Infliximab

The effectiveness of infliximab treatment in patients with RA has been studied in four clinical trials (three randomized, double-blind, placebo-controlled and one open label). A total of 203 patients have been enrolled in these trials.

Open-label Study

An open-label trial evaluated clinical response to infliximab in patients with advanced chronic erosive RA unresponsive to disease-modifying drugs (DMARD) such as methotrexate (MTX), gold, and salazopyrine (51). Twenty patients with a diagnosis of RA (52) were administered either an infusion of 10 mg/kg infliximab that was repeated 2 weeks later or four infusions of 5 mg/kg infliximab administered every 4 days. Patients were required to have discontinued DMARD therapy for at least 4 weeks prior to treatment and to be off DMARD therapy for the duration of the study. Concurrent treatment with nonsteroidal anti-inflammatory drugs (NSAID) or steroids (<10 mg/day) was permitted.

Treatment with infliximab led to rapid improvement in every patient in all assessments of disease activity used for monitoring patients, such as the number of tender joints and number of swollen joints, duration of morning stiffness, combined grip strength of both hands, assessment of pain, ESR, and the CRP concentration. Improvement for these measurements ranged from 57 to 94%. The onset of benefit was rapid, being evident 1 week after the first infusion. Therapy was well tolerated by the patients. This trial provided the first positive efficacy experience in patients using an anti-TNF-a therapy.

Controlled Study

To further establish the efficacy and safety profile of infliximab a randomized, double-blind, placebo-controlled trial was performed in four European centers. Seventy three patients with active advanced RA were randomized to the following three treatment groups: single infusion of placebo or infliximab at a dose of 1 mg/kg or 10 mg/kg (53). Patients had to have failed prior treatment with at least one DMARD and discontinued DMARD therapy at least 4 weeks prior to treatment. Concurrent treatment with NSAID or steroids (<12.5 mg/ day) was permitted.

The primary endpoint of the study was the achievement at week 4 of a Paulus 20% response, a composite of six clinical, observational, and laboratory variables including the number of the tender and swollen joints, the duration of morning stiffness, the patient's and physician's assessment of disease severity, and ESR. Patients were considered to have responded if at least four of the six variables improved, defined as at least 20% improvement in the continuous variables, and at least two grades of improvement or improvement from grade 2 to 1 in the two disease-severity assessments. The more stringent Paulus 50% criteria also was used for the assessment.

All patients were to have active disease as defined by the presence of at least 6 swollen joints of a total of 58 joints and the presence of at least three of the following: duration of morning stiffness of at least 45 min, the presence of 6 or more tender/painful joints of a total of 60 joints, ESR of at least 28 mm/h, or CRP of at least 20 mg/L.

Substantial and highly significant differences were seen in response rates between infliximab and placebo. Only 2 of 24 placebo patients (8.3%) achieved a 20% Paulus response at week 4. By contrast, 19 of 24 patients (79.2%) treated with 10 mg/kg infliximab achieved a response by week 4 (P <.0001 compared with placebo). The response rates in the 1-mg/kg group were intermediate, with 11 of 25 patients (44.0%) responding at week 4 (P = .0083). Analysis of the Paulus 50% response showed similar differences between the groups, with 14 of 24 high-dose infliximab patients responding compared with 2 of 24 patients in the placebo group (P = .0005).

Improvement in both clinical and laboratory disease parameters was seen as early as 3 days after infusion, but maximal improvements were seen at week 2 for both the 1- and 10-mg/kg infliximab treatment groups. Maximal improvement ranged from 55 to 98%, with most measurements of disease activity improving 70% or more. Detailed time-response profiles for four disease-activity assessments are shown in Figure 6. There was no difference in magnitude of improvement between the 1- and 10-mg/kg infliximab treat-

Figure 6 Rheumatoid arthritis disease activity assessments. Values are means of 24 patients at each point (25 for 1-mg/kg group). • = placebo, O = 1 mg/kg infliximab, and ■ = 10 mg/kg infliximab. Significance versus placebo: *P < .05, P < .01, P < .001. (Modified from ref. 53.)

ment groups, but the duration of response was longer in patients receiving the 10-mg/kg dose (53). The results also suggested that a multiple infusion regimen would be necessary to control chronic inflammatory processes in RA.

Controlled Study of Infliximab With or Without Concomitant Methotrexate Therapy

The next trial evaluated the efficacy and safety of multiple infusions of inflix-imab both with and without methotrexate (MTX), which is currently one of the most effective DMARD used for the treatment of RA (54). The rationale for studying infliximab and MTX in combination is that it is likely that new anticytokine therapies would be used in combination with existing drugs (55).

Patients with active RA who were being treated with MTX for a minimum of 6 months before study entry were enrolled into this trial. A total of 101 patients were randomized to one of seven treatment groups. The patients received either intravenous infliximab at 1, 3, or 10 mg/kg, with or without MTX 7.5 mg/day, or intravenous placebo plus MTX 7.5 mg/day at weeks 0, 2, 6, 10, and 14 and were followed through week 26 (56). All patients had to have active disease, defined as the presence of six or more swollen joints and at least one of the following: morning stiffness of at least 45 min, six or more tender/painful joints, ESR of at least 28 mm/h, or CRP of at least 15 mg/L.

Approximately 60-70% of patients receiving infliximab at 3 or 10 mg/ kg with or without MTX achieved the 20% Paulus criteria for a median duration of 10.4 to >18.1 weeks (P-values vs placebo control <.001). An analysis of Paulus 50% responses, which gave an indication of the magnitude of the response, demonstrated initial response rates of about 50-60% and the benefit was generally sustained until exit from the study at 26 weeks (Fig. 7) (56). Longer periods of response were observed when infliximab and MTX were given together, although the differences between infliximab with and without MTX did not reach statistical significance. No dose-response relationship was noted between the 3- and 10-mg/kg doses.

At infliximab 1 mg/kg there was a significant difference among the treatment groups receiving MTX or not receiving MTX in duration of clinical response assessed by the Paulus 20% index (16.5 weeks with MTX vs 2.6 weeks without MTX, P = .001) (Fig. 8). These results show that the most pronounced synergistic effects between infliximab and MTX occur at low doses of infliximab.

A measure of the level of disease control during the trial was demonstrated by the reduction in the individual assessments of disease activity. Following therapy with infliximab, with or without MTX, there was improvement

Figure 7 Efficacy of infliximab therapy based on Paulus 20 and 50% criteria. Results obtained with 3 and 10 mg/kg infliximab with ( + ) or without ( —) methotrexate (MTX) and placebo + MTX. Results shown in the top panel are the total time of response, as median and interquartile (IQ) range, whereas the bottom panel represents the proportion (%) of patients responding at weeks 1, 2, 4, 8, 16, and 26, all patients being included at each time point. • = infliximab + MTX; O = infliximab — MTX; ■ = placebo + MTX. Arrows indicate the times of infusion. (Modified from ref. 56.)

Figure 7 Efficacy of infliximab therapy based on Paulus 20 and 50% criteria. Results obtained with 3 and 10 mg/kg infliximab with ( + ) or without ( —) methotrexate (MTX) and placebo + MTX. Results shown in the top panel are the total time of response, as median and interquartile (IQ) range, whereas the bottom panel represents the proportion (%) of patients responding at weeks 1, 2, 4, 8, 16, and 26, all patients being included at each time point. • = infliximab + MTX; O = infliximab — MTX; ■ = placebo + MTX. Arrows indicate the times of infusion. (Modified from ref. 56.)

Figure 8 Efficacy of infliximab therapy based on Paulus 20 and 50% criteria. Results obtained with 1 mg/kg infliximab with ( + ) or without ( —) methotrexate (MTX) and placebo + MTX. Results shown in the top panel are the total time of response, as median and interquartile (IQ) range, whereas the bottom panel represents the proportion (%) of patients responding at weeks 1, 2, 4, 8, 16, and 26, all patients being included at each time point. • = infliximab + MTX; O = infliximab — MTX; ■ = placebo + MTX. Arrows indicate the times of infusion. The Paulus response is achieved by improvement in four of six of the following: 20 or 50% improvement in tender joint scores, swollen joint scores, duration of morning stiffness, erythrocyte sedimentation rate (ESR), or a two-grade improvement in the patient's and observer's assessment of disease severity. (Modified from ref. 52.)

Figure 8 Efficacy of infliximab therapy based on Paulus 20 and 50% criteria. Results obtained with 1 mg/kg infliximab with ( + ) or without ( —) methotrexate (MTX) and placebo + MTX. Results shown in the top panel are the total time of response, as median and interquartile (IQ) range, whereas the bottom panel represents the proportion (%) of patients responding at weeks 1, 2, 4, 8, 16, and 26, all patients being included at each time point. • = infliximab + MTX; O = infliximab — MTX; ■ = placebo + MTX. Arrows indicate the times of infusion. The Paulus response is achieved by improvement in four of six of the following: 20 or 50% improvement in tender joint scores, swollen joint scores, duration of morning stiffness, erythrocyte sedimentation rate (ESR), or a two-grade improvement in the patient's and observer's assessment of disease severity. (Modified from ref. 52.)

in all of these measurements, which at 3 and 10 mg/kg generally exceeded 60-70% improvements from baseline. Changes in the swollen joint count, tender joint count, and CRP are shown in Figure 9 and demonstrate a marked and sustained improvement, achieving near remission levels, especially when infliximab and MTX were given in combination (56).

In summary, infliximab was effective and well tolerated when given as multiple infusions with the best results at 3 and 10 mg/kg alone or in combination at these doses with MTX. Synergy was observed with infliximab at 1 mg/ kg when given with MTX. The results of the trial provided a strategy for

Figure 9 Serial measurements (median values) of the swollen joint count, tender joint count, and C-reactive protein (CRP) level, which are part of the ACR core set of outcome measures, before (day 0), during (weeks 1-14), and after (weeks 14-26) treatment. Arrows indicate the times of infusions. Median results are included only up to the point at which >50% of the original number of patients remained in the trial (up to week 6 for the placebo + methotrexate (MTX) group, and up to week 14 for the infliximab 1 mg/kg without MTX group). (Modified from ref. 56.)

Figure 9 Serial measurements (median values) of the swollen joint count, tender joint count, and C-reactive protein (CRP) level, which are part of the ACR core set of outcome measures, before (day 0), during (weeks 1-14), and after (weeks 14-26) treatment. Arrows indicate the times of infusions. Median results are included only up to the point at which >50% of the original number of patients remained in the trial (up to week 6 for the placebo + methotrexate (MTX) group, and up to week 14 for the infliximab 1 mg/kg without MTX group). (Modified from ref. 56.)

further evaluation of the efficacy and safety of longer term treatment with infliximab.

Single-Dose Study of Infliximab in Patients with Active RA Receiving Methotrexate Therapy and Repeated-Dose Treatment Extension Study. This was another controlled study evaluating the safety and efficacy of a single dose of placebo, 5, 10, or 20 mg/kg of infliximab in patients with active RA receiving MTX, and also evaluated repeated treatments with three 10-mg/kg infusions of infliximab given 8 weeks apart.

Patients in the study had to have active disease despite having received treatment with MTX for at least 3 months before screening. Patients were stabilized at a dose of 10 mg/week MTX for at least 4 weeks before screening.

Twenty-eight patients received an initial infusion of placebo, 5, 10, or 20 mg/kg of infliximab (seven patients per treatment group). Twenty-three patients received retreatment with one or more open-label infusions of inflix-imab 10 mg/kg.

The American College of Rheumatology (ACR) definition of improvement was the basis for determination of clinical response (57). Other measures of efficacy consisted of the individual clinical and laboratory response parameters that comprise the ACR core set of outcome measurements (the number of swollen joints; number of tender joints; assessment of pain by a visual analog scale [VAS]; physician's and patient's global assessments [VAS]; health assessment questionnaire; ESR; and CRP).

The serum concentration of infliximab showed dose-proportional differences at any given follow-up visit following a single infusion of 5, 10, or 20 mg/kg. With infliximab retreatment, the serum concentration of infliximab demonstrated stable pharmacokinetics.

Single-dose Blinded Study. The proportion of patients who responded according to ACR 20% improvement at any time during the 12-week postinfusion period was significantly higher among all infliximab-treated patients (81.0%) compared to the placebo group (14.3%). There was no relationship to infliximab dose for the number of patients responding at any time (range 71.4-85.7% for the three infliximab treatment groups) (58).

Repeated Treatment Open-label Extension. The clinical benefit obtained during the single-dose blinded study following infliximab was maintained through the last evaluation (12 weeks after the last retreatment, a total of 40 weeks) of the retreatment extension (59).

This study provided additional dose-response information on beneficial effects of infliximab for treatment of RA, and suggested that repeated treatment with infliximab every 8 weeks was well tolerated, was associated with a stable pharmacokinetic profile, and was capable of sustaining the initial treatment benefit of infliximab.

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