Etanercept (Enbrel^®)
Adalimumab (Humira™)
Infliximab (Remicade^®)

Etanercept (Enbrel^®)

OP0003 CLINICAL OUTCOMES OF A DOUBLE-BLIND STUDY OF ETANERCEPT AND METHOTREXATE, ALONE AND COMBINED, IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS (TEMPO TRIAL), YEAR 2 RESULTS
L. Klareskog, D. van der Heijde, J. De Jager, J. Kalden, M. Malaise, A. Gough, E. Martin-Mola, K. Pavelka, J. Sany, L. Settas, J. Wajdula, R. Pedersen, S. Fatenejad Etanercept Study 308 Investigators

The TEMPO trial was designed to compare the safety and efficacy of etanercept and methotrexate (MTX) therapy alone and in combination in patients with active RA, who have failed prior DMARD therapy. Radiographic results are presented in abstract OP0102.

Methods: A total of 686 patients were treated with etanercept 25 mg twice weekly (n= 233), MTX up to 20 mg/weekly, or a combination of etanercept and MTX (n=231) and followed for two years.

Results: Basically, these two years of data presented here mimic the results from year 1 (see year 1 data), in that the efficacy of combination therapy with MTX and etanercept is significantly better than monotherapy with either drug alone. A DAS score of less than 1.6 is considered remission. The group receiving combination therapy achieved a higher rate of DAS remission when compared to the group receiving either etanercept alone or methotrexate alone (40.7%, 23.3%, 15.8%, respectively; p<0.05.) significantly. Additionally, ACR 20, 50, and 70 results favored combination therapy over either etanercept or MTX monotherapy.

The dropout rate was higher in the etanercept and MTX monotherapy groups, compared to the combination group (139.2 14% vs.4%, respectively; p<0.05) No additional adverse events or infections were found.

Conclusion: The clinical efficacy achieved in patients with RA receiving combination therapy of Etanercept and MTX at year 1 were maintained through year 2 of treatment. Combination therapy is significantly more efficacious than treatment with either drug alone.

Editorial Comments: These data are encouraging if not surprising. In every study combining methotrexate with a TNF inhibitor to date, the combination is more efficacious than comparator monotherapy. It is important to keep in mind, however, that ACR and DAS response criteria measured at year 2 are in those who remain in the study, and these patients tend to be those who have had good responses. This problem can always bias the data somewhat. Nonetheless, these data are solid and reassuring.

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Adalimumab (Humira™)

OP0105 EFFICACY AND SAFETY OF ADALIMUMAB (HUMIRA^®) IN EUROPEAN CLINICAL PRACTICE: THE REACT TRIAL
G.R. Burmester, I. Monteagudo Sez, M. Malaise, J. Canas da Silva, D.G. Webber, H. Kupper

Adalimumab Research in Active RA (ReAct) is an open-label, multi-center, Phase IIIb study to assess whether the treatment outcomes observed in controlled clinical trials in patients with RA following adalimumab therapy are predictive of real-life clinical outcomes.

Methods: Patients with active RA were treated with adalimumab 40mg subcutaneously every other week and ACR and EULAR responses were assessed at 12 weeks. Patients were allowed to continue any pre-existing therapy.

Results: 2008 patients were enrolled, of which 872 had complete information on prior therapy. Outcome data at week 12 are listed in the table below.

Additionally, median tender and swollen joint counts in the overall population were reduced to 3, a change of 10 and 7, respectively. Adverse events were consistent with prior controlled trials with no new events observed.

Conclusion: These results indicate that efficacy and safety outcomes in RA patients receiving adalimumab therapy in large, open-label, clinical conditions are consistent with those observed in controlled clinical trials.

Editorial Comments: Short-term outcomes in open label trials such as this can be artifactually high because of expectations of enrolled participants and absence of placebo and blinding. It will be important to see ACR and DAS responses at longer time points and to evaluate drop-out rates over time.

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Infliximab (Remicade™)
OP0183 THE SAFETY AND EFFICACY OF INFLIXIMAB THERAPY IN RHEUMATOID ARTHRITIS: RESULTS OF A LARGE, RANDOMIZED, PLACEBO-CONTROLLED TRIAL IN PATIENTS WITH VARIOUS CO-MORBIDITIES AND BACKGROUND TREATMENTS AS ENCOUNTERED IN CLINICAL PRACTICE (THE START TRIAL)
R. Westhovens, F. Wolfe, M. Rahman, J. Han, A. Berman, I. Strusberg, P. Geusens, D. Yocum: Belgium

In ATTRACT (Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy), the benchmark trial of infliximab therapy in RA, a trend toward an increased risk of serious infections was observed in the group receiving the highest dose of infliximab (i.e. 10mg/kg every 8 weeks). However, also in that trial, a higher than expected number of serious infections was observed in the group receiving placebo. These observations, along with the acknowledgment that patients enrolled in the original clinical trials may not represent general RA patients in clinical practice, prompted the initiation of this study, with a primary objective to investigate the risk of serious infections within the first 22 weeks of therapy with infliximab at different doses.

Methods: Patients with RA for greater than 3 months, six or more tender and swollen joints, stable doses of methotrexate, NSAIDS, and prednisone, and an unremarkable chest radiograph were included. Patients with a positive tuberculin skin test were included if appropriate treatment of latent TB infection had been received. Exclusions included other rheumatic conditions, chronic infections of any kind including active tuberculosis, cyclosporine treatment >5mg/kg/day, congestive heart failure, and lymphoma.

Patients were randomized into one of three groups:

1. Placebo + background methotrexate
2. Infliximab 3mg/kg administered every 8 weeks + background methotrexate
   Note - The study protocol allowed for escalation of infliximab dosing by 1.5 mg/kg at regular intervals depending on clinical response. The maximum dose of infliximab allowed in group 2 is 9 mg/kg.
3. Infliximab 10mg/kg administered every 8 weeks + background methotrexate

The primary endpoint was the development of a serious infection at 22 weeks, as identified by the clinical judgment of the individual investigators and meeting the definition of a serious adverse event. Secondary endpoints were ACR 20, 50, and 70 responses at 22 weeks.

Results: 1,084 subjects were randomized evenly between the three groups. Baseline disease characteristics were comparable and included median CRP 1.24, median HAQ 1.5, median swollen joint count and median tender joint count of 15 joints. 70% of patients were receiving methotrexate at inclusion.

The rate of serious infections at 22 weeks (primary endpoint) was equal in groups 1 and 2 (1.7 cases per 100). The rate of serious infections in group 3 (5.3 cases per 100) was significantly different from placebo (p=0.008) with a relative risk of 3.383 (95% CI 1.299-8.348).

Among the infections encountered, four pneumonias were encountered in group 3 compared to three in group 2. Three cases of tuberculosis were recorded in group 3 compared to one each in groups 1 and 2. Of particular note, all five cases of tuberculosis had negative evaluations for latent tuberculosis infection at screening (including negative tuberculin skin testing). In addition, 45 patients with a history of treated latent tuberculosis infection and 15 patients with history of treated active tuberculosis were enrolled, none of whom developed active tuberculosis on any dose of infliximab.

No cases of demyelinating disease were encountered. One case of lymphoma was diagnosed early in the course of treatment. Other malignancies were evenly distributed between the groups.

ACR 20, 50, and 70 responses were consistent with those encountered in clinical trials of infliximab.

Conclusions: The risk of serious infections, particularly tuberculosis, is increased by more than three-fold in real-world patients with RA within the first 22 weeks of treatment with infliximab at a dose of 10 mg/kg. Patients with a history of treated latent or active tuberculosis do not appear to have an increased risk of recurrent tuberculosis when treated with infliximab.

Editorial Comments: The scale of this study (1000 patients) is required to determine differences in groups for uncommon events and the investigators should be commended for their commitment. Certainly, these data suggest that doses of infliximab at 10 mg/kg should be avoided, at least as initial therapy. However, an important aspect of this study that was not presented in this session was whether the subjects in group 2 with sequential escalation of infliximab to a maximum of 9 mg/kg incurred any additional infection risk over those who remained at a dose of 3 mg/kg. Also, since no cases of tuberculosis were encountered in any of the initial studies of TNF inhibitors in RA, the five cases encountered here (including one in the placebo group) are surprising, but may illustrate the intended difference between real-life patients and those included in clinical trials. An important point is that in this multi-national multi-center trial, local clinical practice regarding tuberculin skin testing positivity was used rather than stringent standardization for the determination of latent tuberculosis infection a fact that may explain the surprising number of tuberculosis cases encountered. If it can be accepted that the subjects who developed active tuberculosis were truly PPD negative at baseline, then these data might suggest that some additional thought on screening for latent tuberculosis infection prior to the initiation of infliximab is warranted.

OP0106 A DOSE ADJUSTMENT IN PATIENTS WITH RHEUMATOID ARTHRITIS NOT OPTIMALLY RESPONDING TO A STANDARD DOSE OF INFLIXIMAB OF 3 MG/KG EVERY 8 WEEKS IS EFFECTIVE: A BELGIAN PROSPECTIVE STUDY
R. Westhovens, P. Durez, F. Van den Bosch, L. Corluy, E. Veys, L. De Clerck, A. Peretz, M. Malaise, J. Devogelaer, N. Vastesaeger; Belgium

This study examines whether infliximab is efficacious in patients with active refractory RA. Additionally, the study asks if patients can regain clinical improvement by increasing the dose of infliximab following loss of response.

Methods: Patients with active RA and prior DMARD failure were treated with IV infusions of 3mg/kg infliximab at weeks 0, 2, 6, and every 8 weeks thereafter. At week 22, patients with insufficient response or loss of response were treated with an increased dose of 100 mg infliximab beginning at week 30. ACR responses were assessed at baseline, week 6, and every 2 months thereafter.

Results: Patients (n=511) with a mean 12 years disease duration, 3.9 prior DMARDs, 29.4mg/L CRP and 15.2 swollen joint count (SJC) began treatment. At week 22, the percent of patients achieving ACR 20, 50, and 70 were 61.4%, 34%, and 14.1%, respectively, with 6.1% achieving remission. In 22% of patients, a partial loss of ACR 20 response occurred following the induction period and the infliximab dose was increased by 100mg. Patients needing a dose increase had overall higher values on baseline assessments, including TJC, SJC, HAQ, and patient and physician global activity, and pain, than those not needing a dose increase. Improvements in ACR 20 responses following a dosage increase in infliximab decayed in a significant portion of patients.

Conclusions: Patients with refractory RA can have significant clinical improvement with infliximab treatment. Additionally, a loss of clinical response to infliximab can be overcome in some patients by increasing the dose during the course of treatment.

Editorial Response: This study, similar to data presented previously from the Swedish registry, show that increasing the dose of infliximab can initially cause improved ACR 20 responses but that this response can decay over time (regression to the mean). It is important, therefore, to follow responses to dosage changes over a prolonged period of time to prove that they are truly durable.

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