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| TNF Inhibitors | ||||||
Etanercept (Enbrel®) | ||||||
| Etanercept (Enbrel®)
FRI0019 Efficacy of Etanercept on Tenosynovitis and Rheumatoid Nodules While etanercept is efficacious in treating rheumatoid arthritis (RA), its effect on extraarticular manifestations is unclear. In this study, Dr. Kaiser et al evaluate 87 patients before and after 180 days of etanercept treatment (25 mg 2x/week) for tenosynovitis and rheumatoid nodules. Of the 72 patients that had tenosynovitis on day 0, symptoms disappeared in 12 patients, improved in 7 patients, remained unchanged in 45 patients, and worsened in 8 patients. Of the 22 nodules present in 10 of the 87 patients, all remained unchanged by day 180, with no new occurrences. These data show that etanercept is not efficacious in treating tenosynovitis or rheumatoid nodules in patients with RA. Editorial Comment: Persistent tenosynovitis and nodules are significant clinical problems that are often resistant to therapy. There is evidence to suggest that nodule formation is driven by TNFaand thus the negative outcome of the study is disappointing. | ||||||
| Infliximab (Remicade®)
FRI0070 Safety and Tolerability of Rapid Infusion of Remicade (Infliximab) in the Treatment of Rheumatoid Arthritis This study assessed the safety and tolerability of reducing infliximab infusion administration from 2 hours to 1 hour. In a multicenter, open-label clinical trial 553 RA patients received 4 infliximab infusions (2 hour administration of 3 mg/kg) at week 0, 2, 6, and 14. A subset of these patients (n=197) then participated in the study extension that consisted of 2 additional infusions (1 hour administration of 3 mg/kg) given 8 weeks apart. Swollen and tender joint counts were done in all 553 patients at baseline and 2 weeks following infusion 4 and, in the subset of 197 patients, 2 weeks following infusion 6. At baseline, the mean swollen and tender joint counts were 18.3 and 20.4, respectively. The mean swollen and tender joint counts were reduced to 7.9 and 6.6 (p<0.001), respectively following infusion 4. This reduction in mean swollen and tender joint counts was maintained in the subset of patients in the extension study receiving the rapid infusion, 7.2 and 5.6 (p<0.001), respectively. Improvements in morning stiffness, pain, and physician and patient global assessments were also maintained in this subset of patients. Adverse events were similar for both the 2-hour and 1-hour infusions. These data support the maintenance of clinical efficacy, as well as safety and tolerability, of a rapid infusion of infliximab for the treatment of RA. Editorial Comment: This study shows that patients who are tolerating 2 hour infusions of infliximab can have their infusions shortened to one hour without increased side effects or decreased efficacy. Shortening the infusion times would add convenience for both patients and physicians. The study does not address the question of whether patients starting infliximab can be infused over 1 hour without increased side effects compared with the 2 hour infusions. Since the infusion reactions are generally infusion rate related, it would seem likely that there would be more side effects using 1 hour infusions, but it would be useful to see this problem quantitated. It seems unlikely that shorter infusion times would have any effect on efficacy. | ||||||
| PEG STNF-R1
FRI0059 The Efficacy and Safety of Pegylated Recombinant Methionyl Human Soluble Tumor Necrosis Factor Receptor Type I (PEG STNF-R1; P55) in a Randomized, Placebo-Controlled, Clinical Study of Patients with Rheumatoid Arthritis (RA) This study was a phase II, multi-center, placebo-controlled clinical trial assessing the safety and efficacy of PEG sTNF-R1 in rheumatoid arthritis (RA) patients with a disease duration > 6 months (mean duration, 13-15 years). (see Phase I data) 194 patients were randomized to receive weekly subcutaneous injections of PEG sTNF-R1 (400 or 800 ug/kg) or placebo for 12 weeks. Patients were allowed to continue taking DMARDs at stable doses. ACR20 criteria was the primary endpoint, with ACR50, ACR70, and SF-36 as secondary endpoints. Measurements were taken at baseline and every 2 weeks. A statistically significant difference in ACR20 response rate was achieved by week 12 in the group of patients receiving 800 ug/kg compared to patients receiving placebo (50% and 26%, p=0.005), respectively. Differences in swollen joint count and C-reactive protein did not reach significance. Patients in the PEG sTNF-R1 treatment groups experienced a slightly higher incidence of infections compared to the patients in the placebo group, 27% vs. 21%. Slightly more noninfectious adverse events were noted in the treatment groups, including diarrhea, nausea, and dizziness. Editorial Comment: Although it is difficult to compare clinical responses from different trials, the ACR20 response rate seen in patients receiving 800 ug/kg PEG sTNF-R1 in this trial appears to be somewhat more modest than the ACR20 responses seen with the other TNF inhibitors. The duration of this trial was very short and the results need to be confirmed in larger, longer term trials Further studies are warranted perhaps using a higher dose, shorter dosing interval, and/or combination with another therapy. | ||||||
| D2E7
OP0062 The Fully Human anti-TNF Antibody Adalimumab (D2E7) in Combination with Methotrexate (MTX) in the Treatment of Active Rheumatoid Arthritis: Results of a Two Year Study
Methods: 54 patients who were partial responders to MTX were randomized to receive D2E7 1 mg/kg, either IV or SC, or placebo for the first two injections. Patients then entered an open label study receiving D2E7 1 mg/kg SC every other week or monthly depending on individual response to treatment.
Results: ACR20 responses at 6, 12, 18 and 24 months were 72%, 63%, 63%, 50% respectively. Corresponding ACR50 responses were 30%, 28%, 43% and 30%.
Editorial Comment: Given the prior positive studies with etanercept and infliximab when added to methotrexate, we would expect the combination of D2E7 to be well tolerated and efficacious. However to make this case, this study has several limitations. Sample size is very small with only 18 patients per initial treatment group. The blinded, placebo controlled portion of the study is too short to determine the true response of adding D2E7 to patients failing methotrexate or to assess adverse events. Doses of D2E7 varied at the discretion of the patients or investigators during the open label portion of the study, making it difficult to assess safety and efficacy of a particular regimen.
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OP0086 The Fully Human anti-TNF Monoclonal Antibody Adalimumab (D2E7), dose ranging study: The 24 week Clinical Results in Patients with Active RA on Methotrexate Therapy (The Armada Trial) E. Keystone, M.E. Weinblatt, M. Weisman, D. Furst, H. Paulus, C. Birbara, S. Fischkoff, E.K. Chartash
Methods: 271 patients with active RA despite stable doses of methotrexate (MTX) were randomized to receive placebo or one of three doses of adalimumab: 20 mg, 40 mg or 80 mg every other week. MTX was continued at stable doses.
Results: | ||||||
| ACR20 | 49.3% | 65.7% | 65.7% | 14.9% | ||
| ACR50 | 31.9% | 53.7% | 52.7% | 8.1% | ||
| ACR70 | 10.1% | 26.9% | 19.2% | 4.8% | ||
Editorial Comment: This trial is well designed and shows the efficacy of adalimumab when added to methotrexate. As the authors note, the ACR50 and ACR70 responses are impressive. In a similarly designed 24 week trial with etanercept added to MTX, Weinblatt et al. (New Engl J Med1999;340:253-259) showed ACR20, 50 and 70 responses of 71%, 39%, 15% with corresponding placebo responses of 27%, 3% and 0%.
