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Etanercept (Enbrel®) Etanercept (Enbrel®) The purpose of this study was to determine the dose response and efficacy of intraarticular injections of etanercept as an alternative medication for steroid injections in joints with active arthritis.
Methods: This was a double-blind, controlled study. 26 rheumatoid arthritis (RA) patients with active synovitis of at least 2 joints, preferably symmetrical, were randomized to receive 2, 4, or 8 mg etanercept injections in one joint while the other joint served as a control. The joints included 16 wrists, 6 MCP, PIP, DIP, or MTP joints, 2 elbows, and 2 ankles. Disease activity before the injection was evaluated clinically and by MRI and ultrasonography (UL). On UL, the pixels on the color Doppler images were calculated as a fraction of the total synovial area. Needle placement and injection was verified by ultrasound.
Results: Because the 2 and 4 mg dose of etanercept was not efficacious in all patients, 8 mg was chosen for the remainder of the study. Visual analog scales (VAS), normalized to the level at onset (1.0) decreased after 1 week in 23 of 25 patients (median 0.62) and after 1 month in 14 of 25 patients (median 0.60). UL decreased after 1 week in 18 of 25 patients (median 0.87) and after 1 month in 21 of 25 patients (median 0.91). One DIP after 2 mg and one wrist after 4 mg showed no activity by UL. One patient reported relief in joints other than the injected wrist.
Conclusion: These data indicate that intraarticular injections of etanercept into joints with active synovitis are efficacious and may serve as an alternative to steroid use.
Editorial Comment: Mostly small joints were injected in this study and these are difficult to assess clinically. It would be interesting to utilize paired knees in this analysis to determine what happens to cell number in the synovial fluid, as well as synovitis by MRI. Another study comparing etanercept to intraarticular steroids would also be of interest, particularly with regard to durability of the response. Intraarticular steroids are inexpensive and have a prolonged effect. It seems doubtful that the cont-benefit ratio of etanercept could exceed that of steroids for intraarticular injection. OP0098 SAFETY OF TNF-ALPHA ANTAGONISTS IN PATIENTS WITH RHEUMATOID ARTHRITIS AND CHRONIC HEPATITIS C Since many rheumatoid arthritis (RA) medications have proven to be hepatotoxic, treating patients with RA who also have hepatitis C has been challenging. The purpose of this study was to determine the effects of TNF inhibitors on the viral load and liver function in patients with RA and chronic hepatitis C. Methods: 22 patients were studied, 16 retrospectively and 6 prospectively. LFTs (albumin, alkaline phosphate, AST, ALT) expressed as percentage of upper limit and HCV viral load (PCR) expressed as mean log viral load were measured at baseline, 1-6, 7-12, and >12 months. Retrospective patients were taking either etanercept or infliximab while all prospective patients were given etanercept. Data below are expressed as the mean percent of the upper limit of normal + SD (median) except viral load is expressed as mean log + SD (number of patients). Results:
No statistical differences over time were seen in any of the parameter measured. The prospective study is ongoing. Conclusion: These data suggest that treatment with the TNF inhibitors, etanercept and infliximab, does not have an effect on the viral load or LFTs of RA patients with chronic stable hepatitis C. Editorial Comment: This is a small, primarily retrospective study without a control arm. No firm conclusions can be drawn. However, it is encouraging that there was no gross worsening of LFTs or viral load during the treatment. OP0099 SERIOUS INFECTION REPORTS WITH ETANERCEPT (ENBREL) THERAPY The relationship between serious infection, requiring hospitalization or parenteral antibiotics, and TNF antagonist therapy in patients with rheumatoid arthritis (RA) is not fully understood. Methods: This study explored the worldwide etanercept safety database through 9/1/01 to provide insight. 117,000 patients, most with RA, were included in their analysis. Results: The average age of RA patients in etanercept clinical trials is 52 years, with 58% receiving concurrent corticosteroids. The rate of serious infections is 4.1/100 patient-years, within range of non-TNF therapy, with no cumulative increase in infections over five years of observation. No serious opportunistic infections have been observed. The average age of RA patients receiving commercial etanercept therapy is also 52 years, with 50% receiving concurrent corticosteroids. While unable to compare to incidence from clinical trails because of incomplete event capture, the rate of serious infections from post-marketing adverse event reports is 0.7/100 patient-years, with no changes over time. 67% of patients reporting serious infection were taking corticosteroid and had an average of 2 comorbidities. No clear temporal association existed between start of etanercept therapy and infection. The rate of reported opportunistic infections is .04/100 patient years with 83% of these patients receiving concurrent corticosteroids and or immunosuppressive drugs. Conclusions: These data suggest that the rate of serious infections in RA patients receiving TNF antagonist therapy is similar to that prior to TNF therapy and are associated with concurrent medications and comorbidities. Editorial Comment: Post-marketing data have considerable inherent selection bias particularly under-reporting of adverse events. Nonetheless, until long-term patient registry information is available, this is the main method for tracking adverse events for a commercially-marketed drug. The continued relatively good safety profile of etanercept is encouraging. However, in view of the under-reporting nature of safety surveillance, vigilant observation of etanercept treated patients for infection is still recommended. OP0071 SWITCHING BETWEEN ETANERCEPT AND INFLIXIMAB: DATA FROM THE STOCKHOLM TNF-ALPHA ANTAGONIST REGISTRY (STURE) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Infliximab (Remicade®) OP0071 SWITCHING BETWEEN ETANERCEPT AND INFLIXIMAB: DATA FROM THE STOCKHOLM TNF-ALPHA ANTAGONIST REGISTRY (STURE) The mechanism of action of etanercept and infliximab is identical (except etanercept also inhibits lymphotoxin). It has been unclear therefore, whether there is a benefit to switch from one to the other if an inadequate clinical response is achieved with the first. Three abstracts were presented that addressed this issue, one of which is summarized here. Methods: 25 patients were identified who had received both infliximab and etanercept at different times during a clinical trial where ACR outcome criteria and DAS28 were assessed at baseline, 3, 6, 12 months, and semi-annually thereafter. Results: 11 patients (9 with RA) switched from infliximab to etanercept, reasons including infusion reaction (6/11), liver toxicity (2/11), and miscellaneous (3/11).
14 patients (10 with RA) switched from etanercept to infliximab, reason being insufficient clinical response in all patients.
The overall clinical impression was of better efficacy in 67% of patients, same (albeit modest) efficacy in 22%, and lack of effect from either treatment in 11%. Conclusions: These data suggest that switching to an alternative TNF inhibitor after failure with a first can have therapeutic benefit. Editorial Comments: These data are uncontrolled and the number of patients studied is very small. Nonetheless, the preliminary data are interesting in suggesting that benefit may be attained by movement in either direction. It is interesting however that the reason for switching from infliximab to etanercept was most commonly due to side effects, while in reverse, lack of efficacy was cited most frequently. We will have to await the study of larger numbers of patients to see if these trends hold true. ((top of page)) (top of section) Adalimumab (D2E7) This abstract reports the results on safety and efficacy of a 6 month, open-label continuation study with adalimumab-treated patients (a total of 12 months of therapy). The data from the initial dosing trial are summarized in last years highlights. (see summary) Methods: In the initial trial, patients received one of 3 doses of adalimumab; 20mg, 40mg, or 80mg every other week. 250 patients participated in the open-label trial and received 40mg of adalimumab subcutaneously every other week in combination with Methotrexate. ACR response criteria, HAQ, and joint counts, and adverse events were assessed at 12 months. Results: The data from the 231 patients that completed the study are summarized in the table below. The 6-month results are from the initial trial and combine all 3 adalimumab dosing groups.
The number of serious adverse events in patients taking adalimumab was 0.11 per patient/year (p/y) in the first 6 months of the study and 0.13 per p/y in the second 6 months. The rate of serious infections (requiring IV antibiotics or hospitalization) was 0.02 per p/y in the first 6 months of the study and 0.03 per p/y in the following 6 months. No cases of TB were reported. Conclusions: Adalimumab in combination with methotrexate shows sustained clinical efficacy after 12 months of therapy, with no increases in adverse events or serious infections. Editorial Comments: This is a 12-month followup of the ARMADA trial. ACR responses were maintained during the 2nd 6-month of the trial; however, this segment of the trial was open-label and therefore subject to observer bias. Nonetheless, long-term maintenance of responses with adalimumab is consistent with similar studies with infliximab and etanercept.
FRI0028 A RANDOMIZED, CONTROLLED, SAFETY TRIAL OF ADALIMUMAB (D2E7), A FULLY HUMAN ANTI-TNF MONOCLONAL ANTIBODY, GIVEN TO RA PATIENTS IN COMBINATION WITH STANDARD RHEUMATOLOGIC CARE: THE STAR (SAFETY TRIAL OF ADALIMUMAB IN RHEUMATOID ARTHRITIS) TRIAL In this study, the safety of adalimumab therapy in combination with concomitant medications for the treatment of rheumatoid arthritis (RA) is assessed. Methods: 636 patients with active RA were randomized to receive either 40mg subcutaneous adalimumab (n=318) or placebo (n=318) every other week for 24 weeks. Active RA was defined as > 6 swollen joints and > 9 tender joints. Primary endpoints included the number of adverse events, serious adverse events, infections, and serious infections. Results: Concomitant DMARD therapy was used by 83.5% of patients (56.0% used one, 27.5% used 2-4 concomitant DMARDs). The percent of patients on DMARDs used were: MTX 59.3%, antimalarials 24.7%, leflunomide 13.4%, sulfasalazine 9.7%, and parenteral gold 5.8%.
The rate of injection site reactions was 8.8% in the adalimumab group and 0.6% in the placebo group. No cases of TB or opportunistic infections were reported. Conclusions: Adalimumab appears to be well tolerated in patients with RA when added to pre-existing antirheumatic therapy, with no changes in rates of adverse events, serious adverse events, infections, or serious infections. Editorial Comments: These results are consistent with a similar safety trial with anakinra. In this trial, patients were likely screened for TB before entering the trial. These data are encouraging as they mimic actual practice. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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