Rheumatoid Arthritis Treatments
Joan Bathon, M.D. and Alan Matsumoto, M.D.
TNF Inhibitors-Long-term Followup
Abstracts #1216-1221 Long-term Followup of Treatment of RA with New Therapies (Enbrel®, Remicade®, D2E7 and Arava®)
Six abstracts were presented outlining the long-term efficacy and safety of new therapies for patients with advanced RA. Three of the therapies reviewed were anti-tumor necrosis factor (TNF) agents, including Remicade® (a chimeric anti-human TNF monoclonal antibody; administered with methotrexate), Enbrel® (a soluble p75 TNF receptor), and D2E7 (a fully human anti-TNF antibody; not yet FDA approved). For Remicade and Enbrel, 2 year followup data were presented. For D2E7, 1 year followup data were presented. Two-year followup data for Arava®, a non-biologic new agent for RA, were also presented. Patients who had been enrolled in double-blind trials (see previous ACR and EULAR highlights) were invited to participate in a long-term open-label treatment phase for each of the agents. In general, for all 4 agents, clinical responses were sustained, and the therapies were well tolerated with no unexpected adverse events emerging during the followup period. Rates of incident serious infections and malignancies were low and not above reported rates for the general population (in the case of malignancies) or for RA population (in the case of infections). In addition, Enbrel® and Remicade® continued to be effective in preventing or slowing radiographic progression during the second year. In one of the Enbrel trials, patients received both Enbrel and methotrexate. In long-term followup of these patients, 28% of patients were able to discontinue MTX entirely while 68% were able to decrease the dose of MTX (while remaining on Enbrel®). In addition, 42% of patients were able to discontinue prednisone completely, while 67% were able to decrease the dose (while remaining on Enbrel®).
Editorial Comments: These data are encouraging as these agents constitute very important, efficacious new therapies for RA (although D2E7 is not yet FDA approved). However, keep in mind with clinical trial data that: 1) Patients who were poor responders in the double blind phase are likely to have dropped out of the study; and, 2) Patients enrolled in clinical trials are carefully selected and may not be representative of the general RA population. Thus, once a drug is FDA approved, it is important to conduct post-marketing surveillance to watch for unexpected adverse events. Several abstracts by the FDA during these meetings, for example, reported more tuberculosis, and rare cases of a multiple sclerosis-like illness, in patients treated with anti-TNF therapies than observed in clinical trials. (see late-breaking abstract below) While these reports are not causes for alarm, screening for past or current TB and avoidance of anti-TNF agents in established multiple sclerosis seems prudent at this time.
Late-Breaking Abstract Postlicensure Reports of Infections During the Use of Etanercept and Infliximab S Gershon, R Wise, M Niu, J Siegel. Food and Drug Administration, Rockville, MD.
The FDA Adverse Event Reproting System (AERS) receives spontaneous reports of adverse events from health care providers wordwide and do not necessarily imply that the drugs are causative. Etanercept has been approved for RA since 1998 and infliximab has been approved for Crohn's since 1998 and RA since 1999. Approximately 80,000 doses of etanercept has been used and 80,000-150,000 doses of infliximab has been given in both RA and Crohn's. Approximately 13,000 adverse events have been reported with etanercept and 1,100 adverse events reported with infliximab. Of these, 22% describe infectious complications. There have been a few reports of fungal infections, listeria, herpes infections, and pneumocystis reported in both the etanercept and infliximab patients without pattern. Tuberculosis has been the most common reported infection with 17 cases (11 European, 6 U.S.) in infliximab treated patients and 3 cases in etanercept patients (U.S.), including 1 soft tissue TB infection and 1 milliary TB case.
Editorial Comments: It is difficult to extrapolate form this data, the risk of TB or other infections with the use of the TNF inhibitors. The reporting is voluntary and health care providers as well as patients may submit reports. Verification of cases is difficult and cases may be reported more than once. The numbers of cases to date from all infections appears to be very small. The higher number of total adverse events reported with etanercept compared with infliximab likely reflects its earlier approval in the U.S. As well, the greater number of TB cases reported with infliximab might be explained by it greater use in Europe which has a higher rate of TB and where skin testing for TB is more difficult because of the use of TB vaccination. The value of this abstract is to alert clinicians to the potential of these infections and to consider TB testing by chest x-ray or skin testing in patients with greater risk of TB exposure.
Leflunomide
Abstract #1216-948 The Combination of Leflunomide (Arava®) and Methotrexate (MTX) in Patients with Active Rheumatoid Arthritis (RA) who are Failing on MTX Treatment Alone: A Double-Blind Placebo Controlled Study J Kremer, J Caldwell, G Cannon, M Genovese, J Cush, J Bathon, J Coleman. Baltimore and Kansas City.
Patients with active RA while on MTX (mean dose = 16-17 mg/wk) were randomized to receive leflunomide (LEF) or placebo (PL). Dosing of leflunomide was 100 mg loading dose followed by 10 mg qd with option to increase to 20 mg qd. The ACR20 response rates at 24 weeks (defined as the primary endpoint) were 46.2% for the LEF + MTX group and 19.5% for the PLC + MTX group. Using the last observation carried forward (LOCF) methodology, the ACR 20, 50 and 70 responses for LEF + MTX were 51.5%, 26.2% and 10.0%, respectively, vs 23.3%, 6.0%, and 2.3%, respectively, for PLC + MTX. Drug related adverse events included diarrhea (22% for LEF + MTX vs 10% for PL + MTX), nausea and dizziness. Increases in LFTs of > 3XULN at any time during the 24 week treatment period for ALT and AST were uncommon (2.3% and 1.5% for LEF + MTX vs 0.8% and 0.0% for PL + MTX).
Editorial Comments: The addition of leflunomide to MTX in a patient who has responded inadequately to MTX, confers a significant advantage over MTX alone and the combination is well tolerated. These results are encouraging since there was concern at the outset that hepatic toxicity would be higher given the fact that both MTX and LEF are potentially hepatotoxic.
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Etanercept
Abstract #1947 Randomized controlled trial of 25 mg vs 50 mg Enbrel® (etanercept) twice weekly in rheumatoid arthritis (RA) M Schiff, P Mease, M Weinblatt, L Moreland, D Burge. Denver, Seattle, Boston, Birmingham.
Etanercept is recommended currently at a dose of 25 mg twice weekly. This study was undertaken to determine whether a higher dose is safe and provides additional efficacy for treatment of RA. The bottom line in this study was that patients treated with 50 mg twice weekly had more rapid improvement in signs and symptoms of RA but, by the end of 6 months, responses were identical to those receiving 25 mg twice weekly.
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D2E7
Abstract #1948 A Dose Escalation Study Designed to Demonstrate the Safety, Tolerability and Efficacy of the Fully Human Anti-TNF Antibody, D2E7, Given in Combination with Methotrexate (MTX) in Patients with Active RA M Weisman, E Keystone, H Paulus, M Weinblatt, D Furst, L Moreland, R Velagapudi, S Fischkoff, E Chartash.
D2E7 has been shown to be efficacious in relieving signs and symptoms of RA in studies comparing it to placebo. In this trial, D2E7 (in increasing doses given IV q 2 wks) was added to a background of MTX in patients who had had inadequate responses to MTX alone. The bottom line here is that all doses of D2E7 were well tolerated, and all doses provided substantial clinical improvement (ACR20 responses of 60-70% at all doses). Interestingly, the half-life of MTX was prolonged from 15 to 19 days in the presence of D2E7.
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B-Lymphocyte Depletion
Abstract #1950 Sustained Improvement in Rheumatoid Arthritis Following B-Lymphocyte Depletion J Edwards, G Cambridge, M Leandro.
Rituximab is a monoclconal antibody directed against the B-lymphocyte surface marker CD20 and has been used for the treatment of B-cell lymphomas. The current study uses rituximab, cylcophosphamide and prednisolone to deplete the peripheral B-lymphocyte population to treat refractory rheumatoid arthritis. In an open label trial 5 patients with severe RA (>5 DMARD failures, functional class III, mean disease duration 22 years) underwent a 3 week course of rituximab 2.1 gm, cyclophosphamide 750 mg IV x 2, and prednisolone 60 mg x 10 days, 30 mg x 12 days. Mean follow-up was 17 months. At 6 months, all patients achieved ACR 50 improvement while 3 achieved ACR 70 improvement. Two patients relapsed at 7 and 9 months respectively, but achieved ACR 70 with retreatment. Adverse events were mild in the five patients.
Editorial comment: The obvious limitations of the study which the authors acknowledge are the very small number of patients and the open label trial design. However, this is a very interesting study from the perspectives of a promising therapy and a new insight into the pathogenesis of RA. In terms of treatment, this finding will need to be verified in a larger trial. However despite the limitations, this is a very impressive result with marked improvement in the most severe and refractory RA population. Clearly, this is an aggressive regimen and toxicity will need to be evaluated as well. Although the autoreactive B cell and rheumatoid factor has been described for years, this study should renew interest in their role in the pathogenesis of RA.
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IL-1 Receptor Antagonist
Abstract #1332 Treatment with Anakinra Reduces the Rate of Joint Destruction and Shows Accelerated Benefit in the Second 6 Months of Treatment for Patients with Rheumatoid Arthritis H Genant, B Bresnihanm, E Ng, S Robbins, R Newmark, D McCabe. San Francisco, Dublin, Amgen, California.
This paper presents the radiographic data from a double blind placebo controlled trial of 472 RA patients who received anakinra (IL-1ra) (30, 75, or 150 mg) or placebo. After the first 6 months of the trial patients treated with placebo were randomized to receive one of the three anakinra doses for an additional 6 months. In the first 6 months, anakinra treated patients increased on average 1.86 Sharp unis , while the placebo group increased 3.61 Sharp units (p=.002). Joint space narrowing increased 0.66 units in the anakinra group versus 1.58 for the placebo group (p=0.002), and for erosions, 1.2 units for the anakinra group, 2.03 for the placebo. These differences were sustained in the next 6 months of the trial.
Editorial Comments: Anakinra has already been shown to produce significant ACR 20 improvement in patients with active RA. This study provides important information that anakinra retards x-ray damage as well. We now have several agents with disease modfying ability-- methotrexate, leflunomide, etanercept and infliximab, and the demonstration of slowing x-ray changes has become the new standard for this class of agents. How anakinra compares with these other agents is impossible to tell from this information.
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COX-2 Inhibitors-Gastrointestinal Safety Studies
Abstract #949 Fewer Gastrointestinal Protective Agents, Procedures and Hospitalizations with Rofecoxib vs Naproxen in the VIGOR (Vioxx GI Outcomes Research) Study C Bombardier, L Lane, A Reicin, D Watson D Ramey, P Reagan. Toronto ON, Canada, Los Angeles, CA and Rahway,NJ.
This abstract and the accompanied abstract 950 present the data of a large prospective study of GI outcomes in rheumatoid arthritis patients treated with rofecoxib vs. naproxen. In the trial 8076 patients were randomized to receive rofecoxib 50 mg daily or naproxen 500 mg bid and followed for a mean duration of 9 months. The results for the following outcomes were presented:
Upper GI perforation, ulcer or bleeding (PUB)
| Rofecoxib | 2.1% per year | relative risk 0.46 |
| Naproxen | 4.5% per year |
New gastroprotective agents (H2 antagonists, sulcrafate, proton pump inhibitors) after trial initiation
| Rofecoxib | 11.2% | p<0.001 |
| Naproxen | 14.5% |
Investigator initiated GI procedures (upper/lower endoscopy, CT abd, abd US, exploratory laporatomies)
| Rofecoxib | 5.6% | p=0.02 |
| Naproxen | 6.9% |
Editorial Comment: This study and other studies comparing the GI effects of the new selective COX-2 inhibitors with older non-selective NSAIDs are important because they assess clinically relevant outcomes, not short term endoscopic differences. This study shows a clear benefit of rofecoxib over naproxen in GI complications including dyspepsia, GI bleed, ulcer and perforation. The accompanied study Abstract 950 showed similar results but interestingly also showed benefit of rofecxoxib over naproxen even in those patients classified as low risk for GI toxicity. Analysis showed that the number of patients needed to treat (NNT) with rofecoxib to prevent one GI event was 41. There were only small number of patients in this study who were taking low dose aspirin for heart attack or stroke prophylaxis. An area of recent controversy has been raiased by a recent study showing that there was no benefit of the COX-2 inhibitors over older non-selective NSAIDs in patients taking low dose aspirin.
Abstract #1907 Celecoxib is associated with lower incidence of serious GI toxicity relative to non-steriodal antiinflammatory drugs (NSAIDS)- The Celecoxib long-term arthritis safety study (CLASS) F Silverstein, L Simon for the CLASS investigators, Seattle WA, Boston, MA and Skokie IL.
(see Osteoarthritis-Treatments)
