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Abatacept is an investigational biologic drug for the treatment of rheumatoid arthritis and its development program was granted Fast Track status by the FDA.  

Abatacept is Bristol-Myers Squibb's first internally discovered biologic and, if approved, would be the first in a new class of agents called selective T-cell co-stimulation modulators.  

Leflunomide/MTX response maintained to 48 weeks in RA

 

Albany, New York - An open-label extension of the randomized, double-blind, placebo-controlled trial that established the efficacy of combination leflunomide (LEF)/methotrexate (MTX) in treating MTX-resistant rheumatoid arthritis (RA) showed that response is maintained to 48 weeks. Patients treated without the loading dose of leflunomide used in the original protocol had similar response rates and considerably less liver toxicity, Dr Joel Kremer (Center for Rheumatology, Albany, NY) reports in the August 2004 issue of the Journal of Rheumatology [1].

"A loading dose was used in the original study, as that was what was recommended at the time. We live and learn," Kremer tells rheumawire.

The 24-week extension study enrolled 168 of the 200 patients who had completed the 24-week double-bind study of adding placebo or leflunomide to stable MTX therapy. Patients (n=86) who had originally been randomized to added leflunomide continued that regimen (LEF 10 mg/day with MTX). This group had initially received a higher loading dose of LEF of 100 mg/day for 2 days. Patients (n=82) who had been randomized to placebo plus MTX switched after week 24 to LEF (10 mg/day) with MTX, but without the loading dose.

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The study patients all had been diagnosed with RA at least 6 months before enrollment in the initial double-blind study, and all continued to have active RA (defined by 3 of 4 criteria: 6 or more swollen joints, 9 or more tender joints, 45 minutes or longer of morning stiffness, erythrocyte sedimentation rate [ESR] of 28 mm/hour or more). Both studies were supported by Aventis Pharmaceuticals.

The primary efficacy end point was ACR20 response at week 48. Secondary end points included ACR50 and ACR70 responses, mean changes from baseline for individual ACR components and rheumatoid factor (RF), and physical function as assessed by changes in the Health Assessment Questionnaire Disability Index (HAQ DI) and health-related quality of life assessed by changes in the Outcome Study Short Form Health Survey (SF-36). Safety assessment included standard adverse-event reporting, hematology, and blood-chemistry tests, including liver-function tests.

Kremer says that the most important findings in the extension study were that the benefit observed with combined LEF/MTX at 24 weeks were durable and maintained to 48 weeks and that patients who had LEF added at 24 weeks reached ACR20-response levels similar to those who had been taking LEF/MTX throughout, although they had somewhat smaller HAQ improvements.

I would monitor AST, ALT, and serum albumin every 2 weeks for the first 4 weeks and then monthly for the first 6 months. If there are increases into the abnormal range in AST or ALT, than I would adjust the dose of either MTX or LEF downward until they disappeared.

The patients who added LEF in the extension study without taking the loading dose had strikingly less liver toxicity than those who took LEF with the loading dose in the double-blind study. "Patients who switched from placebo to LEF for the second 24 weeks of treatment without a loading dose exhibited an incidence of elevated transaminase enzymes (ALT 14.6%; AST 13.7%) that was lower than in those initially randomized to LEF with a loading dose (ALT 31.5%; AST 16.9%) but higher than in patients initially randomized to placebo (ALT 6.8%; AST 4.6%) [in the original trial]. All elevations of transaminase enzymes in this group reversed with no intervention, or a dose reduction, or discontinuation of study medication at or before the end of the study. No patient initiating LEF at week 24 discontinued due to elevated liver-function tests during the open-label phase," Kremer reports.

Kremer has some advice for clinicians starting a patient on LEF in addition to background MTX. "I would monitor AST, ALT, and serum albumin every 2 weeks for the first 4 weeks and then monthly for the first 6 months. If there are increases into the abnormal range in AST or ALT, than I would adjust the dose of either MTX or LEF downward until they disappeared. I would do the same for a significant decrease in serum albumin (for example, to <3.5 from baseline normal)," he says.

	Source   Kremer J, Genovese M, Cannon GW, et al.  Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial.   J Rheumatol 2004; 31:1521-1531.

	Related links   Arava stays on US market: FDA formally denies Public Citizen petition [Rheumawire > News; Apr 2, 2004]   First stage of leflunomide trial confirms safety, efficacy in clinical use [Rheumawire > News; Dec 23, 2003]   Liver toxicity warning added to Arava prescribing information [Rheumawire > News; Nov 25, 2003]   New details of adverse events with TNF inhibitors [Rheumawire > News; Nov 13, 2003]   Calls to modify leflunomide dosing in RA [Rheumawire > News; Oct 2, 2003]

Researchers Find Gene Linked to MS, Arthritis NEW ORLEANS, Apr 25 (Reuters Health) - A study in identical twins has uncovered a previously unknown gene with strong associations to both multiple sclerosis (MS) and rheumatoid arthritis, researchers report. The finding is "just one more piece of the puzzle" in the search to find the causes--and, it is hoped--cures for these two common, debilitating diseases, said graduate student researcher Carolyn Greene of Georgetown University in Washington, DC. She and her colleagues presented the findings here Wednesday at the annual Experimental Biology 2002 meeting. MS and rheumatoid arthritis are both autoimmune disorders, illnesses where the body's immune system inexplicably attacks healthy tissue. In MS, immune cells gradually wear away the protective myelin sheath surrounding nerve fibers in the brain and spine, leading to increasing neurological and motor impairment. In rheumatoid arthritis, tissues lining the joints become the focus of attack, causing patients pain and disability. Seeking to find genes linked to MS, Greene and her co-researchers conducted detailed comparisons of the genetic make-up of a set of identical twins, only one of whom suffered from MS. Just such a gene turned up, and was active at a rate 8.5-times higher in the MS-affected twin compared with the healthy twin. Greene said the gene appears to have been previously unknown, since it "didn't match to anything" in GenBank, the human genome database. To rule out the possibility that the finding was a fluke, the researchers then looked for the gene in a group of healthy individuals and another group of 13 MS patients. As expected, only the MS group had high levels of gene activity. The Georgetown researchers also tested individuals with other forms of autoimmune disease for high levels of gene activity. Five patients with rheumatoid arthritis tested all had high levels, Greene said. On the other hand, patients with another autoimmune condition, Crohn's disease, displayed normal levels of the gene. Greene stressed that both MS and rheumatoid arthritis are complex diseases likely to have both genetic and environmental causes. This discovery, she said, was just one step on a much longer journey. The next step is to try and determine what role the gene might play in triggering either disease.   Back to top ACR Announces New Guidelines To Treat RA Advancements in arthritis research lead to new guidelines The American College of Rheumatology (ACR) has updated its guidelines for the management of rheumatoid arthritis after just 5 years.  The new guidelines, published in the February 2002 issue of Arthritis & Rheumatism, the journal of the ACR, take into account major research advancements and the development of new treatment options.  Over 2 million Americans suffer with the autoimmune disease, rheumatoid arthritis.  The disease, characterized by symmetric, erosive synovitis (inflammation of the joints) and in some cases, systemic involvement (inflammation of other body organs) has an unpredictable course for most patients.  In spite of treatment, it is still possible for progressive joint destruction to occur, as well as deformity, disability, and premature death. The goal in the management of rheumatoid arthritis is to: prevent or control joint damage prevent loss of function decrease pain  The initial steps in the management of rheumatoid arthritis are to: establish the diagnosis perform a baseline evaluation (joint pain, morning stiffness, fatigue, functional status, objective evidence of disease activity, mechanical joint problems, presence of extraarticular disease, radiographic damage, physician and patients global assessment of disease activity, quantitative assessment of pain) estimate the prognosis If the primary care physician is uncertain about any of the initial steps, the ACR strongly recommends that an evaluation be done by a rheumatologist (a specialist in arthritis and related diseases). The initiation of treatment begins with: patient education the start of DMARDS within 3 months of diagnosis for most patients the consideration of NSAIDS as part of the treatment plan the consideration of local or low-dose systemic steroids a consultation with a physical and/or occupational therapist for non-pharmacological treatment (joint protection, conservation of energy, range of motion and strengthening exercises) Patients taking DMARDS should be reassessed periodically for disease activity and toxicity of treatment.  Patients on DMARDS experiencing repetitive flares, unacceptable disease activity (defined as ongoing disease activity following 3 months of maximum therapy) or progressive joint damage require consideration of changes to the DMARD regimen. DMARDS commonly used to treat RA include hydroxychloroquine (plaquenil), sulfasalazine, methotrexate, leflunomide (Arava), etanercept (Enbrel), and infliximab (Remicade).  Less commonly used DMARDS include azathioprine, D-penicillamine, gold salts, minocycline, and cyclosporine. Many factors influence the selection of a particular DMARD.  Initial selection of a DMARD is based on:   relative efficacy convenience of administration requirements of monitoring program cost of medication and monitoring Patient factors which should be assessed in selecting a DMARD: likelihood of compliance comorbid conditions severity and prognosis of patients disease physicians own confidence in administering and monitoring the drug For many years, low cost treatment options existed for RA.  With the advancements in research and the availability of newer NSAIDS (COX-2 Inhibitors), and the biologic agents (Enbrel, Remicade, and Anakinra), cost consideration has become an integral part of the decision when choosing between treatment options. Efficacy and toxicity - if equivalent when comparing different treatment options, it is likely the lower cost agent will be used.  Not all treatments are equivalent in response however, and a trial of the newer,  more expensive drugs can be justified.  What's different in the new guidelines is the issue of "how" these newest targeted drugs work, and also the issue of affordability. REFERENCES: Guidelines For The Management Of Rheumatoid Arthritis - 2002 Update Online at http://www.rheumatology.org   Back to top FDA Approves Remicade (Infliximab), In Combination With Methotrexate, For Rheumatoid Arthritis MALVERN, PA -- January 2, 2001 -- The U.S. Food and Drug Administration (FDA) has approved a drug to inhibit the progression of joint damage in patients with rheumatoid arthritis, a chronic and debilitating disease that affects 2.1 million Americans, mostly women. The FDA granted marketing approval to Remicade® (infliximab), in combination with methotrexate, for inhibiting the progression of structural damage in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate. "For the first time, we now have a drug that can inhibit the progression of joint damage as well as control the pain and stiffness associated with this disease," said Michael Spiegel, M.D., ATTRACT trial investigator, Danbury, CT. "This is excellent news for patients. Remicade can have a tremendous impact on patients." Remicade with methotrexate was first approved for marketing in October 1999 for the treatment of signs and symptoms of rheumatoid arthritis in patients who have had an inadequate response to methotrexate. In patients with rheumatoid arthritis, joint damage is evident as narrowing of the joint space between bones and erosion of the bones at the joint space. Remicade inhibits both of these conditions. "Joint damage progression in rheumatoid arthritis has two key components, joint space narrowing and joint erosion. Clinical data demonstrates that Remicade inhibits not only joint erosions but joint space narrowing as well. This provides considerable benefit to patients while also improving the pain and stiffness associated with the disease," said Thomas Schaible, PhD, senior director, medical affairs, Centocor. Approval was based on 54-week data from the two-year ATTRACT trial (Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy), one of the largest and longest controlled rheumatoid arthritis clinical trials involving 428 patients at 34 centers in North America and Europe. In the double blind, placebo-controlled, randomized clinical study, patients treated with Remicade in combination with methotrexate were compared to those patients treated with methotrexate plus a placebo. Methotrexate is a standard treatment for many patients with rheumatoid arthritis. In the ATTRACT trial, progression of joint damage was measured radiographically using the van der Heijde modified Sharp system, which evaluates changes in joint-space narrowing and bone erosion on a 5-point scale (a higher score indicates more damage). Among all Remicade treatment groups, overall median change from baseline for radiographic scores of 0.0 were reported among patients treated with the combination of Remicade plus methotrexate (n=285) compared to a median change of 4.0 for patients treated with methotrexate alone (n=63). A total of 53 percent of Remicade patients demonstrated 0 percent progression . The methotrexate-only findings (control arm) demonstrated progression comparable to that previously reported for patients with established rheumatoid arthritis treated with methotrexate. Patients on Remicade plus methotrexate also reported significantly greater relief from the pain and stiffness of the disease as well as a reduction in the number of swollen and tender joints. After 54 weeks of therapy, more than half (52 percent) of those treated with Remicade and methotrexate experienced a reduction in the signs and symptoms of RA as measured by ACR 20, a standard assessment for disease activity, compared to 17 percent of patients receiving methotrexate alone. "The prospect of having a therapy that can actually inhibit the damage caused by rheumatoid arthritis is extremely exciting," said Virginia Ladd, president and executive director of the American Autoimmune Related Diseases Association (AARDA). "Rheumatoid arthritis patients and their doctors will now have a new tool at their disposal for managing this terrible disease." In the clinical trials, Remicade was generally well tolerated. The most common adverse events included upper respiratory infection, headache, mild reactions to the infusion, sinusitis, rash and cough. There was no increased incidence of serious adverse events or serious infections in patients receiving Remicade and methotrexate compared to those receiving placebo and methotrexate. The incidence of infusion reactions was also low in Remicade plus methotrexate patients (approximately three percent) for any given infusion compared to those receiving methotrexate alone (approximately two percent). TNF-alpha mediates inflammation and cellular immune response including response to infection. Serious infections, including sepsis and disseminated tuberculosis, have been reported in patients receiving TNF-blocking agents, including Remicade. Some of these infections have been fatal. Many of the serious infections in patients treated with Remicade have occurred in patients on concomitant immunosuppressive therapy that, in addition to their Crohn's disease or rheumatoid arthritis, could predispose them to infections. Caution should be exercised when considering the use of Remicade in patients with a chronic infection or a history of recurrent infection. Remicade should not be given to patients with a clinically important, active infection. Patients should be monitored for signs and symptoms of infection while on or after treatment with Remicade. New infections should be closely monitored. If a patient develops a serious infection including sepsis, Remicade therapy should be discontinued. Patients should be evaluated for the risk of tuberculosis, including latent tuberculosis. Treatment for tuberculosis should be initiated prior to treatment with Remicade. Remicade and other agents that inhibit TNF have been associated in rare cases with exacerbation of clinical symptoms and/or radiographic evidence of de-myelinating disease. Prescribers should exercise caution in considering the use of Remicade in patients with pre-existing or recent onset of central nervous system de-myelinating disorders. Remicade was initially cleared for marketing in the US in 1998, for short term use in patients with Crohn's disease, a serious gastrointestinal disorder. Centocor currently markets Remicade in the United States. Schering-Plough Corporation has rights to Remicade in all other countries throughout the world, except in Japan and parts of the Far East where Remicade will be marketed by Tanabe Seiyaku, Ltd. Related Links: Remicade (infliximab), Centocor and Schering-Plough Corporation.

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