Newswise — Initial use of methotrexate combined with sulfasalazine and hydroxychloroquine is a successful way of controlling rheumatoid arthritis, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Philadelphia, Pa.
Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.
Disease-modifying antirheumatic drugs, or DMARDS as they are commonly called, are often the therapy of choice for patients with RA as they not only reduce inflammation and pain, but can slow the overall progression of the disease.
TNF-antagonists (also called biologics or anti-TNF therapy) are a class of drugs that have been used since 1998; overall, they have been given to more than 600,000 people worldwide. These drugs are given by injection and lessen inflammation by interfering with biologic substances that cause or worsen the inflammatory process.
In a recent investigator-initiated study, researchers looked at the benefit of taking either a combination of three oral disease modifying anti-rheumatic drugs (methotrexate, sulfasalazine, and hydroxychloroquine) or a combination of one DMARD (methotrexate) and an anti-TNF (etanercept) in people with RA. They also looked at the benefit of starting with combination therapy compared to “step-up” therapy, in which additional drugs were added to methotrexate when the clinical response was incomplete.
For two years, researchers followed 755 participants (who were mostly Caucasian women, with an average age of 49). The patients studied had early rheumatoid arthritis, with an average of less than four months from diagnosis, and had not yet received DMARD therapy. Patients were divided into four treatment groups: two began with combination therapy, either with methotrexate, sulfasalazine and hydroxychloroquine or methotrexate and etanercept, while two began with methotrexate then had sulfasalazine and hydroxychloroquine or etanercept added – only if they had persistent disease activity at six months.
This was a double-blind study, in which neither the patients nor their physicians knew which regimen they were receiving.
Researchers found that at six months, either combination therapy approach led to better responses than initial treatment with methotrexate alone. However, during the second year of this trial, they found no differences in the average levels of DAS28, a composite measurement of disease activity, between patients randomized to etanercept or triple DMARD therapy, regardless of whether they received immediate combination treatment or initial therapy with methotrexate with a step-up.
"Data from this investigator-initiated study provides critical information for researchers to perform additional research on the effectiveness of other treatment strategies for patients with rheumatoid arthritis,” explains Larry W. Moreland, MD; chief of rheumatology at the University of Pittsburgh, Pittsburgh, Pa., and lead investigator in the study. “Much more work is needed in order for physicians to be able to better prescribe the most effective therapies for individual patients."
The ACR is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy and practice support that foster excellence in the care of people with or at risk for arthritis and rheumatic and musculoskeletal diseases. For more information on the ACR’s annual meeting, see www.rheumatology.org/annual.
Editor’s Notes: Dr. Moreland will present this research during the ACR Annual Scientific Meeting at the Pennsylvania Convention Center at 11:45 AM on Tuesday, October 20 in Ballroom AB. Dr. Moreland will be available for media questions and briefing at 1:30 PM on Sunday, October 18 in the on-site press conference room, 109 A.
Presentation Number:1895
TEAR: Treatment of Early Aggressive Ra; A Randomized, Double-Blind, 2-Year Trial Comparing Immediate Triple DMARD Versus MTX Plus Etanercept to Step-up From Initial MTX Monotherapy
Larry W. Moreland, MD , Rheumatology & Clinical Immun, Univ of Pittsburgh, Pittsburgh, PA James R. O'Dell, MD , Medicine, University of Nebraska Med Ctr and Omaha VA, Omaha, NE Harold Paulus, M , Medicine, UCLA School of Med, Los Angeles, CA Jeffrey R. Curtis, MD, MPH , Rheumatology and Immunology, The University of Alabama at Birmingham, Birmingham, AL S.L. Bridges Jr., M , Clinical Immunology & Rheum, The University of Alabama at Birmingham, Birmingham, AL Xiao Zhang, PhD , Biostatistics, The University of Alabama at Birmingham, Birmingham, AL George Howard , Biostatistics, The University of Alabama at Birmingham, Birmingham, AL Stacey S. Cofield, PhD , Biostatistics, The University of Alabama at Birmingham, Birmingham, AL
Purpose: No direct data compares triple DMARD (methotrexate [MTX], sulfasalazine [SSZ], hydroxychloroquine [HCQ]) to MTX + anti-TNF therapy (etanercept) in patients with early RA. The relative benefit of a strategy of either combination vs MTX monotherapy with step-up after 6 months is also uncertain. The TEAR trial evaluates both issues.
Methods: The investigator-initiated, multi-center, randomized TEAR trial began in 2004 and enrolled 755 participants to compare immediate (I) vs step-up (S) strategy with MTX, etanercept (E) and triple DMARD (T) in 4 arms: immediate MTX + E (IE) or triple therapy (IT); step-up from MTX to MTX+E (SE) or to T (ST). In SE/ST, if DAS28 ≥ 3.2 at 6 months of MTX, patients were blindly stepped-up to IE/IT. Inclusion criteria: disease duration ≤ 3yrs, diagnosis by ACR criteria; RF+, CCP+ or ≥ 2 radiographic erosions; ≥ 4 tender and 4 swollen joints; MTX naïve. The primary endpoint was mean DAS28 from weeks 48-102. Other endpoints: ACR 20, 50, 70; discontinuation for lack of efficacy, DAS28 remission, QOL and Radiographic progression.
Results: Subjects were 72% female; 80% Caucasian, 11% African American; with a mean age at entry of 49±13 yrs, with 3.6±6.5 months since diagnosis, 90% RF+. The mean DAS28 at entry 5.8±1.1; 28 joint count: 14.3±6.8 painful and 12.8±6.0 swollen joints. As shown in the Table, during the second year of treatment, patients randomized to S arms had clinical responses that were not statistically different than those who received I combination therapy, regardless of treatment arm (p-values: I vs S: 0.95, E vs T: 0.23). There were significant differences in the outcome of ACR response at 6 months between treatment arms: patients initially receiving IE or IT were significantly more likely to achieve an ACR 20/50/70 response at 6 months than those randomized to step-up arms (all p < 0.0001), regardless of treatment (E vs T).
Conclusions: A 2-year double-blinded trial of early RA patients found no differences in the mean levels of DAS28 during weeks 48-102 among patients randomized to etanercept or triple DMARD, regardless of whether they received immediate combination treatment or MTX monotherapy with a step-up. At 6 months immediate combination treatment with either strategy was more effective than MTX monotherapy; however, there were no significant differences in groups at 2 years. Initial use of MTX monotherapy with the addition of SSZ/HCQ or etanercept, if necessary after 6 months, is a reasonable therapeutic strategy for early RA. (View the press release and full abstract at www.rheumatology.org).
Disclosure: L. W. Moreland, Amgen, 2, Barr Pharmaceuticals, 2, Pharmacia, 2, NIAMS-NIH, 2, NIH, 2 ; J. R. O'Dell, Amgen, 5 ; H. Paulus, Amgen, 5 ; J. R. Curtis, Roche Pharmaceuticals, 5, UCB, 5, Proctor & Gamble Pharmaceuticals, 5, Amgen, 5, Centocor, Inc., 5, Corrona, 5, Novartis Pharmaceutical Corporation, 2, Amgen, 2, Proctor & Gamble Pharmaceuticals, 2, Eli Lilly and Company, 2, Roche Pharmaceuticals, 2, Centocor, Inc., 2, Corrona, 2, Novartis Pharmaceutical Corporation, 8, Proctor & Gamble Pharmaceuticals, 8, Eli Lilly and Company, 8, Roche Pharmaceuticals, 8, Merck Pharmaceuticals, 8 ; S. L. Bridges, None; X. Zhang, None; G. Howard, Amgen, 2 ; S. S. Cofield, GlaxoSmithKline, 5 .
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