Window of Opportunity: Early Doses of Methotrexate May Stop Certain Forms of Arthritis Before They Start

Newswise — Can you intervene early in the progression of a disease to prevent it from becoming chronic and full-blown? Evidently yes if those patients with probable rheumatoid arthritis have anti-CCP antibodies, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Washington, DC.

To measure the benefits of early treatment on patients with uncategorized inflammatory arthritis, researchers administered 15 mg a week of methotrexate or a placebo to 110 participants in a randomized PROMPT trial (PROable rheumatoid arthritis Methotrexate versus Placebo Treatment). Those on methotrexate received increased dosages over three-month periods for a year. Study medications were then discontinued. Joint damage was measured every six months with X-rays of hands and feet.

After 30 months, the group taking methotrexate showed somewhat less radiographic progression. The same group was also less likely to go on to develop definitive rheumatoid arthritis according to standard criteria. However, the results were more dramatic in those who tested positive for high levels of anti-CCP at the end of the study. Their progression to rheumatoid arthritis and joint damage had been retarded substantially.

Anti-CCP is a citrullinated peptide antibody that has proven to be a reliable marker of future disease. A high level of CCP, measured by a simple blood test, is strongly associated with joint inflammation in rheumatoid arthritis that results in cartilage and bone destruction. Interestingly, anti-CCP shows up earlier, often two to three years earlier in otherwise healthy individuals, than do symptoms and disease onset.

"This proves that, if you can intervene in a disease process, you can prevent that process from becoming chronic and/or having devastating effects on patients," said Tom W.J. Huizinga, MD, Chairman of the Department of Rheumatology, Professor of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands, and an investigator in the study. "While this window of opportunity for prevention is only possible in patients with inflammatory undifferentiated arthritis who have anti-CCP antibodies, the results should motivate physicians to test for anti-CCP early."

The American College of Rheumatology is the professional organization for rheumatologists and health professionals who share a dedication to healing, preventing disability and curing arthritis and related rheumatic and musculoskeletal diseases. For more information on the ACR's annual meeting, see http://www.rheumatology.org/annual.

Presentation Number: 657Evidence for a Window Of Opportunity in a Double-Blind Randomized Clinical Trial in Patients with Undifferentiated Arthritis: The Probable Rheumatoid Arthritis: Methotrexate Versus Placebo Treatment (the Prompt)-Study

Henrike van Dongen1, Jill van Aken1, Leroy R. Lard1, Herman K. Ronday2, Harry MJ Hulsmans2, Irene Speyer3, Marie-Louise Westedt3, Andre J. Peeters4, Cornelia F. Allaart1, Rene EM Toes1, Ferdinand C. Breedveld1, Tom WJ Huizinga1. 1Leiden University Medical Center, Leiden, The Netherlands; 2HAGA hospital, Den Haag, The Netherlands; 3Bronovo hospital, Den Haag, The Netherlands; 4Reinier de Graaf hospital, Delft, The Netherlands

PURPOSE To determine after 30 months of follow up whether patients with undifferentiated arthritis (UA) with or without the presence of antibodies against cyclic citrullinated peptides (anti-CCP) benefit from treatment with methotrexate (MTX). The main outcomes were fulfilment of the ACR 1987 classification criteria for RA and progression of radiographic joint damage.

METHODS The PROMPT study was a prospective double-blind placebo-controlled randomized multicenter trial in 110 patients with undifferentiated arthritis. Treatment started with MTX 15 mg/wk or placebo tablets, and dose was increased by 3-monthly calculations of the disease activity score (DAS), aiming at a DAS ≤ 2.4. After 12 months, the studymedication was tapered to nil. Patients were followed up for 30 months. When a patient fulfilled the ACR 1987 criteria for RA, the studymedication was changed to MTX. Joint damage was scored on 6-monthly radiographs of hands and feet according to the Sharp/van der Heijde method by two independent observers, with the radiographs in chronological order and masked for patient identity. At the end of the study, the anti-CCP status was determined.RESULTS After 30 months, in the MTX-group, 22/55 patients had progressed to RA versus 29/55 in the placebo-group, the criteria were fulfilled at a later time point (p=0.04), and patients showed less radiographic progression over 18 months. However, the progression to RA and in joint damage was only retarded in patients with anti-CCP and not in anti-CCP-negative disease (see Figures).

CONCLUSIONS Evidence for a window of opportunity induced by early DMARD treatment to delay and possibly prevent progression to RA as defined by the ACR 1987 criteria and to retard radiographic joint damage was only present in UA patients that have anti-CCP antibodies and not in those who do not have these autoantibodies

Disclosure Block: T.W. Huizinga, Dutch Arthritis Foundation grant NR-02-01-301, 2 Research grants.