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Methotrexate Combinations More Effective Than Methotrexate Alone for Slowing Progression in Early RA: Presented at EULAR

By Chris Berrie

AMSTERDAM, THE NETHERLANDS -- June 27, 2006 -- Methotrexate (MTX) combinations with infliximab (IFX) and intravenous pulse methylprednisone (IVMP) are clinically more effective than MTX alone, with MTX/IFX showing superiority to MTX/IVMP for reduction of magnetic resonance imaging (MRI) signs of synovitis and bone edema and for slowing progression of MRI-detected erosive changes in patients with early rheumatoid arthritis (RA).

This prospective, randomized, comparative clinical study was presented here June 21^st at the Annual European Congress of Rheumatology (EULAR) by Patrick Durez, MD, principal investigator and head of clinics, department of rheumatology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium, on behalf of the CIERA Study Investigators.

Because joint damage and disability occurs early on in RA, the emphasis is now on early and aggressive treatment to minimize inflammation and prevent irreversible joint damage. "In early RA, TNF blockers have been shown to slow down radiological progression, and MRI is a useful tool to detect inflammatory changes and early erosive damage," Dr. Durez said.

So the primary aim was to compare the effects of MTX alone or in combination with IFX or IVMP for MRI-detectable synovitis, bone edema, and erosion changes. The secondary aim was a comparison of their clinical and functional outcome.

The primary inclusion criterion was a diagnosis of RA according to American College of Rheumatology (ACR) criteria, with active RA defined as a swollen joint count (SJC) greater than or equal to 6 and a tender joint count (TJC) greater than or equal to 8. Disease duration was < 1 year, and patients needed to be MTX naive.

Exclusion was based on: chronic steroid treatment (> 3 months) or steroids within the prior 4 weeks; previous treatment with MTX, IVMP, cyclophosphamide, cyclosporine A or more than 2 disease-modifying antirheumatic drugs (DMARDs); contraindications to MRI; active or latent tuberculosis; or congestive heart disease. Overall, baseline patient characteristics were similar across the treatment groups.

A total of 44 patients were randomized to 1 of 3 groups: MTX alone (n = 14; mean age, 53.8 years; female, 71%), or in combination with IFX (n = 15; mean age, 50.0 years; female, 67%) or IVMP (n = 15; mean age, 50.3 years; female, 60%). The trial design provided for initial step-up MTX from 7.5 to 20.0 mg/wk over the first 14 weeks, either alone or in combination with IVMP 1 g or IFX 3-mg/kg infusions at weeks 0, 2, and 6 and every 8 weeks thereafter (to week 46).

Gadolinium-enhanced MRI of both hands and feet was carried out at weeks 0, 18, and 52, and scans were assessed in a blind, semiquantitative manner for synovitis, bone edema, and erosions, according to Outcome Measures in RA Clinical Trials (OMERACT) guidelines.

For disease activity, the ACR core dataset was used (SJC, TJC, patient assessment of pain and fatigue, physician assessment of disease activity, and C-reactive protein [CRP]), as was the DAS28-CRP and the Health Assessment Questionnaire.

At week 52, the MRI synovitis score for MTX/IFX was significantly improved versus MTX alone (P = .002), with MTX/IVMP showing a similar, but lesser, trend. The MRI bone edema score at 52 weeks was also significantly better for MTX/IFX over both MTX alone (P = .009) and MTX/IVMP (P = .029).

For the bone erosion scores, MTX/IFX was more promising than MTX/IVMP at week 52 (P = .006). Moreover, while the appearance of new erosions was similar for MTX and MTX/IFX, it was significantly higher for MTX/IVMP (P = .035).

When disease symptoms were considered, the week-22 ACR20, 50, and 70 response rates for MTX/IFX and MTX/IVMP were similar and some 3- to 10-fold better than for MTX alone. By week 52, these differences were reduced, but still around 2-fold better for MTX/IFX and MTX/IVMP over MTX alone, with MTX/IVMP showing a trend for further benefits for ACR70. Similarly, the HAQ score reductions at 52 weeks of treatment were slightly better for MTX/IVMP over MTX/IFX, which were significantly better than MTX alone (P = .002).

"Finally, we looked at the time to obtain EULAR [European League Against Rheumatism] remission, which is an important parameter in early rheumatoid arthritis," said Dr. Durez. Here, MTX/IVMP and MTX/IFX were again similar and showed significant superiority over MTX alone (P = .025). He also noted that this intensive therapy was well tolerated, as they observed only 1 serious, methotrexate-induced adverse event.

This study was funding by a grant from Schering-Plough Corporation, Belgium.


[Study title: A Prospective One-Year Randomised Comparative Clinical and MRI Study of the Effects of Methotrexate Alone or in Combination With Infliximab or Intravenous Pulse Methylprednisone in Early Rheumatoid Arthritis (RA) The CIERA Study. Abstract OP0003]

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