COMMENTARY

Biologics or Not in RA? This Test Could Help Decide

Jonathan Kay, MD

Disclosures

July 31, 2014

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Multibiomarker Disease Activity in Rheumatoid Arthritis

Hello. I am Dr. Jonathan Kay, Professor of Medicine and Director of Clinical Research in the Division of Rheumatology at UMass Memorial Medical Center and the University of Massachusetts Medical School, both in Worcester, Massachusetts.

Welcome to Medscape. I'm here in Paris, where I have been attending the European League Against Rheumatism (EULAR) Annual Scientific Meeting, and I would like to highlight some of the presentations about the multibiomarker disease activity (MBDA) index that were presented here at the EULAR meeting.

A paper was published online at the beginning of May 2014, by Karen Hambardzumyan[1] from the Karolinska Institute, where she was working with Professor Ronald van Vollenhoven. This study looked at the SWEFOT (Swedish Pharmacotherapy) trial, which evaluated the ability of the MBDA index to predict structural progression in patients with early rheumatoid arthritis (RA). This was a post-hoc analysis of 235 patients from the SWEFOT trial in disease-modifying anti-inflammatory drug (DMARD)-naive early RA. The 1-year data for this study were published in The Lancet[2] in 2009; and, subsequently, the 2-year data were published in The Lancet[3] in 2012, with radiographic outcomes.

In this study, patients with RA of less than 1 year duration who had not previously been treated with DMARDs and who had moderate or high disease activity by the disease activity score-28-C-reactive protein (DAS-28-CRP) were treated for 3-4 months with methotrexate monotherapy at a dose of 20 mg weekly.

At 3 months, patients who continued to have moderate to high disease activity were randomly assigned to receive either nonbiologic therapy -- initially methotrexate, sulfasalazine, and hydroxychloroquine triple therapy (if they didn't respond to triple therapy, they could be switched to cyclosporine-A); or biologic therapy -- initially methotrexate with infliximab. The biologic drug could be advanced to etanercept if the response was inadequate at the primary endpoint of 12 months.

Predicting Clinical and Radiographic Progression

In this study, they looked at the MBDA score, which is based on 12 serum biomarkers that are analyzed and combined by an algorithm to yield a final score; an MBDA score > 44 indicates high disease activity.

They looked at this MBDA score as a predictor of radiographic progression, meaning an increase in the Sharp van der Heijde score by more than 5 points after 1 year using baseline serum samples to assess MBDA. In the SWEFOT study, more patients who were treated with biologic therapy achieved a good response at 1 year (39% compared with 25% on triple therapy). As would be expected, there was more radiographic progression among patients treated with conventional nonbiologic therapy than in those treated with biologic therapy.

This study found that the MBDA index was a better discriminator of clinical and radiographic progression over 1 year than the DAS-28, the CRP by itself, the DAS-28 erythrocyte sedimentation rate (ESR), the DAS-28-CRP, or the ESR by itself. This study found that 21% of individuals with a high MBDA score had radiographic progression, as compared with 3.4% of those with a moderate MBDA score (between 30 and 44). None of the patients with a low score (≤ 29) progressed in terms of an increase in the Sharp van der Heijde score of more than 5 over 1 year.

This study showed that in patients with early RA of less than 1 year duration, the baseline MBDA score was an independent predictor of 1-year radiographic progression, both as a continuous variable and as a dichotomized variable, comparing high with the combination of low and moderate MBDA scores. The conclusion and the implication for practice of this study are that when choosing initial treatment in early RA, this MBDA score at baseline may allow you to identify a subgroup of patients at low risk for structural progression who might be treated just as well with nonbiologic therapy at less expense than biologic therapy. When performed at baseline, this test could allow us to predict which patients truly need biologic therapy and which can be continued on nonbiologic therapy without high concern for structural progression.

MBDA as a Better Discriminator

The same group of investigators presented 2 posters at this EULAR meeting.[4,5] The first looked at the MBDA score at baseline to see whether it could serve to increase the number of patients included in the clinical trial.[4] The study required patients to have moderate or high disease activity by DAS-28-CRP, which included DAS scores > 3.2. In a recent Medscape video commentary, I described a paper that we published[6] that looked at the prevalence of patients with both normal ESR and CRP, yet who had active RA with a clinical disease activity index > 2.8. We found that 58% of patients who had active RA had neither elevation of the ESR or CRP.

This study was conducted by the group in Stockholm to find out how many additional patients might meet entry criteria if the MBDA score was used, looking for high MBDA scores (> 44) in addition to a CRP cutoff of 10 mg/L as an entry criterion. They found that they could increase the number of eligible patients by 24% at baseline. When they looked at baseline at the DMARD-naive patients, they found that they could increase the number of patients eligible for the SWEFOT study (to begin methotrexate monotherapy) by 24% if they included patients with a baseline MBDA score > 44, in addition to those with DAS-28-CRP > 3.2.

When they looked at methotrexate nonresponders (patients with persistent moderate-to-high disease activity by the DAS-28-CRP after 3 months of treatment with methotrexate), they found that they could increase the number of individuals eligible for randomization (either to triple therapy or biologic therapy) by 47% by including an MBDA score > 44 in addition to the DAS-28-CRP score > 3.2. This MBDA score identifies additional individuals with high disease activity who are at risk for structural progression and functional decline, beyond that which would be predicted by the DAS-28-CRP. That is probably because a significant number of individuals have active RA with normal levels of acute-phase reactants.

In another post-hoc analysis[5] of the SWEFOT population, the investigators looked at the change in the MBDA score between baseline and 3 months while patients were on methotrexate monotherapy compared with the change in the CRP and the DAS-28-CRP. They found that more patients were eligible for inclusion in the randomized portion of the SWEFOT study on the basis of change in the MBDA score than would be eligible on the basis of change in the DAS-28 (which is what they used in the study) or change in the CRP alone. This is probably because of the significant number of individuals who have normal CRP levels and ESRs despite having active RA.

In summary, the paper that was just published by the group from the Karolinska Institute about the MBDA score predicting structural progression in early RA, as well as their additional analysis of the SWEFOT study population, suggest that the MBDA may be a very appropriate test to use at baseline to determine which patients may not need biologic therapy and may do just as well with nonbiologic therapy, as well as being a baseline inclusion criterion for clinical trials of new therapies for rheumatic diseases. This multibiomarker activity test is available commercially in the United States but not yet in the European Union. Further study will determine its utility in the clinical practice of rheumatology and the management of patients with RA.

I'm Jonathan Kay; thank you very much, and I look forward to seeing you again on Medscape.

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