Choice of Second-Line Therapy in RA Influenced by MBDA Score

Biologics have revolutionized the treatment of rheumatoid arthritis, but in some cases, conventional therapy could lead to better results. If so, when is it appropriate to forgo biologics in place of staying the course with conventional nonbiologic disease-modifying anti-rheumatic drugs (cDMARDs)?

Researchers writing in Arthritis and Rheumatology say that the multi-biomarker disease activity score (MBDA) could be used to determine whether individual patients will respond better to conventional therapeutics or a biologic. This theory has been well-documented in other studies and in this study, led by Karen Hambardzumyan, of Karolinska University Hospital in Sweden, researchers provide additional evidence that highlights the predictive value of MBDA scoring.

“The results presented herein may, if confirmed, have a major bearing on clinical practice,” Dr. Hambardzumyan and colleagues wrote.

Clinical guidelines currently call for methotrexate as the first-line therapy for rheumatoid arthritis, but when it fails, or leads to an insufficient response, rheumatologists usually opt for adding an anti-TNF to the treatment regimen, or escalating to triple therapy. Some data suggests that the addition of an anti-TNF therapy is only slightly better than triple therapy, with the latter being more cost-effective. But then, individual patients may respond differently to treatment, which was a key point of this recently published post-hoc study.

This study is based on samples and data from the Swedish Pharmacotherapy (SWEFOT) trial in which 157 patients with early rheumatoid arthritis were randomized to one of two treatment regimens after an inadequate response to a three-month course of methotrexate. They were randomized to either triple therapy with methotrexate, sulfasalazine and hydroxychloroquine or combination therapy with methotrexate and the anti-TNF inhibitor infliximab.

The study

Patients were started on methotrexate and if after three months they achieved a DAS of ≤ 3.2, methotrexate monotherapy therapy was continued. Patients with a DAS28 greater than 3.2 after three months were randomized to receive triple therapy of methotrexate, sulfasalazine and hydroxychloroquine or methotrexate with the anti-TNF infliximab. Of 258 patients, 157 MBDA scores were analyzed with 12% scoring low, 32% moderate and 56% high. Of low scoring responders, 88%, responded to triple therapy and 18% responded to methotrexate with infliximab (P5 0.006). Of high MBDA scorers, 35% and 58% of patients responded, respectively (P50.040).

Patients with lower MBDA scores were more likely to respond to triple therapy over combo therapy with methotrexate and infliximab.

With an MBDA score of less than 38 at three months (29% of 157 patients), 79% of patients on triple therapy were more likely to respond at one year as compared to 44% of patients on methotrexate/infliximab combination treatment. For the 71% of patients who scored above 38, the response rates were 36% and 58%, respectively (P50.001).

“In the present study, we found that a validated score based on a panel of biomarkers could help predict in a differential manner which subsequent therapy would be most effective in early rheumatoid arthritis patients with an insufficient response to methotrexate monotherapy. Thus, while overall, second-line therapy with anti-TNF was better in terms of the DAS28 (although perhaps only marginally so) at the group level, we found that for patients with lower MBDA scores (≤ 38) at treatment escalation, triple therapy was not only equal, but was in fact a better therapeutic option than anti-TNF in terms of clinical response. In contrast, in patients with higher MBDA scores (> 38), anti-TNF was more efficient in achieving low DAS28 values at year one,” the authors wrote.

The researchers compared these outcomes to conventional clinical and inflammatory markers and only one, ESR (> 25.5mm/hour) showed a similar, but weaker association with combination therapy and an anti-TNF.

Symptomatic parameters and disease remission

Minor symptoms can be undetectable, but they can still influence the underlying biochemical disease process. “A possible explanation for these findings might lie in the fact that an inadequate response to methotrexate monotherapy was based on the DAS28, which is mostly based on symptomatic parameters,” researchers wrote.

Disease remission is not always straightforward. One study they cited showed that biologics are superior to cDMARDs only in the first few months of treatment and after that, the effects begin to wane. In other cases, patients may eventually respond to methotrexate combination therapy when a different biologic is tried. And, some patients respond to triple therapy after having an inadequate response to combination treatment.

“Clinical outcomes do not always reflect radiologic data,” The researchers wrote. The SWEFOT trial showed that patients who were inadequate responders to methotrexate therapy and who received anti-TNF therapy “had a significantly lower proportion of radiographic progression at year two compared with those receiving triple therapy.” But a later study showed that patients with low MBDA scores at the beginning of treatment did not progress radiographically at two years, regardless of the therapy choice.

“The MBDA blood test shows changes on a molecular level, which can show early improvements that are not yet detectable on physical examination,” which would explain why - for patients with lower MBDA scores - moderate to high disease activity persisted after methotrexate monotherapy. These patients eventually responded to the addition of a non-biologic DMARD and the authors suggest that for this group of patients, taking methotrexate longer or a higher dose might lead to a clinical response as well.

“It is therefore conceivable that patients who show biochemical improvements with methotrexate treatment, even when they have insufficient clinical responses, are more likely to respond to intensification of treatment with a drug that acts by the same mechanism rather than switching to a drug with a different mechanism of action. In contrast, patients with a lack of biochemical improvements during methotrexate monotherapy may need a drug with a completely different treatment mechanism (e.g., TNF inhibition) to achieve low levels of disease activity,” they wrote.

Disclosures:

Crescendo Bioscience, Inc. and the Swedish Rheumatism Association provided financial support.

References:

Karen Hambardzumyan, Saedis Saevarsdottir, Kristina Forslind, et al. “A multi-biomarker disease activity score and the choice of second-line therapy in early rheumatoid arthritis after methotrexate failure.”Arthritis & Rheumatology. Vol. 69, No. 5, May 2017, pp 953–963
DOI 10.1002/art.40019