A Multi-Biomarker Disease Activity Score and the Choice of Second-Line Therapy in Early Rheumatoid Arthritis After Methotrexate Failure

Abstract

Objective: To investigate whether the Multi-Biomarker Disease Activity (MBDA) score predicts optimal add-on treatment in patients with early rheumatoid arthritis (RA) who were inadequate responders to MTX (MTX-IRs).

Methods: We analyzed data from 157 MTX-IRs (with a Disease Activity Score using the erythrocyte sedimentation rate [DAS28-ESR] >3.2) from the Swedish Pharmacotherapy (SWEFOT) trial who were randomized to receive triple therapy (MTX plus sulfasalazine plus hydroxychloroquine) versus MTX plus infliximab. The MBDA score as a predictor of the subsequent DAS28-based response to each second-line treatment was analyzed at randomization with the Breslow-Day test for 2 × 2 groups, using both validated categories (low [<30], moderate [30-44], and high [>44]) and dichotomized categories (lower [≤38] versus higher [>38]).

Results: Among the 157 patients, 12% had a low MBDA score, 32% moderate, and 56% high. Of those with a low MBDA score, 88% responded to subsequent triple therapy, and 18% responded to MTX plus infliximab (P = 0.006); for those with a high MBDA score, the response rates were 35% and 58%, respectively (P = 0.040). When using 38 as a cutoff for the MBDA score (29% patients with lower scores versus 71% with higher scores), the differential associations with response to triple therapy versus MTX plus infliximab were 79% versus 44% and 36% versus 58%, respectively (P = 0.001). Clinical and inflammatory markers had poorer predictive capacity for response to triple therapy or MTX plus infliximab.

Conclusion: In patients with RA who had an inadequate response to MTX, the MBDA score categories were differentially associated with response to subsequent therapies. Thus, patients with post-MTX biochemical improvements (lower MBDA scores) were more likely to respond to triple therapy than to MTX plus infliximab. If confirmed, these results may help to improve treatment in RA.

Trial registration: ClinicalTrials.gov NCT00764725.

© 2017, The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Figures

Figure 1

Distribution of disease activity measures at month 3 in responders and nonresponders to second‐line therapy at year 1. The Multi‐Biomarker Disease Activity (MBDA) score (A), C‐reactive protein (CRP) level (B), erythrocyte sedimentation rate (ESR) (C), and Disease Activity Score in 28 joints (DAS28) (D) at month 3 (at the time of randomization) among responders and nonresponders to triple therapy or anti–tumor necrosis factor (anti‐TNF) therapy are shown. Data are shown as box plots. Each box represents the upper and lower interquartile range (IQR). Lines inside the boxes represent the median. Whiskers represent 1.5 times the upper and lower IQRs. Circles indicate outliers.

Figure 2

Proportion of patients with a clinical response to second‐line therapy at year 1 according to a DAS28 score of ≤3.2, stratified by conventional cutoffs of the MBDA score at the start of treatment intensification. Responders at year 1 were evaluated according to low (44) scores on the MBDA at month 3. See Figure 1 for definitions.

Figure 3

Proportion of patients with a clinical response to second‐line therapy at year 1 according to a DAS28 score of ≤3.2, stratified by receiver operating characteristic curve–based cutoffs of disease activity measures at month 3. Responders at year 1 were evaluated according to the MBDA score (A), CRP level (B), ESR (C), and DAS28 (D) at month 3. Overall P values for the 4 groups were calculated using the Breslow‐Day test; P values for triple therapy versus anti‐TNF therapy were calculated using the chi‐square test, except where indicated otherwise. † = P value was calculated using Fisher's exact test. See Figure 1 for definitions.

Figure 4

Proportion of patients achieving low levels of disease activity at year 1 according to a DAS28 score of ≤3.2, stratified by the MBDA scores at month 3 in seropositive and seronegative subsets. Responders at year 1 were evaluated according to rheumatoid factor (RF)–negative (A), RF‐positive (B), anti–cyclic citrullinated peptide (anti‐CCP)–negative (C), and anti‐CCP–positive (D) status. Overall P values for the 4 groups were calculated using the Breslow‐Day test, and P values for triple therapy versus anti‐TNF therapy were calculated using the chi‐square test, except where indicated otherwise. † = P value was calculated using Fisher's exact test. See Figure 1 for other definitions.

Figure 5

Proportions of patients with a good clinical response to second‐line therapy at year 1 according to the European League Against Rheumatism (EULAR) criteria, among those with lower versus higher disease activity at month 3. Responders at year 1 were evaluated according to the MBDA score (A), CRP level (B), ESR (C), and DAS28 (D) at month 3. Overall P values for the 4 groups were calculated using the Breslow‐Day test, and P values for triple therapy versus anti‐TNF therapy were calculated using the chi‐square test, except where indicated otherwise. † = P value was calculated using Fisher's exact test. See Figure 1 for other definitions.