Guide
There are a variety of conventional synthetic disease-modifying antirheumatic drugs (csDMARD) combination treatment strategies for rheumatoid arthritis (RA). Commonly used combinations are triple therapy with methotrexate (MTX), sulfadiazine (SSZ), and hydroxychloroquine (HCQ), and dual therapy with MTX and leflunomide (LEF). However, in clinical practice, the guidelines do not provide recommendations on how physicians should choose between these two combinations, and there is no data to support which regimen is preferable. Therefore, in clinical practice, the prescribing of a combination is usually based on physician preference rather than evidence-based. In this context, foreign scholars have carried out a real-world retrospective study in RA patients to compare the retention rate of the above two combination treatments, and to provide reference for clinical practice.
Study design
This is a real-world retrospective analysis of patients who received triple (MTX+HCQ+SSZ) or dual (MTX+LEF) therapy at or after enrollment in the Ontario Best Practice Research Program (OBRI) and who have not previously used biologics/JAK inhibitors. The study period was from January 1, 2008 to January 1, 2021. The start date of combination therapy is the start date of the last DMARD in two or triple therapy, and the stop date is the earliest stop date of any component of two or triple therapy, respectively. Outcome measures were disease activity, drug retention, and time to discontinuation at 6 and 12 months after the start of combination therapy. Discontinuation of any component of the combination therapy, as well as the combination of any new csDEMARD, indicates a lack of drug retention.
Findings:
The study resulted in the inclusion of 692 patients, including 258 in the triple therapy group and 434 in the dual therapy group. Overall, women accounted for the majority (76.0%), with a mean (±SD) age of 57.4 (±13.0) years. According to the Clinical Disease Activity Index (CDAI), the proportion of patients with low disease activity or remission (LDA/REM) was similar between the two groups, and there was no statistically significant difference between groups.
Compared with triple therapy, patients in the two-combination group were older (mean 58.6 years vs. 55.3 years, P<0.001), more likely to have private health insurance (83.2% vs. 74.6%, P<0.01), longer duration of disease (mean 8.4 years vs. 5.8 years, P<0.001), higher erythrocyte sedimentation rate (ESR) (mean 26.3 versus 23.0 years), and more likely to have comorbidities (43.5 versus 35.7 percent) , P <0.05) and ESR-based disease activity score (DAS28-ESR) were higher (4.6 vs 4.3, P < 0.01).
01
Drug retention rates were similar for both regimens, with longer drug retention for triple therapy
There were 175 (67.8%) discontinuation in the triple therapy group and 287 (66.1 percent) in the two treatment groups, and the median drug retention was longer (15.1 months; 95% CI: 11.2-21.2) compared with the two (9.6 months; 95% CI: 7.03-12.2), but there was no statistically significant difference between groups (Figure 1).
Six months after the start of treatment, 70.3% of patients in the triple therapy group and 59.7% of patients in the dual therapy group were still on the combination, and 12 months after the start of treatment, about half of the patients were still receiving the combination (45.6%) or the dual therapy (54.4%).
41.8% and 28.3% of the two-dose and triple-therapy groups received discontinuation of MTX treatment due to adverse events, respectively. The proportion of LEF discontinuation in the two-combination treatment group was 50.7%, and adverse events were the most common reason for discontinuation. In the triple therapy group, the proportion of SSZ discontinuation (37.2%) was higher than that of MTX (17.8%) and HCQ (19.4%).
Fig.1 Kaplan-Meier curves of drug retention in triplet and two-way regimens
02
Triple therapy is more likely to achieve LDA/REM 6 months after treatment initiation
In terms of disease activity scores at six and 12 months, DAS28-ESR was lower in the triple group compared with two treatments (mean DAS 28 versus 3.4 versus 3.9 at six months, p<0.0001; mean DAS 28 versus 3.5 at 12 months, p=0.0005).
At 6 months, the proportion of LDA/REM patients in the triple therapy group was higher than that in the two therapy groups (50.7% vs. 42.2%; p=0.04). At the time of discontinuation, the proportion of patients in LDA/REM status in the triple therapy group (43.5%) was higher than that in the dual therapy group (36.1%).
03
Female patients and those with at least one comorbidity were more likely to discontinue treatment
Multivariate COX regression analysis showed that the factors associated with discontinuation were female (HR: 1.78; 95% CI: 1.37-2.32), and at least one comorbid (HR: 1.27; 95% CI: 1.03-1.58)。
Conclusions of the study
In summary, the drug retention time of triple therapy (MTX+HCQ+SSZ) was longer than that of dual therapy (MTX+LEF), but there was no significant difference between groups. In addition, triple therapy is more likely to achieve low disease activity, including remission, at 6 months after treatment initiation. Female patients and those with at least one comorbid condition were more likely to discontinue treatment. These findings need to be further validated.
参考文献：Bhavsar SV, Movahedi M, Cesta A, Pope JE, Bombardier C; other OBRI investigators. Retention of triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine compared to combination methotrexate and leflunomide in rheumatoid arthritis. Joint Bone Spine. 2024 Apr 5:105732. doi: 10.1016/j.jbspin.2024.105732.
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