Most Appropriate Conventional Disease‐Modifying Antirheumatic Drug to Combine With Different Advanced Therapies in Rheumatoid Arthritis: A Systematic Literature Review With Meta‐Analysis

Abstract

Objective In rheumatoid arthritis, the association between advanced therapies (including biologic disease‐modifying antirheumatic drugs [DMARDs] and targeted synthetic DMARDs) and methotrexate (MTX) is recommended by international societies. When MTX cannot be used, other conventional synthetic DMARDs (csDMARDs) may be proposed. We aimed to compare the safety and efficacy of MTX and non‐MTX csDMARDs in combination with advanced therapies. Methods We systematically searched the literature for studies comparing the effectiveness, retention rate, and safety of MTX versus non‐MTX csDMARDs (leflunomide or others) in combination with tumor necrosis factor inhibitors (TNFi), abatacept, rituximab, tocilizumab, and JAK inhibitors. Meta‐analysis was performed with RevMan, using an inverse variance approach with fixed or random‐effects models. Risk ratios (RRs) and 95% confidence intervals (95% CIs) were estimated. Results The literature search revealed 3,842 articles; 41 studies were included for the systematic literature review and 21 for the meta‐analysis: 13 with TNFi, 3 with abatacept, and 5 with rituximab. For TNFi, the European Alliance of Associations for Rheumatology (EULAR) response at 6 months was lower for patients receiving non‐MTX csDMARDs than for those using MTX (RR 0.93 [95% CI 0.87, 1.0], P = 0.04; n = 3,843; I2 = 28%), with a lower retention rate at 12 months. For abatacept, effectiveness and safety were similar between the 2 groups. For rituximab, a good EULAR response was higher with leflunomide than MTX (RR 1.38 [95% CI 1.13, 1.68], P = 0.001; n = 2,078; I2 = 0%), with similar adverse event rates. Meta‐analysis for tocilizumab or JAK inhibitors could not be performed. Conclusion The different csDMARDs seem safe and efficient to combine with advanced therapies in RA patients. Although MTX seems slightly superior to other csDMARDs in combination with TNFi, leflunomide might be superior to MTX in combination with rituximab.

Identifying rheumatic disease patients at high risk and requiring shielding during the COVID-19 pandemic

“…Similar reassuring results were observed when combining leflunomide with anti-TNF, abatacept or rituximab. 31 Studies have confirmed that methotrexate-leflunomide combination therapy is safe and well tolerated 32 in patients with refractory RA. There are no recent publications looking at the safety and efficacy of methotrexateazathioprine and methotrexate-cyclosporin combination therapy but a Cochrane review found an increased risk of predominantly gastrointestinal adverse events in the combination groups but did not appear to show an increase in infection.…”

Therapierefraktärer Verlauf einer extended-oligoartikulären juvenilen idiopathischen Arthritis

“…Im Falle einer MTX-Aversion kommt alternativ auch Leflunomid in Betracht. Eine Metaanalyse konnte hinsichtlich Wirksamkeit und Sicherheit der Kombination von Abatacept mit Leflunomid bei Patienten mit RA keine Unterschiede im Vergleich zu MTX nachweisen 9 . Die Kombination von Biologika und JAK-Inhibitoren wird aufgrund einer potenziellen schweren Immunsuppression bei Blockade mehrerer Signalwege und des unklaren Nebenwirkungsprofils kritisch gesehen.…”

Leflunomid w leczeniu chorób reumatycznych — znaczenie różnorodności stosowanych dawek

“…To właśnie A771726 (czynny metabolit leflunomidu) hamuje aktywność występującego u ludzi enzymu dehydrogenazy dihydroorotanu (DHODH) i wykazuje właściwości przeciwproliferacyjne i immunosupresyjne [3]. [10]. Leflunomid daje więc duże możliwości terapeutyczne w monoterapii i politerapii, zarówno w pierwszej, jak i kolejnych liniach leczenia chorób reumatycznych.…”