Summary
Leflunomide has reached the approved stage (maximum clinical phase 4) for at least one indication, so its use in Rheumatoid Arthritis would be drug repurposing rather than first-in-human development. This does not mean it is approved for Rheumatoid Arthritis. ClinicalTrials.gov lists 8 registered trials linking Leflunomide to Rheumatoid Arthritis: 1 is currently recruiting; 6 have completed; 1 is terminated, withdrawn, suspended or of unknown status. The most advanced is Phase 4 (NCT01313208). The largest enrolment is 6393 participants (NCT01646385). Registration activity spans 2001 to 2022. The literature layer holds 14 publications for this pair: 5 Cochrane reviews, 3 meta-analyses, 1 systematic review and 5 clinical trial publications. Publication years run from 2021 to 2026. Because at least one synthesis-level source exists (systematic review, meta-analysis or Cochrane review), this pair has been assessed beyond single studies, although the synthesis may concern a different indication.
The RepurpOS disease-intelligence file for Rheumatoid Arthritis ranks 544 candidate therapeutics from Open Targets, ChEMBL, DGIdb and PubMed; only a minority carry direct clinical evidence, and this page covers one of those. Spontaneous remission context recorded for the condition: 11% achieve drug-free remission (DFR) at median 74 months; most cohorts show 10-15% DFR ceiling.
Evidence table
| Evidence tier | A · Strong |
|---|---|
| Evidence score | 79.5 (trials 29.5, literature 30.0, tier 15, approved bonus 5.0) |
| Registered trials | 8 total: 1 recruiting, 0 active / not yet recruiting, 6 completed, 1 other |
| Linked publications | 14 (5 Cochrane reviews, 5 clinical trial publications, 3 meta-analyses, 1 systematic review) |
| Agent type | Drug (Small molecule) |
| Development stage (any indication) | Approved |
| Mechanism / class | Not recorded |
| Data sources | Open Targets, ChEMBL |
How the evidence score is calculated
- Each registered trial scores by status (recruiting / active / enrolling 3, completed 2.5, not yet recruiting 2, unknown 1, terminated / withdrawn / suspended 0.5) plus a phase bonus (phase 3-4 +2, phase 2 +1, phase 1 +0.5). The trial component is capped at 30.
- Each literature item scores by design (Cochrane review 5, meta-analysis 4, systematic review 3, RCT 3, clinical trial publication 2, curated reference 1.5, other PubMed record 1). The literature component is capped at 30.
- The existing evidence tier adds 15 (A / Strong), 10 (B / Moderate), 5 (C / Preliminary) or 0 (D / Anecdotal).
- Agents approved for any indication (max clinical phase 4) add 5, because an approved agent has an established safety profile that lowers the barrier to repurposing trials.
- The score ranks what has been studied, not what works. It does not read effect sizes or directions of effect.
Registered clinical trials
| NCT ID | Title | Status | Phase | Enrolment |
|---|---|---|---|---|
| NCT01313208 | Moderate Rheumatoid Arthritis (RA) With Etanercept (Enbrel) 2011 | completed | Phase 4 | 210 |
| NCT00579878 | Triple III Comparison of Leflunomide Alone Versus Two DMARD Combinations in the Treatment of Rheumatoid Arthritis 2001 | completed | Phase 3 | 69 |
| NCT00596206 | Leflunomide EfficAcy Response Related to Dosing Regimen in Early Rheumatoid Arthritis 2007 | completed | Phase 3 | 124 |
| NCT00531817 | A Study of Tocilizumab in Combination With DMARDs in Patients With Moderate to Severe Rheumatoid Arthritis 2007 | completed | Phase 3 | 619 |
| NCT02930343 | Comparison of Disease Modifying Antirheumatic Drugs Therapy in Patients With RA Failing Methotrexate Monotherapy 2016 | terminated | Phase 3 | 136 |
| NCT01033656 | Treatment of Refractory Adult-onset Still's Disease With Anakinra: a Randomized Study 2005 | completed | Phase 2 | 23 |
| NCT01646385 | Study to Assess the Safety and Efficacy of Etanercept in Patients Treated Over the Long-term in Real-world Clinical Practice, Using Data Collected by the British Society of Rheumatology Biologics Registry 2012 | completed | Not applicable | 6,393 |
| NCT05782335 | Analysis of T and B Cell Repertoire Changes in Response to Orencia® (Abatacept) in Rheumatoid Arthritis 2022 | recruiting | Not applicable | 72 |
Published literature
- Clinical trial publication Repurposing leflunomide and hydroxychloroquine to treat Sjögren's disease (RepurpSS-II): a randomised, double-blind, placebo-controlled, phase 2b trialWong WY, Rijnenberg D, Baloche VMD et al. · The Lancet. Rheumatology · 2026 · PMID 42161318
- Clinical trial publication Transcriptomic stratification predicts response to rituximab, abatacept, or the association of hydroxychloroquine and leflunomide in 3 randomised controlled clinical trials of Sjögren's diseaseChevet B, Devauchelle-Pensec V, Pontarini E et al. · Annals of the rheumatic diseases · 2026 · PMID 41448992
- Cochrane review Perioperative use of disease-modifying anti-rheumatic drugs (DMARDs) in people with inflammatory arthritisPonkilainen V, Karjalainen TV, Kuitunen I et al. · The Cochrane database of systematic reviews · 2026 · PMID 42159164
- Cochrane review Efficacy of synthetic and biological DMARDs: a systematic literature review informing the 2025 update of the EULAR recommendations for the management of rheumatoid arthritisKonzett V, Laskou F, Smolen JS et al. · Annals of the rheumatic diseases · 2026 · PMID 41997804
- Meta-analysis Effect of monotherapy with conventional synthetic disease-modifying anti-rheumatic drugs or glucocorticoids on radiographic progression in rheumatoid arthritis: a network meta-analysis of 64 treatment arms from 31 randomized controlled trialsGuski LS, Pedder H, Andersn SE et al. · Scandinavian journal of rheumatology · 2026 · PMID 41858241
- Clinical trial publication Proteins linked to type II interferon response in Sjögren's disease: novel indicators for disease monitoring and predicting treatment response to leflunomide and hydroxychloroquine combination therapyWong WY, Leavis HL, Blokland SLM et al. · Frontiers in immunology · 2025 · PMID 41181128
- Clinical trial publication L-carnitine as a novel approach for pain and inflammation relief in rheumatoid arthritisEldisouky AA, Hegazy SK, Abd Elghany SE · Inflammopharmacology · 2025 · PMID 41037123
- Clinical trial publication Effect of a 1-month methotrexate delay on pneumococcal vaccine immunogenicity and disease control in patients with early rheumatoid arthritis (VACIMRA): an open-label randomised trialMorel J, Dernis E, Roux C et al. · The Lancet. Rheumatology · 2025 · PMID 40749694
- Meta-analysis Progression of tuberculosis among patients with rheumatic diseases - A systematic review and meta-analysisSundaram K, Vajravelu LK, Velayutham R et al. · The Indian journal of tuberculosis · 2025 · PMID 40518207
- Cochrane review Risk factors for incidence of interstitial lung disease in patients with rheumatoid arthritis: a systematic review and meta-analysisYu C, Zhang Y, Jin S et al. · BMJ open respiratory research · 2024 · PMID 39551575
- Cochrane review Efficacy of synthetic and biological DMARDs: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritisKerschbaumer A, Sepriano A, Bergstra SA et al. · Annals of the rheumatic diseases · 2023 · PMID 36368906
- Systematic review What are the core recommendations for rheumatoid arthritis care? Systematic review of clinical practice guidelinesConley B, Bunzli S, Bullen J et al. · Clinical rheumatology · 2023 · PMID 37291382
- Cochrane review Comparative efficacy and safety of JAK inhibitors and leflunomide in rheumatoid arthritis: A protocol for systematic review and meta-analysisZhang X, Zhang M, Wang Z et al. · Medicine · 2022 · PMID 36626515
- Meta-analysis Clinical safety of total glucosides of paeony adjuvant therapy for rheumatoid arthritis treatment: a systematic review and meta-analysisLiu B, Meng X, Ma Y et al. · BMC complementary medicine and therapies · 2021 · PMID 33771151
Mechanism and notes
No mechanism of action is recorded for this pair in the source databases.
OSMF's existing evidence tier for this pair is A (Strong), derived from the strength of the disease association recorded in Open Targets and ChEMBL. The tier describes how well the drug-disease link is documented, not how well the drug works.
Frequently asked questions
Is Leflunomide approved for Rheumatoid Arthritis?
Leflunomide has reached the approved stage (maximum clinical phase 4) for at least one indication, so its use in Rheumatoid Arthritis would be drug repurposing rather than first-in-human development. This does not mean it is approved for Rheumatoid Arthritis. Approval status for the specific indication should always be confirmed with the relevant regulator and prescribing information.
Is Leflunomide in clinical trials for Rheumatoid Arthritis?
ClinicalTrials.gov lists 8 registered trials linking Leflunomide to Rheumatoid Arthritis: 1 is currently recruiting; 6 have completed; 1 is terminated, withdrawn, suspended or of unknown status. The most advanced is Phase 4 (NCT01313208). The largest enrolment is 6393 participants (NCT01646385). Registration activity spans 2001 to 2022.
What does the evidence show for Leflunomide in Rheumatoid Arthritis?
Leflunomide has both completed registered trials and synthesis-level publications linked to Rheumatoid Arthritis. That is the strongest profile in this database, but the summaries here do not extract effect sizes, so read the linked reviews for direction and magnitude of benefit. OSMF's existing evidence tier for this pair is A (Strong), derived from the strength of the disease association recorded in Open Targets and ChEMBL. The tier describes how well the drug-disease link is documented, not how well the drug works.
Cite this page
Data: ClinicalTrials.gov, PubMed, Open Targets, ChEMBL, DGIdb and the OSMF therapeutic agent database. Last updated 2026-07-05. Page built 2026-10-07.