Leflunomide for the Management of Rheumatoid Arthritis: Comparative Clinical Effectiveness - CADTH RAPID RESPONSE REPORT: REFERENCE LIST
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CADTH RAPID RESPONSE REPORT: REFERENCE LIST Leflunomide for the Management of Rheumatoid Arthritis: Comparative Clinical Effectiveness Service Line: Rapid Response Service Version: 1.0 Publication Date: January 15, 2019 Report Length: 7 Pages
Authors: Camille Dulong, Robyn Butcher
Cite As: Leflunomide for the management of rheumatoid arthritis: comparative clinical effectiveness. Ottawa: CADTH; 2019 Jan. (CADTH rapid response
report: reference list).
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REFERENCE LIST Leflunomide for the Management of Rheumatoid Arthritis 2Research Question
What is the clinical effectiveness of leflunomide compared with other disease modifying
antirheumatic drugs for the management of rheumatoid arthritis?
Key Findings
One randomized controlled trial was identified regarding the clinical effectiveness of
leflunomide for rheumatoid arthritis management.
Methods
A limited literature search was conducted on key resources including PubMed, the
Cochrane Library, University of York Centre for Reviews and Dissemination (CRD)
databases, Canadian and major international health technology agencies, as well as a
focused Internet search. Methodological filters were applied to limit retrieval to health
technology assessments, systematic reviews, meta-analyses and randomized control trials.
Where possible, retrieval was limited to the human population. The search was also limited
to English language documents published between January 1, 1998 and January 8, 2019.
Internet links were provided, where available.
Selection Criteria
One reviewer screened citations and selected studies based on the inclusion criteria
presented in Table 1.
Table 1: Selection Criteria
Population Adults with moderate to severe, active rheumatoid arthritis who have not responded to or are intolerant to
methotrexate)
Intervention Leflunomide as monotherapy or in combination with other disease-modifying antirheumatic drugs
(DMARDs)
Comparator Monotherapy or combination therapy of DMARDs
Conventional synthetic DMARD (methotrexate, sulfasalazine, hydroxychloroquine);
Tumour necrosis factor (TNF) inhibitors or their biosimilars (etanercept, infliximab, adalimumab,
certolizumab pegol, golimumab);
Non-TNF inhibitors (rituximab, abatacept, tocilizumab, sarilumab);
Janus-associated kinase (JAK) inhibitors (tofacitinib, baricitinib)
Outcomes Clinical benefit and harms using:
Disease severity (ACR 50);
Disease activity (DAS/ DAS-28);
Remission (DAS-28 remission);
Withdrawal due to adverse events
Serious adverse events
Study Designs Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials
REFERENCE LIST Leflunomide for the Management of Rheumatoid Arthritis 3Results
Rapid Response reports are organized so that the higher quality evidence is presented
first. Therefore, health technology assessment reports, systematic reviews, and meta-
analyses are presented first. These are followed by randomized controlled trials.
One randomized controlled trial was identified regarding the clinical effectiveness of
leflunomide compared with other disease modifying antirheumatic drugs for the
management of rheumatoid arthritis. No relevant health technology assessments,
systematic reviews, or meta-analyses were identified.
Additional references of potential interest are provided in the appendix.
Health Technology Assessments
No literature identified.
Systematic Reviews and Meta-analyses
No literature identified.
Randomized Controlled Trials
1. Li R, Zhao JX, Su Y, et al. High remission and low relapse with prolonged intensive
DMARD therapy in rheumatoid arthritis (PRINT): a multicenter randomized clinical trial.
Medicine (Baltimore). 2016;95(28):e3968.
PubMed: PM27428186
REFERENCE LIST Leflunomide for the Management of Rheumatoid Arthritis 4Appendix — Further Information
Previous CADTH Reports
2. Safety of leflunomide and methotrexate as combination therapy for rheumatoid arthritis:
a review of the clinical evidence. (CADTH rapid response report: summary with critical
appraisal). Ottawa (ON): CADTH; 2011: https://www.cadth.ca/safety-leflunomide-and-
methotrexate-combination-therapy-rheumatoid-arthritis-review-clinical Accessed 2019
Jan 14.
Systematic Reviews and Meta-Analyses
Severity of Rheumatoid Arthritis Unspecified
3. Bae SC, Lee YH. Comparative efficacy and tolerability of monotherapy with leflunomide
or tacrolimus for the treatment of rheumatoid arthritis: a Bayesian network meta-
analysis of randomized controlled trials. Clin Rheumatol. 2018;37(2):323-330.
PubMed: PM28967035
4. Calvo Alen J, Perez T, Romero Yuste S, et al. Efficacy and safety of combined therapy
with synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis: systematic
literature review. Reumatol Clin. 2018.
PubMed: PM30241955
Uncertain If Based Solely on Randomized Controlled Trial Information and
Severity of Rheumatoid Arthritis Unspecified
5. Alfaro-Lara R, Espinosa-Ortega HF, Arce-Salinas CA. Systematic review and meta-
analysis of the efficacy and safety of leflunomide and methotrexate in the treatment of
rheumatoid arthritis. Reumatol Clin. 2017.
PubMed: PM28867467
6. Donahue KE, Gartlehner G, Jonas DE, et al. Systematic review: comparative
effectiveness and harms of disease-modifying medications for rheumatoid arthritis. Ann
Intern Med. 2008;148(2):124-134.
PubMed: PM18025440
Alternative Comparator and Severity of Rheumatoid Arthritis Unspecified
7. Conway R, Low C, Coughlan RJ, O'Donnell MJ, Carey JJ. Leflunomide use and risk of
lung disease in rheumatoid arthritis: a systematic literature review and metaanalysis of
randomized controlled trials. J Rheumatol. 2016;43(5):855-860.
PubMed: PM26980577
Severity of Rheumatoid Arthritis and Whether Patient Population was
Intolerant/Failed Methotrexate Unspecified
8. Graudal N, Hubeck-Graudal T, Tarp S, Christensen R, Jurgens G. Effect of combination
therapy on joint destruction in rheumatoid arthritis: a network meta-analysis of
randomized controlled trials. PLoS One. 2014;9(9):e106408.
PubMed: PM25244021
REFERENCE LIST Leflunomide for the Management of Rheumatoid Arthritis 59. Golicki D, Newada M, Lis J, Pol K, Hermanowski T, Tlustochowicz M. Leflunomide in
monotherapy of rheumatoid arthritis: meta-analysis of randomized trials. Pol Arch Med
Wewn. 2012;122(1-2):22-32.
PubMed: PM22353705
10. Osiri M, Shea B, Robinson V, et al. Leflunomide for treating rheumatoid arthritis.
Cochrane Database Syst Rev. 2003(1):Cd002047.
PubMed: PM12535423
11. Hewitson PJ, Debroe S, McBride A, Milne R. Leflunomide and rheumatoid arthritis: a
systematic review of effectiveness, safety and cost implications. J Clin Pharm Ther.
2000;25(4):295-302.
PubMed: PM10971781
Information Not Solely Based on Randomized Controlled Trials and Severity of
Rheumatoid Arthritis Unspecified
12. RTI International–University of North Carolina Evidence-based Practice Center,
Donahue KE, Jonas DE, et al. Drug therapy for rheumatoid arthritis in adults: an update.
(Comparative effectiveness review no. 55). Rockville (MD): Agency for Healthcare
Research and Quality; 2012:
https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/rheumatoid-arthritis-
medicine_research.pdf. Accessed 2019 Jan 14.
PubMed: PM22696776
Randomized Controlled Trials
Severity of Rheumatoid Arthritis Unspecified
13. Wijesinghe H, Galappatthy P, de Silva R, et al. Leflunomide is equally efficacious and
safe compared to low dose rituximab in refractory rheumatoid arthritis given in
combination with methotrexate: results from a randomized double blind controlled
clinical trial. BMC Musculoskelet Disord. 2017;18(1):310.
PubMed: PM28724365
14. De Stefano R, Frati E, Nargi F, et al. Comparison of combination therapies in the
treatment of rheumatoid arthritis: leflunomide-anti-TNF-alpha versus methotrexate-anti-
TNF-alpha. Clin Rheumatol. 2010;29(5):517-524.
PubMed: PM20082236
Severity of Rheumatoid Arthritis and Patient Population Intolerant/Failed
Methotrexate Unspecified
15. Shashikumar NS, Shivamurthy MC, Chandrashekara S. Evaluation of efficacy of
combination of methotrexate and hydroxychloroquine with leflunomide in active
rheumatoid arthritis. Indian J Pharmacol. 2010;42(6):358-361.
PubMed: PM21189905
REFERENCE LIST Leflunomide for the Management of Rheumatoid Arthritis 616. Kremer JM, Genovese MC, Cannon GW, et al. Concomitant leflunomide therapy in
patients with active rheumatoid arthritis despite stable doses of methotrexate. A
randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2002;137(9):726-
733.
PubMed: PM12416946
Randomization Unspecified in Abstract
17. Dougados M, Emery P, Lemmel EM, Zerbini CA, Brin S, van Riel P. When a DMARD
fails, should patients switch to sulfasalazine or add sulfasalazine to continuing
leflunomide? Ann Rheum Dis. 2005;64(1):44-51.
PubMed: PM15271770
18. Scott DL, Smolen JS, Kalden JR, et al. Treatment of active rheumatoid arthritis with
leflunomide: two year follow up of a double blind, placebo controlled trial versus
sulfasalazine. Ann Rheum Dis. 2001;60(10):913-923.
PubMed: PM11557646
REFERENCE LIST Leflunomide for the Management of Rheumatoid Arthritis 7You can also read
