Abstract

Background Giant cell arteritis (GCA) is a type of large vessel vasculitis that causes inflammation, scarring and stenosis in large vessels. Clinical symptoms include headaches, visual changes and myalgias. The standard treatment for GCA consists of glucocorticoid therapy, however long-term use of glucocorticoid therapy poses important health risks. For this reason, there has been a growing interest in exploring other glucocorticoid-sparing therapies, such as leflunomide. The objective of this systematic review is to assess the efficacy and safety of leflunomide in the treatment of GCA.

Methods We will include studies with adult patients who received leflunomide in the treatment of GCA. We will include randomized controlled trials, cohort studies, case-control studies, and case series. The intervention of interest is the use of leflunomide, which may be initiated at any time over the course of the disease. The comparator is glucocorticoid therapy alone. The primary efficacy outcome is the incidence (proportion) of patients who attain GC-free remission, as defined by the following: 1) absence of signs or symptoms of GCA, and/or 2) normalization of inflammatory markers, and/or 3) radiologic response, and 4) complete discontinuation of GC. Outcomes will be assessed after 1 year of follow-up. Quality appraisal will be performed using the respective risk of bias tools. We will perform a meta-analysis using a random-effects model if the included studies are sufficiently homogenous. For quantitative synthesis, we will employ Cochran-Mantel-Haenszel method with odds ratios as a measure of effect and 95% confidence intervals for our primary endpoint.

Discussion The challenge in the treatment of GCA is attaining and maintaining disease remission with the least amount of glucocorticoid therapy possible. The only approved glucocorticoid-sparing agent in the treatment of large vessel vasculitis is tocilizumab. Leflunomide is a molecule with similar downstream effects on dendritic cells and cytokines as tocilizumab. Should leflunomide demonstrate similar benefits, it would be a cost-effective, safe, and user-friendly (oral route) option.

Systematic review registration Our systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42023490373).

Competing Interest Statement

Dr Makhzoum has received consultation or presentation fees from Roche, Otsuka, GlaxoSmithKline, Astra-Zeneca, Sanofi, Amgen, AbbVie, and is an investigator in clinical trials funded by Health Canada, the Vasculitis Clinical Research Consortium (VCRC), Janssen, Astra-Zeneca, AbbVie and Novartis outside the submitted work.

Funding Statement

This study did not receive any funding.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

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Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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Yes

Footnotes

Email: arielle.mendelmcgill.ca

Email: carolyn.rossumontreal.ca

Email: jean-paul.makhzoumumontreal.ca

Data Availability

There are no new data associated with this article.

List of AbbreviationsACRAmerican College of RheumatologyCENTRALCochrane Central Register of Controlled Trials.EULAREuropean League Against RheumatismGCGlucocorticoidGCAGiant cell arteritisGRADEGrading of Recommendations, Assessment, Development, and EvaluationsMeSHMedical Subject HeadingsOROdds ratioORBITOutcome Reporting Bias in TrialsPROSPEROInternational Prospective Register of Systematic ReviewsRCTRandomised controlled trialRoBRisk of biasROBINS-IRisk of Bias in Non-randomised Studies – of InterventionsROBINS-ERisk of Bias in Non-randomised Studies – of Exposure