The search for new treatments continues to be an unmet need in large vessel vasculitis (LVV); i.e., Takayasu Arteritis (TAK) and Giant Cell Arteritis (GCA).

The therapeutic options available for GCA remain very limited. Standardized treatment of GCA consists of high-dose glucocorticoids (GC) to induce remission, followed by a long-term, gradual tapering regimen to maintain remission. Unfortunately, when treated with GC alone, approximately 34%−75% of patients relapse upon dose reduction or drug discontinuation (with over 40% of patients still on GC at five years) [1], [2], [3], and between 86 and 99% of patients develop GC-related side effects or complications [4], [5], [6].

Several synthetic (csDMARD) and biologic disease-modifying anti-rheumatic drugs (bDMARDs) have been investigated for their steroid-sparing effect in GCA. Thus far, only tocilizumab (TCZ) has shown safety and efficacy in reducing relapse and decreasing GC requirements in a randomized controlled trial (RCT). However, approximately 5%−8% of patients receiving TCZ must discontinue treatment because of side effects, 30%−44% of patients on treatment experience flares within one year, and more than half relapse following its discontinuation, highlighting an unmet need for additional therapeutics [7], [8], [9], [10], [11]. In addition, several recent studies demonstrate discordance between clinical and imaging activity assessment by PET/CT scan in GCA patients with extracranial large-vessel involvement undergoing TCZ therapy. Despite clinical remission, most patients showed persistent vascular activity in PET/CT scans [12], [13], [14]. These findings raise important questions about whether TCZ leads to a complete resolution of vascular inflammation as assessed by imaging techniques [11], [12], [13], [14].

GCs have also been the cornerstone of treatment in TAK induction [15], [16], [17], [18]. The remission rate of GC mono-therapy is as high as 60% [18]. Nevertheless, nearly 80% of patients develop progressive or alternating (recurrence and remission) forms of TAK [15], [16], [17], [18]. Therefore, GC must be combined with csDMARD to obtain sustained remission and minimize glucocorticoid-related toxicity [15,16]. There are no RCTs published on the role of csDMARD in TAK; evidence derives from observational cohorts only [17]. Lower quality evidence exists for the use of cyclophosphamide (CYC), methotrexate (MTX), azathioprine (AZA) or mycophenolate mofetil (MMF) to prolong remission and taper GC. However, these treatments do not effectively block inflammatory fibrosis of arterial walls in TAK patients. Structural impairment on radiographic and histopathological evaluation was still found in patients receiving GC and MTX, even though inflammation had been closely controlled [[18], [19]]. As in GCA [20], they alleviate mural inflammation, but do not seem to prevent vascular fibrosis following inflammation. Therefore, finding proper treatments to block vascular fibrosis in patients with TAK is crucial. For patients refractory to csDMARD, biologic therapies such as tumor necrosis factor-α (TNF-α) inhibitor or TCZ are suggested [15,16]. However, there are no trials comparing conventional immunosuppressants and biologic therapies and no clear conclusions about any possible superiority could be drawn [17].

Recently, an increasing number of studies have shown that leflunomide (LEF) might have potential efficacy in treating LVV [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. LEF, a pyrimidine synthesis inhibitor, inhibits the dendritic cell maturation and the production of pro-inflammatory cytokines such as interleukin (IL)−1 and IL-17, which are involved in the pathogenesis of TAK and GCA [35,36]. In addition, it was shown to inhibit the production of adhesion molecules and reduces fibrosis in several animal studies [37], [38], [39] (chronic fibrosis plays a critical role in the progression of TAK) [40].

If this claim could be confirmed, it would have wide implications for the therapeutic positioning of LEF in LVV. In this context, we undertook a systematic literature review (SLR) and meta-analysis to synthesize current evidence on the effectiveness and safety of LEF in TAK and GCA.