Leflunomide shows promise in Takayasu arteritis

Use of the conventional DMARD* leflunomide led to rapid induction and sustained remission rates in patients with Takayasu arteritis (TA) especially in refractory cases, an observational study shows.

“Leflunomide has long been considered an alternative [second-line] immunosuppressive agent for TA … [Its] underlying efficacy, sustained remission, and good tolerance in active TA patients was promising … However, studies with high-grade evidence supporting its efficacy and safety in TA are rare,” said the researchers.

Sixty patients (mean age 32 years, 75 percent female) from the East China TA cohort were prospectively evaluated. Participants received oral leflunomide 10–20 mg daily and were split into two groups: leflunomide-naïve (including new-onset TA) and cyclophosphamide (CYC)-resistant (n=42 and 18, respectively). [Semin Arthritis Rheum 2020;50:59-65]

At 6 months, total complete remission (CR) and response rates were 68 percent and 84 percent, respectively. Laboratory results reflected sharp declines from baseline inflammatory profile levels (from 31 to 19 mm/hour; p=0.02 [ESR**] and from 11 to 4 mg/L; p<0.01 [CRP***]). There was also a significant drop from baseline NIH^# score (0 vs 2; p<0.01).

At 12 months, total CR and response rates were 55 percent and 70 percent, respectively. ESR and CRP levels continued to be low (15 mm/hour; p=0.04 and 3 mg/L; p<0.01, respectively), while the NIH score was maintained.

Of note was the numerically higher 12-month CR rate in the CYC-resistant vs the leflunomide-naïve arm (73 percent vs 49 percent). Moreover, the decline in NIH score was only seen in the CYC-resistant arm. “[These findings suggest] that leflunomide might be a viable alternative for patients with refractory TA,” the researchers pointed out.

The CR rates were also lower than in previous reports which, according to the researchers, could have been due to the more severe complications (ie, syncope, cerebral infarction, vision loss, and renal dysfunction) present among participants. “Another possible reason is the [stricter] criteria for CR in our study.”

Only five participants reported adverse events (AEs; n=2 each for diarrhoea and liver dysfunction; 1 for rash). Patients with diarrhoea and rash switched to other agents. Those with liver dysfunction recovered with laboratory results returning to normal following leflunomide suspension, which was resumed thereafter. No further AEs occurred following resumption of leflunomide use.

The maternal factor

While there were no reports of teratogenicity and gonadal toxicity in the current study, these remain a major concern for leflunomide especially for women of reproductive age, noted the researchers.

Leflunomide was confirmed teratogenic in rats and rabbits with dosages similar to those in humans. [Ann Rheum Dis 2018;77:500-509; Reprod Toxicol 2007;24:310-316] “[Although] leflunomide may not be a human teratogen … women of reproductive potential are recommended to discontinue leflunomide treatment for 2 years before a planned pregnancy,” they said.

Suppression of inflammation

TA is characterized by granulomatous inflammation in the aortic vessel wall which could progress into fibrosis. [Int J Angiol 2015;24:244-248] The ensuing ischaemia due to vascular stenosis and/or occlusion consequently leads to high morbidity and mortality rates. [Vasc Endovasc Surg 2017;51:470-479] Therefore, the primary treatment target is the suppression of vascular and systemic inflammation, said the researchers.

Despite high remission rates associated with glucocorticoids – the cornerstone of TA induction therapy – this comes with a high rate of other forms of TA, hence the need to incorporate conventional DMARDs into the treatment regimen. [Ann Intern Med 1994;120:919-929] However, conventional DMARD use is tied to increased AE rates (eg, infections, renal insufficiency, haemorrhagic cystitis, gastrointestinal reactions, gonadal toxicity). [Clin Exp Rheumatol 2011;29:S43-S48; Rheumatol Int 2017;37:2019-2026; Sci Rep 2016;6:38687]

“[The] favourable responses and sustained stability with adequate safety especially among refractory cases [imply that] leflunomide should be considered an alternative therapy for TA induction and maintenance, even for young women with fertility requirements,” said the researchers. “Leflunomide may help induce remission in the early phase of TA, maintain or improve remission after a longer course of treatment, and even prevent relapse.”

Given the rarity of TA, recruiting an adequate sample to complete trials remains a challenge, noted the researchers. To date, no randomized trials have been conducted to assess conventional DMARDs in this setting. Further exploration is thus warranted, preferably on a larger sample with a longer follow up period, they added.