A small phase 2b trial gives hope to affordable oral combination option.
Combination therapy with leflunomide and hydroxychloroquine significantly improved systemic disease activity in patients with active Sjögren’s disease in a small phase 2b randomised controlled trial.
The results from the 46-patient study, published in The Lancet Rheumatology, have given hope to the idea that conventional disease-modifying antirheumatic drugs might still play some role for a condition that has historically lacked approved therapies.
“To our knowledge, this is the first trial to replicate the positive results of conventional antirheumatic drugs in Sjögren’s disease,” the researchers wrote.
“This is the only positive trial done in the absence of background immunomodulatory therapy beyond the investigational treatment, allowing accurate assessment of treatment effect and providing a robust foundation for future mechanistic analyses to further elucidate the unresolved underlying pathophysiology of Sjögren’s disease, disease activity, and treatment effects.
“The affordability and wide availability of this treatment make it a promising option, even in low-income countries.”
Sjögren’s is a chronic autoimmune condition characterised by lymphocytic infiltration of exocrine glands, leading to severe ocular and oral dryness, fatigue, pain and systemic inflammatory complications.
Around one-third of patients develop extra-glandular manifestations involving organs such as the lungs, nervous system and kidneys, and the disease is associated with increased lymphoma risk.
Despite this morbidity burden, systemic treatment options remain limited and many previous clinical trials involving biologics and targeted immune therapies have failed to demonstrate meaningful clinical benefit.
The RepurpSS-II trial was conducted at the University Medical Centre Utrecht in the Netherlands, and enrolled adults aged 18–75 years who met the 2016 ACR-EULAR classification criteria for Sjögren’s disease. They had moderate-to-severe systemic disease activity, defined as an ESSDAI score of at least five.
Researchers excluded patients who had used leflunomide or hydroxychloroquine within six months before enrolment, as well as those taking other immunosuppressive therapies unless they completed a washout period.
The researchers randomised 46 participants to receive either placebo or oral leflunomide 20mg plus hydroxychloroquine 400mg daily for 24 weeks, while 21 patients received active treatment and 25 received placebo.
The median patient age was 55 years and 93% of participants were women, reflecting the disease’s strong female predominance. Baseline ESSDAI scores were comparable between groups, averaging approximately 9.7 points.
At 24 weeks, the adjusted mean difference in ESSDAI change between treatment groups was –4.135 points in favour of leflunomide–hydroxychloroquine (95% CI –6.558 to –1.709).
The researchers reported that improvements were distributed across several disease domains, particularly biological, glandular, articular, constitutional and lymphadenopathy manifestations.
Clinical ESSDAI scores also improved significantly in the treatment arm compared with placebo.
The researchers said the magnitude of improvement was consistent with the earlier RepurpSS-I proof-of-concept study, which first suggested efficacy for the drug combination in Sjögren’s disease.
The replicated treatment effect was notable because few Sjögren’s trials have demonstrated statistically significant reductions in systemic disease activity, they said.
The observed benefit was comparable to improvements reported in recent studies of investigational agents such as iscalimab, dazodalibep, remibrutinib and telitacicept.
The trial also demonstrated reductions in biomarkers associated with B-cell hyperactivity. At 24 weeks, serum IgG concentrations fell by a mean difference of –1.600 g/L relative to placebo, while rheumatoid factor levels declined by –8.715 IU/mL.
Complement component 4 concentrations increased modestly in the active treatment group, suggesting reduced complement consumption. Investigators argued these immunological findings support the proposed mechanism of additive immune modulation achieved by combining the two agents.
Leflunomide inhibits pyrimidine synthesis and suppresses lymphocyte proliferation, while hydroxychloroquine modulates innate immune signalling pathways, including interferon activation.
The researchers noted that previous mechanistic analyses from RepurpSS-I showed combined therapy reduced B-cell and T-cell activity, interferon signalling and inflammatory chemokines including CXCL9, CXCL10 and CXCL13.
They suggested this broader immunomodulatory profile may explain the treatment’s efficacy in a disease driven by complex interactions between innate and adaptive immune pathways.
Despite improvements in systemic inflammation, the study did not demonstrate statistically significant benefits in patient-reported outcomes measured by ESSPRI, nor in objective measures of oral and ocular dryness such as Schirmer testing, tear breakup time or salivary flow.
The researchers said symptoms such as fatigue, dryness and pain may be driven by both inflammatory and non-inflammatory mechanisms, potentially limiting responsiveness to immunomodulatory treatment alone.
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Post-hoc analyses using newer composite responder endpoints produced more favourable results. Sixty-four per cent of patients in the active treatment group met STAR response criteria compared with 19% in the placebo arm.
Similarly, 57% met CRESS response criteria versus 24% of placebo recipients. The authors said these composite measures may better capture multidimensional treatment responses in Sjögren’s disease by incorporating systemic activity, patient-reported outcomes and objective dryness assessments.
Adverse event rates were similar between groups overall, although gastrointestinal symptoms were more common with active therapy.
The most frequently reported adverse effects included gastrointestinal discomfort, diarrhoea, headache, dizziness and upper respiratory tract infections. Three patients discontinued active treatment because of possible treatment-related adverse effects, including elevated liver enzymes, fatigue and gastrointestinal symptoms.
One patient in the treatment arm experienced a non-ST-elevation myocardial infarction that investigators considered probably unrelated to study medication because of pre-existing cardiac disease. There were no deaths during the study.
The researchers highlighted the study’s exclusion of concomitant DMARD therapy as a key methodological strength. Unlike several recent positive Sjögren’s trials in which patients continued background immunosuppressive therapy, RepurpSS-II evaluated the independent effect of the investigational regimen without confounding from other DMARDs.
They said this design provided stronger evidence that the observed clinical improvements were attributable to leflunomide–hydroxychloroquine itself.
However, they acknowledged limitations including the relatively small sample size and baseline imbalances in some disease domains between groups. They also noted that most patients with Sjögren’s disease had substantial symptom burden despite low systemic activity, meaning the findings may not be generalisable to the broader Sjögren’s population.
Further evaluation is underway in the phase 3 NECESSITY trial, which is examining whether the combination can improve patient-reported symptoms in patients with lower systemic disease activity.
“In summary, the RepurpSS-II trial showed a significant clinical response to leflunomide–hydroxychloroquine treatment in patients with active systemic disease without concomitant DMARDs, validating the findings of the RepurpSS-I trial,” the researchers concluded.
“The treatment was well tolerated, but longer follow-up is warranted for longer-term outcomes. If incorporated into daily practice, long-term tolerability should be the subject of ongoing monitoring.
“In addition, the treatment is administered orally, offering a convenient option for at least a subset of patients.
“Overall, leflunomide–hydroxychloroquine combination therapy is widely affordable, readily available, and has strong potential for clinical use in patients with Sjögren’s disease.”
