LB0005 REPURPSS-II: VALIDATION OF LEFLUNOMIDE-HYDROXYCHLOROQUINE COMBINATION THERAPY IN PATIENTS WITH PRIMARY SJÖGREN'S DISEASE: A DOUBLE-BLINDED, PLACEBO-CONTROLLED, RANDOMIZED TRIAL

Background: Primary Sjögren's disease (pSD) is a systemic autoimmune disease, most often characterized by dryness of the eyes and mouth. Despite numerous clinical studies evaluating the efficacy of both conventional and biological therapies, no effective systemic treatment has been established so far. The RepurpSS-I trial was the first trial involving conventional treatment that demonstrated significant clinical efficacy as measured by the ESSDAI (-4.35 points, p= 0.0078) [1]. Objectives: Based on the positive outcomes of the RepurpSS-I trial, we conducted the RepurpSS-II trial to validate the efficacy and safety of leflunomide-hydroxychloroquine combination therapy. Methods: A placebo-controlled, double-blind, Phase IIb RCT was conducted over 24 weeks, followed by a single-arm crossover and an open extension of 24 weeks. Eligible patients were pSD patients (2016 ACR/EULAR criteria), aged 18-75 years with an ESSDAI score of ≥5 points. They were randomly assigned (1:1) to either the placebo or LEF-HCQ group (leflunomide 20mg and hydroxychloroquine 400mg daily). The primary endpoint was the difference in ESSDAI change between baseline and 24 weeks of verum vs placebo, adjusted for baseline ESSDAI score. Secondary endpoints included the difference in change in serum IgG, C3, C4, rheumatoid factor (RF), unstimulated whole saliva (UWS), Schirmer scores, and ESSPRI after 24 weeks, also adjusted for baseline scores. Exploratory composite endpoints STAR and CRESS, which incorporate patient-reported outcomes and objective dryness assessments in addition to systemic involvement, were also evaluated [2, 3]. An intention-to-treat analysis was performed. Eudra-Ct: 2020-001933-11. Results: The study has been conducted at the University Medical Center Utrecht since October 2021, and the open-label phase is expected to be completed by the end of June 2025. The primary endpoint was completed by February 2025. A total of 85 patients were screened, of whom 46 were enrolled. The placebo group consisted of 25 patients, and 21 patients were allocated to the LEF-HCQ group. At baseline, the LEF-HCQ and placebo groups were comparable in age (median 55 years), sex (female%: 90.5 vs. 96.0), ESSDAI (9.5 vs. 9.9), ESSPRI (7.0 vs. 6.8), and IgG (12.7 vs. 14.0 g/L). The Schirmer scores for dryness of the eye were 4.5 and 2.3 mm/5min, and UWS score for dryness of the mouth was 0.3 and 0.05 mL/5min. In the LEF-HCQ group, the primary endpoint significantly improved, with a mean decrease in ESSDAI of -4.13 points (CI -1.711 to -6.558, p= 0.0016) compared to placebo after 24 weeks. Regarding secondary endpoints, significant improvements were observed in the LEF-HCQ group compared to placebo for serum IgG (-1.6, CI -2.897 to -0.304, p= 0.016), RF (-8.7, CI -15.504 to -1.926, p= 0.013), and C4 levels (0.021, CI 0.002-0.04, p= 0.031). In contrast, no significant changes were observed in several objective measures: C3 levels, UWS, and Schirmer scores. A decrease in patient-reported outcome ESSPRI was observed, although not significantly different. We observed a significant improvement in the composite endpoints STAR and CRESS. The percentage of STAR responders in placebo vs. verum was 19% vs. 64%, respectively ( p= 0.007). For CRESS, responders were 24% and 57% in placebo vs. verum, respectively ( p= 0.046). One serious adverse event occurred in the treated group but was unrelated to study medication (hospital admission for ischemic myocardial infarction). The total incidence and severity of adverse events were similar between the groups. The most frequently observed adverse event was gastrointestinal discomfort, with six patients (28.6%) in verum vs. five (20.0%) in the placebo group. Conclusion: Our study confirms the safety and efficacy of leflunomide-hydroxychloroquine in systemically active Sjögren's patients. The improvement in ESSDAI is consistent with previous results in the RepurpSS-I trial, underscoring the robustness of the response. 1 This therapy is an affordable and widely available option for Sjögren's patients with active systemic disease. Future studies should reveal whether this combination is effective in patients with high patient-reported outcomes and low systemic disease activity. REFERENCES: [1] Van der Heijden EHM, et al. Leflunomide–hydroxychloroquine combination therapy in patients with primary Sjögren's syndrome (RepurpSS-I): a placebo-controlled, double-blinded, randomised clinical trial. Lancet Rheumatol . 2020;2(5):e260-e269. doi:10.1016/S2665-9913(20)30057-6. [2] Arends S, et al. Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS): development and validation of a novel outcome measure. Lancet Rheumatol . 2021;3(8):e553-e562. doi:10.1016/S2665-9913(21)00122-3. [3] Seror R, et al. Development and preliminary validation of the Sjögren's Tool for Assessing Response (STAR): a consensual composite score for assessing treatment effect in primary Sjögren's syndrome. Ann Rheum Dis . 2022;81(7):979-989. doi:10.1136/annrheumdis-2021-222054. Acknowledgements: The authors Wing-Yi Wong and Dewi Rijnenberg share first authorship. We would like to sincerely thank all patients for participating in this study, the Dutch patients' association NVSP, and all rheumatologists that were involved in the recruitment process. We would like to thank A.N. Concepcion, N. Groot, S.A.Y. Hartgring, A.A Kruize, A.C.A. Marijnissen, F.T. Perton, and M.E. Vianen for their valuable contributions to the RepurpSS-II study. Disclosure of Interests: Wing-Yi Wong: None declared, Dewi Rijnenberg: None declared, Valentin Baloche: None declared, Sofie L.M. Blokland: None declared, Paco M.J. Welsing: None declared, Femke Bonte-Mineur: None declared, Cornelis Bekker: None declared, Safae Hamkour: None declared, Céline Bogers: None declared, Timothy Radstake Employee of AbbVie, Helen Leavis: None declared, Joel van Roon: None declared. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.