Leflunomide-hydroxychloroquine combination therapy in patients with primary Sjögren's syndrome (RepurpSS-I): a placebo-controlled, double-blinded, randomised clinical trial

Eefje Hanna Martine van der Heijden; Sofie Liny Marie Blokland; Maarten Reinier Hillen; Ana Paula Pinheiro Lopes; Fréderique Marie van Vliet-Moret; Antoine Johan Wilhelm Peter Rosenberg; Nard Gabriëlle Janssen; Paco Mattheus Jacobus Welsing; Valentina Iannizzotto; Weiyang Tao; Aridaman Pandit; Francesca Barone; Aike Albert Kruize; Timothy Ruben Dirk Jan Radstake; Joel Adrianus Gijsbert van Roon

doi:10.1016/S2665-9913(20)30057-6

Leflunomide-hydroxychloroquine combination therapy in patients with primary Sjögren's syndrome (RepurpSS-I): a placebo-controlled, double-blinded, randomised clinical trial

Lancet Rheumatol. 2020 May;2(5):e260-e269. doi: 10.1016/S2665-9913(20)30057-6. Epub 2020 Mar 26.

Authors

Eefje Hanna Martine van der Heijden¹, Sofie Liny Marie Blokland¹, Maarten Reinier Hillen¹, Ana Paula Pinheiro Lopes², Fréderique Marie van Vliet-Moret², Antoine Johan Wilhelm Peter Rosenberg³, Nard Gabriëlle Janssen³, Paco Mattheus Jacobus Welsing⁴, Valentina Iannizzotto⁵, Weiyang Tao¹, Aridaman Pandit¹, Francesca Barone⁵, Aike Albert Kruize⁴, Timothy Ruben Dirk Jan Radstake¹, Joel Adrianus Gijsbert van Roon⁶

Affiliations

¹ Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Center of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
² Center of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
³ Department of Oral and Maxillofacial Surgery and Special Dental Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
⁴ Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
⁵ Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
⁶ Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Center of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. Electronic address: j.vanroon@umcutrecht.nl.

PMID: 38273473
DOI: 10.1016/S2665-9913(20)30057-6

Abstract

Background: Primary Sjögren's syndrome is a systemic autoimmune disease characterised by secretory gland dysfunction, for which no effective therapy is available. Based on the complementary properties of leflunomide and hydroxychloroquine in inhibiting activation of key immune cells in primary Sjögren's syndrome, we aimed to evaluate the clinical efficacy and safety of leflunomide-hydroxychloroquine combination therapy in patients with primary Sjögren's syndrome.

Methods: We did a placebo-controlled, double-blinded, phase 2A randomised clinical trial in patients with primary Sjögren's syndrome at the University Medical Center Utrecht (Utrecht, Netherlands). Eligible patients were aged 18-75 years, had a European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI) score of 5 or higher, and a lymphocytic focus score of 1 or higher in labial salivary gland biopsy specimens. Patients were randomly assigned (2:1) with block randomisation (block size of six) to receive leflunomide 20 mg and hydroxychloroquine 400 mg daily or placebo for 24 weeks. The primary endpoint was the between-group difference in change in ESSDAI scores from 0 to 24 weeks, adjusted for baseline ESSDAI score. Patients were analysed according to the intention-to-treat principle. This study is registered with EudraCT, 2014-003140-12.

Findings: Between March 7, 2016, and Nov 30, 2017, 37 patients were screened, of whom 29 patients (28 women and one man) were enrolled. 21 patients were assigned to receive leflunomide-hydroxychloroquine and eight patients were assigned to receive placebo. One patient in the placebo group required high-dose prednisone to treat polymyalgia rheumatica at week 13 and was excluded from the primary analysis. From 0 to 24 weeks, the mean difference in ESSDAI score, adjusted for baseline values, in the leflunomide-hydroxychloroquine group compared with the placebo group was -4·35 points (95% CI -7·45 to -1·25, p=0·0078). No serious adverse events occurred in the leflunomide-hydroxychloroquine group and two serious adverse events occurred in the placebo group (hospital admission for pancreatitis and hospital admission for nephrolithiasis). The most common adverse events in the leflunomide-hydroxychloroquine group were gastrointestinal discomfort (11 patients [52%] vs two [25%] in the placebo group), modest transient increases in alanine aminotransferase (ten [48%] vs one [13%]), and short episodes of general malaise and shivering (nine [43%] vs one [13%]).

Interpretation: Leflunomide-hydroxychloroquine was safe and resulted in a clinical response in patients with primary Sjögren's syndrome. These results warrant further evaluation of leflunomide-hydroxychloroquine combination therapy in larger clinical trials.

Funding: ZonMw.