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Abstract Number: L10

Clinical Efficacy of Leflunomide/Hydroxychloroquine Combination Therapy in Patients with Primary Sjogren’s Syndrome: Results of a Placebo-Controlled Double-Blind Randomized Clinical Trial

Timothy R.D.J. Radstake1, Eefje H.M. van der Heijden2, Frederique M. Moret3, Maarten R. Hillen4, Ana P. Lopes5, Toine Rosenberg6, Nard Janssen6, Aike A. Kruize7 and Joel A.G. van Roon3, 1Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, 2Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands, 3Rheumatology & Clinical Immunology/ Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands, 4Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, 5Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands, 6Department of Oral-Maxillofacial Surgery, University Medical Center Utrecht, Utrecht, Netherlands, 7Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands

Meeting: 2018 ACR/ARHP Annual Meeting

Date of first publication: October 4, 2018

Keywords: DMARDs, Late-Breaking 2018, RCT, Sjogren's syndrome and hydroxychloroquine

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Session Information

Date: Tuesday, October 23, 2018

Session Title: Late-Breaking Abstract Poster Session

Session Type: ACR Late-breaking Abstract Session

Session Time: 9:00AM-11:00AM

Background/Purpose: Primary Sjogren’s syndrome (pSS) is a systemic, progressive autoimmune disease characterized by secretory gland dysfunction which lacks effective therapy. Clinical trials in patients with pSS using leflunomide (LEF) or hydroxychloroquine (HCQ) previously effectively inhibited B cell hyperactivity, but induced only modest insignificant effects on clinical parameters. LEF and HCQ have complementary inhibitory properties on different immune cells, including B cells, T cells and pDCs. In vitro LEF and HCQ additively inhibit T and B cell activation as well as CXCL13 production. To study the potentially additive clinical effects of these drugs we conducted a randomized, double–blind, placebo-controlled, mono-center proof of concept study to evaluate the efficacy, safety and tolerability of LEF/HCQ therapy in patients with pSS (REPURpSS-I study).

Methods: Clinically active (ESSDAI≥5) pSS patients (n=29) were randomized to receive LEF 20mg daily and HCQ 400 mg twice daily or placebo/placebo (2:1) for 24 weeks. Primary and secondary endpoints were changes in ESSDAI and stimulated whole saliva (SWS) flow at 24 weeks, respectively. Other outcomes assessed were Patient Reported Indeces (ESSPRI), Multi-dimensional Fatigue Inventory (MFI), Physician’s and Patient’s Global Assessments, SF-36, and various circulating mediators. Outcomes also included safety assessments.

Results: Twenty-nine patients were enrolled: 8 patients received placebo and 21 received LEF/HCQ combination therapy (mean baseline ESSDAI scores of 11.5 and 11.8, respectively). Overall, LEF/HCQ was safe and well-tolerated. There was a single serious AE requiring de-blinding (pancreatitis at week 16 in the placebo cohort). The ESSDAI score at 24 weeks significantly improved in the LEF/HCQ group (p=0.044, n=9 responders with ESSDAI decrease ≥3) compared to baseline, in contrast to those receiving placebo (p=0.818, 1 responder). As anticipated, lymphopenia and elevated CK levels were significantly higher in the LEF/HCQ group. When calculating ESSDAI scores without these, stronger decreases in the LEF/HCQ group (p=0.000) compared to placebo (p=0.940) were observed. In this case eleven patients in the LEF/HCQ group displayed a decline in ESSDAI of ≥3 (average decrease 6.64 points), whereas this was not observed in the placebo group. Oral dryness showed significant improvement (SWS from 823 to 1366 μl/5 minutes, p=0.04) in the LEF/HCQ treated group as compared to decline in the placebo group (SWS from 1125 to 815 μl/5min, p=0.169). Significant improvements in other measures such as ESSPRI, ESSPRI pain, ESSPRI fatigue, Physician’s Global Assessment, and Patient’s Global Assessment were also observed in the LEF/HCQ group (all at least p<0.05) but not in those receiving placebo. Serum IgG, IgM rheumatoid factor (p<0.0001 and 0.001 resp.) and CXCL13 decreased, whereas C3 and C4 increased (p=0.016 and p=0.003) in the LEF/HCQ group, but not in the placebo-treated patients.

Conclusion: This pilot RCT suggests clinical efficacy for LEF/HCQ combination therapy in almost half of the patients with primary Sjögren`s syndrome. Larger RCT’s are needed to confirm the observed effects and to identify potential biomarkers for response.


Disclosure: T. R. D. J. Radstake, None; E. H. M. van der Heijden, None; F. M. Moret, None; M. R. Hillen, None; A. P. Lopes, None; T. Rosenberg, None; N. Janssen, None; A. A. Kruize, None; J. A. G. van Roon, None.

To cite this abstract in AMA style:

Radstake TRDJ, van der Heijden EHM, Moret FM, Hillen MR, Lopes AP, Rosenberg T, Janssen N, Kruize AA, van Roon JAG. Clinical Efficacy of Leflunomide/Hydroxychloroquine Combination Therapy in Patients with Primary Sjogren’s Syndrome: Results of a Placebo-Controlled Double-Blind Randomized Clinical Trial [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/clinical-efficacy-of-leflunomide-hydroxychloroquine-combination-therapy-in-patients-with-primary-sjogrens-syndrome-results-of-a-placebo-controlled-double-blind-randomized-clinical-trial/. Accessed February 23, 2019.
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