Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE): study protocol for a randomized controlled trial

Abstract

Background: Onset of systemic lupus erythematosus (SLE) is preceded by a preclinical phase characterized by expression of autoantibodies and nonspecific clinical symptoms. Hydroxychloroquine is a treatment for lupus that is widely used based on longstanding experience and a very good safety profile. Existing data suggest that treatment with hydroxychloroquine may postpone the onset of disease. However, prospective studies that prove and quantify the efficacy of hydroxychloroquine in the preclinical phase of lupus have not been done. This study will test the hypothesis that early hydroxychloroquine use can prevent accumulation of clinical abnormalities and modify immune responses that define SLE.

Methods: A randomized, double-blind, placebo-controlled trial of hydroxychloroquine vs placebo will be conducted. Participants will have incomplete lupus erythematosus as defined by the presence of antinuclear antibody (ANA) positivity at a titer of 1:80 or greater, as well as one or two additional criteria from the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. The age range will be 15-45 years and the treatment phase will be 96 weeks. The primary endpoint will be the increase in the number of features of SLE defined by the 2012 SLICC classification schema. Secondary outcomes will include the proportion of participants who transition to a classification of SLE as defined by SLICC criteria.

Discussion: A major challenge for improving therapies in patients with SLE is early detection of disease. The ANA test that is widely used to screen for SLE has low specificity and interpretation of its significance is challenging. The Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE) trial will provide insights into the appropriate target population for intervention, and will assess whether hydroxychloroquine can slow progression as measured by the accumulation of criteria. Ophthalmologic safety in this population will be assessed. The study will investigate candidate biomarkers that will guide treatment decisions and will accumulate a specimen biobank that will be available to the lupus research community for further in-depth mechanistic studies. This trial is a first step toward testing the feasibility of disease prevention strategies in SLE.

Trial registration: ClinicalTrials.gov, NCT 03030118 . Registered on 24 January 2017.

Trial registration: ClinicalTrials.gov NCT03030118.

Keywords: Hydroxychloroquine; Incomplete lupus; Prevention; Randomized clinical trial; Systemic lupus erythematosus; Undifferentiated connective tissue disease.

Fig. 1

Schematic of initial or entry phase of the SMILE trial from prescreening, through screening and randomization, followed by treatment phase, through the final ophthalmology visit. SPIRIT Standard Protocol Items: Recommendations for Interventional Trials

Fig. 2

SPIRIT figure of participant timelines. ANA antinuclear antibody, ACR American College of Rheumatology, AE adverse event, CLASI Cutaneous Lupus Erythematosus Disease Area and Severity Index, CSQ Connective Tissue Disease Screening Questionnaire, HCQ hydroxychloroquine, IFA immunofluorescence assay, SLEDAI Systemic Lupus Erythematosus Disease Activity Index, SLICC Systemic Lupus International Collaborating Clinics, SPIRIT Standard Protocol Items: Recommendations for Interventional Trials, Wk week