Background There is clear evidence that clinical and laboratory features of systemic lupus erythematosus (SLE) can be present for many years prior to an individual fulfilling the full disease classification criteria. Most commonly, these features include characteristic serologies, but also isolated hematological findings, rash, serositis, or hypocomplementemia. Such individuals may be considered to have ‘Incomplete Lupus Erythematosus’ or ILE, and some eventually transition to frank SLE over time. There is retrospective evidence that hydroxychloroquine (HCQ) use delayed this progression to SLE. The SMILE trial was undertaken to study the ability of HCQ to prevent progression to lupus in people at risk.

Methods SMILE is an NIH-funded, multi-center, randomized, placebo-controlled study of HCQ in people with an ANA (1:80 by IF) and one or two SLICC criteria for the classification of SLE. Participants can be either sex, ages 15-49, and could not have other definite autoimmune disease or fibromyalgia. The primary end point is the rate of development of new lupus criteria. Subjects are randomized to HCQ or placebo and followed for 24 months or until the development of SLE. Assessments done every 3 months included determination of any new SLICC criteria by history, physical and laboratory, as well as banking of serum, plasma, peripheral blood mononuclear cells, DNA, RNA and urine.

Results Enrollment began in early 2018 and is anticipated to end in the Fall of 2021 with study completion in 2023. Currently, all results remain blinded. As of May 2021, a total of 222 participants were screened and 157 randomized. 31 completed the protocol, 29 were discontinued by clinical staff, and 29 withdrew from the study. 16 participants (10.2%) developed classification criteria for lupus. The remainder of the participants remain in the study. 352 adverse events occurred in 115 subjects; 67 of which were felt to be probably or possibly related to the intervention.

Conclusions Recruitment for a trial of pre-clinical or incomplete lupus is difficult. Barriers included perceived risk of medication for an asymptomatic condition, or desire to take medication, even if not known to work. Nevertheless, a significant number of subjects has transitioned to lupus during the course of the trial. Data comparing HCQ to placebo will be available in 2023.

Acknowledgments This trial is supported by NIH/NIAMS U01 AR071077

Trial Registration ClinicalTrials.gov NCT03030118.