Background Laboratory and clinical features of systemic lupus erythematosus (SLE) may precede the onset of clinically apparent and classifiable disease. Autoantibodies and cytokines have been shown to be present in the blood years before a diagnosis of SLE can be made. Furthermore, nonspecific symptoms such as arthralgias and skin rashes may appear but not be recognized as related to autoimmunity. Patients who have signs, symptoms and laboratory abnormalities associated with SLE but who do not fulfill classification criteria for this condition have been designated as having incomplete lupus erythematosus (ILE). Patients with ILE are at risk for transition to SLE and offer a window into study of therapies that might prevent progressive disease. The SMILE study was designed to investigate whether hydroxychloroquine (HCQ) treatment prevents ILE patients from accumulating additional SLE criteria and developing progressive disease.

Methods SMILE is a multicenter, NIH-funded randomized, placebo-controlled, double blind study of hydroxychloroquine in patients with ILE. Eligible individuals are 15-49 years of age and must have an ANA by IFA of at least 1:80 along with 1 or 2 additional SLICC criteria for SLE. After confirming ophthalmologic safety, patients are randomized (1:1) to receive HCQ or placebo for 24 months. Visits at 3 month intervals assess clinical and laboratory features and record SLICC criteria. Any participant who is found to meet SLICC classification criteria for SLE is required to exit from the trial. Biosamples are collected at each visit for measurement of autoantibody and cytokine arrays; other samples are banked for later studies.

Results Enrollment started at the beginning of 2018 and ended on July 28, 2022. At that time 256 patients had been screened and 185 enrolled into the randomized phase, slightly less than the planned enrollment of 192. The randomized participants are more than 90% female, and the average age is 33 years. The study population is predominantly White, and only 15% are Black or more than one race. A small number (5/256) screen-failed due to ophthalmologic findings. Greater than 45% of enrollees have added SLICC criteria during followup, including approximately 15% who have exited the study after achieving 4 or more SLICC criteria and thus classifying as SLE. No drug-related SAEs have been reported and treatment has not been unblinded for any participant. The last enrollee is predicted to exit the trial in mid-2024.

Conclusions The ILE definition used in SMILE targets a population in which accumulation of additional SLE criteria and transition to classifiable disease is observable within a 2 year study period. The enrolled population has a lower percentage of Black patients than anticipated, and whether this is due to a lower prevalence of the ILE stage of disease in these patients is of interest for further investigation. SMILE is generating a valuable biobank of samples for future mechanistic studies.

Acknowledgements Supported by NIH/NIAMS U01AR071077. ClinicalTrials.gov NCTC03030118