Study of Anti-Malarials in Incomplete Lupus Erythematosus

This project is a multicenter, randomized, placebo-controlled, double-blind clinical trial that is designed to test whether treating patients who are at risk for development of lupus with hydroxychloroquine can slow accumulation of disease features. Effects on clinical progression of symptoms, patient-reported outcomes and changes in the immune markers of response will be measured and toxicity of the treatment will be assessed. This trial is a first step in testing a prevention strategy for lupus.

Systemic lupus erythematosus (SLE) causes major organ damage and shortens lifespan in relatively young persons. Early diagnosis and treatment are essential to improving outcomes for SLE patients. However, evidenced-based approaches to early treatment interventions and the appropriate target population for these interventions are not available. We propose that individuals who have positivity for antinuclear antibodies (ANAs) and who also exhibit some of the other features that are used to classify SLE, are at high risk of progressing to the full systemic form of this disease. These individuals, who have significant levels of ANA with 1 or 2 additional items from the lupus classification criteria, are considered to have incomplete lupus erythematosus (ILE). We propose to treat ILE patients with hydroxychloroquine (HCQ) in the "Study of Anti-Malarials in Incomplete Lupus Erythematosus" or SMILE trial. The primary objective is to determine whether HCQ treatment can prevent acquisition of additional clinical and immunologic features that define SLE.

The major secondary objectives are to determine whether HCQ treatment: (1) lessens lupus disease activity as measured by standard scoring indices; (2) improves patient reported outcomes (3) prevents accumulation of immunologic abnormalities including autoantibodies and cytokines and (4) has an acceptable toxicity profile. The specific aims of this proposal are:

1. To carry out a double-blind, placebo-controlled, multicenter, randomized trial of HCQ vs. placebo in patients with ILE. The study tests the hypothesis that early use of HCQ can modify disease features so that accumulation of abnormalities leading to a classification of SLE can be significantly slowed.
2. To determine effects of HCQ on disease activity and patient-reported outcomes in patients with ILE.
3. To characterize the immunologic profile of HCQ in ILE-treated patients. Autoantibodies, cytokines and chemokines will be measured on multiplex arrays for developing insights into underlying mechanisms.
4. To quantitatively assess the incidence of ophthalmologic toxicity in HCQ-treated ILE patients. All enrolled patients will have standardized ophthalmologic examinations before and after study treatment. Recommendations for use and monitoring in this patient population will be developed.

The SMILE trial will determine whether or not HCQ should be given to ILE patients, will provide insights into the appropriate target population, and will propose candidate biomarkers to guide treatment decisions. While not part of the Precision Medicine Initiative®, SMILE is consistent with its goals. It will be the first step towards testing the feasibility of disease prevention studies in SLE and will accumulate biological samples in a repository that will be available to the lupus research community for further in-depth mechanistic studies.

Eligibility Criteria:
Inclusion Criteria:

1. Between 15 and 49 years of age, inclusive, at Visit 1.
2. Anti-nuclear antibody (ANA) titer of 1:80, or greater, as determined by immunofluorescence assay (IFA).
3. Participants must have at least one (but not three or more) additional clinical or laboratory criterion from the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria.
4. Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study.

Exclusion Criteria:

1. The subject meets the 2012 SLICC classification criteria for SLE at Visit 1 (i.e., ANA plus 3 other criteria, or ANA plus biopsy-proven lupus nephritis).
2. The subject has been diagnosed with another autoimmune disorder, other than autoimmune thyroid conditions.
3. The subject has fibromyalgia, based on clinical history and exam.
4. The subject has previously been or is currently being treated with oral antimalarial agents including hydroxychloroquine, chloroquine, or quinacrine.
5. The subject is currently or has been treated with immunosuppressive, immune modifying, or cytotoxic medications as listed in Section 7.2.
6. Use of any investigational agent within the preceding 12 months.
7. History of primary immunodeficiency.
8. Active bacterial, viral, fungal, or opportunistic infection.
9. Evidence of infection with human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C.
10. Concomitant malignancy or history of malignancy with the exception of adequately treated basal or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
11. The subject has significant findings on ophthalmological examination that, in the opinion of the examining Ophthalmologist, prevent safe use of hydroxychloroquine.
12. The subject has other contraindications to treatment with hydroxychloroquine including pre-existing ocular disease, hepatic impairment, psoriasis, porphyria, or allergy to the drug or class.
13. Co-morbidities requiring systemic corticosteroid therapy greater than 10 mg of prednisone per day, or equivalent, or a change in corticosteroid dose within the 3 months prior to Visit 1.
14. Starting, stopping, or changing the dose of over the counter or prescription non-steroidal anti-inflammatory drugs (NSAIDs) in the three months prior to Visit 1.
15. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study.
16. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
17. Inability to comply with the study visit schedule and procedures.