# Mechanisms of Lupus Disease Transition and Hydroxychloroquine Immune Modulation

> **NIH NIH R01** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2020 · $460,680

## Abstract

The Study of anti-Malarials in Incomplete Lupus Erythematosus or SMILE is the first prevention study for
systemic lupus erythematosus, randomizing 240 individuals with autoantibodies and at least one clinical
feature of lupus to receive either hydroxychloroquine (HCQ) or placebo to assess the ability to delay or prevent
the development of new clinical criteria or transition to classified SLE. Individuals are assessed quarterly for
development of new serologic or clinical evidence of lupus, or other autoimmune rheumatic diseases, and
standard samples are obtained. The ancillary studies proposed in this application will leverage the resources
from this novel clinical trial with the addition of new critical samples required for analyses to test specific
hypotheses of lupus pathogenesis and to identify potential mechanisms of how HCQ modifies the dysregulated
autoimmune system in humans. The studies within this application focus on three critical hypotheses which
have been established and confirmed in the field to be found in lupus after disease classification and will
establish which of these pathways are critical to disease onset and pathogenesis. Autoantibodies are present
in nearly all SLE patients and often occur years before the onset of clinical symptoms or disease classification.
Using novel chip-based autoantigen and peptide arrays, experiments will assess the impact of HCQ on
development of new autospecificities, and determine the degree and timing of diversification in response to
accumulation of new clinical symptoms or SLE disease classification. Increased expression of interferon
responsive genes is also common in SLE and associated with increased disease activity and autoantibody
production. Results from retrospective analyses of serial samples from military and family collections of
individuals who subsequently develop lupus support that interferon pathways are dysregulated before disease
onset with greatest enhancement near classification. Interferon activity, whole blood gene signatures, soluble
mediators and TLR/interferon stimulated responses will be assessed in the serial samples we will collect from
this trial and analyzed in relation to the detailed protocol-driven clinical phenotyping. The influence of HCQ on
these interferon responses, as well as the changes in these responses with the accumulation of additional
lupus clinical features, will be assessed. Finally, autoantibody stimulated interferon production through netosis
and the frequency and function of low density neutrophils will be tested on fresh serial samples to determine
their temporal association with lupus symptom accrual. Finally, serologic sets of markers which have been
identified to associate strongly with future onset of SLE in retrospective analyses will be tested with these
newly available biomarker sets for the ability to predict accumulation of additional lupus criteria, as well as use
the new data from this study to further refine the ability to identif...

## Key facts

- **NIH application ID:** 9970185
- **Project number:** 5R01AR072401-04
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** JUDITH A JAMES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $460,680
- **Award type:** 5
- **Project period:** 2017-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970185

## Citation

> US National Institutes of Health, RePORTER application 9970185, Mechanisms of Lupus Disease Transition and Hydroxychloroquine Immune Modulation (5R01AR072401-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9970185. Licensed CC0.

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