<p>Presentations at the recent<strong> ACR Convergence 2025</strong> meeting discussed systemic lupus erythematosus (SLE) risk across the continuum—from preclinical autoimmunity to symptomatic progression, damage, and mortality. Genetics and environment intertwine in the evolving understanding of biomarkers and proteomic signals, while interventional trials highlight both the limits of and the possibilities for prevention.</p> <p><br></p> <p><em>Following these presentations, featured expert Jennifer L. Rogers, MD, was interviewed by</em> Conference Reporter<em> Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Rogers are presented here.</em></p>

You can think about SLE risk in many ways. One is the risk of developing SLE; another is the risk of damage from SLE, including flares or organ damage, morbidity, and mortality. There were a number of excellent presentations at the ACR Convergence meeting this year focused on SLE risk, SLE prevention, and evolving perspectives on how we conceptualize this disease.

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Traditionally, we have described SLE disease stages as preclinical; asymptomatic with antinuclear antibody positivity or other related manifestations; incomplete; and, finally, overt SLE. A key question in understanding the risk of developing SLE is whether individuals can be identified earlier in this continuum and treated in ways that could halt or slow disease progression.

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At ACR Convergence 2025, outstanding presentations by Karen Costenbader, MD, MPH, and David Karp, MD, PhD, MACR, addressed these questions in the session titled “Prevention Is the Best Medicine: Updates for Rheumatoid Arthritis and Lupus.” They highlighted the complex interplay between genetic susceptibility and environmental exposures in shaping SLE. The discussion emphasized how epigenetic processes can alter our immune system, which, in turn, can increase the risk of developing autoimmune diseases such as SLE. Moreover, Dr Costenbader underscored that, although genetics clearly contributes to the development of SLE, additional factors are also involved. So, the question becomes: Can we prevent disease onset? She presented information on emerging biomarkers and new genetic probability scores that may potentially enhance our ability to predict who is likely going to develop SLE. This work is particularly exciting and represents an important step forward.

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Dr Karp presented updates from the SMILE trial, which enrolled individuals with incomplete SLE, defined as antinuclear antibody positivity with 1 to 2 additional 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) or 2012 Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) classification criteria for SLE. These individuals do not fully meet criteria for SLE. Trial participants received hydroxychloroquine or placebo and were followed for 2 years to determine whether treatment affected the likelihood of developing SLE symptoms or meeting the classification criteria for SLE. The trial did not demonstrate a difference in progression between hydroxychloroquine and placebo groups, which was disappointing.

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However, a related analysis suggested that hydroxychloroquine lowered autoantibody levels measured across a broad panel of antigens in individuals at risk for SLE (poster 1524). This brings us back to a fundamental challenge: not all patients follow the same trajectory. Heterogeneity in SLE endotypes, severity, and clinical presentation complicates efforts to study disease and may explain why the SMILE trial was negative. To truly understand these trajectories, we need larger studies with longer follow-up.

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Despite the primary SMILE findings, another poster presented at the ACR Convergence 2025 meeting by Benjamin Jones, BS, examined longitudinal proteomic effects of hydroxychloroquine in SMILE participants (poster 0023). Investigators reported changes in disease-dependent and -independent molecular effects in patients treated with hydroxychloroquine, including downregulation in toll-like receptors, TNF, and IL-17 signaling pathways in both SLE progressors and nonprogressors. These findings suggest that hydroxychloroquine exerts important biological effects that may be independent of clinical progression.

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I was also intrigued by an integrated analysis of polygenic and environmental risk scores for late-onset SLE, which was presented by Mehmet Hocaoglu, MD, at the meeting (poster 0036). This work underscores that, while polygenic inherited risk is fixed, environmental exposures are cumulative and modifiable. This study assessed environmental factors, including sunlight exposure, depression, sleeplessness, and air pollution, and found that moderate physical activity was protective, which is a practical and encouraging message to share with patients.

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A final poster at ACR Convergence 2025 worth highlighting was presented by Christine Kim, MD, on demographic risk factors and the social vulnerability index (poster 1060). Prior studies have suggested that social determinants of health are associated with worse outcomes in SLE. The study by Dr Kim and colleagues evaluated mortality and showed that social vulnerabilities, socioeconomic status, household characteristics, and race all contribute to an increased risk of death in patients with SLE. The findings are important and raise the question of whether rheumatologists should be screening and discussing social determinants of health. These discussions can be challenging and are often not included in traditional rheumatology. However, incorporating such screenings could help us identify unmet needs and partner with social workers, community centers, and other support services to better assist this vulnerable population.

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Together, these presentations reinforce that understanding and preventing risk across the SLE spectrum will require a multifaceted research approach including genetics, environment, biomarkers, and social determinants of health. Although significant challenges remain, the work highlighted at ACR Convergence 2025 brings us closer to identifying key risks and improving outcomes for people with SLE.