Team: Abs Before SLE, aka “Autoantibodies before SLE”
Region: Ab Workout
Authors: Massachusetts General Hospital Rheumatology Fellowship; Guy Katz, MD, third-year rheumatology fellow; Jacquelyn Nestor, MD, PhD, second-year rheumatology fellow; Steve Witte, MD, PhD, second-year rheumatology fellow; Zandra Walton, MD, PhD, first-year rheumatology fellow; Greg Challener, MD, first-year rheumatology fellow; Marcy Bolster, MD, rheumatology fellowship Program Director
Virtually every player with systemic lupus erythematosus (SLE) harbors autoantibodies as part of their offensive strategies. For decades, these autoantibodies have been powerhouses in the workup and long-term management for patients with SLE and many other systemic autoimmune diseases. Indeed, the ability to analyze the meaning of these tests in different clinical contexts is one of the defining skills of a rheumatologist. However, long after they were discovered to be associated with SLE, there remained critical questions surrounding these autoantibodies. What is their role in disease pathogenesis? When in the disease process do they develop? How should we counsel patients with positive autoantibodies and no clinical evidence of associated autoimmune disease? In the landmark article by Arbuckle et al., answers to these questions were finally uncovered, providing novel insights into SLE and autoimmunity.
Recruiting players from a powerful database of 30 million prospectively collected serum samples, patients with SLE (n=130) and four matched controls each were identified. These samples were then interrogated for the presence of antinuclear antibodies (ANA) at a titer of 1:120 titer or greater as well as antibodies to Ro (SSA), La (SSB), dsDNA, smith (Sm), RNP, and phospholipids. This team effort revealed that SLE-associated antibodies attracted the attention of scouts long before clinical disease manifestations and their tournament debut. Ro and La appeared, on average, starting the shot clock, over 3 years before diagnosis. Likewise, development of other antibodies also predated SLE debuts, and seroconversion cheered the players towards diagnosis with ANA and antiphospholipid antibodies appearing 3 years, dsDNA 2 years, Sm 1.5 years, and RNP nearly 11 months prior to diagnosis. Autoantibodies predicted future performance, with the vast majority of SLE players (about 90%) harboring positive antibodies for more than two years prior to the onset of symptoms. And these estimates on the lead time of antibody positivity prior to clinical disease onset and diagnosis are likely underestimated, as many of the earliest available samples already exhibited autoantibodies.
Impact on Rheumatology
The Arbuckle team not only filled important knowledge gaps in SLE pathophysiology, but it also changed the game for research on preclinical autoimmunity in numerous diseases, which is now one of the areas of investigation in rheumatology at the top of the standings. This team provided answers to real-world clinical questions that rheumatologists and patients encounter every day. Autoantibody positivity—particularly ANA—is one of the most common reasons for rheumatology referral. Only a minority of patients with positive ANA develop ANA-related systemic autoimmune disease, yet it is crucial to identify and provide a defense for those who will develop diseases such as SLE. Nearly two decades after its league debut, we continue to refer to this championship winning team for evidence-based plays on how to coach patients with positive autoantibodies in the absence of clinical manifestations of autoimmune disease. Using the offensive style from this study, clinicians can confidently rank patients with positive autoantibodies and coach them on their odds of developing autoimmune disease using specific game times.
This paper is a much-needed playbook of immune-related events prior to SLE tip-off, which was previously uncharted territory. It provided key plays—answering some of the most common clinical questions rheumatologists face—led to a momentum shift in our understanding of SLE pathogenesis, and it established the field of preclinical autoimmunity. The study directly impacts patients and clinicians every day, and its winning results have gone on to shape our understanding of the playbook of not just SLE, but of many autoantibody-associated autoimmune diseases.
Chances in the Tournament
Since its tournament debut in 2003, this manuscript has consistently been a dynasty in the field of rheumatology, and it is certain to be a fan favorite in RheumMadness 2023. Due to its clinical applicability and broad research implications that extend far beyond SLE, this landmark article has a strong chance of cutting down the net as the tournament champion. Its applicability to numerous autoimmune diseases will likely lead to its landslide victory in the Ab Workout Region, where the other teams apply more narrowly to individual diseases (anti-CCP and RA, ANCA and ANCA-associated vasculitis). If prior tournaments are any indication, landmark clinical trials from TNF Takedown, RA Revamp, Get in the Game, and Jump Ball are likely to be lay-ups in the tournament. However, the broad impact of this study—addressing more than a single disease—is the reason it is likely to be a slam dunk over these trials, none of which have been cited as many times (i.e., has as many wins) as the paper by Arbuckle et al.
Next scouting report: CCP & Enolase
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See the Q&A on theMednet.org for the Ab Workout Region: How do you approach follow up in patients with isolated positive ANA, but no current clinical signs or symptoms of systemic lupus erythematosus?
- Arbuckle MR, et al. Development of autoantibodies before clinical onset of systemic lupus erythematosus. N Engl J Med. 2003 Oct 16;349(16):1526-33. doi: 10.1056/NEJMoa021933.