The large print giveth and the small print taketh away: preemptive treatment of serologically active, clinically quiet systemic lupus erythematosus.

In this issue of Arthritis & Rheumatism, Tseng et al present the final results of an important clinical trial that was initially presented at the 2003 Annual Scientific Meeting of the American College of Rheumatology (1,2). Clinical trials in systemic lupus erythematosus (SLE) are difficult to do, and it is also difficult to recruit sufficient numbers of subjects. The best study designs and end point measures are evolving. Although new funding is available, clinical trials are still not adequately resourced. Tseng et al deserve our admiration and gratitude for their efforts. Their results have relevance for patient management and for experimental therapeutics in SLE. Their study addresses an important and longstanding clinical question in SLE, the roots of which are found in the history of the discovery of the molecular biology of SLE. From Ehrlich’s concept of horror autotoxicus, to the discovery of autoantibodies to nuclear constituents, to their application in the diagnosis and subsetting of phenotypes of SLE, and to the demonstration of autoantibodies and complement products in situ, the essential roles of autoantibodies and complement make a nice story of pathogenesis. This history has stimulated the widespread and often uncritical use of measurements of antibody and complement levels to diagnose and monitor the disease, as well as the idea that these immunologic measures can be used to decide when to initiate, taper, and stop therapy (3,4). These latter clinical conclusions have occurred despite disquieting observations that autoantibodies may be neither sufficiently specific nor sensitive for diagnosis, nor may they be necessarily correlated with clinically “active” disease or predictive of a flare (5–8). In clinical research there are no perfect studies, and good studies beget new questions. The present study illustrates both principles. The authors are appropriately circumspect about the generalizability of their findings. It is unclear which patients at the various centers were referred for screening and how representative these subjects are. The data indicate that the patients to which the study results apply are uncommon. The study accrued subjects over a 5-year period. The authors estimate that 50% of patients were neither eligible nor referred for formal screening for the study. Only 27% of the clinically stable patients were randomized, while nearly half of those who did not experience a serologic flare were censored. Although 40–80% of patients with SLE demonstrate antibodies to double-stranded DNA (anti-dsDNA) at some time during their disease course (7–11), the proportion of these patients who have clinically quiescent disease is uncertain; it is probably a small number of individuals (12,13). The landmark study by Bootsma et al (14), upon which Tseng and coworkers’ study builds, evaluated all available patients with SLE, but randomized those who had anti-dsDNA by blocks in order to balance the participants according to the presence or absence of a major or minor flare in the previous 2 years and by 2 immunosuppression maintenance regimens (stable treatment with corticosteroid and other immunosuppressive agents or decreasing corticosteroid dosage versus no immunosuppressive agents). The Dutch investigators showed that, compared with conventional treatment implemented after clinical relapse, early treatment of increases in the anti-dsDNA antibody titer with prednisone (30 mg/day over the maintenance dosage to a maximum 60 mg/day) reduced the incidence of major and minor flares. This first controlled study used only Supported by grants from the NIH (AR-47782) and Rheuminations, Inc. Ms Simard’s work was supported by a training grant from the NIH (T32-AI-07535). Matthew H. Liang, MD, MPH, Julia F. Simard, SM: Harvard School of Public Health, Robert B. Brigham Arthritis and Musculoskeletal Diseases Clinical Research Center, Brigham and Women’s Hospital, Boston VA Healthcare System, and the Massachusetts Veterans Epidemiology and Research Center, Boston. Address correspondence and reprint requests to Matthew H. Liang, MD, MPH, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, 75 Francis Street, PBB-3, Boston, MA 02115. E-mail: mliang@partners.org. Submitted for publication May 5, 2006; accepted in revised form August 2, 2006.