NEW YORK, NY—Severe flares of systemic lupus erythematosus (SLE) can be prevented by moderate doses of corticosteroids in some patients with clinically stable disease but rising levels of two lupus biomarkers, according to Chung-E Tseng, MD, and colleagues at New York University School of Medicine's Hospital for Joint Diseases in New York City.  The researchers report in Arthritis & Rheumatism that such treatment can largely prevent severe flares in the 27% of SLE patients who have clinically stable disease but rising levels of both anti-double-stranded DNA (anti-dsDNA) and complement C3a.¹

Randomized, Placebo-Controlled Trial

Dr. Tseng and colleagues conducted a prospective, randomized, double-blind, placebo-controlled trial that evaluated 154 SLE patients monthly for up to 18 months. Those who remained clinically stable but had serologic  evidence of flare (defined as both a 25% increase in anti-dsDNA and a 50% increase in C3a over the previous 1–2 monthly visits) were randomized to either prednisone (n = 21) or placebo (n = 20). Prednisone was given at 30 mg/day for 2 weeks, 20 mg/day for 1 week, then 10 mg/day for 1 week.

Six placebo patients but none of the prednisone patients had severe flares <e;90 days after randomization (P =.007). Severe flares were defined as those requiring >40 mg/day of prednisone and/or addition of an immunosuppressive agent. In patients randomized to the prednisone intervention, levels of anti-dsDNA decreased, levels of C4 increased, and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores improved within 1 month after initiation of prednisone.

"These preliminary data support our hypothesis that in a subset of clinically stable SLE patients with a combination of elevated C3a and anti-dsDNA levels, short-term corticosteroid therapy may avert a severe flare," Dr. Tseng concludes.

The investigators warn against over-generalizing from these data and point out that about half of the lupus patients prescreened for the study were excluded for one reason or another, that only 27% of the 154 lupus patients enrolled in the study met the criteria for serologic biomarker warning of flare, and that all of the patients were tested monthly, unlike the situation in typical clinical practice settings. That said, Dr. Tseng points out that the likelihood of a severe flare in the clinically stable patients in the trial was over 30% over a period of 12 weeks and that prednisone effectively averted those flares.

"The preliminary results of this study should, therefore, cause us to reevaluate the current "watch-and-wait" treatment strategies and consider the use of carefully monitored, biomarker-determined intervention with moderate-dose corticosteroids or other mechanism-based therapies in the management of high-risk SLE patients," the investigators conclude.

But Prediction May Be Wrong 60% of the Time

Matthew H. Liang, MD, MPH, and Julia F. Simard, SM, of Brigham and Women's Hospital and the Massachusetts Veterans Epidemiology and Research Center, in Boston, are more cautious. In an accompanying editorial, they write, "We suggest that the Tseng study should not be used as evidence that changes in anti-dsDNA and C3a levels are valid biosurrogates of a clinical flare. A different study design would have been required to show this. However, the study does provide a clue that these are not strong biomarkers. Of the 20 patients in the placebo group who experienced a serologic flare, 8 experienced some form of clinical flare, which corresponds to a positive predictive value of 40% for the serologic change to predict flares. ...Our crude estimates above indicate that prediction of an impending flare may be wrong 60% of the time potentially exposing the patient to the long-term side effects of unneeded corticosteroids."²

Liang and Simard urge more individualized management for the patient who has had anti-dsDNA antibodies in the past and has a recent elevation of anti-dsDNA and C3a levels. Options include no change, more frequent monitoring, or preemptive steroids, and the patient's concerns are likely to include past experiences with severe flare, time since last flare, and "the likelihood of serious side effects and potential toxicity of treatment."

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