Response to placebo in non-renal, non-neuropsychiatric systemic lupus erythematosus: a systematic review and pooled analysis

Abstract

Objectives Most randomized controlled trials (RCTs) in SLE have failed to reach their respective end points, with the rates of response to placebo (plus standard-of-care treatment) being unexpectedly high. The aim of this systematic review was to quantify the response to placebo in non-renal, non-neuropsychiatric lupus. Methods The PubMed database was searched (from 2000 to December 2019) for phase II/III RCTs assessing the efficacy and safety of biologics in non-renal, non-neuropsychiatric SLE. Data on the efficacy and safety of the placebo-treated patients were collected in a pre-established data retrieval form. Descriptive statistics were used. Results A total of 24 RCTs (n = 11 128 in total) were included. Placebo-treated patients (n = 3899) were mostly females (93.5%), Caucasians (60.2%), of mean age 39.7 years, and having a mean disease duration of 7.4 years. Their mean initial SLEDAI 2000 was 10.4, whereas 60.5% had positive anti-dsDNA antibodies, 41.9% low C3 and 35.6% low C4 at randomization. Standard-of-care treatment included glucocorticosteroids in 85.9%, antimalarials in 72.8% and immunosuppressives in 48.5%. The response to placebo was 36.2% for the primary end point (as defined in each study), 39.8% for the SLE Responder Index-4 (SRI-4), 29.2% for SRI-5, 28.4% for SRI-6 and 30.9% for BILAG-based Combined Lupus Assessment response. Regarding safety, there were serious adverse events in 16.3% of patients, serious infections in 5.5% and malignancies in 0.3%, and death occurred in 0.56% of patients. Conclusion More than one-third of the placebo-treated patients achieved their respective primary end points in RCTs with biologics in non-renal, non-neuropsychiatric SLE. The response rate was higher for certain end points, such as the SRI-4, while it decreased with more stringent end points.

Association of Modified Systemic Lupus Erythematosus Responder Index Attainment With Long‐Term Clinical Outcomes: A Five‐Year Prospective Study

“…The rate of mSRI attainment at 1 year in our study was 56%. In comparison, typical SRI response rates in recent clinical trials have ranged from 32% to 48% in the placebo (i.e., standard of care) arms (35), with these lower rates most likely reflecting the restrictions on concomitant medications such as glucocorticoid bursts applied in a trial setting and potential differences in an RCT population compared to an unselected observational cohort. We also examined persistence of mSRI attainment (relative to the baseline active disease visit for each patient) over up to 5 years of follow‐up, and found that 71–75% of mSRI responders at 1 year continued to meet the responder definition at subsequent annual time points.…”

Treat-to-Target in Systemic Lupus Erythematosus: Reality or Pipe Dream

“…Until a few years ago, the therapeutic armamentarium for SLE included GCs, antimalarials, traditional immunosuppressive drugs and few biological drugs. These drugs are valuable aids in achieving targets; of note is how the response to placebo (plus standard of care) is above 36% for all primary endpoints in non-renal, non-neuropsychiatric SLE RCTs [67]. However, reaching therapeutic targets remains an unmet need in a considerable proportion of patients, highlighting the importance of developing new drugs that improve the disease outcomes.…”