Biological drugs for systemic lupus erythematosus or active lupus nephritis and rates of infectious complications. Evidence from large clinical trials

Abstract

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that frequently affects the kidneys, known as lupus nephritis (LN). Such patients are treated with antimalarials, corticosteroids or immunosuppressive drugs, and more recently, target-specific biological drugs. Although efficacy of these therapies improved SLE-related outcomes, SLE remains associated with higher rates of infections. Here, we performed a comprehensive systemic review of infectious complications in clinical trials covering drug interventions for SLE or specifically for active LN. Our search in 15 online registries yielded a total of 1477 studies of which 14 matched our prespecified criteria. These covered the biological drugs anifrolumab, belimumab, and rituximab that were tested in patients with non-renal SLE and active LN.The available safety data from the SLE trials indicated that infectious complications such as herpes zoster, upper respiratory tract infection, nasopharyngitis, bronchitis, and urinary tract infection in patients receiving placebo were quite prevalent especially in the EXPLORER (rituximab) trial. Infections occurred mostly during the first year of LN therapy. Serious adverse events and infectious complications occurred more frequently in placebo-treated patients with active LN, especially in the BLISS-LN (belimumab) and LUNAR (rituximab) trials. Anifrolumab and rituximab increased the number of clinically relevant episodes of herpes zoster compared to belimumab in patients with active LN. Anifrolumab displayed a similar trend for influenza infections, which is consistent with the specific mechanisms-of-action of anifrolumab; highlighting drug-specific effects on infectious complications. In addition, standard-of-care therapy, e.g., MMF and immunosuppressants, as well as a longer SLE duration may also affect the incidence of serious adverse events and certain infectious complications in SLE patients with active LN.Infectious complications are common in SLE but even more common in patients with active LN, especially herpes zoster is strongly associated with active LN and anifrolumab therapy (OR 2.8, 95% CI 1.18 to 6.66, p = 0.018). Immunotherapy seems to impose unspecific and specific risks for infections. The latter may imply specific precautions such as preemptive vaccination and individual risk-benefit assessments.

Keywords: anifrolumab; belimumab; chronic kidney disease (CKD); herpes zoster; infection; lupus; rituximab.

Figure 1

Trial flow chart. The search identified 1.477 trials for lupus from clinical study databases. After excluding 1.463, 14 randomized control trials (RCTs) were used for this systemic review and meta-analysis in which therapies (anifrolumab, belimumab and rituximab) were tested in both patients with systemic lupus erythematosus (SLE, n = 10) without active lupus nephritis (LN) and with active LN (LN, n = 4) patients. S.c., subcutaneous.

Figure 2

Infectious complications in standard-of-care placebo group in SLE without versus with active LN trials. (A) Percentage of serious adverse events in patients receiving placebo in the systemic lupus erythematosus (SLE) without active LN trials that are reported in the anifrolumab (TULIP-1, TULIP-2, MUSE), belimumab (BLISS-76, BLISS-52, LBSL02, Study 113750, EMBRACE, BASE) and rituximab (EXPLORER) trials. (B) Prevalence of herpes zoster, upper respiratory tract infection, nasopharyngitis, bronchitis, nonopportunistic serious infection, urinary tract infection, and influenza in patients receiving placebo in the SLE without active LN trials as listed in (A). (C) Percentage of serious adverse events in patients receiving placebo in the active lupus nephritis (LN) trials that are reported in the anifrolumab (TULIP-LN), belimumab (BLISS-LN) and rituximab (LUNAR) trials. (D) Prevalence of herpes zoster, upper respiratory tract infection, nasopharyngitis, bronchitis, nonopportunistic serious infection, urinary tract infection, and influenza in patients receiving placebo in the SLE without active LN trials as listed in (C). NR, not reported.

Figure 3

Comparison of infectious complications in standard of care placebo group between SLE without versus with active LN trials. (A–E) Comparison of the prevalence of herpes zoster (A), nasopharyngitis (B), upper respiratory tract infection (C), bronchitis (D), and urinary tract infection (E) in patients receiving placebo in the systemic lupus erythematosus (SLE) without active lupus nephritis (LN) trials that are reported for the anifrolumab (TULIP-1, TULIP-2, MUSE), belimumab (BLISS-76, BLISS-52, LBSL02, Study 113750, EMBRACE, BASE) and rituximab (EXPLORER) trials and in the active LN trials that are reported in the anifrolumab (TULIP-LN), belimumab (BLISS-LN) and rituximab (LUNAR) trials in correlation to the trial length (weeks). W/o, without.

Figure 4

Comparison of infectious complications between targeted therapy and placebo group in SLE without versus with active LN trials. (A) Comparison of serious adverse events in patients receiving the targeted therapy versus placebo in the systemic lupus erythematosus (SLE) without active lupus nephritis (LN) trials that are reported in the anifrolumab (TULIP-1, TULIP-2, MUSE), belimumab (BLISS-76, BLISS-52, LBSL02, Study 113750, EMBRACE, BASE) and rituximab (EXPLORER) trials and in the active LN trials that are reported in the anifrolumab (TULIP-LN), belimumab (BLISS-LN) and rituximab (LUNAR/CALIBRATE) trials. (B–G) Comparison of the prevalence of herpes zoster (B), upper respiratory tract infection (C), urinary tract infection (D), nasopharyngitis (E), influenza (F), and bronchitis (G) in patients receiving the targeted therapy versus placebo in the SLE without active LN trials and active LN trials as listed in (A).

Figure 5

Relative risk of infectious complications in SLE without versus with active LN trials. (A–C) Relative risk (RR) of infectious complications including herpes zoster, upper respiratory tract infection, nasopharyngitis, bronchitis, nonopportunistic infection, urinary tract infection, and influenza was calculated for the SLE with and without active LN trials based on the prevalence of infections for anifrolumab (A), belimumab (B), and rituximab (C) as described in the methods. A RR of greater than 1 indicates that the risk of infectious complications is higher with biological drugs compared with placebo in SLE without and with active LN patients, while a RR of less than 1 indicates a lower risk. Data are presented as mean of RR ± standard deviation (SD).