Systemic lupus erythematosus: Updates from EULAR 2020
A number of studies presented at the European League Against Rheumatism E-Congress 2020 (EULAR 2020) have a potential to impact the management of systemic lupus erythematosus (SLE) in the clinic. One phase II study showed that withdrawal of mycophenolate mofetil (MMF) may be safe in quiescent SLE, while a phase III trial demonstrated efficacy and tolerability of the B-lymphocyte stimulator (BLyS) inhibitor belimumab in SLE patients with lupus nephritis (LN). Experts also discussed how latest evidence on early intervention and disease activity assessment can be incorporated into clinical practice.
MMF withdrawal in quiescent SLE
“MMF has become a mainstay of long-term immunosuppression for LN and other manifestations of SLE, but it is associated with significant costs, pregnancy risks, drug monitoring needs, and various side effects,” said Dr Eliza Chakravarty of Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, US.
In a phase II study, Chakravarty and colleagues showed that MMF can be safely withdrawn in SLE patients with prolonged disease quiescence. [Chakravarty E, et al, EULAR 2020, abstract OP0167]
The study included 102 adults with quiescent SLE (defined as Safety of Estrogen in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index [SELENA-SLEDAI] without serologies >4) receiving MMF for ≥2 years for LN or ≥1 year for non-nephritis. The patients were randomized to the MMF withdrawal arm (tapering off MMF over 12 weeks) or MMF maintenance arm (continuing MMF 1,000–3,000 mg/day). The primary endpoint was 60-week clinically significant disease reactivation (CSDR) rate, defined as SELENA-SLEDAI mild-to-moderate or severe flare requiring more intensive immunosuppressive therapy.
“At 60 weeks, CSDR occurred in 17.6 percent of patients in the withdrawal arm vs 10.2 percent in the maintenance arm. Time to disease reactivation was similar between the two arms [mean, 38.5 weeks vs 38.0 weeks],” reported Chakravarty. (Figure 1)
“British Isles Lupus Assessment Group [BILAG] A flares occurred in four patients in the withdrawal arm vs one patient in the maintenance arm,” she added. “The Kaplan-Meier curves of the two arms overlapped for CSDR, SELENA-SLEDAI flares and BILAG flares.” (Figures 1 and 2)
Overall, the adverse event (AE) profile was similar between the two arms. Infections were less common in patients who withdrew MMF (46.2 percent vs 64.0 percent).
“Our study showed a low rate of serious flares in patients continuing or withdrawing MMF, with a similar time to flare. This suggests that MMF withdrawal may be considered in the majority of SLE patients with prolonged quiescent disease,” concluded Chakravarty.
Belimumab in LN
“LN is a serious manifestation of SLE affecting nearly 70 percent of high-risk patients. A post-hoc analysis of belimumab trials demonstrated improvement in renal parameters, suggesting that it may reduce LN development in SLE patients,” said Dr Brad Rovin of the Ohio State University, Columbus, Ohio, US. [Lupus 2013;22:63-72]
Rovin and colleagues conducted the phase III, randomized BLISS-LN study to assess the efficacy and safety of belimumab 10 mg/kg vs placebo, both given on top of standard therapy, in 446 adult patients with SLE and LN. [Furie R, et al, EULAR 2020, abstract OP0164]
“Primary efficacy renal response [PERR] was significantly higher with belimumab vs placebo at week 52 [35.4 percent vs 46.6 percent; odds ratio (OR), 1.59; 95 percent confidence interval (CI), 1.06 to 2.38; p=0.002] and week 104 [43.0 percent vs 32.3 percent; OR, 1.55; 95 percent CI, 1.04 to 2.32; p=0.03],” reported Rovin. “The complete renal response rate was also higher with belimumab at week 104 [30.0 percent vs 19.7 percent; OR, 1.74; 95 percent CI, 1.11 to 2.74; p=0.02].”
“Belimumab reduced the risk of renal-related events or death at week 104 by 49 percent [15.7 percent vs 28.3 percent; HR, 0.51; 95 percent CI, 0.34 to 0.77; p=0.001],” he continued. (Figure 3)
The AE profile was similar between placebo and belimumab, with no notable safety concerns.
“BLISS-LN is the largest LN study to date. It demonstrated that belimumab plus standard therapy significantly improved multiple LN renal responses vs standard therapy alone, while maintaining an acceptable safety profile,” Rovin concluded.
Incorporating latest evidence into clinical practice
Early intervention is key
“The treat-to-target [T2T] guidelines and EULAR guidelines listed various short-term treatment goals for SLE, including achievement of lowest possible disease activity, prevention of flares, maintaining health-related quality of life [HRQoL], and recognizing and treating renal involvement. Long-term treatment goals include increasing long-term survival, preventing organ damage accrual, and control of comorbidities,” said Dr George Bertsias of the University of Crete Medical School, Greece. “Importantly, the guidelines emphasize aiming for the lowest glucocorticoid [GC] dose needed for disease control, and withdrawing GC completely if possible.” [Ann Rheum Dis 2014;73:958-967; Ann Rheum Dis 2019;78:736-745]
“Organ damage is irreversible and accrues early in the course of SLE, leading to increased mortality risk,” he explained. [Semin Arthritis Rheum 2013;43:352-361; J Rheumatol 2002;29:1398-1400] “In SLE, organ damage can be caused by the disease itself as well as GC use. Disease-related damages can accrue even in patients with low-to-moderate disease activity. Meanwhile, patients on GCs are found to accrue more organ damage than steroid-naïve patients, independent of disease activity.” [Autoimmun Rev 2014;13:770-777; Arthritis Care Res 2017;69:252-256; Lancet Rheumatol 2019;2:24-30]
“Early intervention is therefore important to achieve treatment goals, thereby lessening damage accrual and improving patients’ HRQoL,” Bertsias noted.
Adding belimumab early to improve outcomes
“The addition of belimumab to standard therapy was shown to improve overall clinical response and reduce the risk of severe flares in SLE studies. It was also associated with a trend towards a reduction in GC dose, and a low rate of organ damage accrual,” noted Dr Andreas Schwarting of the University of Mainz, Germany. [Ann Rheum Dis 2012;71:1343-1349; Arthritis Rheumatol 2017;69:1016-1027; Ruperto N, et al, EULAR 2019, poster FRI0181; Rheumatology (Oxford) 2020;59:281-291; Ann Rheum Dis 2019;78:372-379]
“Meanwhile, the BASE study showed similar overall mortality and AE rates in SLE patients receiving belimumab vs placebo, except for a higher rate of severe depression requiring mood monitoring in those receiving belimumab,” he highlighted. [Sheikh S, et al, EULAR 2019, poster LB0012]
Belimumab works by inhibiting BLyS, a protein that drives autoantibody-mediated inflammation in patients with autoimmune disease. [J Clin Invest 2009;119:1066-1073; Arthritis Rheum 2013;65:2143-2153]
“Compared with placebo, more patients receiving belimumab had improvements in renal parameters [SELENA-SLEDAI (renal domain) scores, renal flares, and proteinuria], suggesting that the addition of belimumab may offer renal protection in SLE patients,” said Schwarting. [Lupus 2013;22:63-72; GlaxoSmithKline, BEL112341 Clinical Study Report 2016] “Another phase II extension study demonstrated the efficacy of belimumab in reducing specific antibodies associated with kidney involvement.” [J Rheumatol 2014;41:300-309]
In a more recent Italian real-world study, early use of belimumab was associated with more favourable outcomes in patients with active SLE and low organ damage. [Arthritis Rheumatol 2020, doi: 10.1002/art.41253]
“Belimumab should therefore be initiated early in SLE patients, when BLyS is upregulated,” Schwarting advised.
New tool for disease activity assessment
“Seven SLE biomarkers are currently in use in clinical practice, while another 16 are being evaluated,” noted Dr Andrea Doria of the University of Padova, Padova, Italy. [Best Pract Res Clin Rheumatol 2019;33:101422]
“The main treatment target for SLE should be the attainment and maintenance of clinical remission. If this cannot be achieved, clinical low disease activity could be a suitable alternative target,” he said. “However, a single and simple tool to distinguish between remission, low, moderate and moderate-to-severe disease activity is not yet available.” [Nat Rev Rheumatol 2019;15:30-48]
“Our team has recently validated the SLE disease activity score [SLE-DAS] that measures disease activity with a higher sensitivity than the SLEDAI-2K score. This new tool consists of 17 weighted clinical and laboratory SLE parameters that can be assessed at each outpatient visit,” explained Doria. “The SLE-DAS calculator is available at http://sle-das.eu.” [Ann Rheum Dis 2019;78:365-371]