Achieving lupus low-disease activity and remission states under belimumab in refractory systemic lupus erythematosus: time and organ involvement matter
Authors: Nabiha Sbeih, Alexis Mathian, Marc Pineton de Chambrun, Raphael Lhote, Noël Zahr, Micheline Pha, Fleur Cohen-Aubart, Julien Haroche, Miguel Hié, Sophie Jouffroy, Neila Benameur, Hervé Devilliers, Zahir Amoura
Journal: Annals of the Rheumatic Diseases (2019)

Achieving lupus low-disease activity and remission states under belimumab in refractory systemic lupus erythematosus: time and organ involvement matterWe read with much interest the contribution of Oon et al 1 that was published recently in Annals of the Rheumatic Diseases, describing attainment of the lupus low-disease activity state (LLDAS) in a post-hoc analysis of the BLISS trials.At week 52, LLDAS was reached by 12.5% and 14.4% of patients treated with belimumab 10 mg/kg in BLISS-52 and BLISS-76, respectively.The authors conclude that LLDAS is a potential response indicator for future systemic lupus erythematosus (SLE) trials.As opposed to SLE responder index 4 (SRI4), 2 which represents a change from baseline activity, LLDAS 3 and remission 4 are clinical states that should be targeted as they are associated with damage accrual reduction and include the notion of a low prednisone dose. 5Yet, these indicators should be further studied before being introduced into clinical trials.In particular, Oon et al's study lacks data on the time needed to achieve LLDAS and the clinical factors influencing its achievement.It is also important to consider the absence of relapse after an improvement of the disease.In this letter, we wish to provide additional data on the time needed, the probability of and the clinical predictors for achieving stable (ie, without subsequent relapse until month 12) LLDAS and remission state under belimumab.We included all patient with SLE treated with belimumab (intravenous 10 mg/ kg on day 0, 14, 28 and then every 28 days) in our centre from March 2013 to May 2018 for an active disease despite standard therapy.Follow-up was conducted on a monthly basis during the first 6 months and at months 9 and 12 (±1) after belimumab initiation.Primary endpoints were defined as reaching stable SRI4, LLDAS or remission state. 2-4 6Patients who did not achieve a primary endpoint and stopped belimumab before 12 months were considered as non-responders.Patients who achieved a primary endpoint but stopped belimumab before 12 months were excluded from the final analysis for this endpoint.The secondary endpoint was the time to obtain a stable British Isles Lupus Assessment Group (BILAG) D from a baseline BILAG A or B or C in the musculoskeletal and mucocutaneous systems at month 6 (±1) and alternatively, at month 12 (±1). 7 A total of 50 patients fulfilling the SLICC criteria for SLE were enrolled. 8Belimumab indications were persistent arthritis in 44 (88%) cases, active cutaneous lupus in 26 (52%) cases (6 acute cutaneous lupus, 11 subacute cutaneous lupus, 6 discoid rash, 5 chilblains lupus, 7 alopecia, 2 mucosal ulcers and 1 cryoglobulin vasculitis) and serositis in 2 (4%) cases.Disease activity and previous/ongoing treatments at the beginning of belimumab are displayed in table 1. Eleven (22%) patients stopped belimumab before 12 months: 7 treatment failures, 2 adverse events, 1 pregnancy wish and 1 lost to follow-up.The probability of reaching stable SRI4, LLDAS or remission at month 12 according to Kaplan-Meier estimator were: 81.7%, 58.1% and 37.1%, respectively (figure 1A).The median (25%-75% interquartile range) time to meet stable SRI4 was 91 (48-275) days, stable LLDAS 213 (78.5-283.5)days and stable remission 270 (262.5-283.0)days.Survival curves and log-rank test analyses showed that baseline IgG level <12 g/L predicted an increased probability and a shorter timeframe for attaining LLDAS (HR=3.5 (95% CI 1.4 to 6.9), p=0.04) and that the baseline SLICC/American College of Rheumatology (ACR) damage index ≥1 predicted a decreased probability and a longer timeframe for attaining SRI4 (HR=0.4(95%CI 0.2 to 0.4), p=0.04).No significant association was found between the time to achieve SRI4,