Determinants of neuropsychiatric flares in patients with systemic lupus erythematosus: results from five phase III trials of belimumab.

OBJECTIVE: To identify determinants of neuropsychiatric (NP) flares in patients with SLE treated for active SLE yet no ongoing severe NPSLE with non-biologic standard therapy plus belimumab or placebo. METHODS: We analysed data from five phase III trials (BLISS-52, BLISS-76, BLISS-NEA, BLISS-SC, EMBRACE; n = 3638) after exclusion of patients with baseline NP BILAG A. Factors associated with NPSLE flare, defined as a new NP BILAG A or B, were investigated using Cox regression. In a subgroup analysis, we studied patients with baseline NP BILAG E for determinants of de novo NPSLE flare. Organ damage was assessed using the SLICC/ACR Damage Index (SDI). RESULTS: We documented 105 (2.9%) NPSLE flares. In multivariable analysis, male sex (HR = 2.37; 95% CI: 1.31, 4.28; P = 0.004), baseline NP BILAG B-D (HR = 5.91; 95% CI: 3.86, 9.06; P < 0.001), and increasing SDI scores (HR = 1.35; 95% CI: 1.21, 1.50; P < 0.001) were strongly associated with NPSLE flare. Belimumab use yielded no association at any dose or administration form. In analysis of SDI domains, NP damage was the strongest determinant of NPSLE flare (HR = 3.25; 95% CI: 2.72, 3.88; P < 0.001), holding true for cognitive impairment (HR = 14.29; 95% CI: 9.22, 22.14; P < 0.001), transverse myelitis (HR = 21.89; 95% CI: 5.40, 88.72; P < 0.001), and neuropathy (HR = 8.87; 95% CI: 5.59, 14.09; P < 0.001). Male sex was the strongest determinant of de novo NPSLE flare (HR = 3.26; 95% CI: 1.51, 7.04; P = 0.003). CONCLUSION: Male sex, NPSLE history, and NP damage were strong determinants of impending NPSLE flare. No clear protection or predisposition was conferred from add-on belimumab.

Belimumab treatment of adult idiopathic inflammatory myopathy.

OBJECTIVE: To evaluate belimumab addition to the standard of care in patents with refractory idiopathic inflammatory myopathy (IIM). METHODS: We conducted a 40-week multicentre, randomized, double-blind, placebo-controlled trial with 1:1 IV belimumab 10 mg/kg or placebo randomization and a 24-week open-label extension. Clinical responses were measured by the definition of improvement (DOI) and total improvement score (TIS). Flow cytometry analyses were performed on available samples before randomization, at 24 and 60-64 weeks. Descriptive statistics, t-test, Fisher's exact test and analysis of variance tests were used. RESULTS: A total of 17 patients were randomized, 15 received five or more doses of belimumab or placebo and were included in the intention-to-treat analysis. More belimumab patients vs placebo attained a TIS ≥40 [55.5% vs 33.3%; P = non-significant (NS)] and achieved the DOI (33.3% vs 16.7%; P = NS) at weeks 40 and 64; the mean TIS was similar among groups. Two patients achieved major responses (TIS = 72.5) after week 40 in the belimumab arm and none in the placebo arm. No improvement in the placebo arm after switching to the open-label phase was observed. There was no steroid-sparing effect. No new safety signals were detected. Although total B cells were not reduced, belimumab induced naïve B cell depletion while enhancing the number and frequency memory B cells. CONCLUSION: The study did not meet the primary endpoint and no statistically significant differences were observed in clinical responses between arms. More patients achieved sustained TIS ≥40 and reached the DOI. Most patients who received belimumab for >40 weeks had clinical improvement. Phenotypic changes in B cell populations were not associated with clinical responses. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (https://clinicaltrials.gov/), NCT02347891.

Predictors of renal flares in systemic lupus erythematosus: a post-hoc analysis of four phase III clinical trials of belimumab.

OBJECTIVES: To identify predictors of renal flares in patients with SLE treated for active extra-renal disease. METHODS: Data from four clinical trials of belimumab in SLE (BLISS-52, NCT00424476; BLISS-76, NCT00410384; BLISS-NEA, NCT01345253; BLISS-SC, NCT01484496) were used. Patients were assigned to belimumab or placebo on top of standard therapy. We investigated the performance of predictors of renal flares through 52-76 weeks using proportional hazards regression analysis. RESULTS: Of 3225 participants, 192 developed at least one renal flare during follow-up, with the first occurring after a median time of 197 days. Current/former renal involvement (HR: 15.4; 95% CI: 8.3-28.2; p< 0.001), low serum albumin levels (HR 0.9; 95% CI: 0.8-0.9; p< 0.001), proteinuria (HR: 1.6; 95% CI: 1.5-1.7; p< 0.001), and low C3 levels (HR: 2.9; 95% CI: 2.1-4.1; p< 0.001) at baseline appeared robust determinants of renal flares. Anti-dsDNA positivity yielded an increased hazard for renal flares (HR: 2.1; 95% CI: 1.4-3.2; p< 0.001), which attenuated after adjustments. Anti-Sm positivity was associated with renal flares in the placebo (HR: 3.7; 95% CI: 2.0-6.9; p< 0.001) but not in the belimumab subgroup, whereas anti-ribosomal P positivity was associated with renal flares in the belimumab subgroup only (HR: 2.8; 95% CI: 1.5-5.0; p= 0.001). CONCLUSION: A history of renal involvement, high baseline proteinuria, hypoalbuminaemia, and C3 consumption were robust determinants of impending renal flares. Beyond anti-dsDNA, anti-Sm and anti-ribosomal P protein antibody positivity may have value in surveillance of renal SLE.

Belimumab and antimalarials combined against renal flares in patients treated for extra-renal systemic lupus erythematosus: results from 4 phase III clinical trials.

OBJECTIVES: To determine the effect of antimalarial agents (AMA) and different doses and pharmaceutical forms of belimumab on preventing renal flares in patients with SLE treated for extra-renal disease. METHODS: We pooled data from the BLISS-52, BLISS-76, BLISS-SC and BLISS-Northeast Asia trials of belimumab (n = 3225), that included patients with active SLE yet no severe ongoing nephritis. Participants were allocated to receive intravenous belimumab 1 mg/kg, intravenous belimumab 10 mg/kg, subcutaneous belimumab 200 mg, or placebo in addition to standard therapy. We estimated hazards of renal flare development throughout the study follow-up (52-76 weeks) using Cox regression analysis. RESULTS: In total, 192 patients developed a renal flare after a median of 197 days. Compared with placebo, the risk of renal flares was lower among patients receiving intravenous belimumab 10 mg/kg (HR: 0.62; 95% CI: 0.41, 0.92; P = 0.018) and intravenous belimumab 1 mg/kg (HR: 0.42; 95% CI: 0.22, 0.79; P = 0.007), while no significant association was found for subcutaneous belimumab 200 mg. AMA use yielded a lower hazard of renal flares (HR: 0.66; 95% CI: 0.55, 0.78; P < 0.001). The protection conferred was enhanced when belimumab and AMA were co-administered; the lowest flare rate was observed for the combination intravenous belimumab 1 mg/kg and AMA (18.5 cases per 1000 person-years). CONCLUSIONS: The protection conferred from belimumab against renal flare development in patients treated for extra-renal SLE appears enhanced when belimumab was administered along with AMA. The prominent effect of low-dose belimumab warrants investigation of the efficacy of intermediate belimumab doses. CLINICAL TRIAL IDENTIFICATION: BLISS-52: NCT00424476; BLISS-76: NCT00410384; BLISS-SC: NCT01484496; BLISS-NEA: NCT01345253.

Thorough assessment of the effectiveness of belimumab in a large Spanish multicenter cohort of systemic lupus erythematosus patients.

OBJECTIVES: To provide an overview on the current use of belimumab (BLM) in SLE patients in clinical practice and to examine its efficacy in terms of standardized outcomes, drug survival, as well as patient and safety profiles. METHODS: A longitudinal retrospective multicentre cohort including SLE patients treated with BLM at 18 Spanish centers. Data was collected upon initiation of BLM, at 6 and 12 months after initiation, and at the last recorded visit. Changes in SLEDAI-2K, the proportion of patients who achieved LLDAS and DORIS 2021, and number of flares were compared between visits. Changes in damage, glucocorticoids use and employment status pre-BLM and post-BLM were also assessed. RESULTS: A total of 324 patients were included with a mean follow-up of 3.8 (±2.7) years. LLDAS was attained by 45.8%, 62% and 71% of patients, and DORIS by 24%, 36.2% and 52.5% on successive visits, respectively. Twenty-seven-point two percent of patients were in DORIS ≥ 50% of the visits and a 46% in LLDAS-50. Flares and number of flares were significantly lower one year after treatment with BLM and no changes in damage accrual were observed. Mean (±SD) prednisone dose was significantly reduced over time, with 70 (24%) patients discontinuing GC. CONCLUSION: Our study not only demonstrates belimumab´s efficacy in attaining treat-to-target goals in SLE patients, but also confirms its GC-sparing effect, and its prevention of flares and organ damage accrual.

Can the Dose of Belimumab be Reduced in Patients with Systemic Lupus Erythematosus?

OBJECTIVES: The aims of this study were to investigate the prevalence of dose reduction in patients with SLE treated with belimumab (BEL) in Spain, analyze treatment modalities, and determine impact on control of disease activity. METHODS: Retrospective longitudinal and multicentre study of SLE patients treated with BEL. Data on disease activity, treatments and outcomes were recorded before and after reduction (6-12 months), and they were compared. RESULTS: A total of 324 patients were included. The dose was reduced in 29 patients (8.9%). The dosing interval was increased in 9 patients receiving subcutaneous BEL and in 6 patients receiving intravenous BEL. The dose per administration was reduced in 16 patients.Pre-reduction status was remission (2021 DORIS) in 15/26 patients (57.7%) and LLDAS in 23/26 patients (88.5%). After reduction, 2/24 patients (8.3%) and 3/22 patients (13.6%) lost remission at 6 months and 12 months, respectively (not statistically significant [NS]). As for LLDAS, 2/23 patients (8.7%) and 2/21 patients (9.5%) lost their status at 6 and 12 months, respectively (NS). Significantly fewer patients were taking glucocorticoids (GCs) at their 12-month visit, although the median dose of GCs was higher at the 12-month visit (5 [0.62-8.75] vs 2.5 [0-5] at baseline). CONCLUSION: Doses of BEL can be reduced with no relevant changes in disease activity-at least in the short term-in a significant percentage of patients, and most maintain the reduced dose. However, increased clinical or serologic activity may be observed in some patients. Consequently, tighter post-reduction follow-up is advisable.

Considering belimumab during pregnancy: A more viable option over time.

OBJECTIVE: To share our experience with belimumab in lupus pregnant women and to review the relevant published literature on its use in this scenario. METHODS: A prospective observational study of pregnant patients with lupus was conducted. Additionally, MEDLINE and EMBASE databases were searched, and a secondary hand search of the literature was performed. Studies were evaluated and visualised descriptively. RESULTS: Sixteen pregnancies of 12 lupus women were included, six (involving eight pregnancies) received belimumab throughout their illness, five of them during some period of gestation. In this group, there was one miscarriage, one elective termination and seven live foetuses (including two live twins). There was one type I intrauterine growth retardation, and a preterm pregnancy due to premature rupture of membranes (PPROM). One mild lupus flare was detected. There were no cases of pre-eclampsia, gestational diabetes mellitus or hypertension. All neonates had normal Apgar scores at birth, none needed critical care. There were no congenital anomalies. After the search, we identified 10 case reports and case series, and five registries. Among the 39 reported cases (41 pregnancies), there were 5 PPROM, 4 pre-eclampsia, and 1 eclampsia. All women made full recoveries. Nineteen new-borns had low birth weight. There were no malformations. While registries did not indicate an increased risk of birth defects or pregnancy loss, there was a higher risk of neonatal infections. CONCLUSIONS: Belimumab may be an option for pregnant women with difficult-to-control lupus. Further research is needed to confirm the absence of association between belimumab and foetal harm.

Initiation of belimumab with higher daily prednisolone is effective for rapid glucocorticoid reduction: A 96-week retrospective study.

OBJECTIVES: For appropriate glucocorticoid (GC) reduction, we investigated the optimal strategy including baseline factors that could reduce GC more than 50% with 96 weeks of belimumab. METHODS: This is a retrospective cohort study of Kakogawa Central City hospital from 2019 to 2023. We identified SLE patients who were receiving 200 mg of belimumab weekly by subcutaneous injection for 96 weeks. The background at baseline, trends in clinical indicators, and factors involved in GC reduction were statistically analyzed. Finally, univariate and multivariate logistic analyses were carried out to identify baseline factors associated ≥50% GC reduction at 96 weeks. RESULTS: Forty-seven patients were enrolled, with a median daily prednisolone of 5 mg. Almost 90% of them received concomitant immunosuppressants and/or hydroxychloroquine. Serological indices, daily GC dose, and SLEDAI-2K scores showed significant improvement in 96 weeks. At baseline, a significant negative correlation has been shown between the daily dose of GC and the duration from onset or last flare, as well as C4 levels. At 96 weeks, GC reduction rate and SLEDAI-2K scores were negatively correlated with duration from onset or last flare to initiation of belimumab. Mycophenolate mofetil use was significantly frequent in patients with lupus nephritis (LN), which also correlated with the frequency of past flares. In addition, LN presence was associated with higher SLEDAI-2K scores at 96 weeks, and baseline SLEDAI-2K ≥10 was associated with significantly higher GC dose at 96 weeks. Univariate analysis of the factor contributing to achieving ≥50% GC reduction at 96 weeks has pointed shorter disease duration and higher daily GC dose at baseline as significant variables. Finally, we performed a multivariate analysis by combining above two items with age, which extracted the higher daily GC dose at baseline as a significant variable (OR (95% CI) 1.25 (1.00 to 1.56), p = .047). CONCLUSIONS: Our study showed that a delay in belimumab initiation led to higher SLEDAI-2K score and difficulty in achieving a 50% GC reduction at 96 weeks. Since GC-related adverse events increase with long-term administration of GC though with small daily doses, we proposed here that belimumab should be started in combination with higher daily prednisolone.

The use of belimumab on patients with both systemic lupus erythematosus and immune thrombocytopenia: A retrospective cohort study.

OBJECTIVE: The objective of this study is to provide a description of a group of retrospective cohort outcomes in patients with systemic lupus erythematosus (SLE) complicated with immune thrombocytopenia (ITP) receiving belimumab. METHODS: This study reports on the treatment of 10 female patients (mean age 34.3 ± 14.0 years, mean weight 58.7 ± 18.2 kg) with both SLE and ITP who received belimumab in addition to basic drug therapy. The belimumab treatment regimen consisted of a dosage of 10 mg/kg, with an initial infusion every 2 weeks for the first 3 doses, followed by an infusion every 4 weeks. RESULTS: Ten patients were included in the study. The overall response rate of thrombocytopenia was 90% after treatment. The parameters such as platelet count, lymphocyte count, erythrocyte count, hemoglobin, dsDNA, C3, and C4 were significantly improved (p < .05). The SLE Disease Activity Index (SLEDAI), British Islet lupus Assessment Group 2004 (BILAG-2004), and Physician Global assessment (PGA) scores were significantly decreased (p < .05). There were no significant differences in glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST), and serum creatinine (Scr) before and after treatment (p > .05). CONCLUSION: Belimumab shows promising clinical outcomes in the treatment on patients with both SLE and ITP. Further studies are needed to validate these findings in larger patient populations and compare the efficacy of belimumab with other treatments for SLE complicated with ITP. Long-term response rates and adverse events associated with belimumab treatment also warrant further investigation.

Glucocorticoid-free remission in patients with SLE in the era of biologics: Immune complex disease is likely to benefit from current medications.

OBJECTIVES: In addition to various immunosuppressive agents, belimumab and anifrolumab became available in Japan. We aimed to investigate glucocorticoid-free clinical remission in a single-centre retrospective cohort in October 2023. METHODS: Our cohort included patients with SLE who needed to start or increase glucocorticoids for disease activity and were followed up for more than 1 year. We investigated the rate of achievement of clinical remission off corticosteroids (CR off C), defined as no clinical score on the SLEDAI-2K without glucocorticoids, baseline predictors of CR off C, medications used when CR off C was achieved, and flare rates following CR off C. RESULTS: Out of the 60 patients followed for an average of 5.4 (±2.6) years, 17 (28.3%) achieved CR off C in 3.6 (±1.2) years after enrolment. Use of belimumab and anifrolumab accounted for eight (47.1%) of the achievers. Among the baseline data, male sex, recent enrolment, high glucocorticoid dose, and detection of immune complex (IC) significantly predicted CR off C, while lupus nephritis (LN) and a low C3 level tended to predict it. In the multivariate analysis, IC detection was the only predictor of CR off C. Clinical flares were observed in 5.9% of the achievers during a median 1.2 years after achievement of CR off C. CONCLUSION: In the era of biologics, CR off C was achieved in 28.3% of the patient cohort requiring the start or increase of glucocorticoids for disease activity, with a relatively low rate of flares, suggesting that glucocorticoid-free clinical remission is an achievable target in SLE. IC disease, represented by male sex or nephritis, is likely to benefit from currently available medications.

Belimumab-induced periungual pyogenic granulomas: A case report.

Pyogenic granuloma (PG) is a benign vascular neoformation, presenting as a painful red nodule on the skin, mucosa or nail apparatus. It is usually related to local complications such as bleedings and superinfections. The etiology of PG remains still unclear, and several triggers can lead to its formation. In case of multiple lesions, systemic conditions and drugs remain the main causes. Antineoplastic treatments, retinoids, antiretrovirals, hormones and anticonvulsants are frequently implicated in PG formation. In literature, PG has been rarely described in the course of biological treatment due to rheumatological disease. The present case report describes the development of polydactolous PGs in a 21-year-old woman with juvenile systemic lupus erythematosus (jSLE) during treatment with belimumab, a monoclonal antibody directed against BlyS. The clinical presentation, in particular the timing and the multiplicity of the lesions, and the improvement after belimumab discontinuation allowed us to consider PG as drug-induced. This case highlights the importance of considering PG as a potential complication of rheumatologic treatments.

Refractory lupus hepatitis successfully treated with telitacicept who failed to belimumab: A case report and literature review.

Background: Systemic lupus erythematosus (SLE)-associated hepatitis ("lupus hepatitis") was one of the most frequent causes of liver function abnormalities in patients with SLE. Lupus hepatitis (LH) is commonly treated with conventional treatment, including non-steroidal anti-inflammatory drugs, corticosteroids, and immunomodulators. However, in refractory cases, other treatment options may be required.Methodology: We report the case of a patient with lupus hepatitis refractory to both conventional therapy and belimumab who was successfully treated with telitacicept, a new dual B lymphocyte stimulator (BLyS)/APRIL (a proliferation-inducing ligand) inhibitor.Literature review was performed on PubMed search forum.Result: The specific search term was "telitacicept", 23 papers were searched, among them 10 case reports/series articles reporting telitacicept treatment were elected.Apart from our literature reporting the effectiveness of telitacicept in treating LH, there is no report on it in treating LH.Conclusion: This case suggests that telitacicept should be an effective and safe treatment for LH refractory, even to those who failed to belimumab based on the standard treatment, and can reduce the dosage of glucocorticoids.However, further investigations, particularly prospective randomized controlled trials, are warranted to verify our findings and ensure patient safety.

Do we really need cyclophosphamide for lupus nephritis?

A 14-year-old patient presents with hematuria and proteinuria. Clinical evaluation reveals a positive anti-nuclear antibody titer, positive anti-double stranded DNA antibody and hypocomplementemia. Systemic lupus erythematosus (SLE) is diagnosed based on the 2019 EULAR/ACR (European League Against Rheumatism/American College of Rheumatology) classification criteria (Aringer et al. Arthritis Rheumatol 71:1400-1412, 2019). A kidney biopsy is performed that confirms the presence of immune complex glomerulonephritis, ISN-RPS (International Society of Nephrology/Renal Pathology Society) class IV (Bajema et al. Kidney Int 93:789-796, 2018). According to the latest clinical practice guidelines (Rovin et al. Kidney Int 100:753-779, 2021; Fanouriakis et al. Ann Rheum Dis 83:15-29, 2023), there are alternatives to treating this patient with cyclophosphamide. But what if this patient also presented with oliguria and volume overload requiring intensive care and dialysis? What if this patient also presented with altered mental status and seizures, and was diagnosed with neuropsychiatric lupus? What if this patient was also diagnosed with a pulmonary hemorrhage and respiratory failure? The clinical practice guidelines do not address these scenarios that are not uncommon in patients with SLE. Moreover, in some countries worldwide, patients do not have the privilege of access to biologics or more expensive alternatives. The purpose of this review is to evaluate the contemporary options for initial treatment of nephritis in patients with SLE.

Efficacy and safety of belimumab combined with the standard regimen in treating children with lupus nephritis.

The purpose of this study is to evaluate the efficacy and safety of belimumab combined with the standard regimen in treating children with active lupus nephritis. This single-center, retrospective cohort study used clinical data of children with newly active lupus nephritis hospitalized in the Department of Nephrology between December 2004 and February 2023. Patients were divided into a belimumab or traditional treatment group according to whether or not they received belimumab. Renal remission and recurrence rates and glucocorticoid dose were compared between groups. Forty-seven children (median age 11 years) were enrolled, including 30 and 17 children in the traditional treatment and belimumab groups, respectively. The Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2000) score of children in the belimumab group (23.59 ± 7.78) was higher than that in the traditional treatment group (19.13 ± 6.10) (P = 0.035). The two groups showed no significant difference in the frequency of pyuria, gross hematuria, and the levels of 24-h proteinuria and estimated glomerular filtration rate. The complement C3/C4 in the belimumab group recovered faster than that in the traditional treatment group (P < 0.05). There were no between-group differences in the complete renal remission rate at 6 or 12 months (P = 0.442, P = 0.759). There were no between-group differences in 1-year recurrence rate (P = 0.303). Furthermore, 6 and 12 months after treatment, glucocorticoid doses were lower in the belimumab than the traditional treatment group (17.87 ± 6.96 mg/d vs. 27.33 ± 8.40 mg/d, P = 0.000; 10.00 (5.3) mg/d vs. 13.75 (10.0) mg/d, P = 0.007), respectively. CONCLUSION: With an equivalent renal remission rate, belimumab combined with the standard traditional regimen might promote the tapering of glucocorticoids, and the incidence of adverse events is low. WHAT IS KNOWN: • Belimumab is documented as an adjunctive treatment with systemic lupus erythematosus (c-SLE) LN with efficacy. • Due to the paucity of studies, its effects and side effects in children with LN remain unclear. WHAT IS NEW: • This single-center, retrospective cohort study evaluated the efficacy and safety of belimumab combined with the standard regimen in treating children with proliferative LN. • Belimumab combined with the standard traditional treatment might promote the tapering of glucocorticoids, while exhibiting a low occurrence of adverse events.

An overlapping case of IgG4-related disease and systemic lupus erythematosus treated with belimumab: a case-based review.

IgG4-related disease (IgG4-RD) is a systemic condition in which IgG4+ plasma cell infiltration and fibrosis cause organ swelling and lead to diverse clinical manifestations. Although IgG4-RD typically responds to glucocorticoids (GCs), relapse during tapering occurs and an early GC-sparing approach might therefore be beneficial. Systemic lupus erythematosus (SLE) is a chronic inflammatory disease with multiple symptoms that is also treated with GCs as a first-line therapy. Recently, belimumab, a recombinant human IgG-1λ monoclonal antibody that inhibits B-cell activating factor, was approved, but reports of use for IgG4-RD are scarce. Here, we present a rare case of IgG4-RD complicated with SLE which was successfully treated with belimumab. A 67-year-old man was diagnosed with IgG4-RD based on a high serum IgG4 level and histopathological findings. Furthermore, he had pericardial effusion on echocardiography, and laboratory tests revealed thrombocytopenia, autoimmune hemolysis, positive anti-nuclear antibodies, positive anti-DNA antibodies, and hypocomplementemia. These data led to an SLE diagnosis. Treatment was started with prednisolone at 40 mg/day, plus hydroxychloroquine, which initially improved both the SLE and IgG4-RD symptoms. During the GC tapering, belimumab was added and clinical symptoms resolved completely. Our case and the literature review summarize reported rare overlapping cases of IgG4-RD and SLE and suggest that belimumab is a promising candidate for the treatment of IgG4-RD.

Belimumab corticosteroid-sparing treatment in systemic lupus erythematosus: a real-life observational study (BESST study).

Data about the impact of Belimumab on corticosteroid sparing in real life are scarce. To assess the corticosteroid-sparing effect among patients with systemic lupus erythematosus (SLE) treated with Belimumab in real-life settings. Multicentric observational retrospective study including patients with SLE and having received Belimumab for at least 6 months between 2011 and 2020, in eight French hospitals. "Low dose" referred to patients receiving up to 7.5 mg of prednisone a day and "Very low dose" to those receiving strictly ≤ 5 mg prednisone a day The primary endpoint was the reduction of daily prednisone dose after six months of Belimumab. The secondary endpoint was a change in the proportion of patients with low or very low dose of prednisone as well as those without prednisone during the Belimumab course. Censoring occurred for patients who stopped Belimumab. Bivariate analyses were performed using the Wilcoxon signed-rank test. The threshold for statistical significance was set at p < 0.05. Thirty patients were included. All were female with a median age of 38 years. A significant reduction in prednisone dose was observed at month 6 (10 [7-20] vs 6.75 [2-9] mg, p < 0.0001), continued until month 12 (10 [7-20] mg vs 5 [0-7.12] mg, p < 0.001) and was sustained until month 24. The proportion of patients with very low dose of prednisone and those without prednisone progressively increased during the Belimumab course. Introducing Belimumab in patients with SLE, in real-life conditions, is associated with early and sustained corticosteroid-sparing effect.

No clear influence of treatment escalation on flare prevention in serologically active clinically quiescent patients with systemic lupus erythematosus: a retrospective cohort study.

This study aimed to clarify the efficacy and safety of treatment escalation by initiating therapeutic agents in serologically active clinically quiescent (SACQ) patients with systemic lupus erythematosus (SLE). We retrospectively evaluated SACQ patients with SLE for ≥ 180 days, with the introduction of a therapeutic agent for SLE defined as exposure. The efficacy endpoints included the time to flare and time to remission, whereas the safety endpoint was the incidence of adverse events. The efficacy endpoints were assessed via Cox proportional hazards model with time-dependent covariates, which included exposure, serological activity, and prednisolone dose. Among 109 SACQ patients, 24 were initiated on the following therapeutic agents for SLE: hydroxychloroquine (10 patients), belimumab (6 patients), and immunosuppressive agents (8 patients). A total of 37 patients experienced a flare (8 and 29 patients during exposure and nonexposure periods, respectively). The time to flare was comparable between the exposure and control groups. Among 68 patients who were not in remission at the start of observation, 27 patients achieved remission (5 and 22 patients during exposure and nonexposure periods, respectively). Although both groups had a similar time to remission, the exposure group treated with belimumab had a significantly higher rate of remission than the control group. The adverse events were more frequent during the exposure period than during the nonexposure period. Thus, this study did not reveal a clear influence of treatment escalation on flare prevention and remission achievement.

Safety and efficacy of telitacicept in refractory systemic lupus erythematosus patients who failed treatment with belimumab : A case series.

OBJECTIVE: This study aimed to determine the effect and safety of telitacicept, an antagonist of BLyS/APRIL-mediated B cell activation, in patients with systemic lupus erythematosus (SLE) who failed treatment with belimumab and in whom telitacicept was administered combined with conventional therapy. A review of published reports on telitacicept for SLE was also performed. METHODS: A retrospective review was performed of the records of patients seen in the Department of Rheumatology at the Wuhan Hospital of Chinese and Western Medicine, Wuhan, China, with refractory SLE who had failed treatment with belimumab. The terms "systemic lupus erythematosus" and "telitacicept" were used to identify patients reported in the English medical literature. RESULTS: Identified were 14 refractory SLE patients, 3 males (21%) and 11 females (79%). The median age was 32.9 years. The median disease duration was 8.9 years. Patients in this cohort received telitacicept for an average of 34.1 weeks (17-62 weeks) and the total SLE responder index 4 (SRI-4) response rate was 78.9% (n = 11). The mean SLE Disease Activity Index (SLEDAI) score declined from 8.6 at baseline (95% confidence interval [CI] 7.87-9.28) to 4.29 at the endpoint (95% CI 3.4-5.16). All cases (100%) had hypocomplementemia at baseline, and 7 cases (50%) reported normal C3 and C4 levels at the follow-up endpoint. At the observation endpoint, the 24­h urinary protein value of the 13 cases with proteinuria (baseline 24­h urinary protein > 0.5 g/d) displayed a reduction, and 3 values turned negative. Although some patients had low serum total immunoglobulin (Ig) levels, subnormal IgG levels, and absolute counts of peripheral blood lymphocytes after treatment, no serious infection was reported. One case was refractory lupus hepatitis confirmed by liver pathology, and upon change to change to telitacicept treatment, liver function returned to normal. CONCLUSION: This is the first case series in SLE patients who accepted telitacicept treatment after failed treatment with belimumab. Our case series and review of the literature show that telitacicept combined with the original standard treatment may significantly improve disease activity while reducing prednisone use. No major safety issues were seen in this group of patients. Telitacicept may be a promising drug for the treatment of refractory lupus hepatitis.

Usefulness of Belimumab in Adult Patients With Systemic Lupus Erythematosus Evaluated Using Single Indexes: A Meta-Analysis and Systematic Review.

Background: Belimumab is the first antibody drug approved for systemic lupus erythematosus (SLE), and is a fully human monoclonal antibody that inhibits soluble B lymphocyte stimulator protein. In clinical trials, a composite index was used to assess efficacy of belimumab. However, clinical guidelines on SLE treatment currently use single efficacy indexes. Objective: The main objective of this study was to perform a meta-analysis to evaluate the efficacy of belimumab utilizing single indexes used in routine clinical practice, rather than the composite efficacy index used in clinical trials during the development phase. As a secondary endpoint, safety was also evaluated. Methods: Several databases were searched to identify reports published up to December 1, 2021 on randomized controlled trials examining the efficacy of belimumab in adult patients with SLE. From the clinical trial data, efficacy was evaluated using single indexes including the SLE Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group Index, and Physician Global Assessment. Safety was also assessed. Data were synthesized and analyzed using Review Manager 5.4. This study protocol was registered in the UMIN Clinical Trials Registry (Registration number: UMIN000052846). Results: The search identified 12 reports that met the inclusion criteria. Five reports were included in efficacy evaluation and 9 in safety evaluation. The primary endpoint was SLEDAI. Significantly more belimumab-treated patients achieved a ≥4-point reduction in SLEDAI (relative risk 1.28; 95% confidence interval, 1.16-1.40; P < 0.00001) compared with placebo. Other efficacy endpoints were also improved significantly in the belimumab group. No difference in safety was found between belimumab and placebo. Conclusions: The present meta-analysis evaluating clinical trial data using various single indexes recommended by clinical guidelines for SLE verifies that addition of belimumab to standard of care is efficacious for moderate-to-severe SLE.

Efficacy and Safety of Belimumab in Patients With Lupus Nephritis: Subgroup Analyses of a Phase 3 Randomized Trial in the East Asian Population.

RATIONALE & OBJECTIVE: Belimumab improved kidney outcomes in patients with active lupus nephritis (LN) in BLISS-LN, leading to its approval in the United States and the European Union. As data on treatment of East Asian patients with LN are limited, we evaluated the efficacy and safety of belimumab in the BLISS-LN East Asian subgroup. STUDY DESIGN: Prespecified subgroup analysis of BLISS-LN, a phase 3, placebo-controlled, randomized 104-week trial. SETTING & PARTICIPANTS: Adults with biopsy-proven, active LN were randomized (1:1) to belimumab or placebo, plus standard therapy. INTERVENTION: Patients were administered intravenous belimumab 10mg/kg, or placebo, plus standard therapy (oral glucocorticoids and either cyclophosphamide for induction followed by azathioprine for maintenance, or mycophenolate mofetil for both induction and maintenance). At the investigator's discretion, 1-3 intravenous pulses of methylprednisolone, 500-1,000mg each, could be administered during induction. OUTCOMES: The primary end point was primary efficacy renal response (PERR; ie, urinary protein-creatinine ratio≤0.7g/g, estimated glomerular filtration rate no more than 20% below preflare value or≥60mL/min/1.73m2, and no treatment failure) at week 104. Key secondary end points included complete renal response (CRR; urinary protein-creatinine ratio<0.5g/g, estimated glomerular filtration rate no more than 10% below preflare value or≥90mL/min/1.73m2, and no treatment failure) at week 104; PERR at week 52; time to kidney-related event or death; and safety. ANALYTICAL APPROACH: PERR and CRR were analyzed using a logistic regression model, and time to a kidney-related event or death was analyzed using a Cox proportional hazards regression model. RESULTS: 142 patients from mainland China, Hong Kong, South Korea, and Taiwan were included (belimumab, n=74; placebo, n=68). At week 104, more belimumab than placebo patients achieved PERR (53% vs 37%; OR, 1.76 [95% CI, 0.88-3.51]) and CRR (35% vs 25%; OR, 1.73 [95% CI, 0.80-3.74]). At week 52, more belimumab than placebo patients achieved PERR (62% vs 37%; OR, 2.74 [95% CI, 1.33-5.64]). Belimumab reduced the risk of a kidney-related event or death compared with placebo at any time (HR, 0.37 [95% CI, 0.15-0.91]). Safety was similar across treatment groups. LIMITATIONS: Small sample size and lack of formal significance testing. CONCLUSIONS: Safety and efficacy profiles were consistent with BLISS-LN overall population, supporting benefits of belimumab treatment in the East Asian subgroup with LN. FUNDING: This study was funded by GSK (GSK study no. BEL114054). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01639339.