Long-term use of a B-lymphocyte stimulator antagonist in a patient with active lupus nephritis

Dr. Winnie Wan-Yin Yeung
Specialist in Rheumatology
Hong Kong
14 May 2022
Long-term use of a B-lymphocyte stimulator antagonist in a patient with active lupus nephritis

History, presentation and treatment
The patient is a 56-year-old Chi­nese female. In 2001, at the age of 35 years, she was diagnosed with systemic lupus erythematosus (SLE) with cutaneous manifestations. She received low-dose prednisolone 5 mg/day, hydroxychloroquine 200 mg/day, and azathioprine 50 mg/day as treatment for her skin condition, which led to stable disease.

In May 2012, 11 years after ini­tial diagnosis of SLE, the patient had an episode of proteinuria of 1.4 g/day. Azathioprine was increased to 100 mg/day and ramipril 5 mg/day was added. Despite treatment escalation, her complement compo­nent 3 (C3) level was 50 mg/dL and anti-double stranded DNA (anti-dsDNA) antibodies were 125 IU/mL (reference range, <10 IU/mL), indicating active disease. In July 2012, a renal biopsy was performed, which supported the diagnosis of class III and V lupus nephritis (LN).

The patient was started on oral prednisolone 40 mg/day (for 4 weeks followed by dose tapering) and aza­thioprine was switched to mycophe­nolate mofetil (MMF) 2 g/day, which led to an improvement of 24-hour urine protein (from 1.4 g/day to 0.2 g/day) as well as normalization of anti-dsDNA antibodies and C3 after 6 months of treatment. However, she had poor compliance with MMF due to gastrointestinal (GI) upset. In Janu­ary 2013, she experienced arthralgia. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) were negative, showing joint manifestations of lupus without overlapping rheuma­toid arthritis.

In June 2015, at 49 years of age, the patient experienced another flare. Her anti-dsDNA antibodies and 24-hour urine protein level were >300 IU/mL and 1.5 g/day, respectively. Repeat renal bi­opsy revealed class IV LN. Considering that she suffered from GI upset, MMF was switched to mycophenolic acid 360 mg twice a day. Combination ther­apy with belimumab (intravenous [IV] 10 mg/kg Q2W for 3 doses, followed by IV 10 mg/kg every 28 days) and high-dose prednisolone (40 mg/day) was prescribed.1 This led to normal­ization of lupus serology (complement C3: from 40 mg/dL to 96 mg/dL; anti-dsDNA antibodies: from >300 IU/mL to 5 IU/mL), improvement in symptoms, and resolution of proteinuria (from 1.5 g/L to 0.2 g/L) after 6 months.

In March 2021, the patient tran­sitioned to subcutaneous belimumab 200 mg once weekly as subcutane­ous preparation was available in the market. She had been on hydroxy­chloroquine 200 mg/day, ramipril 5 mg/day, and belimumab 200 mg/week, with prednisolone tapered to 5 mg/day, since June 2021.

Last seen in December 2021, the patient was well and has experienced no active lupus symptoms throughout the course of >6 years of belimumab-based combination treatment. Over­all, she tolerated belimumab well without any side effects, and her cre­atinine clearance remained normal all along.

Discussion
Among various clinical manifesta­tions of SLE, LN is the most common severe organ manifestation that af­fects over 50 percent of SLE patients in Hong Kong.2,3 Despite standard-of-care therapies, renal response rates remain low, and up to 30 percent of LN patients progress to end-stage renal disease. Therefore, a newer treatment with better renal response vs standard therapy is needed.4

Belimumab, a B-lymphocyte stim­ulator antagonist, is a biologic which was initially indicated for treatment of active SLE, with a recent label that includes active LN in Hong Kong.The clinical decision to use belim­umab in our patient was supported by the efficacy data in terms of re­ducing disease activity of SLE and LN.3,5-7 In addition, the 2021 Asia-Pacific League of Associations for Rheumatology consensus statement on SLE management indicated that belimumab can be used as an add-on therapy for patients with SLE, in­cluding those with renal disease who did not respond adequately to first-line treatment.Furthermore, our patient’s joint and cutaneous manifestations were predictors of better response to belimumab treatment.9

The clinical efficacy of belimumab in LN treatment was demonstrated in the 2-year, phase III, double-blind, ran­domized, placebo-controlled BLISS-LN trial. Patients (mean age, 33.4 years; female, 88 percent) with active LN were randomized 1:1 to receive IV be­limumab 10 mg/kg (n=224) or placebo (n=224) in addition to standard thera­py (ie, MMF or cyclophosphamide plus azathioprine).3

The primary endpoint was primary efficacy renal response (PERR), de­fined as urinary protein to creatinine ratio (uPCR) ≤0.7, estimated glomer­ular filtration rate (eGFR) not worse than 20 percent below the pre-flare value or ≥60 mL/min/1.73 m2, and no use of rescue therapy for treatment failure. At week 104, more patients in the belimumab vs placebo group achieved a PERR (43 percent vs 32 percent; odds ratio [OR], 1.6; 95 per­cent confidence interval [CI], 1.0 to 2.3; p=0.03).3

The rigorous endpoint of complete renal response (CRR; uPCR <0.5, eGFR no worse than 10 percent below the pre-flare value or ≥90 mL/min/1.73 m2) was met either, with more patients in the belimumab vs placebo group achieving a CRR (30 percent vs 20 per­cent; OR, 1.7; 95 percent CI, 1.1 to 2.7; p=0.02).3

Both CRR and PERR required ste­roid tapering to ≤10 mg from week 24 onwards and confirmation of the re­sponse at two consecutive visits. Tak­en together, use of belimumab nearly halved the risk of a renal-related event or death vs placebo (35 events vs 63 events; hazard ratio [HR], 0.51; 95 per­cent CI, 0.34 to 0.77; p=0.001).3 (Figure)

HK-GLA-406md_01

The Asia-Pacific consensus statement indicates that belimumab is associated with a glucocorticoid-sparing effect without new safety sig­nals, which is consistent with the ex­perience in our patient.8 Overall, the steroid-sparing effect and reduction of lupus activity might contribute to a reduction of organ (ie, kidney, joint, and skin) damage accumulation and support the use of belimumab as a disease-modifying treatment for both SLE and LN.10

The safety data from the BLISS-LN trial were consistent with the known safety profile of belimumab. Adverse events (AEs) were similar between the belimumab and pla­cebo arms, with upper respirato­ry tract infection (12 percent vs 11 percent), post-infusion reactions (12 percent vs 13 percent), and all infections of special interest (13 per­cent vs 15 percent) being the most common.3

In summary, belimumab can be considered as an effective treatment in addition to background immuno­suppressive therapies for patients with active LN to improve renal outcomes, control extra-renal lupus activity, and facilitate glucocorticoid sparing.8,11 In addition, it can be chosen for SLE patients, especially those with cuta­neous and joint manifestations.9

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