Telitacicept as a novel treatment for refractory lupus nephritis complicated by podocytic infolding glomerulopathy

Lupus nephritis (LN), a renal symptom of systemic lupus erythematosus (SLE), frequently causes severe organ damage in SLE patients.1 There is no consensus on the definition of refractory LN, which has been suggested to occur when remission is not achieved after 3–12 months of combined glucocorticoids and immunosuppressive therapy.2 Podocytic infolding glomerulopathy (PIG), a rare type of glomerular morphological alteration, is primarily characterized by the presence of microspheres, microtubular structures, or a combination of the two, which are associated with podocyte infolding into the glomerular basement membrane (GBM).3, 4 The exact pathogenesis of PIG remains unclear, but it may be associated with autoimmune diseases like SLE and Sjögren's syndrome. The occurrence of refractory LN complicated by PIG is rare and poses significant challenges in management. Here, we endeavor to provide the patient with benefits by employing a novel treatment, Telitacicept, which has demonstrated the potential to achieve complete renal remission in such cases. In 2012, a 37-year-old woman presented with photosensitivity, a significant erythematous rash on the face, and a 24-h urinary protein quantification exceeding 3000 mg, seeking medical care at external healthcare facilities. Poor control of urinary protein despite repeated intravenous methylprednisolone treatments over the years. Consequently, she was admitted to our department in August 2021. Laboratory investigations upon admission revealed multiple positive autoantibodies, including antinuclear antibody (ANA) 1:3200, anti-Smith 1.83 AI (normal range: 0–1 AI), anti-RNP 4.43 AI (normal range: 0–1 AI), anti-SSA 2.23 AI (normal range: 0–1 AI), and anti-Ro52 1.76 AI (normal range: 0–1 AI); weakly positive lupus anticoagulant normalized lupus anticoagulant ratio 1.21 (normal range: <1.2); complement 3 at 0.881 g/L (normal range: 0.9–1.8 g/L); urinary protein quantification at 723.87 mg/24 h (normal range: 0–150 mg/24 h); and anti-double stranded DNA of 16.6 IU/mL (normal range: 0–30 IU/mL). Combined with the patient's history, LN was diagnosed. A renal biopsy was performed after admission. Electron microscopy demonstrated podocytes infolding into the GBM, forming microsphere-like structures, leading to the pathological diagnosis of PIG (Supporting information: Figure S1). Considering refractory LN, we explored a TTT approach combining glucocorticoids, mycophenolate mofetil (MMF), and tacrolimus. The treatment regimen included oral methylprednisolone (12 mg daily), hydroxychloroquine (0.2 g twice daily), and MMF (0.5 g twice daily), combined with tacrolimus (1 mg twice daily), enalapril maleate, calcitriol, and calcium carbonate for osteoporosis prevention, along with symptomatic treatments for gastroprotection and renal protection. Postdischarge in October 2021, we gradually reduced the dosage of methylprednisolone to 8 mg daily. However, recurrent instances of "positive urine protein" detected in March 2022 prompted the discontinuation of MMF due to an inadequate therapeutic response. The tacrolimus dosage was increased to 1 mg three times daily. On May 9, 2022, despite interventions, the patient's urinary protein remained poorly controlled at 1685.17 mg/24 h. Subsequently, weekly subcutaneous injections of telitacicept (160 mg) were introduced. After a month of this supplementary treatment, significant improvements were observed on June 6, 2022. Urinary protein quantification sharply decreased to 219.06 mg/24 h, and the Systemic Lupus Erythematosus Disease Activity Index-2000 dropped from 4 to 0 (Figure 1), indicating a substantial reduction in disease activity. Her current treatment regimen comprises oral low-dose glucocorticoids, tacrolimus, hydroxychloroquine, and weekly subcutaneous injections of telitacicept (160 mg), alongside calcitriol and calcium carbonate for osteoporosis prevention. Detailed information about the patient's medication regimen is available in Figure 1. Regular follow-ups are ongoing, maintaining 24-h urinary protein levels consistently below 500 mg (Supporting information: Table S1). No adverse events were reported during treatment. LN complicated by PIG may be mistaken for lupus podocytopathy owing to overlapping pathological mechanisms. Both conditions entail podocyte injury, a pivotal aspect in the advancement of renal diseases. Both conditions are linked to autoimmune diseases, indicating comparable immune-mediated mechanisms driving their pathogenesis. Consequently, it is conceivable that they might exhibit similar responses to treatment. Telitacicept, an innovative recombinant fusion protein, effectively inhibits the interaction of B cell lymphocyte stimulator and a proliferation-inducing ligand, two type II transmembrane proteins associated with B cell development, differentiation, and ultimately antibody production. Telitacicept has proven effective in SLE patients. A multicenter, phase 2b clinical trial conducted in China reported that telitacicept met its primary endpoint and exhibited good tolerability.5 Moreover, telitacicept has been shown to improve treatment response and reduce glucocorticoid dosage in patients with refractory childhood-onset SLE. Given these therapeutic effects, we added telitacicept to the treatment of our patient, who exhibited inadequate responses to glucocorticoids, MMF, or tacrolimus. Her rapid improvement suggests the potential of telitacicept in treating PIG. It is hypothesized that telitacicept may modulate B cell differentiation and restore disrupted podocyte structures and functions, thereby impeding PIG progression. While the outcomes of this case are encouraging, limitations stem from its single-case nature and the restricted observation period. Further investigation, including larger randomized controlled trials, is imperative to comprehensively evaluate the efficacy of this combination therapy. Additionally, elucidating the mechanism of action of telitacicept in such diseases and other types of kidney disorders warrants further research. Xinwang Duan designed the study. Lu Zhou, Haoguang Li, Rongwei Zhang, and Qifeng Jiang collected data. Lu Zhou and Haoguang Li drafted the manuscript. Xinwang Duan revised the manuscript. All authors read and approved the final manuscript. This study was supported by grants from the National Key Research and Development Program of China (2021YFC2501304), the Science and Technology Program of Department of Health of Jiangxi Province (20204254), and the Key Research and Development Program of Jiangxi Municipal Science and Technology Department (20192BBGL70024). The authors declare no conflict of interest. The written informed consent was acquired from the patient. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.