Telitacicept and Tacrolimus Synergy in Managing Refractory Primary Membranous Nephropathy: Case Insights

Introduction

Primary membranous nephropathy (pMN), an autoimmune glomerular disease prevalent among middle-aged and elderly individuals, is characterized by distinct clinical manifestations such as massive proteinuria associated with a pathognomonic pattern of injury in glomeruli, hypoalbuminemia, edema, and hyperlipidemia [1]. With an incidence rate of approximately 1.2/100 000 annually, pMN is an increasingly significant health concern worthy of attention [2]. Although the diagnosis of pMN depends on renal biopsy and examination of PLA2R antibody, there is no standard definition of refractory pMN. Traditionally, refractory pMN referred to cases with persistent proteinuria despite immunosuppression. With PLA2R antibody as a diagnostic marker, it is now defined as an PLA2R-associated condition in patients with detectable antibodies after adequate immunosuppression [3]. The management of pMN is tailored to the risk of progressive kidney function decline, and most individuals categorized as moderate, high, and very high risk should undergo immunosuppressive therapies [4]. pMN is marked by the deposition of immune complexes beneath the glomerular epithelium, disrupting the delicate balance of the filtration barrier [5]. Among them, the presence of autoantibodies targeting glomerular podocyte antigens drives the disease, notably PLA2R, thrombospondin type-1 domain-containing 7A (THSD7A), and emerging potential antigens [6]. According to the 2021 guidelines of the Kidney Disease Improving Global Outcomes (KDIGO), PLA2R antibody bound to PLA2R in glomerular podocytes is a crucial laboratory marker for diagnosing pMN, analyzing treatment effectiveness, and evaluating prognosis. The level of PLA2R antibody correlates with therapeutic response, underscoring the importance of longitudinal monitoring of these antibody levels during treatment to guide therapeutic interventions [4,7–9]. Among PLA2R antibody subtypes, IgG4 may be a more effective biomarker in pMN. Recent studies show that IgG4 is more accurate and sensitive in diagnosis and prognosis of pMN [10–13]. While traditional immunosuppressive therapies have shown some efficacy in treating pMN, biological agents, by specifically inhibiting key molecules involved in lymphocyte activation and differentiation, inhibiting complement activation, and regulating inflammatory cytokines, have demonstrated lower toxicity profiles and higher therapeutic specificity. A variety of biologics have been developed as potential therapeutic targets for autoimmune renal disease [14]. Telitacicept is a new fully human TACI-Fc fusion protein that can bind to B lymphocyte stimulator (BlyS) and proliferation-inducing ligand (APRIL) simultaneously, thereby targeting and regulating the growth process of lymphocytes, including plasma cells (especially long-lived plasma cells) and T lymphocytes (T cells) [15]. However, the use of telitacicept for the treatment of refractory pMN in adults remains limited. The cases presented in October 2023 and June 2024, showing the successful application of telitacicept in treating refractory MN, underscore the remarkable potential of this therapeutic agent [16,17].

Tacrolimus was recommended as the first-line therapy of pMN in patients with moderate or high risk of progression. It can be used alone or in combination with glucocorticoids according to the KIDGO 2021 guidelines. Compared with cyclophosphamide, tacrolimus has better short-term efficacy but higher rates of tremor and increased blood creatinine [18,19]. The present article describes the case of a 32-year-old man with persistent proteinuria due to refractory primary membranous nephropathy, who was treated with telitacicept and tacrolimus, with treatment response monitored by measuring PLA2R antibody levels.

Case Report

One year prior, a 32-year-old man presented to our outpatient clinic with a 6-month history of persistent edema in both lower extremities. Prior external investigations had revealed a strikingly elevated 24-hour urine protein level of 3.65 g, accompanied by a serum creatinine level of 86 μmol/L and a very low serum albumin (ALB) concentration of 23.3 g/L. A renal biopsy showed stage III membranous nephropathy (Figure 1), and PLA2Rab was 66.94 U/ml. He was given prednisone (25 mg per day for 30 days) alternated every other month with cyclophosphamide (100 mg per day for 30 days). The treatment regimen lasted 6 months, consisting of 3 months with corticosteroids and 3 months with cyclophosphamide. This intervention yielded improvements, as evidenced by a notable elevation in ALB from 23.3 g/L to 27.7 g/L. Furthermore, the urine protein-to-creatinine ratio (PCR) and albumin-to-creatinine ratio (ACR) decreased to 4716.96 mg/gCr and 2663.17 mg/gCr, respectively. Subsequently, the prednisone dose was tapered to a maintenance level of 15 mg/d. To optimize the treatment, tacrolimus (3 mg/d) was initially introduced and later adjusted to an appropriate dose (5 mg/d) in the following months. At the same time, diltiazem (90 mg/d) was used in combination to increase the blood concentration of tacrolimus at 5–10 ng/ml. Progressing to the seventh month of therapy, PCR was maintained at 27.9 g/L, with ACR and PCR continuing to trend downwards. However, in the eighth month of treatment, he developed glucocorticoid intolerance, manifesting as vision impairment, necessitating discontinuation of prednisone and continuation with tacrolimus monotherapy. Nevertheless, after 2 months of tacrolimus monotherapy (in the tenth month), the PCR and ACR levels failed to demonstrate significant declines, underscoring the need for more potent therapeutic interventions. Subsequently, a novel biological agent, telitacicept (80 mg subcutaneous injection weekly), was introduced in conjunction with tacrolimus (5 mg/day). This revised regimen swiftly elicited a positive clinical response. Within just 2 weeks, a marked reduction in PLA2R antibody to 21.75 U/ml was observed, suggesting the new treatment approach was effective. By the end of the second month under this regimen (in the twelfth month), PCR and ACR levels had declined to 556.54 mg/gCr and 375.13 mg/gCr, respectively, while ALB rose to 44.43g/L, signifying a profound therapeutic achievement. Ultimately, after 6 months of treatment under the revised regimen (in the sixteenth month), follow-up assessments revealed that PLA2Rab had plummeted to <6 U/ml, further solidifying the therapeutic gains and leading to a substantial improvement in overall health status (Figure 2).

Discussion

In this case, the patient was diagnosed with pMN according to his clinical symptoms and pathology results. With massive proteinuria, hypoalbuminemia, and edema, the patient is diagnosed with nephrotic syndrome. Due to the high levels of PCR and PLA2R antibody, the patient was at high risk of progression according to KDIGO guidelines. During the treatment period, the proteinuria had limited improvement with the classic immunosuppressant therapy, although ALB increased slightly, prompting a reevaluation of our treatment strategy.

Considering the pathogenesis of pMN, we recognized the unique therapeutic potential of telitacicept. We decided to incorporate telitacicept (80 mg per week), combined with tacrolimus (5 mg/d), into the treatment regimen. Consequently, PCR, ACR, and PLA2R antibody levels decreased significantly within 2 weeks. After 6 months of this revised treatment, PLA2R antibody results became negative and the pMN had partial remission. Throughout the treatment period, no notable adverse effects were reported. The cases reported in October 2023 and June 2024 both presented patients with refractory pMN with negative blood PLA2R, who achieved remission of proteinuria in the treatment of glucocorticoid combined with telitacicept [16,17]. However, no cases have been reported using telitacicept in combination with tacrolimus for the treatment of refractory pMN. Furthermore, in addition to monitoring proteinuria levels, the assessment of PLA2R antibody levels also indicates the remission of pMN. It is noteworthy that proteinuria can persist for several months, even after the circulating PLA2R antibody becomes undetectable [1].

There is no clear definition of refractory pMN. However, numerous articles have established criteria for refractory pMN, including resistance to standard treatments and failure to respond to immunosuppressive drugs. The first-line treatments for pMN include cyclophosphamide, rituximab, and calcineurin inhibitors (CNIs). Unfortunately, 15% to 45% of patients are refractory to them, continuing to have persistent nephrotic syndrome. The KDIGO 2021 guidelines advocate for a risk-stratified approach to managing pMN. For low-risk patients, conservative management without specific therapy may be appropriate. However, for those classified as medium to very high risk, the use of glucocorticoids and immunosuppressants is recommended to halt disease progression and preserve renal function [4,20]. In recent years, biologicals are recommended in the treatment for refractory pMN because of their high specificity. New drugs targeting B lymphocytes (B cells) and plasma cells are also currently options for refractory cases, such as Obinutuzumab, Belimumab, proteasome inhibitors, and anti-CD38 agents [21–23]. However, their clinical efficacy and safety need to be further confirmed.

The deposition of immune complexes, arising from the intricate interplay between antigens and antibodies, onto the glomerular filtration barrier is a widely accepted phenomenon in the context of refractory pMN. Notably, PLA2R and THSD7A, 2 prominent podocyte surface antigens, have emerged as key players in the pathogenesis of this disease, further complicating the immunological landscape [24]. These immune complexes are primarily composed of antibodies, meticulously crafted by plasma cells, which avidly bind to aberrant antigens adorning the podocyte surface. This leads to their strategic deposition on the epithelial aspect of the basement membrane, where they perpetuate their deleterious effects. Concurrently, T cells occupy a pivotal position within the intricate pathological machinery of pMN, underscoring the multifaceted nature of the immune dysregulation involved [25]. Amidst this intricate immunological backdrop, telitacicept, a groundbreaking fusion protein pioneered by Yantai Rongchang Pharmaceutical Company in China, offers a ray of hope for the treatment of B cell-mediated autoimmune disorders. Ingeniously crafted through DNA recombinant technology, telitacicept harmoniously fuses the extracellular domains of human transmembrane activators and TACI receptors with the potent Fc region of human IgG. Telitacicept exhibits a remarkable ability to bind and subsequently neutralize the functional activity of 2 vital cell signaling molecules: BlyS and APRIL [26]. Notably, BlyS predominantly influences the development and maturation of B cells, whereas APRIL primarily sustains the survival of plasma cells, including long-lived variants, and orchestrates antibody production within these cells [15]. Long-lived plasma cells exhibit a unique resilience, independent of B cell precursors for their persistence and renewal, enabling them to endure even in the absence of B cells. This autonomy renders them resistant to antiproliferative agents such as cyclophosphamide. Furthermore, the autoantibodies generated by these long-lived memory plasma cells are also decoupled from B cell activation, rendering them impervious to direct targeting strategies, including anti-CD20, anti-CD22, or anti-BAFF antibodies, as well as indirect targeting approaches that inhibit T helper cells [27]. In essence, by virtue of its dual binding to BAFF and APRIL, telitacicept comprehensively inhibits the developmental trajectory and maturation of B cells, thereby achieving a therapeutic efficacy in pMN that addresses the underlying immunological disturbances. Telitacicept has gained approval in China for the treatment of systemic lupus erythematosus and has exhibited favorable safety profiles in phase II clinical trials conducted for IgA nephropathy, primary Sjögren’s syndrome, and myasthenia gravis [26,28–31]. Huang et al also demonstrated the efficacy and safety of telitacicept in patients with lupus nephritis, highlighting its potential value in immune-related nephrology [32]. Nevertheless, its use in pMN remains relatively uncommon. The favorable pharmacokinetic profile, safety, and tolerability of telitacicept demonstrated in a 2022 clinical trial involving healthy Chinese subjects further reinforce its clinical potential. Specifically, the linear pharmacokinetic behavior observed across a dose range of 80–240 mg for total telitacicept and 160–240 mg for free telitacicept underscores its predictable and controlled absorption, distribution, metabolism, and excretion [33]. As for tacrolimus, it has been recommended as the first-line therapy for the patients with moderate to high risk of progression. Furthermore, its efficacy and safety in immune-mediated diseases have been reported, but it increases the risk of kidney dysfunction, new-onset diabetes, and tremors [18,19,34]. Our patient had refractory pMN was not sensitive to traditional immunosuppressive therapy; therefore, telitacicept combined with tacrolimus was given. The patient experienced partial remission of proteinuria, accompanied by a turnover to negativity in PLA2R antibody levels, without any adverse effects. The results showed that telitacicept together with tacrolimus had certain advantages in refractory pMN. Nonetheless, it is imperative to acknowledge the inherent limitations of these cases, including the need for long-term monitoring to assess the durability of the response, the potential emergence of resistance to telitacicept, and the risk of disease progression. Moreover, questions remain regarding the comparative efficacy of telitacicept as monotherapy versus in combination with other immunosuppressants, the full spectrum of its adverse effects, and the influence of serum biomarkers like PLA2R on therapeutic outcomes.

Conclusions

Telitacicept, a novel dual-target biological agent targeting BlyS and APRIL, combined with tacrolimus, was shown to have positive therapeutic effects in refractory pMN and highlights the role of monitoring treatment response by measuring PLA2R antibody levels. However, prospective studies and multicenter clinical trials are needed to confirm this finding.