Novel Sequential Therapy with Obinutuzumab and Telitacicept in Severe Lupus Nephritis with Glucocorticoid-Induced Avascular Necrosis (AVN) of the Femoral Head: A Case Report

Introduction

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multisystem involvement, recurrent flares, and autoantibody production. Its etiology involves genetics, sex hormones, and environmental factors. Without timely intervention, SLE can cause irreversible organ damage and death [1,2].

The kidneys are the most commonly affected organ in SLE, with renal involvement occurring in 50–60% of Asian patients [3–5]. Renal involvement is also a major contributor to SLE-related mortality [6,7]. Despite aggressive treatment, lupus nephritis (LN) exhibits high relapse rates. Conventional regimens based on high-dose glucocorticoids and immunosuppressants often fail to control disease in refractory cases. Moreover, long-term glucocorticoid use is associated with osteonecrosis in 9–40% of patients [8], and exerts profound adverse effects on stem cell differentiation, lipid metabolism, and the vascular system [9], underscoring the urgent need for novel targeted therapies for LN.

B cells are central to SLE pathogenesis through autoantibody production, antigen presentation, cytokine secretion, and immune dysregulation [10–16]. Among key regulators of B-cell biology, the tumor necrosis factor (TNF) family – B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) – have emerged as significant therapeutic targets, promoting B-cell survival, differentiation, and antibody production, with elevated levels observed in patients with SLE. In the past 2 decades, while anti-CD20 monoclonal antibodies (eg, rituximab) effectively deplete circulating B cells, they incompletely target plasma cells, and post-treatment BAFF/APRIL surges may drive renewed autoantibody production and disease activity [17,18].

Obinutuzumab is a type II humanized anti-CD20 monoclonal antibody that demonstrates superior B-cell cytotoxicity and reduced CD20 internalization versus rituximab [17,19–22]. For BAFF/APRIL inhibition, telitacicept’s dual targeting may offer advantages over belimumab (BAFF-only inhibitor) by additionally suppressing plasma cell differentiation [18,23].

We present the first reported case of severe LN with glucocorticoid-induced avascular necrosis (AVN) successfully treated with Obinutuzumab-telitacicept sequential therapy. This 22-year-old woman with recurrent flares and complications despite conventional therapy exemplifies the unmet need in refractory SLE. The sequential strategy – Obinutuzumab for rapid B-cell depletion followed by telitacicept to prevent BAFF/APRIL-mediated reconstitution – addresses key limitations of monotherapies and may enable faster glucocorticoid tapering [18,23,24].

Case Report

Our case involves a 22-year-old woman who was diagnosed with LN (class V) via renal biopsy 6 years ago (May 2018), presenting with facial and bilateral lower-limb edema. Her treatment included prednisone 50 mg qd, tacrolimus 1.5 mg q12 h, and hydroxychloroquine 0.2 g bid, with gradual reduction of glucocorticoid dosage. Four years ago (March 2020), she began experiencing pain in her left knee and hip joint after prolonged sitting. MRI indicated avascular necrosis of the left femoral head and hip joint subluxation. Over the 3 years prior to this admission, she had been hospitalized multiple times for recurrent chest pain and upper-respiratory tract infections, acute pericarditis, and pulmonary hypertension. Her treatment was adjusted to prednisone 2.5 mg qd, mycophenolate mofetil 0.5 g q12 h, and hydroxychloroquine 0.2 g bid when urinary protein turned negative in October 2022.

One year ago (July 2023), she was again hospitalized for an acute upper-respiratory tract infection and moderate lupus activity with an SLEDAI score of 14. Telitacicept 160 mg qw was added to her treatment regimen from July to September 2023, and the dose was reduced to 160 mg q2w from October 2023 to January 2024, leading to a significant reduction in proteinuria, with the urine protein-to-creatinine ratio (uPCR) declining by more than 50% (from 4496 mg/g to 1735 mg/g). She eventually discontinued glucocorticoids without medical supervision in March 2024.

Two weeks prior to her latest hospitalization at our hospital on June 19, 2024, she experienced a fever with a peak temperature of 38.9°C, accompanied by a cough productive of white mucus sputum. Her physical examination revealed a temperature of 37.4°C and, heart rate of 123 bpm. A few moist rales were heard at the lung bases. Cardiac examination revealed a split and accentuated second heart sound with left-sided heart border expansion.

Laboratory tests showed white blood cells (WBC) 2.43×109/L (reference range 3.5–9.5×109/L), hemoglobin (Hb) 106 g/L (reference range 115–150 g/L), and platelets (Plt) 90×109/L (reference range 125–350×109/L). Proteinuria +++ (reference range −), urine red blood cells ++ (reference range 0–2/HP), and 24-hour urinary protein quantification of 1749 mg/24 h (reference range 0–150 mg/24 h). Erythrocyte sedimentation rate (ESR): 28 mm/h (reference range 0–25.7 mm/h); procalcitonin (PCT) <0.05 ng/ml (reference range <0.05 ng/ml). Urea 4.3 mmol/L (reference range 3.1–8.0 mmol/L), creatinine (CRE) 59.81μmol/L (reference range 57–97μmol/L), albumin 20.8 g/L (reference range 40–55 g/L). IgG 17.5 g/L (reference range 7.0–16.0 g/L), IgA 1.8 g/L (reference range 0.7–4.0 g/L), IgM 0.362 g/L (reference range 0.4–2.3 g/L). Anti-dsDNA: 840.51 IU/ml (reference range 0–100 IU/ml), C3 0.263 g/L (reference range 0.9–1.8 g/L), and C4 0.0259 g/L (reference range 0.1–0.4 g/L).

Leukopenia (WBC 2.43×109/L), anemia (Hb 106 g/L), and thrombocytopenia (Plt 90×109/L) indicated active hematological involvement, while hypoalbuminemia (20.8 g/L) and proteinuria (1749 mg/d) confirmed renal flare. With an SLEDAI score of 27, the patient was treated with 125 mg IV methylprednisolone qd for 3 days starting June 20, followed by 40 mg IV methylprednisolone qd for 7 days, and prednisone 25 mg po qd thereafter. The dose was planned to be reduced by 5 mg every 2 weeks. On June 28 and July 12, she was treated with 1000 mg Obinutuzumab IV, which gradually reduced the lupus activity.

By July 27, the patient’s outpatient evaluation showed an SLEDAI score of 10. Her WBC increased from 2.43×109/L to 4.24×109/L, platelets rose from 90×109/L to 186×109/L, albumin levels improved from 20.8 g/L to 32.2 g/L, complement C3 increased from 0.263 g/L to 0.744 g/L, and 24-hour urinary protein levels decreased to 681 mg/d. The treatment was changed to prednisone 15 mg qd, mycophenolate mofetil 0.75 g q12 h, and telitacicept 160 mg qw (Figure 1). Her WBC, platelets, serum albumin, and complement levels gradually increased (Figure 2), while anti-dsDNA, 24-hour proteinuria levels, and SLEDAI score decreased. The 24-hour urinary protein decreased from 1749 mg/d (baseline, June 2024) to 604 mg/d on September 5, indicating partial renal remission (Figure 3A, 3C, 3D). The immunoglobulin G levels decreased initially and remained within the normal range (Figure 3B), and the pericardial effusion disappeared (Figure 4), resulting in effective lupus control. On December 10, the SLEDAI score decreased to 4. During the treatment course, only 1 episode of vaginitis occurred, presenting with vulvar itching, which resolved promptly after topical application of metronidazole suppositories (Figure 1).

Discussion

SLE is a multiorgan and multisystem autoimmune disease. Current treatment regimens primarily rely on high-dose glucocorticoids and immunosuppressants. However, persistent disease activity and infections often lead to suboptimal treatment outcomes. Long-term glucocorticoid therapy is associated with complications such as opportunistic infections, diabetes, and femoral head osteonecrosis. These limitations underscore the urgent need for safer and more effective treatment strategies, especially in refractory SLE.

Despite the involvement of genetic, hormonal, and environmental factors (eg, ultraviolet radiation), B cells play a central role in the pathogenesis of SLE. Abnormal activation of autoimmune B cells leads to the production of various autoantibodies. Defective central tolerance allows autoreactive B cells to escape deletion, differentiate into plasma cells, and produce autoantibodies against dsDNA, Sm, RNP, Ro/SSA, La/SSB, ribosomal P antigens, and phospholipids [10–12]. Additionally, B cells act as effective antigen-presenting cells. Antigen-specific B cells activate T cells by peptide-MHC complexes, contributing to autoimmunity independent of antibody secretion [13,14,25]. B cells produce various cytokines, exhibiting both autocrine and paracrine effects. Upon co-stimulation via the B-cell receptor (BCR) and CD40, human B cells secrete pro-inflammatory cytokines like lymphotoxin, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), which can act as growth and differentiation factors in an autocrine manner and aid the formation of an inflammatory germinal center [15,16].

Obinutuzumab is a glycoengineered humanized type II anti-CD20 monoclonal antibody that binds uniquely to CD20. Its engineered Fc region exhibits enhanced affinity for FcγRIII, resulting in superior antibody-dependent cellular cytotoxicity (ADCC) and direct B-cell killing, while demonstrating reduced complement-dependent cytotoxicity (CDC) compared to Type I antibodies [26]. Unlike Type I anti-CD20 antibodies, Obinutuzumab does not induce CD20 redistribution into lipid rafts nor activate FcγRIIB, thereby minimizing CD20 internalization [19–21]. Clinical advantages of Obinutuzumab over rituximab have been demonstrated in the treatment of chronic lymphocytic leukemia and follicular lymphoma when combined with standard chemotherapy [27,28]. In SLE, Obinutuzumab has shown enhanced B-cell cytotoxicity and NK cell activation, and improved efficacy in murine LN compared to rituximab [17,19,22].

Our patient presented with a critically severe lupus flare (SLEDAI score: 27) after steroid discontinuation, requiring urgent disease control. Obinutuzumab achieves significantly faster B-cell clearance compared to rituximab, as demonstrated in the GAUGUIN study of relapsed/refractory chronic lymphocytic leukemia [29]. The REGENCY trial revealed that the Obinutuzumab group achieved a significantly earlier reduction in proteinuria at 12 weeks (55.5% vs 41.9%, P=0.02), indicating rapid suppression of B-cell-mediated inflammation. By weeks 64 to 76, 42.7% of Obinutuzumab-treated patients attained complete renal response (CRR) with prednisone ≤7.5 mg/day, surpassing the control group (30.9%, P<0.05) [30]. These findings corroborate our observation that profound B-cell depletion accelerates disease control in severe SLE flares.

BAFF and APRIL are elevated in SLE and play crucial roles in B-cell survival and differentiation. BAFF modulates the differentiation and maturation of immature B cells, while APRIL modulates the function and survival of long-lived plasma cells [23,31,32]. Three receptors of BAFF and APRIL have been identified as transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI), B-cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). BAFF-R has a strong selectivity for BAFF, BCMA has a higher affinity for APRIL than for BAFF, while TACI binds both ligands with comparable affinity [33].

Telitacicept is a fusion protein targeting BAFF and APRIL, combining the extracellular soluble portion of TACI with the Fc region of human IgG1 [34]. By binding to BAFF and APRIL (thereby blocking their interaction with receptors on B cells), telitacicept disrupts aberrant B-cell and plasma cell activation. Evidence suggests that TACI-Ig reduces elevated BAFF levels, thereby inhibiting subsequent B-cell activation [35]. Telitacicept also blocks BAFF to inhibit abnormal B-cell maturation and APRIL to prevent plasma cell differentiation and autoantibody production [36]. In SLE, telitacicept demonstrates superior efficacy in achieving SLE Responder Index-4 (SRI-4) response (OR 5.2, 95% CI 1.4–20.0) compared to standard therapy [37].

Belimumab (an anti-BAFF monoclonal antibody) is now also approved for active LN based on the BLISS-LN trial [38]. Belimumab inhibits BAFF but not APRIL, and the APRIL-BCMA pathway is a critical pathway for plasma cell survival and autoantibody production [32,35]. In a real-world single-center observational study, a significantly higher proportion of SLE patients achieved early Lupus Low Disease Activity State (LLDAS) at 4, 12, and 24 weeks of treatment with telitacicept compared to those receiving belimumab (P=0.01) [39].

In refractory LN, a multicenter study (n=49) compared rituximab sequential therapy: telitacicept (n=14) achieved complete remission (78.6% vs 54.3%, P=0.194) and an overall response comparable to belimumab (85.7% vs 80.0%). In both groups, anti-dsDNA antibody levels, complement levels, estimated glomerular filtration rate (eGFR), uPCR, and SLEDAI 2K scores improved, with a significant reduction in prednisone dose. Major adverse effects included immunoglobulin deficiency, respiratory tract infection, and urinary tract infection [40]. In our case, a partial renal response was achieved within approximately 4 weeks, and the monitored IgG levels remained within the normal range, which helped reduce the risk of infections.

Research shows that following B-cell depletion therapy (such as rituximab), B-cell reconstitution is promoted and the expression of B-cell stimulating factors (eg, BAFF) is increased – factors that can cause disease relapse [18]. The combination therapy of B-cell depletion plus BAFF inhibitors for patients with SLE is reasonable. Theoretically, after Obinutuzumab achieves profound B-cell depletion, reducing autoantibody burden, while telitacicept could provide dual blockade of BAFF/APRIL, suppressing the BAFF rebound and prolonging remission duration.

Although the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend cyclophosphamide and voclosporin for LN (class V), the sequential administration of Obinutuzumab followed by telitacicept was a more rational choice for our 22-year-old female patient, who had strong concerns about fertility preservation. This approach avoids cyclophosphamide-induced cumulative ovarian toxicity (aligned with her childbearing aspirations), circumvents the accessibility limitations of voclosporin, and facilitates the steroid withdrawal necessary for managing glucocorticoid-induced AVN of the femoral head.

Notably, while this sequential therapy achieved favorable efficacy in the present case, there remains a lack of sufficient long-term clinical data supporting its use in severe SLE, particularly for treatment durations exceeding several years. Furthermore, previous studies have reported that Obinutuzumab can be associated with infusion-related reactions, infection risks during B-cell depletion, and rare hematological adverse events; however, none of these adverse effects were observed in our patient during treatment. Nevertheless, these known potential risks further underscore the necessity of long-term follow-up for patients receiving this sequential therapy, aimed at comprehensively evaluating its safety and efficacy.

The broader applicability of this sequential therapy requires consideration of regional accessibility and economic factors. Both biologics face availability challenges: telitacicept, while NMPA-approved for SLE in China, remains inaccessible in many countries, and Obinutuzumab access varies by approved indications and healthcare systems. Additionally, the substantial cost of these biologic agents may preclude their use in resource-limited settings, potentially restricting this regimen’s feasibility in low- and middle-income regions. These practical constraints must be weighed when considering therapeutic adaptation across different healthcare environments.

The significance of this case lies in pioneering the novel field of individualized sequential therapy for severe SLE. When conventional agents are limited by complications, mechanism-driven biologic combinations can achieve an optimal balance between deep remission and safety—representing a pivotal direction for lupus precision medicine in the coming decade. The innovative approach for treating severe SLE represents a novel therapeutic strategy worth further investigation and clinical application.

Conclusions

To our knowledge, this is the first documented clinical application of sequential Obinutuzumab-telitacicept therapy in severe SLE complicated by glucocorticoid-induced avascular necrosis of the femoral head. The mechanistic rationale for this sequential biologic approach is Obinutuzumab-mediated profound B-cell depletion followed by telitacicept’s dual blockade of BAFF/APRIL pathways, which overcomes the key limitations of conventional therapy by preventing post-depletion BAFF surge and enabling rapid steroid tapering. This case supports the therapeutic promise of combining B-cell depletion with BAFF/APRIL inhibition in SLE, particularly in those with severe nephritis, recurrent flares, or steroid-dependent disease. Although current clinical experience with this sequential regimen remains limited, this case demonstrates its potential to achieve deep remission with favorable safety outcomes. Further large-scale prospective studies are warranted to validate the efficacy, optimal sequencing, and long-term safety of this novel precision therapeutic paradigm.