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Internal Medicine

Cite as: Archiv EuroMedica. 2026. 16; 4. DOI 10.35630/2026/16/Iss.4.25

Received 23 July 2026;
Accepted 24 August 2026;
Published 26 August 2026

BIOLOGIC AGENTS AND CAR T-CELL THERAPY IN SYSTEMIC LUPUS ERYTHEMATOSUS: CURRENT EVIDENCE AND CLINICAL PERSPECTIVES - NARRATIVE REVIEW

Filip Chodań¹ , Estera Sośniecka¹ ,
Olga Klimczak¹ , Adam Miler¹ ,
Dagmara Laufer¹ , Krystian Domeracki¹

¹ Medical University of Silesia, Katowice, Poland

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  dagmaralaufer@gmail.com

ABSTRACT

Background

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which persistent activity, organ damage, glucocorticoid dependence, and treatment toxicity remain challenges. Advances in SLE immunopathogenesis have enabled pathway-targeted therapies, but their evidence and clinical readiness varies.

Aim

To review established and emerging targeted therapies for SLE, including CAR T cell therapy, with emphasis on mechanisms, efficacy, safety, regulatory status, and clinical roles.

Materials and Methods

PubMed, Google Scholar, and ClinicalTrials.gov were searched for English-language sources from January 2010 to July 2026. The final search was conducted on 10 July 2026. Earlier landmark and mechanistic sources were included. The synthesis comprised 80 publications and registry records; preclinical evidence informed mechanisms only.

Results

Targets included B cells, BAFF and APRIL, type I interferon, CD40 and CD40L, plasma cells, FcRn, TLR7 and TLR8, and complement. Belimumab and anifrolumab have established roles in active extrarenal SLE. Evidence supports belimumab and obinutuzumab in lupus nephritis, although evidence maturity differs. Rituximab remains relevant mainly in refractory disease. Approval status varies by agent, indication, and jurisdiction. Most emerging therapies remain investigational. CAR T cell therapy remains experimental but has yielded encouraging results in small uncontrolled studies of severe refractory SLE. Safety profiles differ, and long-term safety data for emerging approaches are limited.

Conclusions

These approaches differ in regulatory status and clinical readiness. Available therapies should be selected according to phenotype, organ involvement, efficacy, and safety, whereas investigational and experimental approaches require further evaluation. Major gaps concern predictive biomarkers, direct comparisons, optimal sequencing, long-term safety and durability, and validated patient selection criteria.

Keywords: systemic lupus erythematosus; biologic agents; targeted therapy; CAR T cell therapy; lupus nephritis; belimumab; anifrolumab

INTRODUCTION

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation, the production of pathogenic autoantibodies, and inflammation that can affect virtually any organ system. Although relatively uncommon, SLE is associated with substantial morbidity, irreversible organ damage, and increased premature mortality, posing a significant global health burden. A recent global meta-analysis estimated the incidence of SLE at 5.14 cases per 100,000 person-years, corresponding to approximately 400,000 new diagnoses annually and an estimated global prevalence exceeding 3.4 million individuals living with the disease.

Marked geographic variation in both incidence and prevalence has been observed, likely reflecting differences in genetic susceptibility, ethnic background, environmental exposures, healthcare access, and diagnostic practices [1,2]. SLE predominantly affects women, who account for nearly 90% of all cases. The disease most commonly develops during the reproductive years, with peak incidence occurring between 15 and 45 years of age. Despite substantial advances in diagnosis and treatment, patients with SLE continue to experience significantly higher mortality than the general population, with an estimated two- to threefold increase in the risk of death. Cardiovascular disease, severe infections, and irreversible organ damage remain the leading causes of mortality [3].

Genetic susceptibility contributes to SLE through multiple variants that alter key pathways involved in immune regulation, including antigen presentation, type I interferon signaling, and lymphocyte activation. However, genetic susceptibility alone is insufficient to initiate disease, and environmental and hormonal factors contribute to disruption of immune homeostasis.

Environmental triggers such as ultraviolet radiation, cigarette smoking, Epstein–Barr virus infection, and certain medications may promote disease initiation or exacerbation. The marked female predominance of SLE further implicates sex hormones, particularly estrogens, in modulating immune responses and promoting autoimmunity. Together, these factors contribute to loss of immune tolerance and initiation of the immunopathological processes underlying SLE [4–7]. Impaired clearance of apoptotic cells leads to the accumulation of nuclear antigens, which are internalized by antigen-presenting cells and recognized through endosomal Toll-like receptors. This persistent exposure to nuclear autoantigens promotes dendritic cell activation, particularly of plasmacytoid dendritic cells (pDCs), resulting in sustained production of type I interferons (IFN-I). IFN-I signaling further amplifies antigen presentation, autoreactive lymphocyte activation, and chronic inflammation, ultimately contributing to the breakdown of immune tolerance and production of high-affinity autoantibodies, including ANA, anti-dsDNA, and anti-Sm antibodies [8–13].

Persistent activation of innate immunity drives profound dysregulation of adaptive immune responses. T cells exhibit an imbalance characterized by expansion of Th1, Th2, Th17, and particularly follicular helper T (Tfh) cells, accompanied by impaired number and function of regulatory T (Treg) cells [14–16]. Pro-inflammatory cytokines, including interferon-γ (IFN-γ), interleukin-17 (IL-17), interleukin-21 (IL-21), and interleukin-23 (IL-23), sustain chronic inflammation and promote B-cell activation [14].

B-cell dysregulation represents a central event in SLE pathogenesis. Under physiological conditions, B-cell activating factor (BAFF) and A Proliferation-Inducing Ligand (APRIL), regulate B-cell survival, maturation, and differentiation. In SLE, excessive BAFF production, largely driven by type I interferons and activated innate immune cells, promotes the survival and differentiation of autoreactive B cells into autoantibody-producing plasma cells. APRIL further supports the survival of long-lived plasma cells, sustaining chronic autoantibody production and inflammation [17–19].

Additional innate immune abnormalities further amplify inflammation. Macrophages acquire a predominantly pro-inflammatory phenotype, while excessive neutrophil extracellular traps formation by neutrophils contributes to the exposure of nuclear autoantigens [20,21]. Impaired NK-cell cytotoxicity further limits the elimination of autoreactive lymphocytes [22]. The resulting immune complexes activate the complement cascade, amplifying inflammation and tissue injury, particularly in lupus nephritis (LN). Collectively, these mechanisms contribute to progressive organ damage and the heterogeneous clinical manifestations of SLE [23].

The diagnosis of SLE remains challenging because of its heterogeneous clinical presentation and the absence of a single disease-specific diagnostic test. The currently accepted 2019 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) classification criteria require a positive antinuclear antibody (ANA) test at a titer of ≥1:80 as an entry criterion as shown in Table 1. Classification as SLE requires a total score of ≥10 points, including at least one clinical criterion. Within each clinical or immunological domain, only the highest-weighted criterion is counted [24].

The management of systemic lupus erythematosus aims to achieve sustained remission or low disease activity, prevent disease flares and irreversible organ damage, minimize treatment-related toxicity, and improve long-term quality of life. Current therapeutic strategies rely primarily on conventional immunomodulatory and immunosuppressive agents.

Hydroxychloroquine remains the cornerstone of treatment and is recommended for nearly all patients unless contraindicated because of its proven ability to reduce disease activity, prevent flares, limit organ damage accrual, and improve survival. Glucocorticoids are widely used for rapid control of disease activity, particularly during flares, but should be prescribed at the lowest effective dose and tapered as rapidly as clinically feasible because of their well-established long-term toxicity. Conventional immunosuppressive agents, including mycophenolate mofetil (MMF), azathioprine, methotrexate, cyclophosphamide, calcineurin inhibitors such as voclosporin and tacrolimus are selected according to disease manifestations, severity, and the presence of major organ involvement, particularly LN [24–26].

Despite considerable advances in conventional therapy, approximately 40% of patients fail to achieve an adequate response to first-line treatment, while many others continue to experience recurrent disease flares, persistent disease activity, or progressive organ damage despite ongoing immunosuppressive therapy [25]. Long-term glucocorticoid exposure remains a major contributor to treatment-related morbidity and is associated with an increased risk of cardiovascular disease, osteoporosis, diabetes mellitus, infections, cataracts, avascular osteonecrosis, and irreversible organ damage. In addition, conventional immunosuppressive agents are frequently limited by incomplete efficacy and dose-dependent toxicities, including serious infections, retinal toxicity, myelosuppression, hepatotoxicity, nephrotoxicity, gonadal toxicity and infertility, gastrointestinal intolerance, and an increased risk of malignancies [25,27,28].

These limitations, together with the heterogeneous clinical and immunological features of SLE, have driven the development of therapies targeting specific pathogenic pathways and novel approaches such as CAR-T cell therapy. The therapeutic landscape of SLE is rapidly evolving, with an increasing number of biologic agents, targeted therapies, and emerging cellular approaches being investigated in clinical trials. This growing body of evidence has expanded the range of potential treatment options and highlights the need for an updated, clinically oriented synthesis of their mechanisms of action, clinical efficacy, safety, regulatory status, and potential place in treatment.

This review therefore focuses on established and emerging targeted therapies, distinguishing approved treatments from off-label therapies, investigational agents, and experimental cellular approaches.

AIM

The aim of this narrative review is to provide a structured and clinically oriented overview of established and emerging targeted therapies for systemic lupus erythematosus, including biologic agents, other targeted agents, and CAR T cell therapy, with particular emphasis on their mechanisms of action, clinical efficacy, safety, regulatory status, and potential place in treatment.

Objectives

1. To describe the molecular targets and mechanisms of action of the reviewed therapies.
2. To evaluate the available evidence regarding their clinical efficacy and safety, considering the design and maturity of the supporting studies.
3. To compare their regulatory status and potential clinical roles, distinguish established treatments from investigational and experimental approaches, and identify the principal limitations of the current evidence.

MATERIALS AND METHODS

This narrative review was conducted following a structured search of the available scientific literature. Relevant publications were identified through searches of PubMed, Google Scholar, and ClinicalTrials.gov. The primary search included studies published between January 2010 and July 2026, with the final search performed on 10 July 2026. Earlier publications were considered when they provided fundamental insights into the immunopathogenesis of systemic lupus erythematosus (SLE), the mechanisms underlying biologic agents, other targeted therapies, and CAR T cell therapy, or landmark clinical studies that remain highly relevant to current therapeutic strategies. Search terms were tailored to the requirements of each database.

The PubMed search employed the following strategy: ("systemic lupus erythematosus" OR SLE) AND ("biologic therapy" OR "biologic agents" OR "monoclonal antibodies" OR belimumab OR anifrolumab OR rituximab OR obinutuzumab OR daratumumab OR nipocalimab OR "dapirolizumab pegol" OR litifilimab OR afimetoran OR telitacicept OR ianalumab OR eculizumab OR CD38 OR FcRn OR CD40L OR BDCA2 OR TLR7 OR TLR8 OR "BAFF R" OR APRIL OR BCMA OR C5 OR complement OR "CAR T cell therapy"). In Google Scholar, combinations of the keywords systemic lupus erythematosus, biologic therapy, belimumab, anifrolumab, rituximab, obinutuzumab, daratumumab, nipocalimab, dapirolizumab pegol, litifilimab, afimetoran, telitacicept, ianalumab, eculizumab, CD38, FcRn, CD40L, BDCA2, TLR7, TLR8, BAFF R, APRIL, BCMA, C5, complement, CAR T cell therapy, clinical trial, and treatment outcomes were used. ClinicalTrials.gov was searched using the terms systemic lupus erythematosus, belimumab, anifrolumab, rituximab, obinutuzumab, daratumumab, nipocalimab, dapirolizumab pegol, litifilimab, afimetoran, telitacicept, ianalumab, eculizumab, CD38, FcRn, CD40L, BDCA2, TLR7, TLR8, BAFF R, APRIL, BCMA, C5, complement, and CAR T cell therapy to identify completed, ongoing, and recently reported clinical trials.

Sources eligible for inclusion comprised English language randomized controlled trials, prospective and retrospective clinical studies, observational studies, preclinical and experimental research, clinical practice guidelines, review articles, and relevant clinical trial registry records addressing biologic agents, other targeted therapies, or CAR T cell therapy in SLE. Preclinical studies were included solely when they provided relevant information on mechanisms of action and were not used to assess clinical efficacy or safety. Sources were excluded if they were unrelated to systemic lupus erythematosus or the investigated therapies, did not report clinically relevant outcomes or, in the case of preclinical studies, relevant mechanistic findings, were conference abstracts without a corresponding full text publication, letters lacking original data, duplicate reports, or publications in languages other than English.

The screening process involved an initial assessment of titles and abstracts, followed by full text evaluation of potentially relevant publications. Data extracted from the included sources comprised the mechanism of action of each therapy, study design and phase, patient characteristics, clinical efficacy, safety findings, and regulatory status, where applicable. Overall, 80 publications and registry records met the eligibility criteria and were included in the final narrative synthesis. As this work represents a narrative review, the literature selection process was descriptive and was not conducted according to a formal systematic review protocol.

RESULTS

B-cells

Rituximab is a chimeric monoclonal antibody that selectively targets CD20-positive B lymphocytes, leading to selective B-cell depletion while sparing plasma cells and hematopoietic stem cells. The phase II/III, randomised, double-blind, placebo-controlled EXPLORER trial evaluated the efficacy and safety of rituximab in patients with moderately to severely active extrarenal SLE receiving standard background immunosuppressive therapy (mycophenolate mofetil, azathioprine, or methotrexate). The primary endpoint was the achievement and maintenance of a British Isles Lupus Assessment Group (BILAG)-defined major or partial clinical response at week 52. The trial failed to meet its primary endpoint, with no significant differences observed between the rituximab and placebo groups in clinical efficacy. However, prespecified subgroup analyses suggested greater clinical responses among African American and Hispanic patients. The most frequently reported serious adverse events included neutropenia, leukopenia, and hypotension, although most cases of neutropenia were resolved at the subsequent monthly follow-up. Herpes zoster infections were more common among patients receiving rituximab [29]. The subsequent VOYAGER trial, designed to further evaluate rituximab in patients with SLE, also failed to demonstrate superiority over placebo, resulting in premature study termination because of the lack of clinically meaningful efficacy [30]. The phase III, randomised, double-blind, placebo-controlled LUNAR trial evaluated rituximab in patients with class III or IV lupus nephritis receiving mycophenolate mofetil and corticosteroids. The primary endpoint was not met, as rituximab did not significantly improve renal response compared with placebo. Nevertheless, rituximab treatment was associated with greater improvements in serological markers, including increased complement C3 and C4 levels, reduced anti-dsDNA antibody titres, and greater reductions in proteinuria. The safety profile was comparable to placebo [31]. Rituximab is not approved for the treatment of SLE and is therefore used off-label, particularly in patients with severe or refractory disease [25]. Despite the negative results of the major randomised trials, observational studies and clinical experience have supported its use in selected patients. However, these findings should be interpreted with caution as much of the supporting evidence comes from uncontrolled studies and may be affected by patient selection and differences in background treatment [32,33].

Daratumumab is a monoclonal antibody targeting CD38, a surface protein highly expressed on antibody-secreting cells, including plasmablasts and plasma cells. The phase II DARALUP trial, a single-centre, open-label, single-arm study, evaluated the safety and efficacy of daratumumab in 10 female patients with moderate-to-severe SLE who had shown an inadequate response to at least two previous immunosuppressive or immunomodulatory therapies. Treatment resulted in rapid and sustained clinical improvement across all organ domains, with 100% of patients achieving an SLE Responder Index-4 (SRI-4) response at week 12 and 70% maintaining this response at week 36. The study met its primary endpoint, demonstrating marked reductions in anti-dsDNA antibody levels accompanied by significant improvements in overall disease activity. The treatment was generally well tolerated, with hypogammaglobulinaemia, infections, and gastrointestinal disorders being the most common adverse events. No serious adverse events were reported [34]. A Phase II, open-label clinical trial is currently underway to evaluate the safety and efficacy of daratumumab in patients with active LN [35]. Daratumumab remains an investigational therapy for SLE and is not currently approved for this indication. Although the initial results are encouraging, the evidence is limited by the small sample size and uncontrolled, single-arm design of the DARALUP trial, and larger randomised studies are required to confirm its efficacy and safety.

Obinutuzumab is a recombinant humanized monoclonal anti-CD20 antibody , engineered to have greater affinity for the FcγRIII receptor than rituximab, resulting in more potent B-cell depletion through enhanced antibody-dependent cellular cytotoxicity (ADCC). The efficacy and safety of obinutuzumab in patients with LN were evaluated in the phase II, double-blind, placebo-controlled NOBILITY trial. The primary endpoint, complete renal response (CRR), was achieved by 35% of patients treated with obinutuzumab compared with 23% receiving placebo at week 52, increasing to 41% versus 23%, respectively, at week 104. Obinutuzumab was also associated with greater improvements in proteinuria, estimated glomerular filtration rate (eGFR), serological markers, and other renal response measures. The treatment demonstrated a favorable safety profile, with no increase in serious adverse events, serious infections, or deaths compared with placebo. The most commonly reported adverse events were urinary tract infections and bronchitis [36]. The phase III, randomised, placebo-controlled REGENCY trial subsequently confirmed the efficacy and safety of obinutuzumab in patients with class III or IV lupus nephritis. The primary endpoint of complete renal response at week 76 was achieved by 46.4% of patients receiving obinutuzumab compared with 33.1% receiving placebo. The safety profile remained consistent with that observed in the NOBILITY trial, with infections, including COVID-19-related events, representing the most frequently reported adverse events [37]. The phase III, randomised, double-blind, placebo-controlled, multicentre ALLEGORY trial further defined the therapeutic role of obinutuzumab in patients with active systemic lupus erythematosus. The study met its primary endpoint, demonstrating significantly greater efficacy of obinutuzumab compared with placebo. The primary endpoint was achievement of an SRI-4 response at week 52 without worsening in British Isles Lupus Assessment Group (BILAG) scores or the occurrence of intercurrent events, including major protocol-defined concomitant medication violations, use of rescue therapy, or treatment discontinuation due to death, lack of efficacy, or adverse events. At week 52, an SRI-4 response was achieved in 76.7% of patients receiving obinutuzumab compared with 53.5% in the placebo group. Obinutuzumab also demonstrated superiority across multiple secondary endpoints, including higher British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rates, longer time to first BILAG-defined flare, greater rates of sustained glucocorticoid dose reduction, and higher proportions of patients achieving sustained SRI-4 and SRI-6 responses [38]. Obinutuzumab is approved by the FDA for the treatment of active lupus nephritis in adults receiving standard therapy and is recommended by the 2025 EULAR guidelines as an option for combination therapy with mycophenolate in active lupus nephritis, particularly in patients with poor prognostic factors [39]. More recent clinical data also suggest efficacy in systemic disease beyond lupus nephritis, although its current regulatory indication remains limited to lupus nephritis.

Nipocalimab is a fully human monoclonal antibody that selectively targets the neonatal Fc receptor (FcRn) with high affinity, promoting IgG degradation and reducing circulating IgG levels while preserving other immunoglobulin classes and maintaining humoral and cellular immune function [40,41]. The phase II JASMINE trial has been completed; however, peer-reviewed efficacy data are not yet available. Preliminary findings supported continued clinical development, leading to the initiation of the ongoing phase III GARDENIA-SLE trial, a randomised, double-blind, placebo-controlled, multicentre study evaluating nipocalimab in patients with moderate-to-severe SLE. As the results of GARDENIA-SLE have not yet been published, the clinical efficacy of nipocalimab remains to be established [42,43]. Nipocalimab remains investigational for SLE, and its clinical role cannot yet be established because peer-reviewed efficacy data are not available.

Overall, the available evidence supports B-cell-directed therapies as an important component of targeted treatment in SLE, while the clinical evidence remains heterogeneous across therapeutic approaches. Established clinical benefit is best supported for therapies targeting CD20, whereas the potential of newer strategies targeting plasma cells, FcRn, and related pathways remains under investigation.

T-cells

Dapirolizumab pegol (DZP) is an investigational Fc-free PEGylated monoclonal antibody fragment that selectively targets CD40 ligand (CD40L), thereby inhibiting CD40-CD40L signalling involved in T-cell-dependent B-cell activation and maintenance of chronic inflammation as presented in Table 2 [44].

The efficacy and safety of DZP were evaluated in the phase III PHOENYCS GO trial involving 315 patients with moderate-to-severe SLE despite standard therapy. Patients received either DZP or placebo in addition to standard treatment for 48 weeks. The primary endpoint was achieved, with 49.5% of patients receiving DZP attaining a BICLA response compared with 34.6% in the placebo group. Treatment with DZP was also associated with improvements in fatigue, health-related quality of life, and lupus low disease activity state (LLDAS). The safety profile was comparable to placebo, with no significant increase in thromboembolic events [45]. An additional phase III trial is currently ongoing to further evaluate the efficacy and safety of dapirolizumab pegol in patients with active SLE [46]. DZP remains an investigational therapy and is not currently approved for the treatment of SLE. The positive phase III findings support its clinical efficacy, while ongoing studies will help further define its safety and potential role in SLE treatment.

Dendritic cells

Litifilimab is a humanized monoclonal antibody targeting blood dendritic cell antigen 2 (BDCA2), a receptor selectively expressed on plasmacytoid dendritic cells (pDCs), thereby inhibiting type I interferon production [47]. The phase II LILAC study, a randomized, double-blind, placebo-controlled trial, evaluated the efficacy and safety of litifilimab in patients with active SLE, predominantly involving articular and cutaneous manifestations. Litifilimab significantly reduced musculoskeletal disease activity, with a greater reduction in the number of active joints than placebo (−15.0 vs −11.6). In cutaneous lupus erythematosus (CLE), patients treated with litifilimab showed greater improvement in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) scores and higher response rates than those receiving placebo, with a more pronounced effect observed in skin-predominant disease. However, secondary endpoints, including the SLE Responder Index-4 (SRI-4) and BILAG-Based Composite Lupus Assessment (BICLA), did not demonstrate consistent or statistically robust superiority over placebo. Pharmacodynamic analyses confirmed a significant reduction in the type I interferon gene signature and suppression of pDC activity, supporting target engagement and the proposed mechanism of action. The safety profile was generally favorable, with adverse event rates comparable between treatment and placebo groups and no significant increase in severe infections [48]. Currently, the phase III TOPAZ trial is ongoing to further evaluate the clinical efficacy of litifilimab in systemic lupus erythematosus [49]. Litifilimab is not currently approved for SLE and remains under phase III evaluation. The phase II findings provide evidence of activity particularly in musculoskeletal and cutaneous disease, while the inconsistent systemic efficacy endpoints leave its broader clinical role to be established.

Afimetoran is an orally administered selective antagonist of TLR7 and TLR8. By blocking MyD88-dependent signaling downstream of endosomal TLR7/8, afimetoran suppresses activation of the type I interferon pathway, a central driver of immune dysregulation in SLE [50,51]. Afimetoran was evaluated in a phase Ib randomized, double-blind, placebo-controlled study in patients with cutaneous lupus erythematosus (CLE). The study demonstrated a favorable safety profile, with adverse event rates comparable to placebo, and confirmed target engagement through rapid and sustained suppression of the type I interferon gene signature and TLR7/8 pathway-associated cytokines. Exploratory efficacy analyses showed greater improvements in cutaneous disease activity, with 50% of patients receiving afimetoran achieving a ≥50% reduction in CLASI-A scores compared with none in the placebo group [50]. These encouraging findings have supported the initiation of an ongoing phase II study evaluating the efficacy and safety of afimetoran in patients with active SLE [52]. Afimetoran remains an investigational therapy and is not currently approved for SLE. The available evidence is limited to an early phase Ib study conducted primarily in patients with cutaneous lupus, and the exploratory efficacy findings therefore require confirmation in larger studies involving broader SLE populations.

Targeting plasmacytoid dendritic cells and the TLR7/8–type I interferon pathway represents a promising approach, particularly for cutaneous and musculoskeletal manifestations of SLE. However, the clinical evidence remains insufficient to establish the role of these therapies in broader systemic disease, with further phase III and confirmatory studies ongoing.

BAFF

Belimumab is a fully human monoclonal antibody targeting B-cell activating factor (BAFF/BLyS), a key cytokine regulating the survival and maturation of autoreactive B cells as shown in Table 2 . By neutralizing soluble BAFF, belimumab reduces autoreactive B-cell survival, autoantibody production, and downstream adaptive immune activation in SLE [53].

In the pivotal phase III trials, belimumab significantly improved SRI-4 response rates, reduced disease activity, decreased the frequency of severe flares, and facilitated glucocorticoid tapering compared with standard therapy alone [54,55]. These findings were further confirmed in the phase III BLISS-SC trial, which demonstrated that subcutaneous belimumab provided comparable efficacy and safety while offering a more convenient route of administration [56]. Subsequently, the phase III BLISS-LN trial demonstrated significant efficacy of belimumab in patients with active lupus nephritis. The addition of belimumab to standard therapy significantly improved primary efficacy renal response compared with placebo (43% vs 32%), while complete renal response was achieved in 30% versus 20% of patients, respectively. These benefits were maintained throughout the 104-week study period, with sustained improvements in renal response, a reduced risk of kidney-related events or death, and no new safety concerns. [57]. Treatment with belimumab was also associated with reductions in naive and activated B-cell populations, decreased anti-dsDNA antibody titres, gradual normalization of complement C3 and C4 levels [53,58]. Belimumab is approved for the treatment of SLE and active lupus nephritis, with multiple phase III randomized trials supporting its efficacy and safety. Current recommendations support its use as an add-on therapy in patients with active SLE, particularly when additional disease control or glucocorticoid-sparing is needed, and in lupus nephritis in combination with standard therapy [25,39].

Telitacicept is a recombinant TACI-Fc fusion protein that neutralizes both BAFF and APRIL, thereby inhibiting survival signals for B cells and plasma cells as presented in Table 2. This dual blockade may therefore lead to deeper suppression of autoreactive humoral immunity compared with BAFF-only targeting strategies [59]. In a randomized, double-blind, placebo-controlled phase IIb trial, telitacicept demonstrated significantly higher SRI-4 response rates than placebo over 48 weeks of treatment, accompanied by improvements in SLEDAI scores, serological markers, and glucocorticoid-sparing effects [60]. These findings were confirmed in a multicenter phase III trial, which demonstrated significant improvements in disease activity. Telitacicept is approved for SLE in China but has not received regulatory approval for this indication in other major jurisdictions [61]. Its potential role in lupus nephritis is also being evaluated in phase II studies [62]. Although supported by positive randomized phase IIb and III data, further studies are needed to define its long-term safety, generalizability across different patient populations, and potential role in international SLE treatment.

Ianalumab is a fully human monoclonal antibody targeting BAFF receptor (BAFF-R) that combines direct B-cell depletion through antibody-dependent cellular cytotoxicity with inhibition of BAFF-mediated survival signalling [41]. In a phase II randomized, double-blind, placebo-controlled trial, ianalumab achieved significantly higher SRI-4 response rates with protocol-defined corticosteroid tapering than placebo (44.1% vs 9.1%). Clinical responses were maintained through week 52, and treatment was not associated with an increased incidence of serious adverse events or serious infections [63]. Several phase III clinical trials are currently underway to further evaluate the efficacy and safety of ianalumab in patients with SLE and lupus nephritis [64–68]. Ianalumab has not yet received regulatory approval for SLE and is currently under phase III evaluation. The positive phase II findings support further clinical development, while its therapeutic role remains to be established pending the results of ongoing trials.

Overall, BAFF-pathway inhibition has emerged as an established strategy for targeted treatment of SLE, supported by robust randomized evidence for belimumab. Newer approaches targeting BAFF together with APRIL or the BAFF receptor have also shown promising clinical activity, but their broader therapeutic roles remain to be defined.

Cytokines

Anifrolumab is the first biologic agent targeting the type I interferon pathway approved for the treatment of SLE. It binds to the type I interferon receptor subunit 1 (IFNAR1), thereby blocking signalling mediated by all type I interferons and attenuating interferon-driven inflammation [69]. In the phase IIb MUSE trial, anifrolumab significantly improved SRI-4 response rates compared with placebo - 34.3% vs 17.6%, with the greatest benefit observed in patients with a high baseline interferon gene signature. Clinical responses were sustained through week 52, with SRI-4 response rates of 62.6% in the 300 mg group and 53.8% in the 1000 mg group, compared with 40.2% in the placebo group. Influenza and herpes zoster occurred more frequently in patients receiving anifrolumab, whereas the incidence of serious adverse events remained comparable between treatment groups [70]. Although the phase III TULIP-1 trial did not meet its primary SRI-4 endpoint, the subsequent TULIP-2 trial demonstrated significantly higher BICLA response rates with anifrolumab than placebo (47.8% vs 31.5%). Additional benefits included successful glucocorticoid tapering and significant improvement in cutaneous disease activity. Similar to the MUSE trial, herpes zoster and bronchitis were reported more frequently in patients receiving anifrolumab than in those receiving placebo [71,72]. Subsequent studies have provided additional evidence of sustained efficacy and safety and have explored subcutaneous administration and the potential efficacy of anifrolumab in lupus nephritis [73–75]. The ongoing phase III IRIS trial is evaluating anifrolumab in patients with active proliferative lupus nephritis to further define its role in this population [76]. Anifrolumab is currently approved for the treatment of moderate-to-severe SLE and is recommended as a biologic treatment option for patients with active disease despite standard therapy. Its use is also recommended for selected patients with active cutaneous disease, whereas its role in lupus nephritis remains under investigation [25].

Eculizumab is a monoclonal antibody targeting complement component C5, thereby inhibiting terminal complement activation. Current evidence is limited to case reports and observational studies, primarily involving patients with lupus-associated thrombotic microangiopathy as shown in Table 2. A recent systematic review reported favorable clinical and renal outcomes in most treated patients, with no major safety concerns [77]. Eculizumab is not approved for the treatment of SLE and is used off-label as an experimental therapy, primarily in severe lupus-associated thrombotic microangiopathy. The evidence remains substantially weaker than that supporting approved biologic therapies, as no randomized controlled trials have evaluated its efficacy in SLE. Its potential role is therefore restricted to selected patients with severe complement-mediated complications.

Overall, cytokine- and complement-directed therapies demonstrate markedly different levels of clinical evidence, with established randomized evidence supporting type I interferon blockade, while complement inhibition remains an experimental approach supported mainly by observational data. Further studies are needed to define the role of these therapies in specific SLE manifestations, particularly lupus nephritis. The molecular targets, mechanisms of action, main clinical effects, study designs and phases, safety concerns, current or potential clinical roles, and key references for the reviewed therapies are summarized in Table 2.

CAR-T cell therapy

CAR-T cell therapy, as shown in Figure 1, involves the collection of autologous T cells, their ex vivo genetic modification to express a chimeric antigen receptor (CAR), expansion, and reinfusion into the patient, enabling targeted elimination of cells expressing a specific surface antigen. In SLE, current CAR-T strategies primarily target CD19, aiming to achieve profound depletion of autoreactive B cells that cannot be eliminated by conventional immunosuppressive therapies. The first clinical study evaluating autologous CD19 CAR-T cells in SLE included five patients with severe, refractory disease. Three months after treatment, all patients achieved DORIS remission and complete clinical remission according to the SLEDAI-2K, with scores decreasing from 8–16 at baseline to 0. Treatment was also associated with the disappearance of anti-dsDNA antibodies, normalization of complement C3 and C4 levels, and marked improvement in lupus nephritis, including reduced proteinuria and improved renal function. Following B-cell reconstitution after approximately 110 days, repopulating B cells displayed a predominantly naive phenotype without evidence of autoreactivity [78]. These findings were confirmed in a subsequent study including 15 patients with severe autoimmune diseases, of whom eight had SLE. Each patient with SLE reached DORIS remission and a SLEDAI-2K score of 0 within six months. During a median follow-up of 29 months, no disease relapse was observed, while B-cell reconstitution occurred after approximately 100–120 days without re-emergence of autoreactive B-cell populations [79]. To address persistent autoantibody production by long-lived plasma cells, dual-target BCMA/CD19 CAR-T therapy has also been investigated. In a study involving 13 patients with biopsy-confirmed lupus nephritis, treatment resulted in marked depletion of B cells and plasma cells, with the mean SLEDAI-2K score decreasing from 10.6 to 2.7 after three months. Significant renal improvement was observed, including reductions in proteinuria, increased glomerular filtration rate, and resolution of active urinary sediment. B-cell recovery occurred within two to six months and was characterized predominantly by a naïve phenotype. Cytokine release syndrome was generally mild to moderate, indicating a favorable early safety profile [80]. CAR-T cell therapy remains an experimental approach and is not currently approved for the treatment of SLE. The available evidence is based on small, early-phase clinical studies and uncontrolled patient cohorts rather than randomized controlled trials. Nevertheless, the sustained clinical and serological responses observed in patients with severe, refractory disease are encouraging and suggest that CAR-T therapy may have the potential to induce prolonged drug-free remission. Larger controlled studies and longer-term follow-up are required to establish its efficacy, safety, and appropriate place in the treatment of SLE.

DISCUSSION

The expanding landscape of targeted therapies has substantially broadened therapeutic options for patients with systemic lupus erythematosus (SLE) whose disease remains active despite standard treatment. The diversity of therapeutic targets, including B cells, the BAFF system, type I interferon signalling, CD40-CD40L interactions, plasma cells, and complement, reflects the complex and heterogeneous immunopathogenesis of SLE. However, differences in mechanism of action do not in themselves establish the superiority of one therapeutic approach over another. The clinical value of a targeted therapy depends on the disease phenotype, type and severity of organ involvement, magnitude and durability of efficacy, safety profile, and the maturity of the supporting evidence. The absence of direct head-to-head comparisons between most targeted agents further limits the ability to determine whether one biological pathway should be preferentially targeted over another. Among currently available targeted therapies, belimumab, anifrolumab, and obinutuzumab have the most clearly established clinical roles, although their indications and supporting evidence differ. Belimumab and anifrolumab are supported by multiple randomized trials and have become established options for patients with active extrarenal SLE requiring additional disease control or glucocorticoid-sparing treatment [25,54–56,71,75,76]. In lupus nephritis, belimumab and obinutuzumab have demonstrated efficacy in randomized clinical trials and have been incorporated into current treatment recommendations, although the extent of clinical experience and duration of follow-up differ between these agents [36,37,39,57]. Thus, these therapies currently occupy a different position from investigational agents, as their clinical efficacy is supported not only by individual trials but also by regulatory approval, guideline recommendations, and increasing real-world experience. Nevertheless, their use should remain phenotype-driven rather than based solely on their molecular targets, as the available evidence does not establish superiority of one approved biologic over another across the full spectrum of SLE manifestations. The emerging targeted therapies reviewed in this study have generated promising efficacy signals, but their clinical significance should be interpreted according to the maturity of the available evidence. Some agents, such as dapirolizumab pegol and ianalumab, have progressed to advanced clinical development with randomized evidence supporting their efficacy, whereas others, including litifilimab, daratumumab, nipocalimab, and afimetoran, remain supported by earlier-stage studies or require confirmation in ongoing trials [34,35,42,43,45,48,50,52,60–63]. Importantly, efficacy demonstrated in a phase II study, a selected disease manifestation, or an uncontrolled cohort cannot be considered equivalent to the evidence supporting established therapies. This distinction is particularly relevant for agents targeting specific immune pathways, for which improvements in individual organ domains or pharmacodynamic markers may not consistently translate into robust effects on global disease activity. Further randomized studies, longer follow-up, and comparisons with established biologics are therefore required before these therapies can be assigned a defined place in routine SLE treatment. The experience with rituximab illustrates the complexity of translating biological activity into clinical practice. Despite negative results from major randomized trials, rituximab remains clinically relevant in selected patients with severe or refractory SLE, reflecting evidence from observational studies and accumulated clinical experience rather than established efficacy in randomized trials [29–33]. This contrasts with eculizumab, for which the evidence is substantially more limited and largely restricted to severe complement-mediated complications such as lupus-associated thrombotic microangiopathy [77]. These examples demonstrate that regulatory status and strength of randomized evidence do not always fully determine clinical use, particularly in severe or refractory disease where therapeutic alternatives are limited. At the same time, off-label use should be distinguished from evidence-based standard treatment, and the lower certainty of evidence should be considered when assessing the potential benefits and risks of these approaches. Safety represents an important component of the clinical interpretation of targeted therapies and should be considered alongside efficacy rather than separately. The safety profiles observed in randomized trials have generally supported the use of established biologics, although individual mechanisms may be associated with characteristic risks, particularly infections with B-cell depletion or type I interferon blockade. For emerging therapies, the shorter duration of follow-up and smaller study populations limit the ability to identify uncommon or delayed adverse events. This is particularly relevant for therapies producing profound or sustained immune modulation, including plasma-cell-directed approaches and cellular therapies. Consequently, the apparent tolerability observed in early clinical studies should not be interpreted as evidence of long-term safety equivalent to that available for established biologics. CAR T-cell therapy represents a fundamentally different therapeutic strategy from conventional targeted agents. Rather than modulating a single inflammatory pathway, CAR T-cell therapy aims to achieve profound B-cell depletion and broader immune reconstitution, raising the possibility of prolonged treatment-free disease control in patients with severe refractory SLE. Early clinical studies have produced encouraging results; however, the current evidence remains based predominantly on small, uncontrolled cohorts with limited follow-up. The potential for durable remission therefore needs to be balanced against uncertainties regarding long-term safety, durability of response, patient selection, treatment-related complications, and the feasibility and cost of wider clinical implementation. CAR T-cell therapy should consequently remain an experimental approach for carefully selected patients with severe, treatment-refractory disease until larger prospective studies provide more definitive evidence [78–80]. Several important knowledge gaps remain across the targeted treatment landscape. The absence of reliable predictive biomarkers and head-to-head trials limits the ability to individualize treatment and determine whether newer therapies offer clinically meaningful advantages over established biologics. In addition, the optimal treatment sequence after inadequate response or intolerance to initial targeted therapy remains uncertain, while longer-term data are needed to assess the durability of clinical responses and cumulative safety. These limitations are particularly relevant for emerging therapies, for whom promising early efficacy signals do not yet establish a defined role in routine clinical practice.

Limitations

This review has several limitations. It did not follow a predefined systematic review protocol and did not include a formal assessment of methodological quality or risk of bias. The available evidence was heterogeneous in study design, patient characteristics, disease manifestations, treatment regimens, and clinical endpoints, which limits direct comparisons among therapies. Evidence for several emerging therapies, particularly CAR T cell therapy, is based mainly on early phase trials and small observational studies with limited follow up. Therefore, conclusions regarding their comparative effectiveness, long term safety, and durability remain uncertain.

CONCLUSIONS

Targeted therapy has expanded treatment options for patients with systemic lupus erythematosus who have persistent disease activity, organ involvement, and glucocorticoid dependence despite standard treatment. The main therapeutic strategies include targeting B cells and the BAFF system, the type I interferon signaling pathway, CD40 and CD40L interactions, plasma cells, the complement system, and other components of innate immunity. Differences in mechanisms of action provide a basis for selecting therapy according to the clinical phenotype, but do not in themselves demonstrate the superiority of one approach over another.

Belimumab and anifrolumab have an established role in the treatment of active extrarenal manifestations of systemic lupus erythematosus. The efficacy of belimumab and obinutuzumab in lupus nephritis has been confirmed in clinical trials and reflected in current recommendations, although the duration and extent of the available evidence differ between these agents. Rituximab remains relevant mainly in refractory disease, while its regulatory status and specific role in treatment depend on the indication and jurisdiction. Other targeted agents are at different stages of clinical investigation or are being considered for specific disease manifestations. CAR T cell therapy has shown encouraging results in severe refractory systemic lupus erythematosus, but remains experimental. Thus, the reviewed approaches differ substantially in the maturity of their evidence base, regulatory status, and readiness for clinical use.

Treatment selection should be based on the clinical phenotype, type of organ involvement, demonstrated efficacy, safety profile, regulatory status in the relevant jurisdiction, and maturity of the evidence base. The main knowledge gaps include the absence of reliable predictive biomarkers, direct comparisons between therapies, an established treatment sequence, sufficient data on long term safety and durability of therapeutic effects, and validated criteria for selecting patients for emerging treatments.

DISCLOSURE

Author Contributions

Conceptualization: Dagmara Laufer, Filip Chodań. Methodology: Filip Chodań, Adam Miler, Olga Klimczak. Formal analysis: Filip Chodań, Estera Sośniecka. Investigation and data collection: Olga Klimczak, Dagmara Laufer, Adam Miler, Estera Sośniecka. Writing, original draft preparation: Olga Klimczak, Filip Chodań, Dagmara Laufer, Krystian Domeracki. Writing, review and editing: Dagmara Laufer, Estera Sośniecka, Filip Chodań, Adam Miler. Supervision: Filip Chodań.

All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Funding

This research received no external funding.

Conflict of Interest

The authors declare no conflict of interest.

Use of Artificial Intelligence

Artificial intelligence tools, including ChatGPT and other OpenAI systems, were used for language refinement and structural improvement. All changes made with the assistance of artificial intelligence were reviewed and verified by the authors. The authors take full responsibility for the final content of the manuscript.

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