Targeted therapies in systemic lupus erythematosus: mechanistic insights and clinical evidence from phase II and III trials

1 Introduction

Systemic lupus erythematosus (SLE) is a major autoimmune rheumatic disease which often has a relapsing–remitting course and wide-ranging clinical manifestations, which can still result in substantial morbidity and premature mortality (1–7). The pathogenesis of SLE involves complex immune dysregulation, including autoantibody production and immune complex deposition, with the potential to affect virtually any organ or system (2–7). Persistent uncontrolled disease activity leads to irreversible organ damage and increased burden of comorbidities (2, 8, 9).

Despite therapeutic advances, the management of SLE continues to rely largely on non-specific immunosuppressive therapies, which may be associated with limited long-term efficacy and considerable adverse effects. Although recent progress in understanding the immunopathology of SLE has facilitated the development of targeted biologics and small-molecule agents, persistently active and corticosteroid-dependent SLE remains a major therapeutic challenge (1, 2, 6, 10–16).

In this systematic review, we will summarise targeted therapies currently in phase II and III of clinical development for SLE, highlighting agents with the most promising efficacy and safety profiles.

2 Methods

2.1 Study design and eligibility criteria

We conducted a systematic review of randomised, placebo or standard of care-controlled phase II and phase III clinical trials in SLE patients evaluating novel biological and targeted therapies. Inclusion criteria comprised multicentre, international trials that were either published in peer-reviewed journals or registered in clinical trial databases. Trials assessing biological interventions for cutaneous or, rarely, neuropsychiatric lupus, lupus nephritis and moderate to severe SLE were considered, as defined according to Systemic Lupus Erythematosus Disease Activity Index/ Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI/SLEDAI-2 K) or British Isles Lupus Assessment Group Index/ British Isles Lupus Assessment Group 2004 Index (BILAG/BILAG-2004) scores. Notable Interventions included monoclonal antibodies and fusion proteins targeting key immunological pathways, such as B-cell Activating Factor/ B-lymphocyte Stimulator (BAFF/BLyS), the type I interferon receptor, and other inflammatory mediators. Background therapy was allowed. Both successful and unsuccessful trials were included as the latter provide valuable insights into disease pathophysiology. Exclusion criteria included non-randomised, single-centre, open-label trials; studies not conducted in phase II or III; and trials evaluating non-biologic or non-targeted therapies for SLE.

2.2 Information sources and search strategy

A comprehensive literature search was performed using electronic databases and clinical trial registries (all available data from 2000 until 12th January of 2026), including PubMed, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and the European Union Clinical Trials Register. Searches were conducted without language restrictions. The search strategy combined Medical Subject Headings (MeSH) terms and free-text keywords using Boolean operators, including “systemic lupus erythematosus”, “biologic therapy”, “phase II” and “phase III”.

2.3 Study selection

Records identified through database searches were screened for eligibility based upon predefined inclusion criteria. Titles and abstracts were initially reviewed, followed by full-text assessment of potentially relevant studies. Trials were selected according to study phase (preferably most advanced stage of development), type of intervention, and characteristics of the SLE population.

Study selection and reporting were conducted in accordance with PRISMA guidelines— Figure 1.

3 Results

A total of 90 targeted therapies, including 70 biological Disease-Modifying Anti-Rheumatic Drugs (bDMARDs) and 20 targeted synthetic Disease-Modifying Anti-Rheumatic Drugs (tsDMARDs) were assessed across 770 clinical trials. Candidate agents had reached phase II (n = 67) and phase III (n = 23) of clinical development. Trial status at the time of this review was classified as completed (n = 45), active and recruiting (n = 9), active but not recruiting (n = 7), active not yet recruiting (n = 5), terminated (n = 23) and withdrawn (n = 1)— Tables 1, 2.

Table 1. bDMARDs.

Table 2. tsDMARDS.

Based on this systematic review, therapeutic strategies currently under clinical development for SLE were categorised according to their primary target-to-treat approach: intracellular signalling pathways (n = 22), inflammatory cytokines, chemokines or their receptors (n = 15), B-cells (n = 14), B/T cells co-stimulatory molecules (n = 10), Toll-like receptors (n = 6), interferons (n = 5), plasma cells (n = 4), complement pathway (n = 3), plasmacytoid dendritic cells (n = 3), and other immune targets (n = 11).

For the purpose of this review, drugs are classified according to their primary therapeutic target or dominant mechanism of action, despite known diverse pleiotropic effects.

3.1 Drugs targeting B-cells

Multiple abnormalities have been identified within B-cell populations in SLE, highlighting the notion that B-cells play a central role in disease pathogenesis. As a consequence of the generalized B-cell hyperactivity characteristic of active SLE, patients have increased numbers of transitional and memory B-cells, as well as plasma cells, alongside a reduction in naïve B-cells. Several therapeutic approaches have been developed to modulate B-cell-mediated inflammatory responses in patients with SLE. These approaches include B-cell depletion, inhibition of B-cell-activating factor (anti-BAFF) therapy, targeting of plasma cells, interference with B-cell co-stimulation and activation pathways, and antigen-based therapies. These are designed to affect B-cells, selectively, with pathogenic specificities (17).

3.1.1 B-cell depletion therapy

3.1.1.1 Rituximab

Is a chimeric human/murine IgG1 monoclonal antibody targeting CD20. It can initiate an immune response that mediates B cell lysis (12, 18, 19). Two randomised, double-blind, placebo-controlled and multicentric clinical trials failed to show a beneficial effect of rituximab in the clinical response at week 24 (LUNAR and EXPLORER trials). The reasons why these trials failed have been much discussed but may well have included the substantial amount of corticosteroids allowed in the ‘background’ medications (20). Nevertheless, there has been a general acceptance that B cell depletion is effective in with SLE and its effectiveness correlates with the degree and duration of B cell depletion (21). It is notable that European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) recommend the use of rituximab as a second-line or rescue option in patients with lupus nephritis (LN). Recently, there has been interest in higher-affinity and higher-activity anti-CD20 antibodies (22–26).

3.1.1.2 Obinutuzumab

A humanized type II anti-CD20 monoclonal antibody, has a more effective B cell deplete than rituximab with a more potent cytotoxic effect, probably because of more efficient engagement of Fcy receptors on NK cells and neutrophils (27). The phase II NOBILITY trial aimed to evaluate the safety and efficacy of Obinutuzumab in patients with LN showing that a significantly greater proportion of patients in the obinutuzumab group achieved CRR than in the placebo group at week 52 (35% in the obinutuzumab group vs. 23% in the placebo with p = 0.115) and week 104 (41% in the obinutuzumab group vs. 23% in the placebo group with p = 0.026) (28). A post-hoc analysis of the phase II NOBILITY trial concluded that obinutuzumab treatment resulted in superior preservation of kidney function and prevention of lupus nephritis flares (29). The phase III REGENCY trial concluded that in adults with biopsy-proven active LN the addition of obinutuzumab to standard therapy led to 46.4% of patients complete renal response at week 76 than standard therapy alone (33.1%, p = 0.02) (30, 31). Obinutuzumab has been approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2025 and National Institute for Health and Care Excellence (NICE) in 2026 (32–34).

The BELONG trial evaluating Ocrelizumab, an IgG1κ humanized monoclonal antibody targeting CD20, in patients with LN (class III or IV) was halted due to an imbalance of serious and opportunistic infections in the treated patients (vs. placebo arm) (35, 36).

3.1.2 Antagonism of B-cell-activating factor (anti-BAFF) therapy

B-cell-activating factor (BAFF) is a type II transmembrane protein expressed on the surface of various immune cells, mainly those involved in innate immunity. It is a tumour necrosis factor (TNF) family ligand and is a key factor in the survival of mature B-cells. SLE patients with elevated BAFF levels are more likely to develop organ damage as the disease progresses (37–39). Identification of BAFF's key role as a cytokine involved in B-cell survival, activation, and differentiation in SLE pathogenesis has led to the development of several anti-BAFF agents (37, 40, 41).

3.1.2.1 Belimumab

Is a human IgG1λ monoclonal antibody that binds to and antagonises the biological activity of soluble BAFF by blocking its interaction with BAFF receptors (BAFF-R, TACI and BCMA) (42, 43). Two phase III trials, BLISS-52 and BLISS-76, studied the efficacy of intravenous belimumab in active SLE [excluding patients with severe active LN and central nervous system (CNS) manifestations] (44, 45). A statistically significant improvement of disease activity compared with placebo was observed (46). Furthermore, the BLISS-LN trial showed that belimumab added to standard therapy improved renal outcomes in patients with lupus nephritis, with primary efficacy renal response at week 104 achieved in 43% of patients receiving belimumab compared with 32% receiving placebo (p = 0.03) (47).

Belimumab was the first biological agent approved for the treatment of patients with active, non-renal autoantibody positive SLE refractory to standard therapy (FDA approval in 2011 and EMA approval in 2011) (48).

3.1.2.2 Blisibimod

Is a monoclonal antibody targeting BAFF. It has a unique structure consisting of four high-affinity BAFF-binding domains fused to an IgG1-Fc fragment, enabling binding both soluble and membrane-bound forms of BAFF (49–51). Merrill et al, recently reported however, that a phase III clinical trial failed to meet its primary endpoint Systemic Lupus Erythematosus Responder Index-6 (SRI-6) although statistically significant steroid-sparing effects and reductions in proteinuria were achieved (52).

3.1.2.3 Tabalumab

Is a human IgG4 monoclonal antibody that binds to both soluble and membrane-bound forms of BAFF (43). The phase III ILLUMINATE-2 clinical trial evaluated the efficacy, safety and tolerability of two different doses in patients with active SLE. This represented the first time that a BAFF inhibitor achieved efficacy in a primary endpoint. Regarding adverse events, depression and suicidal ideation, although infrequent, were more commonly reported in the tabalumab group compared with placebo (53, 54). Another negative phase III trial (ILLUMINATE-1) using tabalumab was reported (55). This trial had the unfortunate stipulation that any alteration in steroid dose would lead to an individual's participation being terminated. Remarkably this included patients who reduced their steroids, implying the therapy was working. Regrettably Eli Lilly, the manufacturers, insisted on merging the results of the two trials and decided not to proceed with any further studies.

3.1.2.4 Lanalumab

Is a B-cell-depleting monoclonal antibody targeting BAFF receptor (BAFF-R). A phase II, multicentre, double-blind, randomised, placebo-controlled clinical trial evaluated its efficacy and safety in patients with SLE. Potent B-cell depletion was consistently achieved in ianalumab-treated SLE patients and it was well tolerated. The study met its primary endpoint, an SRI-4 response with sustained steroid reduction, along with substantial treatment benefits on overall SRI-4 response, lupus low disease activity state (LLDAS), reductions in moderate and severe flares, and improvements in laboratory markers of autoimmune activity (56, 57). These positive phase II results encourage ongoing phase III development of ianalumab in lupus, based on its dual mechanisms of action (SIRIUS-SLE 1, SIRIUS-SLE 2, and SIRIUS-LN) (58–60).

3.1.2.5 Atacicept

Is a human recombinant soluble fusion protein comprising the extracellular ligand-binding domain of TACI fused to a modified Fc portion of human IgG1. It targets both soluble and membrane-bound forms of BAFF and APRIL. By neutralising BLyS, APRIL, and BLyS-APRIL heterodimers, atacicept inhibits B-cell survival and differentiation (61, 62).

The APRIL-SLE trial evaluated the efficacy and safety of atacicept vs. placebo in preventing new flares in patients with SLE, to identify the optimal therapeutic dose, and to assess the effect of atacicept on mechanistic biomarkers and their correlation to disease activity and progression. The primary endpoint- a reduction in the proportion of patients experiencing a new SLE flare- was not met in the 75 mg atacicept arm compared with placebo. Although serological results in both this and especially in the higher dose arm (150 mg) were promising, unwarranted concerns regarding potential infection risk arose following two deaths in this group led to the higher dose arm being terminated prematurely (63). Notably later trials with atacicept reported no deaths (64, 65).

3.1.2.6 Telitacicept

Is structurally very similar to atacicept. It too inhibits B-cell proliferation and maturation, suppresses immune responses, and may alleviate autoimmune symptoms (66).

A phase III, multicentre, randomised, placebo-controlled, double-blinded study was done in China aimed to evaluate the efficacy and safety of Telitacicept combined with SOC treatment in patients with moderate to severe SLE. This study met its primary endpoint and at week 52, a response on the modified SRI-4 had occurred in 67.1% of the patients receiving telitacicept and in 32.7% of those receiving placebo (p < 0.001) (67, 68). Telitacicept was approved in China in 2021 but is still pending approval by the FDA, EMA and NICE (68, 69).

Nevertheless, showing promising results in earlier studies as a potential therapy for SLE, the withdrawal of REMESLE-1 and REMESLE-2 trials (phase III, multicentre, randomised, placebo-controlled, double-blinded studies), due to a sponsor business decision, indicates that further studies are required to confirm its therapeutic potential in non-chinese population (70, 71).

3.1.2.7 Rozibafusp alfa (AMG 570)

Is a dual inhibitor targeting both inducible T-cell co-stimulator ligand (ICOSL) and BAFF (72). A phase II, multicentre, randomised, double-blind, placebo-controlled study evaluated the efficacy and safety of rozibafusp alfa in patients with active SLE who had an inadequate response to standard-of-care (SOC) therapy. Due to high placebo response rates, this agent did not demonstrate substantial additional benefit over SOC for the treatment of SLE (73).

3.1.3 B-cell modulation via surface receptor targeting

B-cell modulation via surface receptor targeting constitutes an alternative therapeutic approach focused on regulating B-cell activity rather inducing cell depletion. By engaging specific surface receptors involved in B-cell activation and signalling, these approaches aim to reduce B-cell activation, proliferation and autoantibody production, thereby limiting pathogenic B-cell responses while preserving the overall B-cell compartment (74, 75).

3.1.3.1 Epratuzumab

Is an IgG1κ humanized monoclonal antibody targeting CD22, a cell-surface glycoprotein expressed on mature B-cells and various malignant B-cells (76).

The EMBODY 1 and 2 trials studied the clinical efficacy of epratuzumab in patients with SLE. In individuals with moderate to severely active disease, treatment with epratuzumab in addition to standard therapy did not result in improvements in response rates compared with placebo plus standard therapy (77).

3.1.3.2 Obexelimab

Is a humanized monoclonal antibody that binds both to CD19 surface antigen and FcγRIIb, thereby inhibiting B-cells, plasmablasts, and CD19-positive plasma cells without depleting them (78).

A multicentre, randomised, double-blind, placebo-controlled phase II trial sought to determine the efficacy of obexelimab in maintaining SLE remission achieved by a brief course of disease-suppressing steroid therapy. Immunosuppressive medications (excluding antimalarials and low-dose prednisolone) were withdrawn, and patients with non-life or organ-threatening SLE received intramuscular high-dose methylprednisolone, which induces clinical improvement. Although the primary endpoint was not met, secondary analyses demonstrated that the time to loss of improvement (LOI) was significantly increased in obexelimab-treated patients. Further analysis of patient subgroups defined by baseline gene expression patterns indicated the existence of a responsive subpopulation (79).

3.1.3.3 PRV-3279

Is a humanized bispecific dual-affinity re-targeting (DART) molecule targeting the B-cell surface proteins CD32B and CD79B. Simultaneous engagement of these receptors inhibits B-cell function suppressing autoantibody production, thereby regulating B-cells without causing depletion (80).

The PREVAIL-2 study was designed to assess the safety and potential efficacy of PRV-3279 in flare prevention for SLE patients with active disease after improvement induced by corticosteroid treatment. The study was terminated for strategic reasons by the sponsor (81).

Collectively, these agents illustrate an interesting novel approach in SLE therapy, focusing on functional modulation of B-cells rather than outright depletion, which may reduce the risk of infection while selectively targeting pathogenic B-cell subsets.

3.1.4 B-cell tolerogens

Loss of immune tolerance of self-antigens is considered a key pathogenic mechanism in autoimmune diseases. Therapeutic approaches aimed at restoring immune tolerance have been explored as potential adjuvant treatments in SLE. One example is the use of B-cell tolerogens—synthetic molecules designed to bind and cross-link autoantigen-specific B-cell receptors, thereby promoting B-cell inactivation or depletion (82–86).

3.1.4.1 Abetimus sodium (LJP-394)

Is a synthetic tolerogen composed of four identical strands of double-stranded DNA covalently linked to a non-immunogenic carrier platform. It was developed to target anti-dsDNA B-cell receptors, potentially leading to B-cell inactivation and limiting both proliferation and autoantibody production. In addition, abetimus sodium binds soluble anti-dsDNA antibodies, forming small immune complexes that are removed from circulation without activating the complement system (87).

The ASPEN study, which aimed to evaluate whether abetimus sodium could delay the time to renal flare in SLE patients with a history of LN, was halted following an interim efficacy analysis that indicated continuation of the trial would be futile (88).

Overall, these findings highlight both the central role of B-cell dysregulation in SLE pathogenesis and the challenges of translating mechanistic rationale into consistent clinical benefit.

Beyond direct targeting of B-cell survival and function, modulation of B/T cell co-stimulatory pathways has emerged as a potential alternative strategy to dampen autoreactive immune response.

3.2 Drugs targeting B/T cells co-stimulation

Activation of adaptive immune responses requires antigen recognition through the T-cell receptor or B-cell receptor and the delivery of co-stimulatory signals that regulate lymphocyte activation, proliferation, differentiation, and survival. In SLE, dysregulation of B/T cell co-stimulatory pathways contributes to the breakdown of immune tolerance, sustained autoreactive lymphocyte activation, and amplification of pathogenic autoantibody responses. Enhanced expression of co-stimulatory molecules and aberrant immune synapse formation have invariably been observed in patients with active disease (89, 90).

Therapeutic strategies targeting B/T cell co-stimulation aim to selectively attenuate pathological immune activation while preserving basal immune competence. These approaches interfere with key receptor-ligand interactions involved in immune synapse signalling, including the CD40-CD40L and CD28-CD80/CD86 pathways, as well as emerging dual or multi-pathway co-stimulatory checkpoints. By modulating lymphocyte cross-talk rather than inducing broad immune cell depletion, co-stimulation blockade represents a rationale strategy to dampen autoreactive immune responses while potentially reducing infection risk (91, 92).

The following sections review pharmacological agents targeting classical and non-classical B/T cell co-stimulatory pathways, emphasising their mechanism of action, clinical development, and therapeutic implications in SLE.

3.2.1 CD40-CD40L pathway inhibition

3.2.1.1 Dapirolizumab pegol

Is a polyethylene glycol-conjugated antigen-binding (Fab’) fragment that targets CD154 (CD40 ligand). Its original structure with an intact Fc portion structure had the potential for Fc-mediated platelet activation and aggregation. Safety concerns about this led to the discontinuation of earlier trials investigating anti-human CD154 IgG antibodies in SLE (93).

The PHOENYCS GO trial, a multicentre, phase III, randomised, double-blind, placebo-controlled study, evaluated dapirolizumab pegol as an add-on therapy to SOC treatment in patients with moderate to severe SLE. Treatment with dapirolizumab pegol resulted in significant improvement in disease activity and enabled corticosteroid tapering. About 57.2% of patients receiving dapirolizumab pegol and SOC treatment vs. 39.3% receiving placebo and SOC treatment achieved ≥ 50% improvement in CLASI-A score at week 48 (nominal p = 0.0022). Additionally, 65.9% of all patients receiving dapirolizumab pegol and 50.5% of all patients receiving placebo and SOC treatment achieved ≥ 50% decrease in tender/swollen joint counts (nominal p = 0.0089). Patients receiving dapirolizumab pegol plus SOC achieved a British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response compared with those receiving placebo plus SOC. Overall dapirolizumab pegol was generally well tolerated (94). An additional phase III study, PHOENYCS FLY, is currently active and recruiting, aiming to confirm and further characterise the efficacy and safety signals observed in the PHOENYCS GO trial (95).

3.2.1.2 Toralizumab (IDEC-131)

Is a humanized monoclonal antibody designed to target CD154 (CD40 ligand), with a safety profile comparable to that of dapirolizumab pegol (96).

A multicentre, phase II, randomised, double-blind, placebo-controlled study evaluated the safety and efficacy of toralizumab in patients with active SLE. Overall, toralizumab was safe and well tolerated; however, no significant efficacy compared with placebo was demonstrated. Statistically significant improvements from baseline were observed across all treatment arms, including the placebo group (97).

3.2.1.3 Dazodalibep (VIB4920/MEDI4920)

Is a novel non-antibody fusion protein that antagonises CD40 ligand (CD40L), thereby disrupting co-stimulatory signalling between T-cells, B-cells, and APCs. Through inhibition of the CD40-CD40L interaction, dazodalibep has the potential to suppress broadly pathogenic cellular and humoral immune responses that drive autoimmunity in SLE (98).

The VIBRANT trial is a multicentre, phase II, randomised, double-blind, placebo-controlled study evaluating the efficacy of dazodalibep in combination with mycophenolate mofetil and prednisolone in achieving renal response in patients with active LN. The study is currently active and recruiting (99).

3.2.1.4 BI-655064

Is a humanised monoclonal antibody targeting CD40. Its fragment crystallisable (Fc) region contains two-point mutations that disrupt Fc-mediated effector functions, including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and platelet activation. By selectively binding to CD40, BI-655064 blocks the CD40-CD40L interaction and thereby inhibits downstream co-stimulatory signalling (100).

A multicentre, phase II, randomised, double-blind, placebo-controlled study evaluated the long-term efficacy and safety of different doses of BI 655064 compared with placebo as add-on therapy to SOC during maintenance therapy for LN. The trial did not demonstrate a dose-response relationship for the primary endpoint of complete renal response. However, post-hoc analyses suggested a potential therapeutic benefit of BI 655064 at the 180-mg dose in patients with active LN (101).

3.2.1.5 Iscalimab (CFZ533)

Is also a humanised monoclonal antibody targeting CD40, with the same Fc-silent profile as BI-655064 (92).

A multicentre, phase II, randomised, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of iscalimab in patients with moderately active LN. The study met its primary efficacy endpoint [ratio from baseline in urinary protein-to-creatinine ratio (UPCR) at week 24] with iscalimab demonstrating a significant relative improvement in proteinuria from baseline at week 24 compared with placebo in patients with active LN. Overall, iscalimab was clinically effective and generally well tolerated, although some severe infections were reported in patients with comorbidites who were receiving multiple concomitant immunosuppressive therapies (102).

3.2.2 CD28-CD80/CD86 pathway modulation

3.2.2.1 Lulizumab pegol

Is a polyethylene glycol-conjugated anti-CD28 domain antibody that inhibits T-cell activation by blocking CD28-mediated co-stimulatory signalling through equivalent antagonism of CD80 and CD86 (103).

A multicentre, phase II, randomised, double-blind, placebo-controlled study evaluated the safety and efficacy of lulizumab pegol in the treatment of SLE. No significant differences in achieving the primary or secondary endpoint at week 24 (BICLA response rate) were observed between lulizumab pegol and placebo despite evidence of pharmacodynamic target engagement. Lulizumab pegol had a favourable safety profile (104).

3.2.2.2 Abatacept

Is a fusion protein comprising the extracellular domain of cytotoxic T-lymphocyte-associated protein (CTLA)-4 linked to a modified Fc portion of human IgG1. By binding CD80 and CD86 on antigen-presenting cells (APCs) with higher affinity than CD28, abatacept inhibits T-cell co-stimulation without activating the complement pathway, leading to diminution of downstream inflammatory responses (18).

Unfortunately although theoretically interesting a multicentre, phase II, randomised, double-blind, placebo-controlled study evaluating subcutaneous abatacept (125 mg/weekly) in patients with SLE and inflammatory polyarthritis failed to demonstrate significant clinical efficacy compared to placebo. Although musculoskeletal involvement was a key disease domain, the primary endpoint was overall clinical response according to BICLA, rather than isolated reduction in joint counts (105).

In a separate study with similar design, the addition of abatacept to background therapy with mycophenolate mofetil and corticosteroids in patients with active LN did not improve clinical outcomes. This trial was terminated early due to failure to meet the primary efficacy endpoint during the short-term evaluation period (106).

3.2.3 Dual or multi-pathway co-stimulation blockade

3.2.3.1 Acazicolcept (ALPN-101)

Is an Fc fusion protein of a human variant of the ICOSL domain, designed to inhibit simultaneously the CD28 and ICOS co-stimulatory pathways. CD28 and ICOS play nonredundant roles in T-cell activation and differentiation, and concurrent blockade of the pathways has the potential to attenuate autoimmune responses more effectively, than a single-pathway inhibition. In SLE, dysregulated T and B-cell activation is a hallmark of disease pathogenesis, and transcriptional analyses have demonstrated upregulation of CD28 and ICOS/ICOSL related genes. Notably, therapeutic strategies targeting individual co-stimulatory pathways have shown limited clinical efficacy in SLE and related autoimmune diseases, providing a rationale for dual-pathway blockade (107).

The SYNERGY trial evaluated the safety, tolerability, efficacy, immunogenicity, pharmacokinetics, and pharmacodynamics of acazicolcept in adults with moderate to severe active SLE. Results from this study suggest that simultaneous inhibition of the ICOS and CD28 pathways may lead to clinically meaningful improvements in lupus-related inflammation and autoimmunity, with signals of activity superior to those observed agents targeting a single co-stimulatory pathway. Nevertheless, although the trial has been completed, its full results are pending publication and detailed peer-reviewed discussion (108, 109).

3.2.4 Other co-stimulatory or immune synapse-targeting approaches

3.2.4.1 SM101

Is a human, soluble, non-glycosylated form of the inhibitory Fc gamma receptor IIB (FcγRIIB). It binds to the Fc portion of immune complexes, thus preventing their interaction with cell-surface Fcγ receptors and altering downstream inflammatory signalling. By sequestering autoantibody-autoantigen immune complexes, SM101 functions as an immunomodulator which can attenuate immune complex-mediated inflammation in SLE (110, 111).

The SMILE trial reported encouraging results, suggesting that SM101 warrants further clinical investigation as a potential therapy for patients with SLE, including those with nephritis (112).

3.2.4.2 Venanprubart (LY3361237)

Is an agonistic monoclonal antibody targeting B and T lymphocyte attenuator (BTLA), an inhibitory immune checkpoint involved in the regulation of lymphocyte activation. Dysregulation of the BTLA-herpesvirus entry mediator (HVEM) signalling network has been implicated in SLE pathogenesis, with reduced HVEM expression reported in patients (113). Furthermore correlations have been observed between impaired BTLA/HVEM signalling and biomarkers associated with disease activity, flares, and severity. By acting as a BTLA agonist and functionally mimicking HVEM engagement, venanprubart might be able to restore inhibitory signalling in patients with reduced HVEM expression, potentially serving as a replacement strategy for defective co-inhibitory pathways in SLE (113–115).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial studied the efficacy and safety of venanprubart in patients with moderate to severe active SLE. Unfortunately, venanprubart did not demonstrate superiority over placebo in achieving remission of cutaneous and/or articular manifestations. Nevertheless, the treatment was generally safe and well tolerated. The trial was terminated early following an interim analysis due to lack of efficacy (113, 116, 117).

Nevertheless co-stimulation blockade is a mechanistically attractive therapeutic strategy which may yet prove useful in SLE.

3.3 Drugs targeting plasma cells

Plasma cells are the main source of autoantibodies in SLE and play a central role in disease pathogenesis. Unlike naïve or memory B-cells, they are mostly resistant to conventional B-cell-depleting therapies, as they are thought to persist in protected niches in the bone marrow and inflamed tissues (57).

Targeting plasma cells directly aims to reduce pathogenic autoantibody production, reducing disease activity and limiting tissue damage. Current strategies include monoclonal antibodies against plasma cell-specific markers, proteasome inhibitors, and fusion proteins that disrupt survival signals (118).

3.3.1 Cereblon modulators (CELMoDs) and immunomodulatory agents

3.3.1.1 Iberdomide (CC-220)

Is a cereblon modulator that promotes degradation of the transcription factors Ikaros and Aiolos. These are key regulators of B-cell and plasma-cell development and autoimmunity. By modulating these factors, iberdomide reduces pathogenic plasma cell activity and autoantibody production (119).

A phase II, multicentre, randomised, double-blind, placebo-controlled study in patients with active SLE showed a higher proportion of SRI-4 responders in the iberdomide group compared with placebo. In the 0.45 mg iberdomide arm, 54% of patients achieved an SRI-4 response vs. 35% in the placebo arm (p = 1.00). Larger and longer trials are needed to confirm its efficacy and safety of in this population (120).

3.3.1.2 KPG-818

Is also a cereblon modulator that promotes rapid and effective degradation of Aiolos and Ikaros (121).

A phase II, multicentre, randomised, double-blind, placebo-controlled study in patients with mild to moderate SLE provided proof-of-concept evidence of a favourable benefit/risk profile. KPG-818 was well tolerated, but additional trials are needed in SLE (121, 122).

3.3.2 Direct plasma cell-depleting monoclonal antibodies

3.3.2.1 CM313

Is a humanized monoclonal antibody targeting CD38, a surface molecule highly expressed on plasma cells. It induces potent cell killing of these cells through Fc-receptor-dependent mechanisms, leading to depletion of APCs (123).

A phase II, multicentre, randomised, double-blind, placebo-controlled study in patients with SLE evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of CM313. The treatment was generally well tolerated and demonstrated encouraging pharmacodynamic effects and signals of clinical efficacy, but requires phase III trials to be performed (124).

3.3.3 Proteasome inhibition and plasma cell survival disruption

3.3.3.1 Zetomipzomib (KZR-616)

Is a selective inhibitor of the immunoproteasome currently under clinical investigation for autoimmune diseases. By targeting the immunoproteasome, zetomipzomib disrupts the degradation of intracellular proteins that regulate immune cell activation and survival. This degradation results in broad immunomodulatory effects, notably suppression of pro-inflammatory cytokine production, inhibition of T-helper cell polarization and reduction in the formation and survival of both short- and long-lived plasma cells, which are central to autoantibody production in SLE. In addition zetomipzomib downregulates the type I interferon pathway, a key driver of SLE pathogenesis (125).

The PALIZADE trial was designed to evaluate the efficacy and safety of zetomipzomib vs. placebo in achieving renal response in patients with active LN. However, the study was terminated early due to a sponsor decision on strategic business reasons following the temporary halt of the study per the Independent Data Monitoring Committee's (IDMC's) recommendation (126).

3.4 Drugs targeting plasmacytoid dendritic cells (pDC)

Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE through their capacity to produce large amounts of type I interferons in response to nucleic acid-containing immune complexes. Sustained activation of pDCs leads to immune dysregulation, amplification of autoreactive T- and B- cell responses, and perpetuation of systemic inflammation. Therapeutic strategies targeting pDCs aim either to inhibit pDC activation directly through receptor-specific blockade or to modulate intracellular signalling pathways that suppress interferon production (127).

3.4.1 BDCA2-directed pDC-targeting strategies

3.4.1.1 Litifilimab (BIIB059)

Is a humanised monoclonal antibody targeting blood dendritic cell antigen 2 (BDCA2), a receptor found exclusively on pDCs. Binding of litifilimab to BDCA2 induces rapid receptor internalisation, resulting in suppression of type I interferon production and downstream inflammatory mediators (128).

The LILAC trial reviewed the efficacy of litifilimab in reducing disease activity in SLE patients with joint manifestations, as well as in patients with active cutaneous lupus erythematosus (CLE)- including subacute cutaneous lupus erythematosus or chronic CLE, such as discoid lupus erythematosus—with or without systemic involvement. Secondary objectives included assessment of additional efficacy endpoints, pharmacokinetics, safety and tolerability. The trial demonstrated that litifilimab was superior to placebo in reducing cutaneous disease activity, as measured by validated instruments, most notably the Cutaneous Lupus erythematosus Disease Area and Severity Index (CLASI). Litifilimab also significantly reduced the number of swollen or tender joints in patients with SLE. Larger and longer-term studies are required to determine the efficacy and safety of litifilimab in the treatment of cutaneous and SLE (128).

A phase III study, TOPAZ-1, is currently active though not recruiting. It is designed to evaluate the efficacy and safety of litifilimab compared with placebo, in combination with SOC, over one year of treatment in patients with active SLE (129).

3.4.1.2 DB-2304

Is a novel anti-BDCA2-based antibody-drug conjugate designed to target pDCs selectively. Binding of DB-2304 to BDCA2 induces rapid receptor internalisation, enabling intracellular delivery of a glucocorticoid receptor agonist payload. This results in potent suppression of type I interferon production and downstream inflammatory mediators (130).

A multicentre, phase II, randomised, double-blind, placebo-controlled study is currently recruiting to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of DB-2304 in healthy adult participants and in patients with SLE or CLE (131).

3.4.2 pDC functional modulation and interferon suppression

3.4.2.1 VIB7734

Is a human monoclonal antibody that targets immunoglobulin-like transcript 7 (ILT7), a receptor selectively expressed on pDCs. Binding of VIB7734 to ILT7 induce antibody-dependent cellular cytotoxicity, leading to depletion of pDCs and consequent suppression of type I interferon production and downstream inflammatory mediators (132).

The RECAST SLE trial, evaluated the efficacy and safety of VIB7734 in patients with moderate to severe active SLE. No statiscally significant difference vs. placebo or the primary endpoint, was noted largely driven by a high placebo response rate—40.0% (vs. 42.8% and 39.9% in the VIB7734 arm at week 4 and 12, respectively). However, a greater proportion of patients receiving VIB7734 every four weeks achieved lupus low disease activity rate (LLDAS) at week 48 compared with placebo. Positive trends favouring VIB7734 were also observed across several secondary and exploratory endpoints, suggesting a potential treatment effect. VIB7734 was generally well tolerated (133).

3.5 Drugs targeting interferons

Type I interferons play a central role in SLE pathogenesis and are predominantly produced by pDCs. Although mechanistically linked, pDC-targeting therapies and interferon-directed agents were analysed separately to reflect their distinct therapeutic interception points (134).

3.5.1 Type I interferon receptor blockade

3.5.1.1 Anifrolumab

Is a humanised monoclonal antibody targeting the type I interferon receptor subunit 1 (IFNR1). The binding of anifrolumab to IFNAR1 induces receptor internalization, thereby preventing engagement by type I interferons- including IFN-α, IFN-β, and IFN-ω—this in effect inhibits downstream interferon-mediated signalling (135).

The MUSE, TULIP-1 and TULIP-2 trials evaluated the efficacy and safety of anifrolumab compared with placebo in patients with moderate to severe SLE (135–137). The TULIP-1 trial used SRI-4 as a primary endpoint and this was not met but, BICLA as a secondary endpoint was met. In the TULIP-2 study, using BICLA as an endpoint, treatment with anifrolumab resulted in a higher response rate at week 52, (47.8% of patients in the anifrolumab arm vs. 31.5% in the placebo arm- p = 0.001) together with a sustained corticosteroid dose reduction and clinically meaningful improvement in cutaneous disease activity, as reflected by ≥50% reduction in CLASI scores (135).

Based on these positive clinical outcomes, anifrolumab received regulatory approval as an adjunct of SOC of SLE, with approval by the FDA (in full) in 2021 and by the EMA in 2022 (138, 139). Still do the date of the publication of this article, NICE approval of anifrolumab is pending the evidence submission by AstraZeneca (140).

3.5.2 Direct neutralisation of interferon-α

3.5.2.1 Sifalimumab (MEDI 545)

Is a monoclonal antibody that targets the majority of IFN-α subtypes (141).

A multicentre, phase II, randomised, double-blind, placebo-controlled study assessing the efficacy and safety of sifalimumab in patients with moderate to severe SLE has been completed. The study demonstrated that sifalimumab is a promising therapeutic option for SLE, with consistent improvements observed in many clinical endpoints, including both global and organ-specific measures of disease activity (142).

3.5.2.2 Rontalizumab

Is a humanized antibody that blocks all known subtypes of IFN-α (141). The ROSE trial evaluated the safety and efficacy of rontalizumab in patients with moderate to severe SLE. The study failed to meet its primary and secondary endpoints in the overall study population or in patients with high interferon metric (ISM) scores. However, exploratory analyses suggested that rontalizumab treatment was associated with improvement in clinical disease activity, reduced flares rates, and decreased corticosteroid use in patients with SLE with low ISM scores. Rontalizumab was generally well tolerated, with no increase in serious adverse events. Despite these findings, further clinical development of rontalizumab was discontinued (143).

3.5.3 Interferon-targeted immunisation strategies

3.5.3.1 IFN-Kinoid

Is an immunotherapeutic vaccine composed of inactivated recombinant human interferon-α2b (IFN-α2b) conjugated to a T-helper carrier protein keyhole limpet hemocyanin and was designed to induce anti-IFN-α antibodies through active immunisation (144).

A multicentre, phase II, randomised, double-blind, placebo-controlled study evaluated the efficacy and safety of the IFN-Kinoid in patients with active SLE despite SOC. Although the clinical coprimary endpoint, that is, the modified BICLA response at week 36, was not met, IFN-Kinoid induced neutralising anti-IFN-α2b antibodies and significantly reduced the IFN gene signature. At week 36, the IFN-Kinoid arm demonstrated a mean 31% reduction from baseline in the IFN gene signature, an effect not observed in the placebo group (p < 0.0001). The treatment was generally well tolerated, with an acceptable safety profile. Moreover, clinical secondary endpoints were achieved in the IFN-Kinoid group, including attainment of LLDAS and corticosteroid tapering, encouraging evaluation in phase III trials. However, this trial was terminated prematurely due to reorganization proceedings of the sponsor (145, 146).

3.5.4 Alternative interferon pathway inhibitors

3.5.4.1 PF-06823859

Is a fully human monoclonal antibody that targets and neutralises interferon-β (IFN-β). Its mechanism of action is SLE involves binding to circulating IFN-β, thereby preventing IFN-β from interacting with its receptor (IFNAR) on immune cells. By neutralizing IFN-β, PF-06823859 aims to reduce the type I interferon gene signature and associated immune dysregulation seen in most SLE patients. This approach is conceptually similar to other type I interferon-targeting therapies, such as anti-IFN-α antibodies and anti-IFNAR antibodies, such as anifrolumab, which have demonstrated clinical efficacy in SLE by suppressing interferon-driven inflammation. However, PF-06823859 is unique in its specificity for IFN-β, rather than pan-type I interferon blockade (147).

A multicentre, phase II, randomised, double-blind, placebo-controlled study evaluated the efficacy, safety and pharmacokinetics of PF-06823859 in patients with CLE or SLE with active skin involvement. The study was prematurely terminated due to an internal business decision, which was not related to safety concerns, lack of clinical efficacy, or requests from regulatory authorities (148).

3.6 Drugs targeting toll-like receptors

Toll-like receptors (TLRs) play a pivotal role in the innate immune dysregulation underlying SLE. Endosomal TLRs, particularly TLR7 and TLR9, recognize self-nucleic acids and drive the activation of pDCs and B-cells, leading to excessive type I IFN production and autoantibody generation. This aberrant signalling contributes to chronic inflammation and disease activity in SLE. Given their upstream position in the interferon pathways, TLRs are meaningful therapeutic targets in SLE. Pharmacological inhibition of TLRs signalling aims to reduce innate immune activation and downstream inflammatory responses, providing a potential strategy for disease modification (149, 150).

3.6.1 TLR7 and TLR9 antagonists

3.6.1.1 DS-7011a

Is a monoclonal antibody targeting Toll-like receptor 7 (TLR7), an endosomal pattern-recognition receptor that senses single-stranded RNA and promotes the activation of pDCs, B-cells, and other myeloid cells. TLR7 activation encourages the production of type I interferons and pro-inflammatory cytokines, contributing to immune dysregulation in SLE. DS-7011a binds selectively to TLR7, thereby inhibiting receptor activation and downstream signalling. This results in suppression of TLR7-mediated cytokine production, including interleukin-6, and attenuation of interferon-driven immune responses (151).

A multicentre, phase II, randomised, double-blind, placebo-controlled study has evaluated the safety, pharmacokinetics, and proof of biological activity of DS-7011a in patients with SLE. The study has been completed, and results are pending publication (152).

3.6.1.2 E6742

Is a small-molecule antagonist that selectively binds to the interface of TLR7 and Toll-like receptor 8 (TLR8), blocking their activation. In patients with SLE, TLR7 and TLR8 sense self-RNA and trigger pathogenic immune responses, including type I interferon and pro-inflammatory cytokines production by pDCs and B-cells. By inhibiting TLR7/8 signalling, E6742 suppresses downstream cytokine responses, reduces autoantibody production and clinical activity and limits organ damage in preclinical lupus models, supporting its potential as a targeted immunomodulatory therapy in SLE (153).

A multicentre, phase II, randomised, double-blind, placebo-controlled study assessed the safety and tolerability of multiple oral doses of E6742 in patients with SLE. The study has been completed, with results indicating a favourable safety profile, good tolerability, suppression of interferon gene signature responses, and preliminary efficacy signals. These findings provide the first clinical evidence supporting E6742 in SLE and encourage further and larger, longer-term trials (154).

3.6.1.3 Enpatoran

Is a highly selective small-molecule inhibitor of both TLR7 and TLR8, similar to E6742 in its ability to block the pathogenic immune activation driven by self-RNA in SLE (155).

The ELOWEN-1 trial is designed to evaluate the efficacy and safety of enpatoran in patients with active cutaneous manifestations of lupus erythematosus, with or without systemic involvement. This study is not yet recruiting (156).

3.6.1.4 Afimetoran

Is a selective small-molecule inhibitor of both TLR7 and TLR8, similar to E6742 and Enpatoran, and blocks pathogenic immune activation driven by self-RNA in those with SLE (155).

A multicentre, phase II, randomised, double-blind, placebo-controlled study is currently active (but not yet recruiting) to evaluate the efficacy, safety, and tolerability of afimetoran in patients with active SLE (157).

3.6.2 Broad-spectrum or indirect TLR pathway inhibitors

3.6.2.1 Chaperonin 10 (Cpn10)

Selectively modulates innate and adaptive immune responses by targeting Toll-like receptor signalling pathways. This leads to reduced production of pro-inflammatory cytokines and suppression of tissue inflammation. Its immunomodulatory effects are organ-selective, primarily affecting the skin and kidneys, and are mediated through inhibition of downstream TLR-induced activation of nuclear factor kappa B (NFκB) and mitogen-activated protein kinase (MAPK) pathways. The consequence is decreased secretion of cytokines such as TNF-α and IL-6 by mononuclear cells. By specifically modulating local inflammatory responses rather than broadly suppressing the immune system, Cpn10 offers a targeted therapeutic approach for SLE (158).

A multicentre, phase II, randomised, double-blind, placebo-controlled study has evaluated the safety, tolerability and efficacy of Cpn10 in patients with mild to moderate SLE; results are pending publication (159).

3.6.2.2 Edecesertib (GS-5718)

Is a selective small-molecule inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). In SLE, IRAK4 plays a central role in pro-inflammatory signalling downstream of TLRs and interleukin-1 receptors, driving activation of innate immune cells and production of pathogenic cytokines. By inhibiting IRAK4, edecesertib suppresses TLR and IL1-mediated signalling, reducing the release of inflammatory mediators and attenuating the immune cascades that contribute to SLE pathogenesis (160).

A multicentre, phase II, randomised, double-blind, placebo-controlled study was designed to assess the efficacy, safety and tolerability of edecesertib in patients with CLE. This trial is currently active but not recruiting (161).

3.7 Drugs targeting intracellular signalling pathways

Aberrant activation of intracellular signalling pathways is a key controller of immune dysregulation in SLE. Kinases such as JAKs, BTK and TYK2 mediate signalling downstream of cytokine and B-cell receptor pathways, promoting inflammatory cytokine production, autoantibody generation, increased activity and tissue damage. Small-molecule inhibitors targeting these kinases offer a strategy to modulate pathogenic immune responses selectively, potentially reducing inflammation while preserving broader immune function. Several JAK, BTK, TYK2, TYK and SYK inhibitors are currently under investigation in clinical trials for their efficacy and safety in SLE (12, 119, 162).

3.7.1 Janus kinase inhibitors (JAKi)

3.7.1.1 Baricitinib

Is a selective inhibitor of Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2), that interferes with intracellular signalling of multiple cytokines implicated in SLE pathogenesis, including type I interferons, IL-6, IL-12, CXCL10, CCL9, and TNF. By inhibiting JAK-signal transducer and activator of transcriptions (STAT) signalling, baricitinib supresses both innate and adaptive immune activation. In consequence inflammatory gene expression is reduced, attenuation of cytokine-driven pathways and decreased autoantibody production, including anti-dsDNA antibodies (162).

Phase II data, supported by the SLE-BRAVE I study, suggested potential clinical benefit of baricitinib in SLE (163). However, the subsequent SLE-BRAVE II trial, found no significant difference in the primary endpoint, defined as the proportion of SRI-4 responders at week 52, between baricitinib-treated patients and those receiving placebo. Furthermore, none of the key secondary endpoints, including corticosteroid tapering and time to first severe flare, were met. The safety profile of baricitinib in this population was consistent with its previously established safety profile (163–166).

3.7.1.2 Upadacitinib

Is a selective JAK1 inhibitor. By selectively inhibiting JAK1-dependent signalling, upadacitinib modulates the JAK-STAT pathway, thereby suppressing cytokine-mediated inflammatory responses implicated in SLE pathogenesis. Its mechanism of action overlaps with that of baricitinib, although with great selectivity for JAK1 (167).

The phase III SELECT-SLE trial is currently active and recruiting and is evaluating the safety and efficacy of upadacitinib in patients with moderate to severe active SLE (168).

3.7.1.3 Filgotinib

Is a selective JAK1 inhibitor with a mechanism of action similar to that of upadacitinib (169).

A phase II, multicentre, randomised, double-blind, placebo-controlled trial studied the efficacy of filgotinib and lanraplenib in females with moderate to severe active CLE. The primary endpoint was not met. However, predefined subgroups analyses demonstrated numerically greater treatment responses with filgotinib compared with placebo. Both filgotinib and lanraplenib were generally well tolerated. Despite the failure to achieve the primary endpoint, these findings suggest that JAK1 inhibition with filgotinib in CLE may warrant further investigation, whereas SYK inhibition did not demonstrate sufficient clinical signal (170).

3.7.1.4 Ruxolitinib

Is a selective inhibitor of JAK1 and JAK2, with a mechanism of action related to that of baricitinib (171).

A phase II, randomised, single-blind, placebo-controlled study is currently active and recruiting to evaluate the efficacy, safety and tolerability of ruxolitinib in patients with discoid lupus erythematosus (172).

3.7.1.5 Solcitinib (GSK2586184)

Is a selective JAK1 inhibitor with a mechanism of action similar to upadacitinib and filgotinib (173).

A phase II, multicentre, randomised, double-blind, placebo-controlled study evaluating the efficacy, pharmacodynamics, safety and tolerability of solcitinib in patients with mild to moderate SLE was terminated prematurely after meeting a protocol-defined futility, following completion of the final follow-up visit of the last randomised participant (174).

3.7.1.6 Delgocitinib

Is a pan-Janus kinase inhibitor targeting JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). This broad JAK inhibition blocks intracellular signalling of multiple cytokines implicated in SLE pathogenesis, including type I interferons, IL-6, and other pro-inflammatory mediators. By suppressing the JAK-STAT signalling, delgocitinib reduces activation of both innate and adaptive immune responses, reduces autoantibody production, and downregulates inflammatory gene expression and cytokine signalling in target tissues (175).

A phase II, multicentre, randomised, double-blind, placebo-controlled study evaluating the efficacy and safety of delgocitinib in patients with active discoid lupus erythematosus was terminated prematurely due to recruitment challenges (176).

3.7.1.7 Brepocitinib (PF 06700841)

Is a dual inhibitor of JAK1 and TYK2. This combined inhibition modulates a broad range of cytokine-driven inflammation pathways, including those central to lupus flares and organ involvement (177).

A phase II, multicentre, randomised, double-blind, placebo-controlled study reviewed the efficacy and safety of brepocitinib in patients with active SLE. The study has been completed, and results are pending publication (178).

3.7.2 Tyrosine kinase 2 inhibition (TYK2i)

3.7.2.1 Deucravacitinib

Is a selective TYK2 inhibitor. It acts via an allosteric mechanism, binding to the catalytically inactive pseudokinase regulatory domain of TYK2 and stabilizing an inhibitory interaction between the regulatory and catalytic domains (179). This allosteric inhibition blocks TYK2-mediated intracellular signalling for key cytokines implicated in SLE pathogenesis, including type I interferons, IL-12, IL-23, thereby suppressing downstream activation of STAT, reducing pro-inflammatory gene expression, and modulating immune cell activity (180).

The phase III POETYK-SLE-1 trial is currently active though not yet recruiting and is designed to evaluate the efficacy and safety of deucravacitinib in patients with moderate to severe SLE (181).

3.7.2.2 ESK-001

Is a selective TYK2 inhibitor with a mechanism of action similar to that of deucravacitinib (182).

The LUMUS trial is currently active but not recruiting and is designed to evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of ESK-001 in patients with SLE (183).

3.7.2.3 D-2570

Is a selective TYK2 inhibitor with a mechanism of action similar to that of deucravacitinib and ESK-001 (184).

A phase II, multicentre, randomised, double-blind, placebo-controlled trial plans to study the efficacy and safety of D-2570 in patients with active SLE. The study is currently active but not yet recruiting (185).

3.7.2.4 GLPG3667

Is a selective TYK2 inhibitor with a mechanism of action similar to that of deucravacitinib, ESK-001 and D-2570 (186).

The GALACELA trial is currently active but not recruiting. It seeks to assess the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of GLPG3667 in patients with active SLE (187).

3.7.3 Bruton's tyrosine kinase inhibition (BTKi)

3.7.3.1 Fenebrutinib (GDC-0853)

Is a selective Bruton's tyrosine kinase (BTK) inhibitor, a cytoplasmic kinase essential for B-cell receptor and Fcγ receptor signalling in B-cells and myeloid cells. By inhibiting BTK, fenebrutinib suppresses B-cell activation, differentiation, and autoantibody production. It also blocks myeloid cell-mediated inflammatory responses. This results in reduced levels of pathogenic plasmablasts, anti-dsDNA autoantibodies, total IgG and IgM, and increased complement C4, which are all relevant to SLE pathogenesis (188).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of fenebrutinib in patients on SOC with moderate to severe SLE. Although fenebrutinib demonstrated an acceptable safety profile, the primary endpoint, SRI-4 response, was not achieved, despite evidence of robust pathway inhibition (189).

3.7.3.2 Elsubrutinib (ABBV-599)

Is a selective BTK inhibitor, with a mechanism of action overlapping that of fenebrutinib (190).

The phase II SLEek trial evaluated the safety and efficacy of elsubrutinib, upadacitinib and their combination compared with placebo in patients with moderate to severe active SLE. Elsubrutinib monotherapy failed to demonstrate clinical efficacy and was discontinued for futility. In contrast, more encouragingly the high dose elsubrutinib/upadacitinib arm showed significant improvements in disease activity, reduced flare rates, and an acceptable safety profile through 48 weeks (191).

In a long-term extension of this multicentre, randomised, double-blind, placebo-controlled phase II study, upadacitinib monotherapy and the upadacitinib/elsubrutinib combination remained well tolerated and the latter continued to demonstrate beneficial effects on SLE disease activity, glucocorticoid dose reduction, and flare prevention through 104 weeks (192).

3.7.3.3 Branebrutinib

Is a selective BTK inhibitor, with a mechanism of action overlapping that of elsubrutinib and fenebrutinib (193).

A phase II, multicentre, randomised, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of branebrutinib in patients with active SLE and primary Sjögren's Syndrome. Although the study was completed in 2022, the results have not yet been published, which rather suggests it was not successful (194).

3.7.3.4 Zanubrutinib

Is a selective BTK inhibitor, with a mechanism of action overlapping that of elsubrutinib, fenebrutinib and branebrutinib (195).

A phase II, multicentre, randomised, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of zanubrutinib added to SOC in patients with active LN. The study was completed in 2024; however, the results have not yet been published (196).

3.7.3.5 Orelabrutinib (ICP-022)

Is a selective BTK inhibitor, with a mechanism of action similar to that of elsubrutinib, fenebrutinib, branebrutinib and zanubrutinib (197).

A phase II, multicentre, randomised, double-blind, placebo-controlled trial is currently active and recruiting to evaluate the efficacy and safety of orelabrutinib in patients with active SLE (198).

3.7.3.6 TQB3702

Is a selective BTK inhibitor, with a mechanism of action overlapping that of elsubrutinib, fenebrutinib, branebrutinib, zanubrutinib and orelabrutinib (199).

A phase II, multicentre, randomised, double-blind, placebo-controlled trial is planned to study the efficacy and safety of TQB3702 in patients with SLE. The trial is currently active but not yet recruiting (200).

3.7.3.7 Evobrutinib (M2951)

Is a selective BTK inhibitor, with a mechanism of action overlapping that of elsubrutinib, fenebrutinib, branebrutinib, zanubrutinib, orelabrutinib and TQB3702 (201).

A phase II, multicentre, randomised, double-blind, placebo-controlled trial reviewed the efficacy and safety of evobrutinib in patients with SLE. The results demonstrated no treatment effect at any dose level. Nevertheless, evobrutinib was generally well tolerated, with no dose-dependent increase in treatment-emergent adverse events. Safety aspects were comparable between the overall safety population and the high disease activity subpopulation, and long-term exposure was not associated with an increased renal safety burden in this vulnerable patient population (202).

BTK inhibition is thus not an effective treatment in patients with SLE.

3.7.4 Spleen tyrosine kinase inhibition (SYKi)

3.7.4.1 Lanraplenib

Is a selective spleen tyrosine kinase (SYK) inhibitor. SYK is a critical regulator of signalling B-cells, monocytes and macrophages, mediating downstream effects of the B-cell receptor, Fcγ receptor, and other immunoreceptors. Inhibition of SYK suppresses B-cell differentiation and autoantibody production, as well as myeloid cell-driven inflammatory responses, which are central to SLE pathogenesis. This leads to reduced production of pathogenic autoantibodies, attenuation of immune complex-mediated inflammation, and decreased tissue injury in SLE (203).

A phase II, multicentre, randomised, double-blind, placebo-controlled study evaluated the efficacy of filgotinib and lanraplenib in females with moderate to severely active CLE. The primary endpoint, change from baseline in the CLASI-A score at week 12, was not met. However, predefined subgroups analyses demonstrated that numerical differences between filgotinib and placebo were greater in select subgroups: a ≥ 5-point improvement in the CLASI-A score at week 12 was achieved by 50.0, 56.3% and 68.8% in the placebo, lanraplenib and filgotinib arms, respectively; and a numerically greater proportion of patients in the filgotinib arm (50%) also achieved ≥ 50% improvement in the CLASI-A score at week 12 (37.5% in the placebo-arm and 31.3% in the lanraplenib arm). Both filgotinib and lanraplenib were generally well tolerated. Despite the failure to achieve the primary endpoint, these findings suggest that JAK1 inhibition with filgotinib in CLE may warrant further investigation, whereas SYK inhibition did not demonstrate sufficient clinical signal (170).

3.7.4.2 R333

Is a selective spleen tyrosine kinase (SYK) inhibitor with a mechanism of action overlapping that of lanraplenib (204).

A phase II, multicentre, randomised, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of R333 in patients with active discoid cutaneous discoid lesions. Four weeks of treatment with R333 did not result in a significant improvement in lesion activity (205).

3.8 Drugs targeting cytokines, chemokines and their receptors

Cytokines and chemokines are key mediators of immune activation and tissue inflammation in SLE. Dysregulated signalling of pro-inflammatory cytokines, including IL-6, TNF-a, and BAFF, as well as chemokines controlling leukocyte trafficking, contributes to autoimmunity, organ damage, and disease activity. Therapeutic strategies targeting these pathways aim to neutralize pathogenic mediators or block their receptors, thereby modulating immune responses while preserving protective immunity. Several biologics and small molecules are under investigation, offering potential adjunctive therapy to SOC treatments in patients with SLE (2, 206).

3.8.1 Interleukin-12/13 and interleukin-23 axis inhibition

3.8.1.1 Ustekinumab

Is a human monoclonal antibody that targets the p40 subunit shared by interleukin-12 (IL-12) and interleukin-23 (IL-23), preventing their interaction with IL-12Rβ1 receptor on immune cells. This blockade inhibits downstream signalling pathways that drives Th1 and Th17 cell differentiation and activation, pathways implicated in SLE pathogenesis through promotion of chronic inflammation and autoimmunity (207).

A multicentre, phase III, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of ustekinumab in patients with active SLE despite SOC therapy. This study was terminated early following a pre-planned interim analysis, as ustekinumab did not demonstrate superiority over placebo in this population. Adverse events were consistent with known safety profile of ustekinumab (208).

3.8.1.2 Guselkumab

Is a human monoclonal antibody that selectively binds to and inhibits the p19 subunit of IL-23, thus blocking IL-23 signalling. In the context of lupus, particularly LN, its mechanism of action involves suppression of the IL-23/Th17 axis, which is implicated in the pathogenesis of SLE through promotion of pro-inflammatory cytokines such as IL-17A, IL-17F, and IL-2. By inhibiting IL-23, guselkumab reduces the differentiation and maintenance of pathogenic Th17 cells, leading to decreased production of these cytokines and attenuation of tissue inflammation (209).

The ORCHID-LN trial was designed to evaluate the efficacy of guselkumab in participants with active LN. In this small cohort (n = 33), guselkumab in combination with background therapy did not demonstrate superior reduction in proteinuria compared to placebo plus background therapy. Safety findings were consistent with the known safety profile of guselkumab. The trial was terminated early due to enrolment challenges (210).

3.8.2 Interleukin-17 pathway inhibition

3.8.2.1 Secukinumab

Is a human monoclonal antibody that selectively binds to and neutralises interleukin-17A (IL-17A), a pro-inflammatory cytokine implicated in the pathogenesis of SLE and LN. By inhibiting IL-17A, secukinumab prevents its interaction with the IL-17 receptor, causing a reduction in the downstream release of pro-inflammatory cytokines and chemokines that contribute to tissue inflammation and autoimmunity in SLE (211).

The SELUNE trial was designed to check the efficacy and safety of secukinumab in patients with active LN. In this study, secukinumab did not demonstrate superior efficacy compared with placebo. Secukinumab was well tolerated with no new or unexpected safety signals detected. The trial was terminated early by sponsor due following a futility analysis (212).

3.8.3 Interleukin-2 pathway modulation and low-dose interleukin-2 therapies

3.8.3.1 Aldesleukin (ILT-101)

Is a recombinant human interleukin-2 (IL-2). It acts by selectively expanding and restoring the function of regulatory T cells (Tregs), which are reduced in number and functionally impaired in SLE. Low-dose aldesleukin preferentially stimulates the high-affinity IL-2 receptor (CD25) expressed on Tregs, leading to increased Treg numbers and enhanced immune tolerance, while avoiding the broad activation of effector T-cells and natural killer cells that occurs at higher IL-2 doses (213).

The LUPIL-2 trial was designed to evaluate the efficacy and safety of aldesleukin in patients with moderate to severe SLE. The primary endpoint was not met in the intention-to-treat population, owing to a 100% SRI-4 response rate in the placebo group at two sites from Bulgaria. However, a post-hoc per-protocol analysis on a prespecified population excluding patients from these sites demonstrated a statistically significant improvement for the SRI-4 response rates, as well as in two key secondary endpoints, supported by favourable trends across several secondary exploratory endpoints. Aldesleukin was well tolerated, and no anti-drug antibodies were detected (214).

3.8.3.2 Rezpegaldesleukin (LY3471851)

Is a Treg-selective IL-2 receptor agonist. In SLE, it preferentially stimulates the high-affinity IL-2 receptor (CD25) on Tregs, leading to their expansion and enhanced suppressive function. This strategy envisages the restoration immune tolerance and correct the quantitative and functional Treg defects characteristics of SLE, while avoiding the broad activation of effector T-cells or natural killer cells that may occur with non-selective IL-2- based therapies (215).

The ISLAND-SLE trial was designed to evaluate the efficacy and safety of rezpegaldesleukin in patients with SLE. Although the trial completed in 2023, results have not been published in a peer-reviewed medical journal implying it probably was not effective (216).

3.8.3.3 Efavaleukin alfa

Is a novel engineered IL-2 mutein fused to an Fs fragment, designed to activate and expand Tregs selectively by preferentially binding to the high-affinity IL-2 receptor (CD25) expressed on Tregs. This mechanism aims to restore immune tolerance and suppress autoreactive immune responses in autoimmune diseases such as SLE, without broadly activating effector T-cells or natural killer cells. This Treg-selective approach seeks to correct the quantitative and functional Treg defects characteristic of SLE, thereby reducing disease activity and inflammation (217).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of efavaleukin alfa in patients with active SLE. Treatment with efavaleukin alfa did not result in improvement in efficacy endpoints compared with placebo. The safety profile observed was consistent with the known profile of efavaleukin alfa. This trial was terminated prematurely after meeting pre-defined criteria for futility at the third interim analysis (218, 219).

3.8.3.4 MK-6194

Is an engineered IL-2 mutein with a mechanism of action similar to that of efavaleukin alfa (220).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of MK-6194 in patients with active SLE. This trial was terminated prematurely for sponsor-related business reasons, unrelated to safety or efficacy findings (221).

3.8.4 Interleukin-6 pathway inhibition

3.8.4.1 Vobarilizumab (ALX-0061)

Is a high-affinity, selective inhibitor of IL-6 receptor (IL-6R). By blocking IL-6R, vobarilizumab prevents IL-6-driven activation of downstream signalling pathways, notably the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. These pathways are linked to SLE pathogenesis through their roles in promoting B-cell differentiation, autoantibody production, and T-cell activation (2, 222).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of vobarilizumab in patients with moderate to severe SLE. Although the trial was completed in 2018, results have not been published in the peer-reviewed medical literature (223). It thus seems highly unlikely any benefit was observed.

3.8.4.2 Sirukumab (CNTO 136)

Is a high-affinity, selective inhibitor of IL-6 receptor, with a mechanism of action similar to that of vobarilizumab (224).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of sirukumab in patients with active LN. The study did not demonstrate the anticipated clinical efficacy and raised safety concerns, failing to establish acceptable safety profile for sirukumab in this patient population receiving concomitant immunosuppressive treatment (225).

3.8.4.3 Pacibekitug (PF-04236921)

Is a high-affinity, selective inhibitor of IL-6 receptor, with a mechanism of action similar to that of vobarilizumab and sirukumab. By blocking IL-6-mediated signalling, it aims to attenuate inflammatory pathways involved in SLE pathogenesis (226).

The BUTTERFLY trial evaluated the efficacy and safety of Pacibekitug in patients with SLE. Treatment did not result in a statistically significant improvement over placebo for the primary efficacy endpoint (proportion of patients achieving the SRI-4 at week 24). However, a post-hoc analysis suggested evidence of an effect at 10 mg. Overall, safety was considered acceptable at doses up to 50 mg, while 200 mg dose was discontinued due to safety concerns (227).

3.8.5 Tumour necrosis factor (TNF) inhibition

3.8.5.1 Infliximab

Is a monoclonal antibody directed against TNF-α. By binding to TNF-α, infliximab inhibits the TNF-α-mediated pro-inflammatory signalling, resulting in reduced induction of downstream cytokines such as IL-1 and IL-6, decreased leukocyte migration and endothelial activation, and suppression of acute-phase reactants and tissue-degrading enzymes. Theoretically these effects attenuate inflammatory pathways implicated in SLE pathogenesis, particularly in LN and inflammatory arthritis (228).

However, the use of infliximab in SLE remains controversial due to its association with paradoxical induction of autoantibodies in some patients, including antinuclear antibodies (ANA) and anti-double-stranded DNA antibodies (anti-dsDNA), as well as the development of lupus-like syndromes and an increased risk of serious infections. These adverse effects are well documented in the medical literature and reflected regulatory labelling (228, 229).

The TRIAL study was designed to evaluate the safety and efficacy of infliximab in patients with SLE and LN (class V WHO) was terminated prematurely due to difficulties in recruiting patients with membranous LN who had not previously received azathioprine (230). The exclusion of patients on azathioprine in infliximab trials for LN reflects well-documented safety concerns, where the combination of infliximab and azathioprine has been associated with increased risk of serious adverse events, including severe infections, hepatosplenic T-cell lymphoma (particularly in young males with inflammatory bowel disease), and other malignancies, making it necessary to exclude patients on azathioprine to ensure participant safety and avoid confounding the trial's safety assessment (231).

3.8.5.2 Etanercept

Is a human dimeric fusion protein that binds and inhibits TNF, as well as the related lymphotoxin-α (formerly known as TNFβ). By preventing these cytokines from binding to their cell surface TNF receptors, etanercept blocks downstream pro-inflammatory signalling pathways (232).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial assessed the efficacy and safety of etanercept in patients with LN. The trial was terminated prematurely due to perceived unfavourable risk-benefit ratio, based on emerging safety concerns observed in individuals with early active rheumatoid arthritis (233).

3.8.6 Other cytokines or chemokine-targeted approaches

3.8.6.1 BT063

Is a monoclonal antibody targeting IL-10. Serum IL-10 levels are increased in patients with SLE and have been shown to correlate with disease activity. However, the precise role of IL-10 in SLE pathogenesis remains unclear, as IL-10 exhibits both pro and anti-inflammatory properties depending on the immunological context (234).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial was conducted to evaluate the safety and efficacy of BT063 in patients with SLE. Although the trial was completed in 2017, results have not been published in the peer-reviewed medical literature from which we may assume it was not effective (235).

3.8.6.2 Avizakimab (BOS161721)

Is a human monoclonal antibody that targets and neutralizes IL-21, a pleiotropic cytokine produced primarily by T follicular helper cells. IL-21 is implicated in SLE pathogenesis through its role in promoting B-cell activation, differentiation into plasma cells, and autoantibody production. In SLE, elevated IL-21 levels contribute to the expansion of autoreactive B-cells, dysregulation of T-cell subsets, and generation of pathogenic autoantibodies. By blocking IL-21 signalling, avisakimab aims to supress B-cell hyperactivity and autoantibody production, thereby restoring immune tolerance and reduce disease activity (236).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial was conducted to evaluate the assess the safety, tolerability, and immunogenicity of avizakimab in patients with moderate to severe SLE receiving SOC therapy. Although the trial was completed in 2020, results have not been published in the peer-reviewed medical literature, again implying a failure to be of benefit (237).

3.8.6.3 BIIB023

Is a humanized monoclonal antibody that targets and neutralizes tumour necrosis factor-like weak inducer of apoptosis (TWEAK), a cytokine implicated in the pathogenesis of SLE, particularly LN. By binding to TWEAK, BIIB023 blocks its interaction with the fibroblast growth factor-inducible 14 (Fn14) receptor, thereby inhibiting downstream signalling pathways that promote renal inflammation, cell proliferation, apoptosis, vascular activation, and fibrosis. This blockade is intended to reduce glomerular and tubular injury and attenuate overall renal inflammation (238).

The ATLAS trial was designed to assess the efficacy, safety and tolerability of BIIB023 as an add-on to SOC therapy in patients with active LN. The study demonstrated that the addition of BIIB023 did not improve 52-week renal response rates in proliferative LN, despite evidence of pharmacodynamic activity. Notably, the trial employed a unique design that excluded patients who responded rapidly to SOC therapy, thereby enhancing the study population for potentially less responsive disease. The trial was terminated prematurely after pre-specified futility criteria were met, as the results did not demonstrate sufficient efficacy to justify continuation (239).

3.9 Drugs targeting the complement pathway

The complement system is a key effector of innate immunity and plays an important role in the pathogenesis of SLE. Dysregulated activation of complement cascade contributes to immune complex-mediated inflammation, tissue injury, and organ damage, with hypocomplementaemia and complement deposition acting as markers of disease activity (2, 240, 241).

Targeting the complement pathway represents a rational therapeutic strategy to limit inflammatory amplification and tissue damage while preserving essential host defence functions. Advances in complement biology have led to the development of targeted inhibitors, some of which are currently under clinical evaluation as adjunctive therapy to SOC in SLE (240–242).

3.9.1 Alternative pathway inhibition (factor B and factor D)

3.9.1.1 Iptacopan (LNP023)

Is a selective inhibitor of complement factor B that acts by blocking the activity of the alternative complement pathway C3 convertase. In SLE, dysregulation and overactivation of the alternative complement pathway contribute to immune complex-mediated inflammation and end-organ damage, particularly in LN and thrombotic microangiopathies. By inhibiting factor B, iptacopan prevents the formation and activity of the alternative pathways C3 convertase (C3bBb), thereby reducing the generation of downstream effectors including C3a, C5a, and the membrane attack complex (C5b-9), which are central mediators of complement-driven tissue injury in SLE (243, 244).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial is studying the efficacy, safety and tolerability of iptacopan in addition to SOC treatment in patients with active LN. The trial is currently active and recruiting (245).

3.9.1.2 Vemircopan (ALXN-2050)

Is a selective inhibitor of complement factor D. In SLE, its mechanism of action involves blocking factor D activity, which is essential for the activation of the alternative complement pathway, resulting in downstream effects similar to those observed with iptacopan (246, 247).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial was designed to evaluate the efficacy, safety and tolerability of vemircopan, in addition to SOC treatment, in patients with active LN. However, the trial was terminated prematurely following the sponsor's decision (248).

3.9.2 Terminal complement inhibition (C5 blockade)

3.9.2.1 Ravulizumab

Is a humanized monoclonal antibody that targets complement component C5. By inhibiting the cleavage of C5 into C5a and C5b, and thereby preventing the formation of the terminal complement complex (C5b-9, membrane attack complex), it suppresses activation of the terminal complement pathway. This results in a reduction of complement-mediated inflammation, immune complex-driven tissue injury, and cytotoxicity, which are integral to the pathogenesis of LN and other severe SLE manifestations. By inhibiting terminal complement activation, ravulizumab should reduce disease activity and organ damage in complement-driven autoimmune conditions, including SLE (246, 249).

The SANCTUARY trial, designed to evaluate the safety and efficacy of ravulizumab and to demonstrate proof-of-concept in patients with LN, was terminated prematurely following a sponsor decision (250).

3.10 Drugs with alternative or emerging mechanisms of action

This section encompasses therapeutic strategies that do not fit classical immune-target categories but target immune regulation through alternative or emerging mechanisms.

3.10.1 Antigen-specific immune tolerance and peptide-based therapies

3.10.1.1 Rigerimod (IPP-201101 or CEP-33457)

Is a synthetic peptide tolerogen that modulates the immune response by inducing antigen-specific immune tolerance. Rigerimod binds to major histocompatibility complex class II (MHC II) molecules on APCs, leading to altered processing and presentation of autoantigens. This results in downregulating of autoreactive T- and B-cell responses, reduced autoantibody production, and attenuation of disease activity in SLE. The tolerogenic effect is achieved without broad immunosuppression, distinguishing rigerimod from conventional immunosuppressive therapies (251).

The LUPUZOR trial was conducted to evaluate the efficacy and safety of rigerimod in patients with active SLE. Although the trial was completed in 2018, results have not been published in the peer-reviewed medical literature and may assume to be negative (252).

3.10.2 Sphingosine-1-phospate (S1P) receptor modulation

3.10.2.1 Cenerimod

Is a selective sphigosine-1-phospate receptor 1 (S1P₁) modulator. It sequesters autoreactive T and B lymphocytes within lymphoid tissues by functionally antagonizing S1P₁, thereby preventing their egress into circulation and inflamed tissues. This leads to a reduction in circulating lymphocytes, antibody-secreting cells, and pathogenic autoantibodies, such as anti-dsDNA, as well as decreased secretion of pro-inflammatory cytokines and chemokines, including type I interferon-associated biomarkers (253).

The OPUS-1 trial designed to evaluate the efficacy, safety and tolerability of cenerimod in patients with moderate to severe SLE receiving background therapy currently active and recruiting (254).

3.10.2.2 Mocravimod (KRP203)

Is a selective sphigosine-1-phospate receptor 1 (S1P₁) modulator and has a similar mechanism of action as cenerimod (255).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial was undertaken to assess the safety, efficacy, tolerability and proof-of-concept of mocravimod in patients with active subacute CLE. Although the trial was completed in 2012, results have not been published in the peer-reviewed medical literature and must presumably have been negative (256).

3.10.3 RNA-based and nucleic acid-targeting therapies

3.10.3.1 RSLV-132

Is a catalytically active human RNase fused to the Fc domain of human IgG1, designed to degrade extracellular RNA in the circulation. In SLE, its mechanism of action involves the digestion of circulating RNA, particularly RNA contained within immune complexes, thereby reducing activation of TLRs and type I interferon pathways, which are central to SLE pathogenesis. By lowering extracellular RNA levels, RSLV-132 aims to decrease chronic interferon-driven inflammation and downstream immune activation, including BAFF expression and autoantibody production. This approach is distinct from conventional immunosuppressive therapies, as it targets a key upstream trigger of the interferon response in SLE (5, 257, 258).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial assessed the safety, efficacy and tolerability of RSLV-132 in patients with SLE. It showed that RSLV-132 therapy did not significantly improve the mean CLASI score compared to placebo. The entry study criteria selected patients with moderate to severe cutaneous disease activity and no minimum SLEDAI score, resulting in a wide range of systemic disease activity, from inactive to severe. When exploratory analyses of participants with higher SLEDAI and CLASI scores were analysed, a trend towards clinical improvement favouring RSLV-132 was observed. These findings indicate that further evaluation of RSLV-132 in SLE and suggest that patients with more active systemic disease may be most likely to benefit from RNase- based therapy (259).

3.10.4 Small molecules with pleiotropic immunomodulatory effects

3.10.4.1 Lenabasum (JBT-101)

Is a selective cannabinoid receptor type 2 (CB2) agonist that promotes the resolution of inflammation without causing immunosuppression or psychoactive effects. Upon CB2 activation on immune cells, lenabasum stimulates phospholipase A2, leading to the release of arachidonic acid and the subsequent production of specialized pro-resolving mediators (SPMs), such as lipoxin A4 and 15-deoxy-Δ (12, 14) -prostaglandin, J2 via cyclooxygenase-2 and lipoxygenase pathways. These mediators actively reduce inflammation by downregulating pro-inflammatory cytokines, reducing leukocyte infiltration, and promoting apoptosis of inflammatory cells, thereby attenuating chronic inflammation characteristic of SLE (260).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial was conducted to assess the safety, efficacy and tolerability of lenabasum in SLE patients. The study findings suggests that lenabasum was safe and well-tolerated. Although the pre-specified mixed-effects model did not identify significant differences between changes in numeric rating scale pain scores between the active treatment arms and placebo, the frequency of pain category improvement at Day 84 was notably higher in the active arms compared with placebo. Further analyses, utilizing more widely adopted activity assessments such as SLEDAI, BILAG and PGA scores, may help to identify patients most likely to respond to lenabasum (261).

3.10.5 Neonatal Fc receptor (fcRn) inhibition and IgG reduction

3.10.5.1 Efgartigimod

Is a selective antagonist of the neonatal Fc receptor (FcRn), leading to accelerated lysosomal degradation of IgG and a consequent reduction in circulating pathogenic IgG autoantibody levels. FcRn inhibition by efgartigimod does not affect IgG production or T-cell physiology and has been shown to have immunomodulatory effects beyond IgG reduction, such as promoting regulatory plasma cell differentiation in other IgG-mediated autoimmune diseases (262).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial was conducted to assess the safety, efficacy and tolerability of eftgartigimod in patients with LN. Although the trial was completed in 2025, its results are awaited (263).

3.10.5.2 IMVT-1402

Is a monoclonal antibody that targets and inhibits the FcRn. Its mechanism of action in SLE is similar to that of efgartigimod, resulting in accelerated lysosomal degradation of IgG and a reduction in circulating pathogenic IgG autoantibody levels (264).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial was designed to assess the safety, efficacy and tolerability of IMVT-1402 in patients with CLE. The trial is currently active and recruiting (265).

3.10.5.3 Nipocalimab

Is a human monoclonal IgG1 antibody that acts as an FcRn inhibitor. Its mechanism of action in SLE is similar to that of efgartigimod and IMVT-1402, leading to accelerated lysosomal degradation of IgG and a reduction in circulating pathogenic IgG autoantibody levels (266).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial was designed to assess the safety, efficacy and tolerability of nipocalimab in patients with LN. The trial is currently active but not yet recruiting (267).

3.10.6. Other targeted or cytotoxic immunotherapies

3.10.6.1 IMC-002

Is a human IgG4 antibody that targets cluster of differentiation 47 (CD47) and blocks its interaction with signal regulatory protein alpha (SIRPα), thereby interfering with the “don't eat me” signal that normally inhibits macrophage-mediated phagocytosis of target cells. By antagonising CD47-SIRPα signalling, IMC-002 enhances the macrophage-mediated clearance of cells and immunocomplexes, which may help downgrade inflammation and prevent the accumulation of cellular debris that contributes to autoimmunity in SLE (268).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial was designed to assess the safety, efficacy and tolerability of IMC-002 in patients with active SLE. The trial is currently active but not yet recruiting (269).

3.10.6.2 Brentuximab vedotin

Is an antibody-drug conjugate composed of a chimeric anti-CD30 IgG1 antibody linked to monomethyl auristatin E (MMAE) via a protease-cleavable linker. Following binding to CD30, the conjugate is internalized, MMAE is realised, and tubulin polymerization is inhibited, leading to cell death. CD30 is a member of the TNF receptor family expressed on activated T-and B-lymphocytes, particularly under conditions of chronic immune activation. Targeting activated subsets, such as CD30⁺ cells, could provide selective immunomodulation without broad immunosuppression (270).

A multicentre, phase II, randomised, double-blind, placebo-controlled trial was designed to assess the safety, efficacy and tolerability of brentuximab vedotin in patients with active SLE. The trial was terminated prematurely due to the sponsor's decision based on portfolio prioritisation (271).

4 Discussion and conclusions

The therapeutic landscape of SLE is rapidly evolving, with an increasing focus on target modulation of B-cells, T-cells, interferon pathways, TLR signalling, and the complement system. As our understanding of the distinct immunopathological mechanisms driving disease activity, the opportunity to advance personalised medicine in SLE becomes increasingly attainable.

Several promising agents remain under investigation— Table 3. These include B-cell targeted therapies (ianalumab, obexelimab and telitacicept), B/T-cell co-stimulation inhibitors (dapirolizumab pegol, toralizumab, iscalimab and SM101), plasma cell-directed therapies (iberdomide, KPG-818 and CM313), plamacytoid dendritic cell-targeted therapies (litifilimab and VIB7734), interferon pathway inhibitors (sifalimumab), TLR-targeted agents (E6742), cytokine-based approaches (aldesleukin) and therapies acting through alternative mechanisms (RSLV-132 and lenabasum).

Table 3. Promising agents- outcomes table .

This review has some limitations. First, the phase II and III trials included showed considerable heterogeneity with regard to patient populations and disease activity criteria, which limits comparisons between studies. In particular, different outcome measures and disease activity indices, including the SLEDAI/SLEDAI-2 K and BILAG/BILAG-2004, were used across trial. Second, many clinical trials evaluated different primary endpoints and had relatively short follow-up periods, making it difficult to assess long-term efficacy and safety fully. Finally, variation in background treatments and concomitant immunosuppressive therapies may have influenced treatment responses and complicate the interpretation of the overall therapeutic effect. However, the review does offer a comprehensive review of clinical trials that have been undertaken, are recruiting or are envisaged. The recent increase in clinical trials in lupus is remarkable.

This shift towards precision medicine may represent a pivotal step in addressing the complexity and heterogeneity of SLE. By selectively targeting defined immune pathways, biologics and other targeted therapies offer a more nuanced therapeutic strategy with the potential to reduce disease activity, minimise corticosteroid exposure, decrease flare frequency, and ultimately improve patients quality of life.

Advances in biotechnology have expanded the range of therapeutic options available for SLE. In contrast to broad-spectrum immunosuppressants, these novel agents interfere with specific pathogenic mechanism, thereby creating the possibility of tailoring treatment to distinct patient subpopulations. Such an approach holds promise for achieving more effective, safer, and individualised management of this challenging autoimmune rheumatic disease.

5 Disclosure

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. DAI has received honoraria for consulting rom Astra Zeneca, Amgen, Autolus, Novartis, UCB, Viatris, and Servier. These honoraria are passed onto a local arthritis charity.

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Footnotes

Edited by: Ola Grimsholm, Medical University of Vienna, Austria

Reviewed by: Lucio Manenti, Ligurian Social and Health Authority 5 (ASL5), Italy

Rahul Kakalij, University of Nebraska Medical Center, United States