Over the past few years, clinical and translational clinical research efforts have led to significant advances in the management and treatment of SLE. Recently, foreign scholars have reviewed the latest advances in the field of systemic lupus erythematosus (SLE) in the past year, with a special focus on biomarkers, clinical advances, new therapeutic targets, and evidence from real-world studies. Here, the editor compiles its main content for the benefit of readers.
Biomarkers
➤ Type I interferon signaling pathway, serum interferon activity, and interferon-induced genes or proteins are associated with disease activity, predict in-hospital mortality, and can be used as potential indicators for the diagnosis of SLE.
➤ V-set immunoglobulin domain protein (VSIG4) is a potential marker to assess the activity of kidney disease, distinguishing patients with active and inactive lupus nephritis or lupus nephritis (NL) from healthy people.
➤ KLK5, L-selectin, Trappin-2, TCN2, and CST6 in cerebrospinal fluid can help identify neuropsychiatric lesions in SLE.
Clinical evaluation
➤ Anti-U1 ribonucleoprotein, baseline SLE-DAS score, and immunosuppressants were identified as predictors of recurrence in patients with low disease activity status (LLDAS) in lupus. Relapse of refractory extrarenal organs is associated with failure to reach LLDAS after 3 months of treatment.
➤ In patients with lupus nephritis, particularly those on active immunosuppressive therapy, tardive lupus nephritis is associated with a high risk of end-stage renal disease.
➤ When SLE involves the neuropsychiatric system, the presentation is complex and has a significant impact on the patient, and the major central nervous system manifestations are associated with higher annual mortality.
➤ Sleep disturbances, including nightmares, suggest increased brain arousal, and a comprehensive approach is needed to understand and manage these manifestations of SLE.
➤ The assessment of the burden of SLE comorbidities has not been standardized, but there should be a concept of "multimorbidity coexistence" and "frailty".
➤ Cardiovascular risk scores for SLE (e.g., QRISK3 and mFRS) may be better predictive of the development of subclinical atherosclerotic disease than general assessment tools.
➤ The concept of "SLE-related impairment" is changing to measure SLE-related incidence in a more flexible way to guide future research.
New therapeutic targets
Preclinical studies and phase I studies
➤ Toll-like receptors (TLRs) 7 and TLR8 are innate immune system "sensors" whose chronic activation is associated with the pathogenesis of SLE. E6742 is a TLR7 and TLR8 dual antagonist that has demonstrated in animal models that oral administration of E6742 after disease onset inhibits the increase of autoantibodies (antiribosomal P protein) and blocks the progression of organ damage (arthritis score and proteinuria), demonstrating a favorable safety and tolerability profile in healthy subjects.
➤ Dysregulation of Syk activity is associated with the development of SLE. Cho et al. found that a new selective Syk inhibitor, Cevidoplenib, could improve a mouse model of lupus nephritis and reduce levels of IgG autoantibodies, proteinuria, and glomerulonephritis.
➤ Another promising SLE drug is Rozibafusp alfa (AMG 570), a bispecific IgG2 peptide fusion agent that inhibits inducible T cell costimulatory ligands (ICOSL) and B cell activating factor (BAFF). Exhibited as a nonlinear pharmacokinetic profile in healthy subjects, with dose-dependent, reversible, dual-target functioning.
Phase 2 and 3 trials, real-world studies
➤ Non-receptor tyrosine protein kinase 2 (TYK2) is one of the targets of SLE therapy. This intracellular kinase mediates signaling of key cytokines involved in disease pathogenesis, including type I interferon (IFN), interleukin-10 (IL-10), IL-12, and IL-23. The Phase II trial (PAISLEY) is designed to evaluate the efficacy and safety of deuterocolixitinib in adult patients with active SLE. The primary endpoint is SLE Response Index-4 (SRI-4) response rate at week 32.
- The proportion of patients achieving SRI-4 remission was 34 percent in the placebo group, compared with 58 percent in the deuterocolectinib 3 mg twice-daily group, 50 percent in the 6 mg twice-daily group, and 45 percent in the 12 mg once-daily group. With the exception of a higher incidence of infection and skin events (including rash and acne) in patients treated with deuterocoracitinib, the incidence of adverse events was similar across groups, and these results support the potential benefits of TYK2 inhibition in SLE to be explored in larger phase III trials.
➤ Inhibition of B lymphocyte-stimulating factor (BLyS) and proliferation-inducing ligands (April) is another promising approach for the treatment of SLE, which may more completely inhibit autoantibody production. Tetanercept is a novel fusion protein that binds to the extracellular BLyS/April binding moiety. In a phase 2b clinical trial, tetanercept demonstrated favorable efficacy and an acceptable safety profile in patients with active SLE.
- At week 48, the proportion of patients achieving SRI-4 remission was 75.8% in the 240 mg tetanercept group, 68.3% in the 160 mg group, 71.0% in the 80 mg group, and 33.9% in the placebo group (all P<0.001). Tataercept was well tolerated, and the incidence of adverse events and serious adverse events was similar between the tetanercept and placebo groups.
➤ Phase III study BLISS-LN, the largest controlled study of active LN to date, showed that the addition of intravenous (IV) belimumab to standard of care improved renal outcomes in patients with LN. Data from 2023 real-world studies show that belimumab is effective in reducing hormones and promoting treatment goals with a favorable safety profile. Researchers analysed data from five phase III trials to determine the ability of belimumab to prevent NPSLE events, and the results showed that the effect of adding belimumab to standard therapy for the prevention of neuropsychiatric SLE episodes was unclear.
➤ Arunilizumab is a human monoclonal antibody against type I IFN receptor subunit 1 that was recently approved for the treatment of SLE. Patients treated with alunilimab achieved LLDAS earlier, more often, and more durably than placebo, and real-world studies have shown that alunilimab has a high drug retention rate, improves disease activity, and reduces hormone use, especially in patients with mild relapse after reaching LLDAS. For lupus nephritis, a two-year extension study demonstrated efficacy in improving renal outcomes with an acceptable safety profile.
➤ Voclosporin is a calcineurin inhibitor that has recently been approved in combination with mycophenolate mofetil for the treatment of LN. In real-world studies, its effectiveness and safety have been confirmed across different races and ethnicities.
参考文献：Schilirò D, Silvagni E, Ciribè B, et al. Systemic lupus erythematosus: one year in review 2024. Clin Exp Rheumatol. 2024 Mar; 42(3):583-592. doi: 10.55563/clinexprheumatol/mnvmvo. Epub 2024 Mar 27. PMID: 38545801.
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