Background/Objectives: CTLA-4 is a key checkpoint of peripheral immune regulation, yet its biology cannot be reduced to inhibitory signaling alone. This review discusses CTLA-4 as a dynamic regulatory pathway shaped by ligand handling, intracellular trafficking, recycling, and cell-type-specific function, and examines how these features link molecular mechanism to human disease and therapy. Methods: We synthesized the structural, mechanistic, translational, and clinical literature spanning CTLA-4 molecular biology, cell-type-specific function, inborn errors of immunity, polygenic autoimmunity, transplantation, cancer immunotherapy, and immune-related adverse events. Results: CTLA-4 function depends on surface availability, trans-endocytosis of CD80/CD86, and tight control of endosomal trafficking. These features help explain why CTLA-4 haploinsufficiency, LRBA deficiency, and DEF6 deficiency converge clinically despite different upstream lesions, and why subtler CTLA-4 variation contributes to polygenic autoimmunity. Therapeutic studies also provide mechanistic insight. Abatacept can partly replace pathway function in monogenic disease, whereas belatacept highlights the limits of ligand blockade when endogenous coinhibition is also lost. In oncology, anti-CTLA-4 antibodies act through a more complex interplay involving checkpoint blockade, Fc biology, intratumoral Treg depletion, and receptor recycling. Emerging next-generation agents aim to retain antitumor activity while reducing systemic toxicity through more selective use of these mechanisms. Conclusions: Rather than a static inhibitory receptor, CTLA-4 is better viewed as a context-dependent regulatory pathway whose function depends on trafficking, surface availability, and cellular context. This perspective links molecular mechanism to clinical phenotype and supports more precise CTLA-4-targeted therapy.

Objective To assess the effectiveness of belimumab (BEL) in improving anaemia, thrombocytopenia, lymphopenia and leucopenia in patients with SLE.Methods The BeRLiSS (Belimumab in Real Life Setting Study) 2.0 cohort included patients with SLE from 14 Italian referral centres treated with BEL for active joint or skin involvement, based on physician judgement, between June 2013 and May 2024. Clinical and laboratory parameters were recorded at baseline and every 6 months. Patients were eligible if they had baseline haematological abnormalities defined according to British Isles Lupus Assessment Group (BILAG) (grade C or higher): haemoglobin (Hb) ≤10.9 g/dL, platelets (Plts) ≤149×109/L, lymphocytes (Lym) ≤1.0×109/L or leucocytes (Leuc) ≤3.0×109/L. Follow-up data up to month 48 were available for 33 patients with anaemia, 20 with thrombocytopenia, 44 with lymphopenia and 18 with leucopenia.Results At baseline, 76 patients had anaemia, 44 thrombocytopenia, 107 lymphopenia and 53 leucopenia. Hb levels increased significantly from 9.9±0.6 g/dL to 11.7±1.4 g/dL at month 48 (p<0.001). Platelet counts rose from 110.2±38.1×109/L to 176.6±88.7×109/L (p=0.004), Lym counts from 0.72±0.21×109/L to 1.14±0.45×109/L (p<0.001) and leucocyte counts from 2.437±0.533×109/L to 4.732±1.897×109/L at 48 months (p<0.001). Improvement in Hb (p=0.97), Plts (p=0.12), Lym (p=0.86) and Leuc (p=0.73) was similar regardless of the use of concomitant immunosuppressants. Glucocorticoid (GC) doses decreased significantly across all manifestations, except for leucopenia: anaemia (12.9±12.1 to 3.6±4.9 mg/day, p=0.003), thrombocytopenia (10.8±9.6 to 4.4±5.5 mg/day, p=0.004), lymphopenia (10.6±8.6 to 3.1±3.2 mg/day, p<0.001). Proportion of GC users declined over 48 months: anaemia 96.1–60.7%, thrombocytopenia 93.1–80%, lymphopenia 96.3–70.3% and leucopenia 95.3–80%.Conclusion In this real-world cohort, BEL treatment was associated with improvement in anaemia, thrombocytopenia, lymphopenia and leucopenia with over half of patients achieving normalisation of blood counts. Haematological responses were similar regardless of concomitant immunosuppressive therapy, supporting the role of BEL as a therapeutic option for haematological abnormalities in SLE.

OBJECTIVE:International guidelines recommend early combination of standard therapy with innovative agents in lupus nephritis (LN) to prevent kidney damage. Whether this accelerates renal response is unclear. We aimed to compare renal response trajectories, predictors and glucocorticoid (GC) burden in LN patients receiving early belimumab plus standard-of-care (SoC) vs SoC alone. METHODS:Consecutive adult patients with biopsy-proven LN treated with belimumab plus SoC as initial therapy were enrolled from Italian lupus referral centres and compared with a historical SoC cohort (1990-2016). Data were collected at baseline and during follow-up. Propensity score matching based on baseline proteinuria, estimated glomerular filtration rate, standard initial treatment and histological class led to comparable groups. Complete renal response (CRR) was defined per 2019 EULAR/EDTA. Cox regression was used to assess predictors. RESULTS:Ninety-one belimumab patients were matched to 91 SoC patients. At 6 months, CRR was higher in the belimumab group (35.9% vs 16.5%, odds ratio [95% CI]: 2.81 [1.30, 6.29], P = 0.005), while response rates at 12 months were similar (P = 0.87). Time-to-CRR was shorter with belimumab (median [interquartile range] 5.64 [4.08, 7.80] vs 7.92 [5.28, 11.04] months, P < 0.01). At CRR, GC dose was lower in the belimumab group (5 [5-15] vs 15 [10-20] mg/day, P = 0.018). Independent predictors of earlier CRR were baseline proteinuria (hazard ratio per g/24 h increase [95% CI]: 0.89 [0.80, 0.98], P = 0.019) and belimumab use (1.70 [1.11, 2.62], P = 0.016). CONCLUSION:Early belimumab combination therapy accelerates CRR and reduces GC exposure. Achieving early CRR with lower GC is a key target to limit kidney and GC-related damage, supporting early belimumab integration in LN management.

Human leukocyte antigen (HLA) polymorphisms are central to anti-infective pharmacogenetics and to inter-individual variability in infection outcomes and vaccine responses, but clinical relevance depends on whether an association changes treatment or prevention decisions. This narrative review is organized around two complementary pillars: first, severe, typically T cell–mediated adverse drug reactions to anti-infective agents, where HLA can support prevention when genetic effect, phenotype precision, and therapeutic alternatives converge; and second, selected, replicated HLA-region associations with infection outcomes or vaccine immunogenicity, where biological effects may be robust yet individual-level clinical translation is often limited. Within the adverse drug reaction pillar, the clearest preventive paradigm remains HLA-B*57:01-guided abacavir prescribing, with additional high-signal examples including dapsone hypersensitivity and flucloxacillin-induced liver injury that illustrate how large effect sizes do not always justify routine screening. Within the infection and vaccine pillar, HIV, HCV, and hepatitis B vaccine response provide the strongest evidence that HLA shapes clinically relevant host-response heterogeneity. Across both domains, the key pharmacological distinction is between mechanistically persuasive associations and those that are sufficiently robust, transportable, and decision-relevant to change practice.

BackgroundHypereosinophilic Syndrome (HES) is a rare disorder with a heterogeneous clinical presentation. If not recognized, it can lead to diagnostic delay and worse prognosis. Our study aimed to describe the real-world scenario of patients presenting with hypereosinophilia (HE), diagnosed with HES in an Italian Immunology Excellence University Centre. In addition, we also assessed the feasibility of a two-tailed approach for HES diagnosis, which consists of proceeding from the beginning with the differential diagnosis and systematic evaluation of organ damage.MethodsA retrospective observational single-center study was conducted. All patients underwent blood and instrumental tests to simultaneously identify HES etiology and any organ damage, through a process we called the “two-tailed approach”.ResultsTwo hundred forty-seven patients with HE referred to our center underwent the two-tailed approach. Due to either the presence of a straightforward underlying disease associated with HE, or the lack of sustained hypereosinophilia, 168 patients (68.0%) were excluded from the study. Seventy-nine patients (31 females, 39.2%) with a mean age of 54.9 years were finally diagnosed with HES. 19 (24.1%) patients were diagnosed with reactive HES, 15 (19.0%) with overlap HES, 1 (1.3%) with myeloid-HES, 10 (12.7%) with lymphocytic HES, and 8 (10.1%) with idiopathic HES. Sixty-three patients showed involvement of at least two organs: the lung (32/63, 50.7%), the skin (24/63, 38.1%), the bowel (23/63, 36.5%), and the peripheral nervous system (25.4%). Eight patients (8/63, 12.7%) showed heart involvement. The diagnosis was achieved in 4 ± 1.8 months, and no deaths were observed.ConclusionHE is a common reason for consultations with allergists and clinical immunologists, and the two-tailed approach, which tests simultaneously for diagnosis and organ damage, should be implemented from the initial evaluation of patients with HE. The lower rate of idiopathic HES diagnosis and the higher frequency of heart involvement we found confirm the usefulness of the tool in reducing the risk of mistakes in classifying HES subtypes and the diagnostic delay, thus allowing prompt and tailored treatment and better outcomes.

Background and aim Systemic Lupus Erythematosus (SLE) and Lupus Nephritis (LN) are prototypes of autoimmune diseases. Mechanisms determining the renal evolution in SLE patients and the identification of predictive biomarkers remain an open issue. Methods We reviwed data on serum levels of potential factors involved in SLE pathogenesis (i.e., NETs and dsDNA degradation) and autoantibodies associated with renal pathology (anti-dsDNA, anti-Histone 2 A and 3, anti-C1q, anti-ENO1, anti-ANXA1, anti-SOD2 IgG2) in patients recruited within the Italian collaborative Zeus study at the onset of renal symptoms (T0) and after 12 months (T12). Results Clustering analysis based on a few serum parameters allowed the stratification of LN/SLE/controls into well-separated groups. High dsDNA degradation and high anti-ENO1 antibody levels contributed to stratifying SLE and LN, respectively. Anti-ENO1, anti-SOD2, and anti-H2 A/-H3 antibodies paralleled proteinuria levels during the follow up (high at T0 and normalized after 12 months), whereas anti-dsDNA and anti-C1q IgG2 remained high for the whole observation period. Hazard Risk regression analysis indicated that anti-ENO1 and anti-H2 A IgG2 were associated with proteinuria (>1 g) and renal failure (eGFR <60 mL/min) (HRs and 95% CI highly significant). Conclusions Anti-ENO1 and anti-Histones 2A serum levels identify LN patients at the onset of renal symptoms and decrease following response to therapies. Both antibodies are associated with proteinuria and renal function loss. Our data support their use as predictive biomarkers for LN follow-up.

[This corrects the article DOI: 10.1016/j.waojou.2025.101095.].

Background/Objectives: Systemic lupus erythematosus (SLE) is frequently accompanied by psychological distress. Alexithymia, an impairment in identifying and describing emotions, has been reported in SLE, but its clinical and serological correlates remain insufficiently characterized. We aimed to estimate the prevalence of clinically significant alexithymia in SLE and to explore its clinical, laboratory, and coping-related correlates. Methods: In this cross-sectional observational study, adult outpatients fulfilling the 2019 ACR/EULAR SLE classification criteria were assessed at a tertiary referral centre (2024-2025). Alexithymia was measured using the Toronto Alexithymia Scale-20 (TAS-20), and clinically significant alexithymia was defined as a total score >60. Coping strategies were assessed with the 60-item COPE inventory (Italian version). Clinical indices (SLEDAI-2K, Lupus Low Disease Activity State (LLDAS), and SLICC/ACR Damage Index (SDI)), organ involvement, antiphospholipid syndrome (APS), selected autoantibodies, complement levels, and treatments were recorded. Group comparisons and exploratory logistic regression were performed. Results: Sixty-eight patients were included (94.1% female). Clinically significant alexithymia was present in 23.5%. In univariate analysis, alexithymia was more frequent among patients with APS. Alexithymic participants reported higher use of emotional venting and lower use of positive reinterpretation. In an exploratory multivariable logistic regression model, APS (adjusted OR 35.79, 95% CI 3.74-341.7), emotional venting (adjusted OR 1.684, 95% CI 1.162-2.44), and positive reinterpretation (adjusted OR 0.514, 95% CI 0.349-0.755) remained associated with alexithymia. Conclusions: Alexithymia was frequent in this SLE cohort and, in exploratory analyses, was associated with APS and specific coping patterns. These findings suggest that assessment of emotional processing and coping may provide complementary clinical information, particularly in patients with APS, but should be interpreted as associative and hypothesis-generating.

IntroductionHypereosinophilic syndrome (HES) is defined by persistent hypereosinophilia Q5 associated with eosinophil-mediated organ damage. However, the relationship between HES etiology and organ-involvement patterns remains incompletely defined, particularly in non-hematological forms. This study aimed to describe organ involvement across HES subtypes and to explore clinical associations with multiorgan disease. MethodsIn this retrospective single-center study, 105 patients referred for hypereosinophilia were classified after a standardized two-tailed diagnostic work-up as reactive HES, single-organ HES, lymphocytic-variant HES (L-HES), overlap HES, idiopathic HES, myeloid HES, or HEus. Demographic data, absolute eosinophil count (AEC) at onset, organ domains, organ burden, and exploratory associations with multiorgan disease were analyzed. ResultsMean age at onset was 54.6 ± 18.9 years, and 60.0% of patients were male. Thirteen patients were classified as HEus and had no detectable organ involvement, whereas all HES categories showed at least one involved organ domain. Among recorded organ domains, lung involvement was the most frequent (39.0%), followed by gastrointestinal (30.5%) and cutaneous involvement (29.5%). Peripheral nervous system involvement occurred in 19.0% of patients, whereas cardiac, renal, thrombotic, and central nervous system involvement occurred in 6.7%, 4.8%, 1.9%, and 1.0%, respectively. Multiorgan involvement occurred in 34 patients (32.4%).DiscussionOrgan burden differed significantly across subtypes, with overlap HES, mainly driven by eosinophilic granulomatosis with polyangiitis (EGPA), showing the highest multiorgan burden. L-HES and idiopathic HES were predominantly associated with cutaneous disease, whereas single-organ HES involved only the gastrointestinal tract or lung. AEC correlated with the number of involved organs and was strongly associated with multiorgan involvement. Organ involvement in HES is common, heterogeneous, and unevenly distributed across subtypes. Integrating etiological classification with systematic organ phenotyping may improve risk stratification and guide diagnostic and follow-up strategies.

Objective:To evaluate the effectiveness of belimumab in different joint and skin phenotypes of systemic lupus erythematosus (SLE). Methods:The BeRLiSS-JS 2.0 is a decade-long observational study including adult SLE patients from 14 Italian Centers treated with belimumab (intravenous/subcutaneous) stratified by articular (nondeforming nonerosive arthritis -NDNE-, Jaccoud's arthropathy, Rhupus) and cutaneous phenotypes (acute -ACLE-, subacute -SCLE-, and chronic cutaneous lupus erythematosus -CCLE-, and nonspecific manifestations). Outcome variables measured every 6 months up to 36 months included Disease Activity Score-28 joints (DAS28) and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) scores, remission rates (DAS28<2.6; CLASI-A=0), and prednisone intake (mg/day). Results:Of 443 patients, 221 (49.9%) had NDNE, 30 (6.8%) Jaccoud's arthropathy, 21 (4.7%) rhupus, 112 (25.3%) had ACLE, 54 (12.2%) SCLE, and 18 (4.1%) CCLE. At 6 months a significant decrease of DAS28 was observed in NDNE (p<0.001) and by CLASI-A in ACLE and SCLE (both p<0.001). Non-specific cutaneous manifestations did not improve significantly. CLASI-D scores remained stable over 36 months. Remission rates were higher in NDNE and ACLE patients (at 6 months: NDNE 59.6%, Jaccoud's 18.8%, rhupus 30.3% - p=0.002; at 18 months: ACLE 75.9%, SCLE 56.4%, CCLE 33.3% - p=0.018). Daily prednisone dosage decreased in all organ-specific phenotypes, but more pronouncedly in patients with NDNE, ACLE, and SCLE. Higher baseline CLASI-A and DAS28 and CLASI-D were associated with lower remission rates. Conclusion:Treatment with belimumab was associated with reduced disease activity and increased remission especially in NDNE and ACLE patients. Glucocorticoid-sparing effect was also found.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs and the production of anti-double-stranded DNA (anti-dsDNA) antibodies. This study evaluated the associations between anti-dsDNA levels and smoking, oral corticosteroid (OCS) use, and immunosuppressive therapy in SLE patients. A retrospective monocentric analysis was performed on 119 SLE patients. Data on smoking history, OCS dosage, and immunosuppressive treatments were collected. Anti-dsDNA levels were assessed using fluorescent enzyme immunoassays and confirmed via indirect immunofluorescence. Smoking was significantly associated with higher anti-dsDNA levels (Spearman’s ρ = 0.292, p = 0.0014). Logistic regression identified pack-years (PPY) as a predictor of high anti-dsDNA levels (≥75 U/mL), with a 50% probability at 12.51 PPY and a 75% probability at 17.65 PPY (p < 0.001). OCSs were used by 58.82% of patients, with a median prednisone-equivalent dose of 5.0 mg; higher OCS doses correlated weakly but significantly with anti-dsDNA levels (R2 = 0.066, p < 0.001). Anti-dsDNA levels differed across treatments (p = 0.027): MTX vs. AZA/MMF, and belimumab vs. AZA/MTX. Smoking, OCS use, and immunosuppressants influence anti-dsDNA levels. Belimumab showed greater reduction compared to conventional therapies. Personalized treatment strategies are needed, considering the effects of smoking and cortico-steroids.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organs and systems with a broad and heterogeneous spectrum of clinical manifestations. National disease-specific datasets and registries are crucial for clinical research since they can provide real-world and long-term data about clinical aspects, biomarkers, and treatments. Registries collect data from actual patients over time, outside the controlled environment of randomized controlled trials. This can help enhance the understanding of the natural history of a disease, provide information about how treatments work in everyday settings and elucidate potential variations in care and outcomes across different geographic areas. Here, we present a protocol for the creation of a standardized national disease-specific dataset for patients with SLE—the Systemic Lupus Erythematous Network (LUNET) Registry—which will facilitate data sharing, cross-comparison, and interoperability among centers. The LUNET registry is intended to serve as a comprehensive primary data source, capturing real-world longitudinal clinical information and the heterogeneity of patient presentations that are often underrepresented in traditional clinical trials. Ultimately, the LUNET registry will help to optimize SLE management in routine clinical practice by enabling the compilation of real-world evidence to inform clinical decision-making and health policy.

Objectives To prospectively evaluate the impact and the rapidity of the effect of mepolizumab on the ANCA-associated vasculitis patient-reported outcomes (AAV-PRO) questionnaire and patient global assessment (PtGA) in an international, multicentre cohort of patients with eosinophilic granulomatosis with polyangiitis (EGPA). Methods Patients with active EGPA initiating treatment with mepolizumab were included. PtGA and the AAV-PRO score were assessed at baseline and after 7, 14, 30, 90 and 180 days. Predictors of response of the AAV-PRO questionnaire were investigated. Results Seventy patients were included: female 54.3%, median age 56 years (48—65), 63 (90%) with a relapsing/refractory course. PtGA showed a statistically significant decrease within 7 days. At 14 days, all the AAV-PRO domains, except treatment side effects, showed a statistically significant decline. The improvement at 6 months was greatest in organ-specific symptoms (ratio 0.53), physical function (ratio 0.57), and PtGA (ratio 0.58). PtGA and higher disease activity positively correlated with the AAV-PRO scores throughout the study. Female patients reported a greater burden in terms of systemic symptoms, treatment side effects, social and emotional impact, and concerns about the future. Conversely, age, educational level, damage accrual, mepolizumab dose and ANCA status had no effect on the AAV-PRO scores. Conclusions Mepolizumab was associated with a quick and remarkable improvement of health-related quality of life in patients with EGPA. These findings highlight its early and sustained benefits beyond disease control and support the integration of the AAV-PRO questionnaire into routine clinical practice.

Background: The COVID-19 pandemic significantly increased the demand for allergy consultations to evaluate the risk of hypersensitivity reactions in patients either before receiving their first dose of an anti-SARS-CoV-2 vaccine (Group 1) or following suspected allergic reactions after vaccination (Group 2). Methods: We conducted a retrospective analysis of patients referred to the Immunology and Allergy Unit of the Azienda Ospedaliera Ordine Mauriziano in Turin, Italy, between December 2020 and December 2022. Risk assessment was performed according to Italian and European guidelines, and allergy skin tests were administered when necessary. Patient data were cross-referenced with the SIRVA platform (Regional Vaccination Management Information System) to assess vaccine eligibility, administration, and outcomes. Results: A total of 1222 patients were evaluated (mean age: 52 years; female-to-male ratio 4:1). In Group 1 (n = 914), 137 patients (15%) underwent skin testing, of whom 15 (1.6%) tested positive. Vaccination was recommended for 899 patients (98%), though 184 (20%) did not proceed. Among those vaccinated, 679 (74%) received additional doses, with 48% receiving a third and 11% a fourth dose. In Group 2 (n = 308), 104 patients (33%) underwent skin testing, with 9 (8%) testing positive. Vaccination without restrictions was recommended for 299 patients (97%), but 45 patients (15%) did not proceed. Among the remaining, 262 (85%) received a second dose, 183 (59%) a third, and 29 (9%) a fourth dose. Overall, 1198 patients (98%) had no specific contraindications to vaccination. Only 5 patients (0.4%) were completely exempted from vaccination due to confirmed sensitivity to both polyethylene glycol (PEG) and polysorbate 80 (PS80). An alternative vaccine was recommended for 19 patients; 16 of them proceeded with vaccination and tolerated it without adverse effects. Conclusions: Our findings demonstrate that the majority of high-risk allergic patients can safely receive anti-SARS-CoV-2 vaccines following allergological evaluation. The rate of confirmed excipient allergy was very low, and vaccine adherence was comparable to the general population. This is, to our knowledge, the first study to longitudinally assess the number and types of vaccine doses administered to high-risk allergic individuals.

PV278 / #445 Poster Topic:AS24 - SLE-Treatment To evaluate factors associated with belimumab’s efficacy on different skin and joint manifestations in a nationwide multicenter cohort (BeRLISS-NeJS) of patients with systemic lupus erythematosus (SLE). In this retrospective observational study, adult SLE patients treated with belimumab (10 mg/kg/month IV or 200 mg/week SC) were stratified by joint (non-deforming nonerosive arthritis (NDNE), Jaccoud’s arthropathy, rhupus) and skin phenotypes (acute-ACLE, subacute-SCLE, chronic cutaneous lupus erythematosus-CCLE). We analyzed DAS28, CLASI-A, CLASI-D scores as well as DAS28 and CLASI-A remission rates (respectively DAS28<2.6 and CLASI-A=0) at 6, 12, 24, 36 months from baseline. Parametric and non-parametric tests were used according to data distribution. A total of 443 patients (88.9% female, mean treatment duration 30 months (range 12-60) were enrolled. At belimumab initiation, 272 patients (61.4%) had joint manifestations: 221 NDNE (50.7%), 30 Jaccoud’s arthropathy (6.9%), and 21 rhupus (4.8%); 231 patients (52.1%) had skin manifestations: 112 ACLE (25.3%), 54 SCLE (12.2%), 18 CCLE (4.1%), and 47 aspecific skin manifestations (10.6%). Patients with Jaccoud’s arthropathy or rhupus had a longer disease duration before belimumab initiation compared to NDNE patients. The NDNE subtype was associated with higher DAS28 remission rates than Jaccoud’s and rhupus at 6 and 36 months (Figure). Higher baseline DAS28 in NDNE patients correlated with lower remission rates at 6 and 12 months (p<0.001 and p=0.003). Smoking was associated with less probability to achieve remission at 12 months (p=0.003), while higher baseline prednisone intake was associated with higher remission rates at 12 months (p=0.046). Prior methotrexate treatment was negatively associated with remission at 6 and 24 months (p=0.006 and p=0.027), but concurrent methotrexate treatment did not affect remission rates. In Jaccoud’s patients, baseline DAS28 was not associated with remission rates. Prior methotrexate use was associated with lower remission rates at 12 months (p=0.027) and 36 months (p=0.022). In rhupus patients, higher baseline DAS28 was associated with lower remission rates at 6 months (p=0.016). Concurrent and prior methotrexate use did not influence remission rates. When considering remission in patients with skin manifestations, ACLE showed higher CLASI-A remission rate compared to the SCLE and CCLE at 18, 24, and 36 months (Figure). In ACLE patients, older age at belimumab initiation negatively correlated with CLASI remission at 6 (p=0.047) and 12 months (p=0.015). High baseline CLASI-A negatively impacted on remission at 6 (p<0.001), 12 (p=0.003), and 24 months (p=0.002), but not at 36 months (p=0.082). High baseline CLASI-D was associated with lower remission at 6 (p=0.002), 12 (p=0.030), and 24 months (p<0.001). In SCLE patients, high baseline CLASI-A was negatively associated with remission at 6 (p<0.001), 12 (p=0.001), and 24 months (p<0.001). High baseline CLASI-D correlated with lower remission rates at 6 (p=0.049), 12 (p=0.005), and 24 months (p=0.026). Anti-SSB antibodies at baseline negatively impacted on remission at 6 (p=0.025) and 24 months (p=0.012). In CCLE patients, high baseline CLASI-A negatively impacted remission at 24 months (p=0.016). Baseline CLASI-D did not affect remission; however, this subset had few patients. Figure. DAS28 and CLASI-A remission stratified for different joint and skin phenotypes, respectively. P values were assessed by Chi-squared test with Bonferroni corrextion (α=0.05). Please note that the p-values shown refer to the comparison in remission rotes among different phenotypes for that given timepoint. Patients with NDNE arthritis and ACLE more frequently achieved DAS28 and CLASI-A remission, respectively. Univariate analyses indicated that active disease (high DAS28 and CLASI-A) and damage (high CLASI-D) at baseline were associated with lower remission rates, particularly in NDNE and ACLE patients. Prior methotrexate use was associated to lower remission rates, suggesting that methotrexate-refractory patients may benefit less from belimumab.

Bispecific antibodies (bsAbs) have emerged as one of the most versatile innovations in immunotherapy, capable of simultaneously engaging two distinct epitopes within a single molecule and thereby expanding the functional repertoire of conventional monoclonal antibodies. Their capacity to integrate checkpoint blockade, co-stimulatory activation and cytokine modulation renders them particularly attractive in conditions driven by dysregulated or redundant immune pathways, including cancer, autoimmunity, chronic inflammation and infectious diseases. Technological advances such as knobs-into-holes, dual-affinity retargeting (DART) constructs and IgG-like asymmetric designs have refined stability, pharmacokinetics and manufacturability, enabling clinical translation beyond oncology. Nevertheless, significant challenges remain, including immunogenicity, cytokine release syndrome, neurotoxicity and adaptive resistance mediated by antigen modulation or tissue microenvironmental adaptation. To mitigate these, innovative approaches, ranging from protease-activatable constructs and Fc engineering to albumin-binding fusion proteins and bispecific antibody-drug conjugates, are under active investigation. In addition, bsAbs are being integrated with other immunomodulatory strategies such as CAR-T cells, therapeutic vaccines and checkpoint inhibitors, offering the potential for synergistic benefit across diverse immune-mediated diseases. In this review, we chart the trajectory of bsAb development from molecular design to clinical translation in cancer and immune regulation. We highlight structural optimisation, pharmacokinetic tuning and mechanisms of immune regulation, aiming to provide a framework for their rational use in reshaping immune response in cancer and beyond.