OBJECTIVES:To describe the prevalence of gastrointestinal (GI) symptoms in SSc and Very Early Diagnosis of SSc (VEDOSS), identify clinical and serological features associated with GI involvement and explore a cranio-caudal pattern of symptom distribution, using data from the Italian SPRING-SIR registry. METHODS:This cross-sectional analysis included patients fulfilling 2013 ACR/EULAR SSc or VEDOSS criteria. GI involvement was defined as symptoms in at least one GI tract segment and categorized as upper and lower. Associations between GI involvement and clinical variables were assessed using logistic and ordinal regression models, adjusting for demographics, disease characteristics and autoantibodies. RESULTS:Among 1917 SSc patients, 56% had GI symptoms, associated with longer disease duration, dcSSc, interstitial lung disease (ILD), digital ulcers (DU), telangiectasias and tobacco exposure. Extensive GI involvement correlated with more severe disease. Ordinal regression identified female sex, dcSSc, ILD, DU, telangiectasias, tobacco exposure and anti-centromere antibodies as variables significantly associated with more extensive GI involvement. Disease duration did not show a significant association with GI symptom extent. Among 211 VEDOSS patients, 41.2% reported GI symptoms (mostly oesophageal), significantly associated with puffy fingers and dyspnoea. Among VEDOSS, puffy fingers and anti-centromere antibodies were independent predictors of presence of oesophageal symptoms. CONCLUSION:GI involvement in SSc is linked to more severe disease and longer disease duration. Disease duration resulted linked to the presence of GI symptoms rather than extent of GI involvement. Puffy fingers and anti-centromere antibodies may associate with presence of early oesophageal symptoms in VEDOSS.

Insufficient treatment response is common in systemic lupus erythematosus (SLE) and may be associated with progressive organ damage, yet the molecular underpinnings of treatment resistance remain elusive. RNA sequencing was performed in blood samples from 21 SLE patients who failed to achieve Lupus Low Disease Activity State after six months of treatment with cyclophosphamide (n = 9), rituximab (n = 5), or belimumab (n = 7). Molecular endotypes were identified via unsupervised clustering of Functional Analysis of Individual Microarray Expression (FAIME) scores and cluster stability was validated in an independent cohort (n = 23). Endotype-specific druggability was assessed using the L1000CDS2 platform. The pathway-based molecular stratification revealed three major endotypes among patients with inadequate treatment response: (i) a T cell-centric cluster characterized by enrichment of PD-1 signaling and DNA damage response pathways along with downregulation of CD28 co-stimulatory signaling, indicative of T cell senescence; (ii) a cytokine-driven cluster defined by elevated IL-6 and IL-17 signaling and reduced IL-2 signaling, suggesting a Th17/Treg imbalance and potential responsiveness to cytokine inhibition or low-dose IL-2 therapy; and (iii) an inflammasome-dominant cluster. A multinomial LASSO regression-derived Molecular Endotype Classification Index (MECI) - validated via 1000-fold bootstrap resampling - demonstrated potential as a surrogate marker for endotype assignment (median AUC-ROC 0.889). Transcriptome reversal analysis suggested that patients of the T cell-dominant endotype may be more responsive to CD19 CAR-T cell therapy. In summary, distinct molecular endotypes underlie insufficient response to therapy in SLE, providing a framework for personalized treatment strategies and improved clinical trial design.

Laboratory markers represent a highly valuable tool to support the diagnosis of systemic autoimmune diseases. However, their correct interpretation is essential to avoid misdiagnoses, with particular attention to the most common errors in their clinical use. It is also crucial for clinicians to understand when serological autoimmune markers should be requested, in order to reduce unnecessary, inappropriate, or costly testing for the healthcare system. A diagnostic approach based on the formulation of the right clinical questions is necessary to ensure the appropriate use of immunological markers. This review focuses on the most commonly used and requested autoimmune markers, with particular emphasis on connective tissue diseases and rheumatoid arthritis. Furthermore, common pitfalls and a diagnostic workflow are proposed to assist clinicians in the evaluation of patients with suspected systemic autoimmune diseases.

OBJECTIVES:To assess the relationship between disease duration and the prevalence/distribution of nailfold videocapillaroscopy (NVC) patterns, named according to the current classification as 'early', 'active' and 'late', in a large cohort of systemic sclerosis (SSc) patients. METHODS:A cross-sectional analysis was conducted on 1689 patients undergoing standardized NVC. Clinical-serological data and treatments were collected. Statistical comparisons and multivariable logistic regression models were applied, including analyses based on disease duration. RESULTS:The prevalence of NVC patterns was as follows: 'early' 21.6%, 'active' 47.4%, 'late' 25.7% and normal/non-specific 5.3%. The distribution by disease duration showed that the three main patterns were always present. While the 'early' and 'active' progressively decreased (from 30.3% and 51.9% in patients with ≤5 yrs, to 14.6% and 43.5% in those >10 yrs, P < 0.01), the 'late' pattern increased from 13.2% (≤5 yrs) to 36.0% (>10 yrs) (P < 0.001) and was associated with internal organ involvement, anti-topoisomerase antibodies and more therapies (P < 0.01). Conversely, the 'early' and 'active' patterns were associated with the limited-cutaneous subset (P < 0.01) and anti-centromere antibodies (P < 0.001). Multivariable analysis confirmed a strong association between the 'late' pattern and skin/peripheral vascular involvement. Notably, the presence of the 'late' pattern in patients with ≤2 yrs (10.9%) was significantly associated with scleroderma renal crisis (P = 0.012). CONCLUSION:SSc-NVC patterns are not strictly time-dependent and can be observed at any stage of the disease, suggesting that microvascular damage progression is heterogeneous across different disease periods. Therefore, a revised classification of NVC changes considering both disease duration and NVC severity could improve its prognostic accuracy.

Objective To evaluate the feasibility and safety of belimumab dose spacing and withdrawal in patients with SLE in long-standing remission on belimumab.Methods Patients with SLE fulfilling the 2019 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) criteria who underwent belimumab spacing and/or discontinuation were identified across four tertiary rheumatology centres. The shared belimumab step-down strategy consisted of spacing to subcutaneous (SC) 200 mg/10 days (or intravenous (IV) 10 mg/kg/6 weeks). In the absence of flares, belimumab could be progressively tapered every 6–12 months to SC 200 mg/14 days (or IV 10 mg/kg/8 weeks), SC 200 mg/21 days (or IV 10 mg/kg/12 weeks), SC 200 mg/28 days (or IV 10 mg/kg/16 weeks) and eventually discontinued. Primary endpoint: SLE flares occurrence.Results Among 152 patients with SLE treated with belimumab, 22 (14.5%) underwent spacing for sustained remission (21 females (95.5%), mean±SD age 47±11 years). Spacing patients had longer mean remission duration compared with standard-dose belimumab (67±30 vs 33±32 months, p<0.001), less serological activity (low complement and/or positive anti-double stranded DNA 31.8% vs 54.6%, p=0.048), lower SLE Disease Activity Index 2000 (0.77±1.23 vs 1.98±2.01, p<0.001) and were less often on glucocorticoids (22.7% vs 47.7%, p=0.029) or additional immunosuppressants (0.0% vs 50.8%, p<0.001). During the 21±5.4 months of follow-up, no SLE flares occurred. None of the patients required glucocorticoid dose escalation or reduced the dose interval. Seven patients discontinued belimumab.Conclusion Progressive belimumab dose spacing and withdrawal, coupled with clinical monitoring, could be a practicable approach in selected patients with SLE with long-standing disease remission on minimal glucocorticoid doses, no additional immunosuppressants and low serological activity.

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) significantly impacts exercise capacity and contributes to morbidity and mortality in affected individuals. Inspiratory muscle training (IMT) has demonstrated benefits in improving inspiratory muscle strength and respiratory efficiency in various cardiopulmonary conditions, including interstitial lung disease. This case-control study hypothesises that IMT can enhance inspiratory muscle strength and exercise capacity in patients with SSc-ILD, likely through improved ventilatory patterns during exercise. In this randomised, placebo-controlled trial, 24 patients with SSc-ILD (4 males, 20 females) were randomly assigned to the IMT (n=12) or sham (n=12) groups. The IMT group performed training at 60% of maximal inspiratory pressure (MIP) for 5 weeks, while the sham group received a placebo intervention at 5% MIP. Baseline and post-intervention assessments included pulmonary function tests, 6-min walk test (6MWT) with combined wearable metabolic system to measure minute ventilation (V'E), respiratory frequency (f R), tidal volume (V T) and ventilatory equivalent for CO2 (V'E/V'CO2 ). At rest, IMT increased MIP and prolonged expiratory time. The IMT group showed significant improvements in 6-min walking distance and oxygen uptake during the 6MWT. An increase in V'E was observed primarily through an enhanced V T. These improvements are likely mediated by optimised breathing patterns, potentially reducing physiological dead space thanks to increased V T during exercise. Further studies are needed to evaluate the long-term effects of IMT on functional outcomes.

OBJECTIVE:Mycophenolate mofetil (MMF) use in limited cutaneous systemic sclerosis (lcSSc) is relatively uncommon because of the lower fibrotic burden and the predominance of vascular complications. In vitro observations and clinical data from transplanted patients suggest a protective effect of MMF on endothelial function. Our aim was to evaluate the reasons for prescribing MMF treatment in patients with lcSSc and its impact on the need for escalation of vascular complication-related treatments during follow-up. METHODS:Patients with lcSSc enrolled in the Italian Systemic Sclerosis Progression Investigation registry were retrospectively evaluated. All patients treated with MMF were matched to patients not treated with MMF, which was based on a roll-entry time-dependent propensity score built on demographics, clinical features, and baseline treatment. The escalation of vasoactive or vasodilator treatment up to 60 months was defined as the introduction of iloprost, endothelin receptor antagonists, or phosphodiesterase-5 inhibitors on top of the ongoing treatment, because of uncontrolled or newly diagnosed vascular complications. A hazards Cox model was also adopted to quantify the association of MMF treatment with treatment escalation. RESULTS:A total of 1,435 patients with lcSSc were evaluated, of whom 152 were prescribed MMF (17.1% male; mean age at lcSSc onset 48.7 ± 13.9 years, 54.6% anti-Scl70 positive). The prescription of MMF was more common in men and in anti-Scl70 positive, anticentromere negative patients with interstitial lung disease, myositis, and without a history of digital ulcers. After matching 107 patients with MMF-untreated controls, the overall incidence of vasoactive/vasodilator treatment escalation events related to digital ulcers over a median follow-up of 40.5 months (interquartile range 23.3-60.0) was 0.3 per 100 patient-years in the MMF-treated group and 5.4 per 100 patient-years in the matched control group, with a significant difference in treatment escalation-free survival between the two groups (hazard ratio 0.05, 95% confidence interval 0.01-0.38; P value = 0.004). CONCLUSION:In patients with lcSSc, the introduction of MMF has reduced the need for escalation of vasoactive or vasodilator treatment, suggesting that it may also help to prevent vascular complications, which frequently affect patients with lcSSc.

BackgroundSystemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by loss of self-tolerance, causing inflammation and tissue damage in multiple organs. Although animal models have advanced our understanding of SLE’s molecular basis, recent regulatory changes and longstanding concerns regarding reproducibility and translatability have renewed the need to critically evaluate how these models mirror human disease. Understanding pathway-level similarities and differences between mouse models and human disease is essential, given the marked clinical and molecular heterogeneity of SLE.MethodsFour spontaneous SLE mouse models were studied: MRLlpr/lpr, NZB/W, BXSB.Yaa, and Tlr7.Tg6. Transcriptome sequencing from blood, spleen, and kidney; flow cytometry from the spleen; and cytokines and autoantibody measurement in plasma were performed at four time points. Similar molecular datasets from the human PRECISESADS SLE cohort were used for the integration.ResultsThe study identified specific molecular pathways driving the phenotype in each mouse model and established a framework describing the dynamics of these phenotype-associated molecular signatures, thereby facilitating the selection of time points of interest for future mouse-oriented experimental designs. In addition, by comparing these pathways with those observed in human SLE, we identified the most similar ones and their relationship with disease activity, providing crucial insight into their translational relevance. Importantly, disease severity across models was linked to both the extent and timing of molecular dysregulations. As expected, MRLlpr/lpr showed the most aggressive phenotype with early immune activation and apoptosis dysregulation, while Tlr7.Tg6 presented late-onset signatures associated with interferon and inflammation. Shared molecular features with human SLE included interferon responses, T and B cell depletion, and neutrophil activation. Integration analysis revealed distinct, yet overlapping, immune pathways between models and species, with some signatures such as age-associated B cells and double-negative memory T cells being model-specific but potentially relevant to early disease processes.ConclusionsThese findings provide a valuable framework for future SLE research and reinforce the utility of mouse models for studying specific molecular pathways related to human SLE pathogenesis and heterogeneity. The integration of longitudinal mouse and human molecular information highlights the models that best recapitulate key aspects of human disease, offering guidance for the study of specific immunopathological mechanisms or therapeutic targets.

Background Tocilizumab (TCZ) has shown beneficial effects on interstitial lung disease (ILD) in systemic sclerosis (SSc). We aimed to assess the real-life safety and effectiveness of TCZ on several SSc-related domains using data from a French-Italian multicentre cohort.Methods We conducted a retrospective analysis of patients with SSc treated with TCZ across 15 referral centres. The following clinical data were collected at 12 months before TCZ initiation, at baseline and at 12 and 24 months of treatment: modified Rodnan skin score (mRSS), pulmonary function tests, Disease Activity Score in 28 joints using C reactive protein, digital ulcers and cardiac biomarkers. ILD progression was defined as a decline ≥5 in %predicted forced vital capacity (%pFVC) over 12±3 months.Results 197 patients were included (88% female; median age 57 years; median disease duration 9 years); 67% were antitopoisomerase I positive. TCZ monotherapy was used in 29% of cases, methotrexate was the most frequent combined treatment (35%). In SSc-associated ILD, %pFVC declined significantly from −12 months to baseline (81% to 77%; p=0.003). On TCZ introduction, %pFVC stabilised and the proportion of progressors declined from 43% to 24% (p=0.015). Among diffuse cutaneous patients, mRSS decreased significantly at 12 and 24 months. Digital ulcers, arthritis activity and cardiac biomarkers also improved. Infections were the most frequent adverse events (22.8%). TCZ was discontinued in 32% of patients, mainly for inefficacy. Pulmonary arterial hypertension and older age predicted TCZ failure, whereas elevated CRP predicted better response.Conclusions In this large real-life cohort, TCZ was safe and associated with consistent benefits across different domains, supporting its role as a potential disease-modifying treatment in selected patients with SSc.

Background:The sequence and temporal relationship between Raynaud's phenomenon (RP) and the first non-Raynaud's sign/symptom (NRP) in systemic sclerosis (SSc) have been partially investigated. Objectives:To evaluate whether the mode and ages of clinical onset are associated with disease endotype and survival in SSc. Design:We included SSc patients from the Systemic sclerosis Progression INvestiGation registry of the Italian Society of Rheumatology (SPRING-SIR) registry in a cohort study, with post hoc cross-sectional and longitudinal analysis. Methods:Patients were grouped based on age-RP and age-NRP quartiles. Additionally, categories were defined based on mode of onset: RP group-RP onset at least 1 year before NRP; Simultaneous group-RP onset within the same year of NRP; NRP group-RP onset after at least 1 year after NRP. Comparisons were made using Chi-square and ANOVA tests. Logistic, linear, and multinomial regression models were applied to assess associations, while Kaplan-Meier curves and Cox regression were used to assess mortality. Results:A total of 1748 patients were eligible: 682 (39.0%) in the RP group, 1026 (58.8%) in the simultaneous group, and 39 (2.2%) in the NRP group. A higher prevalence of anti-centromere antibodies was found In the RP group, while the simultaneous group had more diffuse cutaneous SSc (dcSSc), anti-topoisomerase-I antibodies, and higher Rodnan's skin score (mRSS). The NRP group presented higher prevalence of pulmonary arterial hypertension. On logistic regression, the simultaneous group was associated with a higher prevalence of dcSSc compared to the RP group (odds ratio, 1.491, 95% confidence interval (CI): 1.032-2.154). Younger age at RP onset was associated with lower systolic pulmonary artery pressure and mRSS. In 943 patients with available follow-up (median 24 months), the simultaneous group had higher mortality compared to the RP group (hazard ratio, 1.975, 95% CI: 1.002-3.893). Conclusion:The timing of RP and NRP onset may help define SSc endotype and survival. Patients with simultaneous RP-NRP onset have more severe disease features and higher mortality risk, emphasizing the relevance of onset timing in disease stratification.

OBJECTIVES:Systemic lupus erythematosus (SLE) is a complex autoimmune disease with pronounced clinical heterogeneity and symptom burden. Despite growing knowledge of SLE biology, sensitive noninvasive biomarkers for monitoring disease activity remain lacking. This study aimed to characterise the breath metabolome in SLE and to explore associations between volatile organic compounds (VOCs) and clinical features, including disease activity and fatigue. METHODS:Exhaled breath was collected from 30 SLE patients and 30 matched healthy controls using the ReCIVA Breath Sampler and analysed by thermal desorption gas chromatography-mass spectrometry. VOCs were identified using high-resolution libraries and classified by confidence levels. Associations with clinical and patient-reported outcomes were evaluated, including disease activity indices, fatigue scores, Definition Of Remission In SLE remission, and Lupus Low Disease Activity State. RESULTS:Of 1433 detected VOCs, 539 exhibited levels over background and were considered breath-derived. Distinct breathomic signatures discriminated patients from controls and stratified patients by SLE activity and fatigue burden. Five VOC clusters were identified. Methyl acetate was inversely associated with disease activity and fatigue, suggesting a role in immune homeostasis. A cluster of branched alkenes and alcohols was associated with active disease and greater fatigue, aligning with oxidative stress and lipid peroxidation. Nitrogen-containing heterocycles displayed U-shaped patterns across disease states, potentially reflecting varying intestinal permeability. CONCLUSIONS:This is the first study to characterise the breath metabolome in SLE. VOC signatures reflected immunometabolic perturbations, oxidative stress, and gut barrier integrity. Breathomics may provide a noninvasive means to monitor disease activity and symptom burden in SLE.

Objectives Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease with heterogeneous manifestations that cause substantial morbidity and premature mortality. Beyond organ damage, patients experience persistent symptoms such as fatigue, pain, and functional limitation, which profoundly impair quality of life and are often under-recognized by physician-assessed indices.[1] Patient-reported outcomes (PROs) are essential for capturing treatment benefit, yet their responsiveness and alignment with clinical activity across disease trajectories remain incompletely defined. Methods We pooled patient-level data from 4 phase III belimumab trials in adults with active SLE (n=1065). Patients were stratified into 4 previously defined disease trajectory classes according to baseline disease activity (high vs moderate) and treatment response (responder vs non-responder). [2] PROs included Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), 36-Item Short Form physical (PCS) and mental (MCS) component summaries, EuroQol 5-Dimension (EQ-5D), and EuroQoL Visual Analog Scale (EQ-VAS). Responsiveness was assessed with standardized response means (SRMs) across timepoints and classes. Correlations with SLEDAI-2K, BILAG, and Physician’s Global Assessment (PGA) were examined using Spearman’s coefficients and compared with Steiger’s Z (α=0.05). Sensitivity analyses were performed using complete-case datasets at each timepoint. Results FACIT-F and SF-36 PCS were the most responsive PROs and showed the strongest correlations with clinical indices (Table 1). FACIT-F was most responsive early (up to week 20), particularly among non-responders and moderately active responders, while SF-36 PCS was most responsive later (weeks 20-52), especially among responders. EQ-5D consistently demonstrated the lowest responsiveness (peak SRM 0.54) and weakest correlations. PGA correlated most strongly with PRO changes; SLEDAI-2K correlations were weak and inconsistent. Data completeness declined modestly from 95% at baseline to 82% at week 52. Analyses restricted to patients with complete 52-week follow-up yielded results consistent with the main findings, with FACIT-F and SF-36 PCS remaining the most responsive instruments and EQ-5D showing minimal change detection. Table 1. Correlation of patient-reported outcome measures with physician-assessed disease activity indices at weeks 24 and 52, stratified by disease trajectory class. Conclusion This is the first study to longitudinally evaluate PRO performance by disease trajectory in SLE using pooled patient-level data from belimumab trials. We show that PRO performance is dynamic, trajectory-dependent, and domain-specific. FACIT-F and SF-36 PCS consistently outperformed EQ-5D in capturing clinically meaningful change and aligning with physician assessments. The consistently poor responsiveness of EQ-5D underscore limitations of generic preference-based measures in SLE. These findings emphasize the importance of selecting sensitive, patient-centered instruments in clinical trials, routine care, and health technology assessments. Failure to do so risks underestimating the true value of therapies in a complex, symptom-driven disease such as SLE. References [1.] Cornet A. Autoimmun Rev 2025;24:103838. [2.] Parodis I. Rheumatology (Oxford) 2025;64:2697-2705.

OBJECTIVES:Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of mortality in systemic sclerosis (SSc), yet its genetic architecture remains incompletely understood. Therefore, given the key role of the major histocompatibility complex (MHC) in SSc, we aimed to perform a comprehensive MHC-wide association study in the largest SSc-ILD cohort to date. METHODS:We analysed 2412 patients with SSc-ILD⁺, 3550 patients with SSc-ILD⁻, and 15,076 controls of European ancestry from 10 international cohorts. After quality control, the MHC region was imputed, and inverse variance weighted meta-analysis was performed. Subsequently, conditional stepwise analyses, adjustment for antitopoisomerase autoantibody (ATA) status, and functional annotation of significant single-nucleotide polymorphisms were performed. Finally, we constructed a composite score combining genetic, clinical, and demographic variables to predict SSc-ILD. RESULTS:After conditional analysis, we detected 12 significant associations within class I and class II human leukocyte antigen (HLA) genes. ATA adjustment reduced the significance of class II HLA variants, whereas class I HLA variants remained unaffected. Finally, the built composite score had an area under the curve of 0.754, significantly outperforming the models including any of the variables alone. CONCLUSIONS:In this study, we identify genetic mechanisms underlying SSc-ILD that support the potential implication of CD8+ T cells and ATAs in its pathogenesis. Moreover, we also demonstrate the enhanced efficacy of integrating genetic information into predictive models to detect patients at high risk of SSc-ILD. These findings provide new insights into disease pathogenesis and suggest potential biomarkers and therapeutic targets for improved patient management.

Background:Microvascular alterations can be detected with nailfold videocapillaroscopy, useful for systemic sclerosis (SSc) diagnosis upon identification of the "scleroderma pattern" (NVC-SP). However, this pattern is missing in a subset of SSc patients. Methods:This retrospective analysis on the multicenter Italian SPRING cohort of SSc patients assessed the prevalence and characteristics of patients without NVC-SP. Associations with demographic and clinical features were evaluated using logistic regression (cross-sectional) and mixed-effects models (longitudinal). Results:Out of 1689 SSc patients with available NVC information, 90 (5.3%) did not have the NVC-SP. These patients were older at SSc onset (53 vs. 49 years) and more frequently sine scleroderma (31% vs 12%, p < 0.001). The overall burden of vascular complications was milder in this subset, with a lower prevalence of pitting scars (33% vs 48%), telangiectasias (52% vs 74%), and calcinosis (3.4% vs 12%). During the follow-up, mRSS remained lower (60-month mean 4 vs 7, p = 0.002), as well as the estimated probability of vascular complications. Moreover, despite comparable values at baseline, DLCO remained significantly higher in patients without NVC-SP at the following time points (12, 24, and 60 months, p < 0.05). The presence of "late" NVC-SP was independently associated with ILD (OR 1.83, 95% CI 1.05-3.18). Conclusions:The absence of NVC-SP in 5.3% of SPRING SSc patients may identify a subset characterized by milder disease, with a lower burden of vascular and organ complications. Conversely, lung involvement was more frequently observed in patients with more severe NVC microangiopathy.

OBJECTIVES:Giant cell arteritis (GCA) is a clinically heterogeneous disease, which complicates both diagnosis and management. This study aimed to identify genetic risk factors associated with GCA clinical manifestations and evaluate their utility for defining clinical phenotypes. METHODS:Genome-wide genotype data from 3498 patients with GCA and 15,550 controls were analysed to investigate the genetic architecture of GCA manifestations. Logistic regression was used to compare patients with and without each manifestation, as well as each subgroup of patients vs controls. Gene annotation was conducted based on functional information using Functional Mapping and Annotation of Genome-Wide Association Studies (FUMA GWAS). Latent class analysis (LCA) was applied to evaluate the ability of associated variants to classify patients with GCA into genetic subgroups. RESULTS:We identified 7 human leukocyte antigen (HLA) variants specifically associated with different clinical features. Furthermore, 7 non-HLA associations across 6 clinical manifestations were found. Gene prioritisation highlighted biologically relevant candidate genes for GCA pathogenesis, including IL17A (limb claudication) and IL22RA1 (jaw claudication), both involved in the Th17 pathway, and ATP2A2 (extracranial form), encoding a transporter that promotes aortic aneurysms. Notably, LCA grouped GCA clinical predisposition into 4 classes capturing cranial-predominant, mixed, extracranial, and ischaemic/occlusive patterns, the latter representing a high-risk subgroup for severe ischaemic and ocular complications. CONCLUSIONS:This first genome-wide association study stratified by GCA-specific manifestations deepens our understanding of the genetic basis underlying GCA clinical heterogeneity. Our findings highlight HLA and non-HLA contributors to specific disease phenotypes and support the potential of genetic profiling to guide early diagnosis and personalised management in GCA.