OBJECTIVES:Pulmonary arterial hypertension (PAH) is a life-threatening complication of systemic sclerosis (SSc). Although selexipag is approved for SSc-PAH, available data are limited. We evaluated the long-term safety and clinical predictors associated with selexipag therapy in a multicentre Italian cohort of SSc-PAH patients. METHODS:We retrospectively analysed consecutive SSc patients with PAH diagnosed by right heart catheterization and treated with selexipag. Survival, treatment persistence, one-year mortality risk (COMPERA 2.0) and predictors of clinical outcomes were assessed using appropriate statistical methods. RESULTS:Fifty-one SSc-PAH patients (94% female, median age 71 years) received selexipag for a median (interquartile range-IQR) duration of 22 (11-44) months. The estimated survival at 3 and 5 years from PAH diagnosis was 88% and 70%, respectively; a lower COMPERA 2.0 was the only significant protective factor. Right ventricular enlargement was associated with higher mortality risk (aOR 0.01, 95%CI 0.01-0.27), higher tricuspid annular plane systolic excursion with lower risk (aOR 1.35, 95%CI 1.04-1.75). After 12 months of treatment, the COMPERA 2.0 was improved in all patients, but a low risk of death was significantly more frequent in patients starting selexipag within one year from PAH onset (38% vs 8%, p < 0.01). Treatment persistence reached 84% at 12 months and baseline combination PAH therapy was associated with lower rates of selexipag discontinuation. CONCLUSIONS:Selexipag demonstrated a favourable long-term safety profile in SSc-PAH patients. A preserved right ventricular function represents a key determinant for survival, while early therapeutic combination strategies including selexipag are associated with more favourable COMPERA 2.0 mortality risk.
SSc is the rheumatic disease with the highest individual mortality rate and is associated with substantial morbidity that severely affects quality of life. Organ fibrosis is a major contributor to irreversible damage in SSc, whereas early inflammatory manifestations largely reflect disease activity and may still respond to early immunomodulatory treatment. New imaging modalities, as well as novel applications of established techniques-such as lung US or improved US assessment of synovial involvement-offer promising opportunities to objectively distinguish activity i.e. early inflammation and early fibrosis from damage (i.e. late irreversible fixed vasculopathy or fibrosis) at the organ level. Differentiating these processes is essential for refining the therapeutic window of opportunity in this rare but devastating disease. This narrative review aims to provide an up-to-date overview of available and emerging imaging tools that may help discriminate activity from damage across organ systems involved in SSc, with a specific focus on early fibrotic and inflammatory manifestations.
OBJECTIVE:To evaluate whether the modified disease activity index (mDAI) predicts subsequent disease progression and organ damage in systemic sclerosis (SSc). METHODS:We analyzed 227 patients diagnosed with SSc who were enrolled in a prospective SSc registry. Baseline disease activity was assessed using the mDAI; with active disease being defined as an mDAI ≥ 2.5. The primary outcome was a composite of disease-related clinically meaningful complications-based on revised CRISS step 1 events (interstitial lung disease progression, precapillary pulmonary hypertension, scleroderma renal crisis, heart failure, severe digital ischemia, or severe gastrointestinal dysfunction)-or all-cause mortality. Associations were examined using Cox proportional hazards models. RESULTS:At baseline, 42 (18.5%) had active disease. During a median follow-up period of 38 months, 45 (19.7%) patients had experienced the primary outcome. Active disease was associated with a higher risk of events (log-rank p < 0.001). In multivariable analysis, baseline active disease (HR 2.21, 95% CI 1.06-4.59) and a lower forced vital capacity (HR 0.98 per %, 95% CI 0.96-0.99) independently predicted adverse outcomes. Results were consistent across sensitivity analyses using alternative endpoint definitions. CONCLUSION:Baseline mDAI and forced vital capacity independently predict disease-related clinically meaningful complications and mortality in SSc. The mDAI provides a simple, feasible tool for risk stratification beyond progression of interstitial lung disease.
OBJECTIVES:To investigate influence of sex, diagnosis (granulomatosis with polyangiitis (GPA) vs. microscopic polyangiitis (MPA)), and familial factors on cardiovascular disease and thromboembolism (CVD-TE) risk in patients with anti-neutrophil cytoplasmic antibody-associated vasculitides (AAV). METHODS:Adults with a diagnosis of GPA or MPA were identified from National Patient Registers (2005-2020) with five age- and sex-matched population controls randomly selected per patient. First-degree siblings of patients and matched controls were included. Outcomes were defined using ICD codes and included myocardial infarction (MI), ischemic or haemorrhagic stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), CVD-TE-related death, and a composite CVD-TE endpoint. Hazard ratios (HRs) with 95% confidence intervals were estimated using Cox proportional hazards models. RESULTS:4,317 AAV patients, 21,582 controls, and 25,568 siblings were included. Both GPA and MPA were associated with increased CVD-TE risk compared with controls (HR 2.04 [1.83,2.38] and HR 2.45 [2.00,2.99]), with no differences between GPA and MPA for individual outcomes. Both sexes had increased DVT and PE risks. In GPA, only males had increased MI risk (HR 2.25 [1.74,2.92]), whereas only females had increased ischemic stroke risk (HR 1.64 [1.25,2.17]). Siblings of AAV patients had no excess CVD-TE risk. The highest CVD-TE risk occurred within three months of diagnosis (HR 7.69 [5.93,9.99]). CONCLUSION:GPA and MPA were associated with comparable increased risks of CVD-TE, with the highest risk within three months following AAV diagnosis and with sex-specific differences in GPA. Lack of increased risk among siblings emphasize the vasculitis per se as a risk factor for CVD-TE.
OBJECTIVES:IgG4-related disease (IgG4-RD) predominantly affects middle-aged and elderly individuals; however, the impact of aging on lesional immune architecture remains poorly understood. METHODS:Bulk transcriptomic analyses were performed using IgG4-RD lesion tissues across a broad age spectrum. Age-associated genes, Hallmark pathways, and immune/stromal module scores were evaluated using correlation-based analyses, network analysis, and fibrosis pseudo-staging. RESULTS:Principal component analysis demonstrated age-associated transcriptomic shifts in IgG4-RD lesions. Aging was associated with increased expression of cytotoxic/exhaustion-related genes, including IFNG, GZMA, GZMH, and PRDM1, together with activation of inflammaging- and senescence-associated programs. Module analysis demonstrated positive correlations between age and fibroblast, exhaustion, macrophage/M2, fibrosis-associated macrophage (FAM), inflammaging, and senescence-associated secretory phenotype (SASP) signatures, whereas germinal center B-cell programs showed minimal association with age. Hallmark pathway analysis revealed enrichment of interferon-γ response, IL6-JAK-STAT3 signaling, TNFα/NFκB signaling, epithelial-mesenchymal transition, and TGF-β signaling in aging lesions. Network analysis demonstrated segregation between adaptive immune modules and aging-associated fibro-inflammatory modules. Advanced fibrosis pseudo-stages were enriched in older patients. CONCLUSIONS:Aging in IgG4-RD was associated with coordinated immune ecosystem remodeling characterized by inflammaging, exhaustion-associated immune programs, stromal activation, and relative reduction in the prominence of adaptive germinal center immunity. These findings suggest that aging-associated immune remodeling may contribute to chronic fibro-inflammatory disease evolution in IgG4-related dacryoadenitis and sialadenitis.
OBJECTIVES:Systemic lupus erythematosus (SLE) with concurrent inflammatory myositis (IIM) has a distinct clinical phenotype, yet its impact on long-term outcomes has been poorly defined. We aimed to determine the risk of mortality, malignancy, and severe renal disease in a large SLE cohort stratified by the presence of myositis. METHODS:We conducted a retrospective analysis of prospectively maintained, single-center cohort of 855 SLE patients followed between 1978 and 2024. Patients were stratified into two groups: SLE without myositis (n = 819) and SLE-myositis overlap (n = 36). Demographic, clinical, serological, and long-term outcome data were compared. Survival was analyzed using the Kaplan-Meier method and multivariable using cox proportional hazards regression. The study was an audit, not requiring formal hospital ethics approval or individual consent, due to the observational retrospective nature of the study using de-identified data-no individualized or identifiable data are presented in this study. RESULTS:Myositis was identified in 4.2% (36/855) of the SLE cohort. The SLE-myositis overlap group was characterized by a higher proportion of patients of Afro-Caribbean ethnicity (38.9% vs. 16.8%; p < 0.001) a greater frequency of interstitial lung disease (ILD) (13.8% vs. 1.2%; p < 0.001) and higher rates of anti-RNP positivity (61.1% vs. 20.1%; p < 0.001). All-cause mortality over a median follow-up of 22.4 years was over two-fold higher in the SLE-myositis group (30.5% vs. 14%; log-rank p < 0.001). Multivariable Cox regression confirmed that the presence of myositis was an independent predictor of mortality. ILD (HR 5.5, 95% CI 3.61-9.6; p = 0.004) and malignancy (HR 3.1, 95% CI 2.9-11.6; p < 0.001) were also independently associated with increased mortality. CONCLUSION:SLE-myositis overlap syndrome represents a clinically important subgroup characterized by a predominance of non-Caucasian patients and a higher burden of extra-renal disease.The presence of myositis is an important prognostic marker associated with increased long-term mortality in patients with SLE.
OBJECTIVES:To validate the diagnostic performance of the HScore for Still's disease (SD)-associated macrophage activation syndrome (MAS; SD-MAS) in adults compared with those of the HLH-2004 diagnostic criteria used with modifications (HLH-04) and the 2016 EULAR/ACR/PRINTO classification criteria for systemic juvenile idiopathic arthritis-associated MAS (MAS-2016). METHODS:This multicentre case-control study, conducted at three medical centres in Japan between 2004 and 2023, enrolled patients ≥16 years with active SD and allocated them into SD without MAS and SD-MAS groups by an expert panel. For each patient, we calculated the HScore, HLH-04, MAS-2016, and modified HScore, which excluded haemophagocytosis on bone marrow aspirate. Receiver operating characteristic curve analysis was used to assess the discriminative ability of each criterion. Logistic regression analysis was performed separately for 'model-1' (HScore and HLH-04) and 'model-2' (MAS-2016 and modified HScore). RESULTS:This study included 86 patients with SD, 25 of whom had SD-MAS. The HScore showed the best area under the curve at 0.991 (95% confidence interval [CI]: 0.977-1.000), with a cut-off value of 192 (sensitivity, 96.0%; specificity, 96.7%). The optimal cut-off for the modified HScore was 171 (sensitivity, 92.0%; specificity, 83.6%). Multivariate analysis identified only the HScore in model-1 (odds ratio [OR]: 1.271; 95% CI: 1.006-1.606), whereas both MAS-2016 (OR: 4.249; 95% CI: 1.636-11.041) and modified HScore (OR: 1.066; 95% CI: 1.017-1.118) were identified in model-2. CONCLUSIONS:The HScore and modified HScore could be useful tools for diagnosing SD-MAS in adults with and without bone marrow aspiration, respectively.
OBJECTIVES:The 'Treat-to-Target' approach significantly improves treatment outcomes in rheumatoid and psoriatic arthritis (RA/PsA). Methotrexate (MTX) is commonly used as a first-line treatment upon diagnosis. However, 50-70% of treated patients do not achieve clinical remission after 6 months. We previously developed a quantitative methylation-sensitive qPCR (qMSP) assay to quantify DNA-methylation levels of the TNFA gene. We demonstrated its predictive value for RA diagnosis. Here, we assessed the utility of this qMSP-assay for predicting MTX treatment outcome and investigated changes in DNA methylation levels after 6 months of MTX. METHODS:Early untreated RA (n = 201) and PsA (n = 77), were included with healthy controls (n = 39). The TNFA-qMSP assay was performed by qPCR on bisulphite-converted DNA extracted from frozen peripheral blood mononuclear cells. The outcome predictive-value of DNA-methylation levels was analysed using binary logistic regression and area-under-the-curve (AUC). RESULTS:Pre-treatment DNA-methylation levels of the TNFA gene were reduced in RA (p = 1.8x10-13) and PsA (p = 0.007) compared to controls. Higher DNA-methylation levels were associated with MTX-induced remission in RA (AUC=0.721) and substantially improved the performance of a predictive model when combined with clinical data (AUC=0.760) compared to clinical data only (AUC=0.699). Levels of methylation reduced over time, irrespective of response to MTX in RA. In PsA, DNA-methylation levels were not associated with treatment outcome. CONCLUSION:The TNF qMSP assay has potential clinical utility as a biomarker for predicting MTX-induced remission specifically in early RA, but not in PsA. However, MTX does not appear to prevent the reduction of DNA-methylation levels at the TNFA loci over time.
OBJECTIVE:To describe clinical phenotype, selected imaging findings and remission trajectories in adults with acute parvovirus B19-associated inflammatory musculoskeletal disease referred for rheumatological assessment. METHODS:This was a non-interventional multicentre observational study in GIRRCS rheumatology units. Adults with new-onset inflammatory musculoskeletal manifestations, positive anti-parvovirus B19 IgM and symptom onset within 4 weeks were enrolled. Clinical, laboratory and clinically indicated imaging data were collected. Time to first documented clinical remission was defined as the interval from symptom onset to the first rheumatologist-confirmed assessment showing resolution of inflammatory musculoskeletal manifestations. Patients requiring disease-modifying escalation were analysed separately. RESULTS:Twenty-four adults were enrolled; 18 were women (75.0%) and mean age was 44.4 ± 14.8 years. Clinical involvement was polyarticular in 14 patients (58.3%) and oligoarticular in 10 (41.7%); enthesitis occurred in 4 (16.7%) and dactylitis was absent. Inflammatory markers were modestly elevated, and most patients with complete autoantibody data were seronegative. Imaging was performed selectively and documented inflammatory abnormalities in clinically indicated examinations. Follow-up data were available for 21 patients, of whom 20 (95.2%) achieved clinical remission without DMARD escalation; median documented remission timing was 21 days (IQR 10-60; range 7-135). One patient required biologic escalation for persistent inflammatory disease. Exploratory regression analyses did not identify robust associations with documented remission timing. CONCLUSION:Acute parvovirus B19-associated inflammatory musculoskeletal disease may mimic inflammatory rheumatic disease in adults referred for rheumatological assessment. Most patients achieved remission without disease-modifying escalation, although remission timing varied and one patient required biologic therapy for persistent inflammatory disease.
OBJECTIVE:To characterize in-hospital mortality, respiratory failure requiring endotracheal intubation and associated comorbidities among hospitalized children with JIA using nationwide data from Thailand. METHODS:This was a retrospective study using administrative inpatient data from Thailand's National database from January 2015 to December 2023. All hospital admissions for patients younger than 18 years with JIA were included. Primary outcomes were in-hospital mortality and respiratory failure, defined by endotracheal intubation. Demographics, JIA subtypes, hospital level, healthcare utilization and comorbidities were analysed. Multivariable logistic regression identified comorbidities independently associated with intubation, reported as adjusted odds ratios (aORs) with 95% confidence intervals. RESULTS:Among 3754 JIA admissions, 52.7% of patients were female, with a median age of 10 years (interquartile range 6-13). Endotracheal intubation occurred in 39 admissions (1.0%), and 17 patients died, yielding an in-hospital mortality rate of 0.5%; mortality among intubated patients was 33.3%. Length of stay and costs were substantially higher among intubated patients and non-survivors. Pneumonia was common in both groups. Myocarditis showed the strongest association with intubation (aOR 294.74), followed by pulmonary haemorrhage, acute kidney injury and septic shock. Macrophage activation syndrome was identified in 43 admissions (1.2%) and was more frequent among non-survivors (23.5% vs 1.0%; P < 0.001). CONCLUSION:Although overall mortality and intubation rates were low, respiratory failure identified a small, high-risk subgroup with substantial mortality and healthcare burden. Severe outcomes were driven by acute multi-organ complications, underscoring early recognition and aggressive management of high-risk comorbidities.
OBJECTIVES:To evaluate the potential of fractional exhaled nitric oxide (FeNO) value in patients with IgG4-related disease (IgG4-RD) as a non-invasive disease activity marker. METHODS:Patients fulfilling the 2019 ACR/EULAR classification criteria of IgG4-RD were enrolled. All patients who had never received oral glucocorticoids underwent FeNO measurement and computed tomography. Disease activity was evaluated using the IgG4-RD responder index (IgG4-RI). The cutoff for FeNO was set at 36 parts per billion (ppb), based on a Japanese normal upper limit. Spearman's rank correlation was used to assess the association between FeNO values and clinical parameters. Receiver operating characteristic analysis was used to identify the involvement of specific organs. RESULTS:A total of 35 patients (21 males, 72.0 [IQR 64.5, 77.0] years old) were enrolled. The median FeNO value was 48.0 [IQR 33.0, 99.5] ppb, with 23 (65.7%) patients exceeding the cutoff. The FeNO value was correlated with serum IgG4 levels (r = 0.48, P = 0.020), the number of organ involvements (r = 0.47, P = 0.020) and IgG4-RI (r = 0.47, P = 0.020). Dividing into two groups by the FeNO cutoff, lung involvement was more frequent in the high FeNO group (8.3% vs. 52.2%, P = 0.029). Area under the curve for the lung involvement was 0.88, and the optimal cutoff for identifying lung involvement using the Youden index was 55.2 ppb. CONCLUSION:FeNO value was elevated in patients with IgG4-RD and was associated with disease activity. Moreover, it can be associated with lung involvement.
OBJECTIVES:Systemic autoimmune rheumatic diseases (SARDs) relapse and remit, with periods of increased disease activity called "flares". This study compared patient and clinician perspectives of flares. METHODS:Mixed-methods approach combining an international co-produced survey and in-depth interviews. SLE patients and clinicians rated statements about flares on Likert scales from "never" to "always". Quantitative data were analysed using t-tests and ANOVA. Patient and clinician interviews were analysed thematically. Quantitative and qualitative analyses were triangulated by exploring converging, diverging and explanatory findings across the datasets. RESULTS:Qualitative (N = 31 SARD patients, N = 12 clinicians) and quantitative (N = 443 SLE patients, N = 258 clinicians) results indicated differential patient and clinician perspectives. The main themes identified were: characteristics/consequences of flares; recognition of flares; and treatment for flares (medical and/or self-management). Patients and clinicians had significantly different mean ratings for 12/17 flare statements. Notably, regarding flare onset, 39% of patients compared to 14% of clinicians said flares "often" or "always" started within minutes or hours (p < 0·001). We found differences in identification of flares, with patients rating "patient can tell" significantly higher than clinicians (p<·001), including awareness of prodromal symptoms. Clinicians were significantly more likely to think flares required increased (p = 0·005) or new (p<·001) medication. There was consensus about the impact of flares on wellbeing. CONCLUSION:We highlight differences in how SARD patients and clinicians describe flares, notably related to onset, recognition and intervention. These differences challenge the prevailing reliance on clinician-derived disease activity measures and biomarkers for flare assessment, highlighting the need for integration of patient and clinician perspectives.
