Search Results (97)

Nailfold capillaroscopy has earned its place as a cornerstone of clinical assessment in systemic sclerosis (SSc). Its ability to detect early microvascular changes, distinguish primary from secondary Raynaud’s phenomenon, and contribute to disease classification has fundamentally reshaped the clinical approach to early diagnosis and disease stratification. The recognition of distinct capillaroscopic patterns offers a structured framework for tracking disease evolution and identifying patients who warrant closer surveillance or proactive therapeutic intervention. The inclusion of capillaroscopic abnormalities in the ACR/EULAR 2013 classification criteria validates its diagnostic importance and facilitates identification of patients with early or limited cutaneous disease. Beyond diagnosis, emerging evidence supports prognostic applications, particularly for predicting digital ulcers, though the predictive value for other organ complications requires further validation. As a non-invasive, safe, and reproducible technique, capillaroscopy is particularly well-suited to long-term disease monitoring. Quantitative scoring systems allow for rigorous, objective tracking of microangiopathic progression and hold considerable promise as outcome measures in clinical trials targeting vasculopathy. Ongoing technological advances, particularly in automated image analysis and integration with functional assessment tools, promise to enhance the clinical utility of capillaroscopy while reducing operator dependency. Standardization efforts and validation of capillaroscopic parameters as clinical trial endpoints will be crucial for realizing the full potential of this technique. Full article

Background: Sjögren’s disease (SjD) is a chronic autoimmune rheumatic disorder primarily affecting exocrine glands, leading to dryness and systemic involvement. B-cell hyperactivity and autoantibody production drive its pathogenesis and contribute to increased lymphoma risk. Although several long-term studies exist, we present a review of a closely monitored cohort assessed over 40 years. Methods: Retrospective observational study at University College London Hospital included patients fulfilling the 2016 ACR/EULAR criteria for SjD between 1986–2025. Patients with associated SjD were excluded. Associations between serological markers and clinical features were analysed using chi-square or Fisher’s exact tests (p < 0.05). Differences between ethnic groups were also assessed. Results: 283 patients were included, 93.3% female, with mean age at diagnosis of 50.1 ± 15.2 years and mean follow-up of 12.5 ± 8.6 years. Common manifestations were fatigue (61.5%), parotid swelling (30.5%), arthritis (25.8%), and Raynaud’s phenomenon (27.6%). Anti-Ro and anti-La antibodies were present in 75.7% and 45.2%, respectively; rheumatoid factor in 57.3%. Lymphoma developed in 9.9% (mostly non-Hodgkin MALT) and was associated with hypergammaglobulinemia (p = 0.03; RR = 2.56) and parotid swelling (p < 0.001; RR = 5.53). Serological markers correlated with systemic features including lymphadenopathy, vasculitis, and pulmonary involvement. Caucasian patients showed higher mortality (p < 0.001; RR = 3.89) and peripheral nervous system involvement (p = 0.02; RR = 2.18), and less ANA positivity (p = 0.004; RR = 0.88), anti-Ro (p = <0.001; RR = 0.77) and RF (p = 0.04; RR = 0.81) and hypergammaglobulinemia (p = <0.001; RR = 0.63) when compared with non-Caucasian patients. Conclusions: This long-term cohort confirms the strong association between B-cell activation markers and adverse outcomes in Sjögren’s disease. Hypergammaglobulinemia and parotid swelling emerged as key predictors of lymphoma, supporting their role in risk stratification. These findings reinforce the importance of long-term monitoring and may help guide personalized clinical management and surveillance strategies. Full article

Background/Objectives: Predictors of ischemic vascular complications (IVCs)—including coronary artery disease (CAD), ischemic stroke, and digital gangrene—in patients with early SSc remain insufficiently defined. Therefore, we aim to determine the incidence, risk factors, and mortality associated with IVCs in early SSc. Methods: An inception cohort of patients with early SSc at the Rheumatology Clinic, Maharaj Nakorn Chiang Mai Hospital, Thailand, was studied from January 2010 to December 2023. Clinical, laboratory, and cardiopulmonary assessments were performed at baseline and annually thereafter. Results: A total of 146 patients (83 female, 119 DcSSc) were enrolled, with a mean disease duration of 11.5 ± 8.9 months from the first non-Raynaud’s phenomenon (NRP). The mean follow-up was 8.0 ± 3.9 years. Seventeen patients (11.6%) developed IVCs, three CAD, four ischemic stroke, eight digital gangrene, and two digital gangrene plus CAD. The median time to first IVCs was two years. The overall incidence rate of IVCs from the NRP was 1.44 per 100 person-years (95% CI 0.89–2.32). Independent factors associated with IVCs included baseline (BL) digital ulcer, traumatic ulcer, LVEF < 50%, elevated pro-BNP, and any atrial fibrillation. BL pro-BNP and dyslipidemia were independently associated with CAD, whereas BL pro-BNP and any atrial fibrillation were associated with ischemic stroke. BL digital ulcer, traumatic ulcer, and any LVEF < 50% were associated with digital gangrene. All-cause mortality was higher among patients with IVCs than those without (9 [52.9%] vs. 37 [28.7], p = 0.043). Conclusions: In this study, IVCs were uncommon in early SSc, but were associated with increased mortality. Digital ulcers, traumatic ulcers, atrial fibrillation, impaired LVEF, and elevated pro-BNP identified the patients at higher risk of IVCs. Full article

Background: Systemic sclerosis (SSc) is characterized by endothelial dysfunction leading to progressive vascular injury and fibrosis. While microvascular involvement is well established as an early disease feature, macrovascular disease has been historically underrecognized and poorly investigated in very early disease stages. Integrated assessments across the SSc spectrum, including very early diagnosis of systemic sclerosis (VEDOSS), remain limited. Methods: In this cross-sectional observational study, patients with established SSc, VEDOSS, and primary Raynaud’s phenomenon (PRP) were prospectively enrolled between October 2023 and April 2025. Participants underwent comprehensive microvascular and macrovascular evaluation, including nailfold videocapillaroscopy, multisegmental arterial Doppler ultrasound (carotid, aortic, and lower limb districts), flow-mediated dilation, and measurement of endothelial biomarkers (vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and circulating endothelial cells (CECs)). Traditional cardiovascular risk was estimated using Systematic Coronary Risk Estimation 2 (SCORE2). Results: Sixty-two female subjects were included (34 SSc, 14 VEDOSS, and 14 PRP). Microvascular abnormalities followed the expected disease continuum, with capillaroscopic changes present in 57% of VEDOSS and 91% of SSc patients. Although SCORE2 estimates and carotid intima–media thickness were comparable across groups, macrovascular abnormalities were more frequent in SSc (52.9%) and VEDOSS (50%) compared with PRP (21.4%). VCAM-1, ICAM-1, and CEC levels were significantly increased in SSc compared with PRP, whereas no significant differences were observed between VEDOSS and PRP. Conclusions: These findings support a unified micro- and macro-vascular disease model in SSc and demonstrate that macrovascular involvement is detectable already in the VEDOSS phase. Conventional cardiovascular risk scores underestimate the true vascular burden, highlighting the need for disease-specific risk stratification tools integrating vascular imaging and endothelial biomarkers. Full article

Background: Raynaud’s phenomenon of the tongue is a rare manifestation that may be associated with systemic diseases. The clinical manifestations, etiologies and management of this condition are poorly described. Methods: We report 10 cases of lingual Raynaud’s phenomenon (LRP) and 26 cases from a structured literature review. Results: In 38.8% of cases, the LRP occurred in the context of a previously diagnosed systemic sclerosis; 16.6% followed radiotherapy for head and neck cancer; and 27.8% of patients presented with an idiopathic-like form. The manifestations classically included a syncopal phase (91.7%) associated with hypoesthesia (88.9%) and possible dysarthria (52.8%). Atypical presentations with a primary cyanotic phase were also observed, particularly in the context of vasculitis, notably cryoglobulinemic vasculitis (four patients). Active smoking was a significant triggering factor in idiopathic forms (60%). Across all patients—both primary and secondary forms—the most common triggering factor was cold exposure (75%). Vasodilator use showed good efficacy and should be considered for all highly symptomatic patients. Conclusions: In summary, LRP is more frequently associated with systemic sclerosis, manifesting as blanching of the tongue associated with hypoesthesia and dysarthria in more than half of cases. Vasodilators may reduce symptoms. Larger studies are needed to confirm these findings. Full article

Background/Objectives: Interstitial pneumonia with autoimmune features (IPAF) is a recently defined entity characterized by interstitial lung disease (ILD) with clinical, serological, and radiological features suggestive of autoimmunity that do not fulfil the criteria for a defined connective tissue disease (CTD). This study aimed to evaluate the clinical characteristics, treatment modalities, and outcomes of patients with IPAF in a tertiary referral center. Methods: We retrospectively analyzed 72 patients who fulfilled the IPAF classification criteria. Demographic, clinical, serological, radiological, pulmonary function, treatment, and survival data were collected and evaluated. Logistic regression analysis was performed to identify factors associated with mortality. Results: The cohort consisted of 62.5% female patients, with a mean age of 62.7 (SD, 10.4) years at diagnosis. The most frequent radiological pattern was nonspecific interstitial pneumonia (83.3%). Raynaud’s phenomenon (6.9%) and arthritis (2.8%) were the most common rheumatological manifestations. Antinuclear antibodies positivity at titers ≥1:320 was observed in 27.8% of patients. Azathioprine was the most frequently prescribed agent (20.8%), followed by mycophenolate mofetil (11.1%). After a median follow-up of 30.1 months (IQR, 52.8), 16 patients (22.22%) died, with a 5-year survival rate of 70%. Glucocorticoid therapy at doses ≥20 mg/day was independently associated with increased mortality (OR 6.13 (95% CI 1.17–32.21). Conclusions: IPAF predominantly affects middle-aged females. Glucocorticoid use at doses ≥20 mg/day was associated with mortality; however, this observational association may reflect underlying disease severity rather than a causal effect of high-dose treatment. Further prospective studies are needed to optimize management strategies in patients with IPAF. Full article

Background: Limited cutaneous systemic sclerosis (lcSSc) is an autoimmune disease with a wide range of different biomarkers, while inflammation-based ratios have been less extensively investigated. This study aimed to evaluate the associations between inflammation-based ratios, disease-specific parameters, and endothelial dysfunction, as well as to assess the predictive role of inflammation-based ratios in lcSSc. Methods: A total of 38 lcSSc patients and 38 matched controls with primary Raynaud’s phenomenon were analyzed at baseline regarding inflammation-based ratios, lcSSc-specific parameters, and parameters of endothelial dysfunction. LcSSc patients were prospectively observed during a 3-year follow-up period in which lcSSc complications were recorded annually. Results: LcSSc patients had a significantly higher neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio (MLR), fibrinogen-to-albumin ratio, monocyte/high-density lipoprotein (HDL) ratio, and neutrophil/HDL ratio versus controls (all p < 0.05). During follow-up, the MLR, C-reactive protein (CRP)/albumin ratio, monocyte/HDL ratio, and neutrophil/HDL ratio increased significantly (all p < 0.05) in lcSSc patients. The monocyte/HDL ratio correlated positively with the DETECT score step 2 (r = 0.453, p = 0.032) and negatively with the UCLA SCTC GIT total score (r = −0.469, p = 0.024). The CRP/albumin ratio correlated significantly with the EUSTAR index (r = 0.473, p = 0.024) and the fibrinogen-to-albumin ratio correlated with asymmetric dimethylarginine (r = 0.452, p = 0.044). The MLR and CRP/albumin ratio were associated with development of pulmonary arterial hypertension (p = 0.036, p = 0.006), and the lymphocyte/HDL ratio was associated with newly developed interstitial lung disease (p = 0.004). Conclusions: Readily available inflammation-based ratios may reflect vascular and inflammatory activity and could contribute to risk stratification for pulmonary complications in lcSSc; however, these exploratory findings require confirmation in larger cohorts. Full article

Objective: To evaluate the real-world safety and efficacy of macitentan (MACI) in patients with systemic autoimmune rheumatic diseases (SARDs) and refractory digital ulcers (DUs). Methods: We conducted a retrospective observational study of 42 patients treated with MACI (10 mg/day) on a compassionate-use basis across Spanish reference hospitals. Given the cohort’s heterogeneity, a two-step analysis was performed: a global assessment of all patients, followed by a subgroup analysis restricted to those with systemic sclerosis (SSc) or fulfilling very early SSc (VEDOSS) criteria to explore predictors of response. Efficacy was defined as complete healing, partial response, or a lack of response based on physician assessment. Safety was evaluated through analysis of adverse events. Results: In the global cohort, MACI demonstrated a high rate of complete ulcer healing (82.9%) at the 3-month follow-up, with a significant reduction in median ulcer count (p < 0.001). Subgroup analysis within the SSc/VEDOSS cohort (n = 36) revealed that the presence of gastrointestinal involvement (GI) and a higher baseline DUs were significant predictors of a poorer therapeutic response (p = 0.022 and p = 0.028). The drug was well-tolerated; adverse events were infrequent and rarely led to treatment discontinuation. Conclusions: In this real-world refractory population, MACI was associated with rapid DU healing and a favorable safety profile. GI and higher ulcer burden predicted diminished treatment response in SSc patients. These results support the use of MACI as a valuable therapeutic option for severe digital vasculopathy in SARDs, although further prospective studies are warranted to confirm these observations. Full article

Systemic sclerosis (SSc) is a complex connective tissue disease that affects the skin and internal organs and is characterized by immune dysregulation, progressive fibrosis, and microvascular dysfunction. Chronic tissue ischemia, accompanied by impaired angiogenesis, leads to the gradual loss of small vessels, resulting in clinical complications, such as Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, and renal crisis. Emerging evidence highlights the crucial regulatory role of microRNAs (miRNAs) in vascular homeostasis through the modulation of key signaling pathways and endothelial cell activity. Dysregulated miRNAs influence fibroblast proliferation, inflammatory responses, and immune cell activity in SSc, contributing to disease progression. Current knowledge is still limited, highlighting the need for further research to elucidate the miRNAs network involved in the etiopathogenesis of SSc. The use of miRNA-based biomarkers is gaining tremendous attention for early diagnosis, risk stratification, classification, and the prediction of therapeutic responses. This review provides insights into angiogenesis-related miRNAs involved in SSc pathogenesis, discusses their relevance as biomarkers, and explores their promise as therapeutic targets. Advancing our knowledge of miRNAs-mediated regulatory networks may open new possibilities for personalized approaches to SSc management. Full article

Background/Objectives: To compare clinical features of patients with joint hypermobility syndrome/hypermobile Ehlers Danlos Syndrome (JHS/hEDS) who tested positive or negative for anti-nuclear antibodies (ANA), and to determine antibody titers, staining patterns, and reactivity to common nuclear autoantigens. Methods: ANA results were determined by Hep2 immunofluorescence assay. Reactivity to the most common nuclear autoantigens was measured by the Multiplex assay. Clinical manifestations were compared between three subgroups: total ANA+, ANA+ who did not have evidence of systemic autoimmune inflammatory disease (SAID), and ANA−. Results: Of 289 patients, 210 patients had a Beighton score > 5 and were tested for ANA antibodies. One hundred and thirty-one patients had a positive ANA test. Twenty patients in this subgroup were classified as SAID+ while the remaining 111 patients did not meet criteria for any systemic disease. Speckled staining was the most observed pattern in both ANA+SAID+ (75.00%) and ANA+SAID− (72.97%) subgroups. In the latter subgroup, the target of nuclear autoreactivity remained elusive in 80% of patients. The most common clinical manifestations were diffuse arthralgias, myofascial pain, sicca symptoms, Raynaud’s phenomenon, gastrointestinal manifestations, and chronic fatigue. Joint dislocations were observed more commonly in the ANA− subgroup compared to ANA+SAID− patients (30.38% vs. 12.61%, adjusted p < 0.05). Conclusions: Similar clinical characteristics were observed in ANA+ and ANA− subgroups of JHS/hEDS, except for joint dislocations which were more common in the ANA− subgroup. The target of ANA reactivity was unknown in 80% of ANA+JHS/hEDS patients and needs to be determined in future studies. Full article

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), represent a spectrum of systemic disorders characterized by necrotizing inflammation of small- to medium-sized vessels. Nailfold videocapillaroscopy (NVC) is a validated, non-invasive technique routinely employed in the assessment of microvascular involvement in systemic sclerosis and in the differential diagnosis of Raynaud’s phenomenon; its application in the context of AAV, particularly EGPA, has not been investigated yet. The present study aims to assess the presence and the possible pattern of microcirculatory abnormalities detected by NVC in EGPA patients, and to explore potential correlations between capillaroscopic findings and disease activity status. Methods: A total of 29 patients with EGPA (19 women and 10 men), aged between 51 and 73 years, and 29 age- and sex-matched healthy controls were retrospectively enrolled between October 2023 and April 2025, after providing informed consent and meeting the inclusion and exclusion criteria. NVC was conducted in both groups to assess various morphological parameters, and mean capillary density was also calculated. Results: This study observed the presence of capillaroscopic alterations in the EGPA group, including decreased capillary density (38%), neoangiogenesis (72%), rolling (100%), pericapillary stippling (66%), and inverted capillary apex (52%). Overall, when comparing healthy controls with EGPA patients, microcirculatory abnormalities were significantly more prevalent in the latter. Specifically, scores for neoangiogenesis, capillary rolling, pericapillary stippling, and inverted capillary apex showed p-values < 0.001. Conclusions: Our study demonstrates a higher prevalence of four nailfold videocapillaroscopic abnormalities in patients with EGPA compared to healthy controls. However, the identification of these capillaroscopic alterations as specific to EGPA requires further confirmation. Ongoing studies aim to explore the potential role of NVC as a diagnostic marker and to investigate its correlation with the clinical manifestations of EGPA. Full article

Background and Clinical Significance: Antisynthetase syndrome (ASyS) is a rare autoimmune entity defined by the presence of anti-aminoacyl-t ribonucleic acid (RNA) synthetase autoantibodies and classically associated with a triad of interstitial lung disease (ILD), inflammatory myopathy, and arthritis. Additional clinical features may include Raynaud’s phenomenon and “mechanic’s hands”. Among antisynthetase antibodies, anti-PL-12 is notably associated with predominant or isolated ILD and may occur in the absence of clinically evident myositis, thereby complicating timely diagnosis. Case Presentation: We are presenting a 45-year-old non-smoking female patient with a prior diagnosis of seronegative rheumatoid arthritis (RA) who developed progressive dyspnea, dry cough, and sicca symptoms. High-resolution computed tomography revealed a nonspecific interstitial pneumonia (NSIP) pattern. Despite normal creatine kinase and lactate dehydrogenase levels, serological work-up revealed positive anti-PL-12 and anti-Ro52 antibodies, supporting a diagnosis of antisynthetase syndrome without myositis, fulfilling the diagnostic criteria for ASyS per Connors and Solomon. Treatment with corticosteroids and cyclophosphamide induced clinical and functional respiratory improvement, while azathioprine was initiated for maintenance. Conclusions: This case underscores the clinical heterogeneity of antisynthetase syndrome and highlights the diagnostic challenge posed by anti-PL-12–associated ILD in the absence of myositis. Importantly, it demonstrates that in patients with pre-existing rheumatologic diagnoses, the emergence of atypical pulmonary manifestations warrants repeat serologic evaluation to assess ASyS and other autoimmune conditions. Early diagnosis and immunosuppressive treatment are essential to optimize outcomes. Full article

Metabolome studies have already been carried out in patients with systemic sclerosis (SSc). However, polyneuropathy (PNP) as a complication of SSc has been overlooked in these studies. To the best of our knowledge, this is the first study to examine metabolic changes in SSc patients with PNP. Patients with SSc (n = 62) and a healthy control group (HC) (n = 72) were recruited from two Latvian hospitals. Blood plasma samples were collected and analyzed using an LC-MS-based targeted metabolomics workflow. Our plasma sample cohort consisted of 62 patients with SSc, 42% of whom had PNP. Differences between SSc patients and the HC group with fold changes > 2 were observed for aspartic acid, glutamic acid, valine, and citrulline, all of which were reduced. In contrast to the SSc to HC discrimination, no metabolites had a high fold change; only minor changes were observed using FC > 1.3. We identified elevated concentrations of kynurenine, asparagine, and alanine. Changes in metabolite regulation in patients with SSc, compared to controls, are not identical to those observed in SSc patients with PNP, with elevated concentrations of kynurenine and alanine specific to the SSc subgroup. SSc patients with PNP should probably be considered a distinct population with important metabolomic features. Full article

Background: Antiphospholipid syndrome (APS) is one of the highest risk factors for obstetric complications. This article contains a case report of a patient with obstetric APS who experienced fetal loss during their first pregnancy and experienced a successful second pregnancy upon treatment with acetylsalicylic acid (ASA), low-molecular-weight heparin (LMWH), and hydroxychloroquine (HCQ). We compare placental pathology in these two pregnancies and discuss the impact of antiphospholipid antibodies and clinical management on pregnancy outcomes. We also propose methods to monitor obstetric antiphospholipid syndrome (OAPS) patients during pregnancy. Methods: A 26-year-old woman presented with a history of stillbirth at 25 weeks of pregnancy due to placental insufficiency. Before pregnancy, she experienced symptoms suggestive of autoimmune disease (thrombocytopenia, recurrent mouth aphthous ulcers, and Raynaud’s phenomenon) but had no diagnosis. Placental dysfunction correlated with the high ratio of sFlt-1/PIGF (soluble fms-like tyrosine kinase 1 and the placental growth factors index). Laboratory tests revealed the presence of antinuclear antibodies (ANAs) and triple positivity for antiphospholipid antibodies (aPLs). Results: Following the initiation of treatment for OAPS and regular monitoring consistent with current guidelines, the patient conceived and successfully delivered a healthy child. Conclusions: Adequate therapy and close monitoring during pregnancy, including clinical observation, placental biomarkers and regular ultrasonography, may help to reduce the risks and increase chances for optimal pregnancy outcomes. Additionally, pathological examination and clinical collaboration are essential components in future pregnancy counseling and should be a part of multidisciplinary management. Full article

Systemic sclerosis (SSc) is a heterogeneous disease characterized by vascular alterations, immune dysregulation, and fibrosis. Solid evidence supports the hypothesis that endothelial dysfunction is the key player in SSc vascular injury and a critical factor concurring to the initiation of SSc pathogenesis. This narrative review reports on persistent endothelial dysfunction, resulting from oxidative stress, autoimmunity, and impaired vascular repair, in the course of SSc, and how it can trigger and sustain fibrotic remodeling of various organs. In this paper, we also analyze the impact on SSc of impaired angiogenesis and vasculogenesis, diminished endothelial progenitor cell function, and endothelial-to-mesenchymal transition, which can collectively disrupt vascular homeostasis and promote myofibroblast activation. These pathologic events underlie the hallmark clinical manifestations, i.e., Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. The review highlights how recognizing SSc as a paradigm of systemic endothelial dysfunction may reframe our understanding of its physiopathology, modify current therapeutic strategies, and unveil new therapeutic targets. Full article