Connective Tissue Disease Research Articles

Multiparametric risk predictions for morbidity and mortality in patients with pulmonary arterial hypertension: insights from a nation-wide registry

Abstract Background and aims In this retrospective analysis of a nation-wide registry on pulmonary arterial hypertension (PAH), group IV and V, we aimed to evaluate risk predictions for morbidity and mortality. Methods This study included 903 patients enrolled from 24 cardiology centers participating in the RegiStry on clInical outcoMe and sUrvival in pulmonaRy hypertension Groups (SIMURG II). ESC/ERS 2022 risk scoring, COMPERA 2.0 and REVEAL lite 2 models were used for baseline risk predictions, and COMPERA 2.0 model was used for risk evaluation at follow-up. Composite endpoint (CEP) definitions were adopted from the SERAPHIN and GRIPHON trials. Results Age (mean +SD) was 51.27 + 21.37 years, and 72 % of patients were female. Incident cases were noted in 65.9 % of overall study group. Idiopathic PAH (IPAH), PAH-associated with congenital heart diseases (CHD-PAH), PAH-associated with connective tissue diseases (CTD-PAH), porto-PAH, Group IV and V pulmonary hypertension (PH) were documented in 33 %, 33.5 %, 12 %, 1.6 %, 20 % and 1.7 % of overall patients, respectively. Background mono and dual targeted combinations, and sequential dual or triple combinations were noted in 17 %, 57 % and 26 % of patients, respectively. According to the ESC/ERS 2022 baseline risk scoring, low-, intermediate-, and high-risk were noted in 1.2 %, 14.1 %, and 84.7 %, respectively. Median follow-up time was 867 (412-1667) days. Overall rates of mortality and CEP were 26 % and 39%, respectively. Prevalent versus incident cases were associated signifinatly lower mortality and CEP ( p=0.028 and p=0.024, respectively). Mortality and CEP rates were 31 % and 44 % in IPAH, 20 % and 39 % in CHD-PAH, 31 % and 43 % in CTD-PAH, and 25 % and 30 % in group IV patients, respectively. Baseline high versus intermediate /low risk status were associated with a lower survival estimates for mortality and CEP in patients with PAH ( p=0.03 and p=0.003, respectively). Baseline COMPERA 2.0 risk status revealed significant differences in overall survival and CEP-free survival among risk groups ( p<0.0001 for both), but 1st year COMPERA 2.0 score did not (p=0.39 and p=0.06, respectively) . As compared to baseline, 1st year COMPERA 2.0 score decreased in 31 %, and remained unchanged in 34 % of patients. Baseline REVEAL lite 2.0 score was associated with mortality (hazard ratio (HR): 1.14;1.08-1.2, p<0.0001) and CEP (HR:1.17;1.1-1.25, p<0.0001) risks. Male sex (HR: 1.73; 1.2-2.51, p = 0.004), six-minute walk distance (p<0.001), functional class III/IV (HR: 2.52;1.47-4.32, p<0.001) and baseline low-risk status (HR:0.37;0.21-0.65, p<0.001) were independent predictors of mortality. Conclusions Our nation-wide data revealed current insights concerning the multiparametric risk predictions for morbidity and mortality in PAH.

Systemic manifestations of connective tissue abnormalities in patients with Mitral Valve Prolapse assessed by Cardiac Magnetic Resonance

Abstract Background Mitral valve prolapse (MVP) reflects a connective tissue abnormality of the mitral leaflets leading to myxomatous degeneration. Early echocardiography and semeiotic assessment investigations suggested that connective tissue abnormalities might be extended to heart chambers, great vessels, and the skeletal system. Cardiac Magnetic Resonance (CMR) has unique potentials in evaluating MVP, cardiac chambers, aortic dimensions, and Haller Index, an expression of the deformity of the thoracic cage, at one time. Purpose We aimed to investigate the potential phenotypic systemic expressions of connective tissue disease in patients with MVP by CMR assessment. Methods This case-control study included consecutive patients with MVP and a control group of healthy volunteers undergoing CMR at our Institution from September 2020 to November 2023. Patients with more than mild mitral or aortic regurgitation, bicuspid aortic valve, or known systemic connective diseases were excluded. The MVP, cardiac chambers, aortic dimensions, and Haller Index were assessed according to standard practice. Results 103 patients with MVP and 57 healthy volunteers (51± 17 vs. 47±18 years, p=0.2, and 5% females vs. 54.4% females, p=0.8, respectively) were enrolled. Patients with MVP showed greater left ventricular end-diastolic (91±25 vs. 78±17 ml/m2; p=0.005) and end-systolic volumes (36±12 vs. 27±6; ml/m2; p<0.001), aortic annulus (13±2 vs. 12±2 mm/m2; p<0.001), sino-tubular junction (15±3 vs. 14±3 mm/m2; p=0.03), aortic root (19±3 vs. 17±3 mm/m2; p<0.001), and descending aorta (13±2 vs. 12±2 mm/m2; p=0.03), and higher Haller Index (2.8±0.6 vs. 2.6±0.4; p=0.02) than healthy controls. No differences were found in ascending aorta (18±3 vs. 17±3 mm/m2; p=0.3), pulmonary trunk (13±2 vs. 13±2 mm/m2; p=0.5), left atrial volume (38±18 vs. 30±15 ml/m2; p=0.20), right ventricular end-diastolic-volume (86±20 vs. 81±20 ml/m2; p=0.3) were found. At ANCOVA, sex and MVP affected the Haller Index values (p = 0.005 and 0.04). The association between MVP and Haller Index persisted after controlling for sex, age, and body surface area. In multivariate regression analysis, MVP and sex had an independent impact on ventricular and aortic dimensions, with MVP and male patients showing greater values. In particular, MVP was associated with an increase in the aortic annulus (Coefficient=1.2; p< 0.001), aortic root (Coefficient=1.5, p=0.001), descending aorta (Coefficient=0.7, p = 0.026), left ventricular end-diastolic-volume (Coefficient=11.1, p=0.01) and mass (Coefficient=5.7, p=0.02) after controlling for sex, age, and body surface area. Conclusions This pivotal study assessing systemic connective tissue disorders by CMR suggests abnormalities in the aorta and the skeletal system of patients with MVP, paving the way to larger investigations exploring the clinical impact of these findings.CMR findings in the study populationBox plots showing variables distribution

Recruitment of CCR5-positive T cells in pulmonary vascular lesions in idiopathic- and connective tissue disease associated- pulmonary arterial hypertension

Abstract Background C-C chemokine receptor type 5 (CCR5) is a chemokine receptor predominantly expressed on leukocytes including T cells, macrophages, and dendritic cells, and is involved in the process by which T cells are attracted to specific tissues and organs. Although CCR5 has been shown to be expressed on macrophages and pulmonary artery smooth muscle cells in lung samples from human idiopathic pulmonary arterial hypertension (PAH) and some animal models, its expression on T cells in human PAH lungs has not been investigated. Purpose To investigate the immunohistochemical expression of CCR5 on T cells infiltrating in pulmonary vascular lesions of human PAH tissues, particularly from patients with idiopathic PAH and PAH associated with connective tissue disease (CTD-PAH), where inflammation has been implicated in the pathogenesis. Methods Subjects included 25 postmortem cases of idiopathic PAH (14 cases, a mean age of 34 ± 10 years, 8 female cases) and CTD-PAH (11 cases, 48 ± 13 years, all female). We performed immunohistochemistry using antibodies against CCR5 and CD3 (for T cells) on formalin-fixed paraffin-embedded sections. To semi-quantify, we selected the three small muscular pulmonary arteries (80-150 µm in external diameter) with the strongest CCR5-positive cell infiltration in each case, counted the number of positive cells, and the average were shown as the number of cells per vessel. Results In all cases, regardless of whether IPAH or CTD-PAH, a subset of infiltrating inflammatory cells into or accumulating around vessels was CCR5-positive. Specifically, CCR5-positive inflammatory cells were found in remodelled pulmonary arteries, such as plexiform lesions and constrictive lesions with intimal thickening and/or medial hypertrophy, as well as perivascular space. The average number of CCR5-positive cells per small muscular pulmonary artery was 8.1/vessel. Where pulmonary venous occlusive lesions were seen, CCR5-positive cells were also present in and around them. The majority of CCR5-positive inflammatory cells appeared to be T cells, based on morphology and CD3 immunopositivity in the serial sections. Conclusion(s) Activated T cells showing CCR5 immunopositivity were recruited to remodelled pulmonary vascular lesions in both idiopathic PAH and CTD-PAH. This implicates CCR5-positive T cells as a common key player and that CCR5 signalling is involved in the pathogenesis of PAH in concert with other inflammatory cells, vascular endothelial cells, and pulmonary artery smooth muscle cells.

Rheumatoid arthritispresenting by combined pulmonary fibrosis and emphysema with clubbing and pulmonary hypertension: A rare case report.

A 60-year-old male smoker came with dyspnea. A rare condition known as combined pulmonary fibrosis and emphysema (CPFE) was observed on a chest CT scan. Decreased DLCO in combination with normal FVC can help diagnose CPFE. Concomitant connective tissue diseases, including rheumatoid arthritis, should be checked in CPFE patients.

Association of lifelong exercise characteristics with aortic pathology in patients with Marfan syndrome

Abstract Background Marfan syndrome (MFS) is a genetic connective tissue disease with an increased risk for aortic root dilatation and aortic dissection. Current guidelines, based on expert consensus, recommend exercise restrictions due to concerns that exercise-induced hemodynamic stress may accelerate aortopathy. Studies examining exercise characteristics and their association with aortopathy in MFS patients are lacking. Purpose To assess the association of lifelong exercise characteristics (volume, intensity and type) with the presence of aortic dilatation in MFS patients. Methods An international multi-centre study was conducted in MFS adults. Patients were classified as sedentary (<500 metabolic equivalent of task minutes per week [MET-min/wk]), active (500-1000 MET-min/wk), or highly active (≥1000 MET-min/wk) based on lifelong exercise volumes assessed by a validated questionnaire. Patient’s dominant exercise intensity was classified as moderate (3-6 MET) or vigorous (≥6 MET), and sport type as skill, power, mixed, or endurance. Echocardiography was used to assess diameters at the sinuses of Valsalva (SoV) and ascending aorta (AA), and Campens Z-scores were calculated. Aortic dilatation was evaluated as a diameter ≥40, ≥45 mm, a Z-score ≥2 or ≥3 respectively. Results 315 patients (36[27-49] years, 53% male) were included of which 104 were sedentary, 77 active and 134 highly active (Fig. 1). 42 patients did not perform sport-related exercise, whereas 147 and 121 patients predominantly participated in moderate or vigorous intensity sports. Patients performing sports were allocated to the skill (n=13), power (n=27), mixed (n=158), endurance (n=66) or non-dominant (n=9) exercise type group. Mean SoV and AA diameters were 42.9±7.7 mm and 33.9±7.3 mm. SoV or AA diameters of ≥40 mm were present in 200 (64%) and 41 (13%) patients, whereas 223 (71%) and 81 (26%) patients had a Z-score ≥2 for the SoV or AA. Exercise volume was not associated with SoV dilatation (Fig. 2). Moderate and vigorous intensity sports were associated with a lower prevalence of SoV Z-score ≥3. Power sport was associated with a lower prevalence of all definitions of SoV dilatation, whereas mixed and endurance sports were associated with a lower prevalence of SoV Z-score ≥3. No associations were found with AA dilatation. Of the 17 (5%) patients who suffered from an aortic dissection, 1 case occurred during walking (type A dissection) whereas all other cases were not exercise-related. Conclusions Lifelong exercise volumes were not associated with aortic dilatation in MFS patients. Power sports and vigorous intensity exercise were inversely related to SoV dilatation. Further investigation is warranted to clarify whether this association reflects that patients engaging in these activities have a less severe cardiovascular phenotype, or that they are protected from exercise-related aortic complications, and if patients may miss health benefits due to too exercise restrictions.

Immunological characteristics of bronchoalveolar lavage fluid and blood across connective tissue disease-associated interstitial lung diseases.

Interstitial lung disease (ILD) is a serious complication of connective tissue diseases (CTDs). The heterogeneity of ILDs reflects differences in pathogenesis among diseases. This study aimed to clarify the characteristics of CTD-ILDs via a detailed analysis of the bronchoalveolar lavage fluid (BALF) and blood immune cells. BALF and blood samples were collected from 39 Japanese patients with newly diagnosed ILD: five patients with Sjögren's syndrome (SS), eight patients with dermatomyositis (DM), six patients with rheumatoid arthritis (RA), six patients with systemic sclerosis, four patients with anti-neutrophil cytoplasmic antibody-associated vasculitis, and 10 patients with idiopathic interstitial pneumonia. We performed single-cell RNA sequencing to analyze the gene expression profiles in these patients' immune cells. In patients with SS, B cells in the BALF were increased and genes associated with the innate and acquired immunity were enriched in both the BALF and blood. In contrast, patients with DM showed an upregulation of genes associated with viral infection in both the BALF and blood. In patients with RA, neutrophils in the BALF tended to increase, and their gene expression patterns changed towards inflammation. These disease-specific characteristics may help us understand the pathogenesis for each disease and discover potential biomarkers.

Antibodies to HIV-1 gp120 in an experimental model of atherosclerosis caused by immunization with native high-density lipoproteins

Antibodies to bacterial and viral antigens are detected in some systematic autoimmune diseases in the absence of infection. Autoimmune MRL mice and patients with mixed connective tissue disease produce antibodies to gp120 HIV-1, despite the fact that they had never been exposed to HIV-1. Conversely, viral infections may be accompanied by pathological autoimmune reactions. Reactivity to viral antigens in autoimmune diseases and autoimmune reactions in viral diseases are caused by the induction of antibodies via idiotype-anti-idiotype interactions between autoclones and lymphocyte clones against foreign antigens or homology of foreign antigens and autoantigens. Cardiovascular diseases caused by atherosclerosis are currently one of the main causes of mortality in HIV infected patients. It is assumed that HIV infection accelerates atherogenesis. The mechanisms of the association between HIV infection and atherosclerosis are not completely clear. Chronic activation of the immune system, disturbance of cytokine regulation caused by HIV infection, induction of autoantibodies against oxidized low-density lipoproteins (LDL) and antibodies to ApoB-D are considered as possible factors of atherogenesis in HIV infection. The aim of this research was to determine whether an atherogenic immune response against native human high-density lipoproteins (nHDL) could induce antibodies to gp120 HIV-1. Studies were conducted on model of autoimmune atherosclerosis caused by immunization with native human HDL in rabbits. Rabbits (n = 6) were one-time intradermally immunized with human nHDL at a dose of 200 μg of protein per animal in incomplete Freund’s adjuvant. Antibodies to gp120 HIV-1 were measured before immunization of rabbits and on the 28th and 42th day after immunization with HDL, and antibodies to HDL were weekly measured within 42 days after immunization. Histological analysis of the aorta was conducted after eight months after immunization. Transient anti-gp120 HIV-1 antibody production was detected in rabbits immunized with native HDL. The appearance of antibodies to gp120 HIV-1 in response to immunization with native HDL which causes atherosclerosis suggests that the immune response to gp120 HIV-1 during HIV infection may be accompanied by the production of atherogenic antibodies to HDL. Consequently, the antibodies to native lipoproteins caused by an immune response against gp120 HIV-1 may be a factor in atherogenesis during HIV-1 infection.

Capillaroscopic Insights: Exploring the Connection Between Microvascular Changes and Pulmonary Manifestations in Systemic Sclerosis.

Systemic sclerosis (SSc) is a complex connective tissue disease characterized by microangiopathy, immune dysregulation, and fibrosis. Early detection of microvascular abnormalities using nailfold videocapillaroscopy (NVC) is crucial in assessing disease progression and associated disease's involvement such as interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). This study aims to explore the relationships correlation between NVC patterns, clinical manifestations, and systemic complications in SSc. We analyzed the data of 63 patients, predominantly female (95%), with a mean age of 49 years and an average disease duration of 42 months. Patients were categorized into early, active, and late patterns based on NVC findings. Clinical features, including digital ulcers (DU), ILD, and PAH, were assessed. Pearson correlation analyses were performed to evaluate the relationships between capillary loss, neoangiogenesis, ILD, and PAH. The early pattern group (mean mRSS 2.36) exhibited minimal microvascular damage and systemic involvement, with no DUs. In the active pattern group (mean mRSS 10.40), 34.38% had diffuse cutaneous SSc (dcSSc), with 15.63% presenting DUs, 65.63% ILD, and 37.5% PAH. The late pattern group (mean mRSS 18.00) showed the most severe disease, with 80% having DUs, 70% dcSSc, 90% ILD, and 70% PAH. Pearson correlation analyses revealed strong correlations between capillary loss and ILD (r = 0.7255) and PAH (r = 0.6369). A moderate correlation was found between neoangiogenesis and PAH (r = 0.5592). The study demonstrates that progressive microvascular damage in SSc, as visualized by NVC, correlates strongly with the severity of systemic complications. Early detection of capillary loss and neoangiogenesis using NVC is critical for timely interventions, which could improve patient outcomes by mitigating the progression of ILD and PAH.

Autoantibody against aquaporin-5 may be a new diagnostic biomarker for primary Sjögren's syndrome.

The study aims to assess the diagnostic and clinical significance of autoantibodies against aquaporin-1 (anti-AQP1) and aquaporin-5 (anti-AQP5) in primary Sjögren's syndrome (pSS). A total of 163 participants were categorized into three groups: pSS group, other connective tissue diseases (CTD) group, and healthy control (HC) group. The levels of anti-AQP1 and anti-AQP5 autoantibodies in serum were determined using enzyme-linked immunosorbent assay (ELISA), and clinical data from patients were collected for statistical analysis. Our results showed that the level of anti-AQP1 in the pSS group was higher than in the HC group (P < 0.05), and no significant difference was observed between the pSS group and the CTD group (P > 0.05). ROC showed that the anti-AQP1 had no diagnostic value for pSS (P > 0.05). The anti-AQP5 level of 39 healthy adults was all below the cut-off value (14.10ng/ml) (P < 0.05). The level of anti-AQP5 in the pSS group was higher than the CTD group (P < 0.05), the AUC was 0.86 (95% CI 0.80-0.93), with a sensitivity of 0.95 (95% CI 0.87-0.99) and a specificity of 0.70 (95% CI 0.58-0.84). No correlation was found between anti-AQP5 levels and the EULAR primary Sjögren's syndrome disease activity index score, anti-SSA, anti-SSB, antinuclear antibodies, rheumatoid factor, anti-ds-DNA, salivary gland flow rate, complement 3, and lymphocyte count in pSS samples (P > 0.05), respectively. Therefore, the elevated anti-AQP5 may emerge as a novel diagnostic biomarker for pSS patients due to high sensitivity and specificity.

Nerandomilast Improves Bleomycin-Induced Systemic Sclerosis-Associated Interstitial Lung Disease in Mice by Regulating the TGF-β1 Pathway.

Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common complication of SSc and a major contributor to SSc-related deaths. Besides nintedanib and tocilizumab, there are currently no clinically approved drugs for SSc-ILD, highlighting the urgent need for new treatment strategies. Previous studies have shown that cyclic adenosine monophosphate (cAMP) plays a crucial role in the pathogenesis of SSc and lung fibrosis. Phosphodiesterases (PDEs) are enzymes that specifically hydrolyze cAMP, making PDE inhibitors promising candidates for SSc-ILD treatment. Nerandomilast, a preferential phosphodiesterase 4B (PDE4B) inhibitor currently undergoing phase III clinical trials for idiopathic pulmonary fibrosis and progressive fibrosing interstitial lung diseases (PF-ILD), has good preference for PDE4B but lacks studies for SSc-ILD. Our research demonstrates that nerandomilast effectively inhibits skin and lung fibrosis in a bleomycin-induced mouse model of SSc-ILD. For lung fibrosis, we found that nerandomilast could improve bleomycin-induced SSc-ILD through inhibiting PDE4B and the TGF-β1-Smads/non-Smads signaling pathways, which provides a theoretical basis for potential therapeutic drug development for SSc-ILD.

Fibroblast activation protein inhibitor PET/CT as an emerging diagnostic modality in interstitial lung disease and other fibrotic conditions.

Interstitial lung diseases (ILD) encompass a wide range of disorders characterized by alveolar inflammation and fibrotic tissue remodeling, marked by significant morbidity and mortality. Systemic sclerosis (SSc), among other connective tissue diseases, is a frequent cause of ILD. Assessment of pulmonary fibrosis is frequently constrained by the delayed manifestations of profibrotic activation of fibroblasts, which results in late macroscopic alterations detectable by standard imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) scans. 68Ga-labeled fibroblast activation protein inhibitors (68Ga-FAPI [fibroblast activation protein inhibitor]) are novel radionuclides used in the selective positron emission tomography/computed tomography (PET/CT) detection of profibrotic fibroblasts, a key player in fibrotic tissue remodeling. Application of 68Ga-FAPI in different target organs undergoing fibrosis, such as lung and heart, highlights its efficacy in detecting ongoing fibrotic processes, since FAPI tracer uptake has been correlated with clinical disease progression markers in SSc-ILD. This feature could enable physicians to detect subclinical fibrotic activity and tailor an individualised therapy plan on a case by case basis. The use of 68Ga-FAPI in ILD and other fibrotic conditions may emerge as a novel tool in future clinical practice for both activity monitoring and treatment optimisation. Other tracers tested in ILD of different etiologies have shown promising results and may in future also be considered for potential application in SSc-ILD.

Use of rituximab in the of immunoinflammatory rheumatic diseases combined with Graves' disease (autoimmune polyglandular syndrome in adults): case report and literature review

Rituximab (RTM) is a chimeric (murine and human) monoclonal antibody against B-lymphocytes (CD20). RTM is widely used in hematology for lymphoproliferative diseases and in rheumatology for rheumatoid arthritis, Sjögren's disease, some types of vasculitis and systemic connective tissue diseases. The administration of RTM is associated with a depletion of B-cells mediated by the regulation of apoptosis and cytotoxic effects via complement-dependent and antibody-dependent mechanisms. Considering the pathogenesis of autoimmune damage in Graves' disease (GD), an autoimmune thyroid disease associated with thyrotoxicosis, the use of RTM could be effective in this pathology. We present three patients with a combination of diffuse toxic goiter and rheumatic pathology treated with RTM; different outcomes of GD were observed.

The frequency of fibromyalgia in patients with systemic lupus erythematosus and associated factors: a systematic review and meta-analysis.

Fibromyalgia (FM) in systemic lupus erythematosus (SLE) patients contributes to increased fatigue, anxiety, depression, and mental exhaustion. This study's objective is to systematically review the literature and to determine the frequency of FM in patients with SLE and its associated factors. A literature review was conducted to assess the prevalence of FM in SLE patients and to identify FM-associated factors. This involved searching the PubMed and Cochrane Library databases from 1959 to 2023. Cohorts, case-control, and population-based studies were included, while those not focusing on FM rates in SLE patients were excluded. Data on FM-associated factors and FM frequency in control or connective tissue disease (CTD) groups were obtained if available. Secondary analyses compared FM frequencies in SLE and other groups (healthy controls or CTD groups). Fifty-six studies met the eligibility criteria. Out of the 56 studies, nine included comparative data between SLE patients and healthy controls, while six presented data comparing the frequency of FM in patients with SLE and other CTDs. The combined cohorts included 58,052 SLE patients. Among 5063 SLE patients, FM was detected. The overall random-effects pooled prevalence of FM was 15.8% (95% CI, 13.4-18.5) with high heterogeneity (I2, 97.9%). Our analysis revealed a significantly higher risk of FM in patients with SLE compared to controls (OR, 3.7; 95% CI, 2.74-5.0). There was a higher risk of FM in SLE patients compared to other rheumatic diseases, but the difference was not significant. Our study showed that the prevalence of FM is higher in patients with SLE compared to the general population. FM in SLE may act as a confounding factor when assessing disease activity and treatment response. Research results indicate that concurrent FM is a frequent comorbidity in SLE, emphasizing the importance of recognizing its occurrence in SLE patients.

Rare connective tissue diseases in patients with C1-inhibitor deficiency hereditary angioedema: first evidence on prevalence and distribution from a large Italian cohort study.

In patients with Hereditary Angioedema (HAE) related to primary C1 inhibitor deficiency (C1INH), the defective clearance of immune complexes and apoptotic materials along with impairment of normal humoral response potentially leads to autoimmunity. Few studies report evidence on autoimmune diseases in C1INH-HAE, but no large population studies focus on rare connective tissue diseases (RCTDs). We aim at evaluating for the first time prevalence and distribution of RCTDs - Systemic Lupus Erytematosus (SLE), primary Sjogren Syndrome (SjS), primary antiphospholipid syndrome (APS), Systemic Sclerosis (SSc), and mixed connective tissue diseases (MCTD) in a large Italian cohort of C1INH-HAE patients. A multicenter observational study includes C1INH-HAE patients from ITACA Centers throughout Italy (time frame Sept 2023-March 2024). Inclusion criteria are i. a defined diagnosis of type I or type II C1INH-HAE; ii. age ≥15 years (puberty already occurred); iii. enrollment in the ITACA Registry. The diagnosis of SLE, primary SjS, primary APS, SSc, and MCTD are made in accordance with international classification criteria. Data are collected from a total of 855 C1INH-HAE patients referring to 15 ITACA Centers. Patients with concomitant RCTDs were 18/855 (2.1%) with F:M ratio 3.5 and a prevalent type I C1INH-HAE diagnosis (87.2%). A diagnosis of SLE results in 44.5% of cases (n=8) while the remaining diagnoses are primary SjS (22.2%, n=4), primary APS (16.6%, n=3), SSc (11.2%, n=2), and a single case of MCTD (5.5%). The female gender is prevalent in all the RCTDs. Patients on long term prophylaxis (LTP) are significantly prevalent in RCTDs group than in the whole C1INH-HAE population (p<0.01). A relevant prevalence of RCTDs is documented in C1INH-HAE patients, mainly SLE. Patients with RCTDs are on LTP in a significant proportion supporting the idea of a bidirectional link between C1INH-HAE and autoimmunity.

Microvascular alterations of the ocular surface and retina in connective tissue disease-related interstitial lung disease.

To examine the disparities in macular retinal vascular density between individuals with connective tissue disease-related interstitial lung disease (CTD-ILD) and healthy controls (HCs) by optical coherence tomography angiography (OCTA) and to investigate the changes in microvascular density in abnormal eyes. For a retrospective case-control study, a total of 16 patients (32 eyes) diagnosed with CTD-ILD were selected as the ILD group. The 16 healthy volunteers with 32 eyes, matched in terms of age and sex with the patients, were recruited as control group. The macular retina's superficial retinal layer (SRL) and deep retinal layer (DRL) were examined and scanned using OCTA in each individual eye. The densities of retinal microvascular (MIR), macrovascular (MAR), and total microvascular (TMI) were calculated and compared. Changes in retinal vascular density in the macular region were analyzed using three different segmentation methods: central annuli segmentation method (C1-C6), hemispheric segmentation method [uperior right (SR), superior left (SL), inferior left (IL), and inferior right (IR)], and Early Treatment Diabetic Retinopathy Study (ETDRS) methods [superior (S), inferior (I), left (L), and right (R)]. The data were analyzed using Version 9.0 of GraphPad prism and Pearson analysis. The OCTA data demonstrated a statistically significant difference (P<0.05) in macular retinal microvessel density between the two groups. Specifically, in the SRL and DRL analyses, the ILD group exhibited significantly lower surface density of MIR and TMI compared to the HCs group (P<0.05). Furthermore, using the hemispheric segmentation method, the ILD group showed notable reductions in SL, SR, and IL in the superficial retina (P<0.05), as well as marked decreases in SL and IR in the deep retina (P<0.05). Similarly, when employing the ETDRS method, the ILD group displayed substantial drops in superficial retinal S and I (P<0.05), along with notable reductions in deep retinal L, I, and R (P<0.05). In the central annuli segmentation method, the ILD group exhibited a significant decrease in the superficial retinal C2-4 region (P<0.05), whereas the deep retina showed a notable reduction in the C3-5 region (P<0.05). Additionally, there was an observed higher positive likelihood ratio in the superficial SR region and deep MIR. Furthermore, there was a negative correlation between conjunctival vascular density and both deep and superficial retinal TMI (P<0.001). Patients with CTD-ILD exhibits a significantly higher conjunctival vascular density compared to the HCs group. Conversely, their fundus retinal microvascular density is significantly lower. Furthermore, CTD-ILD patients display notably lower superficial and deep retinal vascular density in comparison to the HCs group. The inverse correlation between conjunctival vascular density and both superficial and deep retinal TMI suggests that detecting subtle changes in ocular microcirculation could potentially serve as an early diagnostic indicator for connective tissue diseases, thereby enhancing disease management.

Analysis of 179 posterior communicating artery infundibular dilations demonstrating low risk for transformation to aneurysm or rupture and the usefulness of the “round defect”

ObjectiveOutpouchings, particularly those originating from the posterior communicating artery off the internal carotid artery (Pcom-Ops), are often unable to be categorized definitively as aneurysms or infundibula resulting in frequent clinical imaging and follow-up. We aimed to investigate potential correlations between growth and rupture rates and easily definable imaging characteristics in Pcom-Ops. MethodsWe analyzed CT and MR imaging of Pcom-Ops identified in a case series of patients seen between 2007 and 2022. For each outpouching, the length of the base, hypotenuse, and round defect, defined as the deviation from triangular shape, were calculated. These measurements were used to estimate the conical volume and eccentricity of the Pcom-Op. Results179 Pcom-Ops were identified from 152 patients who were followed for an average of for 3.2 ± 3.2 years. Bilateral Pcom-Ops were present in 17.8 % patients and 7.2 % had an underlying connective tissue disease. Only one Pcom-Op in a patient with polycystic kidney disease subsequently became a clear aneurysm after 6.3 years. The average approximated volume and round defect at presentation were 2.3 ± 2.2 mm3 and 0.29 ± 0.16 mm, respectively. Volume and round defect changed minimally over time followed. Outlier analysis of round defect, determined by Z-score more than 3 standard deviations above the mean, was not associated with evolution into clear aneurysms. ConclusionPcom-Ops rarely enlarge or rupture. Pcom-Op eccentricity does not predict high risk Pcom-Ops. Thus Pcom-Ops in general may not require close follow-up over time. However, Pcom-Ops in patients with connective tissue diseases should be monitored more closely.

Central retinal artery occlusion as the initial manifestation of mixed connective tissue disease in a young woman: a case report

BackgroundRetinal artery occlusions are rare amongst young adults, and relevant risk factors and etiology remain unclear. In this report, we present a case of central retinal artery occlusion (CRAO) as the initial manifestation of mixed connective tissue disease (MCTD) in a young woman.Case presentationA 22-year-old female presented to the emergency department with a sudden decrease in visual acuity in her right eye for 1 hour. She reported a similar episode in her left eye five years prior, which resolved spontaneously after 2 hours. Initially misdiagnosed with optic neuritis in the right eye at another hospital, she was referred to our institution the following day. Clinical examination revealed a CRAO in her right eye. A detailed medical history revealed that she had developed livedo reticularis (LR) on both lower limbs five years ago, which had been overlooked and untreated. Further rheumatologic history, hematologic tests, and an autoimmune work-up confirmed a diagnosis of mixed connective tissue disease (MCTD).ConclusionIn young patients presenting with CRAO, further examinations should be conducted to investigate systemic disease or an embolic source to prevent future sequelae.

Mechanisms of Lung Endothelial Cell Injury and Survival in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive, chronic, and incurable inflammatory pulmonary vascular disease characterized by significant sex bias and largely unexplored microbial-associated molecular mechanisms that may influence its development and sex prevalence across various subgroups. PAH can be subclassified as idiopathic, heritable, or associated with conditions such as connective tissue diseases, congenital heart defects, liver disease, infections, and chronic exposure to drugs or toxins. During PAH progression, lung vascular endothelial cells (ECs) undergo dramatic morphofunctional transformations in response to acute and chronic inflammation. These transformations include the appearance and expansion of abnormal vascular cell phenotypes such as those derived from apoptosis-resistant cell growth and endothelial-to-mesenchymal transition (EndoMT). Compelling evidence indicates that these endothelial phenotypes seem to be triggered by chronic lung vascular injury and dysfunction, often characterized by reduced secretion of vasoactive molecules like nitric oxide (NO) and exacerbated response to vasoconstrictors such as Endothelin-1 (ET-1); both long-term known contributors of PAH pathogenesis. This review sheds light on the mechanisms of EC dysfunction, apoptosis, and EndoMT in PAH, aiming to unravel the intricate interactions between ECs, pathogens, and other cell types that drive the onset and progression of this devastating disease. Ultimately, we hope to provide an overview of the complex functions of lung vascular ECs in PAH, inspiring novel therapeutic strategies that target these dysfunctional cells to improve the treatment landscape for PAH, particularly in the face of current and emerging global pathogenic threats.

Fever of Unknown Origin in Children

Fever is a common symptom in children and fever of unknown origin (FUO) is not uncommon in paediatric age group. The FUO remains a challenging clinical problem and is an important cause of morbidity and mortality in children. These undifferentiated prolonged fevers need step-wise approach for diagnosis. Details and proper history taking, thorough serial physical examination, critical analysis of sign-symptoms diary and investigation reports are crucial to get a clue that led to the diagnosis. Though in some aspect more concerned with developing countries data, this article is based on reviewing of published papers from both developed and developing countries. Worldwide infection remains the most common cause of FUO in children, followed by collagen vascular diseases, neoplasm, miscellaneous diseases and undiagnosed illnesses. Indiscriminate use of antimicrobials and other medications may mask the real diagnosis. Awareness of primary-level healthcare providers about the cause and logical management approach of pediatric FUO is important for better outcome. Journal of Monno Medical College December, 2023; 9 (2):78-84

Chinese expert consensus on the etiological diagnosis of adult bronchiectasis

Bronchiectasis is a highly heterogeneous chronic airway disease for which accurate etiological diagnosis is crucial for effective management. A group of experts from the China Bronchiectasis Alliance and the Infection Assembly of the Chinese Thoracic Society conducted a comprehensive review of recent research into the etiology of bronchiectasis. Using the widely accepted Delphi methodology, the experts reached a consensus on the etiological diagnosis of bronchiectasis through multiple rounds of discussion and revision. The consensus is divided into four sections: the definition and classification of the etiology of bronchiectasis, the etiological diagnostic procedures for bronchiectasis, the treatable causes of bronchiectasis, and other causes of bronchiectasis. The ultimate goal of this consensus is to improve the diagnostic accuracy and optimize the management of bronchiectasis in China. The main recommendations of Section 1 focused on chest thin-section computed tomography (CT) for the diagnosis of bronchiectasis and the etiological classification. The main recommendations of Section 2 focused on the medical history collection for bronchiectasis and the etiological diagnostic protocol for bronchiectasis. The main recommendations of Section 3 focused on the recommendations of the diagnosis of bronchiectasis secondary to COPD, the diagnosis of bronchiectasis due to asthma, diffuse pan-bronchiolitis, allergic bronchopulmonary aspergillosis, connective tissue disease (CTD)-related bronchiectasis or gastroesophageal reflux disease (GERD)-related bronchiectasis. The main recommendations of Section 4 focused on suspected primary ciliary dyskinesia (PCD)-associated bronchiectasis, cystic fibrosis and the diagnosis of congenital airway malformations.