Systemic Sclerosis Research Articles

Combined radiographic and ultrasound evaluations to decipher joint involvement in the hands of patients with systemic sclerosis

Abstract Objective The objective of this study was to explore the etiologies and contributing factors of synovial and tenosynovial involvement in SSc, as well as to assess the phenotype of patients with these synovial and tenosynovial features. Methods 171 SSc patients with hand manifestations (either vascular, skin or joint manifestations) who underwent standard X-rays of both hands and hand ultrasound (US), were included. Two independent evaluators recorded the presence or absence of acro-osteolysis, calcinosis, microcrystalline and degenerative rheumatisms, including osteophytosis on X-Rays. The presence of synovitis and tenosynovitis (active or fibrotic) was assessed through US by a third evaluator, blinded for X-ray parameters. Results In multivariate analysis, the characteristics associated with active synovitis and tenosynovitis were CRP>10mg/L (p = 0.013), fibrotic tenosynovitis on US (p = 0.005), anti-RNA polymerase III antibodies (p = 0.043) and poly-osteophytosis on hand X-rays (p = 0.001). After exclusion of patients with RA (n = 5) and/or poly-osteophytosis (n = 53), 14 remaining patients (12.7%) had active synovitis and/or tenosynovitis on US. In multivariate analyses, parameters associated with active synovitis and/or tenosynovitis in this selected population were scleroderma renal crisis (p = 0.012) and fibrotic tenosynovitis on US (p < 0.001). Conclusion Our study confirms that osteophytosis is a significant contributor of joint involvement in SSc patients based on real life data. After exclusion of potential confounders, more than 10% of SSc patients still had active synovitis and/or tenosynovitis on US, providing indirect evidence for the existence of a specific SSc-related synovial and/or tenosynovial involvement.

Lower modified rodnan skin score values and complement 4 levels are associated with arterial endothelial dysfunction in patients with systemic sclerosis

Abstract Background Systemic sclerosis (SSc) is a multisystem autoimmune disease affecting skin and multiple organs. Although immunopathological evidence supports direct arterial involvement leading to tissue ischemia in SSc, factors associated with arterial involvement are not precisely determined due to the rarity of SSc. In this study, we aimed to investigate aortic stiffness and endothelial functions in patients with SSc. Methods Patients under treatment of our Rheumatology department and healthy controls have been included in our study. Aortic stiffness was examined by pulse wave velocity (PWV) exam and endothelial functions were assessed by flow mediated dilation (FMD). Individuals with known atherosclerotic risk factors were excluded from our study. A thorough biochemical examination of all individuals and immunologic markers of patients with SSc was completed. All of the organ involvements in patients with SSc were noted and modified Rodnan skin score (MRSS) was calculated. Results A total of 61 patients and 75 healthy controls were included in our study. Brachial-ankle PWV values were significantly higher (6.89±0.93 vs 6.49±0.22 m/sec; p:0.001) and brachial FMD values were significantly lower (16.7±6.7 % vs 18.7±3.8 %; p: 0.03) in patients with SSc. We have also grouped individuals according to severe FMD impairment (FMD < 10%). None of the healthy controls had severe impairment whereas 15 patients with SSc had FMD values lower than 10%. Higher anti-smooth muscle (Sm) antibody positiveness (40 % vs 15.4 %), lower complement 4 levels (23.6±16.7 vs 31.1±11.1 mg/dL), higher plasma iron values (70.3±43.6 vs 31.4±45.2 mcg/dL) and lower MRSS values (11.4±4.8 vs 20.7±10.9) were observed in SSc patients with severe FMD impairment. When we have put these variables in multivariate logistic regression analysis (backward elimination model), we have found an independent association of complement 4 levels (OR: 0.03, [95 % CI: 0.01-0.491], p:0.04) and MRSS values (OR: 0.853, [95 % CI: 0.761-0.955], p:0.006) with significant FMD impairment in patients with SSc. Conclusion Arterial stiffness is significantly increased and endothelial functions, as assessed by FMD is significantly decreased in patients with SSc, when compared to healthy controls. Lower complement 4 levels and lower modified Rodnan skin scores seem to be independently associated with significant severe FMD impairment. Although our study included a remarkable amount of patients with SSc, an infrequent autoimmune disease, number of patients included in our study is not adequate to make more precise comments. Further prospective studies with higher amount of patients are required for certain results.

Impaired retinal micro-vascular function in patients with a systemic sclerosis

Abstract Background Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by widespread and progressive multi-organ fibrosis and vascular abnormalities. Endothelial dysfunction is an early manifestation of SSc and an important contributor to the progression and prognosis of the disease. Dynamic retinal vascular analysis (DVA) is a new method for non-invasive and precise determination of microvascular function. The primary aim was to assess micro- and macro-vascular function in patients with SSc. Methods In this study, vascular function was measured non-invasively with flicker-light induced vasodilation of retinal arterioles (FIDart) and branchial arterial flow-mediated vasodilation (FMD). Patients with SSc were prospectively enrolled in the study (n = 40; mean ± SD age 56±11 years, females 73 %) and compared with age- and sex-matched HC (n = 40; mean age 56±15 years, females 73%). Results Retinal microvascular function was significantly impaired in patients with SSc compared to matched HC (2.3±2.0% versus 3.1±1.9% respectively, p=0.04, figure 1). There was a trend for lower FMD in patients with SSc in comparison to HC (5.0± 3.2% versus 6.2±3.2% respectively, p=0.07). Conclusion Patients with SSc have severe impairment of retinal vascular function compared to matched HC. Thus, microvascular dysfunction in these patients is of systemic nature and retinal vessel analysis may serve as an important marker for SSc disease, severity and prognosis. These results set the stage for further studies on retinal function in SSc patients.Figure 1

Healthcare utilization in general practice and hospitals preceding a diagnosis of systemic sclerosis: a nationwide registry study.

Irreversible tissue damage is frequently present at the time of diagnosis in systemic sclerosis (SSc), which calls for earlier diagnosis. This study estimated healthcare utilization three years before the diagnosis of SSc. We conducted a population-based cohort study using data from Danish national registries. Incident patients diagnosed with SSc between January 1, 2005, and December 31, 2018, were matched by age and gender with 10 references without SSc. The date of diagnosis was the index date. We estimated quarterly rates and adjusted incidence rate ratios (IRRs) with 95% confidence intervals (CI) of healthcare utilization in the three years preceding the diagnosis for patients with SSc and their references. A total of 1,650 SSc patients (1,255 women and 395 men) and 16 500 non-SSc references were included. The mean age was 58 years (interquartile range 48-68). Three years before diagnosis, patients with SSc had more contacts with general practice (IRRwomen= 1.43 [95% CI: 1.33; 1.53], IRRmen= 1.47 [95% CI: 1.26; 1.71]) and hospitals (IRRwomen= 1.86 [95% CI: 1.62; 2.14], IRRmen= 2.70 [95% CI: 2.04; 3.58]) compared with their references. In the last three months before diagnosis, patients with SSc had significantly more contacts with general practice (IRRwomen= 2.30 [95% CI: 2.16; 2.44], IRRmen= 2.98 [95% CI: 2.64; 3.35]) and hospitals (IRRwomen= 5.62 [95% CI: 5.08; 6.20], IRRmen= 9.53 [95% CI: 7.81; 11.63]). The higher use of healthcare services in general practice and hospitals in the three years before diagnosis suggests an opportunity to facilitate earlier diagnosis and treatment of SSc.

Assessment of sub clinical right ventricular ischemia using oxygen sensitive cardiac magnetic resonance imaging in patients with systemic sclerosis: mechanistic insights from advanced cardiac imaging

Abstract Background Cardiac involvement in Systemic Sclerosis (SSc) is common, with manifestations ranging from subclinical to life-threatening 1. Cardiopulmonary complications, including, right ventricular (RV) dysfunction is the leading cause of SSc-related mortality2. Pulmonary arterial hypertension (PAH) occurs in 8-12% of SSc patients and remains a leading cause of death, with a 3-year survival rate around 50%2. The progressive decline in RV function in PAH is often attributed to RV ischemia3. Oxygen Sensitive Cardiac Magnetic Resonance imaging (OS-CMR) has been previously used by our group to assess RV myocardial oxygenation in patients with PAH3, including SSc-associated PAH 3. The objective of this study was to use OS-CMR to assess RV myocardial oxygenation in SSc patients prior to the onset of PAH. Methodology In this prospective, multicentre study, three study groups were established. Group 1 comprised SSc patients without PAH or known cardiac disease. Group 2 included stable PAH patients confirmed by right heart catheterization, matched for age and sex, but without SSc. Group 3 comprised healthy normal volunteers (NV), matched for age and sex. All patients underwent a 3T CMR which included: cine images, rest cine OS-CMR, stress cine OS-CMR, native T1 mapping, stress perfusion, and late gadolinium enhancement (LGE). The primary outcome was change in inferior RV myocardial signal intensity (SI) in diastole, measured by the change in OS-CMR between rest and stress within each group. Two experienced independent reviewers performed the CMR analysis with an inter-assessor correlation coefficient of 0.8, 95% Cl [0.3, 0.9]. Results A total of 44 patients were enrolled. Of these, n=26 group 1 (SSc), n=8 group 2 (PAH), n=10 group 3 (NV). Study results are listed in Table 1. Mean age within the SSc, PAH, and NV groups were 59±10, 67±12 and 57 ±7 years respectively (p=0.482). The RV OS-CMR SI was significantly lower in the SSc group when compared to the NV group (p=0.017). In contrast, there was no significant difference between the PAH and SSc groups (p=0.426), indicating a similar degree of RV ischemia in the established PAH patients and the SSc patients. All SSc patients exhibited inferior and anterior RV insertion fibrosis, with no perfusion defects noted. Five (19%) of SSc patients presented with LGE hyperenhancement in the LV. Eighteen (69%) of SSc patients obtained at least 1 abnormal T1 mapping segment in the LV. Conclusion SSc patients without overt PAH had a similar degree of RV ischemia when compared to patients with overt PAH from other causes. Our findings imply that in SSc, RV adverse effects occur prior to the onset of PAH, and that this effect is mediated by RV ischemia secondary to changes in the microvasculature. Our findings may have screening and/or therapeutic implications.

B-Lines in the Assessment of Interstitial Lung Disease Associated with Scleroderma: The Role of Handheld Devices

Background: Timely detection and aggressive management of interstitial lung disease (ILD) in systemic sclerosis (SSc) are essential to improving outcomes and reducing risks of irreversible lung injury. Objective: to explore the usefulness of an ultraportable ultrasound device for the management of SSc-related ILD and to compare it with clinical and instrumental data. Methods: A total of 19 consecutive SSc patients underwent a comprehensive pulmonary evaluation: clinical, pulmonary function tests (PFTs) (spirometry, DLCO), lung CT (1.5 mm slice thickness reconstruction; HRCT), and lung ultrasound (LUS). A total score was calculated based on the number of color-coded B-lines recorded for each lung sliding. B-lines were analyzed against dyspnea, cough, Velcro, CT imaging (Warrick’s score), and PFTs. Global and subgroup analysis were performed (diffuse versus limited cutaneous SSc, Warrick’s < 7 versus >7). Results: Symptomatic lung involvement with varying degrees of dyspnea was reported in about 74% of cases (functional NYHA > 2 in more than half), chronic dry cough in one-third, Velcro rales in 42%. A total of 84.24% were classified as SSc with ILD on CT imaging. Statistically significant mild-to-moderate correlations between B-lines and clinical manifestations were demonstrated, as well as PFTs and Warrick’s scores (more B-lines, lower pulmonary function, but higher extent and severity on CT) (p < 0.05); there were differences between SSc patients without and with ILD in terms of the number and distribution of B-lines (p < 0.05), as well as different B-lines patterns and numbers in diffuse versus limited SSc (p < 0.05). Conclusions: Ultraportable handheld LUS is a promising method suitable for the management (screening, early detection, and evaluation) of SSc patients.

Early left atrial changes in patients with systemic sclerosis by two-dimensional speckle tracking echocardiography

Abstract Background Systemic Sclerosis (SSc) is an autoimmune disease that affects multiple organs 1. Primary myocardial involvement is not uncommon in SSc, with poor prognosis when symptomatic2-4. Pulmonary hypertension and right-sided affection of the heart are well-studied in SSC. Changes in the function of the left atrium (LA) in patients with SSc are early signs of left-sided affection of the heart, which has not yet been well investigated. Two-dimensional (2D) speckle tracking echocardiography (STE) is useful for detecting these early changes. Aim To assess the LA strain parameters in patients with SSC by 2D STE compared to age and sex-matched healthy subjects. Methods This study analyzed prospectively collected data from 30 consecutive SSc patients, excluding those with systemic hypertension and diabetes mellitus and a control group including 30 healthy female volunteers with a mean age of 35.6±7.7. Most SSC patients were females (28/30), with a mean age of 39±10.8. After obtaining informed consent, all participants underwent clinical evaluation and transthoracic echocardiography, including strain analysis. Results Left atrial reservoir (38.1±3.8 % vs. 45.33.7 %; p<0.001), conduit (21.82.7 % vs. 25.73.2 %; p<0.001), and contractile (16.23 % vs. 19.6±2 %; p<0.001) strain parameters were significantly reduced in the SSc population than the healthy controls. The LA stiffness index was also significantly higher in SSc patients (0.186±0.042 vs 0.138±0.018; p<0.001). The total emptying fraction (59.9±7 % vs. 64.73 %; p=0.003), expansion index (160.945.8 % vs. 185.224.1%; p=0.007), and passive emptying fraction (37.37.4 % vs. 40.7±8.5%; p=0.012) were significantly lower in SSc patients compared to the controls. However, the active emptying fraction showed no significant difference between the 2 groups. LA maximal volume was similar between the 2 groups. Conclusion Patients with systemic sclerosis demonstrate reduced LA phasic function even without LA enlargement, as compared to healthy individuals, based on 2D speckle-tracking echocardiography (STE).

Assessment of circulating biomarkers and hemodynamic response during stress to detect early cardiopulmonary complications in systemic sclerosis

Abstract Background Systemic sclerosis (SSc) is characterised by persistent immune-inflammatory system activation and excessive extracellular matrix (ECM) accumulation leading to fibrosis. Exercise Doppler Echocardiography (EDE) is a promising method to detect the early changes of fibrosis-related pulmonary and myocardial complications, like elevated left ventricular filling pressure or stress-induced pulmonary hypertension (PH). Aims The study aims to assess the linkage between the activity of fibrosis markers and abnormal exercise haemodynamics during stress in patients with SSc. Methods A total of 18 patients with SSc were enrolled in the single-centre prospective study (age 54±15,5years, 94,4 % women). SSc patients with resting PH and moderate to severe pulmonary fibrosis were excluded. According to a standardised protocol, all subjects underwent resting and exercise echocardiography on a semi-recumbent cycle ergometer with an incremental (25 watts) workload up to the maximally tolerated workload. Measurements focused on the left ventricular diastolic function (E/e’) and right ventricular haemodynamics (estimated systolic pulmonary pressure: PASP, right ventricular coupling: TAPSE/PASP, pulmonary vascular resistance: PVR). Blood samples were taken immediately before the stress test, and the Matrix Metalloproteinase-9 and 2 (MMP-9, MMP-2) levels were assessed with gelatin zymography method. Results During the EDE, PASP from baseline increased significantly (24,6mmHg±11 vs 38±16mmHg, p <0,0001), also PVR (1,2±0,49 vs 1,5±0,15 Wood unit, p<0,001) RV coupling was decreased significantly (1,2±0,68 vs 0,93±0,5, p<0,001). Left ventricular E/e’ was also increased during the stress (8,2±2 vs 10,5±5,1, p<0,05). Enzymatically active MMP-9 level was significantly correlated with RV coupling at rest and stress (p<0,05, r 0,63 at rest and r 0,52 at stress) and negatively correlated with PASP (p<0,05, r:-0,62 at rest and r -0,5 at stress). MMP-2 level only negatively correlated with resting PASP (p<0,05, r:-0,527). The left ventricular parameters did not show any relationship with MMP levels. Conclusions The level of circulating MMP-9 predicts haemodynamic behaviour during stress in SSc. MMPs could be a promising marker for detecting early changes in the right ventricle-pulmonary circulation unit.

Genome-wide integrated DNA methylome and transcriptome analysis reveals a strong dysregulated myeloid component in the epigenetic landscape of Systemic Sclerosis.

Non-genetic factors influence Systemic Sclerosis (SSc) pathogenesis, underscoring epigenetics as a relevant contributor to the disease. We aimed to unravel DNA methylation abnormalities associated with SSc through an epigenome-wide association study (EWAS). We analyzed DNA methylation data from whole blood samples in 179 SSc patients and 241 unaffected individuals, to identify differentially methylated positions (DMPs) with a FDR<0.05. These results were further integrated with RNA-seq data from the same patients to assess their functional consequence. Additionally, we examined the impact of DNA methylation changes on transcription factors and analyzed the relationship between alterations of the methylation and gene expression profile and serum proteins levels. This analysis yielded 525 DMPs enriched in immune-related pathways, being leukocyte cell-cell adhesion the most significant (FDR=4.91x10-9), prioritizing integrins as they were exposed by integrating methylome and transcriptome data. Furthermore, through this integrative approach we observed an enrichment of neutrophil related pathways, highlighting this myeloid cell type as a relevant contributor in SSc pathogenesis. In addition, we uncovered novel profibrotic and proinflammatory mechanisms involved in the disease. Finally, the altered epigenetic and transcriptomic signature revealed an increased activity of CCAAT/enhancer-binding protein (CEBP) transcription factor family in SSc, which is crucial in the myeloid lineage development. Our findings uncover the impaired epigenetic regulation of the disease and its impact on gene expression, identifying new molecules for potential clinical applications and improving our understanding of SSc pathogenesis.

Patients with systemic sclerosis frequently use phytopharmaceuticals: a cross-sectional survey.

The use of complementary and alternative medicine (CAM) has increased. Phytotherapy, also known as herbal medicine, is one of the CAM therapies that involves using medicinal plants and plant-derived substances. This study aims to evaluate the use of phytopharmaceuticals and the factors associated with their use in patients with Systemic sclerosis (SSc). Our study is designed as a survey and consists of two parts with 32 questions. The first part gathers demographic data with 14 questions, and the second part assesses participants' knowledge about phytotherapy with 18 questions. The questionnaire was administered face-to-face to patients with SSc who consented to participate. One hundred participants completed the survey. Fifty-two (52%) participants had diffuse sclerosis. Raynaud's phenomenon affected 97 (97%) participants; 53 (53%) participants suffered from lung involvement, and 64 (64%) had musculoskeletal system involvement. A total of 55 (55%) participants had used phytopharmaceuticals after SSc diagnosis. Phytotherapy users and non-users had similar demographic and clinical characteristics in terms of age, gender, disease duration, type of SSc, organ involvement, and education level. Participants mostly used the following phytopharmaceuticals: 23 participants used Camellia sinensis (green tea), 16 used Hypericum perforatum, and 12 used Curcuma longa (curcumin). The most improved symptoms with phytopharmaceuticals were musculoskeletal system findings and skin thickness, as stated by participants. A significant portion of SSc patients used phytopharmaceuticals in their disease duration. Although patients stated that they benefited from phytopharmaceuticals, studies on the effectiveness of these treatments are insufficient.

Left atrial volumetric-mechanical coupling index as a marker of subclinical primary heart involvement in systemic sclerosis

Abstract Background Primary heart involvement in systemic sclerosis (SSc) is a common yet often clinically silent marker of poor prognosis. Up to 80% of patients have histopathological evidence of heart involvement, highlighting the need for better screening and diagnostic methods. N-terminal pro-brain natriuretic peptide (NTproBNP), a well-established cardiac biomarker, is often increased in patients with SSc, but with a not fully understood mechanism. Meanwhile, left atrial volumetric-mechanical coupling index (LACI), a new echocardiographic parameter, has been shown to predict cardiovascular outcomes in heart failure patients and the general population, but it has not been studied in SSc. Purpose To identify new echocardiographic parameters, particularly related to left atrial volume and function, as markers of increased NTproBNP in SSc patients without overt heart involvement. Methods Consecutive SSc patients without overt heart disease referred for routine cardiac screening underwent 2D and 3D transthoracic echocardiography, including atrial and ventricular strain analysis. LACI was calculated by both 2D and 3D echocardiography as the ratio between the left atrial volume index and the tissue-Doppler-imaging septal a’ velocity. Patients with significant structural and functional changes suggestive of systolic or diastolic dysfunction or pulmonary hypertension, and those with impaired global left ventricular strain were excluded. Logistic regression, Pearson correlation coefficients, and area under the receiver-operating characteristic curve (AUC) are used to analyze the association and predictive power of LACI for elevated NTproBNP. Results A total of 36 SSc patients (55±10 years old; 34 (94%) women; mean disease duration 14±11 years) were included. Sixteen (44.4%) had diffuse cutaneous involvement (dcSSc). Seventeen (47%) patients had increased NTproBNP levels (i.e. &amp;gt;125 pg/mL). Among all tested variables, 3D LACI had the best correlation with NTproBNP values (r = 0.63, p&amp;lt;0.001). A 3D LACI of &amp;gt;2 associated with NTproBNP of &amp;gt;125 pg/mL (odds ratio 7.33 [95%CI 1.38-38.8]; p=0.01) and predicted these increased values with a sensitivity of 76.9% and a specificity of 81.2% (AUC 0.78). NTproBNP was also correlated with 2D LACI (r=0.55, p&amp;lt;0.001), peak left atrial longitudinal strain (r=-0.42, p=0.01), and left atrial contraction strain (r=0.48, p=0.005). Compared to patients with limited cutaneous involvement, those with dcSSc had higher NTproBNP values (250±139.6 vs 107.2±110.9 pg/mL, p=0.001), higher 3D LACI values (2.6±0.9 vs 1.9±0.5, p=0.02), with similar left atrial and ventricular strain parameters. Conclusion Left atrial volumetric-mechanical coupling index assessed by 3D echocardiography is significantly associated with and predictive of elevated NTproBNP levels in SSc patients without overt heart disease and may be a potentially useful non-invasive marker for screening for early subclinical heart involvement in SSc patients.

Prognostic evaluation with cardiac magnetic resonance in patients with systemic sclerosis

Abstract Systemic sclerosis (SSc) is an autoimmune disease with multiorgan involvement. Cardiac involvement is common and impact in prognosis. Cardiac magnetic resonance (CMR) allows an evaluation in ventricular and atrial function and hemodynamics forces. Our study aimed to assess RVD prevalence in SSc patients and analyze its impact on cardiovascular events. Methods In this retrospective study, we included patients diagnosed with SSc and followed-up in a specialized unit. We collected clinical, hemodynamic, and imaging data, including baseline CMR studies. Pulmonary function tests were also performed. RVD was defined as a right ventricular ejection fraction ≤52% in men and ≤51% in women. Patients were monitored for a composite endpoint consisting of cardiovascular death and/or admissions due to heart failure (HF). We assessed the predictors of this endpoint using Cox regression analysis. Results The study included 74 patients with SSc, most were female (81 %) with a mean age of 60±12 years. RVD prevalence was 32 %. Patients with RVD had greater ventricular volumes (160±44.9 vs 130±36.2; p=0.003), lower right ventricular global strain (-18 % vs. -26 %; p &amp;lt;0.001) and lower right atria strain (19% vs 29%; p=&amp;lt;0.001). We don’t found differences in presence of LGE of both ventricles. In the multivariate analysis RVEF (HR 2.9.; p = 0.022), pulmonary trunk dilatation (HR 1.15; p= 0.004, pulmonary hypertension at baseline (HR 2.98; 0.09); RV GLS (HR 1.08; p = 0.03) and RA GLS (HR 0.96; p = 0.024) were predictors of composite outcome of cardiovascular death and/or heart failure hospitalization. During a mean follow-up of 46 months, patients with RVD had higher rates of heart failure admissions (38% vs. 12%; p = 0.01) and cardiovascular mortality (29% vs. 6%; p 0.01). No ventricular arrhythmias occurred. Conclusion RVD is common among SSc patients. RVEF and pulmonary hypertension are the strongest variables linked to increased adverse cardiovascular clinical events and decreased survival in these patients.

Usefulness of monitoring mycophenolic acid exposure in systemic sclerosis-related interstitial lung disease: a retrospective cohort study

BackgroundSystemic sclerosis-related interstitial lung disease (SSc-ILD) represents a significant cause of morbidity and mortality in Systemic Sclerosis (SSc). Mycophenolate mofetil (MMF) is currently the first line treatment for SSc-ILD. There is no recommendation on the dosage of mycophenolic acid (MPA) blood concentrations, so we aimed to study the correlation between MPA exposure and respiratory outcomes in this population.MethodsWe conducted a retrospective cohort study of SSc-ILD patients treated with MMF in our center. According to our policy, a complete patient evaluation was performed approximately one year after MMF initiation, during which the mycophenolic acid (MPA) residual rate (RR) was measured. We analyzed the association between RR and changes in forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) over time.ResultsForty-three SSc-ILD patients were included. Patients with higher RR levels (≥ 1.5 mg/L) had a significantly better FVC evolution with a higher proportion of stabilization and lower proportion of FVC decrease (p = 0.024). RR above 1.5 mg/L was a predictive factor of reduced FVC decline compared with lower RR levels adjusting for MMF dose and duration of MMF exposure (p = 0.008). There was no difference regarding DLCO outcome.ConclusionOur study suggests that optimal MPA exposure, as indicated by RR levels, may better protect against FVC decline in SSc-ILD patients treated with MMF. Routine monitoring of MPA exposure could be beneficial in optimizing treatment outcomes. Prospective, multicenter studies are needed to further explore the relationship between MPA exposure and clinical outcomes in SSc-ILD.

Scleroderma renal crisis, an increasingly rare but persistently challenging condition: a retrospective cohort study

Abstract Objective Scleroderma renal crisis (SRC) is associated with high morbidity and mortality and there remain unmet needs regarding early identification and treatment. We aimed to assess risk factors for and the outcomes of SRC at a large Australian tertiary hospital. Methods Seventeen incident SRC cases were diagnosed between 2012–2022. Demographic, systemic sclerosis (SSc) manifestations, and treatment data were extracted. Using data from the Australian Scleroderma Cohort Study (ASCS) (n = 483), logistic regression analysis was performed to identify risk factors for SRC. Results The prevalence of SRC was 3.52%. The median SSc disease duration at SRC onset was 2 (IQR 1–4) years. Peak creatinine occurred at a median of 11 (IQR 5–14) days post-SRC diagnosis with a median peak creatinine of 144 (IQR 86–306) µmol/l. Nine (52.94%) SRC patients had evidence of acute neurologic and/or cardiac complications. Acute hemofiltration was required in 3 (17.65%) patients. Over the follow-up period, 7 (41.18%) SRC patients died 2.75 (IQR 0.74–7.25) years after SRC onset. Patients with SRC were more likely to be male (OR 9.73, 95%CI 3.57–26.56), have diffuse disease (OR 23.16, 95%CI 5.22–102.80), and have antibodies to Scl70 (OR 3.34, 95%CI 1.24–9.04) or RNA polymerase III (RNAPIII) (OR 5.15, 95%CI 1.91–13.89). Conclusion SRC is an uncommon manifestation, but outcomes remain poor. A significant proportion of patients presenting with SRC in Australia are positive for Scl70 or RNAPIII antibody. Despite relatively low peak serum creatinine and rates of renal replacement therapy, SRC was still associated with significant mortality.

Umbilical Cord Blood-Derived Products in Autoimmune Systemic Syndromes with Severe Dryness: A Pilot Study

Background and Objectives: Human umbilical cord blood serum (HUCBS) stands out as a potent adjunct to conventional therapies for ocular surface disorders (OSDs) caused by, among many, autoimmune systemic syndromes. By expediting ocular surface regeneration and fostering epithelial integrity, HUCBS not only enhances subjective patient experiences but also improves objective clinical indicators. This makes it particularly useful in patients with corneal ulcers through ocular surface regeneration and anti-inflammatory activity. This study aims to explore the efficacy of HUCBS in patients who had previously received other treatments unsuccessfully. Materials and Methods: This study was a prospective, non-comparative, interventional case series study involving 49 patients (30 females and 19 males) aged 15–82 years with severe OSDs who were unresponsive to standard treatments. The study was conducted at the San Marco Hospital, Catania, Italy. Patients were categorized into four groups based on the etiology of their severe OSDs: Group I consisted of twenty four patients with filamentary keratitis and corneal ulcers associated with rheumatologic diseases such as Sjogren’s syndrome and systemic sclerosis; Group II comprised thirteen patients with graft-versus-host disease; Group III consisted of nine patients with corneal neurotrophic ulcers; and Group IV included three patients with Steven–Johnson syndrome. The outcomes were evaluated before and after treatment using the following assessments: OSDI (Ocular Surface Disease Index) and SANDE (Symptom Assessment in Dry Eye) questionnaires, VAS (Visual Analog Scale), Slit Lamp Examination, Esthesiometry, Lissamine Green Staining, NIBUT (Non-Invasive Break-Up Time), BUT (Break-Up Time), Fluorescein Staining with Photography and Oxford Classification, The Schirmer Test, Best-Corrected Visual Acuity (BCVA), and Meibography. Results: We observed a significant improvement in the outcomes from the SANDE, VAS, and OSDI questionnaires, The Schirmer Test, BUT, BCVA, and Oxford Classification, after treatment with UCBS. Clinical variables, such as corneal inflammation, conjunctivalization, corneal neovascularization, and pain, were also considered individually. Nevertheless, pain and inflammation reduced markedly over time until complete healing was achieved in all cases. Conclusions: Our pilot study highlights the substantial efficacy of HUCBS in patients with systemic autoimmune diseases who have shown inadequate responses to prior treatments for dry eye. This underscores the need for further comprehensive investigations in this field.

Treatment of Systemic Sclerosis Complicated By Cardiac Arrhythmia: A Case Report

Cardiac manifestations are occasionally observed in Systemic Sclerosis patients. Primary cardiac involvement may occur as a direct consequence of the disease. Arrhythmias are also thought to be a direct result from conduction system fibrosis. Early diagnosis and treatment of arrhythmia can be rewarding for this patient as if intreated may lead to a fatal outcome. Beta blockers used to treat arrythmia may worsen Raynaud’s symptom in systemic sclerosis. So there has been a controversy regarding the treatment of arrhythmia in Systemic Sclerosis. Here we are reporting a case of Systemic Sclerosis who presented with palpitation and digital gangrene. Her resting ECG showed multiple premature ventricular complexes whereas echocardiogram did not show any significant abnormality. Then She was treated with non-selective beta blocker without any progression of her Raynaud’s. For her digital gangrene, along with other conventional treatment (like nifedipine &amp; tadalafil) she was treated with endothelin receptor antagonist (bosentan) and showed good response. J Dhaka Med Coll. 2023; 32(1) : 92-95

Anti-SRP Antibodies and Myocarditis in Systemic Sclerosis Overlap Syndrome with Immune-Mediated Necrotizing Myositis (IMNM)

Overlap syndrome of systemic sclerosis and idiopathic inflammatory myopathies is an increasingly frequent entity, but the association with immune-mediated necrotizing myositis has rarely been described. While myositis or myopathy may be features of scleroderma, it is imperative to correctly diagnose an overlap syndrome of these two, since it can be considered a different entity with specific management and a worse prognosis. Anti-signal recognition particle (anti-SRP) antibodies target the striated muscle fiber and inhibit myoblast regeneration, resulting in myofiber atrophy and necrosis. Anti-SRP antibodies are specific in immune-mediated necrotizing myopathy characterized by myonecrosis and minimal inflammatory reaction, with proximal muscle weakness and typical extra-muscular manifestation. There are controversial data on the association of cardiac manifestations and the presence of these antibodies, and recent studies cannot prove a significant correlation between the two. Myocarditis is a complication with an unpredictable, potentially severe outcome from heart failure and dilated cardiomyopathy to fatality. It can be difficult to diagnose, and a myocardial biopsy can be problematic in daily practice; thus, most practitioners rely on cardiac magnetic resonance with suggestive images for the correct diagnosis. This paper seeks to address the challenges associated with the diagnosis and treatment of collagen diseases by evaluating the role of anti-SRP antibodies in the pathogenesis of cardiac involvement.

Features of proinflammatory activation of macrophages in patients with rheumatoid arthritis and systemic lupus erythematosus

Autoimmune rheumatic diseases (ARDs) are chronic pathological conditions that arise from an abnormal immune response and are accompanied by systemic inflammation. The most common ARDs include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). The exact pathogenesis of ARDs remains unclear, but the complex influence of genetic, immunological and external environmental factors leads to the occurrence and further progression of ARDs. It has been shown that the cause of chronic inflammation may be proinflammatory activation of macrophages, in which an increase in the secretion of cytokines is observed. The aim of this study was to evaluate the inflammatory response of macrophages in patients with RA, SLE and SSc. Materials and methods. The study included 143 participants: 47 patients with RA, 45 patients with SLE, 34 patients with SSc, and 17 people without ARDs and other chronic diseases. Isolation of a primary culture of monocytes was carried out by centrifugation in a ficoll gradient using magnetic separation from the whole blood of study participants. Lipopolysaccharide (LPS) was added to stimulate cells along the proinflammatory pathway. Cell cultivation was carried out for 24 hours. Determination of basal and LPS-stimulated secretion of IL-8 by macrophages was carried out in the culture fluid using an enzyme-linked immunosorbent assay (ELISA). Proinflammatory activation of macrophages was calculated as the ratio of LPS-stimulated and basal IL-8 secretion. Research results. Basal secretion of IL-8 by macrophages was statistically significantly higher in the groups of patients with RA and SSc compared with the SLE and control groups. LPS-stimulated secretion of IL-8 by macrophages in the SSc group had statistically higher values compared to the RA and SLE groups. Proinflammatory activation of macrophages was reduced in the group of patients with RA compared to patients with SLE and the control group, and was also statistically significantly lower in patients with SSc compared to the control group.

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.

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.