Systemic Sclerosis Disease Research Articles

Value of nail fold video capillaroscopy and carotid intima media thickness in assessment of micro and macro-vascular disease in systemic sclerosis patients

Aim of the work: To assess micro and macro-vascular involvement in systemic sclerosis (SSc) patients and their possible association with variable disease parameters using non invasive imaging techniques. Patients and Methods: Thirty (SSc) patients and twenty four controls were enrolled. Skin thickness was assessed using modified Rodnan skin score (mRss). Nailfold videocapillarscopy (NVC) was employed to detect microangiopathy and carotid intima media thickness (IMT) was assessed by power Doppler ultrasound. Results: Patients were 96.7% females and 3.3% males, mean age was 41.6 ± 11.5 years, with mean disease duration 4.7 ± 3 years. 73.3% had limited form while 26.7% had diffuse form. The mean mRss was 18.6 ± 8.5. Microangiopathic patterns detected by NVC were: early, active and late (36.65%), (26.7%) and (36.65%) respectively, and structural alterations included: scar (70%), large capillaries (60%), hemorrhage (41.4%), scanty (36.7%), branched (20%), mega capillaries (16.7%), and tall (10%), but neither crossed nor ramified capillaries were detected. The mean IMT was higher in patients (1 ± 0.2 mm) compared to controls (0.7 ± 0.09 mm) (p < 0.001). A significant inverse correlation was found between high density lipoprotein (HDL) with capillary length (r = −0.27, p = 0.05), arterial and venous loop diameters (r = −0.29,p = 0.03)(r = −0.41, p = 0.003) respectively. On linear regression for prediction of HDL, only the relation to venous loop was significant (p = 0.03). Atherosclerosis on carotid doppler showed significant association with arterial loop diameter (p = 0.04), venous loop diameter (p = 0.02) and capillary length (p = 0.001). Conclusion: Micro- and macro-vascular disease in SSc are different entities that do not simultaneously exist in every patient, although endothelial dysfunction can eventually lead to both, and should be meticulously evaluated.

Association Between Immunosuppressive Therapy and Incident Risk of Interstitial Lung Disease in Systemic Sclerosis

Association Between Immunosuppressive Therapy and Incident Risk of Interstitial Lung Disease in Systemic Sclerosis

Performance of finger systolic blood pressure measurement to detect digital occlusive arterial disease in systemic sclerosis.

Digital ulcers related to digital occlusive arterial disease (DOAD) are frequent in patients with SSc. Finger systolic blood pressure (FSBP) and digital-brachial pressure index (DBI) using laser Doppler flowmetry constitute a non-invasive means of detecting DOAD in SSc, although thresholds have yet to be established for defining DOAD. The purpose of this study was to ascertain FSBP and DBI thresholds to detect DOAD in SSc patients. The intra/interday reproducibility of curve reading by four vascular physicians in relation to finger pressure measurement was also investigated. SSc patients were followed in this single-centre study (Rennes University Hospital, France) between November 2017 and October 2019.These patients underwent tests before and after heating at two visits spaced 10 days apart. DOAD was diagnosed on the basis of post-warming skin blood flow of ≤206 arbitrary units measured by laser Doppler flowmetry, contingent on previous results validated by arteriography as a gold standard. An interday kappa coefficient with a 95% confidence interval was used to assess reproducibility. Sixteen [10 females; mean age: 63 (9) years] SSc patients were included. Mean time interval between visits was 9 (5) days. The best FSBP threshold for DOAD diagnosis was 76 mmHg and DBI was 0.74 after warming. FSBP and DBI sensitivity/specificity were 59.1% (95% CI: 49.6, 68.5%)/92.5% (95% CI: 85.3, 99.6%) and 73.3% (95% CI: 64.9, 81.8%)/83.0% (95% CI: 72.9, 93.1%), respectively. Intra/interday reproducibility ranged from fair to good. The conclusions drawn from this study suggest that FSBP ≤ 76 mmHg and DBI ≤ 0.74 thresholds are potentially reliable indicators of DOAD and demonstrate fair to good intra- and interday reproducibility. ClinicalTrials.gov, www.clinicaltrials.gov, NCT03264820.

Correlation Between Serum Tumor Marker Levels and Connective Tissue Disease-Related Interstitial Lung Disease.

ObjectiveThe main aims of this study were to explore the relationships between serum tumor markers and connective tissue disease-related interstitial lung disease (CTD-ILD) and to evaluate the clinical value of tumor markers for investigating interstitial lung disease (ILD) in patients with connective tissue disease (CTD).MethodsThe study included 235 patients with CTD (90 CTD without ILDs, 145 CTD-ILD). Clinical information and the levels of inflammatory and tumor markers, including carbohydrate antigen (CA) 19–9, CA125, carcinoembryonic antigen (CEA), CA153, and cytokeratin 19 fragments (CYFRA21-1), were obtained in all the patients.ResultsA significant difference between CTD with or without ILD and higher levels of tumor markers was observed in the CTD-ILD group, including CA19-9 (p<0.001), CEA (p<0.001), CA153 (p<0.001), and CYFRA21-1 (p<0.001). There was no significant difference in serum tumor marker levels in the various types of CTD (rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, inflammatory myositis, systemic sclerosis, and mixed connective tissue disease). The levels of CA153 [odds ratio (OR)=1.159] and CYFRA21-1 (OR=2.269) were clearly related to the risk of CTD-ILD. The diagnostic value of CA153 [area under receiver operating characteristic curve (AUC)=0.736] and CYFRA21-1 (AUC=0.718) was confirmed for ILDs in CTD patients, at cut-off values of 9.45 U/mL and 2.13 ng/mL, respectively.ConclusionThere is a positive correlation between serum tumor marker levels and CTD-ILD. Higher levels of CA153 and CYFRA21-1 suggest an increased risk of developing ILD and may therefore be useful as biomarkers for detecting CTD-ILD in the clinical setting.

Association between gastroprotective agents and risk of incident interstitial lung disease in systemic sclerosis

ObjectivesAlthough interstitial lung disease (ILD) occurs in over half of systemic sclerosis (SSc) patients and represents a leading cause of mortality, there are currently no preventative strategies. We evaluated if gastroprotective agents were associated with a lower incident risk of SSc-ILD. MethodsAn SSc cohort without clinically apparent ILD at baseline was constructed from the Canadian Scleroderma Research Group registry. The primary exposure was any use of gastroprotective agents. Treatment with promotility agents was assessed as a secondary exposure. Time to development of clinically apparent ILD was compared between exposed and unexposed person-time, using a multivariable marginal structural Cox model incorporating inverse probability of treatment weights to address time-varying confounding. ResultsIn total, 798 subjects met inclusion criteria. At cohort entry, median disease duration was 7.6 (IQR 3.9–15.6) years. During a median 4.4 (IQR 2.6–7.2) years of follow-up, 158 new ILD cases were diagnosed, for a crude incidence of 4.4 (95% CI 3.8–5.1) events per 100 person-years. Most (2085, 73.4%) person-visits were exposed to gastroprotective agents, 579 (20.4%) were exposed to promotility agents, and 554 (19.5%) were exposed to both agents. The marginal structural weighted hazard ratio (HR) for incident ILD related to gastroprotective agents was 0.86 (95% CI 0.52–1.41). When exposure was defined as treatment with promotility agents, the weighted adjusted HR was 0.79 (95% CI: 0.35–1.77). ConclusionIn this large retrospective cohort study, we were unable to demonstrate a protective role for gastroprotective and promotility agents in preventing clinically apparent SSc-ILD.

Peripheral cells from patients with systemic sclerosis disease co-expressing M1 and M2 monocyte/macrophage surface markers: Relation to the degree of skin involvement

The monocyte/macrophage lineage cells were found involved in the pathogenesis of systemic sclerosis (SSc) disease. The naïve macrophages are activated either to M1 cells with proinflammatory roles or to M2 cells that function to resolve inflammation with tissue repair. Recently, cells with dual phenotypes were detected in SSc disease. So, we aimed in this study to demonstrate different monocyte/macrophage phenotypes in peripheral cells from a group of Egyptian SSc patients, correlating percentages of these cells with the clinical findings in patients.The study participants comprised 41 patients with diffuse cutaneous SSc disease and 25 healthy individuals as controls. Clinical, radiological, and laboratory tests were conducted for SSc patients. Different phenotypes of the monocyte/macrophage subsets were identified in peripheral blood of patients and controls by flow cytometry for characteristic M1 (CD80, CD86, and TLR4) and M2 (CD204, CD163 and CD206) markers.SSc patients showed higher percentages of peripheral cells of the M1, M2, and mixed M1/M2 phenotypes within the monocyte/macrophage lineage compared to controls. Different cell phenotypes were associated significantly with the disease duration, modified Rodnan’s score, the Medsger skin score, and the Medsger lung in SSc patients. Some cells with the M1/M2 phenotypes were higher in SSc patients with pitting scars, arthritis, and myalgia.

POS0424 DETERMINING CIRCULATING ENDOTHELIAL CELLS USING CELLSEARCH SYSTEM IN SYSTEMIC SCLEROSIS PATIENTS

Background:Endothelial damage and fibroproliferative vasculopathy of small vessels are pathological hallmarks of Systemic Sclerosis (SSc). Detection and analysis of circulating endothelial cells (CECs) detached from affected blood vessels may be an informative tool to study vascular dysfunction and could be considered a novel biomarker of scleroderma vasculopathy. Our group first showed the presence of CECs in SSc by fluorescence-activated cell sorting (FACS), demonstrating that a raised counts of active CECs may represent direct evidence of active vascular disease in SSc. Despite these interesting data, issues related to difficulties in CEC counting through FACS analysis, due their very low concentration in peripheral blood, prevented further investigations in this field. Recently, a specific kit for the detection of CECs has been developed through the CellSearch System (CS), a semi-automated device for the standardized analysis of rare cells, such as CECs, in peripheral blood.Objectives:To assess the counts of CECs determined by the CS in SSc patients and to evaluate their clinical implication and potential as vascular biomarker in SSc.Methods:10mL of blood samples were collected from 29 subjects (19 SSc patients and 10 healthy donors - HDs) and stored in tubes containing a specific preservative, to allow the analysis of 4mL of blood within 72 hours, according to manufacturer instructions. Out of 19 SSc patients, 18 were female, 10 had the limited form and 9 the diffuse cutaneous variant of SSc. CS uses a proprietary kit containing a ferrofluid-based reagent, that target CD146 to magnetically capture CECs, and the immunofluorescent reagents to stain the CECs, defined as CD146+, CD105-PE+, DAPI+ and CD45-APC-. Clinical, laboratoristic and demographic data were also collected.Results:The mean number of CECs in patients with SSc was significantly higher in comparison to HDs (554/4mL vs. 53.5/4 mL, p=0.0042). When analyzed according to disease subset, both lcSSc and dcSSc showed significantly increased levels of CECs in comparison with HDs (p=0.003 and p=0.005, respectively). No statistical difference was observed in the mean number of CECs in patients with lcSSc compared to those with dcSSc. Regarding vascular involvement, the CECs counts strictly correlated with the presence of digital ulcers (DUs) (p=0.0001) showing a median of 863cells/4mL for the SSc patients with DUs versus a median of 276.2/4mL for the SSc patients without DUs. No statistical correlation was found between CECs and serological autoantibody pattern, skin parameters, or joint and muscle involvement. Patients with active disease, according to the EUSTAR Activity Index, showed a higher CECs value than those with inactive disease (p=0.0012).Conclusion:The amount of CECs detectable in peripheral blood has been recently proposed as a marker of endothelial damage in different vascular diseases, including SSc. However, currently no standardized method is available to determine CEC counts, which makes reported data on CECs reliable and suitable. The CS system is a commercially available semi-automated system that enables standardized determination of CECs. Thus, we examined clinical utility of CECs count by this system in SSc patients. Our results confirm that baseline CEC counts, evaluated by a new standardized method, may represent direct evidence of endothelial damage in SSc and could be a promising tool for monitoring active disease and evaluating therapeutic responses to vascular and immunosuppressive treatments.

OP0174 SUBCLINICAL INTERSTITIAL LUNG DISEASE IS FREQUENT AND PROGRESSES ACROSS DIFFERENT CONNECTIVE TISSUE DISEASES

Background:Based on the argument that symptoms define disease, physicians commonly apply the terms “preclinical” or “subclinical” disease to describe patients with disease-related findings but no accompanying symptoms for connective tissue disease associated interstitial lung disease (CTD-ILD). The term subclinical frequently applies to patients with mild ILD changes on high resolution chest tomography (HRCT), normal forced vital capacity (FVC), and without respiratory symptoms. Previous work in systemic sclerosis (SSc)-ILD did show that patients with even minor extent of ILD at baseline often progressed and had increased mortality risk, suggesting that it is not appropriate to define these patients as “subclinical.”Objectives:To identify the prevalence of subclinical ILD across CTD diagnoses, and assess the rate of progression of lung fibrosis compared to CTD without ILD and with clinical ILD.Methods:All CTD patients, including SSc, anti-synthetase syndrome (ASS) and mixed connective tissue disease (MCTD) from the Oslo University Hospital diagnosed before 2015 and assessed for the presence of ILD by HRCT were included. The year 2015 was chosen to secure an observation time of at least five years from ILD diagnosis to study end on 01.01.2021 or time of death. All patients fulfilled the respective CTD classification criteria. Subclinical ILD was defined as an ILD extent &lt;5% by semi-quantitative assessment of baseline HRCT, preserved lung function with FVC &gt;80% predicted and without respiratory symptoms. Clinical ILD was defined as &gt;5% extent of ILD or &lt;5% extent of ILD on HRCT with respiratory symtoms or FVC&lt;80%. The outcome was ILD progression, defined as increasing extent of ILD from basline to follow-up HRCT by semi-quantitative assessment. Vital status was available in all patients and mortality was evaluated. Descriptive statistical analyses were conducted and time to ILD progression determined by Kaplan-Meier estimates.Results:We identified 525 CTD patients, including 296 with SSc, 135 with MCTD and 94 with ASS who had conducted a baseline HRCT. Of these, 227 (43%) had no ILD, 67 (13%) subclinical and 231 (44%) clinical ILD (Table). Of the 67 subclinical ILD patients, 45 (15%) had SSc, 13 (10%) MCTD and 9 (10%) ASS of thespecific cohorts. Over a median time of 4.5 years between baseline and follow-up HRCT, 95/395 (24%) showed progression of ILD, including 72 (26%) SSc and 23 (19%) MCTD patients. Disease progression frequently occurred in both subclinical ILD (38%) and clinical ILD (51%) patients (Figure). Age, gender, underlying CTD, and baseline lung function were not predictive for the progression of lung fibrosis. Progression was too infrequent to allow for meaningful multivariable regression analyses. After a median observation period of 12 years, 153 (29%) of the patients died. The 1-, 5- and 10-year survival rates in those without ILD, subclinical and clinical ILD were 97%/97%/99%, 88%/91%/82%, and 82%/85%/68% (p&lt;0.001), respectively.Table 1.Clinical characteristics, demographics and outcomeNo ILD (n=227)Subclinical ILD (n=67)Clinical ILD (n=231)Age, y (SD)50 (15.4)51 (14.4)52 (15.3)Male sex, n (%)89 (39)22 (33)111 (48)Deceased, n (%)50 (22)12 (18)91 (39)Observation period, y median (range)13.7 (18.6)13.9 (17.9)11.5 (17.1)FVC% (SD)97 (18.6)99 (17.9)81 (20.9)FVC decline% (SD)-0.70 (11.1)-0.81 (16.5)-1.61 (15.9)DLCO% (SD)73 (19.4)73 (16.9)55 (17.4)Extent of ILD% (SD)0 (0)2.3 (1.5)19.3 (16.8)ILD progression% (SD)0.08 (1.0)3.1 (6.2)3.6 (9.9)ILD progressors, n (%)3 (2)20 (38)72 (51)Figure 1.Time to ILD progression in CTD without ILD, with subclinical and clinical ILDConclusion:Subclinical ILD is frequently present across CTDs and progresses over time in a substantial subgroup of patients, comparable to patients with clinical ILD. Our findings question the terms sub- and preclinical ILD, which may potentially lead to a suboptimal “watchful waiting management strategy”. Monitoring all CTD patients with any ILD is of high importance to identify disease progression early.Disclosure of Interests:Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Roche, Merck Sharp &amp; Dohme, Lilly and Medscape, Consultant of: Actelion, Boehringer Ingelheim, Bayer, ARXX, and Medscape, Grant/research support from: Boehringer Ingelheim, Helena Andersson: None declared, Silje Reiseter: None declared, Håvard Fretheim Consultant of: Actelion, Bayer., Imon Barua: None declared, Torhild Garen: None declared, Øyvind Midtvedt: None declared, Ragnar Gunnarsson: None declared, Mike Durheim Speakers bureau: Boehringer Ingelheim and Roche, Consultant of: Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim, Trond M Aaløkken: None declared, Øyvind Molberg: None declared

Association of cytochrome P2D6 gene polymorphism with the susceptibility of Egyptian patients to systemic sclerosis disease

BackgroundSystemic Sclerosis (SSc) is a chronic disease of the connective tissue caused by an autoimmune inflammatory process. Genetic polymorphisms of cytochrome P2D6 (CYP2D6) enzymes have been implicated in the SSc disease etiopathogenesis. AimOur work was designed to investigate the association between the CYP2D6 gene mutation and the risk of SSc development and its relation to different SSc clinical manifestations. MethodsOne hundred SSc patients were involved in the study and one hundred healthy individuals were included to serve as a contol group.CYP2D6 *1, CYP2D6 *3, CYP2D6 *4 allelic frequencies were analyzed by the Polymerase Chain Reaction- Fragment Length Polymorphism (PCR-RFLP) method. ResultsThe heterozygous extensive metabolizers (CYP2D6 *1/*4) genotype showed a statistically significant risk for developing SSc, assessed by the odds ratio (OR = 2.4, P = 0.003). The homozygous extensive metabolizers (CYP2D6 *1/*1) which are the wild genotypes, were expressed less frequently in SSc patients with a significant difference (OR = 0.23) in comparison with the control group. As for the alleles frequency, a significant increase in the risk of SSc was associated with the mutant CYP2D6 *4 allele frequency (OR = 2.2), indicating that the presence of allele CYP2D6*4 is a risky genetic factor for SSc. Diffuse type systemic sclerosis, gastrointestinal (GIT), cardiac, pulmonary manifestations, positive anti-scleroderma 70, moderate restriction in pulmonary function tests, and abnormal Echocardiographic findings were significantly associated with the (CYP2D6 *1/*4) genotype. ConclusionFinding of the study revealed a higher prevalence of the heterozygotes extensive metabolizers (CYP2D6 *1/*4)genotypes and the mutant alleles (CYP2D6*4) in SSc patients, suggesting the high impact of the CYP2D6 gene mutation on the SSc development.

Dysbiosis and Gut Microbiota Modulation in Systemic Sclerosis.

Gastrointestinal (GI) involvement is an early manifestation in systemic sclerosis (SSc), affecting more than 90% of patients, and severe GI disease is a marker of poor prognosis and mortality. Recent studies have hypothesized that alterations of the intestinal microbiota, known as dysbiosis, may represent 1 of the possible environmental factors influencing SSc disease status. In addition, specific microorganisms may be associated with SSc pathogenesis, progression, and GI manifestations. Therapeutic approaches aiming to modulate the intestinal microbiota have emerged, as alternatives to treat GI symptoms, and dietary interventions, probiotic administration, and fecal microbiota transplantation are potential therapies for SSc patients. However, given the complexity and variability of pathogenesis and clinical manifestations in SSc, these therapies need to be combined with additional interventions that target other disease components. Here, we summarize studies addressing intestinal dysbiosis in SSc and discuss the potential of microbiota modulators to treat SSc-related GI disorders.

Serpentine Supravenous Hyperpigmentation Following Intravenous Docetaxel

Serpentine supravenous hyperpigmentation is a rare, cutaneous sequela of intravenous chemotherapeutic agents, collagen vascular diseases (systemic sclerosis, systemic lupus erythematosus, and rheumatoid arthritis), and infections like leprosy and HIV. The condition manifests clinically as a peculiar, patterned eruption characterized by hyperpigmented streaks following the superficial venous network on the skin. Here, we report a case of a middle-aged lady with breast carcinoma, who developed serpentine supravenous hyperpigmentation after intravenous docetaxel.

The Relationship between Pulmonary Damage and Peripheral Vascular Manifestations in Systemic Sclerosis Patients.

Systemic sclerosis (SSc) is an autoimmune disease, characterized by the presence of generalized vasculopathy and tissue fibrosis. Collagen vascular disorder in SSc is due to fibroblast and endothelial cell dysfunctions. This leads to collagen overproduction, vascular impairment and immune system abnormalities and, in the last stage, multi-organ damage. Thus, to avoid organ damage, which has a poor prognosis, all patients should be carefully evaluated and followed. This is particularly important in the initial disease phase, so as to facilitate early identification of any organ involvement and to allow for appropriate therapy. Pulmonary disease in SSc mainly involves interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). High-resolution computed tomography (HRCT) and pulmonary function tests (PFT) have been proposed to monitor parenchymal damage. Although transthoracic echocardiography is the most commonly used screening tool for PAH in SSc patients, definitive diagnosis necessitates confirmation by right heart catheterization (RHC). Moreover, some studies have demonstrated that nailfold videocapillaroscopy (NVC) provides an accurate evaluation of the microvascular damage in SSc and is able to predict internal organ involvement, such as lung impairment. This review provides an overview of the correlation between lung damage and microvascular involvement in SSc patients.

Developing a core set of outcome measure domains to study Raynaud's phenomenon and digital ulcers in systemic sclerosis: Report from OMERACT 2020

Raynaud's phenomenon (RP) and digital ulcers (DUs) are important disease manifestations of systemic sclerosis (SSc) that can lead to significant pain and disability. It is essential when studying these disease features to utilize outcome measures that fully evaluate the complexities of RP and DUs . The Outcome Measures in Rheumatology (OMERACT) Vascular Disease in SSc Working Group is applying the OMERACT filter 2.1 to identify a core set of disease domains that encompass the full burden of SSc-related RP and DUs. Progress to date and future research plans were presented during a Special Interest Group held in December 2020.

Role of Osteopontin as a Potential Biomarker of Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis and Other Connective Tissue Diseases (CTDs).

Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue diseases (CTD). Its early diagnosis is essential to start effective treatment. In the present paper, we aimed to evaluate the role of plasma osteopontin (OPN) as a candidate biomarker of PAH in a cohort of CTD patients. OPN is a pleiotropic protein involved in inflammation and fibrogenesis and, therefore, potentially promising in this specific clinical context. We performed a cross-sectional observational study on a cohort of 113 CTD patients (females N = 101, 89.4%) affected by systemic sclerosis N = 88 (77.9%), mixed connective tissue disease N = 10 (8.8%), overlap syndrome N = 10 (8.8%) or undifferentiated connective tissue disease N = 5 (4.4%). CTD-PAH patients showed significantly higher OPN plasma values than patients with CTD alone (241.0 (188.8–387.2) vs. 200.7 (133.5–281.6) ng/mL; p = 0.03). Although OPN levels were directly correlated with age and inversely with glomerular filtration rate, they remained associated with PAH at multivariate analysis. In conclusion, OPN was significantly associated with PAH among patients with CTD, suggesting it may have a role as a non-invasive disease biomarker of PAH.

A complex intervention to improve anxiety in people with systemic sclerosis during COVID-19.

The COVID-19 pandemic has had a profound effect on the mental health of people with pre-existing systemic sclerosis (scleroderma) and other autoimmune diseases who are susceptible to severe complications from COVID-19. People with systemic sclerosis have had increased fear, worry, anxiety, uncertainty, and stress since the start of the pandemic.1 Given that comorbid anxiety is associated with increased disability and poorer quality of life, it is important that elevated anxiety is detected, and treated with evidence-based treatments.

Efficacy and safety of rituximab therapy in patients with systemic sclerosis disease (SSc): systematic review and meta-analysis.

The clinical benefits of rituximab in systemic sclerosis (SSc) are still contentious. The present meta-analysis aimed to systematically assess rituximab's safety and efficacy profile in SSc patients. A systematic online query was performed in PubMed, Scopus, Web of Science, and Embase. The studies on the application of rituximab for patients with SSc were reviewed comprehensively for over two years. In terms of efficacy profile, mRSS, MS, LVEF, sPAP, FVC, DLCO, TLC, FEV, DAS, severity activity, HAQ-DI and SF36 were assessed for organ involvement and quality of life. The level of biological and immunological markers was also evaluated in SSc patients treated with RTX. In total, 24 studies met the criteria. Although they did not have a high quality, they were free from heterogeneity and publication bias. The pooled results revealed a long-term improvement in mRSS and MS. HAQ-DI was improved to 0.78 after 12 months, and DAS was significantly reduced to 0.33, 0.23, and 0.24 following 6, 12, and 24 months of treatment, respectively (p = 0.00 for both parameters). The rest of the parameters remained stable over time in patients with SSc. The pooled analysis of these patients demonstrated that the induction of death, cancer, infection, and infusion were 9, 5, 18 and 10%, respectively. Based on the pooled results of this meta-analysis, rituximab improves skin score and disease indices and stabilizes organ involvement in SSc patients. Rituximab seems to possess reasonable safety, similar to previous data from other autoimmune diseases.

Immunosuppression use in early systemic sclerosis may be increasing over time.

Immunosuppression remains the main treatment for progressing skin involvement, interstitial lung disease and inflammatory joint or muscle disease in systemic sclerosis. This study investigated the pattern and trends in immunosuppressive agents used in early systemic sclerosis (diagnosed before and after 2007) to determine whether the changes in the preferred type, timing and combination of immunosuppression took place over the past decade. In total, 397 Canadian Scleroderma Research Group database patients (183 diffuse cutaneous systemic sclerosis and 214 limited cutaneous systemic sclerosis) who had baseline and follow-up visits within 3 years (mean: 1.8 ± 0.8) after disease onset were included: 82% females, age at diagnosis 53 ± 13 years. Bivariate, chi-square, analysis of variance and adjusted regression analyses were used. In total, 115 diffuse cutaneous systemic sclerosis patients (63%) and 62 limited cutaneous systemic sclerosis (29%) received immunosuppressive drugs, most commonly methotrexate, followed by mycophenolate mofetil and cyclophosphamide. In diffuse cutaneous systemic sclerosis, immunosuppressants were prescribed after 2007 more often (74% vs 50%, p = 0.001), especially methotrexate (p = 0.02) and mycophenolate mofetil (p = 0.04), and earlier (peak at 2 years after onset). Immunosuppressive therapy was associated with male gender, interstitial lung disease, anti-Scl70 positivity, ACA negativity and inflammatory joint disease in limited cutaneous systemic sclerosis and with ACA negativity and a higher modified Rodnan skin score in diffuse cutaneous systemic sclerosis. Multivariate regression analysis showed that the use of immunosuppressants after 2007 was predicted only by ACA negativity in limited cutaneous systemic sclerosis and by younger age in diffuse cutaneous systemic sclerosis. Over the past decade, there has been a trend to prescribe immunosuppressants more often and earlier in diffuse cutaneous systemic sclerosis patients, regardless of modified Rodnan skin score. Methotrexate is being more frequently used, and mycophenolate mofetil has gained favour over cyclophosphamide. Autoantibody status was the most consistent predictor of immunosuppressive therapy.

Relevance of immunomodulatory therapy for interstitial lung disease in systemic sclerosis.

Systemic sclerosis is an autoimmune disease that prominently leads to skin and tissue fibrosis. The efficacy of autologous stem cell transplantation not only attests to the autoimmune pathophysiology for systemic sclerosis, but also for interstitial lung disease as its most frequent manifestation of fatal organ involvement. Accordingly, a variety of immunomodulatory therapies were tried on patients with systemic sclerosis-interstitial lung disease. Until very recently, all of these therapeutic approaches constituted off-label treatment for systemic sclerosis, given that neither of these therapies was approved by the United States Food and Drug Administration (FDA) or the European Medicines Agency. For tocilizumab, this has now changed with FDA approval in March 2021. Already 2020, nintedanib, which is an antifibrotic drug that does not target autoimmunity, became the first approved drug for interstitial lung disease in systemic sclerosis. The present review analyzes the evidence for immunomodulatory treatment of systemic sclerosis-associated interstitial lung disease. The review focuses on randomized controlled trials, which provides evidence for the effects of drugs such as cyclophosphamide, mycophenolate, rituximab and tocilizumab.

Interstitial lung disease in systemic sclerosis (systemic scleroderma)

In systemic sclerosis (SSc), interstitial lung disease (ILD) is common (&gt;80%) and worsens the prognosis of the disease, but severe progressive damage develops only in 8–10% of cases. Interstitial changes in the lungs occur early (within the first 3–5 years of the disease). The histological manifestations are similar to those of idiopathic ILD.The main tool for screening and diagnosing of ILD associated with SSc is high-resolution computed tomography of the lungs, resulting data influence the choice of therapy. In most patients a relatively intact and stable forced vital capacity of the lungs is recorded for a long time, but the diffusion capacity of the lungs decreases early and steadily. Pulmonary functional tests have prognostic value.The choice of the optimal therapy for SSc with lung lesions is based on general disease activity (the severity of inflammation and fibrosis) and the its severity, rate of progression of the disease in general and the leading pathology – interstitial pneumonia (IP) – in particular. In patients with SSc and severe or progressive IP, treatment with mycophenolate mofetil (MMF), cyclophosphamide, nintedanib, or nintedanib in combination with MMF if appropriate, should be considered. If this therapy is ineffective, rituximab may be used.

Spectrum of childhood interstitial and diffuse lung diseases at a tertiary hospital in Egypt.

BackgroundChildhood interstitial and diffuse lung diseases (chILD) encompass a broad spectrum of rare pulmonary disorders. In most developing Middle Eastern countries, chILD is still underdiagnosed. Our objective was to describe and investigate patients diagnosed with chILD in a tertiary university hospital in Egypt.MethodsWe analysed data of consecutive subjects (aged <18 years) referred for further evaluation at the Children's Hospital, Ain Shams University (Cairo, Egypt). Diagnosis of chILD was made in accordance with the ChILD-EU criteria. The following information was obtained: demographic data, clinical characteristics, chest computed tomography findings, laboratory studies, spirometry, bronchoalveolar lavage and histopathology findings.Results22 subjects were enrolled over 24 months. Median age at diagnosis was 7 years (range 3.5–14 years). The most common manifestations were dyspnoea (100%), cough (90.9%), clubbing (95.5%) and tachypnoea (90.9%). Systematic evaluation led to the following diagnoses: hypersensitivity pneumonitis (n=3), idiopathic interstitial pneumonias (n=4), chILD related to chronic granulomatous disease (n=3), chILD related to small airways disease (n=3), post-infectious chILD (n=2), Langerhans cell histiocytosis (n=2), idiopathic pulmonary haemosiderosis (n=2), granulomatous lymphocytic interstitial lung disease (n=1), systemic sclerosis (n=1) and familial interstitial lung disease (n=1). Among the subjects who completed the diagnostic evaluation (n=19), treatment was changed in 13 (68.4%) subjects.ConclusionSystematic evaluation and multidisciplinary peer review of chILD patients at our tertiary hospital led to changes in management in 68% of the patients. This study highlights the need for an Egyptian chILD network with genetic testing, as well as the value of collaborating with international groups in improving healthcare for children with chILD.