Explore the vast range of titles available.

Background Systemic sclerosis (SSc) is a rare, complex, connective tissue disorder. Interstitial lung disease (ILD) is common in SSc, occurring in 35–52% of patients and accounting for 20–40% of mortality. Evolution of therapeutic options has resulted in a lack of consensus on how to manage this condition. This Delphi study was initiated to develop consensus recommendations based on expert physician insights regarding screening, progression, treatment criteria, monitoring of response, and the role of recent therapeutic advances with antifibrotics and immunosuppressants in patients with SSc-ILD. Methods A modified Delphi process was completed by pulmonologists (n = 13) and rheumatologists (n = 12) with expertise in the management of patients with SSc-ILD. Panelists rated their agreement with each statement on a Likert scale from − 5 (complete disagreement) to + 5 (complete agreement). Consensus was predefined as a mean Likert scale score of ≤  − 2.5 or ≥  + 2.5 with a standard deviation not crossing zero. Results Panelists recommended that all patients with SSc be screened for ILD by chest auscultation, spirometry with diffusing capacity of the lungs for carbon monoxide, high-resolution computed tomography (HRCT), and/or autoantibody testing. Treatment decisions were influenced by baseline and changes in pulmonary function tests, extent of ILD on HRCT, duration and degree of dyspnea, presence of pulmonary hypertension, and potential contribution of reflux. Treatment success was defined as stabilization or improvement of signs or symptoms of ILD and functional status. Mycophenolate mofetil was identified as the initial treatment of choice. Experts considered nintedanib a therapeutic option in patients with progressive fibrotic ILD despite immunosuppressive therapy or patients contraindicated/unable to tolerate immunotherapy. Concomitant use of nintedanib with MMF/cyclophosphamide can be considered in patients with advanced disease at initial presentation, aggressive ILD, or significant disease progression. Although limited consensus was achieved on the use of tocilizumab, the experts considered it a therapeutic option for patients with early SSc and ILD with elevated acute-phase reactants. Conclusions This modified Delphi study generated consensus recommendations for management of patients with SSc-ILD in a real-world setting. Findings from this study provide a management algorithm that will be helpful for treating patients with SSc-ILD and addresses a significant unmet need.

ObjectivesDetermine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.MethodsSkin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.ResultsSSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.ConclusionsSkin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

Background Early diffuse cutaneous systemic sclerosis (dcSSc) has the highest case fatality among rheumatic diseases. We report baseline characteristics, current immunosuppressive therapies, progression of skin and internal organ involvement, and mortality in a multicenter prospective cohort from the United States (US) of America. Methods We performed a longitudinal analysis of participants from 12 US centers, from April 2012 to July 2020. All participants had early dcSSc or were at-risk for dcSSc, with ≤2 years since the first non-Raynaud’s phenomenon (RP) symptom. Results Three hundred one patients were included with a baseline median disease duration of 1.2 years since RP and a mean modified skin score of 21.1 units. At baseline, 263 (87.3%) had definite dcSSc and 38 (12.7%) were classified as at-risk; 112 (49.6%) patients were positive for anti-RNA polymerase III antibodies. The median follow-up duration was 24.5 months (IQR = 10.3–40.7 months). One hundred ninety (63.1%) participants were treated with an immunosuppressive therapy, of which mycophenolate mofetil was most used at baseline and follow-up. Of 38 who were classified as at-risk at baseline, 27 (71%) went on to develop dcSSc; these patients were characterized by higher baseline mean HAQ-DI (0.8 versus 0.4, p = 0.05) and higher baseline mRSS (8.8 versus 4.4, p < 0.01) in comparison with those who remained as limited cutaneous SSc. In the overall cohort, 48 participants (21.1%) had clinically significant worsening of skin fibrosis, mainly occurring in the first year of follow-up; 41 (23.3%) had an absolute forced vital capacity decline of ≥10%. Twenty participants (6.6%) died, of which 18 died in the first 3 years of follow-up. Cardiac involvement (33.3%), gastrointestinal dysmotility (22.2%), and progressive interstitial lung disease (ILD) (16.7%) were the main causes of death. Conclusion This US cohort highlights the management of early SSc in the current era, demonstrating progression of skin and lung involvement despite immunosuppressive therapy and high mortality due to cardiac involvement.

Areas of increased lung attenuation visualized by computed tomography are associated with all-cause mortality in the general population. It is uncertain whether this association is attributable to interstitial lung disease (ILD). To determine whether high-attenuation areas are associated with the risk of ILD hospitalization and mortality in the general population. We performed a cohort study of 6,808 adults aged 45-84 years sampled from six communities in the United States. High-attenuation areas were defined as the percentage of imaged lung volume with attenuation values between -600 and -250 Hounsfield units. An adjudication panel determined ILD hospitalization and death. After adjudication, 52 participants had a diagnosis of ILD during 75,232 person-years (median, 12.2 yr) of follow-up. There were 48 hospitalizations attributable to ILD (crude rate, 6.4 per 10,000 person-years). Twenty participants died as a result of ILD (crude rate, 2.7 per 10,000 person-years). High-attenuation areas were associated with an increased rate of ILD hospitalization (adjusted hazard ratio, 2.6 per 1-SD increment in high-attenuation areas; 95% confidence interval, 1.9-3.5; P < 0.001), a finding that was stronger among men, African Americans, and Hispanics. High-attenuation areas were also associated with an increased rate of ILD-specific death (adjusted hazard ratio, 2.3; 95% confidence interval, 1.7-3.0; P < 0.001). Our findings were consistent among both smokers and nonsmokers. Areas of increased lung attenuation are a novel risk factor for ILD hospitalization and mortality. Measurement of high-attenuation areas by screening and diagnostic computed tomography may be warranted in at-risk adults.

Background The modified Rodnan skin score (mRSS), a measure of systemic sclerosis (SSc) skin thickness, is agnostic to inflammation and vasculopathy. Previously, we demonstrated the potential of neural network-based digital pathology applied to SSc skin biopsies as a quantitative outcome. Here, we leverage deep learning and histologic analyses of clinical trial biopsies to decipher SSc skin features ‘seen’ by artificial intelligence (AI). Methods Adults with diffuse cutaneous SSc ≤ 6 years were enrolled in an open-label trial of belumosudil [a Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor]. Participants underwent serial mRSS and arm biopsies at week (W) 0, 24 and 52. Two blinded dermatopathologists scored stained sections (e.g., Masson’s trichrome, hematoxylin and eosin, CD3, α-smooth muscle actin) for 16 published SSc dermal pathological parameters. We applied our deep learning model to generate QIF signatures/biopsy and obtain ‘Fibrosis Scores’. Associations between Fibrosis Score and mRSS (Spearman correlation), and between Fibrosis Score and mRSS versus histologic parameters [odds ratios (OR)], were determined. Results Only ten patients were enrolled due to early study termination, and of those, five had available biopsies due to fixation issues. Median, interquartile range (IQR) for mRSS change (0–52 W) for the ten participants was -2 (-9—7.5) and for the five with biopsies was -2.5 (-11—7.5). The correlation between Fibrosis Score and mRSS was R = 0.3; p  = 0.674. Per 1-unit mRSS change (0–52 W), histologic parameters with the greatest associated changes were (OR, 95% CI, p -value): telangiectasia (2.01, [(1.31—3.07], 0.001), perivascular CD3 + (0.99, [0.97—1.02], 0.015), and % of CD8 + among CD3 + (0.95, [0.89—1.01], 0.031). Likewise, per 1-unit Fibrosis Score change, parameters with greatest changes were (OR, p -value): hyalinized collagen (1.1, [1.04 – 1.16], < 0.001), subcutaneous (SC) fat loss (1.47, [1.19—1.81], < 0.001), thickened intima (1.21, [1.06—1.38], 0.005), and eccrine entrapment (1.14, [1—1.31], 0.046). Conclusions Belumosudil was associated with non-clinically meaningful mRSS improvement. The histologic features that significantly correlated with Fibrosis Score changes ( e.g., hyalinized collagen, SC fat loss) were distinct from those associated with mRSS changes ( e.g., telangiectasia and perivascular CD3 +). These data suggest that AI applied to SSc biopsies may be useful for quantifying pathologic features of SSc beyond skin thickness.

Background Interstitial lung disease (ILD) is a rare complication of antiphospholipid syndrome (APS), but circulating antiphospholipid antibodies have been detected in patients with ILD without APS. Whether antiphospholipid antibodies are associated with subclinical ILD phenotypes is unknown. We aim to examine the associations between anticardiolipin (aCL) and B-2 glycoprotein-1 (B2GP1) isotypes and high attenuation areas (HAA) and interstitial lung abnormalities (ILA) on CT scans in the Multi-Ethnic Study of Atherosclerosis (MESA). Methods We measured serum aCL and B2GP1 isotypes and calculated proportion of HAA on cardiac CT scan in 6623 MESA participants at baseline. The presence of ILAs were assessed on full lung CT scans at Exam 5. We used linear and logistic regression to examine these associations. We examined interactions by age, race, and smoking status. Results In adjusted models, every doubling of aCL IgA, IgG, and IgM was associated with 0.36% (95% CI 0.03 to 0.70), 0.31% (95% CI 0.08 to 0.54), and 0.30% (95% CI 0.10 to 0.50) higher HAA in White participants, respectively. No association was found in participants of other races/ethnicities. Smoking modified the association between B2GP1 isotypes and HAA: in individuals with moderate smoking history, every doubling of B2GP1 IgA, IgG and IgM was associated with 0.84% (95% CI 0.30 to 1.38), 0.97% (95% CI 0.43 to 1.52) and 0.65% (95% CI 0.11 to 1.20) higher HAA, respectively. There was no association between antiphospholipid antibodies and ILA. Conclusions Antiphospholipid antibodies are associated with HAA, a quantitative measure of lung injury, inflammation and fibrosis.

Connective tissue diseases (CTDs) can be associated with various forms of pulmonary hypertension, including pulmonary arterial hypertension (PAH), pulmonary veno‐occlusive disease, pulmonary venous hypertension, interstitial lung disease‐associated pulmonary hypertension, chronic thromboembolic pulmonary hypertension, and sometimes a combination of several processes. The prevalence of PAH varies among the different CTDs, with systemic sclerosis (SSc) having the highest at 8%–12%. The most recent European Society of Cardiology/European Respiratory Society guidelines recommend routine annual screening for PAH in SSc and CTDs with SSc features. As CTDs can be associated with a myriad of presentations of pulmonary hypertension, a thorough evaluation to include a right heart catheterization to clearly delineate the hemodynamic profile is essential in developing an appropriate treatment plan. Treatment strategies will depend on the predominant phenotype of pulmonary vasculopathy. In general, management approach to CTD‐PAH mirrors that of idiopathic PAH. Despite this, outcomes of CTD‐PAH are inferior to those of idiopathic PAH, with those of SSc‐PAH being particularly poor. Reasons for this may include extrapulmonary manifestations of CTDs, including renal disease and gastrointestinal involvement, concurrent interstitial lung disease, and differences in the innate response of the right ventricle to increased pulmonary vascular resistance. Early referral for lung transplant evaluation of patients with CTD‐PAH, particularly SSc‐PAH, is recommended. It is hoped that in the near future, additional therapies may be added to the armamentarium of effective treatments for CTD‐PAH. Ultimately, a better understanding of the pathogenesis of CTD‐PAH will be required to develop targeted therapies for this morbid condition.

Background Many types of interstitial lung diseases (ILDs) may transition to progressive chronic-fibrosing ILDs with rapid lung function decline and a negative survival prognosis. In real-world clinical settings, forced vital capacity (FVC) measures demonstrating progressive decline may be linked to negative outcomes, including increased risks of costly healthcare resource utilization (HRU). Thus, we assessed the relationship between rate of decline in lung function and an increase in HRU, specifically inpatient hospitalization, among patients with chronic fibrosing ILD. Methods This study utilized electronic health records from 01-Oct-2015 to 31-Oct-2019. Eligible patients (≥ 18 years old) had ≥ 2 fibrosing ILD diagnosis codes, clinical activity for ≥ 15 months, and ≥ 2 FVC tests occurring 6 months apart. Patients with missing demographic data, IPF, or use of nintedanib or pirfenidone were excluded. Two groups were defined by relative change in percent of predicted FVC (FVC% pred) from baseline to 6 months: significant decline (≥ 10%) vs. marginal decline/stable FVC (decrease < 10% or increase). The primary outcome was defined as the occurrence of an inpatient hospitalization 6 months after the first FVC value. Descriptive and multivariable analysis was conducted to examine the impact of FVC decline on occurrence of inpatient hospitalization. Results The sample included 566 patients: 13% (n = 75) with significant decline and 87% (n = 491) with marginal decline/stable FVC; their mean age (SD) was 65 (13.7) years and 56% were female. Autoimmune diagnoses were observed among 40% of patients with significant decline, and 27% with marginal decline/stable FVC. The significant decline group had better lung function at baseline than the marginal/stable group. For patients with FVC% <80% at baseline, reduction of FVC% ≥10% was associated with significantly increased odds of an inpatient hospitalization (odds ratio [OR] 2.85; confidence interval [CI] 1.17, 6.94 [p = 0.021]). Conclusion Decline in FVC% ≥10% was associated with increased odds of inpatient hospitalization among patients with reduced lung function at baseline. These findings support the importance of preserving lung function among patients with fibrosing ILD.

Tocilizumab, an interleukin-6 receptor blocker, has been used in the inflammatory phase of COVID-19, but its impact independent of corticosteroids remains unclear in patients with severe disease. In this retrospective analysis of patients with COVID-19 admitted between March 2 and April 14, 2020 to a large academic medical center in New York City, we describe outcomes associated with tocilizumab 400 mg (without methylprednisolone) compared to a propensity-matched control. The primary endpoints were change in a 7-point ordinal scale of oxygenation and ventilator free survival, both at days 14 and 28. Secondary endpoints include incidence of bacterial superinfections and gastrointestinal perforation. Primary outcomes were evaluated using t-test. We identified 33 patients who received tocilizumab and matched 74 controls based on demographics and health measures upon admission. After adjusting for illness severity and baseline ordinal scale, we failed to find evidence of an improvement in hypoxemia based on an ordinal scale at hospital day 14 in the tocilizumab group (OR 2.2; 95% CI, 0.7-6.5; p = 0.157) or day 28 (OR 1.1; 95% CI, 0.4-3.6; p = 0.82). There also was no evidence of an improvement in ventilator-free survival at day 14 (OR 0.8; 95% CI, 0.18-3.5; p = 0.75) or day 28 (OR 1.1; 95% CI, 0.1-1.8; p = 0.23). There was no increase in secondary bacterial infection rates in the tocilizumab group compared to controls (OR 0.37; 95% CI, 0.09-1.53; p = 0.168). There was no evidence to support an improvement in hypoxemia or ventilator-free survival with use of tocilizumab 400 mg in the absence of corticosteroids. No increase in secondary bacterial infections was observed in the group receiving tocilizumab.

Background: The World Health Organization (WHO) introduced the International Classification of Functioning, Disability, and Health (ICF) as a scientific method of disability data collection comprised of >1,200 categories describing the spectrum of impairment types (functional, symptoms-based and anatomical) under the bio-psycho-social model with consideration of environmental and personal factors (pf). ICF Core Sets and ICF Checklists are streamlined disease-specific resources for clinical use, service provision, and for use in health economics and health policy. ICF can disclose strengths and weaknesses across multiple patient-reported outcome measures (PROMs) and help consolidate best-fitting question-items from multiple PROMs. Interstitial lung diseases (ILDs), are generally progressive, with restrictive physiology sometimes occurring in the context of multi-organ autoimmunity/inflammatory conditions such as connective tissue diseases (CTDs). In spite of significant associated morbidity and potential disability, ILD has yet to be linked to the ICF. Methods: Each instrument and their question-items within the consensus-recommended core sets for clinical trials in ILD were deconstructed to single concept units, and then linked per updated ICF linkage rules. Inter-linker agreement was established. Three additional subsequently validated measures were also included. Results: One-hundred-eleven ICF categories were identified for ten PROMs and three traditional objective measures that were amenable to ICF linkage. The proportion of agreement ranged from 0.79 (95% CI: 0.62, 0.91) to 0.93 (0.76, 0.99) with the overall proportion of inter-linker agreement being very high 0.86 (0.82, 0.89) for the initial instruments, with 94–100% for the three additional PROMs. Thirty-four new ‘Personal Factors’ emerged to capture disease-specific qualities not elsewhere described in ICF, e.g. ‘pf_embarrassed by cough’ or ‘pf_panic/afraid when can’t get a breath’. Conclusion: This first known effort in ICF linkage of ILD has provided important revelations on the current utility of the ICF in lung disease. Results have indicated areas for meaningful assessment of ICF descriptors for lung impairment. The mapping across PROMs provides insight into possibilities of developing more streamline and precise instrumentation. Finally, familiarity with the ICF in ILD may enable clinicians to experience a smoother transition with the imminent harmonization of ICD and ICF, ICD-11.