CONQUER Scleroderma: association of gastrointestinal tract symptoms in early disease with resource utilization.

OBJECTIVES: SSc is associated with increased health-care resource utilization and economic burden. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative that collects longitudinal follow-up data on SSc patients with <5 years of disease duration enrolled at scleroderma centres in the USA. The objective of this study was to investigate the relationship between gastrointestinal tract symptoms and self-reported resource utilization in CONQUER participants. METHODS: CONQUER participants who had completed a baseline and 12-month Gastrointestinal Tract Questionnaire (GIT 2.0) and a Resource Utilization Questionnaire (RUQ) were included in this analysis. Patients were categorized by total GIT 2.0 severity: none-to-mild (0-0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00). Clinical features and medication exposures were examined in each of these categories. The 12-month RUQ responses were summarized by GIT 2.0 score categories at 12 months. RESULTS: Among the 211 CONQUER participants who met the inclusion criteria, most (64%) had mild GIT symptoms, 26% had moderate symptoms, and 10% severe GIT symptoms at 12 months. The categorization of GIT total severity score by RUQ showed that more upper endoscopy procedures and inpatient hospitalization occurred in the CONQUER participants with severe GIT symptoms. These patients with severe GIT symptoms also reported the use of more adaptive equipment. CONCLUSION: This report from the CONQUER cohort suggests that severe GIT symptoms result in more resource utilization. It is especially important to understand resource utilization in early disease cohorts when disease activity, rather than damage, primarily contributes to health-related costs of SSc.

Expert consensus on the management of systemic sclerosis-associated interstitial lung disease.

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.

The Collaborative National Quality and Efficacy Registry for Scleroderma: association of medication use on gastrointestinal tract symptoms in early disease and the importance of tobacco cessation.

OBJECTIVES: Systemic Sclerosis (SSc) is frequently associated with gastrointestinal tract (GIT) involvement. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative study collecting longitudinal follow up data on SSc patients with less than 5-years disease duration enrolled at Scleroderma centres of excellence. This manuscript presents the GIT natural history and outcomes in relation to other scleroderma manifestations and medication exposures. METHODS: CONQUER participants that had completed a minimum of two serial Scleroderma Clinical Trials Consortium GIT Questionnaires (GIT 2.0) were included in this analysis. Patients were categorised by total GIT 2.0 severity at baseline, and by category change: none-to-mild (0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00) at the subsequent visit. Based on this data, four groups were identified: none-to-mild with no change, moderate-to-severe with no change, improvement, or worsening. Clinical features and medications, categorised as gastrointestinal tract targeted therapy, anti-fibrotic, immunosuppression, or immunomodulatory drugs, were recorded. Analysis included a proportional odds modelaccounting for linear and mixed effects of described variables. RESULTS: 415 enrolled CONQUER participants met project inclusion criteria. Most participants had stable mild GIT symptoms at baseline and were on immunomodulatory and anti-reflux therapy. In most patients, anti-reflux medication and immunosuppression initiation preceded the baseline visit, whereas anti-fibrotic initiation occurred at or after the baseline visit. In the proportional odds model, worsening GIT score at the follow-up visit was associated with current tobacco use (odds ratio: 3.48 (1.22, 9.98, p 0.020). CONCLUSIONS: This report from the CONQUER cohort, suggests that most patients with early SSc have stable and mild GIT disease. Closer follow-up was associated with milder, stable GIT symptoms. There was no clear association between immunosuppression or anti-fibrotic use and severity of GIT symptoms. However, active tobacco use was associated with worse GIT symptoms, highlighting the importance of smoking cessation counselling in this population.

Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile.

OBJECTIVES: Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease. METHODS: Skin 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. RESULTS: SSc 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. CONCLUSIONS: Skin 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.

Recent progress in systemic sclerosis-interstitial lung disease.

PURPOSE OF REVIEW: Systemic sclerosis is a systemic autoimmune disorder wherein interstitial lung disease (ILD) is the major source or morbidity and mortality. Research into mechanisms of fibrosis and its intersection with autoimmunity, specifically lung fibrosis, has accelerated and been applied to autoimmune disorders such as scleroderma. This review highlights important emerging insights and treatment trials. RECENT FINDINGS: The important elements of this review focus on the challenges faced in identifying patients not only who develop lung disease but who are at a higher risk for progression given the heterogeneous natural history of ILD in scleroderma. Risk assessment scoring models using radiographic and physiologic parameters are highlighted and recent and ongoing clinical trials in scleroderma ILD are discussed. SUMMARY: The implications of much of this ongoing work is a potential paradigm shift in our ability to identify those patients at risk for progression, and to offer novel therapies that can limit the progression of inflammatory and fibrotic lung disease in this challenging group of patients.

Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis.

Lysophosphatidic acid (LPA) is an important mediator of pulmonary fibrosis. In blood and multiple tumor types, autotaxin produces LPA from lysophosphatidylcholine (LPC) via lysophospholipase D activity, but alternative enzymatic pathways also exist for LPA production. We examined the role of autotaxin (ATX) in pulmonary LPA production during fibrogenesis in a bleomycin mouse model. We found that bleomycin injury increases the bronchoalveolar lavage (BAL) fluid levels of ATX protein 17-fold. However, the LPA and LPC species that increase in BAL of bleomycin-injured mice were discordant, inconsistent with a substrate-product relationship between LPC and LPA in pulmonary fibrosis. LPA species with longer chain polyunsaturated acyl groups predominated in BAL fluid after bleomycin injury, with 22:5 and 22:6 species accounting for 55 and 16% of the total, whereas the predominant BAL LPC species contained shorter chain, saturated acyl groups, with 16:0 and 18:0 species accounting for 56 and 14% of the total. Further, administration of the potent ATX inhibitor PAT-048 to bleomycin-challenged mice markedly decreased ATX activity systemically and in the lung, without effect on pulmonary LPA or fibrosis. Therefore, alternative ATX-independent pathways are likely responsible for local generation of LPA in the injured lung. These pathways will require identification to therapeutically target LPA production in pulmonary fibrosis.-Black, K. E., Berdyshev, E., Bain, G., Castelino, F. V., Shea, B. S., Probst, C. K., Fontaine, B. A., Bronova, I., Goulet, L., Lagares, D., Ahluwalia, N., Knipe, R. S., Natarajan, V., Tager, A. M. Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis.

Clonal expansion of CD4(+) cytotoxic T lymphocytes in patients with IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4(+) T cells constitute the major inflammatory cell population in IgG4-RD lesions. OBJECTIVE: We used an unbiased approach to characterize CD4(+) T-cell subsets in patients with IgG4-RD based on their clonal expansion and ability to infiltrate affected tissue sites. METHODS: We used flow cytometry to identify CD4(+) effector/memory T cells in a cohort of 101 patients with IgG4-RD. These expanded cells were characterized by means of gene expression analysis and flow cytometry. Next-generation sequencing of the T-cell receptor ß chain gene was performed on CD4(+)SLAMF7(+) cytotoxic T lymphocytes (CTLs) and CD4(+)GATA3(+) TH2 cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined by using quantitative multicolor imaging. RESULTS: CD4(+) effector/memory T cells with a cytolytic phenotype were expanded in patients with IgG4-RD. Next-generation sequencing revealed prominent clonal expansions of these CD4(+) CTLs but not CD4(+)GATA3(+) memory TH2 cells in patients with IgG4-RD. The dominant T cells infiltrating a range of inflamed IgG4-RD tissue sites were clonally expanded CD4(+) CTLs that expressed SLAMF7, granzyme A, IL-1ß, and TGF-ß1. Clinical remission induced by rituximab-mediated B-cell depletion was associated with a reduction in numbers of disease-associated CD4(+) CTLs. CONCLUSIONS: IgG4-RD is prominently linked to clonally expanded IL-1ß- and TGF-ß1-secreting CD4(+) CTLs in both peripheral blood and inflammatory tissue lesions. These active, terminally differentiated, cytokine-secreting effector CD4(+) T cells are now linked to a human disease characterized by chronic inflammation and fibrosis.

Emerging cellular and molecular targets in fibrosis: implications for scleroderma pathogenesis and targeted therapy.

PURPOSE OF REVIEW: To summarize the recent advances in understanding the novel cytokine pathways, intracellular signaling molecules, cell-fate decisions, cellular aging and senescence, and the cross-talk of effector cells and the extracellular matrix (ECM) in the pathogenesis of systemic sclerosis (SSc) fibrosis. RECENT FINDINGS: Studies from the animal models and human beings implicate novel molecular pathways such as Wnts, the chemokines, chemokine (C-X-C motif) ligand 4 and chemokine (C-C motif) ligand 2, and the lipid mediators lysophosphatidic acid and sphingosine-1-phosphate in the pathogenesis of SSc. These signals, coupled with the mesenchymal cell-fate decisions, contribute to aberrant fibroblast activation and myofibroblast accumulation. The resulting deposition and remodeling of ECM alters the biomechanical environment, and leads to further cross-talk of mechanical signals with biochemical mediators such as focal adhesion kinase, integrin signaling, and Yes-associated protein-transcriptional coactivator with PDZ-binding motif signaling pathways. SUMMARY: Progress in understanding the cellular, molecular, and biomechanical regulators of fibrosis has led to the identification of novel targets for interrupting the fibrotic process in SSc. Efforts to antagonize cytokine pathways, affect mesenchymal cell fates, attenuate senescence, and clear activated myofibroblasts, along with modifying the ECM mechanical environment, may ultimately lead to effective therapies in SSc.

Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials.

RATIONALE: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. METHODS: The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). RESULTS: A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. CONCLUSION: Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

Pulmonary Hypertension: How to Best Treat the Different Scleroderma Phenotypes?

Pulmonary hypertension (PH) is a leading cause of morbidity and mortality in systemic sclerosis (SSc). PH is a heterogenous condition and several different forms of PH are associated with SSc, including pulmonary arterial hypertension (PAH) resulting from a pulmonary arterial vasculopathy, PH due to interstitial lung disease, PH due to left heart disease, and PH due to thromboembolic disease. Extensive research has led to an improved understanding of the mediators involved in the pathogenesis of SSc-PH. Initial combination therapy is the preferred treatment approach for SSc-PAH and requires coordinated care with a multidisciplinary team including rheumatology, pulmonology, and cardiology.

Clinically Recognized Depression and Mental Health Treatment in a Single Center Cohort of Patients with Systemic Sclerosis.

Introduction: In this study, we investigated the prevalence of depression, depression treatment, and symptom burden in patients with systemic sclerosis (SSc) and examined their associations with the center for epidemiologic studies depression scale revised (CESD-R) scores. Methods: The Prospective Registry in Scleroderma at Massachusetts General Hospital (PRISM) is a longitudinal registry of patients with SSc. Among participants with CESD-R score ≥ 16, indicating possible depression, a chart review was performed for mental health diagnoses and treatments. We examined the relation of demographic and clinical factors to the presence of mental health diagnoses or treatment using logistic regression. We evaluated the association of SSc symptoms and the COVID-19 pandemic with a CESD-R score using quantile regression. Results: Of 214 patients enrolled in PRISM, 129 participants (38% diffuse and 59% limited) completed at least one CESD-R questionnaire. In the first survey, 29% had possible depression (CESD - R ≥ 16) and 16% had probable depression (CESD - R ≥ 23). Of 20 participants with probable depression, 90% received treatment for a mood disorder. In a multivariable logistic regression model among participants with CESD - R ≥ 16, none of the evaluated variables (CESD-R score, age, gender, employment status, race, and ethnicity) was associated with mental health diagnosis or treatment. Higher baseline dyspnea index, modified Rodnan skin score, and the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal total score and subscores were associated with higher CESD-R score. Conclusion: In this single-center cross-sectional study, 16% of participants had significant depressive symptoms. Dyspnea, extent of skin involvement, and gastrointestinal symptoms were associated with depression symptoms.

Lipids and eicosanoids in fibrosis: emerging targets for therapy.

PURPOSE OF REVIEW: Lipid mediators including the lysophospholipids, sphingolipids and eicosanoids have long been implicated in inflammation, cancer and numerous other diseases. Over the last decade, new research suggests a role for these mediators in fibrosis. RECENT FINDINGS: Recent developments in the study of fibrotic mediators have centered on lysophospholipids and eicosanoids. New research is evaluating metabolic-profiling strategies to quantitatively measure lipid mediators in human plasma. Lysophosphatidic acid receptor antagonists are currently under development with early phase trials scheduled for idiopathic pulmonary fibrosis and scleroderma dermal fibrosis. Eicosanoids have long been implicated in maintaining tissue homeostasis, and the balance of profibrotic and antifibrotic effects has drawn attention in recent years. Targeting the prostanoids, specifically PGE2 and PGI2, as well as the leukotrienes is now being considered for antifibrotic therapies. SUMMARY: Lipid mediators have significant roles in many disease processes. Significant research now suggests a critical role for these mediators in the pathogenesis of fibrosis. Targeting these mediators is a promising area of drug discovery.

Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma.

OBJECTIVE: Scleroderma (systemic sclerosis [SSc]), is characterized by progressive multiorgan fibrosis. We recently implicated lysophosphatidic acid (LPA) in the pathogenesis of pulmonary fibrosis. The purpose of the present study was to investigate the roles of LPA and two of its receptors, LPA1 and LPA2, in dermal fibrosis in a mouse model of SSc. METHODS: Wild type (WT), and LPA1-knockout (KO) and LPA2-KO mice were injected subcutaneously with bleomycin or phosphate buffered saline (PBS) once daily for 28 days. Dermal thickness, collagen content, and numbers of cells positive for α-smooth muscle actin (α-SMA) or phospho-Smad2 were determined in bleomycin-injected and PBS-injected skin. In separate experiments, a novel selective LPA1 antagonist AM095 or vehicle alone was administered by oral gavage to C57BL/6 mice that were challenged with 28 daily injections of bleomycin or PBS. AM095 or vehicle treatments were initiated concurrently with, or 7 or 14 days after, the initiation of bleomycin and PBS injections and continued to the end of the experiments. Dermal thickness and collagen content were determined in injected skin. RESULTS: The LPA1 -KO mice were markedly resistant to bleomycin-induced increases in dermal thickness and collagen content, whereas the LPA2-KO mice were as susceptible as the WT mice. Bleomycin-induced increases in dermal α-SMA+ and phospho-Smad2+ cells were abrogated in LPA1-KO mice. Pharmacologic antagonism of LPA1 with AM095 significantly attenuated bleomycin-induced dermal fibrosis when administered according to either a preventive regimen or two therapeutic regimens. CONCLUSION: These results suggest that LPA/LPA1 pathway inhibition has the potential to be an effective new therapeutic strategy for SSc, and that LPA1 is an attractive pharmacologic target in dermal fibrosis.

Change in calcinosis over 1 year using the scleroderma clinical trials consortium radiologic scoring system for calcinosis of the hands in patients with systemic sclerosis.

INTRODUCTION: Calcinosis cutis is a debilitating complication of systemic sclerosis (SSc). We previously developed a radiographic scoring system to assess severity of calcinosis affecting the hands in patients with SSc. We sought to further validate our radiographic scoring system to assess for change over 1 year and to identify factors associated with improvement or progression. MATERIALS AND METHODS: Baseline and 1-year antero-posterior hand radiographs were obtained in 39 SSc patients with calcinosis prospectively enrolled at 6 centers within the US, Canada, Mexico and Australia. Two readers (one radiologist and one rheumatologist) scored all radiographs using the calcinosis scoring system and a 5-point Likert scale (1 = A lot better, 2 = A little better, 3=No change, 4 = A little worse, 5 = A lot worse) on follow-up. By maximizing the Kappa coefficient of agreement between grouped Likert scale (better/no change/worse) and the percentage of change of calcinosis in the radiographic scoring system, we defined progressive calcinosis as >25% increase in score from baseline at 1-year, stable calcinosis as change in score between -25% to 25%, and improvement of calcinosis as decrease in score by >25%. Nineteen SSc patients from an independent cohort were used for validation. RESULTS: Inter-rater reliability of the calcinosis scoring system was high with intra-class correlation coefficient of 0.93 (0.89-0.95). The median percentage of change from baseline to 1 year was 12.8% (range -89.3 to 290.2%). Sixteen patients (41%) experienced progression of calcinosis over 1 year; 18 (46%) remained stable; and 5 (13%) had improvement. Patients with progressive calcinosis had lower T-score on bone densitometry (-3.3 vs -1.7, p = 0.044) and higher prevalence of loss of digital pulp on physical exam (56% vs 22%, p = 0.027), with a trend towards lower baseline modified Rodnan skin score (mRSS) (3.8 vs. 5.9, p = 0.057), than patients who did not progress. Patients who experienced improvement in calcinosis had lower prevalence of digital pitting scars (20% vs 71%, p = 0.047) than patients whose calcinosis did not improve. In multivariable analysis, loss of digital pulp remained a predictor of calcinosis progression (OR 5.8, p = 0.023, CI 1.27 - 26.36). In the validation cohort, 2 (11%) patients improved, 10 (53%) remained stable, and 7 (37%) progressed. CONCLUSIONS: We confirmed the excellent inter-rater reliability of our radiographic calcinosis scoring system and demonstrated its usefulness to detect change over time. Approximately 40% of patients experienced progression of calcinosis over 1 year. Loss of digital pulp was predictive of progressive calcinosis providing further evidence that digital ischemia contributes to the progression of calcinosis.

The Association of Illness-related Uncertainty With Mental Health in Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: Patients with systemic autoimmune rheumatic diseases (SARDs) face illness-related uncertainty, but little is known about the psychological profiles and psychosocial and health needs associated with uncertainty among adults with SARDs. METHODS: Patients from the Massachusetts General Hospital with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), IgG4-related disease (IgG4-RD), and systemic sclerosis (SSc) completed the Mishel Uncertainty in Illness Scale, 8-item Patient Health Questionnaire depression scale, 7-item General Anxiety Disorder scale, Sickness Impact Profile, and a survey of psychosocial needs. The associations of uncertainty and self-reported needs with depression, anxiety, and sickness impact were assessed. RESULTS: One hundred thirty-two patients with AAV (n = 41, 31%), IgG4-RD (n = 61, 46%), or SSc (n = 30, 23%) participated. The mean age was 64 years, 52% were female, and 83% were White. Greater illness-related uncertainty was positively correlated with higher levels of depression (r = 0.43, P < 0.001), anxiety (r = 0.33, P < 0.001), and sickness impact (r = 0.28, P = 0.001). We observed variations in these measures across SARDs, such that uncertainty was more strongly associated with depression and sickness impact in AAV or SSc compared to IgG4-RD. The primary needs that patients endorsed were services for managing physical symptoms (53%), self-care (37%), and emotional concerns (24%), with greater needs strongly associated with greater illness-related uncertainty. CONCLUSION: Among patients with SARDs, illness-related uncertainty is correlated with levels of depression, anxiety, and sickness impact, as well as psychosocial needs. Findings also implicate the need for targeted interventions to address uncertainty and needs among subgroups of patients with different illness profiles.

Computed Tomography of the Chest to Screen for Interstitial Lung Disease in Patients With Systemic Sclerosis at Expert Scleroderma Centers in the United States.

OBJECTIVE: Although a high-resolution computed tomography (HRCT) scan of the chest is the gold standard test for the detection of interstitial lung disease (ILD), there is no consensus among rheumatologists regarding the use of HRCT to screen for ILD in their patients with systemic sclerosis (SSc). The aims of this study were to describe the HRCT ordering practices at SSc centers in the United States and to determine which patient characteristics are associated with HRCT performance. METHODS: We performed a prospective cohort study of patients with SSc enrolled in the US-based Collaborative National Quality and Efficacy Registry (CONQUER). We performed univariate logistic regression followed by multivariable logistic regression to determine which patient characteristics were associated with HRCT performance. RESULTS: Of the 356 patients with SSc enrolled in CONQUER, 286 (80.3%) underwent HRCT at some point during their disease course. On multivariable analyses, missing total lung capacity percent predicted (odds ratio [OR] 3.26, 95% confidence interval [CI]: 1.53-7.41, P = 0.007) was positively associated with ever having undergone HRCT, whereas a positive anti-centromere antibody (OR 0.27, 95% CI: 0.12-0.61, P = 0.008) and missing forced vital capacity percent predicted (OR 0.29, 95% CI: 0.10-0.80, P = 0.005) were negatively associated with ever having undergone HRCT. There was a trend toward a positive association between crackles on pulmonary exam and ever having undergone HRCT (OR 2.28, 95% CI: 0.97-6.05, P = 0.058), although this relationship did not reach statistical significance. CONCLUSION: The majority of patients with SSc enrolled in CONQUER underwent HRCT. A positive anti-centromere antibody was the key clinical variable inversely associated with performance of HRCT.

Baseline characteristics of systemic sclerosis patients with restrictive lung disease in a multi-center US-based longitudinal registry.

AIM: Interstitial lung disease (ILD) is the leading cause of disease-related death in systemic sclerosis (SSc). Here, we assess baseline characteristics of SSc subjects with and without restrictive lung disease (RLD) in a multi-center, US-based registry. METHODS: SSc patients within 5 years of disease onset were enrolled in the Collaborative National Quality and Efficacy Registry (CONQUER), a multi-center US-based registry of SSc study participants (age ≥ 18 years) enrolled at 13 expert centers. All subjects met 2013 American College of Rheumatology / European League Against Rheumatism criteria. Subjects with a pulmonary function test (PFT) at baseline before April 1, 2020 were included. High-resolution computed tomography scan of the chest was not available to characterize ILD for all subjects. RLD was defined as forced vital capacity (FVC) <80% or total lung capacity (TLC) <80% predicted. RESULTS: There were 160 (45%) SSc subjects characterized as having RLD. There was no significant difference in age, gender or disease duration. RLD subjects had a mean disease duration from date of first non-Raynaud's symptom of 2.6 years and a mean FVC% predicted of 67% at baseline. In multivariable analysis, non-White race, higher physician global health assessment and modified Medical Research Council (mMRC) dyspnea scores, were independently associated with RLD. In the subgroup of RLD subjects with ILD, ILD had a negative correlation with RNA polymerase III antibody. CONCLUSION: CONQUER is the largest, multi-center, prospective cohort of early SSc patients in the US. Non-White race was independently associated with RLD. In addition, 45% of CONQUER subjects already had RLD, highlighting the importance of screening for SSc-ILD at initial diagnosis.

E-Cigarette Use, Small Airway Fibrosis, and Constrictive Bronchiolitis.

BACKGROUND: Vaping, including the use of electronic cigarettes (e-cigarettes), has become increasingly prevalent, yet the associated long-term health risks are largely unknown. Given the prevalence of use, particularly among adolescents early in their lifespan, it is vital to understand the potential chronic pathologic sequelae of vaping. METHODS: We present the cases of four patients with chronic lung disease associated with e-cigarette use characterized by clinical evaluation, with pulmonary function tests (PFTs), chest high-resolution computed tomography (HRCT), endobronchial optical coherence tomography (EB-OCT) imaging, and histopathologic assessment. RESULTS: Each patient presented with shortness of breath and chest pain in association with a 3- to 8-year history of e-cigarette use, with mild progressive airway obstruction on PFTs and/or chest HRCT findings demonstrating evidence of air trapping and bronchial wall thickening. EB-OCT imaging performed in two patients showed small airway-centered fibrosis with bronchiolar narrowing and lumen irregularities. The predominant histopathologic feature on surgical lung biopsy was small airway-centered fibrosis, including constrictive bronchiolitis and MUC5AC overexpression in all patients. Patients who ceased vaping had a partial, but not complete, reversal of disease over 1 to 4 years. CONCLUSIONS: After thorough evaluation for other potential etiologies, vaping was considered to be the most likely common causal etiology for all patients due to the temporal association of symptomatic chronic lung disease with e-cigarette use and partial improvement in symptoms after e-cigarette cessation. In this series, we associate the histopathologic pattern of small airway-centered fibrosis, including constrictive bronchiolitis, with vaping, potentially defining a clinical and pathologic entity associated with e-cigarette use. (Funded in part by the National Institutes of Health.).

The impact of rheumatological evaluation in the management of patients with interstitial lung disease.

OBJECTIVE: We hypothesized that multi-disciplinary assessment of patients with interstitial lung disease (ILD) would lead to improved diagnosis and management. METHODS: Our multi-disciplinary ILD group evaluated 50 patients referred to our tertiary care practice over a 12-month period. Evaluation consisted of independent assessments by a pulmonologist and rheumatologist, including complete history and physical examination, review of laboratory data, as well as review of imaging and pathological specimens in conjunction with a radiologist and pathologist experienced in ILD. Therapy was initiated or changed in collaboration with the referring physicians. RESULTS: Mean age was 65 years for patients with rheumatic or CTD-related ILD (CTD-ILD) and 70 years for those with idiopathic pulmonary fibrosis (IPF). The final diagnosis after evaluation in the clinic was 25 patients with CTD-ILD, 15 patients with IPF and 10 patients with other forms of lung disease. Of the patients with a final diagnosis of CTD-ILD, 28% were referred with a diagnosis of IPF. Among those referred with CTD-ILD, 36% had their diagnosis changed to an alternate CTD-ILD. In total, the diagnosis was changed in 54% of patients who presented to the ILD clinic. Changes in therapy occurred in 80% of patients with CTD-ILD and in 27% of patients with IPF. CONCLUSION: A multi-disciplinary ILD clinic offers patients an innovative mode of health-care delivery that can enhance diagnosis, affect treatment regimens and improve quality of care. Rheumatologists play a significant role in the clinical care of these patients and should evaluate all patients with ILD.

Detection and Management of Interstitial Lung Diseases Associated With Connective Tissue Diseases.

Interstitial lung disease (ILD) is a common manifestation of connective tissue diseases (CTDs). A proportion of patients with CTD-ILDs develop progressive fibrosing ILD, which is characterized by worsening fibrotic abnormalities on high-resolution computed tomography scan, decline in lung function, worsening symptoms, and early mortality. Here, we review the impact of ILD in patients with CTDs, the importance of prompt diagnosis and close monitoring, and the evidence available to guide the management of CTD-ILDs. Management of patients with CTD-ILDs should be individualized and involve close collaboration between rheumatologists and pulmonologists. Immunosuppression is the mainstay of therapy for CTDs, but evidence for its effectiveness in slowing the progression of ILD is limited. Recently, nintedanib has been approved to slow decline in lung function in patients with systemic sclerosis-associated ILD and chronic fibrosing ILDs with a progressive phenotype. The results of ongoing clinical trials will help clinicians take a more evidence-based approach to the treatment of CTD-ILDs.