A Post-Pandemic Enigma: The Cardiovascular Impact of Post-Acute Sequelae of SARS-CoV-2.

COVID-19 has become the first modern-day pandemic of historic proportion, affecting >600 million individuals worldwide and causing >6.5 million deaths. While acute infection has had devastating consequences, postacute sequelae of SARS-CoV-2 infection appears to be a pandemic of its own, impacting up to one-third of survivors and often causing symptoms suggestive of cardiovascular phenomena. This review will highlight the suspected pathophysiology of postacute sequelae of SARS-CoV-2, its influence on the cardiovascular system, and potential treatment strategies.

Treatment of Systemic Sclerosis-associated Interstitial Lung Disease: Evidence-based Recommendations. An Official American Thoracic Society Clinical Practice Guideline.

Background: Interstitial lung disease (ILD) is a significant cause of morbidity and mortality in patients with systemic sclerosis (SSc). To date, clinical practice guidelines regarding treatment for patients with SSc-ILD are primarily consensus based. Methods: An international expert guideline committee composed of 24 individuals with expertise in rheumatology, SSc, pulmonology, ILD, or methodology, and with personal experience with SSc-ILD, discussed systematic reviews of the published evidence assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Predetermined conflict-of-interest management strategies were applied, and recommendations were made for or against specific treatment interventions exclusively by the nonconflicted panelists. The confidence in effect estimates, importance of outcomes studied, balance of desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention, and implications for health equity were all considered in making the recommendations. This was in accordance with the American Thoracic Society guideline development process, which is in compliance with the Institute of Medicine standards for trustworthy guidelines. Results: For treatment of patients with SSc-ILD, the committee: 1) recommends the use of mycophenolate; 2) recommends further research into the safety and efficacy of (a) pirfenidone and (b) the combination of pirfenidone plus mycophenolate; and 3) suggests the use of (a) cyclophosphamide, (b) rituximab, (c) tocilizumab, (d) nintedanib, and (e) the combination of nintedanib plus mycophenolate. Conclusions: The recommendations herein provide an evidence-based clinical practice guideline for the treatment of patients with SSc-ILD and are intended to serve as the basis for informed and shared decision making by clinicians and patients.

Impact of lung function and baseline clinical characteristics on patient-reported outcome measures in systemic sclerosis-associated interstitial lung disease.

OBJECTIVE: The SENSCIS® trial demonstrated a significant reduction of lung function decline in patients with SSc-associated interstitial lung disease (SSc-ILD) treated with nintedanib, but no significant effect on health-related quality of life (HRQoL). To assess whether SSc/SSc-ILD severity and large changes in lung function correlate with HRQoL, a post-hoc analysis of SENSCIS®, aggregating treatment arms, was undertaken. METHODS: Patient-reported outcome (PRO) measures [St. George's Respiratory Questionnaire (SGRQ), Functional Assessment of Chronic Illness Therapy (FACIT)-Dyspnoea, and HAQ-Disability Index (HAQ-DI), incorporating the Scleroderma HAQ visual analogue scale (SHAQ VAS)] at baseline and week 52 were assessed for associations to SSc-ILD severity. RESULTS: At baseline and at week 52, forced vital capacity (FVC) <70% predicted was associated with worse PRO measure scores compared with FVC ≥70% predicted [week 52: SGRQ 45.1 vs 34.0 (P < 0.0001); FACIT-Dyspnoea 48.9 vs 44.5 (P < 0.0001); HAQ-DI 0.7 vs 0.6 (P < 0.0228); SHAQ VAS breathing problems 3.6 vs 2.6 (P < 0.0001)]. Patients with diffuse cutaneous SSc and other characteristics associated with SSc-ILD severity had worse PRO measure scores. Patients requiring oxygen or with >30% fibrosis on high-resolution computed tomography at baseline demonstrated worse PRO measure scores at week 52. After 1 year, patients with a major (>10%) improvement/worsening in FVC demonstrated corresponding improvement/worsening in SGRQ and other PRO measures, significant for the SGRQ symptom domain (P < 0.001). CONCLUSION: Severe SSc-ILD and major deteriorations in lung function have important impacts on HRQoL. Treatments that slow lung function decline and prevent severe SSc-ILD are important to preserve HRQoL. TRIAL REGISTRATION: clinicaltrials.gov, www.clinicaltrials.gov, NCT02597933.

Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease.

BACKGROUND: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. RESULTS: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was -52.4 ml per year in the nintedanib group and -93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of -0.21 (95% CI, -0.94 to 0.53; P = 0.58) and 1.69 (95% CI, -0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. CONCLUSIONS: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.).

Continued treatment with nintedanib in patients with systemic sclerosis-associated interstitial lung disease: data from SENSCIS-ON.

OBJECTIVES: In the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) versus placebo, with adverse events that were manageable for most patients. An open-label extension trial, SENSCIS-ON, is assessing safety and FVC decline during longer term nintedanib treatment. METHODS: Patients who completed the SENSCIS trial or a drug-drug interaction (DDI) study of nintedanib and oral contraceptive on treatment were eligible to enter SENSCIS-ON. Adverse events and changes in FVC over 52 weeks of SENSCIS-ON were assessed in patients who received nintedanib in SENSCIS and continued nintedanib in SENSCIS-ON ('continued nintedanib' group) and in patients who received placebo in SENSCIS and initiated nintedanib in SENSCIS-ON or who received nintedanib for ≤28 days in the DDI study ('initiated nintedanib' group). RESULTS: There were 197 patients in the continued nintedanib group and 247 in the initiated nintedanib group. Diarrhoea was reported in 68.0% and 68.8% of patients in these groups, respectively. Adverse events led to discontinuation of nintedanib in 4.6% and 21.5% of the continued nintedanib and initiated nintedanib groups, respectively. Mean (SE) changes in FVC from baseline to week 52 of SENSCIS-ON were -58.3 (15.5) mL in the continued nintedanib group and -44.0 (16.2) mL in the initiated nintedanib group. CONCLUSIONS: The safety profile of nintedanib over 52 weeks of SENSCIS-ON was consistent with that reported in SENSCIS. The change in FVC over 52 weeks of SENSCIS-ON was similar to that observed in the nintedanib group of SENSCIS.

Cutaneous iontophoresis of vasoactive medications in patients with scleroderma-associated pulmonary arterial hypertension.

BACKGROUND: It remains unknown whether the cutaneous microvascular responses are different between patients with scleroderma-associated pulmonary arterial hypertension (SSc-PAH) and SSc without pulmonary hypertension (PH). METHODS: We included 59 patients with SSc between March 2013 and September 2019. We divided patients into 4 groups: (a) no PH by right heart catheterization (RHC) (n = 8), (b) no PH by noninvasive screening tests (n = 16), (c) treatment naïve PAH (n = 16), and (d) PAH under treatment (n = 19). Microvascular studies using laser Doppler flowmetry (LDF) were done immediately after RHC or at the time of an outpatient clinic visit (group b). RESULTS: The median (IQR) age was 59 (54-68) years, and 90% were females. The responses to local thermal stimulation and postocclusive reactive hyperemia, acetylcholine, and sodium nitroprusside iontophoresis were similar among groups. The microvascular response to treprostinil was more pronounced in SSc patients without PH by screening tests (% change: 340 (214-781)) compared with SSc-PAH (naïve + treatment) (Perfusion Units (PU) % change: 153 (94-255) % [p = .01]). The response to A-350619 (a soluble guanylate cyclase (sGC) activator) was significantly higher in patients with SSc without PH by screening tests (PU % change: 168 (46-1,296)) than those with SSc-PAH (PU % change: 22 (15-57) % [p = .006]). The % change in PU with A350619 was directly associated with cardiac index and stroke volume index (R: 0.36, p = .03 and 0.39, p = .02, respectively). CONCLUSIONS: Patients with SSc-PAH have a lower cutaneous microvascular response to a prostacyclin analog treprostinil and the sGC activator A-350619 when compared with patients with SSc and no evidence of PH on screening tests, presumably due to a peripheral reduction in prostacyclin receptor expression and nitric oxide bioavailability.

Development of the Pulmonary Hypertension Functional Classification Self-Report: a patient version adapted from the World Health Organization Functional Classification measure.

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by progressive limitations on physical activity, right heart failure, and premature death. The World Health Organization functional classification (WHO-FC) is a clinician-rated assessment used widely to assess PAH severity and functioning, but no equivalent patient-reported version of PAH symptoms and activity limitations exists. We developed a version of the WHO-FC for self-completion by patients: the Pulmonary Hypertension Functional Classification Self-Report (PH-FC-SR). METHODS: Semistructured interviews were conducted with three health care providers (HCPs) via telephone to inform development of the draft PH-FC-SR. Two rounds of semi-structured interviews were conducted with 14 US patients with a self-reported PAH diagnosis via telephone/online to elicit concepts and iteratively refine the PH-FC-SR. RESULTS: HCPs reported that the WHO-FC was a useful tool for evaluating patients' PAH severity over time and for making treatment decisions but acknowledged that use of the measure is subjective. Patients in round 1 interviews (n = 6) reported PAH symptoms, including shortness of breath (n = 6), fatigue (n = 5), syncope (n = 5), chest pains (n = 3), and dizziness (n = 3). Round 1 patients identified challenges with the original WHO-FC, including comprehensibility of clinical terms and overlapping descriptions of class II and III, and preferred the Draft 1 PH-FC-SR over the original WHO-FC. After minor changes were made to Draft 2, round 2 interviews (n = 8) confirmed patients understood the PH-FC-SR class descriptions, interpreting them consistently. CONCLUSIONS: The HCP and patient interviews identified and confirmed certain limitations inherent within the clinician-rated WHO-FC, including subjective assessment and overlapping definitions for class II and III. The PH-FC-SR includes patient-appropriate language, symptoms, and physical activity impacts relevant to patients with PAH. Future research is recommended to validate the PH-FC-SR and explore its correlation with the physician-assessed WHO-FC and other outcomes.

Performance of diagnostic criteria in patients clinically judged to have cardiac sarcoidosis: Is it time to regroup?

BACKGROUND: The diagnosis of cardiac sarcoidosis (CS) is challenging. Because of the current limitations of endomyocardial biopsy as a reference standard, physicians rely on advanced cardiac imaging, multidisciplinary evaluation, and diagnostic criteria to diagnose CS. AIMS: To compare the 3 main available diagnostic criteria in patients clinically judged to have CS. METHODS: We prospectively included patients clinically judged to have CS by a multidisciplinary sarcoidosis team from November 2016 to October 2017. We included only incident cases (diagnosis of CS within 1 year of inclusion). We applied retrospectively the following diagnostic criteria: the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG), the Heart Rhythm Society (HRS), and the Japanese Circulation Society (JCS) 2016 criteria. RESULTS: We identified 69 patients. Diagnostic criteria classified patients as follows: WASOG as highly probable (1.4%), probable (52.2%), possible (0%), some criteria (40.6%), and no criteria (5.8%); HRS as histological diagnosis (1.4%), probable (52.2%), some criteria (40.6%), and no criteria (5.8%); JCS as histological diagnosis (1.4%), clinical diagnosis (58%), some criteria (39.1%), and no criteria (1.4%). Concordance was high between WASOG and HRS (κ = 1) but low between JCS and the others (κ = 0.326). CONCLUSIONS: A high proportion of patients clinically judged to have CS are unable to be classified according to the 3 main diagnostic criteria. There is low concordance between JCS criteria and the other 2 criteria (WASOG and HRS).

Safety and tolerability of nintedanib in patients with systemic sclerosis-associated interstitial lung disease: data from the SENSCIS trial.

OBJECTIVES: To characterise the safety and tolerability of nintedanib and the dose adjustments used to manage adverse events in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: In the SENSCIS trial, patients with SSc-ILD were randomised to receive nintedanib 150 mg two times per day or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg two times per day. We assessed adverse events and dose adjustments over 52 weeks. RESULTS: A total of 576 patients received nintedanib (n=288) or placebo (n=288). The most common adverse event was diarrhoea, reported in 75.7% of patients in the nintedanib group and 31.6% in the placebo group; diarrhoea led to permanent treatment discontinuation in 6.9% and 0.3% of patients in the nintedanib and placebo groups, respectively. In the nintedanib and placebo groups, respectively, 48.3% and 12.2% of patients had ≥1 dose reduction and/or treatment interruption, and adverse events led to permanent discontinuation of the trial drug in 16.0% and 8.7% of patients. The adverse events associated with nintedanib were similar across subgroups defined by age, sex, race and weight. The rate of decline in forced vital capacity in patients treated with nintedanib was similar irrespective of dose adjustments. CONCLUSIONS: The adverse event profile of nintedanib in patients with SSc-ILD is consistent with its established safety and tolerability profile in patients with idiopathic pulmonary fibrosis. Dose adjustment is important to minimise the impact of adverse events and help patients remain on therapy.

Interdependence of hypoxia and ß-adrenergic receptor signaling in pulmonary arterial hypertension.

The ß-adrenergic receptor (ßAR) exists in an equilibrium of inactive and active conformational states, which shifts in response to different ligands and results in downstream signaling. In addition to cAMP, ßAR signals to hypoxia-inducible factor 1 (HIF-1). We hypothesized that a ßAR-active conformation (R**) that leads to HIF-1 is separable from the cAMP-activating conformation (R*) and that pulmonary arterial hypertension (PAH) patients with HIF-biased conformations would not respond to a cAMP agonist. We compared two cAMP agonists, isoproterenol and salbutamol, in vitro. Isoproterenol increased cAMP and HIF-1 activity, while salbutamol increased cAMP and reduced HIF-1. Hypoxia blunted agonist-stimulated cAMP, consistent with receptor equilibrium shifting toward HIF-activating conformations. Similarly, isoproterenol increased HIF-1 and erythropoiesis in mice, while salbutamol decreased erythropoiesis. ßAR overexpression in cells increased glycolysis, which was blunted by HIF-1 inhibitors, suggesting increased ßAR leads to increased hypoxia-metabolic effects. Because PAH is also characterized by HIF-related glycolytic shift, we dichotomized PAH patients in the Pulmonary Arterial Hypertension Treatment with Carvedilol for Heart Failure trial (NCT01586156) based on right ventricular (RV) glucose uptake to evaluate ßAR ligands. Patients with high glucose uptake had more severe disease than those with low uptake. cAMP increased in response to isoproterenol in mononuclear cells from low-uptake patients but not in high-uptake patients' cells. When patients were treated with carvedilol for 1 wk, the low-uptake group decreased RV systolic pressures and pulmonary vascular resistance, but high-uptake patients had no physiologic responses. The findings expand the paradigm of ßAR activation and uncover a novel PAH subtype that might benefit from ß-blockers.

Microvascular involvement in systemic sclerosis and systemic lupus erythematosus.

Microvascular changes play central roles in the pathophysiology of SSc and SLE, and represent major causes of morbidity and mortality in these patients. Therefore, clinical tools that can assess the microvasculature are of great importance both at the time of diagnosis and follow-up of these cases. These tools include capillaroscopy, laser imaging techniques, infrared thermography, and iontophoresis. In this review, we examined the clinical manifestations and pathobiology of microvascular involvement in SSc and SLE as well as the methodologies used to evaluate the microvasculature.

Counting Steps: A New Way to Monitor Patients with Pulmonary Arterial Hypertension.

RATIONALE: Activity levels in patients with pulmonary arterial hypertension (PAH) have correlated with surrogate markers of disease severity. It is not known whether physical activity measures are useful in monitoring patients with PAH. OBJECTIVES: This pilot study aimed to evaluate whether change in physical activity measured by an accelerometer correlates with changes in six-minute walk distance (6MWD), echocardiographic parameters, NT-proBNP, or health-related quality-of-life measures (HRQOL). METHODS: The study design was a prospective, observational study in subjects with prevalent PAH. Subjects wore a wrist-worn accelerometer (Fitbit Charge HR®) between two outpatient visits. Daily step count and activity levels were recorded, and the change over time was correlated with changes in 6MWD, echocardiographic parameters, HRQOL, and NT-proBNP. MEASUREMENTS AND MAIN RESULTS: 30 subjects were enrolled, of which 20 patients had adequate accelerometer data to be analyzed over the study duration. The mean duration of follow-up was 136.4 ( ± 47.3) days. The change in daily step count correlated with a change in 6MWD (r 0.43, p 0.05). Changes in duration spent in moderately active (r 0.52, p 0.02), lightly active (r 0.48, p 0.05), and sedentary activity levels (r - 0.54, p 0.02) correlated with a change in HRQOL. Changes in activity levels did not correlate with echocardiographic measures or NT-pro BNP. CONCLUSIONS: Changes in daily step count and time spent at fairly active, lightly active, and sedentary activity levels correlate with changes in 6MWD, and HRQOL in subjects with PAH suggesting that accelerometry may be a useful monitoring tool.

A single-institution study of concordance of pathological diagnoses for interstitial lung diseases between pre-transplantation surgical lung biopsies and lung explants.

BACKGROUND: By comparing diagnoses made by pre-transplant surgical lung biopsy (SLB) and the final pathologic diagnosis of the explanted pathology (EP), we aimed to study the factors that could impact pathologic diagnoses in patients with interstitial lung disease (ILD). METHODS: We retrospectively reviewed the lung transplant database at Cleveland Clinic [01/01/2006-12/31/2013] to include all lung transplant recipients with a prior diagnosis of ILD. Two pulmonary pathologists independently reviewed each SLB and lung explant. The diagnoses were labeled as concordant (same diagnosis on SLB and explant) or discordant (diagnosis on SLB and explant were different) by consensus. RESULTS: Of 389 patients transplanted for ILD, 217 had an SLB before transplant. Pathological diagnoses were concordant in 190 patients (87.6%) [165 UIP (86.8%), 13 NSIP (6.8%), 8 CHP (4.2%) and 4 other diagnoses (2.1%). In 27 cases (12.4%), the diagnosis on SLB differed from EP. 8/27 were diagnosed with UIP on SLB and of these, 5 were re-classified as NSIP. 14/19 (73.7%) patients with a SLB diagnosis "other than UIP" were re-categorized as UIP based on explant. Discordant cases had a greater time between SLB and EP than concordant cases (1553 days vs 1248 days). CONCLUSIONS: The pathologic diagnosis of ILD by SLB prior to lung transplant is accurate in most patients, but may be misleading in a small subset of patients. The majority of discordant cases that were reclassified as UIP could be due to a sampling error, or perhaps, an increased time from the date of the SLB to transplant. Future studies examining how multidisciplinary consensus diagnosis affects this discordance are necessary.

Pulmonary manifestations of systemic lupus erythematosus and Sjögren's syndrome.

PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) and Sjögren syndrome are chronic autoimmune inflammatory disorders that can present with multiorgan involvement including the lungs. This review will focus on recent literature pertaining to the epidemiology, pathogenesis, clinical presentation and diagnosis and management of SLE and Sjögren syndrome-associated pulmonary conditions. RECENT FINDINGS: Pulmonary manifestations of both disease entities have been well characterized and lung involvement can be observed during the course of the disease in most cases. Pulmonary manifestations of SLE and Sjögren syndrome can be classified based on anatomical site of involvement; and the large and small airways, lung parenchyma, lung vasculature, pleura and respiratory muscles can be involved. The pleura is most commonly involved in SLE, whereas the airways are most commonly involved in primary Sjögren's syndrome (pSS). Sleep disturbances have also been described in both entities. SUMMARY: Although further research into treatment strategies for the pulmonary complications seen in SLE and pSS is needed, the clinician should be aware of the risk factors and clinical presentation of the various pulmonary complications in SLE and pSS in order to identify patients who should be screened and/or have modifications in treatment strategies to mitigate the morbidity and mortality associated with these complications.

Bacterial meningitis as a cause of death in lung transplant donors: Early outcomes in recipients.

BACKGROUND: Lung transplant remains an established treatment for end-stage lung disease, but limited organ availability remains a major barrier and contributor to waitlist mortality.1 Only 20% of available organs are considered suitable for lung transplantation (Am J Transplant, 16, 2016 and 141; Thorac Surg Clin, 25, 2015 and 35). Successful lung transplantation has been reported from donors infected with bacterial or fungal organisms, but there is a paucity of evidence regarding the use of donors with bacterial meningitis (Transplant Proc, 32, 2000 and 75; Transplantation, 64, 1997 and 365; Ann Thorac Surg, 86, 2008 and 1554). METHOD: The Cleveland Clinic lung transplant database was retrospectively reviewed for patients between January 1998 and December 2014. Post-transplantation outcomes collected included graft dysfunction, infectious complications, and survival. RESULTS: The recipients were identified as having lungs from donors with bacterial meningitis. All recipients remained free of infectious organisms responsible for bacterial meningitis related in the donor. Severe primary graft dysfunction (PGD) was not seen in these recipients. CONCLUSION: In our study, lung transplantation from increased risk donors with bacterial meningitis was not associated with an increased risk of early infectious complications in recipients. Donors with bacterial meningitis should be considered for lung donation and may expand the donor pool safely.

Design of a randomised, placebo-controlled clinical trial of nintedanib in patients with systemic sclerosis-associated interstitial lung disease (SENSCIS™).

OBJECTIVES: Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF). The pathological pathways involved in fibrogenesis in IPF and interstitial lung disease associated with systemic sclerosis (SSc-ILD) show commonalities; both involve fibroblast activation, myofibroblast accumulation and deposition of extracellular matrix. The SENSCIS™ trial is a randomised, placebo-controlled Phase III trial that will evaluate the efficacy and safety of nintedanib in patients with SSc-ILD (NCT02597933). METHODS: Approximately 520 patients with SSc (based on 2013 American College of Rheumatology/European League Against Rheumatism criteria) and ILD (≥10% fibrosis of the lungs, confirmed by central assessment of chest high resolution computed tomography), forced vital capacity (FVC) ≥40% predicted and diffusing capacity for carbon monoxide of 30-89% predicted will be enrolled. Patients will be randomised (1:1) to nintedanib 150 mg twice daily or placebo, stratified by the presence of anti-topoisomerase I antibody. To reflect real-world management, patients receiving prednisone (≤10 mg/day) and/or a stable dose of mycophenolate or methotrexate, will be eligible. The primary endpoint is the annual rate of decline in FVC (mL/ year) assessed over 52 weeks. Patients will remain on blinded study treatment until the last patient completes 52 weeks of treatment or for a maximum of 100 weeks of treatment. Key secondary endpoints are absolute changes from baseline in modified Rodnan skin score and St George's Respiratory Questionnaire at week 52. RESULTS: Recruitment for the trial began in November 2015. CONCLUSIONS: This trial will assess the efficacy and safety of nintedanib in patients with SSc-ILD.

Six-Minute Walk Test as a Predictor of Diagnosis, Disease Severity, and Clinical Outcomes in Scleroderma-Associated Pulmonary Hypertension: The DIBOSA Study.

BACKGROUND: Pulmonary hypertension (PH) is a common complication of scleroderma (SSc) and is a leading cause of morbidity and mortality. OBJECTIVES: To explore the utility of the 6MWT in the prediction of SSc-PH and to assess its prognostic implications. METHODS: A retrospective review of SSc patients from 2003 to 2013, with 6MWT and echocardiogram (n = 286), was conducted. Presence of PH was defined by right heart catheterization. Patients were randomized into development and validation cohorts. Using regression techniques, we developed a scoring system to predict the presence of SSc-PH and tested it in our validation cohort. Trends of mortality and disease severity were studied for incremental scores. RESULTS: The DIBOSA scoring system includes DIstance walked in 6 min, BOrg dyspnea index, and SAturation of oxygen at 6 min. The DIBOSA score in the development cohort ranged from 0 to 3, resulting in an area of 0.858 (P < 0.0001) under the ROC curve. A score of 0 had a NPV of 100% and a score of 3 had a PPV of 86.58%. The validation cohort had an area under the ROC curve of 0.842. The DIBOSA score correlated with both pulmonary artery pressures and mortality. The 3-year survival rates for DIBOSA scores of 0, 1, 2, and 3 were 100, 100, 87.67, and 66.67%, respectively (HR = 3.92, P < 0.0001). CONCLUSIONS: DIBOSA score is a sensitive tool for the prediction of SSc-PH. The DIBOSA score is a direct predictor of mortality in SSc-PH and strongly correlates with pulmonary pressures. 6MWT can be used to predict clinical outcomes in SSc-PH.

Pulmonary Artery Dimensions as a Prognosticator of Transplant-Free Survival in Scleroderma Interstitial Lung Disease.

BACKGROUND: Systemic sclerosis is a chronic debilitating autoimmune disease characterized by endothelial dysfunction and multi-organ fibrosis. Interstitial lung disease, a common manifestation of SSc, is termed scleroderma-related interstitial lung disease (SSc-ILD) and along with pulmonary hypertension contributes to a majority of deaths in SSc. SSc-ILD patients frequently develop pulmonary hypertension, which prognosticates a poorer outcome. We investigated pulmonary artery dimensions as an outcome predictor in patients with SSc-ILD. METHODS: A retrospective chart review abstracting data from SSc-ILD patients evaluated at a large tertiary care center was performed. HRCT imaging was reviewed and pulmonary artery (PA) and ascending aorta (Ao) diameters were measured for calculation of the PA:Ao ratio. Additionally, demographics, vital signs, spirometric parameters, comorbidities, and mean pulmonary artery pressures were collected when available. Outcome analysis with lung transplant or death events within 4 years based on pulmonary artery size as well as PA:Ao ratio was performed. RESULTS: 70 SSc-ILD patients were identified. Mean pulmonary artery diameter and PA:Ao ratio was 31.17 and 1.07 mm, respectively. Patients with a pulmonary artery diameter ≥32 mm had higher risk of lung transplantation or death (p < 0.001) within 4 years. Patients with a PA:Ao ratio ≥1.1 also had higher risk of lung transplantation or death (p < 0.001) within 4 years. Unadjusted outcomes analyses also identified PA:Ao ratio ≥1.1 as an independent outcome predictor (hazard ratio 3.30, p < 0.001). CONCLUSIONS/CLINICAL IMPLICATIONS: In SSc-ILD patients, a PA:Ao ratio ≥1.1 is associated with higher risk of lung transplant or death. These data suggest that PA:Ao dimension may be used for prognostication in SSc-ILD.

Recent advances in scleroderma-associated pulmonary hypertension.

PURPOSE OF REVIEW: This review summarizes recent advances in pulmonary hypertension, a leading cause of morbidity and mortality in scleroderma (SSc). RECENT FINDINGS: Although WHO Group I pulmonary arterial hypertension (PAH) is the most common cause of pulmonary hypertension, all WHO Groups can occur. PAH is now a criterion for the diagnosis of SSc. Results of recent research have resulted in greater insight into the epidemiology of SSc-pulmonary hypertension with regard to prevalence, incidence and clinical risk factors. There is also greater understanding of the role of inflammation in the pathogenesis of SSc-PAH. Advances have also been made in the evaluation and screening of patients with SSc-PAH, and early detection has been shown to improve survival in a disease that typically has worse outcomes than other forms of PAH. Finally, recommendations have been made with regard to goal-directed therapy. SUMMARY: Although there have been many recent advances in SSc-pulmonary hypertension, further research is needed in order to prevent/cure this deadly complication.

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.