The Impact of Degenerative Connective Tissue Disorders on Outcomes Following Endovascular Aortic Intervention in the Global Registry for Endovascular Aortic Treatment.

OBJECTIVE: Endovascular therapy for the management of aortic pathology in patients with degenerative connective tissue disorder (DCTD) is controversial. Current guidelines are based on a paucity of literature and registry data are lacking. This study reports on medium term outcomes of patients with diagnosed DCTD compared to those without DCTD who were included in the W.L. Gore Global Registry for Endovascular Aortic Treatment (GREAT). METHODS: Patients included in the GREAT registry who underwent treatment for any thoracic or abdominal aortic pathology were included and grouped according to the presence or absence of a DCTD. Baseline demographic and procedural data were collected as well as data relating to key outcomes within 5 years follow-up, including all-cause mortality, aortic-related mortality, reinterventions and serious adverse events (SAE). Multivariable Cox proportional hazards models were built to determine if any association existed between the presence of DCTD and any key outcomes. RESULTS: The analysis included 92 (1.9%) with DCTD and 4741 (98.1%) without DCTD. Patients with DCTD were more likely to be female (34.8% vs. 18.5%, P < .0001) and younger (66.8 [15.1] vs. 71.7 [10.3] years, P = .013) than those without DCTD. They were also more likely to have had prior aortic intervention (22.8% vs. 13.9%, P = .015) and an associated branch vessel procedure with the index operation (30.3% vs. 18.6%, P = .005). The majority of reinterventions in both groups occurred within the first 2 years and multivariable models demonstrated that the presence of DCTD was not predictive of all-cause mortality, aortic-related mortality, reinterventions or SAE within 5 years. CONCLUSIONS: Within the limitations of registry data, this work demonstrates the medium term safety and durability of endovascular stent-grafts across a spectrum of aortic pathology in some patients with DCTD. More work is required to determine the applicability of these findings to specific sub-types of DCTD and aortic pathology.

Predictors for progressive fibrosis in patients with connective tissue disease associated interstitial lung diseases.

BACKGROUND: Connective tissue disease associated interstitial lung disease (CTD-ILD) is associated with decreased quality of life and high mortality risk. Outcome and treatment response is unpredictable. This study aimed to identify clinical predictors for CTD-ILD with poor outcome. METHODS: We performed a retrospective single centre cohort study in outpatients with CTD-ILD seen between 2004 and 2018. Clinical and biochemical data, pulmonary function tests (PFT) and high-resolution computed tomography (HRCT) results were analysed. Overall survival and progressive fibrosing ILD (PF-ILD, defined as a significant deterioration of PFT or HRCT) after two years of follow-up were assessed. RESULTS: In total, 150 patients with CTD-ILD were included. Thirty (20%) deaths occurred during a median follow-up of 40 months (IQR 27.3-60.8), which were attributed to pulmonary infection in six (4%), respiratory failure due to PF-ILD in ten (7%) and due to other causes in fourteen patients. PF-ILD occurred in 76 (50.7%) patients and was associated with poor overall survival (adjusted HR 5.73, 95%CI 1.17-28.11). Age, smoking, C-reactive protein, and steroid-use were independently associated with increased mortality risk as well. Furthermore, patients with diabetes mellitus (adjusted OR 4.52, 95%CI 1.10-18.51), steroid-use (adjusted OR 2.26, 95%CI 1.04-4.93), and a fibrotic HRCT pattern at baseline (adjusted OR 3.11, 95%CI 1.15-8.38) had a higher risk of PF-ILD. CONCLUSION: PF-ILD is associated with increased mortality in patients with CTD-ILD. Patients with a fibrotic HRCT pattern at baseline, diabetes mellitus and steroid-use have a higher risk of developing PF-ILD.

The role of interleukin-6 as a prognostic biomarker for predicting acute exacerbation in interstitial lung diseases.

BACKGROUND: Interstitial lung diseases (ILDs) are chronic, parenchymal lung diseases with a variable clinical course and a poor prognosis. Within various clinical courses, acute exacerbation (AE) is a devastating condition with significant morbidity and high mortality. The aim of this study was to investigate the role of interleukin-6 (IL-6) to predict AE and prognosis in patients with ILD. METHODS: Eighty-three patients who were diagnosed with ILD from 2016 to 2019 at the Haeundae Paik Hospital, Busan, South Korea, were included and their clinical data were retrospectively analyzed. RESULTS: The median follow-up period was 20 months. The mean age was 68.1 years and 65.1% of the patients were men with 60.2% of patients being ever-smokers. Among ILDs, idiopathic pulmonary fibrosis was the most common disease (68.7%), followed by connective tissue disease-associated ILD (14.5%), cryptogenic organizing pneumonia (9.6%), and nonspecific interstitial pneumonia (6.0%). The serum levels of IL-6 were measured at diagnosis with ILD and sequentially at follow-up visits. During the follow-ups, 15 (18.1%) patients experienced an acute exacerbation (AE) of ILD and among them, four (26.7%) patients died. In the multivariable analysis, high levels of IL-6 (OR 1.014, 95% CI: 1.001-1.027, p = 0.036) along with lower baseline saturations of peripheral oxygen (SpO2) were independent risk factors for AE. In the receiver operating characteristic curve analysis, the area under the curve was 0.815 (p < 0.001) and the optimal cut-off value of serum IL-6 to predict AE was 25.20 pg/mL with a sensitivity of 66.7% and specificity of 80.6%. In the multivariable Cox analysis, a high level of serum IL-6 (HR 1.007, 95% CI: 1.001-1.014, p = 0.018) was only an independent risk factor for mortality in ILD patients. CONCLUSIONS: In our study, a high level of serum IL-6 is a useful biomarker to predict AE and poor prognosis in patients with ILD.

Mortality and Cause of Death in Patients With Vertebral Fractures: A Longitudinal Follow-Up Study Using a National Sample Cohort.

STUDY DESIGN: A retrospective study using the Korean Health Insurance Review and Assessment Service-National Sample Cohort was performed. OBJECTIVE: To determine the rate and causes of mortality in vertebral fracture patients. SUMMARY OF BACKGROUND DATA: Vertebral fractures are associated with increased mortality in prior studies. METHODS: Of 1,125,691 patients, we collected data of 23,026 patients of all ages who experienced thoracic or lumber vertebral fractures between 2002 and 2013. The vertebral fracture participants were matched 1:4 with control participants, accounting for age, group, sex, income, and region of residence. Finally, 21,759 vertebral fracture participants and 87,036 control participants were analyzed. The index date was the date of diagnosis of vertebral fracture; participants from the control group were followed from the same index date as their matched counterparts. The follow-up duration was the index date to the death date or the last date of study (December 31, 2013). Patients were followed until death or censoring of the data. Death was ascertained in the same period, and causes of death were grouped into 12 classifications according to the Korean Standard Classification of Disease. A stratified Cox proportional hazards model was used. RESULTS: The adjusted hazard ratio (HR) for mortality of vertebral fracture was 1.28 (P < 0.001) with the higher adjusted HR in younger patients. Mortalities caused by neoplasms; neurologic, circulatory, respiratory, digestive, and muscular diseases; and trauma were higher in the vertebral fracture group (P < 0.05), with muscular disease showing the highest odds ratio for mortality. CONCLUSION: Vertebral fractures were associated with increased mortality in Korean. Disease in muscuoskeletal system and connective tissue that possibly be associated with the fractures was most responsible for elevated death rates following vertebral fracture. Our findings may help caregivers provide more effective care, ultimately decreasing the mortality rate of vertebral fracture patients. LEVEL OF EVIDENCE: 3.

Clinical features and outcome of acute exacerbation in connective tissue disease-associated interstitial lung disease: A single-center study from India.

BACKGROUND: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is associated with high mortality, but there is limited clinical data on AE of interstitial lung disease (ILD) in connective tissue disease-associated ILD (CTD ILD). The present study was conducted to provide prevalence and clinical features of AE, as well as various risk factors associated with mortality among AE CTD ILD patients. METHODS: Between May 2013 and April 2018, 15 patients who developed AE among 105 consecutive patients with CTD with chronic ILD were included. AE was defined using the criteria recently proposed by the IPF net, with slight modification for adaptation to CVD-IP6 (collagen vascular disease-associated interstitial pneumonia), and patients having CTD with AE met all the criteria. RESULTS: Fifteen patients with mean age of 45.8 ± 13.9 years developed AE; the most common subgroup (n = 5, 33%) was systemic sclerosis. The mean duration (months) between diagnosis of ILD and AE was 56.5 ± 38.0 with mean follow-up duration of 24 ± 18.1 months. The baseline arterial oxygen pressure (PaO2 ) was 81.7 ± 8.1 mm Hg and mean forced vital capacity (%) was 57.9 ± 8.9. Five patients requiring mechanical ventilation died. Patients with shorter duration (months) of disease between onset of ILD to AE had higher mortality, 40.4 ± 45.1 vs 64.6 ± 33.6. Those who had significantly lower baseline PaO2 (mean ± SD), 72.6 ± 3.4 vs 86.2 ± 5.3 mm Hg (P = .002) had higher mortality. CONCLUSIONS: In our study, the majority of patients with AE CTD ILD had systemic sclerosis. Patients with lower baseline PaO2 and those requiring mechanical ventilation had higher mortality.

Lung Cancer development and mortality in interstitial lung disease with and without connective tissue diseases: a five-year Nationwide population-based study.

BACKGROUND: Connective tissue disease associated with interstitial lung disease (CTD-ILD) and interstitial lung disease (ILD) alone have same pathological and imaging backgrounds. However, the differences between lung cancer development and the mortality risk between these two conditions are unclear. Incidence of primary lung cancer and all-cause mortality were studied between interstitial lung disease patients with and without connective tissue disease. METHODS: Data were extracted from the Korean National Health Insurance Research Database in 2009. A total of 12,787 cases of ILD without idiopathic pulmonary fibrosis and 2491 cases of CTD-ILD were diagnosed in 2009. The cohort was followed up until June 30, 2014. Incident lung cancers and all-cause mortality were ascertained. RESULTS: The overall incidence of lung cancer was 165.7 and 161.8 per 10,000 person-years in the CTD-ILD and ILD-only, respectively (rate ratio, 1.08; 95% confidence interval, 0.89-1.30). CTD-ILD patients in the 40-49 and 50-59 years old age groups had lung cancer incidence rates of 92.5 and 139.2, which were 2.0 and 1.7 times higher than those in the ILD-only, respectively. All-cause mortality was significantly higher in the CTD-ILD group compared to ILD-only group in patients aged 50-79 years. All-cause mortality of women in the 50-59, 60-69 and 70-79 age groups was 2.0, 1.8, and 1.4 times higher in the CTD-ILD group than in the ILD-only group, respectively. CONCLUSIONS: CTD-ILD patients aged < 60 years had a higher lung cancer incidence than ILD-only patients in the same age group. Furthermore, CTD-ILD patients aged 50-79 years had higher all-cause mortality than ILD-only patients in the same age group.

Mortality and causes of death across the systemic connective tissue diseases and the primary systemic vasculitides.

Objectives: Studies assessing relative mortality risks across the spectrum of systemic inflammatory rheumatic diseases are largely missing. In this study, we wanted to estimate standard mortality ratios (SMRs) and causes of death in an ethnically homogeneous cohort covering all major CTDs and primary systemic vasculitides (PSVs). Methods: We prospectively followed all incident CTD and PSV cases included in the Norwegian CTD and vasculitis registry (NOSVAR) between 1999 and 2015. Fifteen controls for each patient matched for sex and age were randomly drawn from the Norwegian National Population Registry. Causes of death were obtained from the National Cause of Death Register, death certificates and hospital charts. Results: The cohort included 2140 patients (1534 with CTD, 606 with PSV). During a mean follow-up time of 9 years, 279 of the patients (13%) died, compared with 2864 of 32 086 (9%) controls (P < 0.001). Ten years after diagnosis, the lowest survival was 60% in dcSSc, 73% in anti-synthetase syndrome (ASS) and 75% in lcSSc. In the CTD group, the highest SMRs were observed in dcSSc (SMR 5.8) and ASS (SMR 4.1). In the PSV group, Takayasu arteritis (SMR 2.5) and ANCA-associated vasculitis (SMR 1.5) had the highest SMRs. Major causes of death were cardiovascular disease (CTD 27%, PSV 28%), neoplasms (CTD 25%, PSV 27%), chronic respiratory disease (CTD 20%, PSV10%) and infections (CTD 9%, PSV 16%). Conclusion: We observed premature deaths across the spectrum of CTDs and PSVs, with highest SMRs in dcSSc and ASS. The overall mortality was highest in the CTD group.

Treatment of thoracoabdominal aortic disease in patients with connective tissue disorders.

OBJECTIVE: Aneurysmal degeneration of the entire aorta is common in patients with connective tissue disorders (CTDs). Potential treatment options of these aneurysms include open repair and endovascular repair. Our objective herein was to review available evidence for different approaches to treatment of thoracoabdominal aortic disease in patients with CTDs. METHODS: We performed a systematic literature review using PubMed and referenced manuscripts on open and endovascular treatment of thoracoabdominal aortic aneurysms and dissections in patients with CTDs. RESULTS: A total of 28 studies were identified for inclusion in this review, 8 reporting on outcomes after open thoracoabdominal aortic aneurysm repair in patients with CTD, 8 on open branched graft use, and 12 on endovascular aortic repair in this population of patients. Reported outcomes were characterized by low perioperative morbidity and mortality, good branch patency, and low rate of reintervention for open repair and significant rates of endograft-related complications and substantial need for secondary endovascular interventions and open conversions for endovascular repair. CONCLUSIONS: There is a lack of high-quality evidence to support any particular approach to aortic repair in patients with CTD and a dearth of comparative data between open repair and endovascular repair. There are distinct differences in the published lengths of follow-up between the two repair approaches as well as in the prevalence of their use in an acute vs elective setting. It is evident that endovascular interventions for aortic disease in patients with CTDs are associated with many device- and aorta-related complications both in the short term and in the long term. Despite the lack of level 1 evidence, open repair currently remains the standard approach to treatment of aortic disease due to CTDs. Open branched graft repair in particular is the preferred technique. Endovascular interventions may be cautiously used in patients with CTDs in selective circumstances.

Rising stars of DPLD survival: FVC and exercise desaturation (a single-center study)

Background/aim: Diffuse parenchymal lung diseases (DPLDs) comprise a broad, heterogeneous group of diseases with common functional characteristics and a common final pathway, usually leading to irreversible fibrosis. We investigated the effects of the physiological and functional parameters and of pulmonary hypertension (PH) on survival in DPLDs. Materials and methods: The study included 158 patients with DPLDs. Patient data were examined retrospectively, and survival status was obtained through phone calls. Results: Patients were divided into five groups according to their diagnosis: idiopathic pulmonary fibrosis (IPF), non-IPF idiopathic interstitial pneumonias, connective tissue diseases, sarcoidosis, and other DPLDs. Median survival was 42.9 months. The significant negative effects of older age, presence of delta saturation (DeltaSat; difference between oxygen saturation at rest and after the 6-min walking test), 6-min walking distance (<350 m), systolic pulmonary artery pressure (sPAP; ≥50 mmHg), and baseline percentage of diffusing capacity of the lungs for carbon monoxide (<80%) with percentage of forced vital capacity (FVC%; <80%) were detected on survival (P < 0.05). A one-unit decrease in FVC% was related to a 6% increase in mortality. Another unique finding indicated that higher DeltaSat (>10%) correlated strongly with sPAP (>50 mmHg) and thus with a worse survival rate. Conclusion: The current study determined that FVC% is important in the prediction of mortality. Moreover, it demonstrated a strong relationship between exercise desaturation and PH.

Unclassifiable-interstitial lung disease: Outcome prediction using CT and functional indices.

BACKGROUND: Unclassifiable-interstitial lung disease (uILD) represents a heterogeneous collection of pathologies encompassing those fibrosing lung diseases which do not fulfill current diagnostic criteria. We evaluated baseline and longitudinal functional and CT (visual and quantitative computer [CALIPER] analysis) variables to identify outcome predictors in uILD. METHODS: Consecutive patients with uILD on multidisciplinary review (n = 95) had baseline functional (FVC, DLco, CPI [composite physiologic index]) and CT features (visual evaluation: CT pattern, fibrosis extent, honeycombing presence, traction bronchiectasis severity, pulmonary artery (PA) diameter; CALIPER evaluation: fibrosis extent, pulmonary vessel volume (PVV)) examined in univariate and multivariate Cox regression models. Change in functional and CT variables were examined in a patient subset (n = 37), to identify indicators of outcome. RESULTS: On univariate analysis, CPI was the most powerful functional predictor of mortality (p < 0.0001). Visual traction bronchiectasis (p < 0.0001), PA diameter (p < 0.0001) and honeycombing presence (p = 0.0001) and CALIPER PVV (p = 0.0003) were the strongest CT outcome predictors. On multivariate analysis of baseline indices, traction bronchiectasis (p = 0.003), PA diameter (p = 0.003) and CPI (p = 0.0001) independently predicted mortality. Colinearity with functional indices precluded the evaluation of CALIPER PVV in multivariate models. On evaluation of longitudinal variables, increasing CALIPER fibrosis extent was the strongest outcome predictor, and remained so following adjustment for baseline disease severity, and when FVC declines were marginal. CONCLUSIONS: In uILD patients, CPI, traction bronchiectasis severity and PA diameter independently predicted outcome at baseline. Increasing fibrosis extent measured by CALIPER was the most powerful index of outcome regardless of baseline disease severity and strongly predicted outcome in patients with marginal FVC declines.

A 10-year institutional experience with open branched graft reconstruction of aortic aneurysms in connective tissue disorders versus degenerative disease.

OBJECTIVE: Aortic reconstruction for complex thoracoabdominal aortic aneurysms (TAAAs) can be challenging, especially in patients with connective tissue disorders (CTDs) in whom tissue fragility is a major concern. Branched graft reconstruction is a more complex operation compared with inclusion patch repair of the aorta but is frequently necessary in patients with CTDs or other pathologies because of anatomic reasons. We describe our institutional experience with open branched graft reconstruction of aortic aneurysms and compare outcomes for patients with CTDs vs degenerative pathologies. METHODS: We retrospectively analyzed all patients undergoing open aortic reconstruction using branched grafts at our institution between July 2006 and December 2015. Postoperative outcomes, including perioperative morbidity and mortality, midterm graft patency, and the development of new aneurysms, were compared for patients with CTD vs degenerative disease. RESULTS: During the 10-year study period, 137 patients (CTD, 29; degenerative, 108) underwent aortic repair with branched graft reconstruction. CTD patients were significantly younger (39 ± 1.9 vs 68 ± 1.0 years; P < .001) and had fewer comorbidities (hypertension, chronic obstructive pulmonary disease, coronary artery disease; P < .05) but a higher prevalence of aortic dissections (55% vs 16%; P < .001) and aneurysms involving the thoracic aorta (90% vs 60%; P = .003) than patients with degenerative disease. Perioperative mortality (CTD: 10% [n = 3] vs degenerative: 6% [n = 6]; P = .40) and any complication (62% vs 55%; P = .47) were similar between groups. At a median follow-up time of 14.5 months (interquartile range: 6.5, 43.9 months), CTD patients were more likely to develop both new aortic (21%) and nonaortic (14%) aneurysms compared with the degenerative group (7% and 4% for aortic and nonaortic aneurysms, respectively; P = .02). Loss of branch graft patency occurred in 0 of 99 grafts (0%) in CTD patients and in 13 of 167 grafts (7.8%) in degenerative disease patients (P = .005). Loss of branch graft patency occurred most commonly in left renal artery bypass grafts (77%) and was clinically asymptomatic (creatinine: 1.77 ± 0.13 mg/dL currently vs 1.41 ± 0.25 preoperatively; P = .22). CONCLUSIONS: CTD patients with aortic aneurysms who undergo open branched graft reconstruction have reasonable outcomes compared with patients with degenerative pathology, including better branched graft patency and a similar risk of perioperative mortality and complications. Open repair of aortic aneurysms with branched graft reconstruction can be performed safely in both populations with low perioperative mortality, but ongoing surveillance is critical for the detection of new aneurysms, especially among patients with CTD.

The long-term outcome of interstitial lung disease with anti-aminoacyl-tRNA synthetase antibodies.

RATIONALE: Anti-aminoacyl transfer RNA synthetase antibodies (anti-ARS) are a group of myositis-specific autoantibodies that are detected in the sera of patients with polymyositis and dermatomyositis (PM/DM) and also in those of patients with idiopathic interstitial pneumonias without any connective tissue disease (CTD), including PM/DM. Although we reported the clinical characteristics of interstitial lung disease with anti-ARS antibodies (ARS-ILD) with and without PM/DM, the long-term prognosis of ARS-ILD remains undetermined. As our previous studies revealed that ARS-ILD without PM/DM was similar to CTD-associated ILD, and that ARS-ILD with PM/DM was radiologically suggestive of a nonspecific interstitial pneumonia (NSIP) pathological pattern, we hypothesized that the prognosis of ARS-ILD might be distinct from that of idiopathic pulmonary fibrosis (IPF) without anti-ARS. OBJECTIVES: To elucidate the long-term outcome of ARS-ILD with and without PM/DM and compare it to that of IPF. METHODS: A two-center retrospective study was conducted. The study population comprised 36 patients with ARS-ILD (8 with PM, 12 with DM, and 16 without myositis throughout the course), 100 patients with IPF without anti-ARS, and 7 patients with NSIP without anti-ARS. The presence of anti-ARS was determined by RNA immunoprecipitation using the sera obtained at the time of diagnosis before specific treatment. MEASUREMENTS AND MAIN RESULTS: During the observational period (median 49 months; range, 1-114 months), 7 patients with ARS-ILD (19%; 3 with PM, 1 with DM, and 3 without PM/DM) and 51 patients with IPF (51%) died. Patients with ARS-ILD had better overall survival than those with IPF (log-rank test, P < 0.001) and similar survival compared to those with NSIP (log-rank test, P = 0.59). The prognosis for patients with ARS-ILD was similar between those with and without myositis (log-rank test, P = 0.91). At the median follow-up time of 76.5 months, 14 of the 36 patients with ARS-ILD had deteriorated. Both a decline in forced vital capacity or an initiation of long-term oxygen therapy during the course (odds ratio [OR], 5.34) and acute exacerbation (OR, 28.4) significantly increased the mortality risk. CONCLUSIONS: The long-term outcome of ARS-ILD was significantly better than that of IPF regardless of the presence or absence of myositis.

Survival and outcomes after lung transplantation for non-scleroderma connective tissue-related interstitial lung disease.

BACKGROUND: Patients with non-scleroderma connective tissue-related lung disease (NS-CTLD), including rheumatoid arthritis, idiopathic inflammatory myopathies, Sjögren syndrome, mixed connective tissue disease, and systemic lupus erythematosus, may be at risk for worse outcomes after lung transplantation because of immune dysregulation or extrapulmonary manifestations of their underlying disease. We compared survival, acute and chronic rejection, and extrapulmonary organ dysfunction after transplantation in patients with NS-CTLD and idiopathic pulmonary fibrosis (IPF). METHODS: This was a retrospective cohort study of patients with NS-CTLD and IPF who were listed in the Scientific Registry of Transplant Recipients and underwent lung transplantation from May 5, 2005, to March 1, 2016. RESULTS: Patients with NS-CTLD (n = 275) were younger, a higher percentage female and non-white than patients with IPF (n = 6,346). NS-CTLD patients did not have worse adjusted survival (hazard ratio, 1.14, 95% confidence interval [CI], 0.92-1.42; p = 0.24). They were not more likely to have an episode of acute cellular rejection (odds ratio, 0.96; 95% CI, 0.72-1.28; p = 0.77) or to develop bronchiolitis obliterans syndrome (odds ratio, 0.82; 95% CI, 0.60-1.12; p = 0.21). Patients with NS-CTLD were not more likely to require plasmapheresis or dialysis or to develop a lymphoproliferative malignancy or liver disease after transplantation. CONCLUSIONS: We found no significant differences in survival, acute or chronic rejection, or extrapulmonary organ dysfunction in patients who underwent lung transplantation for NS-CTLD compared with IPF. In appropriately selected candidates, NS-CTLD should not be considered a contraindication to lung transplantation.

Evaluation of computer-based computer tomography stratification against outcome models in connective tissue disease-related interstitial lung disease: a patient outcome study.

BACKGROUND: To evaluate computer-based computer tomography (CT) analysis (CALIPER) against visual CT scoring and pulmonary function tests (PFTs) when predicting mortality in patients with connective tissue disease-related interstitial lung disease (CTD-ILD). To identify outcome differences between distinct CTD-ILD groups derived following automated stratification of CALIPER variables. METHODS: A total of 203 consecutive patients with assorted CTD-ILDs had CT parenchymal patterns evaluated by CALIPER and visual CT scoring: honeycombing, reticular pattern, ground glass opacities, pulmonary vessel volume, emphysema, and traction bronchiectasis. CT scores were evaluated against pulmonary function tests: forced vital capacity, diffusing capacity for carbon monoxide, carbon monoxide transfer coefficient, and composite physiologic index for mortality analysis. Automated stratification of CALIPER-CT variables was evaluated in place of and alongside forced vital capacity and diffusing capacity for carbon monoxide in the ILD gender, age physiology (ILD-GAP) model using receiver operating characteristic curve analysis. RESULTS: Cox regression analyses identified four independent predictors of mortality: patient age (P < 0.0001), smoking history (P = 0.0003), carbon monoxide transfer coefficient (P = 0.003), and pulmonary vessel volume (P < 0.0001). Automated stratification of CALIPER variables identified three morphologically distinct groups which were stronger predictors of mortality than all CT and functional indices. The Stratified-CT model substituted automated stratified groups for functional indices in the ILD-GAP model and maintained model strength (area under curve (AUC) = 0.74, P < 0.0001), ILD-GAP (AUC = 0.72, P < 0.0001). Combining automated stratified groups with the ILD-GAP model (stratified CT-GAP model) strengthened predictions of 1- and 2-year mortality: ILD-GAP (AUC = 0.87 and 0.86, respectively); stratified CT-GAP (AUC = 0.89 and 0.88, respectively). CONCLUSIONS: CALIPER-derived pulmonary vessel volume is an independent predictor of mortality across all CTD-ILD patients. Furthermore, automated stratification of CALIPER CT variables represents a novel method of prognostication at least as robust as PFTs in CTD-ILD patients.

Technical aspects of branched graft aortic reconstruction in patients with connective tissue disorders.

Connective tissue disorders (CTDs) predispose patients to dilation of the entire aorta, resulting in the development of extensive aneurysms. Aortic reconstruction in CTD patients can be challenging and demands specific approaches to ensure initial success and lasting stability of aortic repair. Herein, we describe technical approaches to aortic reconstruction in patients with CTDs and briefly report our outcomes on the use of branched grafts for reconstruction in this unique population of patients. We conclude that aortic reconstruction in CTD patients with branched grafts can be performed safely, with a low morbidity and mortality and excellent branch patency. Branched surgical grafts should be used preferentially over the inclusion patch technique during open repair to minimize the late development of patch aneurysms.

Beyond the Aortic Root: Staged Open and Endovascular Repair of Arch and Descending Aorta in Patients With Connective Tissue Disorders.

BACKGROUND: Improvements in care have prolonged survival of patients with connective tissue disorders (CTDs), but their entire native aorta remains at risk. Little data are available to guide treatment. Objectives were to characterize patients, describe repair methods, and assess outcomes. METHODS: From 1996 to 2012, 527 patients with CTDs underwent cardiovascular operations. Beyond the root, arch and descending repair was performed in 121 patients (23%) for aneurysm (n = 17), acute complicated dissection (n= 5), or chronic dissection with aneurysmal degeneration (n = 99). CTD diagnoses included Marfan (n = 107), marfanoid (n = 7), Ehlers-Danlos (n = 4), and Loeys-Dietz (n = 3) syndromes. Eighty-seven (72%) had a previous ascending aorta repair, including 51 (57%) for type A dissection. Median interval to distal operation was 8.4 years. Index procedures for repair beyond the root were elephant trunk (ET) stage I (n = 63), open descending repair (n = 26), thoracoabdominal repair (n = 13), total arch replacement (n = 13), and stent-grafting (n = 6: frozen ET 3, thoracic endovascular aortic repair [TEVAR] 3). Median follow-up was 4.4 years. RESULTS: Operative mortality was 2.5% (3 of 121). No paralysis occurred, but 3 patients (2.5%) had nonpermanent stroke, 4 (3.3%) required dialysis, 12 (10%) required tracheostomy, and 13 (11%) underwent reoperation for bleeding. During follow-up, 67 patients underwent 85 additional distal aortic procedures (58 open, 27 endovascular, 49 of which were stage II ET). By 10 years, probability of at least 1 reintervention was 61%. At 1, 5, and 10 years, estimated survival was 91%, 79%, and 62%, and event-free survival was 52%, 35%, and 24%, respectively. CONCLUSIONS: Most patients with CTDs who require operations beyond the aortic root have aortic dissection and require multiple reinterventions. Staged repair strategies, including open repair in combination with TEVAR, are feasible, and benefits outweigh risks. These patients require lifelong imaging surveillance.

Assessment of risks of pulmonary infection during 12 months following immunosuppressive treatment for active connective tissue diseases: a large-scale prospective cohort study.

OBJECTIVE: Pulmonary infections (PI) are leading causes of death in patients with connective tissue diseases (CTD). The PREVENT study (Pulmonary infections in patients REceiving immunosuppressiVE treatmeNT for CTD) assessed risk of PI in patients with active CTD in the contemporary era of advanced immunosuppressive therapy. METHODS: In patients who started corticosteroids (n = 763), conventional immunosuppressants or biologics for active CTD were enrolled. Clinical and laboratory data, usage of drugs, and occurrence of PI were collected for 12 months. Baseline risk factors were investigated using Cox regression analysis. A nested case-control (NCC) study was performed with 1:2 matched case-control pairs to assess the risk for each drug category. RESULTS: During the observation period, 32 patients died (4.2%) and 66 patients were lost to followup (8.6%). Patients with PI (n = 61, 8%) had a significantly worse accumulated survival rate than patients without (p < 0.01). Cox hazard regression analysis using baseline data showed that these factors were significantly associated with PI: age ≥ 65 years (HR 3.87, 95% CI 2.22-6.74), ≥ 20 pack-years of smoking (2.63, 1.37-5.04), higher serum creatinine level (1.21, 1.05-1.41 per 1.0 mg/dl increase), and maximum prednisolone (PSL) dose during the first 2 weeks of treatment (2.81, 1.35-5.86 per 1.0 mg/kg/day increase). Logistic regression analysis by an NCC study revealed that maximum PSL dose within 14 days before PI (OR 4.82, 95% CI 1.36-17.01 per 1.0 mg/dl increase; 2.57, 1.28-5.16 if ≥ 0.5 mg/kg/day) was significantly associated with the events, while other immunosuppressants were not. CONCLUSION: Physicians should be aware of the higher risks for corticosteroids of PI than other immunosuppressants and assess these risk factors before immunosuppressive treatment, to prevent PI.

Pneumocystis jirovecii pneumonia in mycophenolate mofetil-treated patients with connective tissue disease: analysis of 17 cases.

The association of Pneumocystis jirovecii pneumonia (PJP) with connective tissue disease (CTD) and mycophenolate mofetil's (MMF) potent activity against PJP have been separately reported. Until now, there have been no papers describing the occurrence of PJP following MMF treatment in CTD patients. The objective of this study was to describe the clinical features, risk factors, outcomes of PJP in patients with CTD and investigates the effects of MMF on the occurrence of PJP in China. In this retrospective cohort study, we performed a chart review, analyzing clinical features, treatment, and outcomes of PJP in patients with CTD in a single hospital. A total of 17 cases met the inclusion criteria of having PJP and a CTD diagnosis: systemic lupus erythematosus; polymyositis; dermatomyositis; rheumatoid arthritis; Wegener's granulomatosis; and microscopic polyangiitis. Sixteen patients were treated with glucocorticoids (GCs) plus immunosuppressive drugs. Only one patient had GCs without immunosuppressive drugs. Ten subjects (62.5 %) received MMF (1-1.5 g/day), and all ten had lymphopenia. The mortality rates of MMF and non-MMF patients were 50 and 14 %, respectively. This study is the first report of PJP following MMF plus GC treatment in patients with CTD. CTD itself may be a risk factor for PJP. When CTD patients receiving MMF therapy have low lymphocyte counts and/or CD4 lymphocyte counts <250/µL, we should be care of occurrence of PJP.

Connective tissue disease related fibrotic lung disease: high resolution computed tomographic and pulmonary function indices as prognostic determinants.

PURPOSE: To determine high resolution computed tomography (HRCT) patterns and pulmonary function indices which are associated with increased mortality in patients with connective tissue disease related fibrotic lung disease (CTD-FLD). METHODS: HRCTs from 168 patients with CTD-FLD were scored by 2 observers for a variety of HRCT patterns and traction bronchiectasis. A radiological diagnosis of usual interstitial pneumonia (UIP), fibrotic non-specific interstitial pneumonia (NSIP) or indeterminate was also assigned. Using Cox regression analysis, associations with mortality were identified. Honeycombing and traction bronchiectasis scores were converted to binary absence/presence scores and also tested. A subgroup analysis of patients with biopsy material (n=51) was performed by classifying patients according to radiological and histopathological diagnoses, as concordant UIP, discordant UIP and fibrotic NSIP. The prognostic separation of this classification was also evaluated. RESULTS: Severity of traction bronchiectasis (HR 1.10, p=0.001, 95% CIs 1.04 to 1.17), increasing extent of honeycombing (HR 1.08, p=0.021, 95% CI 1.03 to 1.13) and reduction in DLco (HR 0.97, p=0.013, 95% CI 0.95 to 0.99) were independently associated with increased mortality. Interobserver agreement and prognostic strength were higher for binary traction bronchiectasis scores (weighted κ (κw)=0.69, HR 4.00, p=0.001, 95%CI 1.19 to 13.38), than binary honeycombing scores (κw=0.50, HR 2.87, p=0.022, 95% CI 1.53 to 5.43). The radiological-histopathological classification was strongly associated with increased mortality (HR 2.74, p<0.001, 95% CI 1.57 to 4.77) and patients with discordant UIP had a better prognosis than concordant UIP but worse prognosis than fibrotic NSIP. CONCLUSIONS: Severity of traction bronchiectasis, extent of honeycombing and DLco are strongly associated with mortality in CTD-FLD. Interobserver agreement for traction bronchiectasis is higher than for honeycombing. In CTD-FLD, radiological diagnosis has survival implications in biopsy proven UIP.

Survival and extrapulmonary course of connective tissue disease after lung transplantation.

BACKGROUND: Connective tissue disease (CTD)-related lung dysfunction is a common cause of morbidity and mortality; however, few lung transplantations (LTs) are performed in this population secondary to uncertainty regarding the posttransplant survival, outcome, and management. OBJECTIVES: The objectives were to evaluate the survival and the pulmonary and extrapulmonary courses of CTD after LT. METHODS: Survival outcomes of patients documented within the Organ Procurement and Transplantation Network who had undergone a LT for CTD were compared with those who underwent LT for chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In addition, the pulmonary and extrapulmonary courses of the CTD were evaluated after LT. RESULTS: From 1991 to 2009, there were 284 documented LT in patients with CTD. Post-LT cumulative survival of patients with CTD was less than that for COPD through 5 years, with a difference that peaked at 1 year (72.7% vs. 83.1%, P < 0.001). When patients with CTD were compared with those with IPF, a difference was only noted at 1 year (72.7% vs. 77.7%, P = 0.049). There were no documented post-LT pulmonary recurrences of the CTD, and extrapulmonary flares of the CTD were rare (1 possible flare per 20.3 patient-years and 1 probable flare per 81.0 patient-years). CONCLUSIONS: Cumulative survival of patients with CTD who underwent LT is similar to those with IPF and slightly less than those with COPD, with an increased risk of mortality that was most prominent at 6 months after transplant followed by subsequent narrowing of the survival differences over time. Lung transplantation may be a viable therapeutic option for patients with end-stage lung dysfunction resulting from a CTD.