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Hakyoung Kim,1,* Hongseok Yoo,2,* Hongryull Pyo,3 Yong Chan Ahn,3 Jae Myoung Noh,3 Sang Gyu Ju,4 Woojin Lee,4 Byoungsuk Park,4 Jin Man Kim,4 Noeul Kang,2 Sun Hye Shin,2 Man Pyo Chung,2 Sumin Shin,5 Hye Seung Kim,6 Minsu Park,6 Hye Yun Park2 1Department of Radiation Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, South Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 3Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 4Department of Radiation Oncology, Samsung Medical Center, Seoul, South Korea; 5Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 6Statistics and Data Center, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea*These authors contributed equally to this workCorrespondence: Hye Yun ParkDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of KoreaTel +82-2-3410-3429Fax +82-2-3410-3849Email hyeyunpark@skku.eduHongryull PyoDepartment of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of KoreaTel +82-2-3410-2438Fax +82-2-3410-2619Email hr.pyo@samsung.comPurpose: Current guidelines recommend definitive radiotherapy for patients with medically inoperable early-stage non-small cell lung cancer (NSCLC). However, the impact of underlying pulmonary diseases on survival in those patients remains unclear.Methods: We retrospectively reviewed the medical records of 234 patients with stage I-II NSCLC treated with definitive radiotherapy alone at Samsung Medical Center between January 2010 and October 2017. We compared survival outcomes according to the presence of underlying pulmonary diseases, including chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis and emphysema (CPFE), and idiopathic pulmonary fibrosis (IPF). The control group in this study was stage I-II NSCLC patients who were non-COPD, non-CPFE, and non-IPF.Results: The median follow-up duration was 17 (range, 1–92) months. The median survival times of the control, COPD, CPFE, and IPF groups were 32, 49, 17, and 12 months, respectively (P

An elevated serum lactate level is associated with morbidity and mortality in patients with severe sepsis and septic shock. In patients with hepatic dysfunction, however an elevated serum lactate level may be due to either impaired lactate clearance or excessive production. Thus, we evaluated whether the initial serum lactate level was also associated with mortality in septic shock patients with hepatic dysfunction. A retrospective observational study enrolled 307 patients with septic shock admitted to the intensive care unit (ICU) between May 2007 and July 2009. Hepatic dysfunction was defined as a serum total bilirubin > 34.2 micromol/l (2 mg/dl). Selected patients were divided into high (> or = 4 mmol/l) and low (< 4 mmol/l) lactate groups, according to the initial serum lactate level. Of 307 patients with septic shock, 118 (38%) patients with hepatic dysfunction were eligible for this study. The median lactate levels were 5.9 (interquartile range 4.7 to 9.0) and 2.6 (interquartile range 1.7 to 3.2) mmol/l for the high and low lactate groups respectively (P < 0.001). The initial serum lactate level was strongly associated with in hospital mortality in a univariate analysis (P < 0.001). After adjusting for potential confounding factors, the initial serum lactate level remained significantly associated with in-hospital mortality (odds ratio 1.281, 95% confidence interval 1.097 to 1.496, P = 0.002). In conclusion, the serum lactate level could be useful in predicting the outcome of patients with septic shock regardless of hepatic dysfunction. [ABSTRACT FROM AUTHOR]

Objective: The decision to start chemotherapy in critically ill cancer patients is extremely complex in the intensive care unit (ICU). Therefore, this study evaluated the outcomes and prognostic factors in critically ill cancer patients receiving chemotherapy in the ICU.Methods: A retrospective analysis was performed using 62 cancer patients who received chemotherapy in the ICU between October 2002 and December 2008. The dataset included 49 hematologic malignancies (79%) and 13 solid tumors (21%).Results: Twenty (32%) patients were admitted to the ICU with septic shock, 15 (24%) with respiratory failure, and 14 (23%) with renal failure. The median SOFA and SAPS II scores at the time of chemotherapy were 10 (interquartile range, 6-14) and 53 (interquartile range, 41-68), respectively. Twenty-three (37%) patients had concomitant infections when chemotherapy was initiated. Thirty-eight (61%) patients received mechanical ventilation, and 19 (31%) patients underwent renal replacement therapy at the moment of chemotherapy. Overall, 25 (40%) patients died in the ICU; death occurred due to septic shock (13, 52%), cancer progression (9, 36%), or bleeding (2, 8%). ICU mortality after chemotherapy was correlated with respiratory failure requiring mechanical ventilation (OR, 6.26; 95% CI, 1.12-34.95) and a SOFA score of ≥10 (OR, 9.66; 95% CI, 1.43-65.47) upon initiating chemotherapy.Conclusions: Chemotherapy in the ICU for critically ill cancer patients can be considered even when infection or organ failure is present. However, the severity of organ failure, including respiratory failure requiring mechanical ventilation, was associated with an increased mortality after chemotherapy during an ICU stay. [ABSTRACT FROM AUTHOR]

Rationale: The 2002 American Thoracic Society/European Respiratory Society classification of idiopathic interstitial pneumonias identified nonspecific interstitial pneumonia (NSIP) as a provisional diagnosis. Concern was expressed that NSIP was a "wastebasket" category, difficult to distinguish from other idiopathic interstitial pneumonias. Objectives: The following questions were addressed: (1) Is idiopathic NSIP a distinct entity? 2) If so, what are its clinical, radiologic and pathologic characteristics? (3) What is the role of radiology and pathology in establishing the diagnosis? (4) To make a diagnosis of idiopathic NSIP, what other disorders need to be excluded and how should this be done? Methods: Investigators who had previously reported cases of idiopathic NSIP were invited to submit cases for review (n = 305). After initial review, cases with complete clinical, radiologic, and pathologic information (n = 193) were reviewed in a series of workshops. Measurements and Main Results: Sixty-seven cases were identified as NSIP. Mean age was 52 years, 67% were women, 69% were never-smokers, and 46% were from Asian countries. The most common symptoms were dyspnea (96%) and cough (87%); 69% had restriction. By high-resolution computed tomography, the lower lung zones were predominantly involved in 92% of cases; 46% had a peripheral distribution; 47% were diffuse. Most showed a reticular pattern (87%) with traction bronchiectasis (82%) and volume loss (77%). Lung biopsies showed uniform thickening of alveolar walls with a spectrum of cellular to fibrosing patterns. Five-year survival was 82.3%. Conclusions: Idiopathic NSIP is a distinct clinical entity that occurs mostly in middle-aged women who are never-smokers. The prognosis of NSIP is very good. [ABSTRACT FROM AUTHOR]

Flexible bronchoscopy is a useful diagnostic procedure in patients with respiratory failure due to unexplained pulmonary infiltrates, but its safety and usefulness in ventilator-dependent patients with severe thrombocytopenia have not been established. A retrospective review of the medical records of all patients who underwent bronchoscopy while receiving mechanical ventilation support at Samsung Medical Centre, Seoul, Korea between January 2002 and July 2006 was conducted. The medical records of 37 patients with severe thrombocytopenia (platelet count <50,000 /microl) at the time of bronchoscopy were analysed. Mean platelet count was 27,300+/-12,500 /microl. The most common underlying condition was haematologic malignancy, which occurred in 21(56.7%) patients, followed by severe sepsis in five (13.6%) and post-liver transplantation complications and autoimmune disease in four each (10.8%). The procedures performed were bronchoalveolar lavage in 33 patients, washing in three and transbronchial lung biopsy in five. Two patients died within 24 hours of completing the procedure. In patients surviving longer than 24 hours, there was no significant decline in oxygenation index (PaO2/FiO2), sequential organ failure assessment score or simplified acute physiological score II after the procedure. Lung compliance significantly decreased at two hours post-bronchoscopy but recovered to the pre-bronchoscopy level by 24 hours. Intensive care unit mortality was 51.4% (19 of 37 patients). Bronchoscopy was helpful in confirming the diagnosis in 17 patients (45.9%). Therapeutic modifications were made in 14 patients (37.8%) after bronchoscopy. Severe thrombocytopenia per se should not preclude bronchoscopy, even in patients receiving mechanical ventilation. [ABSTRACT FROM AUTHOR]

Study Objectives: To determine whether inactive hepatitis B surface antigen (HBsAg) carriers are at a higher risk of drug-induced hepatotoxicity than control subjects during antituberculosis treatment with standard short-course regimens of isoniazid, rifampin, ethambutol, and/or pyrazinamide. Design: Retrospective case-control study. Setting: Tertiary university medical center. Patients: One hundred ten inactive HBsAg carriers with newly diagnosed active tuberculosis who had been treated with isoniazid, rifampin, ethambutol, and/or pyrazinamide were included in the study population. Inactive HBsAg carriers were defined as follows: (1) positive for HbsAg; (2) negative for hepatitis B e antigen (HBeAg), positive for antibody to HBeAg; (3) < 10(5) copies per mL of serum hepatitis B virus DNA; and (4) normal pretreatment aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels. Ninety-seven HBsAg-negative patients who received standard antituberculosis medication were selected as control subjects. Results: The baseline characteristics of the 110 inactive HBsAg carriers were similar to those of the 97 noncarriers. A total of 85% of persons in both groups had received an initial treatment regimen that included pyrazinamide. Thirty-eight inactive HBsAg carriers (35%) and 19 control subjects (20%) exhibited elevated liver enzyme levels during antituberculosis treatment (p = 0.016). Drug-induced hepatotoxicity, which was defined as a liver transaminase level of >/= 120 IU/L, occurred more frequently in HBsAg carriers (9 of 110 carriers; 8%) than in control subjects (4 of 97 control subjects; 4%), although this was not a statistically significant discrepancy (p = 0.230). More importantly, HBsAg carriers (n = 9; 8%) who received antituberculosis therapy evidenced a higher proportion of moderate-to-severe drug-induced hepatotoxicity when compared with the control subjects (n = 2; 2%; p = 0.05). Isoniazid and rifampin were reintroduced as therapy after AST/ALT levels returned to baseline values in 10 patients (6 HBsAg carriers and 4 control subjects) among the 13 patients exhibiting drug-induced hepatotoxicity, and these retrials proved to be successful in 7 patients (5 HBsAg carriers and 2 control subjects). Conclusions: Tuberculosis treatment in HBsAg-positive and HBeAg-negative inactive carriers could be pursued in the usual manner, using standard short-course regimens of isoniazid, rifampin, ethambutol, and/or pyrazinamide, with the condition that monthly liver function tests are performed. [ABSTRACT FROM AUTHOR]

Objective: To determine the clinical phenotype and outcomes of patients with idiopathic inflammatory myopathies (IIMs) and myocarditis., Methods: Using the Johns Hopkins Myositis Center Research Registry, we identified 31 adult patients with IIM-out of a total of 3082 with confirmed or suspected muscle disease-with an encounter code of myocarditis from 2004 to 2021. Of these, 14 adult patients with IIM were adjudicated to have clinical myocarditis. Information about demographics, autoantibodies, and clinical outcomes was retrospectively collected and analyzed., Results: Of 14 patients with IIM with clinical myocarditis, the median age at IIM diagnosis was 49 (IQR 35-56) years, and the median age at myocarditis diagnosis was 54 (IQR 36-61) years. The median duration between IIM diagnosis and myocarditis was 3 (IQR 2-9) years. The majority of patients were female (8/14, 57%) and Black (10/14, 71%). Antisynthetase syndrome was the most common IIM subtype (9/14, 64%). Anti-Jo1 (n = 4) and anti-PL12 (n = 3) were the most frequent autoantibodies. At myocarditis diagnosis, most patients (11/14, 79%) had active myositis, defined as elevated creatine kinase and/or muscle weakness; required hospitalization (13/14, 93%); and had reduced left ventricular ejection fraction (LVEF < 50%; 10/14, 71%). Despite intensification of immunosuppression, the 5-year overall survival rate from IIM diagnosis was 84%, and the 5-year overall survival rate from myocarditis diagnosis was 53%. Systolic dysfunction (LVEF < 40%) at final evaluation was observed in all expired patients (n = 6)., Conclusion: Clinical presentations of myocarditis in this select cohort of patients with IIM were severe and heterogeneous with poor outcomes despite intensification of immunosuppression, potentially reflecting late detection of myocarditis., (Copyright © 2023 by the Journal of Rheumatology.)

Background: Recent reports have suggested that pneumonitis is a rare complication following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, its clinical features and outcomes are not well known. The aim of this study was to identify the clinical characteristics and outcomes of patients with vaccine-associated pneumonitis following vaccination against SARS-CoV-2., Methods: In this nationwide multicenter survey study, questionnaires were distributed to pulmonary physicians in referral hospitals. They were asked to report cases of development or exacerbation of interstitial lung disease (ILD) associated with the coronavirus disease 2019 vaccine. Vaccine-associated pneumonitis was defined as new pulmonary infiltrates documented on chest computed tomography within 4 weeks of vaccination and exclusion of other possible etiologies., Results: From the survey, 49 cases of vaccine-associated pneumonitis were identified between February 27 and October 30, 2021. After multidisciplinary discussion, 46 cases were analyzed. The median age was 66 years and 28 (61%) were male. The median interval between vaccination and respiratory symptoms was 5 days. There were 20 (43%), 17 (37%), and nine (19%) patients with newly identified pneumonitis, exacerbation of pre-diagnosed ILD, and undetermined pre-existing ILD, respectively. The administered vaccines were BNT162b2 and ChAdOx1 nCov-19/AZD1222 each in 21 patients followed by mRNA-1273 in three, and Ad26.COV2.S in one patient. Except for five patients with mild disease, 41 (89%) patients were treated with corticosteroid. Significant improvement was observed in 26 (57%) patients including four patients who did not receive treatment. However, ILD aggravated in 9 (20%) patients despite treatment. Mortality was observed in eight (17%) patients., Conclusion: These results suggest pneumonitis as a potentially significant safety concern for vaccines against SARS-CoV-2. Clinical awareness and patient education are necessary for early recognition and prompt management. Additional research is warranted to identify the epidemiology and characterize the pathophysiology of vaccine-associated pneumonitis., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Background: Interstitial lung abnormalities (ILAs) are associated with the risk of lung cancer and its mortality. However, the impact of ILA on treatment-related complications and survival in patients who underwent curative surgery is still unknown., Research Question: This study aimed to evaluate the significance of the presence of computed tomography-diagnosed ILA and histopathologically matched interstitial abnormalities on postoperative pulmonary complications (PPCs) and the long-term survival of patients who underwent surgical treatment for lung cancer., Study Design and Methods: A matched case-control study was designed to compare PPCs and mortality among 50 patients with ILA, 50 patients with idiopathic pulmonary fibrosis (IPF) and 200 controls. Cases and controls were matched by sex, age, smoking history, tumour location, the extent of surgery, tumour histology and pathological TNM stage., Results: Compared with the control group, the OR of the prevalence of PPCs increased to 9.56 (95% CI 2.85 to 32.1, p<0.001) in the ILA group and 56.50 (95% CI 17.92 to 178.1, p<0.001) in the IPF group. The 5-year overall survival (OS) rates of the control, ILA and IPF groups were 76% (95% CI 71% to 83%), 52% (95% CI 37% to 74%) and 32% (95% CI 19% to 53%), respectively (log-rank p<0.001). Patients with ILA had better 5-year OS than those with IPF (log-rank p=0.046) but had worse 5-year OS than those in the control group (log-rank p=0.002)., Conclusions: The presence of radiological and pathological features of ILA in patients with lung cancer undergoing curative surgery was associated with frequent complications and decreased survival., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease (ILD) with variable and heterogeneous clinical course. The GAP (gender, age, and physiology) model had been used to predict mortality in patients with IPF, but does not contain exercise capacity. Therefore, our aim in this study was to develop new prognostic scoring system in the Korea IPF Cohort (KICO) registry., Materials and Methods: This is a retrospective study of Korean patients with IPF in KICO registry from June 2016 to August 2021. We developed new scoring system (the GAP6) based on the GAP model adding nadir saturation of percutaneous oxygen (SpO 2 ) during six-minute walk test (6MWT) in the KICO registry and compared the efficacy of the GAP and the GAP6 model., Results: Among 2,412 patients in KICO registry, 966 patients were enrolled. The GAP6 model showed significant prognostic value for mortality between each stage [HR Stage II vs. Stage I = 2.89 (95% CI = 2.38-3.51), HR Stage III vs. Stage II = 2.68 (95% CI = 1.60-4.51)]. In comparison the model performance with area under curve (AUC) using receiver operating characteristic (ROC) curve analysis, the GAP6 model showed a significant improvement for predicting mortality than the GAP model (AUC the GAP vs. the GAP6, 0.646 vs. 0.671, p  < 0.0019). Also, the C-index values slightly improved from 0.674 to 0.691 for mortality., Conclusion: The GAP6 model adding nadir SpO 2 during 6WMT for an indicator of functional capacity improves prediction ability with C-index and AUC. Additional multinational study is needed to confirm these finding and validate the applicability and accuracy of this risk assessment system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee, Jang, Jang, Kim, Chung, Yoo, Jeong, Song, Lee, Choi, Kim, Kim, Park, Park, Jegal, Lee, Uh, Kim, Kim, Shin, Lee, Yang, Lee, Kim, Lee, Choi, Kang, Heo, Lee and Park.)

Background: Pirfenidone, an antifibrotic medication approved for the treatment of idiopathic pulmonary fibrosis (IPF), often requires dose reduction owing to adverse events. In this study, we evaluated if pirfenidone's reduced dose has any impact on clinical outcomes in patients with IPF. Methods: We used the data of a prospective post-marketing study of pirfenidone conducted at 10 hospitals in South Korea from 2014 to 2017. Dose reduction was defined when the pirfenidone dose was temporarily or permanently reduced to manage adverse events or when the treatment dose failed to reach the standard dose. Study patients were classified based on the most frequently administered dose during 48-week follow-up-1800 mg, 1,200 mg, and <1,200 mg/days. The following clinical outcomes were compared between the groups: death, hospitalization, acute exacerbation, pulmonary function decline, and changes in severity of dyspnea and cough. Results: The median follow-up duration in all 143 patients was 11 months. During the study period, 70.6% experienced at least one dose reduction. Patients treated with standard-dose pirfenidone tended to be young and had the lowest diffusing capacity. Pulmonary function changes did not differ depending on the pirfenidone dose. The three groups were not significantly different in terms of the proportion of death, hospitalization, and acute exacerbation. The symptom changes were also similar between the groups. Conclusion: Reduced doses did not negatively impact clinical outcomes compared with the standard-dose pirfenidone in patients with IPF. Dose reduction may be a useful method to manage adverse events while maintaining therapeutic efficacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kang, Chung, Park, Oh, Lee, Kim, Park, Uh, Kim, Jegal and Song.)

Background: Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) that results from an immune-mediated reaction involving various antigens in susceptible individuals. However, the clinical characteristics and outcomes of HP in South Korea are not well understood., Objectives: This study was conducted to identify the clinical characteristics and outcomes of HP in South Korea., Design: This is a retrospective observational study investigating patients with pathologically confirmed HP at our center, along with a comprehensive review of published HP cases in the Republic of Korea., Methods: This retrospective study analyzed 43 patients with pathologically proven HP at a single tertiary hospital in Korea between 1996 and 2020. In addition, case reports of HP published in Korea were collected. The clinical characteristics, etiologies, treatment, and outcomes of patients from our center, as well as case reports, were reviewed. Patients from our hospital were divided into fibrotic and nonfibrotic subtypes according to the ATS/JRS/ALAT guidelines., Results: Among 43 patients with biopsy-proven HP, 12 (27.9%) and 31 (72.1%) patients were classified into the fibrotic and nonfibrotic subtypes, respectively. The fibrotic HP group was older (64.6 ± 8.5 versus 55.2 ± 8.3, p  = 0.002) with less frequent complaints of fever (0% versus 45.2%, p  = 0.013) compared to the nonfibrotic HP group. The most common inciting antigen was household mold (21, 48.8%), followed by inorganic substances (6, 14.0%). Inciting antigens were not identified in eight (18.6%) patients. Treatment of corticosteroids was initiated in 34 (79.1%) patients. An analysis of 46 patients from Korea by literature review demonstrated that reported cases were relatively younger and drugs were the most common etiology compared to our cohort., Conclusion: The analysis of reported cases, as well as our cohort, showed that exposure history and clinical manifestations are heterogeneous for patients with HP in South Korea.

Purpose of Review: This review highlights current and emerging pharmacologic therapies for the treatment of dermatomyositis (DM). Current clinical evidence, in addition to recently published and ongoing clinical trials for various drugs in development, are summarized in this review., Recent Findings: There has been significant progress in the research and development of potential treatments in DM. The FDA recently approved Octagam ® 10% Immune Globulin Intravenous (IVIg) for the treatment of DM. Several drug targets are being explored as viable therapeutic options in phase 2 and phase 3 clinical trials; at the forefront of these are JAK inhibitors (tofacitinib and baricitinib) and T-cell co-stimulation blockers (i.e. abatacept). In addition, clinical trials are currently under way for therapeutics targeting novel molecular pathways, including immunoproteasome inhibitors, anti-B cell therapy, anti-interferon drugs, complement inhibitors, and phosphodiesterase-4 inhibitors., Summary: With the large number of clinical trials, multiple novel therapeutics in development, and improved classification and outcome measures, the treatment landscape for DM will continue to rapidly evolve in the coming years as more options become available.

Objective: To investigate whether obstetric complications prior to systemic sclerosis (SSc) diagnosis are more common in SSc patients compared to the general obstetric population., Methods: A case-control study was performed at Kaiser Permanente Northern California to compare prior obstetric complications in adult women who later developed SSc (cases) with women from the general obstetric population who did not develop SSc (controls; matched 10:1 by age and year of delivery) from 2007 to 2016. Exposures included past hypertensive disorders of pregnancy (preeclampsia, eclampsia, gestational hypertension), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), maternal infections, neonatal intensive care unit (NICU) admission, and preterm birth. Fischer's exact tests were used to compare categorical variables. Conditional logistic regression models estimated the odds ratio (OR), and corresponding 95% confidence intervals (95% CIs) for the outcome SSc., Results: Seventeen SSc cases and 170 non-SSc controls were identified, with median maternal age at delivery 34 years (range 23-46 years) and median time from delivery to SSc diagnosis 2 years (range 0.2-7.3 years). Women with SSc were more likely to be Hispanic and Black. Prior obstetric complications appeared higher in women with an eventual SSc diagnosis compared to controls (70.6% versus 50%), including hypertensive disorders (17.7% versus 9.4%), PROM (11.8% versus 4.1%), IUGR (5.9% versus 1.8%), maternal infection (29.4% versus 14.1%), NICU admissions (23.5% versus 7.7%), and preterm delivery (29.4% versus 21.8%). Women with SSc had a higher odds of delivering infants requiring NICU admission (OR 4.7 [95% CI 1.2-18.8])., Conclusion: Women who eventually develop SSc had trends toward more complicated pregnancy histories before overt diagnosis., (© 2020 American College of Rheumatology.)

Objectives: We evaluated the safety and efficacy of oral treprostinil in preventing progression of SSc-associated calcinosis., Methods: This prospective open-label study enrolled 12 SSc patients meeting 2013 ACR/EULAR classification criteria with confirmed clinical and radiographic evidence of one or more calcinosis deposit in the hands. Patients received oral treprostinil for 1 year. Primary endpoints were safety/tolerability and percentage of patients without radiographic progression of calcinosis at 1 year (<25% increase in Scleroderma Clinical Trials Consortium radiographic score). Secondary endpoints included 1-year changes in Scleroderma HAQ (SHAQ), Cochin Hand Functional Scale, Medical Outcomes Survey Short Form 36 (SF-36), Raynaud Condition Score and patient/physician assessment of calcinosis severity., Results: Twelve female patients were enrolled, half with diffuse cutaneous disease; median age was 55 years (range 35-68 years). Five patients completed the study. Seven patients withdrew due to intolerable adverse effects (n = 3), intercurrent unrelated illness (n = 2, cirrhosis, cancer), progressive SSc (n = 1) and personal reasons (n = 1). Most patients developed headaches and gastrointestinal adverse effects. Four of 11 (36%) patients with 1-year follow-up hand radiographs experienced progression of calcinosis. Of five who completed treatment, calcinosis was stable in four (80%) with progression in one. Based on SF-36 Physical and Mental Component and Domain scores, transition question and SF-6D utility score, all patients who finished the trial reported overall improvement or no change compared with baseline., Conclusion: Oral treprostinil was poorly tolerated in SSc patients with calcinosis. Of five patients who completed treatment, most (80%) had documented stability of calcinosis on hand radiographs at 1 year., Clinicaltrials.gov Identifier: NCT02663895., (Published by Oxford University Press on behalf of the British Society for Rheumatology 2021. This work is written by US Government employees and is in the public domain in the US.)

Objective: To determine whether perifollicular hypopigmentation in systemic sclerosis (SSc) is associated with demographics, distinct clinical features, and autoantibody profiles., Methods: Patients with SSc were prospectively enrolled, with a standardized data form used to collect anatomic distribution of perifollicular hypopigmentation. Associations between hypopigmentation and features of SSc were assessed., Results: Of 179 adult patients with SSc, 36 (20%) patients had perifollicular hypopigmentation. Of these 36 patients, 94% (n = 34) were female and 33% (n = 12) had limited cutaneous SSc. In univariable logistic regression, Black race (odds ratio [OR] 15.63, 95% CI 6.6-37.20, P < 0.001), diffuse cutaneous SSc (dcSSc; OR 4.62, 95% CI 2.11-10.09, P < 0.001), higher maximum modified Rodnan skin score (mRSS; OR 1.05, 95% CI 1.02-1.08, P = 0.003), myopathy (OR 3.92, 95% CI 1.80-8.57, P < 0.001), pulmonary fibrosis (OR 2.69, 95% CI 1.20-6.02, P = 0.02), lower minimum forced vital capacity % predicted (OR 0.96, 95% CI 0.94-0.99, P = 0.001), and lower minimum diffusing capacity for carbon monoxide % predicted (OR 0.97, 95% CI 0.95-0.99, P = 0.009) were associated with hypopigmentation. Anticentromere antibodies inversely associated with hypopigmentation (OR 0.24, 95% CI 0.07-0.86, P = 0.03). After adjusting for age, race, and disease duration, dcSSc (OR 4.28, 95% CI 1.46-12.53, P = 0.008) and increased mRSS (OR 1.07, 95% CI 1.02-1.12, P = 0.009) were significantly associated with hypopigmentation., Conclusion: Perifollicular hypopigmentation is observed in a subset of patients with SSc and associated with diffuse subtype. Larger prospective studies determining whether perifollicular hypopigmentation precedes end-organ involvement and whether specific patterns associate with internal organ involvement are needed., (Copyright © 2022 The Journal of Rheumatology.)

Connective tissue diseases (CTDs) demonstrating features of interstitial lung disease (ILD) include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), dermatomyositis (DM) and polymyositis (PM), ankylosing spondylitis (AS), Sjogren syndrome (SS), and mixed connective tissue disease (MCTD). On histopathology of lung biopsy in CTD-related ILDs (CTD-ILDs), multi-compartment involvement is an important clue, and when present, should bring CTD to the top of the list of etiologic differential diagnoses. Diverse histologic patterns including nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia, apical fibrosis, diffuse alveolar damage, and lymphoid interstitial pneumonia can be seen on histology in patients with CTD-ILDs. Although proportions of ILDs vary, the NSIP pattern accounts for a large proportion, especially in SSc, DM and/or PM and MCTD, followed by the UIP pattern. In RA patients, interstitial lung abnormality (ILA) is reported to occur in approximately 20-60% of individuals of which 35-45% will have progression of the CT abnormality. Subpleural distribution and greater baseline ILA involvement are risk factors associated with disease progression. Asymptomatic CTD-ILDs or ILA patients with normal lung function and without evidence of disease progression can be followed without treatment. Immunosuppressive or antifibrotic agents for symptomatic and/or fibrosing CTD-ILDs can be used in patients who require treatment., (© 2022 The Authors.)

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., (Published by Elsevier Inc.)

Background: The Korea Interstitial Lung Disease Study Group has made a new nationwide idiopathic pulmonary fibrosis (IPF) registry because the routine clinical practice has changed due to new guidelines and newly developed antifibrotic agents in the recent decade. The aim of this study was to describe recent clinical characteristics of Korean IPF patients., Methods: Both newly diagnosed and following IPF patients diagnosed after the previous registry in 2008 were enrolled. Survival analysis was only conducted for patients diagnosed with IPF after 2016 because antifibrotic agents started to be covered by medical insurance of Korea in October 2015., Results: A total of 2,139 patients were analyzed. Their mean age at diagnosis was 67.4±9.3 years. Of these patients, 76.1% were males, 71.0% were ever-smokers, 14.4% were asymptomatic at the time of diagnosis, and 56.9% were at gender-agephysiology stage I. Occupational toxic material exposure was reported in 534 patients. The mean forced vital capacity was 74.6% and the diffusing capacity for carbon monoxide was 63.6%. Treatment with pirfenidone was increased over time: 62.4% of IPF patients were treated with pirfenidone initially. And 79.2% of patients were treated with antifiboritics for more than three months during the course of the disease since 2016. Old age, acute exacerbation, treatment without antifibrotics, and exposure to wood and stone dust were associated with higher mortality., Conclusion: In the recent Korean IPF registry, the percentage of IPF patients treated with antifibrotics was increased compared to that in the previous IPF registry. Old age, acute exacerbation, treatment without antifibrotics, and exposure to wood and stone dust were associated with higher mortality.

Aim: Several studies have reported favorable outcomes of nonspecific interstitial pneumonia (NSIP); however, its prognosis and prognostic factors remain unclear. This study aimed to determine the outcomes of fibrotic NSIP and the prognostic factors for progression, relapse, and survival., Methods: In this retrospective study, we reviewed the clinical data of 204 patients diagnosed with fibrotic NSIP by surgical lung biopsy at Samsung Medical Center. The factors associated with survival and disease progression or relapse were determined using Cox proportional hazard analysis., Results: The median age of patients was 54 years and 67 (33%) patients were male. Also, 47 patients (23%) were current or ex-smokers. In all, 141 (69%) patients were diagnosed with idiopathic NSIP, while 63 (31%) patients were associated with connective tissue diseases. Progression or relapse was observed in 100 (49%) patients. The 5-year and 10-year survival rates were 94.6% and 90.4%, respectively. The factors associated with disease progression and relapse were diffusing capacity for carbon monoxide (DLco) <60% [adjusted hazard ratio (HR), 1.739; 95% confidence interval (CI), 1.036-2.921; p  = 0.036], bronchoalveolar lavage (BAL) lymphocyte >15% (adjusted HR, 0.592; 95% CI, 0.352-0.994; p  = 0.047), and treatment with corticosteroid and azathioprine (adjusted HR, 0.556; 95% CI, 0.311-0.955; p  = 0.048). Disease progression or relapse was associated with mortality (adjusted HR, 7.135; 95% CI, 1.499-33.971; p  = 0.014)., Conclusion: Preserved lung function, BAL lymphocytosis, and treatment with corticosteroids and azathioprine were associated with lower risks of disease progression and relapse, which were risk factors for mortality.

Background: Peripheral blood leucocyte telomere length (PBL-TL) is associated with outcomes in patients with idiopathic pulmonary fibrosis. Whether PBL-TL is associated with progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is unknown., Methods: A retrospective observational cohort study was performed using prospectively collected data from 213 patients with SSc followed at the University of California San Francisco (UCSF) Scleroderma Center. PBL-TL was measured by quantitative PCR of DNA isolated from peripheral blood. Associations between PBL-TL and pulmonary function test trends in patients with SSc-ILD were assessed by longitudinal analysis using Generalised Linear Mixed Models. Findings were validated in a cohort of 61 patients with SSc-ILD enrolled in the Stanford University Scleroderma Center database., Results: Patients with UCSF SSc with ILD were found to have shorter PBL-TL compared with those without ILD (6554±671 base pairs (bp) vs 6782±698 bp, p=0.01). Shorter PBL-TL was associated with the presence of ILD (adjusted OR 2.1 per 1000 bp TL decrease, 95% CI [1.25 to 3.70], p=0.006). PBL-TL was shorter in patients with SSc-ILD lacking SSc-specific autoantibodies compared with seropositive subjects (6237±647 bp vs 6651±653 bp, p=0.004). Shorter PBL-TL was associated with increased risk for lung function deterioration with an average of 67 mL greater loss in per year for every 1000 bp decrease in PBL-TL in the combined SSc-ILD cohorts (longitudinal analysis, adjusted model: 95% CI -104 mL to -33 mL, p<0.001)., Conclusions: These findings suggest that telomere dysfunction may be associated with SSc-ILD progression and that PBL-TL measurement may be useful for stratifying risk for SSc-ILD progression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Idiopathic pulmonary fibrosis, which is one of the lung diseases, is quite rare but fatal in nature. The disease is progressive, and detection of severity takes a long time as well as being quite tedious. With the advent of intelligent machine learning techniques, and also the effectiveness of these techniques, it was possible to detect many lung diseases. So, in this paper, we have proposed a model that could be able to detect the severity of IPF at the early stage so that fatal situations can be controlled. For the development of this model, we used the IPF dataset of the Korean interstitial lung disease cohort data. First, we preprocessed the data while applying different preprocessing techniques and selected 26 highly relevant features from a total of 502 features for 2424 subjects. Second, we split the data into 80% training and 20% testing sets and applied oversampling on the training dataset. Third, we trained three state-of-the-art machine learning models and combined the results to develop a new soft voting ensemble-based model for the prediction of severity of IPF disease in patients with this chronic lung disease. Hyperparameter tuning was also performed to get the optimal performance of the model. Fourth, the performance of the proposed model was evaluated by calculating the accuracy, AUC, confusion matrix, precision, recall, and F1-score. Lastly, our proposed soft voting ensemble-based model achieved the accuracy of 0.7100, precision 0.6400, recall 0.7100, and F1-scores 0.6600. This proposed model will help the doctors, IPF patients, and physicians to diagnose the severity of the IPF disease in its early stages and assist them to take proactive measures to overcome this disease by enabling the doctors to take necessary decisions pertaining to the treatment of IPF disease.

Rationale: In recent decades, diagnosis and treatment recommendations for idiopathic pulmonary fibrosis (IPF) have changed. In Korea, the average life expectancy has increased, unmet healthcare needs have been reduced, and the number of computed tomographic examinations performed has nearly doubled. The Korean Interstitial Lung Disease Study Group conducted a nationwide cohort study for idiopathic interstitial pneumonia, including IPF, and established a registry for IPF. Objectives: Using study data collected by the study group, this study aimed to evaluate longitudinal changes in clinical features, diagnosis, treatment, and mortality and analyze the extent to which changes in medication usage affected IPF-associated mortality. Methods: The study population included newly diagnosed patients with IPF from a cohort study (January 2002 to September 2008, n  = 1,839, 2008 group) and prospective registry (January 2012 to August 2018, n  = 1,345, 2018 group). Survival curves were estimated using the Kaplan-Meier method, and Cox regression models were used to identify mortality-associated risk factors in each group. Results: The 2018 group was younger, had fewer symptoms, had less honeycombing, underwent more serologic autoimmune marker and pulmonary function tests, had higher oxygen partial pressure and lower carbon dioxide partial pressure values, was less frequently diagnosed by surgical biopsy, and had better survival than the 2008 group. Steroid use and conservative care declined, whereas N -acetylcysteine use increased in this group. Antifibrotic agents were used in only the 2018 group. In the 2008 group, N -acetylcysteine was associated with lower mortality, whereas conservative care was associated with higher mortality. In the 2018 group, the use of antifibrotic agents was associated with lower mortality, and steroid use was associated with higher mortality. The survival rates in the 2008 and 2018 non-antifibrotic agent subgroups were similar. Conclusions: This study analyzed national IPF cohort data spanning 17 years. In clinical practice, the IPF diagnosis was made earlier, steroid and immunosuppressive agent use was reduced, and antifibrotic agents were administered. The survival of patients with IPF has improved over the decades, and antifibrotic use was consistently associated with improved survival.Clinical trial registered with clinicaltrials.gov (NCT04160715).

Objective: Interstitial lung disease (ILD) is a major cause of morbidity and mortality in connective tissue diseases (CTDs). We aimed to assess the effect of rituximab ± mycophenolate mofetil (MMF) compared with MMF on pulmonary function and prednisone dosage in patients with CTD-related ILD (CTD-ILD)., Methods: This retrospective study included 83 patients from Stanford and Centre Hospitalier de l'Universite de Montreal. Fifteen patients received rituximab ± MMF (rituximab group), and 68 patients received MMF only (control group)., Results: Median ILD duration at the start of treatment was longer in the rituximab group at 47 months (range: 4-170) versus 6.5 months (range: 0-164) in controls. Forced vital capacity (FVC) decreased by 3.0% (range: 11%-21%) after treatment in the rituximab group, whereas it increased by 2.0% (range: 14%-25%) in the control group (p = 0.025). Diffusing capacity of carbon monoxide (DLCO) decreased by 3.0% (range: 10%-12%) after treatment in the rituximab group, whereas it increased by 4.5% (range: 30%-36%) in the control group (p = 0.046). Mixed model analysis controlling for ILD duration, baseline DLCO, systemic sclerosis, pulmonary hypertension, and prednisone use showed no significant difference in FVC or DLCO between groups at 6 months or 1 year. The average daily prednisone dose score decreased after treatment in the rituximab group, whereas it remained unchanged in the control group (p = 0.017)., Conclusion: Rituximab ± MMF did not significantly change pulmonary function compared with MMF alone, but it did result in a relative decrease in average daily prednisone dose in a population with recalcitrant CTD-ILD., (© 2020 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The connective tissue diseases (CTDs) demonstrating features of interstitial lung disease (ILD) include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), progressive systemic sclerosis (PSS), dermatomyositis (DM) and polymyositis (PM), ankylosing spondylitis (AS), Sjogren's syndrome (SS), and mixed connective tissue disease (MCTD). In RA patients in particular, interstitial lung abnormality (ILA) (of varying degrees; severe vs. mild) is reported to occur in approximately 20-60 % of individuals and CT disease progression occurs in approximately 35-45 % of them. The ILAs have been associated with a spectrum of functional and physiologic decrement. The identification of progressive ILA may enable appropriate surveillance and the commencement of treatment with the goal of improving morbidity and mortality rates of established RA-ILD. Subpleural distribution and higher baseline ILA/ILD extent were risk factors associated with disease progression. At histopathologic analysis, connective tissue disease-related interstitial lung diseases (CTD-ILDs) are diverse and include nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia (OP), apical fibrosis, diffuse alveolar damage (DAD), and lymphoid interstitial pneumonia (LIP). Even though proportions of ILDs vary, NSIP pattern accounts for a large proportion, especially in PSS, DM/PM and MCTD, followed by UIP pattern. Evidence has been published that treatment of subclinical CT lung abnormalities showing a tendency to progress to ILD may stabilize the CT alterations. The identification of subclinical lung abnormalities can be appropriate in the management of the disease and CT appears to be the gold standard for the evaluation of lung parenchyma., Competing Interests: The authors report no declarations of interest., (© 2020 The Authors.)

Objective: Gastric antral vascular ectasia (GAVE) is a vascular manifestation of systemic sclerosis (SSc) that can lead to iron deficiency anemia or acute gastrointestinal (GI) bleeding. We aimed to identify clinical features associated with GAVE., Methods: We performed a cohort study of SSc patients who were seen at Stanford between 2004 and 2018 and had undergone esophagogastroduodenoscopy (EGD). We compared the clinical features of those with and without GAVE, and multivariable logistic regression was performed to identify clinical correlates with GAVE., Results: A total of 225 patients with SSc who underwent EGD were included in this study and 19 (8.4%) had GAVE. Those with GAVE were more likely to have scleroderma renal crisis (SRC) (21% vs 3%; p < 0.01), positive anti-RNA polymerase III antibody (71% vs 19%; p < 0.01), nucleolar pattern of anti-nuclear antibody (ANA) (33% vs 11%; p=0.04), and negative ANA (<1:80 by immunofluorescence) (33% vs 11%; p=0.02). On multivariate analysis with multiple imputation, anti-RNA polymerase III positivity (OR 4.57; 95% CI (1.57 - 13.23), p < 0.01) and ANA negativity (OR 3.75; 95% CI (1.21 - 11.62), p=0.02) remained significantly associated with GAVE., Conclusion: Positive anti-RNA polymerase III antibody and ANA negativity were significantly associated with GAVE. Further studies are necessary to determine whether patients with these autoantibody profiles should undergo screening endoscopies for GAVE., (Published by Elsevier Inc.)

Background: The easy-to-calculate gender, age, and lung physiology (GAP) model shows good predictive and discriminative performance in the prognosis of idiopathic pulmonary fibrosis (IPF). However, the GAP model was not effective in predicting the prognosis accurately in previous Japanese and Korean IPF cohort studies. Therefore, we developed a modified GAP model for the East-Asian populations by weighing the GAP variables. The validity of the modified GAP model was subsequently evaluated in East-Asian IPF patients., Methods: The derivation cohort comprised 326 patients with IPF. Weights of the variables were adjusted on the basis of coefficients derived from Cox regression models. The total points were distributed to the three stages of the disease so that the number of patients included in each stage was appropriate. The validity of the modified model was analyzed in another Japanese cohort of 117 patients with IPF and a nationwide cohort of Korean patients with IPF., Results: Predicted survival rates differed significantly in the derivation cohort using the modified GAP model for each stage of IPF (log-rank test: stage I vs. stage II, p < 0.001; stage II vs. stage III, p < 0.001). Model performance improved according to Harrell's C-index (at three years: 0.696 in the original GAP model to 0.738 in the modified model). The performance of the modified model was validated in the Japanese validation and Korean national cohorts., Conclusions: Our modification of the original GAP model showed improved performance in East-Asian IPF patient populations., Competing Interests: Conflict of Interest YK received honoraria from Nippon Boehringer Ingelheim Co. Ltd. SH belongs to the endowed department sponsored by Teijin-Pharma Co. Ltd., Chugai-Pharma Co. Ltd., Asahikasei-Pharma Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., and Shionogi Co. Ltd., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Dermatomyositis (DM) is a rare idiopathic inflammatory myopathy characterized by muscle weakness and cutaneous manifestations in adults and children. Calcinosis, a complication of DM, is the abnormal deposition of insoluble calcium salts in tissues, including skin, subcutaneous tissue, tendons, fascia, and muscle. Calcinosis is more commonly seen in juvenile DM (JDM), but also develops in adult DM. Although the mechanism of calcinosis remains unclear, several pathogenic hypotheses have been proposed, including intracellular accumulation of calcium secondary to an alteration of the cellular membrane by trauma and inflammation, local vascular ischemia, dysregulation of mechanisms controlling the deposition and solubility of calcium and phosphate, and mitochondrial damage of muscle cells. Identifying calcinosis biomarkers is important for early disease detection and risk assessment, and may lead to novel therapeutic targets for the prevention and treatment of DM-associated calcinosis. In this review, we summarize myositis autoantibodies associated with calcinosis in DM, histopathology and chemical composition of calcinosis, genetic and inflammatory markers that have been studied in adult DM and JDM-associated calcinosis, as well as potential novel biomarkers., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier B.V.)

Periarterial sympathectomy and arterial bypass are microsurgical techniques which the literature suggests can provide improvement in digital pain and ulceration in patients with systemic sclerosis (SSc) who have persistent symptoms despite medication management. This review summarizes the relevant anatomy, medical therapies, operative techniques, and surgical outcomes and complications associated with the management of the vascular manifestations of SSc in the hand. Multidisciplinary collaboration between dermatology, rheumatology, and hand surgery can facilitate optimal medical and surgical management for SSc patients.

Aim: The efficacy and safety of pirfenidone have been previously demonstrated in patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF). However, the effect of pirfenidone in patients with advanced IPF remains unclear. Here, we investigated the effects of pirfenidone against advanced IPF in a real-world setting., Methods: A prospective nationwide post-marketing study was conducted on 258 patients from 10 Korean institutions. Patients with a predicted forced vital capacity (FVC) less than 50% or a diffusing capacity of the lung for carbon monoxide (DLco) less than 35% at baseline were classified as the advanced IPF group., Results: Of 219 patients included in the analysis, the majority were male (76.3%); the mean age was 67.3 years, and the advanced group accounted for 17.8% of the patients. The median treatment duration was 298 days. Among the subjects, 86.3% experienced adverse events (AEs), of which a decreased appetite (32.4%) and a photosensitivity reaction (13.7%) were the most frequent. The incidence of AEs was similar between the advanced and non-advanced groups (92.3% vs. 85.0%, respectively; p = 0.229). Although the overall discontinuation rate was higher in the advanced group than in the non-advanced group (74.4% vs. 50.0%, respectively; p = 0.006), the percentages of the patients who discontinued treatment as a result of AEs were similar in both groups (20.5% vs. 23.3%, respectively; p = 0.704). In all patients, the rates of decline in the predicted FVC and DLco over 48 weeks were - 4.3 ± 1.3% and - 4.4 ± 1.7%, respectively. There was no between-group difference in the rate of lung function decline., Conclusions: Pirfenidone used for the treatment of patients with IPF in a real-world setting was well tolerated, with an acceptable safety profile and a consistent therapeutic effect, regardless of the disease severity., Trial Registration: ClinicalTrials.gov NCT03761082; the trial was retrospectively registered on December 3, 2018.

Objective: The objective of this study is to evaluate racial/ethnic differences in disease manifestations and survival in a US cohort of patients with systemic sclerosis (SSc), with a focus on Asian patients., Methods: A retrospective cohort study was conducted among Kaiser Permanente Northern California adults with an incident SSc diagnosis by a rheumatologist from 2007 to 2016, confirmed by a chart review to fulfill 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria. Self-reported race/ethnicity was categorized as non-Hispanic white, Asian, Hispanic, and black. Disease manifestations and survival were compared, using white patients as the reference., Results: A total of 609 patients with incident SSc were identified: 89% were women, and 81% had limited cutaneous SSc, with a mean age at diagnosis of 55.4 ± 14.8 years. The racial/ethnic distribution was 51% non-Hispanic white (n = 310), 25% Hispanic (n = 154), 16% Asian (n = 96), and 8% black (n = 49). Compared with white patients, black patients had a greater prevalence of diffuse disease (14.5% vs. 44.9%; P < 0.001), and Asians had higher rates of anti-U1-RNP antibodies (32.1% vs. 11.9%; P = 0.005). Nine-year overall survival rates following SSc diagnosis were lower in Asian (52.3%), black (52.2%), and Hispanic patients (68.2%) compared with white patients (75.8%). Pulmonary hypertension and infections were the leading causes of death in Asian patients. Asian race was associated with higher mortality on univariable (hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.08-2.99]; P = 0.020) and multivariable analyses (HR 1.80 [95% CI 0.99-3.16]; P = 0.047) when adjusting for age, sex, body mass index, cutaneous subtype, smoking status, interstitial lung disease, pulmonary hypertension, renal crisis, and malabsorption syndrome., Conclusion: Asian patients with SSc in this US cohort had increased mortality compared with white patients. These patients warrant close monitoring for disease progression., (© 2020 The Authors. ACR Open Rheumatology published by Wiley Periodicals Inc on behalf of American College of Rheumatology. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Introduction : Systemic sclerosis (SSc) is an autoimmune connective tissue disease that is characterized by excessive collagen deposition, vascular dysfunction, and fibrosis of cutaneous and visceral organs. Current therapeutic options are limited and provide only modest benefit. Areas covered : This review summarizes investigational agents in recent Phase I and II clinical trials evaluated for the treatment of SSc with a focus on skin in patients with early diffuse disease and interstitial lung disease. We performed a search on Pubmed and https://clinicaltrials.gov with keywords systemic sclerosis, Phase I clinical trial, and Phase II clinical trial to identify relevant studies from 2015 to 2019. Expert opinion : Therapeutic interventions in SSc should be guided by the level of disease activity and the degree of organ involvement. While most novel agents have failed to meet the primary endpoints of reducing skin thickening as measured by the modified Rodnan skin score, some have shown promise in improving the Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis (CRISS), reducing lung function decline, or improving patient-reported outcomes. However, most of the current evidence is based on small or open-label clinical trials. Well-designed, large, randomized, Phase III clinical trials are necessary to define the roles of investigational agents in treating SSc.

Idiopathic interstitial pneumonia (IIP) is a histologically identifiable pulmonary disease without a known cause that usually infiltrates the lung interstitium. IIP is largely classified into idiopathic pulmonary fibrosis, idiopathic non-specific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease (ILD), cryptogenic organizing pneumonia, desquamative interstitial pneumonia, and acute interstitial pneumonia. Each of these diseases has a different prognosis and requires specific treatment, and a multidisciplinary approach that combines chest high-resolution computed tomography (HRCT), histological findings, and clinical findings is necessary for their diagnosis. Diagnosis of IIP is made based on clinical presentation, chest HRCT findings, results of pulmonary function tests, and histological findings. For histological diagnosis, video-assisted thoracoscopic biopsy and transbronchial lung biopsy are used. In order to identify ILD associated with connective tissue disease, autoimmune antibody tests may also be necessary. Many biomarkers associated with disease prognosis have been recently discovered, and future research on their clinical significance is necessary. The diagnosis of ILD is difficult because patterns of ILD are both complicated and variable. Therefore, as with other diseases, accurate history taking and meticulous physical examination are crucial., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright©2019. The Korean Academy of Tuberculosis and Respiratory Diseases.)

Background: Lung cancer is a common comorbidity of idiopathic pulmonary fibrosis (IPF) and has poor outcomes. The incidence and clinical factors related to development of lung cancer in idiopathic pulmonary fibrosis (IPF) are unclear. The aim of this study was to elucidate the cumulative incidence, risk factors, and clinical characteristics of lung cancer in IPF., Methods: In this retrospective study, we analyzed clinical data for 938 patients who were diagnosed with IPF without lung cancer between 1998 and 2013. Demographic, physiologic, radiographic, and histologic characteristics were reviewed. Cumulative incidence of lung cancer and survival were estimated by the Kaplan-Meier method. Risk factors of lung cancer development were determined by Cox proportional hazard analysis., Results: Among 938 IPF patients without lung cancer at initial diagnosis, lung cancer developed in 135 (14.5%) during the follow-up period. The cumulative incidences of lung cancer were 1.1% at 1 year, 8.7% at 3, 15.9% at 5, and 31.1% at 10 years. Risk factors of lung cancer were male gender, current smoking at IPF diagnosis, and rapid annual decline of 10% or more in forced vital capacity (FVC). Patients who developed lung cancer were mostly elderly men with smoking history. Squamous cell carcinoma followed by adenocarcinoma was the most common histologic type. Lung cancer was frequently located in areas abutting or within fibrosis. Survival was significantly worse in patients with lung cancer compared to patients with IPF alone., Conclusion: Lung cancer frequently developed in patients with IPF and was common in current-smoking men with rapid decline of FVC.

Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) share common risk factors. They could therefore be expressed in a single patient. However, the prevalence, clinical characteristics and prognosis of individuals with comorbid IPF and COPD are not known. From 2003 to 2007, the Korean Interstitial Lung Disease Study Group created a register for idiopathic interstitial pneumonia using 2002 ATS/ERS (American Thoracic Society/European Respiratory Society) criteria. Of the 1546 IPF patients assessed, 143 had decreased lung function consistent with COPD (IPF-COPD). COPD was diagnosed based on age (≥40 years) and pulmonary function (forced expiratory volume in 1 sec [FEV 1 ]/forced vital capacity [FVC] ratio < 0.7). The median age of the IPF-COPD group was 71.0 years (interquartile range 66.0-76.0); most patients were male (88.1%). FVC (%) was significantly higher in the IPF-COPD group; however, FEV 1 (%) was significantly lower in the IPF-COPD group ( P < 0.001). Diffusing capacity of the lung for carbon monoxide (DL CO ) was not significantly different between the two groups. In survival analysis, age and FVC (%), but not COPD, were significantly associated with prognosis (respectively P = 0.003, 0.001 and 0.401). COPD severity was also not related to prognosis ( P = 0.935). The prevalence of IPF-COPD was estimated to be ∼9.2% among all IPF patients; prognosis of patients with IPF-COPD was not worse than those with IPF alone. .

IgG4-related disease is a systemic inflammatory disease and is known as IgG4-related lung disease (IgG4-RLD) when it involves the respiratory system. Primary lung cancer arising from a background of IgG4-RLD is very rare. Herein, we report a case of adenosquamous carcinoma arising from the background of IgG4-RLD and presenting as an interstitial lung disease pattern. A 66-year-old man underwent lobectomy under the impression of primary lung cancer. Grossly, the mass was ill-defined and gray-tan colored, and the background lung was fibrotic. Microscopically, tumor cells showed both squamous and glandular differentiation. Dense lymphoplasmacytic infiltration with fibrosis and obliterative phlebitis were seen in the background lung. IgG4 immunohistochemical stain showed diffuse positivity in infiltrating plasma cells. Primary lung adenosquamous carcinoma has not been reported in a background of IgG4-RLD. Due to the rarity of IgG4-RLD, physicians must follow patients with IgG4-RLD over long periods of time to accurately predict the risk of lung cancer.

Background: The clinical course of IPF varies. This study sought to identify phenotyping with quantitative computed tomography (CT) fibrosis and emphysema features using a cluster analysis and to assess prognostic impact among identified clusters in patient with idiopathic pulmonary fibrosis (IPF). Furthermore, we evaluated the impact of fibrosis and emphysema on lung function with development of a descriptive formula., Methods: This retrospective study included 205 patients with IPF. A texture-based automated system was used to quantify areas of normal, emphysema, ground-glass opacity, reticulation, consolidation, and honeycombing. Emphysema index was obtained by calculating the percentage of low attenuation area lower than -950HU. We used quantitative CT features and clinical features for clusters and assessed the association with prognosis. A formula was derived using fibrotic score and emphysema index on quantitative CT., Results: Three clusters were identified in IPF patients using a quantitative CT score and clinical values. Prognosis was better in cluster1, with a low extent of fibrosis and emphysema with high forced vital capacity (FVC) than cluster2 and cluster3 with higher fibrotic score and emphysema (p = 0.046, and p = 0.026). In the developed formula [1.5670-fibrotic score(%)*0.04737-emphysema index*0.00304], a score greater ≥ 0 indicates coexisting of pulmonary fibrosis and emphysema at a significant extent despite of normal spirometric result., Conclusions: Cluster analysis identified distinct phenotypes, which predicted prognosis of clinical outcome. Formula using quantitative CT values is useful to assess extent of pulmonary fibrosis and emphysema with normal lung function in patients with IPF., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The aim of this study was to analyze the incidence, symmetry, concurrence of second mesiobuccal canal (MB2) and determine geometric relationships between each orifice of maxillary first and second molars by cone-beam computed tomography (CBCT) analysis., Methods: A total of 216 qualified individuals' (503 teeth) CBCT image were enrolled in the present study. The consistency of bilateral symmetry and concurrent appearance of MB2 canals were analyzed among individuals with contralateral and adjacent molar teeth. The inter-orifice distances and angulations of first and second molars were also measured., Results: The overall incidence of MB2 canal of maxillary molars was 39.2%, in which 45.9% and 32.3% in the first and second molars, respectively. The distribution of MB2 canal in contralateral molar teeth has significant gender difference in second molars (p = 0.024) while analyzing the frequency of MB2 canal appearing in contralateral molar pairs. The simultaneous occurrence of MB2 canal was 22.4% for contralateral molars, and the prevalence of concurrent appearance of MB2 canal in the adjacent molars was 43.4%. After adjusting for gender, age, and tooth type, the inter-orifice distances of mesiobuccal to palatal (odds ratios = 1.891) and to distobuccal (odds ratios = 1.448) canals, demonstrated significant differences between molars with and without MB2 canals., Conclusions: The clinical significance of the results presents critical information on the geometric features, including inter-orifice distances and angulations between each orifice in maxillary molar teeth. Further studies should be conducted to investigate the exact anatomic coordination between each orifice and its impact on access preparation and external crown morphology., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Despite widespread implementation of policies to address mistreatment, the proportion of medical students who experience mistreatment during clinical training is significantly higher than the proportion of students who report mistreatment. Understanding barriers to reporting mistreatment from students' perspectives is needed before effective interventions can be implemented to improve the clinical learning environment., Objective: We explored medical students' reasons for not reporting perceived mistreatment or abuse experienced during clinical clerkships at the David Geffen School of Medicine at UCLA (DGSOM)., Design: This was a sequential two-phase qualitative study. In the first phase, we analyzed institutional survey responses to an open-ended questionnaire administered to the DGSOM graduating classes of 2013-2015 asking why students who experienced mistreatment did not seek help or report incidents. In the second phase, we conducted focus group interviews with third- and fourth-year medical students to explore their reasons for not reporting mistreatment. In total, 30 of 362 eligible students participated in five focus groups. On the whole, 63% of focus group participants felt they had experienced mistreatment, of which over half chose not to report to any member of the medical school administration. Transcripts were analyzed via inductive thematic analysis., Results: The following major themes emerged: fear of reprisal even in the setting of anonymity; perception that medical culture includes mistreatment; difficulty reporting more subtle forms of mistreatment; incident is not important enough to report; reporting process damages the student-teacher relationship; reporting process is too troublesome; and empathy with the source of mistreatment. Differing perceptions arose as students debated whether or not reporting was beneficial to the clinical learning environment., Conclusions: Multiple complex factors deeply rooted in the culture of medicine, along with negative connotations associated with reporting, prevent students from reporting incidents of mistreatment. Further research is needed to establish interventions that will help identify mistreatment and change the underlying culture.

Background: Pulmonary alveolar proteinosis (PAP) is a rare disease of unknown origin, characterized by impaired surfactant metabolism. In some patients, residual disease is observed after treatment; notably, this may progress to end-stage pulmonary fibrosis. This study was performed to evaluate changes in lung abnormalities on serial CT scans performed on the lungs of patients diagnosed with PAP, as well as to identify factors that can be used to predict clinical improvement in PAP., Methods: Twenty-five patients (16 men, nine women) were diagnosed with PAP at a single tertiary hospital. The extent and distribution of PAP were assessed on baseline and follow-up CT scans (median, 38 months; range, 2-96 months). Serial CT scans and clinical findings were analyzed to identify the predictive factors for clinical improvement in PAP., Results: Baseline CT scans of patients diagnosed with PAP revealed that ground-glass opacity was the most common abnormality (100%); the second most common abnormality was interlobular/intralobular septal thickening (88%). Importantly, the final follow-up CT scans showed that the extent of lung abnormalities had decreased (n=13), including complete resolution (n=5), unchanged (n=9), and increased (n=3). Traction bronchiectasis and architectural distortion were detected in two patients (8%). On univariate and multivariate analyses, the change in the overall extent of lung abnormalities was a predictive factor for clinical improvement in PAP (odds ratio: 55.780; P=0.038)., Conclusions: Most patients with PAP exhibited residual disease; however, progression to pulmonary fibrosis was rare. Analyses of overall changes, with respect to lung abnormalities on serial CT scans, may be predictive of the extent of clinical improvement in given patient., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Introduction: The aim of this study was to determine the prevalence of C-shaped canal configurations (CSs) and radicular grooves (RGs) in permanent mandibular first premolars (MPs) and to investigate the relevance of such complexities with the presence of distolingual roots (DLRs) in permanent mandibular first molars (MMs)., Methods: A total of 800 pairs of MPs and MMs were investigated using a cone-beam computed tomographic system (NewTom 5G; QR srl, Verona, Italy). The frequency and symmetry of DLRs in MMs along with the occurrence of RGs and CSs in examined MPs were evaluated. Multivariable logistic regression analysis was applied to examine the correlation between the CSs of MPs with the appearance of DLRs in MMs., Results: In the examined teeth, 23.0% of MMs had a DLR, whereas 16.6% of MPs had RGs and 12.5% of MPs had C-shaped canals. Although the most common canal configuration in MPs is the single canal (74.1%), the other 25.9% still possess complicated root canals. Of these MPs that have different canal configurations, 54.6% had 2 canals, whereas 44.4% had CSs. Specifically, the CS showed a high prevalence of C3 morphologies at 98.9% followed by C1 at 1.1%. A corresponding and increasing frequency was noted in CSs and RGs of MPs and MMs with DLRs (P < .001). After adjusting for related categoric variables, the adjusted odds ratios for CSs of MPs in the bilateral DLR group compared with the non-DLR group was 3.294 (P < .001)., Conclusions: This study showed an increased appearance of CSs in MPs when DLRs were present in MMs in the Taiwanese population., (Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Background/purpose: Presence of pulp stones increase the difficulty of locating canal orifice during endodontic treatment. This study aims to determine the prevalence of pulp stones in a northern Taiwanese population through analysis of cone beam computed tomography (CBCT)., Materials and Methods: A total of 144 patients and 2554 teeth were used in the present study which were collected from a CBCT image archive. To determine the presence of pulp stones, images of pulp chamber and root canals were analyzed in the sagittal, axial and coronal planes and from the occlusal to apical direction. Correlations between pulp stones and gender, age, tooth type, dental arch or side were also examined., Results: Of the 144 patients, 120 patients (83.3%) and 800 (31.3%) teeth were found to have one or more pulp stones through CBCT examination. Prevalence of pulp stones between dental arches and tooth types were significantly different ( P  < 0.001). Pulp stones were found to be the most prevalent in first molars (50.0%) and most scarce in first premolars (18.8%). There was no significant correlation between pulp stones and gender, increasing age, or dental sides., Conclusion: Pulp stones are more frequent in maxillary teeth compared to mandibular teeth. Pulp stones in molar teeth were significantly more common than premolars and incisors. CBCT could be a sensitive tool to detect pulp stones, especially simplifying identification of pulp stones in radicular pulp. Knowledge of pulp stones distribution can aid dentists in clinical endodontic treatment.

Introduction: The aim of this study was to assess the prevalence of complicated root canals in permanent mandibular central incisors (PMCIs) and its correlation with the presence of a distolingual root (DLR) in permanent mandibular first molars (PMFMs) using cone-beam computed tomographic imaging in a Taiwanese population., Methods: A total of 400 patients (800 pairs of PMCIs and PMFMs) were qualified for further analysis. The prevalence of DLRs in PMFMs along with root canal configurations of PMCIs were assessed at subject and tooth levels. Multivariable logistic regression analysis was used to evaluate the correlation between the root canal configurations of PMCIs with the existence of DLRs in PMFMs., Results: The prevalence of PMFMs with DLRs and complicated root canal configurations in PMCIs was 23.0% and 15.6%, respectively. A significant difference in age (<50 years vs ≥50 years) was found for complicated root canal configurations in PMCIs. The most prevalent root canal system in PMCIs was Vertucci type I (84.4%) followed by type III (13.5%). A positive correlation between the presence of DLRs in PMFMs and complicated root canal configurations in PMCIs was noted. After adjusting for categoric variables including sex, age, and side, the odds ratios for the occurrence of complicated root canal configurations of PMCIs in the unilateral DLR group and the bilateral DLR group compared with the non-DLR group were 2.13 and 2.53, respectively., Conclusions: The concurrent appearance of DLRs in PMFMs and complicated root canal morphology in PMCIs is prominent in Taiwanese individuals., (Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Pleuroparenchymal fibroelastosis (PPFE) is classified as a rare idiopathic interstitial pneumonia, and its clinicopathologic features remain unclear. We sought to investigate the clinical, radiologic, and pathologic features of patients with histologically proven PPFE., Methods: Seven patients who had histologic features of PPFE that were definitive or consistent with PPFE were included. Clinical data and radiologic findings of chest computed tomography were obtained. Histologic evaluation was performed by 2 pathologists., Results: Four patients had elevated serum autoantibodies, 3 had a history of organ transplantation, and 1 had acute Aspergillus infection. All patients had various degrees of restrictive patterns on pulmonary function tests. Histologic examination revealed a variable extent of PPFE. Fibroblastic foci, patchy lymphocytic infiltration, and pneumothorax were observed, but these findings were nonspecific. Radiologically, PPFE lesions were distributed diffusely, rather than being limited to the upper lungs., Conclusions: PPFE seems to be a histologic finding that may partly overlap with other chronic lung diseases. There can be various underlying clinical states., (© 2017 John Wiley & Sons Ltd.)