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

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

Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial.

BACKGROUND: DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. METHODS: Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). FINDINGS: Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. INTERPRETATION: Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. FUNDING: Daiichi Sankyo and AstraZeneca.

A mouse model of progressive lung fibrosis with cutaneous involvement induced by a combination of oropharyngeal and osmotic minipump bleomycin delivery.

Systemic sclerosis (SSc) with interstitial lung disease (SSc-ILD) lacks curative pharmacological treatments, thus necessitating effective animal models for candidate drug discovery. Existing bleomycin (BLM)-induced SSc-ILD mouse models feature spatially limited pulmonary fibrosis, spontaneously resolving after 28 days. Here, we present an alternative BLM administration approach in female C57BL/6 mice, combining oropharyngeal aspiration (OA) and subcutaneous mini-pump delivery (pump) of BLM to induce a sustained and more persistent fibrosis, while retaining stable skin fibrosis. A dose-finding study was performed with BLM administered as 10 µg (OA) +80 mg/kg (pump) (10 + 80), 10 + 100, and 15 + 100. Forty-two days after OA, micro-computed tomography (micro-CT) imaging and histomorphometric analyses showed that the 10 + 100 and 15 + 100 treatments induced significant alterations in lung micro-CT-derived readouts, Ashcroft score, and more severe fibrosis grades compared with saline controls. In addition, a marked reduction in hypodermal thickness was observed in the 15 + 100 group. A time-course characterization of the BLM 15 + 100 treatment at days 28, 35, and 42, including longitudinal micro-CT imaging, revealed progressing alterations in lung parameters. Lung histology highlighted a sustained fibrosis accompanied by a reduction in hypodermis thickness throughout the explored time-window, with a time-dependent increase in fibrotic biomarkers detected by immunofluorescence analysis. BLM-induced alterations were partly mitigated by Nintedanib treatment. Our optimized BLM delivery approach leads to extensive and persistent lung fibrotic lesions coupled with cutaneous fibrotic alterations: it thus represents a significant advance compared with current preclinical models of BLM-induced SSc-ILD.NEW & NOTEWORTHY This study introduces an innovative approach to enhance the overall performance of the mouse bleomycin (BLM)-induced model for systemic sclerosis with interstitial lung disease (SSc-ILD). By combining oropharyngeal aspiration and subcutaneous mini-pump delivery of BLM, our improved model leads to sustained lung fibrosis and stable skin fibrosis in female C57BL/6 mice. The optimized 15 + 100 treatment results in extensive and persistent lung fibrotic lesions and thus represents a significant improvement over existing preclinical models of BLM-induced SSc-ILD.

New therapies in anti-MDA5 antibody-positive dermatomyositis.

PURPOSE OF REVIEW: This review focuses on treatments for anti-MDA5 antibody-positive dermatomyositis (MDA5-DM), which is a subgroup of dermatomyositis and characterized by frequent rapidly progressive interstitial lung disease and the high mortality rate. Despite conventional immunosuppressive therapies, there are still refractory cases. Newer treatment options are needed. RECENT FINDINGS: The triple combination therapy (high-dose glucocorticoids, calcineurin inhibitor, and intravenous cyclophosphamide) improved patient survival compared to high-dose glucocorticoids and step-wise addition of the immunosuppressants. The triple therapy now has been widely used, but there are still refractory cases. In addition to the conventional-type immunosuppressants, recently the efficacy of Janus kinase inhibitors, biologic agents such as rituximab, plasma exchange, and polymyxin B perfusion for refractory MDA5-DM patients have been reported. However, the majority of those reports regarding new treatments are limited to case series, retrospective studies, and small single-arm studies. Adding antifibrotic drugs to immunosuppressive therapies might have some ancillary benefits. SUMMARY: Several new therapies for MDA5-DM patients have emerged, although the optimal use of those therapies is still unknown. Further research and evidence accumulation will be needed. It is also noted that the intensive immunosuppressive therapies are associated with the higher infection risk.

Updates on interstitial lung disease and other selected extra-articular manifestations of rheumatoid arthritis.

PURPOSE OF REVIEW: To discuss changes in epidemiology, recent advances in understanding of the pathogenesis and management of selected extraarticular manifestations of rheumatoid arthritis (ExRA). RECENT FINDINGS: The incidence of ExRA overall and subcutaneous rheumatoid nodules in particular is declining after 2000. These trends reflect improved RA disease activity with early effective immunosuppressive treatments; changing environmental risk factors can be contributing. ExRA continues to carry a two-fold increased mortality risk. RA-associated interstitial lung disease (RA-ILD) is a major contributor to mortality, with no decline in incidence and scant therapeutic options. Individualized risk stratification for RA-ILD based on patient-level risk factors and biomarker profile is evolving with MUC5B as a major genetic risk factor. Clinical trials are underway to evaluate the benefits of novel antifibrotic therapies and targeted therapies for RA-ILD. The risk of cardiovascular disease in RA is generally amendable to treatment with disease-modifying antirheumatic drugs, although cardiovascular risk associated with JAK inhibition is not fully understood. SUMMARY: Despite reduction in incidence of ExRA overall, the incidence of RA-ILD shows no significant decline and remains a major therapeutic challenge. The use of novel antifibrotics and immunosuppressive drugs shows promise in slowing the progression of RA-ILD.

Survival analysis from the INCREASE study in PH-ILD: evaluating the impact of treatment crossover on overall mortality.

OBJECTIVE: A post-hoc analysis of the INCREASE trial and its open-label extension (OLE) was performed to evaluate whether inhaled treprostinil has a long-term survival benefit in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD). METHODS: Two different models of survival were employed; the inverse probability of censoring weighting (IPCW) and the rank-preserving structural failure time (RPSFT) models both allow construction of a pseudo-placebo group, thereby allowing for long-term survival evaluation of patients with PH-ILD receiving inhaled treprostinil. Time-varying stabilised weights were calculated by fitting Cox proportional hazards models based on the baseline and time-varying prognostic factors to generate weighted Cox regression models with associated adjusted HRs. RESULTS: In the INCREASE trial, there were 10 and 12 deaths in the inhaled treprostinil and placebo arms, respectively, during the 16-week randomised trial. During the OLE, all patients received inhaled treprostinil and there were 29 and 33 deaths in the prior inhaled treprostinil arm and prior placebo arm, respectively. With a conventional analysis, the HR for death was 0.71 (95% CI 0.46 to 1.10; p=0.1227). Both models demonstrated significant reductions in death associated with inhaled treprostinil treatment with HRs of 0.62 (95% CI 0.39 to 0.99; p=0.0483) and 0.26 (95% CI 0.07 to 0.98; p=0.0473) for the IPCW and RPSFT methods, respectively. CONCLUSION: Two independent modelling techniques that have been employed in the oncology literature both suggest a long-term survival benefit associated with inhaled treprostinil treatment in patients with PH-ILD.

Effects of nintedanib on symptoms in patients with progressive pulmonary fibrosis.

BACKGROUND: Dyspnoea and cough can have a profound impact on the lives of patients with pulmonary fibrosis. We investigated the effects of nintedanib on the symptoms and impact of pulmonary fibrosis in patients with progressive pulmonary fibrosis (PPF) in the INBUILD trial using the Living with Pulmonary Fibrosis (L-PF) questionnaire. METHODS: Patients had a fibrosing interstitial lung disease (ILD) (other than idiopathic pulmonary fibrosis) of >10% extent on high-resolution computed tomography (HRCT) and met criteria for ILD progression within the prior 24 months. Patients were randomised 1:1 to receive nintedanib or placebo. Changes in L-PF questionnaire scores from baseline to week 52 were assessed using mixed models for repeated measures. RESULTS: In total, 663 patients were treated. Compared with placebo, there were significantly smaller increases (worsenings) in adjusted mean L-PF questionnaire total (0.5 versus 5.1), symptoms (1.3 versus 5.3), dyspnoea (4.3 versus 7.8) and fatigue (0.7 versus 4.0) scores in the nintedanib group at week 52. L-PF questionnaire cough score decreased in the nintedanib group and increased in the placebo group (-1.8 versus 4.3). L-PF questionnaire impacts score decreased slightly in the nintedanib group and increased in the placebo group (-0.2 versus 4.6). Similar findings were observed in patients with a usual interstitial pneumonia-like fibrotic pattern on HRCT and in patients with other fibrotic patterns on HRCT. CONCLUSION: Based on changes in L-PF questionnaire scores, nintedanib reduced worsening of dyspnoea, fatigue and cough and the impacts of ILD over 52 weeks in patients with PPF.

Characterization of a mouse-adapted strain of bat severe acute respiratory syndrome-related coronavirus.

Bats carry genetically diverse severe acute respiratory syndrome-related coronaviruses (SARSr-CoVs). Some of them utilize human angiotensin-converting enzyme 2 (hACE2) as a receptor and cannot efficiently replicate in wild-type mice. Our previous study demonstrated that the bat SARSr-CoV rRsSHC014S induces respiratory infection and lung damage in hACE2 transgenic mice but not wild-type mice. In this study, we generated a mouse-adapted strain of rRsSHC014S, which we named SMA1901, by serial passaging of wild-type virus in BALB/c mice. SMA1901 showed increased infectivity in mouse lungs and induced interstitial lung pneumonia in both young and aged mice after intranasal inoculation. Genome sequencing revealed mutations in not only the spike protein but the whole genome, which may be responsible for the enhanced pathogenicity of SMA1901 in wild-type BALB/c mice. SMA1901 induced age-related mortality similar to that observed in SARS and COVID-19. Drug testing using antibodies and antiviral molecules indicated that this mouse-adapted virus strain can be used to test prophylactic and therapeutic drug candidates against SARSr-CoVs. IMPORTANCE The genetic diversity of SARSr-CoVs in wildlife and their potential risk of cross-species infection highlights the importance of developing a powerful animal model to evaluate the antibodies and antiviral drugs. We acquired the mouse-adapted strain of a bat-origin coronavirus named SMA1901 by natural serial passaging of rRsSHC014S in BALB/c mice. The SMA1901 infection caused interstitial pneumonia and inflammatory immune responses in both young and aged BALB/c mice after intranasal inoculation. Our model exhibited age-related mortality similar to SARS and COVID-19. Therefore, our model will be of high value for investigating the pathogenesis of bat SARSr-CoVs and could serve as a prospective test platform for prophylactic and therapeutic candidates.

Resveratrol attenuates inflammation and fibrosis in rheumatoid arthritis-associated interstitial lung disease via the AKT/TMEM175 pathway.

BACKGROUND AND PURPOSE: Interstitial lung disease (ILD) represents a significant complication of rheumatoid arthritis (RA) that lacks effective treatment options. This study aimed to investigate the intrinsic mechanism by which resveratrol attenuates rheumatoid arthritis complicated with interstitial lung disease through the AKT/TMEM175 pathway. METHODS: We established an arthritis model by combining chicken type II collagen and complete Freund's adjuvant. Resveratrol treatment was administered via tube feeding for 10 days. Pathological changes in both the joints and lungs were evaluated using HE and Masson staining techniques. Protein expression of TGF-ß1, AKT, and TMEM175 was examined in lung tissue. MRC-5 cells were stimulated using IL-1ß in combination with TGF-ß1 as an in vitro model of RA-ILD, and agonists of AKT, metabolic inhibitors, and SiRNA of TMEM175 were used to explore the regulation and mechanism of action of resveratrol RA-ILD. RESULTS: Resveratrol mitigates fibrosis in rheumatoid arthritis-associated interstitial lung disease and reduces oxidative stress and inflammation in RA-ILD. Furthermore, resveratrol restored cellular autophagy. When combined with the in vitro model, it was further demonstrated that resveratrol could suppress TGF-ß1 expression, and reduce AKT metamorphic activation, consequently inhibiting the opening of AKT/MEM175 ion channels. This, in turn, lowers lysosomal pH and enhances the fusion of autophagosomes with lysosomes, ultimately ameliorating the progression of RA-ILD. CONCLUSION: In this study, we demonstrated that resveratrol restores autophagic flux through the AKT/MEM175 pathway to attenuate inflammation as well as fibrosis in RA-ILD by combining in vivo and in vitro experiments. It further provides a theoretical basis for the selection of therapeutic targets for RA-ILD.

Effects of nintedanib in patients with limited cutaneous systemic sclerosis and interstitial lung disease.

OBJECTIVES: To investigate the course of interstitial lung disease (ILD) and the effects of nintedanib in patients with limited cutaneous systemic sclerosis (lcSSc). METHODS: In the SENSCIS trial, patients with SSc-ILD were randomized to receive nintedanib or placebo. Patients who completed the SENSCIS trial were eligible to enter SENSCIS-ON, in which all patients received open-label nintedanib. RESULTS: Among 277 patients with lcSSc treated in the SENSCIS trial, the rate (s.e.) of decline in forced vital capacity (FVC; ml/year) over 52 weeks was -74.5 (19.2) in the placebo group and -49.1 (19.8) in the nintedanib group (difference: 25.3 [95% CI -28.9, 79.6]). Among 249 patients with data at week 52, mean (s.e.) change in FVC at week 52 was -86.4 (21.1) ml in the placebo group and -39.1 (22.2) ml in the nintedanib group. Among 183 patients with lcSSc who participated in SENSCIS-ON and had data at week 52, mean (s.e.) change in FVC from baseline to week 52 of SENSCIS-ON was -41.5 (24.0) ml in patients who took placebo in the SENSCIS trial and initiated nintedanib in SENSCIS-ON and -45.1 (19.1) ml in patients who took nintedanib in the SENSCIS trial and continued it in SENSCIS-ON. CONCLUSION: Patients with lcSSc may develop progressive fibrosing ILD. By targeting pulmonary fibrosis, nintedanib slows decline in lung function in patients with lcSSc and ILD. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT02597933 and NCT03313180.

Group 3 Pulmonary Hypertension: From Bench to Bedside.

Pulmonary hypertension (PH) because of chronic lung disease is categorized as Group 3 PH in the most recent classification system. Prevalence of these diseases is increasing over time, creating a growing need for effective therapeutic options. Recent approval of the first pulmonary arterial hypertension therapy for the treatment of Group 3 PH related to interstitial lung disease represents an encouraging advancement. This review focuses on molecular mechanisms contributing to pulmonary vasculopathy in chronic hypoxia, the pathology and epidemiology of Group 3 PH, the right ventricular dysfunction observed in this population and clinical trial data that inform the use of pulmonary vasodilators in Group 3 PH.

Lymphoid interstitial pneumonia in a patient with systemic lupus erythematosus: Case report and literature review.

Lymphoid interstitial pneumonia (LIP) is a rare form of interstitial pulmonary disease, which has been described in association with a wide range of autoimmune disorders. Although the association of this entity with Sjogren's syndrome is well known, only a few cases are reported in relation to systemic lupus erythematosus (SLE). The aim of this paper is to review the cases reported in literature to date, as well as to describe the characteristics of these patients including the new case presented herein. We will be focusing on the case of a 36-year-old female patient diagnosed with SLE on hydroxychloroquine treatment who develops pleuritic chest pain and progressive dyspnea after 3 years of follow-up. The chest CT scan showed pleural thickening and both multiple and bilateral micronodules. A lung biopsy was also performed, revealing an infiltration of lymphocytes, plasma cells, and histiocytes in the alveolar septa suggestive of LIP. After conducting a review of the literature, we identified seven other cases describing SLE in association with LIP. The majority of them were young women, and LIP tends to appear early in the course of the disease, even as a form of initial presentation in some cases. Symptoms included cough, dyspnea, and pleuritic pain, with the exception of one case which was asymptomatic. It is noteworthy that half of the patients were positive for anti-SSA/anti-SSB autoantibodies, and some of them also met criteria for Sjogren's syndrome. Treatment with steroids and other immunosuppressive agents improved symptoms in all of them.

A validation of register-derived diagnoses of interstitial lung disease in patients with inflammatory arthritis: data from the NOR-DMARD study.

OBJECTIVE: There is a lack of knowledge concerning the validity of the interstitial lung disease (ILD) diagnoses used in epidemiological studies on rheumatic diseases. This paper seeks to verify register-derived ILD diagnoses using chest computed tomography (CT) and medical records as a gold standard. METHOD: The Norwegian Anti-Rheumatic Drug Register (NOR-DMARD) is a multicentre prospective observational study of patients with inflammatory arthritis who start treatment with disease-modifying anti-rheumatic drugs. NOR-DMARD is linked to the Norwegian Patient Registry (NPR) and Cause of Death Registry. We searched registers for ILD coded by ICD-10 J84 or J99 among patients with rheumatoid arthritis, psoriatic arthritis, or spondyloarthritis. We extracted chest CT reports and medical records from participating hospitals. Two expert thoracic radiologists scored examinations to confirm the ILD diagnosis. We also searched medical records to find justifications for the diagnosis following multidisciplinary evaluations. We calculated the positive predictive values (PPVs) for ILD across subsets. RESULTS: We identified 71 cases with an ILD diagnosis. CT examinations were available in 65/71 patients (91.5%), of whom ILD was confirmed on CT in 29/65 (44.6%). In a further 10 patients, medical records confirmed the diagnosis, giving a total of 39/71 verified cases. The PPV of a register-derived ILD diagnosis was thus 54.9%. In a subset of patients who had received an ILD code at two or more time-points and had a CT scan taken within a relevant period, the PPV was 72.2%. CONCLUSION: The validity of register-based diagnoses of ILD must be carefully considered in epidemiological studies.

Comparing the safety and efficacy of nintedanib starting dose in patients with connective tissue disease-associated interstitial lung diseases.

OBJECTIVE: This study aimed to analyse whether initiating nintedanib treatment at a reduced dose could improve the treatment continuation rate while maintaining efficacy in patients with connective tissue disease (CTD)-associated interstitial lung disease. METHOD: In total, 51 patients (age 61.6 ± 13.2 years; 38 women, 13 men) were retrospectively analysed. The primary endpoint was the cumulative discontinuation rate due to adverse events. Secondary endpoints included changes in drug dosage, efficacy evaluated based on annual changes in forced vital capacity (FVC), and safety assessed based on the frequency of adverse events. RESULTS: Eighteen patients who started treatment at the standard dose of 300 mg (standard dosage group) were compared with 33 patients who started treatment at a reduced dose (reduced dosage group). Systemic sclerosis was the most common CTD (n = 32), followed by idiopathic inflammatory myopathies and, rarely, rheumatoid arthritis. Both groups exhibited comparable cumulative discontinuation rates due to adverse events and similar frequencies of adverse events. No significant differences were observed in maintenance doses between the two groups; however, patients in the reduced dosage group had a lower cumulative dose for up to 52 weeks than those in the standard dosage group. No significant differences were observed in changes in FVC between the two groups. CONCLUSION: There was no evidence for a difference between the two groups in terms of discontinuation rates, efficacy, and safety. To provide further evidence, future studies using more precise dose-escalation protocols are warranted.

Clinical features of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with macrophage activation syndrome.

OBJECTIVES: This study aimed to describe the clinical features of patients with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatomyositis (DM) who had macrophage activation syndrome (MAS). METHODS: We retrospectively examined 44 patients with anti-MDA5-positive DM and compared the clinical features between patients with MAS (n = 11) and those without (n=33). Patients without MAS were selected randomly in the same year as those with MAS at a ratio of 3:1. Among patients with MAS, we compared the features between non-survivors and survivors. We used Fisher's exact test, Student's t test, the Mann-Whitney U test and the log-rank test for statistical analysis. RESULTS: Patients complicated with MAS had a significantly higher incidence of infection, heliotrope sign, Gottron's papule, V-neck sign, and higher serum levels of ferritin, aspartate aminotransferase (AST), lactic dehydrogenase (LDH), and creatine kinase (CK) than those without MAS (p<0.05). Among the 11 patients with MAS, 4 (36.4%) died after intensive treatment. Deceased patients were older, given more combination therapy with tofacitinib (TOF) and had a higher incidence of rapid progressive interstitial lung disease, infection, heart failure and renal impairment than those who survived (p<0.05). CONCLUSIONS: Among anti-MDA5-positive DM, Infection, DM typical rashes, and higher serum levels of ferritin, AST, LDH, and CK were more common in patients complicated with MAS. The mortality of patients with MAS was high, particularly among patients who were older, given more combination therapy with TOF, and had RP-ILD, infection, heart failure and renal impairment.

Interstitial lung disease caused by niraparib in ovarian cancer patient: a case report and literature review.

Drug-induced interstitial lung disease (DIILD) is one of the most common and important adverse drug reactions. Still, the details of the clinical presentation of DIILD caused by poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are unknown. A 73-year-old Japanese woman was started on niraparib maintenance therapy after radical surgery and adjuvant chemotherapy for high-grade serous carcinoma originating from the fallopian tube. Forty-seven days after starting niraparib, she presented to the hospital with dyspnea and was diagnosed with DIILD caused by niraparib. The drug was discontinued, and the patient was treated with steroid pulse therapy, and her condition improved. In clinical trials of PARP inhibitors, DIILD was reported in 0.13% of patients with olaparib, but no DIILDs, including pneumonia or pneumonitis, were reported in any patient with niraparib. This is the first report of DIILD caused by niraparib worldwide. In the future, the frequency of DIILD caused by niraparib should be clarified in real-world data.

Overview of Rheumatoid Arthritis-Associated Interstitial Lung Disease and Its Treatment.

Interstitial lung disease (ILD) is a common pulmonary complication of rheumatoid arthritis (RA), causing significant morbidity and mortality. Optimal treatment for RA-ILD is not yet well defined. Reliable prognostic indicators are largely byproducts of prior ILD progression, including low or decreasing forced vital capacity and extensive or worsening fibrosis on imaging. In the absence of validated tools to predict treatment response, decisions about whether to initiate or augment treatment are instead based on clinical judgment. In general, treatment should be initiated in patients who are symptomatic, progressing, or at high risk of poor outcomes. Retrospective data suggest that mycophenolate mofetil, azathioprine, and rituximab are likely effective therapies for RA-ILD. Abatacept is also emerging as a potential first-line treatment option for patients with RA-ILD. Further, recent data demonstrate that immunosuppression may be beneficial even in patients with a usual interstitial pneumonia (UIP) pattern on imaging, suggesting that immunosuppression should be considered irrespective of imaging pattern. Recent randomized controlled trials have shown that antifibrotic medications, such as nintedanib and likely pirfenidone, slow forced vital capacity decline in RA-ILD. Consideration can be given to antifibrotic initiation in patients progressing despite immunosuppression, particularly in patients with a UIP pattern. Future research directions include developing tools to predict which patients will remain stable from patients who will progress, discriminating patients who will respond to treatment from nonresponders, and developing algorithms for starting immunosuppression, antifibrotics, or both as first-line therapies.

Comparison of Effects of Sugammadex and Neostigmine on Postoperative Neuromuscular Blockade Recovery in Patients with Interstitial Lung Diseases Undergoing Transbronchial Cryobiopsy: A Randomized Trial.

BACKGROUND While many studies have been conducted on sugammadex sodium and neostigmine in patients undergoing general anesthesia, few have explored their effects in patients with interstitial lung diseases (ILDs). MATERIAL AND METHODS Sixty-three patients who underwent transbronchial cryobiopsy under general anesthesia were enrolled in a prospective randomized study. The patients were randomly divided into 2 groups: neostigmine combined with atropine group (group C, n=32) and sugammadex group (group S, n=31). Induction and maintenance of anesthesia were the same in both groups. Patients received rocuronium during anesthesia. At the end of the procedure, when the T2 of the train-of-four stimulation technique (TOF) monitoring appeared, neostigmine 0.04 mg/kg combined with atropine 0.02 mg/kg was injected intravenously in group C, and sodium sugammadex 2 mg/kg was injected intravenously in group S. Time from administration of muscle relaxant antagonist to recovery of TOF ratio (TOFr) to 0.9 and extubation time were recorded. The residual rate of neuromuscular blockade at 1, 3, 5, 7, and 10 min after extubation was calculated. RESULTS Compared to group C, group S had a significantly shorter recovery time of TOFr to 0.9 (4.0[2.0] min vs 14.0[11.0] min, P<0.001) and extubation time (4.0[3.0] min vs 11.0[7.0] min, P<0.001). The residual rate of neuromuscular blockade was remarkably lower in group S than in group C at 3, 5, and 7 min after extubation (3.2% vs 31%, 0% vs 25%, 0% vs 6%, P<0.05). CONCLUSIONS Sugammadex is more effective than neostigmine in reversing the muscle-relaxant effect of rocuronium bromide in patients with ILDs.

Pretransplant ribavirin and interferon-α therapy for rhinovirus interstitial pneumonia in a RAG1-deficient infant.

Severe combined immunodeficiency (SCID) is one of the most serious inborn errors of immunity leading to a fatal infection in early infancy. Allogeneic hematopoietic cell transplantation (HCT) or elective gene therapy prior to infection or live-attenuated vaccination is the current standard of curative treatment. Even in the era of newborn screening for SCID, pretransplant control of severe infection is challenging for SCID. Multiple pathogens are often isolated from immunocompromised patients, and limited information is available regarding antiviral strategies to facilitate curative HCT. We herein present a case of successfully controlled pretransplant pneumonia after ribavirin and interferon-α therapy in an infant with RAG1-deficiency. A four-month-old infant presented with severe interstitial pneumonia due to a co-infection of rhinovirus and Pneumocystis jirovecii. The tentative diagnosis of SCID prompted to start antibiotics and trimethoprim-sulfamethoxazole on ventilatory support. Because of the progressive respiratory failure four days after treatment, ribavirin and then pegylated interferon-α were started. He showed a drastic response to the treatment that led to a curative HCT 32 days after admission. This patient received the genetic diagnosis of RAG1-deficiency. Currently, he is an active 3-year-old boy with normal growth and development. The review of literature indicated that rhinovirus had a comparable or rather greater impact on the mortality of pediatric patients than respiratory syncytial virus. Considered the turn-around time to the genetic diagnosis of SCID, prompt ribavirin plus interferon-α therapy may help to control severe rhinovirus pneumonia and led to the early curative HCT for the affected infants.

Progress in the Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease.

Pulmonary hypertension, frequently complicating the course of patients with fibrotic interstitial lung disease, is associated with significantly increased morbidity and mortality. The availability of multiple medications to treat pulmonary arterial hypertension has resulted in these agents being used beyond their original indication, including in patients with interstitial lung disease. Whether pulmonary hypertension in the context of interstitial lung disease is an adaptive response not to be treated or a maladaptive phenomenon amenable to therapy has been uncertain. Although some studies have suggested a benefit of treatment, there have been others demonstrating harm. This concise clinical review provides an overview of prior studies and the issues that have plagued drug development for a patient population in dire need of treatment options. More recently, there has been a paradigm shift, with the largest study to date demonstrating benefit, resulting in the first approved therapy in the United States for patients with interstitial lung disease complicated by pulmonary hypertension. A pragmatic management algorithm in the context of changing definitions, comorbid contributors, and an available treatment option is provided, as are considerations for future clinical trials.