Antisynthetase syndrome-related interstitial lung disease (ASyS-ILD): longitudinal imaging findings.

OBJECTIVES: Interstitial lung disease (ILD) impacts mortality in antisynthetase syndrome (ASyS). Computed tomographic (CT) patterns and evolution in ASyS ILD are not well described. We report longitudinal CT patterns in ASyS-ILD and their impact on survival. METHODS: This is a monocentric retrospective study of 47 patients with ASyS-ILD. Longitudinal CT patterns and fibrosis severity (severity of radiographic features indicating fibrosis) were analyzed by two radiologists in consensus. The association between imaging features and survival was examined using univariate Cox regression analysis. RESULTS: In total, 211 CT scans were analyzed with an average of 4 ± 2 CT scans/patient with a median follow-up of 79 months in 47 patients. Non-fibrotic patterns were present initially in 63.8% (n = 30) of patients, while fibrotic patterns occurred in 36.2% (n = 17). The initial non-fibrotic patterns/abnormalities resolved in 23.3% (n = 7), evolved in 6.7% (n = 2), persisted in 13.3% (n = 4), and progressed in 56.7% (n = 17), while initial fibrotic patterns persisted in 82.4% (n = 14) and progressed in 17.6% (n = 3). Radiographic progression of ILD (progression in CT pattern or increased fibrosis severity) occurred in 53.2% (n = 25) of patients. Advanced age and radiographic progression were associated with decreased survival (all p < 0.05). The presence of ground-glass opacities (GGO) and predominant lower lung distribution of abnormalities on initial CTs were associated with increased survival (all p < 0.05). CONCLUSION: Progression occurred in 56.7% of ASyS-ILD patients presenting with non-fibrotic patterns. Fibrotic patterns tended to persist. Age and radiographic progression were associated with reduced survival while the initial presence of GGO and predominant lower lobe distribution were associated with increased survival. KEY POINTS: • In ASyS-ILD, initial non-fibrotic patterns such as OP, cNSIP, or OP-cNSIP tended to progress to fNSIP. • Fibrotic patterns such as fNSIP or UIP in ASyS-ILD tended to persist without pattern changes. • GGO and lower lung predominance on initial CT were associated with better survival while advanced baseline age and radiographic ILD progression during follow-up were associated with decreased survival.

Pharmacological read-through of R294X Mecp2 in a novel mouse model of Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). More than 35% of affected individuals have nonsense mutations in MECP2. For these individuals, nonsense suppression has been suggested as a possible therapeutic approach. To assess the viability of this strategy, we created and characterized a mouse model with the common p.R294X mutation introduced into the endogenous Mecp2 locus (Mecp2R294X). Mecp2R294X mice exhibit phenotypic abnormalities similar to those seen in complete null mouse models; however, these occur at a later time point consistent with the reduced phenotypic severity seen in affected individuals containing this specific mutation. The delayed onset of severe phenotypes is likely due to the presence of truncated MeCP2 in Mecp2R294X mice. Supplying the MECP2 transgene in Mecp2R294X mice rescued phenotypic abnormalities including early death and demonstrated that the presence of truncated MeCP2 in these mice does not interfere with wild-type MeCP2. In vitro treatment of a cell line derived from Mecp2R294X mice with the nonsense suppression agent G418 resulted in full-length MeCP2 protein production, demonstrating feasibility of this therapeutic approach. Intraperitoneal administration of G418 in Mecp2R294X mice was sufficient to elicit full-length MeCP2 protein expression in peripheral tissues. Finally, intracranial ventricular injection of G418 in Mecp2R294X mice induced expression of full-length MeCP2 protein in the mouse brain. These experiments demonstrate that translational read-through drugs are able to suppress the Mecp2 p.R294X mutation in vivo and provide a proof of concept for future preclinical studies of nonsense suppression agents in RTT.

R-scale for pulmonary fibrosis: a simple, visual tool for the assessment of health-related quality of life.

RATIONALE: Patients with idiopathic pulmonary fibrosis (IPF) experience impaired health-related quality of life (HRQoL). Several tools have been developed to objectively assess HRQoL in this patient population, but none are in use in routine clinical practice. OBJECTIVES: To develop a rapid, specific tool that can be used for patients with IPF during routine clinic visits. METHODS: A novel and simple five-item numerical rating scale was developed and compared with two other previously validated tools. 100 consecutive patients with IPF managed at a centre for interstitial lung disease were recruited to complete the Raghu scale for pulmonary fibrosis (R-Scale-PF), King's Brief Interstitial Lung Disease questionnaire (K-BILD), and the EuroQol Five-Dimensional Five-Level questionnaire (EQ-5D-5L) in addition to pulmonary function and 6-min walk tests. MEASUREMENTS AND MAIN RESULTS: All 100 patients successfully completed the three HRQoL tools with 53 completing them again at follow-up visits. Internal consistency was high (Cronbach's α 0.825) with minimal floor/ceiling effect. Concurrent validity of the R-Scale-PF was moderate to high compared with the K-BILD (r=-0.713) and the EQ-5D-5L (r=-0.665). Concurrent validity was moderate with physiologic measures (forced vital capacity, r=-0.307, 6-min walking distance, r=-0.383). The R-Scale-PF demonstrated good known-groups validity when comparing scores across stages of disease severity. CONCLUSIONS: The R-Scale-PF correlates well with the K-BILD and EQ-5D-5L. It is hoped that this novel simple numerical rating scale tool, subject to validation in patients from other centres, will provide an opportunity to objectively measure HRQoL in routine clinical practice for patients with IPF.

Diagnosis of Hypersensitivity Pneumonitis in Adults. An Official ATS/JRS/ALAT Clinical Practice Guideline.

Background: This guideline addresses the diagnosis of hypersensitivity pneumonitis (HP). It represents a collaborative effort among the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax.Methods: Systematic reviews were performed for six questions. The evidence was discussed, and then recommendations were formulated by a multidisciplinary committee of experts in the field of interstitial lung disease and HP using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.Results: The guideline committee defined HP, and clinical, radiographic, and pathological features were described. HP was classified into nonfibrotic and fibrotic phenotypes. There was limited evidence that was directly applicable to all questions. The need for a thorough history and a validated questionnaire to identify potential exposures was agreed on. Serum IgG testing against potential antigens associated with HP was suggested to identify potential exposures. For patients with nonfibrotic HP, a recommendation was made in favor of obtaining bronchoalveolar lavage (BAL) fluid for lymphocyte cellular analysis, and suggestions for transbronchial lung biopsy and surgical lung biopsy were also made. For patients with fibrotic HP, suggestions were made in favor of obtaining BAL for lymphocyte cellular analysis, transbronchial lung cryobiopsy, and surgical lung biopsy. Diagnostic criteria were established, and a diagnostic algorithm was created by expert consensus. Knowledge gaps were identified as future research directions.Conclusions: The guideline committee developed a systematic approach to the diagnosis of HP. The approach should be reevaluated as new evidence accumulates.

Systemic sclerosis-associated interstitial lung disease.

PURPOSE OF REVIEW: In this review, the authors discuss systemic sclerosis-associated interstitial lung disease (SSc-ILD) with a focus on recent developments in diagnosis, surveillance, and management. RECENT FINDINGS: With advances in the management of SSc, the importance of ILD has been increasingly recognized and is the leading cause of mortality. Early detection is essential, and a combination of lung function testing and chest imaging are key tools in diagnosis and surveillance. The foundation of treatment is immunomodulation with recent studies identifying several potential new agents. The use of therapies targeting pro-fibrotic pathways have demonstrated significant effects on lung function decline and represent the latest advance in therapy for SSc-ILD. SUMMARY: Recent studies support the use of newer therapies in SSc-ILD including antifibrotic agents. The identification and management of comorbidities is important, and lung transplantation is a viable option for patients with advanced disease.

Broad domains of histone 3 lysine 4 trimethylation are associated with transcriptional activation in CA1 neurons of the hippocampus during memory formation.

Transcriptional changes in the hippocampus are required for memory formation, and these changes are regulated by numerous post-translational modifications of chromatin-associated proteins. One of the epigenetic marks that has been implicated in memory formation is histone 3 lysine 4 trimethylation (H3K4me3), and this modification is found at the promoters of actively transcribed genes. The total levels of H3K4me3 are increased in the CA1 region of the hippocampus during memory formation, and genetic perturbation of the K4 methyltransferases and demethylases interferes with forming memories. Previous chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) analyses failed to detect changes in H3K4me3 levels at the promoters of memory-linked genes. Since the breadth of H3K4me3 marks was recently reported to be associated with the transcriptional outcome of a gene, we re-analyzed H3K4me3 ChIP-seq data sets to identify the role of H3K4me3 broad domains in CA1 neurons, as well as identify differences in breadth that occur during contextual fear conditioning. We found that, under baseline conditions, broad H3K4me3 peaks mark important learning and memory genes and are often regulated by super-enhancers. The peaks at many learning-associated genes become broader during novel environment exposure and memory formation. Furthermore, the important learning- and memory-associated lysine methyltransferases, Kmt2a and Kmt2b, are involved in maintaining H3K4me3 peak width. Our findings highlight the importance of analyzing H3K4me3 peak shape, and demonstrate that breadth of H3K4me3 marks in neurons of the hippocampus is regulated during memory formation.

Circulating Troponin I Level in Patients with Acute Ischemic Stroke.

PURPOSE OF REVIEW: Cardiac troponin levels in the blood are an important biomarker of acute coronary events, but may also be elevated in the context of acute ischemic stroke without an obvious concurrent myocardial insult. The objective of this study and systematic review is to determine how high the circulating troponin I level can rise due to ischemic stroke. RECENT FINDINGS: Anonymized medical records from Vanderbilt University Medical Center were reviewed identifying 151,972 unique acute ischemic stroke events, of which 1226 met criteria for inclusion in this study. Included patients had at least one measurement of troponin I level documented during the hospital visit when an acute ischemic stroke was diagnosed and were free of known cardiac/coronary disease, renal impairment, sepsis, or other confounders. In this group, 20.6% had a circulating troponin I level elevated over the reference range, but 99% were below 2.13 ng/mL. This is significantly lower than the distribution observed in a cohort of 89,423 unique cases of acute coronary syndrome (p < 2.2-16). A systematic review of published literature further supported the conclusion that troponin I level may increase due to an acute ischemic stroke, but rarely rises above 2 ng/mL. Because of the shared risk factors between stroke and coronary artery disease, clinicians caring for patients with acute ischemic stroke should always have a high index of suspicion for comorbid cardiac and cardiovascular disease. In general, troponin I levels greater than 2 ng/mL should not be attributed to an acute ischemic stroke, but should prompt a thorough evaluation for coronary artery disease.

Interstitial Lung Disease in India. Results of a Prospective Registry.

RATIONALE: Interstitial lung disease (ILD) is a heterogeneous group of acute and chronic inflammatory and fibrotic lung diseases. Existing ILD registries have had variable findings. Little is known about the clinical profile of ILDs in India. OBJECTIVES: To characterize new-onset ILDs in India by creating a prospective ILD using multidisciplinary discussion (MDD) to validate diagnoses. METHODS: Adult patients of Indian origin living in India with new-onset ILD (27 centers, 19 Indian cities, March 2012-June 2015) without malignancy or infection were included. All had connective tissue disease (CTD) serologies, spirometry, and high-resolution computed tomography chest. ILD pattern was defined by high-resolution computed tomography images. Three groups independently made diagnoses after review of clinical data including that from prompted case report forms: local site investigators, ILD experts at the National Data Coordinating Center (NDCC; Jaipur, India) with MDD, and experienced ILD experts at the Center for ILD (CILD; Seattle, WA) with MDD. Cohen's κ was used to assess reliability of interobserver agreement. MEASUREMENTS AND MAIN RESULTS: A total of 1,084 patients were recruited. Final diagnosis: hypersensitivity pneumonitis in 47.3% (n = 513; exposure, 48.1% air coolers), CTD-ILD in 13.9%, and idiopathic pulmonary fibrosis in 13.7%. Cohen's κ: 0.351 site investigator/CILD, 0.519 site investigator/NDCC, and 0.618 NDCC/CILD. CONCLUSIONS: Hypersensitivity pneumonitis was the most common new-onset ILD in India, followed by CTD-ILD and idiopathic pulmonary fibrosis; diagnoses varied between site investigators and CILD experts, emphasizing the value of MDD in ILD diagnosis. Prompted case report forms including environmental exposures in prospective registries will likely provide further insight into the etiology and management of ILD worldwide.

Laparoscopic anti-reflux surgery for idiopathic pulmonary fibrosis at a single centre.

We sought to assess whether laparoscopic anti-reflux surgery (LARS) is associated with decreased rates of disease progression in patients with idiopathic pulmonary fibrosis (IPF).The study was a retrospective single-centre study of IPF patients with worsening symptoms and pulmonary function despite antacid treatment for abnormal acid gastro-oesophageal reflux. The period of exposure to LARS was September 1998 to December 2012. The primary end-point was a longitudinal change in forced vital capacity (FVC) % predicted in the pre- versus post-surgery periods.27 patients with progressive IPF underwent LARS. At time of surgery, the mean age was 65 years and mean FVC was 71.7% pred. Using a regression model, the estimated benefit of surgery in FVC % pred over 1 year was 5.7% (95% CI -0.9-12.2%, p=0.088) with estimated benefit in FVC of 0.22 L (95% CI -0.06-0.49 L, p=0.12). Mean DeMeester scores decreased from 42 to 4 (p<0.01). There were no deaths in the 90 days following surgery and 81.5% of participants were alive 2 years after surgery.Patients with IPF tolerated the LARS well. There were no statistically significant differences in rates of FVC decline pre- and post-LARS over 1 year; a possible trend toward stabilisation in observed FVC warrants prospective studies. The ongoing prospective randomised controlled trial will hopefully provide further insights regarding the safety and potential efficacy of LARS in IPF.

Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage.

Rett syndrome (RTT) is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in the gene Methyl-CpG-binding protein 2 (MECP2), which encodes the MeCP2 protein. RTT is a MECP2-related disorder, along with MECP2 duplication syndrome (MDS), caused by gain-of-function duplications of MECP2. Nearly two decades of research have advanced our knowledge of MeCP2 function in health and disease. The following review will discuss MeCP2 protein function and its dysregulation in the MECP2-related disorders RTT and MDS. This will include a discussion of the genetic underpinnings of these disorders, specifically how sporadic X-chromosome mutations arise and manifest in specific populations. We will then review current diagnostic guidelines and clinical manifestations of RTT and MDS. Next, we will delve into MeCP2 biology, describing the dual landscapes of methylated DNA and its reader MeCP2 across the neuronal genome as well as the function of MeCP2 as a transcriptional modulator. Following this, we will outline common MECP2 mutations and genotype-phenotype correlations in both diseases, with particular focus on mutations associated with relatively mild disease in RTT. We will also summarize decades of disease modeling and resulting molecular, synaptic, and behavioral phenotypes associated with RTT and MDS. Finally, we list several therapeutics in the development pipeline for RTT and MDS and available evidence of their safety and efficacy.

Safety and efficacy of genetic MECP2 supplementation in the R294X mouse model of Rett syndrome.

Rett syndrome is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in MECP2, encoding transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Although no disease-modifying therapies exist at this time, some proposed therapeutic strategies aim to supplement the mutant allele with a wild-type allele producing typical levels of functional MeCP2, such as gene therapy. Because MECP2 is a dosage-sensitive gene, with both loss and gain of function causing disease, these approaches must achieve a narrow therapeutic window to be both safe and effective. While MeCP2 supplementation rescues RTT-like phenotypes in mouse models, the tolerable threshold of MeCP2 is not clear, particularly for partial loss-of-function mutations. We assessed the safety of genetically supplementing full-length human MeCP2 in the context of the R294X allele, a common partial loss-of-function mutation retaining DNA-binding capacity. We assessed the potential for adverse effects from MeCP2 supplementation of a partial loss-of-function mutant and the potential for dominant negative interactions between mutant and full-length MeCP2. In male hemizygous R294X mice, MeCP2 supplementation rescued RTT-like behavioral phenotypes and did not elicit behavioral evidence of excess MeCP2. In female heterozygous R294X mice, RTT-specific phenotypes were similarly rescued. However, MeCP2 supplementation led to evidence of excess MeCP2 activity in a motor coordination assay, suggesting that the underlying motor circuitry is particularly sensitive to MeCP2 dosage in females. These results show that genetic supplementation of full-length MeCP2 is safe in males and largely so females. However, careful consideration of risk for adverse motor effects may be warranted for girls and women with RTT.

Diagnosis and Management of Fibrotic Interstitial Lung Diseases.

Nonidiopathic pulmonary fibrosis (non-IPF) progressive fibrotic interstitial lung diseases (PF-ILDs) are a heterogeneous group of ILDs, often challenging to diagnose, although an accurate diagnosis has significant implications for both treatment and prognosis. A subgroup of these patients experiences progressive deterioration in lung function, physical performance, and quality of life after conventional therapy. Risk factors for ILD progression include older age, lower baseline pulmonary function, and a usual interstitial pneumonia pattern. Management of non-IPF P-ILD is both pharmacologic and nonpharmacologic. Antifibrotic drugs, originally approved for IPF, have been considered in patients with other fibrotic ILD subtypes, with favorable results in clinical trials.