Sonye K. Danoff

Short telomeres are a risk factor for idiopathic pulmonary fibrosis

Idiopathic interstitial pneumonias (IIPs) have a progressive and often fatal course, and their enigmatic etiology has complicated approaches to effective therapies. Idiopathic pulmonary fibrosis (IPF) is the most common of IIPs and shares with IIPs an increased incidence with age and unexplained scarring in the lung. Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components, hTERT and hTR, underlie inheritance in a subset of families with IPF. To examine the hypothesis that short telomeres contribute to disease risk in sporadic IIPs, we recruited patients who have no family history and examined telomere length in leukocytes and in alveolar cells. To screen for mutations, we sequenced hTERT and hTR. We also reviewed the cases for features of a telomere syndrome. IIP patients had shorter leukocyte telomeres than age-matched controls (P < 0.0001). In a subset (10%), IIP patients had telomere lengths below the first percentile for their age. Similar to familial cases with mutations, IPF patients had short telomeres in alveolar epithelial cells (P < 0.0001). Although telomerase mutations were rare, detected in 1 of 100 patients, we identified a cluster of individuals (3%) with IPF and cryptogenic liver cirrhosis, another feature of a telomere syndrome. Short telomeres are thus a signature in IIPs and likely play a role in their age-related onset. The clustering of cryptogenic liver cirrhosis with IPF suggests that the telomere shortening we identify has consequences and can contribute to what appears clinically as idiopathic progressive organ failure in the lung and the liver.

Inositol 1,4,5-trisphosphate receptors : distinct neuronal and nonneuronal forms derived by alternative splicing differ in phosphorylation

We have identified two distinct transcripts of inositol 1,4,5-trisphosphate receptor by using the PCR on first-strand cDNAs from various rat tissues. The longer form, corresponding to the previously cloned adult rat brain inositol 1,4,5-trisphosphate receptor, contains a 120-nucleotide insert between the two cAMP-dependent protein kinase phosphorylation consensus sequences. The shorter form (lacking the insert) predominates in fetal brain and peripheral tissues and appears to represent a nonneuronal receptor, whereas the longer form is found in adult brain and appears to be exclusively neuronal. The phosphorylation kinetics by cAMP-dependent protein kinase and the phosphopeptide maps differ for inositol 1,4,5-trisphosphate receptors purified from tissues predominantly expressing different forms of the transcript.

Interstitial Lung Disease Associated With the Idiopathic Inflammatory Myopathies: What Progress Has Been Made in the Past 35 Years?

Interstitial lung disease is commonly associated with the autoimmune inflammatory myopathies dermatomyositis and polymyositis and accounts for significant morbidity and mortality in these conditions. In the 35 years since the association between inflammatory myopathy and interstitial lung disease was initially described, there has been progress in diagnosing and treating this dis-order. Nevertheless, there remains much about pathogenesis and therapeutics to be learned. This review examines the changes in the understanding of this complex condition, highlighting recent advances and areas deserving of further study.

Thalidomide for the Treatment of Cough in Idiopathic Pulmonary Fibrosis: A Randomized Trial

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder of unknown cause with no effective treatment. Cough affects up to 80% of patients with IPF, is frequently disabling, and lacks effective therapy. OBJECTIVE To determine the efficacy of thalidomide in suppressing cough in patients with IPF. DESIGN 24-week, double-blind, 2-treatment, 2-period crossover trial. (ClinicalTrials.gov registration number: NCT00600028) SETTING 1 university center. PARTICIPANTS 98 participants were screened, 24 were randomly assigned, 23 received treatment (78.3% men; mean age, 67.6 years; mean FVC, 70.4% predicted), and 20 completed both treatment periods. MEASUREMENTS The primary end point was cough-specific quality of life measured by the Cough Quality of Life Questionnaire (CQLQ). Secondary end points were visual analogue scale of cough and the St. Georges Respiratory Questionnaire (SGRQ). For all measures, lower scores equaled improved cough or respiratory quality of life. RESULTS CQLQ scores significantly improved with thalidomide (mean difference vs. placebo, -11.4 [95% CI, -15.7 to -7.0]; P < 0.001). Thalidomide also significantly improved scores on the visual analogue scale of cough (mean difference vs. placebo, -31.2 [CI, -45.2 to -17.2]; P < 0.001). In participants receiving thalidomide, scores from the total SGRQ, SGRQ symptom domain, and SGRQ impact domain improved compared with those of participants receiving placebo. Adverse events were reported in 74% of patients receiving thalidomide and 22% receiving placebo; constipation, dizziness, and malaise were more frequent with thalidomide. LIMITATION This was a single-center study of short duration and small sample size focused on symptom-specific quality of life. CONCLUSION Thalidomide improved cough and respiratory quality of life in patients with IPF. A larger trial is warranted to assess these promising results. PRIMARY FUNDING SOURCE Celgene Corporation.

Anti-melanoma differentiation-associated protein 5-associated dermatomyositis: expanding the clinical spectrum.

Autoantibodies against melanoma differentiation–associated protein 5 (MDA‐5) have been described in several Asian dermatomyositis (DM) cohorts, often associated with amyopathic DM and rapidly progressive interstitial lung disease (ILD). A recent study of a DM cohort seen at a US dermatology clinic reports that MDA‐5 autoantibodies are associated with a unique cutaneous phenotype. Given the widening spectrum of clinical findings, we evaluated the clinical features of anti–MDA‐5–positive patients seen at a US myositis referral center.

Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease

INTRODUCTION Previous studies of interstitial lung disease (ILD) suggest that prognosis and therapeutic response are influenced by the presence of underlying collagen vascular disease (CVD). Yet, what proportion of patients presenting with ILD have CVD is largely unknown. We sought to determine the frequency of a new CVD diagnosis in an ILD referral population. MATERIALS/PATIENTS AND METHODS We retrospectively studied 114 consecutive patients evaluated at the Johns Hopkins Interstitial Lung Disease Clinic for the development of CVD. RESULTS In this retrospective cohort, nearly one-third of the 114 patients with confirmed ILD satisfied published criteria for a CVD diagnosis. Seventeen (15%) patients were diagnosed with a new CVD as a direct consequence of their ILD evaluation. Patients with new CVD diagnosis were younger than those without new CVD diagnosis: 51.4years (95% CI 45-58years) and 60years (95% CI 57-63), respectively (p=0.01). Moreover, an ANA>or=1:640 (p=0.03) and elevated levels of creatine phosphokinase (CPK) or aldolase (p<0.001) were associated with a new CVD diagnosis. CONCLUSIONS Unrecognized collagen vascular disease may be more common than previously appreciated among patients referred with ILD. High titer ANA and an elevated CPK or aldolase are associated with a CVD diagnosis in this referral population.

Association of fine specificity and repertoire expansion of anticitrullinated peptide antibodies with rheumatoid arthritis associated interstitial lung disease

Background Interstitial lung disease (ILD) is associated with high morbidity and mortality in rheumatoid arthritis (RA). Citrullinated proteins are observed in RA lung tissues; however, the association of specific anticitrullinated peptide antibodies (ACPA) with ILD in RA is unknown. Methods RA patients underwent multidetector CT (MDCT) of the chest, from which ILD features and a semiquantitative ILD Score (ILDS; range 0–32) were assessed. Anti-CCP (CCP2) and levels of a panel of antibodies against 17 citrullinated and four non-citrullinated peptides were assessed from concurrent serum samples using a custom Bio-Plex bead array. High level ACPA was defined as ≥the group 75th percentile. Results Among the 177 RA patients studied, median levels of CCP2 and all specific ACPAs were 46–273% higher among RA patients with versus those without ILD (all p values <0.05), and higher levels correlated with higher ILDS. In contrast, levels of non-citrullinated protein antibodies were not higher in those with ILD. RA patients had a median of 2 high level ACPA reactivities (range 0–16), with each high level ACPA associated, on average, with a 0.10 unit higher ILDS (p=0.001). This association remained significant after adjusting for characteristics associated with ILD (age, gender, current and former smoking, Disease Activity Score for 28 joints, current prednisone and leflunomide use). More high level ACPA were observed in those with versus without pulmonary function restriction or impaired diffusion. Conclusions Our findings of a broader ACPA repertoire in RA ILD suggest a possible role for ACPA in the pathogenesis of ILD.

Lung transplantation in telomerase mutation carriers with pulmonary fibrosis

Lung transplantation is the only intervention that prolongs survival in idiopathic pulmonary fibrosis (IPF). Telomerase mutations are the most common identifiable genetic cause of IPF, and at times, the telomere defect manifests in extrapulmonary disease such as bone marrow failure. The relevance of this genetic diagnosis for lung transplant management has not been examined. We gathered an international series of telomerase mutation carriers who underwent lung transplant in the USA, Australia and Sweden. The median age at transplant was 52 years. Seven recipients are alive with a median follow-up of 1.9 years (range 6 months to 9 years); one died at 10 months. The most common complications were haematological, with recipients requiring platelet transfusion support (88%) and adjustment of immunosuppressives (100%). Four recipients (50%) required dialysis for tubular injury and calcineurin inhibitor toxicity. These complications occurred at significantly higher rates relative to historic series (p<0.0001). Our observations support the feasibility of lung transplantation in telomerase mutation carriers; however, severe post-transplant complications reflecting the syndromic nature of their disease appear to occur at higher rates. While these findings need to be expanded to other cohorts, caution should be exercised when approaching the transplant evaluation and management of this subset of pulmonary fibrosis patients. Telomerase mutation carriers with IPF may be prone to complications from their underlying telomere syndrome after LTx http://ow.ly/wmy6P

Sleep Quality and Health-Related Quality of Life in Idiopathic Pulmonary Fibrosis

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive disorder resulting in irreversible scarring of the lung parenchyma. Although fatigue is a prominent symptom for patients with IPF, little is known about sleep quality in patients with IPF. METHODS In this cross-sectional study of 41 patients with IPF from a prospectively designed cohort, we ascertained sleep quality by means of the Pittsburgh sleep quality index (PSQI) and the Epworth sleepiness scale. Health status, baseline demographics, and physiologic parameters were also assessed. RESULTS Patients with IPF reported extremely poor sleep quality and high frequency of daytime sleepiness, which differs significantly from normal control populations. Further, poor sleep quality was not associated with body mass index, age, gender, or lung function. This population also demonstrated extremely poor health status in a number of domains, including physical function and vitality. Poor sleep quality (by the global PSQI) was significantly associated with decreased quality of life (QOL) in several domains, including role of physical function (r = - 0.58, p = 0.001), vitality (r = - 0.43, p = 0.015), and role of emotions (r = - 0.40, p = 0.023). CONCLUSIONS Poor sleep quality is extremely common in patients with IPF and is not predicted by variables traditionally associated with sleep-disordered breathing. Further, poor sleep quality is associated with poor QOL. These findings suggest that systematic evaluation of the cause of poor sleep quality in IPF is merited.

Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials

Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology—a non-profit international organisation dedicated to consensus methodology in identification of outcome measures—conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.