Treatment of Granulomatous Inflammation in Pulmonary Sarcoidosis.

The management of pulmonary sarcoidosis is a complex interplay of disease characteristics, the impact of medications, and patient preferences. Foremost, it is important to weigh the risk of anti-granulomatous treatment with the benefits of lung preservation and improvement in quality of life. Because of its high spontaneous resolution rate, pulmonary sarcoidosis should only be treated in cases of significant symptoms due to granulomatous inflammation, lung function decline, or substantial inflammation on imaging that can lead to irreversible fibrosis. The longstanding basis of treatment has historically been corticosteroid therapy for the control of granulomatous inflammation. However, several corticosteroid-sparing options have increasing evidence for use in refractory disease, inability to taper steroids to an acceptable dose, or in those with toxicity to corticosteroids. Treatment of sarcoidosis should be individualized for each patient due to the heterogeneity of the clinical course, comorbid conditions, response to therapy, and tolerance of medication side effects.

Treatment of Sarcoidosis: A Multidisciplinary Approach.

Sarcoidosis is a systemic disease of unknown etiology defined by the presence of noncaseating granulomatous inflammation that can cause organ damage and diminished quality of life. Treatment is indicated to protect organ function and decrease symptomatic burden. Current treatment options focus on interruption of granuloma formation and propagation. Clinical trials guiding evidence for treatment are lacking due to the rarity of disease, heterogeneous clinical course, and lack of prognostic biomarkers, all of which contribute to difficulty in clinical trial design and implementation. In this review, a multidisciplinary treatment approach is summarized, addressing immunuosuppressive drugs, managing complications of chronic granulomatous inflammation, and assessing treatment toxicity. Discovery of new therapies will depend on research into pathogenesis of antigen presentation and granulomatous inflammation. Future treatment approaches may also include personalized decisions based on pharmacogenomics and sarcoidosis phenotype, as well as patient-centered approaches to manage immunosuppression, symptom control, and treatment of comorbid conditions.

Diagnosis and Detection of Sarcoidosis. An Official American Thoracic Society Clinical Practice Guideline.

Background: The diagnosis of sarcoidosis is not standardized but is based on three major criteria: a compatible clinical presentation, finding nonnecrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. There are no universally accepted measures to determine if each diagnostic criterion has been satisfied; therefore, the diagnosis of sarcoidosis is never fully secure.Methods: Systematic reviews and, when appropriate, meta-analyses were performed to summarize the best available evidence. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation approach and then discussed by a multidisciplinary panel. Recommendations for or against various diagnostic tests were formulated and graded after the expert panel weighed desirable and undesirable consequences, certainty of estimates, feasibility, and acceptability.Results: The clinical presentation, histopathology, and exclusion of alternative diagnoses were summarized. On the basis of the available evidence, the expert committee made 1 strong recommendation for baseline serum calcium testing, 13 conditional recommendations, and 1 best practice statement. All evidence was very low quality.Conclusions: The panel used systematic reviews of the evidence to inform clinical recommendations in favor of or against various diagnostic tests in patients with suspected or known sarcoidosis. The evidence and recommendations should be revisited as new evidence becomes available.

Delphi consensus recommendations for a treatment algorithm in pulmonary sarcoidosis.

Pulmonary sarcoidosis presents substantial management challenges, with limited evidence on effective therapies and phenotypes. In the absence of definitive evidence, expert consensus can supply clinically useful guidance in medicine. An international panel of 26 experts participated in a Delphi process to identify consensus on pharmacological management in sarcoidosis with the development of preliminary recommendations.The modified Delphi process used three rounds. The first round focused on qualitative data collection with open-ended questions to ensure comprehensive inclusion of expert concepts. Rounds 2 and 3 applied quantitative assessments using an 11-point Likert scale to identify consensus.Key consensus points included glucocorticoids as initial therapy for most patients, with non-biologics (immunomodulators), usually methotrexate, considered in severe or extrapulmonary disease requiring prolonged treatment, or as a steroid-sparing intervention in cases with high risk of steroid toxicity. Biologic therapies might be considered as additive therapy if non-biologics are insufficiently effective or are not tolerated with initial biologic therapy, usually with a tumour necrosis factor-α inhibitor, typically infliximab.The Delphi methodology provided a platform to gain potentially valuable insight and interim guidance while awaiting evidenced-based contributions.

Income and Other Contributors to Poor Outcomes in U.S. Patients with Sarcoidosis.

Rationale: Socioeconomic factors are associated with worse disease severity at presentation in sarcoidosis, but the relative importance of socioeconomic variables on morbidity and disease burden has not been fully elucidated.Objectives: To determine the association between income and sarcoidosis outcomes after controlling for socioeconomic and disease-related factors.Methods: Using the Sarcoidosis Advanced Registry for Cures database, we analyzed data from 2,318 patients with sarcoidosis in the United States to determine the effect of income and other variables on outcomes. We divided comorbidities arising after diagnosis into those likely related to steroid use and those likely related to sarcoidosis. We assessed the development of health-related, functional, and socioeconomic outcomes following the diagnosis of sarcoidosis.Measurements and Main Results: In multivariate analysis, low-income patients had significantly higher rates of new sarcoidosis-related comorbidities (<$35,000, odds ratio [OR], 2.4 [1.7-3.3]; $35,000-84,999, OR, 1.4 [1.1-1.9]; and ≥$85,000 [reference (Ref)]) and new steroid-related comorbidities (<$35,000, OR, 1.3 [0.9-2.0]; $35,000-84,999, OR, 1.5 [1.1-2.1]; and ≥$85,000 [Ref]), had lower health-related quality of life as assessed by the Sarcoidosis Health Questionnaire (P < 0.001), and experienced more impact on family finances (<$35,000, OR, 7.9 [4.9-12.7]; $35,000-84,999, OR, 2.7 [1.9-3.9]; and ≥$85,000 [Ref]). The use of supplemental oxygen, need for assistive devices, and job loss were more common in lower income patients. Development of comorbidities after diagnosis of sarcoidosis occurred in 63% of patients and were strong independent predictors of poor outcomes. In random forest modeling, income was consistently a leading predictor of outcome.Conclusions: These results suggest the burden from sarcoidosis preferentially impacts the economically disadvantaged.

Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions.

Autosomal recessive diseases, such as cystic fibrosis (CF), require inheritance of 2 mutated genes. However, some studies indicate that CF carriers are at increased risk for some conditions associated with CF. These investigations focused on single conditions and included small numbers of subjects. Our goal was to determine whether CF carriers are at increased risk for a range of CF-related conditions. Using the Truven Health MarketScan Commercial Claims database (2001-2017), we performed a population-based retrospective matched-cohort study. We identified 19,802 CF carriers and matched each carrier with 5 controls. The prevalence of 59 CF-related diagnostic conditions was evaluated in each cohort. Odds ratios for each condition were computed for CF carriers relative to controls. All 59 CF-related conditions were more prevalent among carriers compared with controls, with significantly increased risk (P < 0.05) for 57 conditions. Risk was increased for some conditions previously linked to CF carriers (e.g., pancreatitis, male infertility, bronchiectasis), as well as some conditions not previously reported (e.g., diabetes, constipation, cholelithiasis, short stature, failure to thrive). We compared our results with 23,557 subjects with CF, who were also matched with controls; as the relative odds of a given condition increased among subjects with CF, so did the corresponding relative odds for carriers (P < 0.001). Although individual-level risk remained low for most conditions, because there are more than 10 million carriers in the US, population-level morbidity attributable to the CF carrier state is likely substantial. Genetic testing may inform prevention, diagnosis, and treatment for a broad range of CF carrier-related conditions.

Approach to tapering antisarcoidosis therapy.

PURPOSE OF REVIEW: Sarcoidosis is a multisystemic granulomatous disease, which commonly affects the lung. The natural course of the disease and prognosis are variable from asymptomatic, spontaneous remission to progressive disease, which requires treatment. Once treatment is initiated, tapering therapy can be problematic. RECENT FINDINGS: Corticosteroids are recommended as first-line therapy, but optimal regimen and duration of treatment is not well established. Treatment may differ based on severity of disease, extrapulmonary involvement, physician and patient preferences. We reviewed currently recommended regimens, particularly, in pulmonary sarcoidosis and the use of alternative treatments as corticosteroid-sparing agents. SUMMARY: Corticosteroid use is quite effective as initial therapy but is associated with significant side effects. An approach to tapering sarcoidosis therapy is not standardized, given the lack of evidence-based data. This review provides guidance based on the current literature.

Airway surface liquid from smokers promotes bacterial growth and biofilm formation via iron-lactoferrin imbalance.

BACKGROUND: Smoking is a leading cause of respiratory infections worldwide. Tobacco particulate matter disrupts iron homeostasis in the lungs and increases the iron content in the airways of smokers. The airway epithelia secrete lactoferrin to quench iron required for bacteria to proliferate and cause lung infections. We hypothesized that smokers would have increased bacterial growth and biofilm formation via iron lactoferrin imbalance. METHODS: We collected bronchoalveolar lavage (BAL) samples from non-smokers and smokers. We challenged these samples using a standard inoculum of Staphylococcus aureus and Pseudomonas aeruginosa and quantified bacterial growth and biofilm formation. We measured both iron and lactoferrin in the samples. We investigated the effect of supplementing non-smoker BAL with cigarette smoke extract (CSE) or ferric chloride and the effect of supplementing smoker BAL with lactoferrin on bacterial growth and biofilm formation. RESULTS: BAL from smokers had increased bacterial growth and biofilm formation compared to non-smokers after both S. aureus and P. aeruginosa challenge. In addition, we found that samples from smokers had a higher iron to lactoferrin ratio. Supplementing the BAL of non-smokers with cigarette smoke extract and ferric chloride increased bacterial growth. Conversely, supplementing the BAL of smokers with lactoferrin had a concentration-dependent decrease in bacterial growth and biofilm formation. CONCLUSION: Cigarette smoking produces factors which increase bacterial growth and biofilm formation in the BAL. We propose that smoking disrupts the iron-to-lactoferrin in the airways. This finding offers a new avenue for potential therapeutic interventions to prevent respiratory infections in smokers.

Effect of vitamin D3 on the antimicrobial activity of human airway surface liquid: preliminary results of a randomised placebo-controlled double-blind trial.

INTRODUCTION: Vitamin D3 supplementation has been reported to prevent lung infections and increase the gene expression of antimicrobial peptides such as cathelicidin. We investigated the effect of vitamin D3 supplementation on the antimicrobial activity of airway surface liquid (ASL) in human subjects. Since smoking can increase the risk of respiratory infections, we also investigated the effect of smoking in the cathelicidin response to vitamin D3 in human airway epithelia in vitro. METHODS: This study is a subanalysis of single-centre community-based randomised placebo-controlled double-blind trial. Participants were randomised to receive 1000 international units per day of oral vitamin D3 or identical placebo for 90 days. Blood and ASL samples were collected preintervention and postintervention. 105 participants were originally enrolled, 86 completed the trial, and due to low protein concentration in the samples, 40 participants were finally analysed. Our primary outcome was ASL antimicrobial activity. We also considered secondary outcomes including changes in serum concentration of 25-hydroxyvitamin D3 (25(OH)D3), 1,25-hydroxyvitamin D3, calcium and parathyroid hormone (PTH). In addition, we studied the effect of cigarette smoke extract (CSE) exposure to primary human airway epithelial cell cultures on the gene expression of cathelicidin in response to vitamin D3 and expression of CYP27B1 (1-alpha hydroxylase), responsible for vitamin D3 activation. RESULTS: Vitamin D3 supplementation significantly increased both ASL antimicrobial activity and serum concentration of 25(OH)D3. In a subgroup analysis, we found that smokers did not increase their baseline antimicrobial activity in response to vitamin D3. Exposure to CSE on human airway epithelia decreased baseline CYP27B1 gene expression and cathelicidin response to 25(OH)D3. CONCLUSION: Vitamin D3 supplementation for 90 days increases ASL antimicrobial activity. Data from this preliminary study suggest that smoking may alter the ability of airway epithelia to activate vitamin D3 and increase the gene expression of cathelicidin antimicrobial peptide. TRIAL REGISTRATION NUMBER: NCT01967628; Post-results.

Lower limit of normal based spirometric abnormalities associated with radiographic abnormality in an elderly cohort at low risk for exposure.

BACKGROUND: Although the relation between radiographic abnormalities and spirometric impairment in people with asbestosis has been studied extensively, the extent of spirometric impairment associated with milder radiographic abnormalities is not established. OBJECTIVE: To test associations between mild radiographic abnormalities and Lower Limit of Normal (LLN)-based spirometry interpretation. METHODS: Spirometry and CXRs were collected for 1,026 at low risk of exposure to pneumoconiotic agents participants in a medical screening program. RESULTS: Individuals with each type of isolated or combined International Labour Organization (ILO) abnormalities had up to over sixfold statistically significant increase in odds of LLN-based restrictive pattern physiology (OR = 1.96, 95%CI 1.03-3.73 for parenchymal to OR = 6.09, 95%CI 1.94-19.10 for parenchymal and pleural) compared to those with normal films. CONCLUSIONS: The findings from this study confirm the association of mild profusion abnormalities with clinically relevant, LLN-based lung function abnormalities.

Inclusion body myositis and sarcoid myopathy: coincidental occurrence or associated diseases.

Inclusion body myositis (IBM) is a slowly progressive inflammatory myopathy characterized by selective weakness of finger flexors and quadriceps muscles commonly refractory to treatment. Another chronic inflammatory disorder, sarcoidosis, commonly involves muscle. The comorbidity of inclusion body myositis and sarcoid myopathy is rare. We describe clinical and muscle biopsy findings of a patient with sarcoidosis and inclusion body myositis. A 66-year-old man presented with a 6-year history of progressive, asymmetrical and selective weakness of the quadriceps, biceps and finger flexor muscles; he had a remote history of pulmonary sarcoidosis. A quadriceps muscle biopsy revealed a chronic inflammatory myopathy with ubiquitinated inclusion bodies, rimmed vacuoles, expression of major histocompatibility complex class I, numerous COX-negative fibers and TDP-43 cytoplasmic aggregates (features of IBM) and multiple non-necrotizing granulomata (feature of sarcoidosis). Clinical and histopathologic features of the current illness suggested the patient had sarcoidosis with inclusion body myositis overlap. This patient may represent the coincidental occurrence of both idiopathic inflammatory disorders. Alternatively, sarcoidoisis may promote the development of inclusion body myositis by a similar immune-mediated pathophysiologic process.

The high frequency of healthcare use in patients one year prior to a sarcoidosis diagnosis.

BACKGROUND: The clinical presentation of sarcoidosis can be varied. Prior investigations have shown that diagnosis is often delayed over six months, particularly in patients with pulmonary symptoms. Delays may lead to high healthcare use prior to diagnosis.  OBJECTIVE: To investigate healthcare use prior to diagnosis of sarcoidosis for a cohort of insured patients. METHODS: We conducted a case-control study using a de-identified limited dataset of private health insurance claims.  Cases were identified as persons with sarcoidosis from 2003-2009. Controls with other respiratory-related diagnoses (asthma, chronic obstructive pulmonary disease, pneumonia) were matched by age, gender, and diagnosis date. We compared frequencies of doctor visits, prescriptions, and imaging in the year prior to established diagnosis. RESULTS: We identified 206 cases and 2060 controls and compared healthcare use patterns in the year prior to diagnosis. Among those receiving prescriptions, a larger proportion of cases received two or more antibiotic courses (69% vs. 55%, p=0.0020) or two or more corticosteroid prescriptions (63% vs. 50%, p=0.0137). On average, cases had more doctor visits (14.7 vs. 7.8, p<0.0001), saw more specialties (3.9 vs. 2.1, p<0.0001), and underwent more chest x-rays (2.0 vs. 1.5, p<0.0001). A larger proportion of cases underwent two or more chest x-rays (54% vs. 24%, p<0.0001). CONCLUSIONS: Patients with sarcoidosis undergo a large amount of healthcare prior to diagnosis, some of which may not be necessary, compared to controls with respiratory-related disease. These results highlight the need for improved diagnostic algorithms to identify patients with sarcoidosis and avoid potentially excessive delays in diagnosis.

Morbidity and mortality in sarcoidosis.

PURPOSE OF REVIEW: Chronic sarcoidosis is a complex disease with numerous comorbid conditions and can be fatal in some cases. Recognizing causes of morbidity and mortality is important to effectively select treatments, manage symptoms and improve outcomes. The purpose of this review is to examine emerging knowledge on morbidity and mortality in sarcoidosis. RECENT FINDINGS: Approximately 1-5% of patients with sarcoidosis die from complications of sarcoidosis. Recent population studies indicate that mortality may be increasing over the past decade. The reasons behind these trends are unclear, but could include increasing incidence, detection rates, severity of disease or age of the population. Morbidity of sarcoidosis is reflected by a trend of increased hospitalizations over recent years and increased use of healthcare resources. Morbidity can be caused by organ damage from granulomatous inflammation, treatment complications and psychosocial effects of the disease. Recent studies are focused on morbidity related to cardiopulmonary complications, bone health and ageing within the sarcoidosis population. Last, sarcoidosis is associated with autoimmune diseases, pulmonary embolism and malignancy; however, the underlying mechanisms linking diseases continue to be debated. SUMMARY: Morbidity in sarcoidosis is significant and multifactorial. Mortality is infrequent, but may be increasing over the years.

A microRNA processing defect in smokers' macrophages is linked to SUMOylation of the endonuclease DICER.

Despite the fact that alveolar macrophages play an important role in smoking-related disease, little is known about what regulates their pathophysiologic phenotype. Evaluating smoker macrophages, we found significant down-regulation of multiple microRNAs (miRNAs). This work investigates the hypothesis that cigarette smoke alters mature miRNA expression in lung macrophages by inhibiting processing of primary miRNA transcripts. Studies on smoker alveolar macrophages showed a defect in miRNA maturation. Studies on the miRNA biogenesis machinery led us to focus on the cytosolic RNA endonuclease, DICER. DICER cleaves the stem-loop structure from pre-miRNAs, allowing them to dissociate into their mature 20-22-nucleotide single-stranded form. DICER activity assays confirmed impaired DICER activity following cigarette smoke exposure. Further protein studies demonstrated a decreased expression of the native 217-kDa form of DICER and an accumulation of high molecular weight forms with cigarette smoke exposure. This molecular mass shift was shown to contain SUMO moieties and could be blocked by silencing RNA directed at the primary SUMOylating ligase, Ubc9. In determining the cigarette smoke components responsible for changes in DICER, we found that N-acetylcysteine, an antioxidant and anti-aldehyde, protected DICER protein and activity from cigarette smoke extract. This massive down-regulation of miRNAs (driven in part by alterations in DICER) may be an important regulator of the disease-promoting macrophage phenotype found in the lungs of smokers.

Coordinated DNA methylation and gene expression changes in smoker alveolar macrophages: specific effects on VEGF receptor 1 expression.

Cigarette smoking is implicated in numerous diseases, including emphysema and lung cancer. The clinical expression of lung disease in smokers is not well explained by currently defined variations in gene expression or simple differences in smoking exposure. Alveolar macrophages play a critical role in the inflammation and remodeling of the lung parenchyma in smoking-related lung disease. Significant gene expression changes in alveolar macrophages from smokers have been identified. However, the mechanism for these changes remains unknown. One potential mechanism for smoking-altered gene expression is via changes in cytosine methylation in DNA regions proximal to gene-coding sequences. In this study, alveolar macrophage DNA from heavy smokers and never smokers was isolated and methylation status at 25,000 loci determined. We found differential methylation in genes from immune-system and inflammatory pathways. Analysis of matching gene expression data demonstrated a parallel enrichment for changes in immune-system and inflammatory pathways. A significant number of genes with smoking-altered mRNA expression had inverse changes in methylation status. One gene highlighted by this data was the FLT1, and further studies found particular up-regulation of a splice variant encoding a soluble inhibitory form of the receptor. In conclusion, chronic cigarette smoke exposure altered DNA methylation in specific gene promoter regions in human alveolar macrophages.

Smoking inhibits the frequency of bronchovascular bundle thickening in sarcoidosis.

RATIONALE/OBJECTIVES: Smoking has been associated with decreased incidence and prevalence of sarcoidosis, but few studies have evaluated effects of smoking on clinical parameters of the disease. The objectives were to determine the association of smoking with radiographic patterns and to evaluate the associations of these smoking-related radiographic patterns on airflow obstruction in sarcoidosis. MATERIALS AND METHODS: Clinical data and computed tomography (CT) scans of 124 patients with sarcoidosis were reviewed. CT scans were assessed for lymph nodes, nodules, bronchiectasis, bronchovascular bundle thickening, displaced hilum, fibrosis, ground glass, emphysema, pleural changes, and alveolar opacities. CT patterns were compared between patients with and without a history of smoking. The effect of smoking on the associations between radiographic patterns and airflow obstruction was assessed with multivariable analysis. RESULTS: Smokers had less frequency of bronchovascular bundle thickening than nonsmokers (11/38 subjects [29%] vs 50/86 subjects [58%], P = .003) and more emphysema (7/38 subjects [18%] vs 1/86 subjects [1%], P = .001). Patients who had bronchovascular bundle thickening were less likely to have ever smoked (11/61 subjects [18%] vs 27/63 subjects [43%], P = .003) or be current smokers (4/61 subjects [7%] vs 15/63 subjects [24%], P = .008). Age (P = .003) and bronchovascular bundle thickening (P = .02) were independent predictors of airflow obstruction. There were no differences in smoking history between patients with airflow obstruction versus those without (10/37 subjects [27%] vs 28/87 subjects [32%], P = .63). CONCLUSIONS: In patients with sarcoidosis, smoking is associated with decreased frequency of bronchovascular bundle thickening, an important clinical manifestation of the lung disease. Further, bronchovascular bundle thickening and age are the only independent predictors of airflow obstruction, and smoking does not confound these associations.

The immunology of sarcoidosis.

Sarcoidosis continues to be a disease of research interest because of its complicated immune mechanisms and elusive etiology. So far, it has been established that granulomatous inflammation in sarcoidosis is predominantly a T-helper 1 immune response mediated by a complex network of lymphocytes, macrophages, and cytokines. The cause of progression to a chronic and potentially fibrotic form is unclear but may involve loss of apoptotic mechanisms, loss of regulatory response, or a persistent antigen that cannot be cleared. Recent genomic and proteomic technology has emphasized the importance of host susceptibility and gene-environment interaction in the expression of the disease.