Transcriptional blood signatures distinguish pulmonary tuberculosis, pulmonary sarcoidosis, pneumonias and lung cancers.

RATIONALE: New approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations. OBJECTIVES: To determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases. METHODS: We compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations. MEASUREMENTS AND MAIN RESULTS: An Interferon-inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls. CONCLUSIONS: Tuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the heterogeneity of their profiles and their transcriptional response to treatment.

Clinical characteristics, haemodynamics and treatment of pulmonary hypertension in sarcoidosis in a single centre, and meta-analysis of the published data.

Pulmonary hypertension (PH) in sarcoidosis is associated with bad outcomes. Although there is interest in using pulmonary vasodilators (PVs) for PH in sarcoidosis, there are few data to support their use. In this study, a retrospective review of a cohort of patients with PH and sarcoidosis was conducted, focusing on those treated with PVs, and a meta-analysis of published reports indexed in MEDLINE was performed. Twenty-four patients were found. The rate of mortality or transplantation rate was 41.2%. Median survival without transplantation was 5.3 years. More patients who died or underwent transplantation during follow-up had moderate or severe lung fibrosis (66.7% vs 15.4%), had right ventricular dysfunction (80% vs 7.7%), and were in World Health Organization class IV (66.7% vs 30.8%). Body surface areas were lower in patients with events, as was cardiac output. Mortality was not different between patients treated with PVs and those not treated (54.5% vs 38.5%, p = 0.44) despite the treated patients' having more right ventricular dysfunction and worse hemodynamics. In a Cox regression survival model, lower body surface area, right ventricular dysfunction, and the presence of moderate or severe lung fibrosis were predictors of worse outcomes, but not treatment with PVs. PV-treated patients (n = 11) showed improved 6-minute walk distances and decreased N-terminal pro-B-type natriuretic peptide levels during follow-up. There was a trend toward improvement in hemodynamic profile. Four studies plus the data from this study were included in the meta-analysis. Six-minute walk distance improved by 30.64 m after treatment. Hemodynamics improved, with a reduction in mean pulmonary arterial pressure of 8.03 mm Hg and a decrease in pulmonary vascular resistance of 4.23 Wood units. In conclusion, PH in sarcoidosis is associated with adverse outcomes, particularly when accompanied by right ventricular dysfunction and/or moderate or severe lung fibrosis. Treating selected patients can improve hemodynamics and functional parameters.

Autoimmune hepatitis associated with Kikuchi-Fujimoto's disease.

We describe a 20-year-old woman with autoimmune hepatitis (AIH) with cirrhosis who developed Kikuchi-Fujimoto's disease (KFD) and de novo minor features of systemic lupus erythematosus (SLE). This is the first report of a patient with histologically confirmed AIH developing KFD (histiocytic necrotizing lymphadenitis). One previous case described KFD after AIH (diagnosed clinically but without biopsy). KFD is a rare condition of unknown aetiology, first described in 1972, characterized by fever and cervical adenopathy and has a self-limiting course. KFD is associated with SLE, and SLE in turn can be associated with abnormal liver function tests, which in a minority of cases may be due to AIH. The association of AIH, KFD, and SLE in our patient suggests an autoimmune pathogenesis of KFD.

Gastrointestinal sarcoidosis. A review.

BACKGROUND AND AIMS: Sarcoidosis is a multisystem granulomatous disorder. The gastrointestinal system is not commonly involved and is frequently asymptomatic. It can be associated with significant morbidity and indeed mortality. The aim of this article is to review the common and rare gastrointestinal and hepatobiliary manifestations of sarcoidosis. METHODS: All literature on gastrointestinal sarcoidosis was found using a computerized Pubmed search from 1966 to January 2006. The keywords used were 'Gastrointestinal', 'Hepatobiliary', and 'Sarcoidosis'. RESULTS: The article reviews each 'section' of the gastrointestinal and hepatobiliary tracts in turn, discusses difficulties in achieving a diagnosis, differential diagnoses and treatment options. CONCLUSIONS: This review highlights the difficulties in establishing a firm diagnosis of gastrointestinal sarcoidosis as it is frequently asymptomatic and can often mimic other non-caseating diseases. It also highlights some of the other disease associations such as with other biliary tract disorders and provides information on treatments, particularly the role of biologic therapies.

Functional prostaglandin-endoperoxide synthase 2 polymorphism predicts poor outcome in sarcoidosis.

RATIONALE: The majority of patients with sarcoidosis resolve their condition; however 5-10% of patients with sarcoidosis develop pulmonary fibrosis with poor prognosis. Prostaglandin-endoperoxide synthase 2 (PTGS2) is a key regulatory enzyme in the synthesis of the antifibrotic agent prostaglandin E(2) and is reduced in sarcoidosis lung. A promoter polymorphism in PTGS2, -765G>C, is reported to reduce its expression. OBJECTIVES: To investigate if -765G>C is associated with susceptibility to, and poorer outcome within, sarcoidosis and to examine a possible mechanism by which -765G>C reduces PTGS2 expression. METHODS: We used a case-control design study and genotyped -765G>C in a white British population of 198 patients with sarcoidosis and 166 control subjects. Patients with sarcoidosis were classified before genotyping as having persistent or nonpersistent disease using clinical criteria that included chest radiography staging, need for treatment, lung function, and longitudinal follow-up. Electrophoretic mobility shift assays were used to identify changes in transcription factor binding caused by the -765G>C polymorphism. RESULTS: Carriage of the -765C allele was strongly associated with susceptibility to sarcoidosis (odds ratio, 2.50; 95% confidence interval, 1.51-4.13; p=0.006) and, within this disease, with poorer outcome (odds ratio, 3.11; 95% confidence interval, 1.35-7.13; p=0.008). The association with sarcoidosis was replicated in a second Austrian population. Electrophoretic mobility shift assays revealed that the -765C allele causes a loss of Sp1/Sp3 transcription factor binding and an increase in Egr-1 binding to the region. CONCLUSION: Our data suggest that the -765G>C polymorphism identifies individuals who are susceptible to sarcoidosis and, more importantly, at risk of pulmonary fibrotic disease. An altered Sp1/Sp3 binding to the -765 region may contribute to the mechanism by which -765G>C reduces PTGS2 expression.

The neurological complications of systemic sarcoidosis.

Involvement of the central nervous system in sarcoidosis arises predominantly due to infiltration of the meninges leading to pachymeningitis with cranial neuropathies, hydrocephalus, encephalopathy and hypothalamic dysfunction. Less frequently cerebral mass lesions occur, and spinal cord lesions have been reported. Involvement of the peripheral nervous system leading to radiculopathies, peripheral neuropathy and mononeuritis multiplex also occurs and muscle involvement may be difficult to diagnose until advanced stages. If neurological syndromes arise in patients with established biopsy proven systemic sarcoidosis, the diagnosis is usually easy to make, but oftentimes patients may present de novo with neurological symptoms and signs without systemic involvement. Subsequent investigations may lead on to the identification of systemic granulomata, but on other occasions these are not found; it has not yet been established what relationship such cases has to those with the systemic disorder in whom neurological complications arise.

Nuclear factor-kappaB activation in alveolar macrophages requires IkappaB kinase-beta, but not nuclear factor-kappaB inducing kinase.

Cytokine mediated activation of alveolar macrophages (AMs) is an important event in the pathogenesis of fibrosing alveolitis (FA). Through membrane-associated antigens, cytokines (e.g., tumor necrosis-factor-alpha and interleukin-1) are believed to activate a common kinase cascade that initiates the cytoplasmic degradation of IkappaB and nuclear translocation of "nuclear factor-kappaB" (NF-kappaB). In the nucleus, NF-kappaB promotes the transcription of genes encoding chemokines and cytokines involved in chronic inflammation. Preventing cytokine-mediated NF-kappaB activation is a potential strategy for attenuating the lung injury that occurs in FA. Previously, we have demonstrated that, unlike AMs from healthy volunteers, AMs from patients with inflammatory lung diseases express the coxsackie/adenovirus receptor and the alphav integrins required for adenovirus (Adv) infection. This property allows Adv-mediated transgene delivery to diseased, but not normal, AMs and analysis of molecular pathways involved in gene transcription. In this study, AMs were infected with Adv constructs expressing a defective beta subunit of IkappaB kinase (AdvIKKbetakd) and a defective NF-kappaB inducing kinase (AdvNIKkd) to investigate the contribution of these molecules to NF-kappaB activation. We observed that IKKbeta, but not NIK, was required for NF-kappaB activation. The results of this study identify IKKbeta, but not NIK, as a potential therapeutic target in diseases that involve NF-kappaB-dependent gene transcription.