Approaches to the treatment of some of the troublesome manifestations of sarcoidosis.

Sarcoidosis can be a major therapeutic challenge given its multiplicity of clinical presentations, variable combination of organ involvement and severity, and unpredictable longitudinal behaviour. Six manifestations of sarcoidosis are especially difficult to manage because of (i) an incomplete knowledge of causation - fatigue and small fibre neuropathy, (ii) the rare occurrence in sarcoidosis - intra-abdominal complications or (iii) the potentially life-threatening consequences in some patients - neurological disease, pulmonary hypertension and hypercalcaemia. In none of these situations have a prospective, double-blind, placebo-controlled trial of any therapy been conducted. Despite this absence of any firm evidence base to support therapeutic recommendations, these six entities can be extremely problematic for the practising clinician. It is for this reason that we have focused in this review on these six disease manifestations and provided a synopsis of each problem together with suggested treatment approaches, based on an analysis of the current literature.

Optimal scoring of serial change on chest radiography in sarcoidosis.

BACKGROUND: The optimal means of quantifying change on chest radiography in sarcoidosis is uncertain. In current guidelines, the role of serial measurement of carbon-monoxide diffusing capacity (DLco) remains undefined and the prevalence of discordance between serial chest radiographic change and pulmonary function tends is unknown. OBJECTIVE: To identify and explore key uncertainties in the monitoring of sarcoidosis by serial pulmonary function tests and chest radiography. DESIGN: 354 patients with sarcoidosis and concurrent tests (chest radiography and PFTs within three months at baseline, two years and/or four years) were studied. Chest radiographs were assessed by two radiologists for changes in stage and disease extent. Radiographic change and pulmonary function trends were quantified and compared. RESULTS: Change in radiographic extent of lung disease was always more frequent than change in stage (p < 0.0001) and there was poor agreement between change in stage and change in radiographic extent (Kw = 0.21 at two years; Kw = 0.23 at four years). Change in disease extent on chest radiography was linked to PFT trends on analysis of variance (p < 0.0005 for FEV1, FVC, DLco), whereas change in radiographic stage was not. Changes in gas transfer were often isolated or discordant with other serial data. Discordance between pulmonary function data and chest radiographic data was observed in 50% of cases. CONCLUSIONS: Change in radiographic extent is more applicable to routine monitoring in sarcoidosis than change in radiographic stage. In future guidelines, the role of serial gas transfer estimation and reconciliation of divergent chest radiographic and functional trends might usefully be addressed.

Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.

The clinical outcome of sarcoidosis is quite variable. Several scoring systems have been used to assess the level of disease and clinical outcome. The definition of clinical phenotypes has become an important goal as genetic studies have identified distinct genotypes associated with different clinical phenotypes. In addition, treatment strategies have been developed for patients with resolving versus non resolving disease. A task force was established by the World Association of Sarcoidosis and Other Granulomatous diseases (WASOG) to define clinical phenotypes of the disease based on the clinical outcome status (COS). The committee chose to examine patients five years after diagnosis to determine the COS. Several features of the disease were incorporated into the final nine categories of the disease. These included the current or past need for systemic therapy, the resolution of the disease, and current status of the condition. Sarcoidosis patients who were African American or older were likely to have a higher COS, indicating more chronic disease. The COS may be useful in future studies of sarcoidosis.

T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis.

Upregulation of genes for interferon (IFN)-γ and CXC chemokine receptor (CXCR)3 expression, two crucial molecules in sarcoid inflammation and granuloma formation, is directly controlled by the T-helper (Th)1 transcription factor T-bet (T-box, expressed in T-cells). However, there is no information on T-bet expression in sarcoidosis or its relationship with "sarcoidosis-associated" genes. Therefore, we investigated expression of T-bet mRNA and, in parallel, a spectrum of genes known to be involved in sarcoidosis pathogenesis. Transcripts were determined in bronchoalveolar lavage (BAL) cells from 62 sarcoidosis patients and 25 controls by quantitative RT-PCR; T-bet protein was localised by immunohistochemistry. Patient's BAL cells expressed higher mRNA T-bet levels than those of controls (mean ± sd fold change 3.64 ± 1.72; p = 0.00006). T-bet mRNA expression did not vary between clinical phenotypes as assessed by chest radiography stage, presence/absence of Löfgren's syndrome, extrapulmonary/pulmonary involvement or progressing/remitting disease (p > 0.05). T-bet mRNA expression correlated with expression of IFN-γ, CC chemokine ligand 5, CXC chemokine ligand (CXC)10, interleukin (IL)-2 receptor/IL-15 receptor ß, CXCR3 and CXCR6 (p < 0.01). T-bet protein was localised to alveolar macrophages and lymphocytes, tissue multinucleated giant cells, macrophages and lymphocytes. In pulmonary sarcoidosis, T-bet upregulation is associated with changes in expression of IFN-γ, CXCR3 and chemokines/receptors involved in the pathogenesis of sarcoidosis, which suggests a role for T-bet in this Th1 disease, including modulation of some sarcoidosis-associated genes.

Imaging the inflammatory activity of sarcoidosis: sensitivity and inter observer agreement of (67)Ga imaging and (18)F-FDG PET.

AIM: The aim of this study was to investigate sensitivity of 67Ga imaging and 18F-FDG PET for sarcoidosis activity and their inter observer variability. METHODS: Thirty-four newly diagnosed, histologically proven sarcoidosis patients were analyzed prospectively. (67)Ga imaging and (18)F-FDG PET were performed, the presence of pulmonary and extra pulmonary lesions was evaluated and inter observer variability of both techniques was assessed. RESULTS: Overall sensitivity to detect active sarcoidosis was 88% for (67)Ga imaging and 97% for (18)F-FDG PET. Although these results were not significantly different, 18F-FDG PET detected more lesions in the mediastinum (P<0.05), hila (P<0.05), lymph nodes (P<0.001) and extra pulmonary regions in general (P<0.001). Inter observer agreement was poor to moderate for (67)Ga imaging (kappa 0.19-0.59) and good to very good for (18)F-FDG PET (kappa 0.65-1.00). CONCLUSION: (18)F-FDG PET is more sensitive than (67)Ga imaging in the assessment of sarcoidosis activity with regard to the mediastinum, hila, lymph nodes and extra pulmonary lesions in general. Furthermore, (18)F-FDG PET demonstrates a very good inter observer agreement in contrast with (67)Ga imaging and (18)F-FDG PET is therefore the nuclear imaging technique of choice in sarcoidosis assessment.

Increased epithelial permeability in pulmonary fibrosis in relation to disease progression.

Epithelial injury contributes to pathogenesis in idiopathic pulmonary fibrosis (IPF) but its role in the interstitial lung disease (ILD) of systemic sclerosis (SSc) is uncertain. We quantified the prognostic significance of inhaled technetium-99m ((99m)Tc)-labelled diethylene triamine pentacetate (DTPA) pulmonary clearance, a marker of the extent of epithelial injury, in both diseases. Baseline (99m)Tc-DTPA pulmonary clearance was evaluated retrospectively in patients with SSc-ILD (n = 168) and IPF (n = 97) against mortality and disease progression. In SSc-ILD, the rapidity of total clearance (hazard ratio (HR) 1.02, 95% CI 1.01-1.03; p = 0.001) and the presence of abnormally rapid clearance (HR 2.10; 95% CI 1.25-3.53; p = 0.005) predicted a shorter time to forced vital capcity (FVC) decline, independent of disease severity. These associations were robust in both mild and severe disease. By contrast, in IPF, delayed clearance of the slow component, an expected consequence of honeycomb change, was an independent predictor of a shorter time to FVC decline (HR 1.01, 95% CI 1.00-1.02; p<0.01). Epithelial injury should be incorporated in pathogenetic models in SSc-ILD. By contrast, outcome is not linked to the overall extent of epithelial injury in IPF, apart from abnormalities ascribable to honeycombing, suggesting that core pathogenetic events may be more spatially focal in that disease.

The complex interrelationships between chronic lung and liver disease: a review.

Lung complications may occur as a result of hepatic disease from any cause and represent a highly heterogeneous group of conditions. Early recognition of such complications may be challenging but is crucial both in forming a meaningful differential diagnosis and in avoiding severe sequelae and irreversible damage. Although a number of different pathogenetic mechanisms are likely to be involved, chronic liver dysfunction may cause pulmonary manifestations because of alterations in the production or clearance of circulating cytokines and other mediators. This is likely to be the case in hepatopulmonary syndrome, portopulmonary hypertension and primary biliary cirrhosis, although their pathogenesis remains largely speculative. Moreover, the severity of lung manifestations may or may not correspond to that of liver impairment, making disease outcome often unpredictable. Congenital and inflammatory disorders, however, may primarily affect both the liver and lung. Apart from specific diseases, a number of medications can also result in pulmonary and hepatic toxic effects. This is particularly important with cytokine therapy - used to treat viral hepatitis, among other diseases - because treatment consists of drug discontinuation, which, in turn, may cause reactivation or progression of the underlying disease that the drug was used for. This review summarizes salient diagnostic and therapeutic aspects of these often misdiagnosed conditions and highlights, based on the most recent literature, the need for early referral of such patients to centres with specific expertise in the field. In fact, a multidisciplinary approach involving pulmonologists, hepatologists and, in particularly severe cases, transplant surgeons has been already proven successful.

Strategies for treating idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is the most common and most lethal diffuse fibrosing lung disease, with a mortality rate that exceeds that of many cancers. Recently, there have been many clinical trials of novel therapies for IPF. The results have mostly been disappointing, although two treatment approaches have shown some efficacy. This Review describes the difficulties of treating IPF and the approaches that have been tried or are in development, and concludes with suggestions of future therapeutic targets and strategies.

CC chemokine receptor 5 gene polymorphisms in beryllium disease.

CC chemokine receptor 5 (CCR5) is expressed on type-1 T-helper cells, which are involved in the pathogenesis of the granulomatous lung disease chronic beryllium disease (CBD). CCR5 gene (CCR5) polymorphisms are associated with sarcoidosis severity. The present study explores associations between CCR5 polymorphisms and CBD and its disease progression. Eight CCR5 polymorphisms were genotyped in CBD (n = 88), beryllium sensitisation (BeS; n = 86) and beryllium-exposed nondiseased controls (n = 173) using PCR with sequence-specific primers. Pulmonary function and bronchoalveolar lavage data were examined for associations with genotypes. There were no significant differences in genotype and allele frequency between CBD, BeS individuals and controls. In CBD, associations were found with decline in forced expiratory volume in 1 s and forced vital capacity and the CCR5 -3458 thymidine (T)T genotype (p<0.0001), and an increase in alveolar-arterial oxygen tension difference at rest (p = 0.003) and at maximum exercise (p = 0.01) and the -5663 adenine allele. Increased bronchoalveolar lavage lymphocyte numbers were associated with CCR5 -2459 guanine/-2135T (p = 0.01) only in the combined CBD and BeS group. This is the first study showing that CCR5 polymorphisms are associated with worsening pulmonary function over time in CBD, suggesting that CCR5 is important in the progression of pulmonary function in CBD. Further studies would be useful to clarify the mechanism whereby CCR5 polymorphisms affect progression of CBD.

Quality of life and dyspnoea in patients treated with bosentan for idiopathic pulmonary fibrosis (BUILD-1).

No therapy is known to improve health-related quality of life (HRQoL) or dyspnoea in patients with idiopathic pulmonary fibrosis. The present study investigated longitudinal changes in HRQoL and dyspnoea and explored the effects of bosentan on these end-points during the Bosentan Use in Interstitial Lung Disease (BUILD)-1 trial. In total, 154 subjects received oral bosentan (n = 71) or placebo (n = 83). Changes in HRQoL and dyspnoea from baseline to month (M) 6 and up to M12 were measured using the St George's Respiratory Questionnaire (SGRQ), 36-item short-form health survey (SF-36), Transition Dyspnoea Index and Borg dyspnoea index. Overall, minimal changes occurred in measures of HRQoL and dyspnoea among placebo-treated subjects during the study. The effects of bosentan treatment on HRQoL and dyspnoea in the all-treated population were minimal. However, in the subset of subjects who had undergone surgical lung biopsy for diagnosis of idiopathic pulmonary fibrosis, treatment effects were observed up to M12 in the impact domain of the SGRQ and the physical functioning, general health and role emotional domains of the SF-36. HRQoL and dyspnoea changed minimally during the course of the present study. Observations from exploratory analyses suggested benefits of bosentan on HRQoL among patients who had undergone surgical lung biopsy for diagnosis, and they merit further investigation.

CARD15/NOD2 polymorphisms are associated with severe pulmonary sarcoidosis.

Sarcoidosis and Crohn's disease are heterogeneous systemic diseases characterised by granulomatous inflammation. Caspase recruitment domain (CARD)15 is a major susceptibility gene for Crohn's disease, and specifically for ileal and fibrostenotic subtypes. The C-C chemokine receptor (CCR)5 gene has been associated with both parenchymal pulmonary sarcoidosis and perianal Crohn's disease. This study explored associations between CARD15 polymorphisms, CCR5 haplotype and distinct pulmonary sarcoidosis subtypes. 185 Caucasian sarcoidosis patients were genotyped for CARD15 and CCR5 polymorphisms. The genetic data were compared with 347 healthy controls and were examined for associations with serial pulmonary function tests and chest radiographs. CARD15 genotypes did not differ between the unselected sarcoidosis cohort and controls. However, patients carrying the functional 2104T (702W) polymorphism were more likely to have radiographic stage IV disease at 4-yr follow-up. All patients possessing both CARD15 2104T and CCR5 HHC haplotype had stage IV disease at presentation. Carriage of 2104T was associated with worse forced expiratory volume in 1 s, whereas carriage of the CARD15 1761G (587R) polymorphism was associated with better lung function. For the first time, an association between two CARD15 polymorphisms and specific sarcoidosis phenotypes has been demonstrated, as well as an additive effect of possessing CARD15 2104T and CCR5 HHC haplotype.

Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis.

In therapeutic studies in idiopathic pulmonary fibrosis (IPF), the low prevalence of significant change in pulmonary functional tests (PFTs) has been a major constraint. The prognostic value of "marginal" changes in PFTs in IPF and fibrotic non-specific interstitial pneumonia (NSIP) was evaluated. In patients with biopsy-proven IPF (n = 84) and NSIP (n = 72), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (D( L,CO)) trends at 6 months were categorised as "significant" (FVC >10%; D(L,CO) >15%) or "marginal" (FVC 5-10%; D(L,CO) 7.5-15%). Proportional hazards analysis and time-dependent receiver operating characteristic methodology were used to examine PFT trends against mortality. In IPF, reductions in FVC were significant in 22 cases (26%) and marginal in 19 cases (23%). Mortality was higher in patients with a significant decline in FVC (hazard ratio (HR) 2.80, 95% CI 1.54-5.06; p<0.001) and those with a marginal decline in FVC (HR 2.31, 95% CI 1.19-4.50; p = 0.01) than in those with stable disease. Progression-free survival was lower when the decline in FVC was marginal than in stable disease (HR 2.34, 95% CI 1.19-4.60; p = 0.01). Marginal changes in D(L,CO) in IPF and marginal changes in FVC and D (L,CO) in fibrotic NSIP did not provide useful prognostic information. Marginal change in FVC in IPF denotes a poor outcome. These findings are applicable to clinical practice and to the selection of patients with more progressive disease for therapeutic studies.

Multiplex immune serum biomarker profiling in sarcoidosis and systemic sclerosis.

Multiplex protein technology has the potential to identify biomarkers for the differentiation, classification and improved understanding of the pathogenesis of interstitial lung disease. The aim of this study was to determine whether a 30-inflammatory biomarker panel could discriminate between healthy controls, sarcoidosis and systemic sclerosis (SSc) patients independently of other clinical indicators. We also evaluated whether a panel of biomarkers could differentiate between the presence or absence of lung fibrosis in SSc patients. We measured 30 circulating biomarkers in 20 SSc patients, 21 sarcoidosis patients and 20 healthy controls using Luminex bead technology and used Fisher's discriminant function analysis to establish the groups of classification mediators. There were significant differences in median concentration measurements between study groups for 20 of the mediators but with considerable range overlap between the groups, limiting group differentiation by single analyte measurements. However, a 17-analyte biomarker model correctly classified 90% of study individuals to their respective group and another 14-biomarker panel correctly identified the presence of lung fibrosis in SSc patients. These findings, if they are corroborated by independent studies in other centres, have potential for clinical application and may generate novel insights into the modulation of immune profiles during disease evolution.

Exercise peripheral oxygen saturation (SpO2) accurately reflects arterial oxygen saturation (SaO2) and predicts mortality in systemic sclerosis.

BACKGROUND: Measures of oxygenation have not been assessed for prognostic significance in systemic sclerosis-related interstitial lung disease (SSc-ILD). METHODS: 83 subjects with SSc-ILD performed a maximal cardiopulmonary exercise test with an arterial line. The agreement between peripheral oxygen saturation (SpO2) and arterial oxygen saturation (SaO2) was examined and survival differences between subgroups of subjects stratified on SpO2 were analysed. Cox proportional hazards analyses were used to examine the prognostic capabilities of SpO2. RESULTS: At maximal exercise the mean (SD) difference between SpO2 and SaO2 was 2.98 (2.98) and only 15 subjects had a difference of >4 points. The survival of subjects with SSc-ILD whose maximum exercise SpO2 (Spo(2)max) fell below 89% or whose SpO2max fell >4 points from baseline was worse than subjects in comparator groups (log rank p = 0.01 and 0.01, respectively). The hazard of death during the median 7.1 years of follow-up was 2.4 times greater for subjects whose SpO2max fell below 89% (hazard ratio 2.4, 95% CI 1.1 to 4.9, p = 0.02) or whose SpO2max fell >4 points from baseline (hazard ratio 2.4, 95% CI 1.1 to 5.0, p = 0.02). CONCLUSION: In patients with SSc-ILD, SpO2 is an adequate reflection of SaO2 and radial arterial lines need not be inserted during cardiopulmonary exercise tests in these patients. Given the ease of measurement and its prognostic value, SpO2 should be considered as a meaningful clinical and research outcome in patients with SSc-ILD.

Protein levels of CC chemokine ligand (CCL)15, CCL16 and macrophage stimulating protein in patients with sarcoidosis.

The objective of this study was to assess protein levels for candidate cytokines, chemokines, growth factors, matrix metalloproteinases and their inhibitors in bronchoalveolar lavage fluid (BALF) in patients with polar forms of pulmonary sarcoidosis, i.e. Löfgren's syndrome (LS) and more advanced chest X-ray (CXR) stage III disease. Twenty-four inflammatory molecules were analysed in unconcentrated BALF samples from 10 sarcoidosis patients with CXR stage III and 10 patients with LS by semiquantitative protein array. Four novel molecules [CC chemokine ligand (CCL)15, CCL16, macrophage migration inhibitory factor (MIF) and macrophage stimulating protein (MSP)], detected for the first time in association with sarcoidosis, were then quantified by enzyme-linked immunosorbent assay in a second cohort of 68 sarcoidosis patients and 17 control subjects. The protein levels of CCL15, CCL16, CCL24, CXCL8, CXCL9, CXCL10, interleukin-16, MIF, MSP and matrix metallopeptidase 1 were increased in CXR stage III patients when compared with patients with LS. CCL15 and MSP up-regulation in CXR stage III patients in comparison with LS patients and controls was confirmed by enzyme-linked immunosorbent assay. Moreover, MSP was associated with treatment requirement (P = 0.001) and CCL15 was elevated in patients with disease progression at 2-year follow-up (P = 0.016). CCL16 levels were increased in sarcoidosis versus controls (P < 0.05), but no difference was observed between patient subgroups. MIF up-regulation was not confirmed in a larger patient group. In conclusion, chemokines CCL15, CCL16 and MSP were found elevated for the first time in BALF from sarcoidosis patients; our results showed that CCL15 and MSP may affect disease course.

Use of intravenous cyclophosphamide in known or suspected, advanced non-specific interstitial pneumonia.

BACKGROUND: In severe, progressive interstitial lung disease (ILD), specific diagnosis is often difficult, and treatment therefore empirical. An effective, rapidly acting, well-tolerated therapy is desirable. This study reviews the tolerability and efficacy of i.v. cyclophosphamide in known or suspected non-specific interstitial pneumonia (NSIP) following the introduction of an i.v. cyclophosphamide protocol. METHODS: Records of 54 patients with biopsy-proven (n = 7) or suspected NSIP, based on clinico-radiological consensus (n = 47), receiving i.v. cyclophosphamide over 2004-6 were reviewed (excluding systemic sclerosis). Lung-function trends over six months were evaluated, and comparative analysis of paired pulmonary-function before and after the start of therapy was performed. RESULTS: IV cyclophosphamide was well tolerated, with two withdrawals from therapy, and four deaths, not directly related to treatment. IV cyclophosphamide was associated with disease stability at six-months. Despite having severe, progressive disease, patients receiving i.v. cyclophosphamide had stable lung function at six months. A greater therapeutic response was associated with coexistent HRCT abnormalities indicative of organizing pneumonia. In 22 patients with paired pulmonary-function tests, pulmonary function trends were significantly improved (p = 0.03) and change in DLco differed significantly (p < 0.0001), following cyclophosphamide treatment. CONCLUSION: In the empirical treatment of advanced, rapidly progressive known or suspected NSIP, i.v. cyclophosphamide is a well tolerated, rapidly acting immunosuppressant, associated with improvement or stability in most cases.