Methotrexate treatment efficacy in sarcoidosis might be related to TNF-α polymorphism: real life preliminary study.

INTRODUCTION: Methotrexate therapy improves lung function in selected sarcoidosis patients. Variation in TNF gene was associated with response to treatment. Aim: To determine the predictive role of-308 G/A, -857C/T, -863 C/A and -1031 T/C TNF-α polymorphism in the efficacy of MTX for progressive pulmonary sarcoidosis. MATERIAL AND METHODS: Twenty-eight sarcoidosis patients treated with MTX (6-24 months) were genotyped for TNF-α polymorphisms: -1031 T/C, -857C/T, -308 G/A and -863 C/A. Pulmonary function test (PFT) were performed every 6 months to determine treatment response, until the drug withdrawal. RESULTS: No correlation between the initial clinical presentation of sarcoidosis and TNF α polymorphisms was found, neither for every allele nor for combined genotypes distribution. According to PFT evaluation we have discovered 3 types of response to MTX: early (ER), late (LR) and No-response (NR). TNF-α-308 A allele carriers have got significantly higher chance to be LR, p=0.02, RRI:83%. TNF-α-308 GG genotype transferred the 3-fold higher probability of early vs late response to MTX, p=0.02. Combined genotyping allowed to distinguish LR from ER and NR groups. ER and NR patients are genetically similar (-857CC-308GG). LR are "genetically" different group of patients (-857C/T-308GG or -857CC-308A/G) with 5-fold greater probability to be LR than TNF-α-857CC-308GG patients, p=0,005 sensitivity 85%, specificity: 43%, PPV 58%, NPV 75%. TNF-α-308GG-857CC patients have significantly lower chance to be LR comparing to other response type p=0.03 OR=0,075 95% CI=0.07-0.08. CONCLUSION: Two types of positive response to MTX therapy (early and late) in chronic respiratory sarcoidosis are associated with polymorphic changes in TNF gene.

The influence of comorbidities on mortality in sarcoidosis: a observational prospective cohort study.

AIM: The aim of this study was to identify the frequency and prevalence of comorbidities in sarcoid patients and to assess their influence on overall mortality in the cohort of patients with sarcoidosis. MATERIALS AND METHODS: A cohort of 557 patients with histologically confirmed sarcoidosis diagnosed between 2007 and 2011 and a group of non-sarcoid controls were observed. All patients were carefully observed for comorbidities and mortality. RESULTS: 291 males (52.2%) and 266 females (47.8%) with mean age 48.4 ± 12.0 years in sarcoidosis group and a group of 100 controls with mean age (49.25 ± 10.3) were observed. The mean number of comorbidities in both groups was similar (0.9 ± 0.99 vs 0.81 ± 0.84 NS). The frequency of thyroid disease was significantly higher in sarcoidosis group comparing to controls at the time of diagnosis (OR = 3.62 P = 0.0144). During the observation period (median 58.0 months), 16 patients died (2.9%). The mean number of comorbidities was significantly higher in the groups of non-survivors as compared to survivors (2.8 ± 1.0, vs 0.8 ± 0.9), P < 0.0001. CONCLUSION: The comorbidity burden has strong impact on mortality in sarcoidosis. Thyroid diseases are more frequent in sarcoidosis than in non-sarcoid controls.

Methotrexate as a single agent for treating pulmonary sarcoidosis: a single centre real-life prospective study.

INTRODUCTION: The first-line therapy in chronic sarcoidosis, according to WASOG/ATS/ERS recommendations, is GCS. This therapy is associated with significant adverse effects and finally does not alter the natural history of the disease. The objective of our study was to evaluate the efficacy and safety of monotherapy with MTX, as an alternative to GCS, in progressive pulmonary sarcoidosis. MATERIAL AND METHODS: An open prospective real-life, single-centre trial was performed on 50 patients with biopsy proven sarcoidosis, 28M and 22F, mean age 45.55 ± 8.9 years. The average duration of disease before MTX therapy was 12.34 ± 20.49 years, GCS therapy in the past was applied in 41 patients. All patients received MTX (10 mg or 15 mg weekly) between 2004 and 2013 because of chronic progressive pulmonary sarcoidosis. Therapy was planned for 24 months. Patients underwent regular clinical evaluation, pulmonary function assessment, exercise ability testing (6MWT), and chest radiography for therapy effectiveness every six months and side effects monitoring every 4-6 weeks. Forty-nine patients were included for statistical analysis of treatment efficacy. They were retrospectively allocated to "MTX responder" group if an improvement of 10% of FEV1, FVC, TLC, or 15% of DLCO from the initial value was documented for at least one parameter or "non-responders" if the patient did not meet the above-mentioned criteria. RESULTS: Duration of treatment ranged from 6 to 24 months, mean time 60.75 ± 34.1 weeks. For the whole cohort significant improvement after MTX therapy was observed for minimal SaO2 (%) (p = 0.043) and for decrease of DSaO2 (%) (p = 0.048) in six-minute walk test. The results were significantly better for patients treated with 15 mg than for those treated with 10 mg weekly and for those who obtained a greater total amount of MTX during therapy. Significant difference of DLCO%pred was observed after six months of MTX therapy between groups treated 15 mg vs 10 mg weekly (73.27 ± 12.7% vs. 63.15 ± 16.4%, p = 0.03). Twenty-five patients (55%) met the criteria of "MTX responders" group. Patients who responded well to treatment had significantly lower TLC and FVC initial values comparing to "MTX non-responders". After treatment the only significant difference in PFT between groups was noted for DLCO%pred. Eleven patients (22%) stopped the treatment due to adverse events of MTX, mild hepatic abnormalities were observed in ten patients (20%), and concomitant infection was found in four patients. There were no patients with a fatal outcome. CONCLUSIONS: MTX as a single agent in the treatment of sarcoidosis has proved to be a safe and effective steroid alternative. Selected patients with chronic pulmonary sarcoidosis experience definite PFT improvements after MTX treatment. There is need to search for predictors of MTX treatment effectiveness.

[Markers of fibrosis and inflammation in exhaled breath condensate (EBC) and bronchoalveolar lavage fluid (BALF) of patients with pulmonary sarcoidosis -- a pilot study]. / Markery wlóknienia i zapalenia w kondensacie powietrza wydychanego (EBC) oraz w plynie z plukania oskrzelowo-pecherzykowego (BALF) u chorych na sarkoidoze pluc - badanie pilotazowe.

INTRODUCTION: Sarcoidosis is a disease of unknown etiology. Little is known of predictive factors of fibrosis. It was suggested that PAI-1, uPA, TGF-beta1, VEGF, IL-8, TNF-alpha influence this process. AIMS: To assess airway inflammatory and fibrosis markers in EBC in sarcoidosis and the effect of fiberoptic bronchoscopy (FOB), bronchoalveolar lavage fluid (BALF), transbronchial lung biopsy (TBLB) and bronchial mucosa membrane biopsy on their production in the airways. MATERIAL AND METHODS: The study group consisted of 11 patients (5 women, 6 men; mean age 40 +/- 9 yrs, mean +/- SD) with sarcoidosis stage I-III. PAI-1 (ng/ml), uPA (ng/ml), TGF-beta1 (pg/ml), VEGF (pg/ml), IL-8 (pg/ml), TNF-alpha (pg/ml) levels were measured in BALF and EBC collected before and 48 hours after FOB. RESULTS: No significant changes in EBC levels of VEGF, PAI-1, TGF-beta1, TNF-alpha (respectively: 8.02 +/- 4.97 pg/ml; 1.1 +/- 1.2 ng/ml; 2909.7 +/- 206.6 pg/ml; 10.7 +/- 19.9 pg/ml) after FOB were observed when compared to baseline. In contrast, IL-8 concentration in EBC (pg/ml) decreased after FOB (0.073 +/- 0.13 v. 0.061 +/- 0.1, p = 0.006) and was significantly lower than in BALF (BALF 0.95 +/- 0.62, p < 0.05). Also, mean level of VEGF was higher in BALF than in EBC both pre- and post- FOB (BALF 66.38 +/- 36.95, EBC pre-FOB 6.75 +/- 3.67 and EBC post-FOB 8.02 +/- 4.97). Significant relationship between TNF-alpha in post-FOB EBC and BALF was also shown (b = 0.63, p = 0.04). CONCLUSIONS: FOB does not significantly affect levels of airway inflammation and fibrosis markers present in EBC before and after FOB; they were also comparable to the concentrations marked by BALF. The lack of correlation between markers levels in EBC and BALF indicates that these methods are not equivalent. Due to repeatibility, and less invasive, simple method of EBC test it seems reasonable to continue the research on the larger number of patients.

[Simultaneous detection of tumor cells and the positive result of genetic test for Mycobacterium tuberculosis in pleural effusion]. / Jednoczesne wykrycie komórek nowotworowych i materialu genetycznego pratków gruzlicy w plynie oplucnowym.

Pleural effusion is a frequently observed lesion in the course of respiratory diseases such as inflammatory process and cancer metastasis. Its cause may be either tuberculosis (the most common extrapulmonary location is the pleura) and malignant disease of the pleura. Confirmation of tuberculosis is often troublesome. The primary site of cancer may be also difficult to find despite the application of difficult diagnostic methods. Below we present history of 79-year-old female in whom carcinomatous cells and positive result of PCR for Mycobacterium tuberculosis in pleural fluid were discovered simultaneously suggesting the tuberculosis and cancer of unknown primary origin.

[Obstructive sleep apnea in patient with Prader-Willi syndrome]. / Obturacyjny bezdech senny u pacjenta z zespolem Pradera-Williego.

Prader-Willi syndrome (PWS) is a genetic disorder caused by loss of function of genes situated within the 15q11-q13 region of chromosome 15. The disorder is characterized by central obesity, short stature, dysfunction of several hypothalamic centers. These symptoms lead to progressive metabolic, respiratory, circulatory and orthopedic complications. Because of the etiology of the disorder there is no known causal treatment. Patients should comply with dietary restrictions and behavioral modifications as it may reduce the risk of obesity related diseases. In this paper we present case of a 34-years old obese patient with PWS who was diagnosed with obstructive sleep apnea, and whom CPAP treatment was offered.

[Relationship between age and cardiovascular complications in obstructive sleep apnoea]. / Ocena zwiazków pomiedzy wiekiem oraz wystepowaniem powiklan sercowo-naczyniowych u chorych na obturacyjny bezdech senny.

INTRODUCTION: Obstructive sleep apnoea (OSA) is a risk factor for cardiovascular morbidity and mortality. The aim of this study was to assess relations between cardiovascular diseases (CVD) and age in OSA subjects. MATERIAL AND METHODS: Consecutive OSA subjects (AHI/RDI > 10, Epworth score > 9 points) were evaluated. The chest X-ray, spirometry, arterial blood gases, ECG, blood morphology and biochemistry were performed during trial treatment with autoCPAP. RESULTS: We studied 533 consecutive OSA patients, mean age 55.6 +/- 10.3 years (range 24-81), with obesity (BMI 34.4 +/- 6.6 kg/m(2)) and severe OSA (AHI/RDI 37.8 +/- 21.8). To evaluate relations between CVD and age, patients were divided into three groups. Group 1 < 50 years (123 subjects, 23.1%), Group 2 aged 50-60 years (250 subjects, 46.9%) and Group 3 > 60 years (160 subjects, 30%). Subjects < 50 years were more obese and had higher AHI/RDI when compared to older groups. Incidence of arterial hypertension, coronary artery disease, atrial fibrillation, heart failure and stroke increased with age (higher in subjects > 60 years). CONCLUSIONS: Cardiovascular diseases were prevalent in OSA patients > 60 years. However the youngest group presented with more severe obesity and higher AHI/RDI.

[Metabolic abnormalities in obstructive sleep apnea patients]. / Zaburzenia metaboliczne u chorych na obturacyjny bezdech senny.

INTRODUCTION: Obstructive sleep apnea (OSA) is a well-recognized risk factor of cardiovascular disorders and is related to metabolic syndrome. The aim of this study was to evaluate the effect of BMI and AHI/RDI on metabolic disturbances in patients suspected of OSA. MATERIAL AND METHODS: Ninety-nine patients referred with suspected OSA underwent standard polysomnography or limited sleep study. AHI/RDI > or = 10/hour was considered relevant for OSA diagnosis. Subjects with AHI/RDI < 10 were considered as controls. We assessed apnea-hypopnea index or respiratory disturbances index (AHI/RDI), Epworth sleepiness scale (ESS), body mass index (BMI), C-reactive protein (CRP, mg/l), glycosylated haemoglobin (HbA1c, %), fasting serum total cholesterol, HDL-, LDL-cholesterol, triglycerides (TG), glucose (G), insulin (INS, IU/ml) and HOMA index. RESULTS: Data are presented as mean +/- SD or median (interquartile range) for parametric and nonparametric data respectively. Twenty-two patients were included as controls (age 51.8 +/- 10 vs. 55 +/- 11 in OSA; p = NS). AHI/RDI in the OSA group was 23 (16-31.3) and 7 (3.8-8.1) in controls (p < 0.001). BMI in OSA 32.2 +/- 5.8 vs. 30.4 +/- 4.6 in controls (p = NS). Patients with OSA had higher TG (160 +/- 75.9 vs. 130.2 +/- 51.9 mg/dl, p = 0.046), G (5.04 +/- 0.6 vs. 4.47 +/- 0.6, p = 0.0037), HOMA (2.31 +/- 1.5 vs. 1.85 +/- 1.7, p = 0.046). G correlated best with AHI/RDI (p < 0.001, r = 0.41). Significant differences were observed in OSA patients between obese (51 pts, BMI 35.2 +/- 4.8) and non-obese (26 pts, BMI 26.61 +/- 1.9) pts in: HDL-cholesterol (50.8 +/- 13.2 vs. 60.9 +/- 18.4 mg/dl; p = 0.02), TG (178.7 +/- 69.9 vs. 124 +/- 75.3 mg/dl, p < 0.001), G (5.15 +/- 0.7 vs. 4.8 +/- 0.5 mmol/l, p = 0.01), INS (11.7 +/- 5.9 vs. 6.57 +/- 4.7, p < 0.001), HOMA (2.7 +/- 1.4 vs. 1.4 +/- 1.2, p < 0.001), HbA(1c) (5.89 +/- 0.9 vs. 5.4 +/- 0.8, p = 0.03), CRP (2.2 +/- 2.9 vs. 1.09 +/- 1.2, p = 0.01). CONCLUSIONS: Our findings support the results of previous studies showing the influence of OSA alone on metabolic disturbances. However, BMI has major impact on metabolic variables.