Clinical Patterns of Sarcoidosis Patients with and without Uveitis: Insights from a Dutch Sarcoidosis Centre.

PURPOSE: Uveitis is a common ocular manifestation in individuals with sarcoidosis, a multisystem inflammatory disorder. This study aimed to explore clinical and genetic factors associated with the presence or absence of uveitis in sarcoidosis patients. METHODS: Total 625 Dutch sarcoidosis patients were included. Among these, 170 underwent ophthalmic examination, and 61 were diagnosed with uveitis. Demographic and clinical data, including age, gender, race, biopsy status, chest radiography findings, TNF-α inhibitor treatment, and uveitis classification were collected retrospectively from medical records. Genetic data was available for HLA haplotypes, TNF-α G-308A, and BTNL2 G16071A polymorphisms. RESULTS: The majority of the patients presented with bilateral uveitis (80.3%). The proportion of women was higher in the uveitis group compared to the non-uveitis group (67.2% and 47.7%; p = 0.014). Pulmonary involvement (chest radiographic stage II-III) was significantly lower in patients with uveitis (36.1% versus 64.2%; p < 0.001). Patients with uveitis were more often treated with TNF-α inhibitors (67.2% versus 29.4%; p < 0.001) and the outcome was better compared with the non-uveitis group, 92% vs 68%, responders (p < 0.012). Uveitis patients treated with TNF-α inhibitors (either adalimumab or infliximab) were more likely to suffer from intermediate or posterior uveitis than anterior uveitis. Genetic analysis identified a significant association between the BTNL2 G16071A GG genotype and uveitis (p = 0.012). CONCLUSION: This study highlights distinctive demographic, clinical and genetic features associated with uveitis in sarcoidosis patients. Ocular sarcoidosis was more prevalent in women. Further research is warranted to explore the implications of these findings for treatment strategies and prognostic assessments.

Is a Vitamin K Epoxide Reductase Complex Subunit 1 (VKORC1) Polymorphism a Risk Factor for Nephrolithiasis in Sarcoidosis?

Sarcoidosis is a systemic inflammatory disorder characterized by granuloma formation in various organs. It has been associated with nephrolithiasis. The vitamin K epoxide reductase complex subunit 1 (VKORC1) gene, which plays a crucial role in vitamin K metabolism, has been implicated in the activation of proteins associated with calcification, including in the forming of nephrolithiasis. This study aimed to investigate the VKORC1 C1173T polymorphism (rs9934438) in a Dutch sarcoidosis cohort, comparing individuals with and without a history of nephrolithiasis. Retrospectively, 424 patients with sarcoidosis were divided into three groups: those with a history of nephrolithiasis (Group I: n = 23), those with hypercalcemia without nephrolithiasis (Group II: n = 38), and those without nephrolithiasis or hypercalcemia (Group III: n = 363). Of the 424 sarcoidosis patients studied, 5.4% had a history of nephrolithiasis (Group I), only two of whom possessed no VKORC1 polymorphisms (OR = 7.73; 95% CI 1.79-33.4; p = 0.001). The presence of a VKORC1 C1173T variant allele was found to be a substantial risk factor for the development of nephrolithiasis in sarcoidosis patients. This study provides novel insights into the genetic basis of nephrolithiasis in sarcoidosis patients, identifying VKORC1 C1173T as a potential contributor. Further research is warranted to elucidate the precise mechanisms and explore potential therapeutic interventions based on these genetic findings.

Drug-Gene Risk Stratification in Patients with Suspected Drug-Induced Interstitial Lung Disease.

BACKGROUND: Pulmonary toxicity has been associated with drug use. This is often not recognized in clinical practice, and underestimated. OBJECTIVE: We aimed to establish whether polymorphisms in certain genes corresponding with a metabolic pathway of drug(s) used are associated with pulmonary toxicity in patients with suspected drug-induced interstitial lung disease (DI-ILD). METHODS: This retrospective observational study explored genetic variations in three clinically relevant cytochrome P450 (CYP) iso-enzymes (i.e., CYP2D6, CYP2C9, and CYP2C19) in a group of patients with a fibroticinterstitial lung disease, either non-specific interstitial pneumonia (n = 211) or idiopathic pulmonary fibrosis (n = 256), with a suspected drug-induced origin. RESULTS: Of the 467 patients, 79.0% showed one or more polymorphisms in the tested genes accompanied by the use of drug(s) metabolized by a corresponding affected metabolic pathway (60.0% poor metabolizers and/or using two or more drugs [likely DI-ILD], 37.5% using three or more [highly likely DI-ILD]). Most commonly used drugs were statins (63.1%) with a predominance among men (69.4 vs 47.1%, p < 0.0001). Nitrofurantoin, not metabolized by the tested pathways, was prescribed more frequently among women (51.9 vs 4.5%, p < 0.00001). CONCLUSIONS: In our cohort with suspected DI-ILD, 79% carried one or more genetic variants accompanied by the use of drugs metabolized by a corresponding affected pathway. In 60%, the diagnosis of DI-ILD was likely, whereas in 37.5%, it was highly likely, based on CYP analyses. This study underlines the importance of considering both drug use and genetic make-up as a possible cause, or at least a contributing factor, in the development and/or progression of fibrotic lung diseases. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00267800, registered in 2005.

Drug-induced comorbidities in patients with sarcoidosis.

PURPOSE OF REVIEW: Sarcoidosis is a chronic multisystemic inflammatory disease of unknown aetiology with a wide range of highly variable clinical manifestations and unpredictable disease course. Sarcoidosis patients may present with specific organ-related symptoms involving functional impairments, and less specific symptoms. The decision whether and when to treat a sarcoidosis patient with pharmacotherapy depends on two major factors: risk of organ failure and/or death and impairment of quality of life. This decision is complex and not standardized. RECENT FINDINGS: Glucocorticoids (GCs) are recommended as initial treatment, when needed. Subsequent GC-sparing alternatives frequently follow. Comorbidities or adverse drug reactions (ADRs) from drugs used in sarcoidosis treatment are sometimes very hard to differentiate from symptoms associated with the disease itself, which may cause diagnostic dilemmas. An ideal approach to minimalize ADRs would involve genetic screening prior to prescribing certain 'high-risk drugs' and therapeutic drug monitoring during treatment. Pharmacogenomic testing aims to guide appropriate selection of medicines, with the potential of reducing unnecessary polypharmacy while improving clinical outcomes. SUMMARY: A multidisciplinary approach to the management of sarcoidosis may avoid unnecessary ADRs. It is important to consider the possibility of drug-induced damage in sarcoidosis, especially if the clinical situation deteriorates after the introduction of a particular drug.

Role of Drug-Gene Interactions and Pharmacogenetics in Simvastatin-Associated Pulmonary Toxicity.

INTRODUCTION: Simvastatin has previously been associated with drug-induced interstitial lung disease. In this retrospective observational study, cases with non-specific interstitial pneumonia (NSIP) or idiopathic pulmonary fibrosis (IPF) with simvastatin-associated pulmonary toxicity (n = 34) were evaluated. OBJECTIVE: To identify whether variations in genes encoding cytochrome P450 (CYP) enzymes or in the SLCO1B1 gene (Solute Carrier Organic anion transporting polypeptide 1B1 gene, encoding the organic anion transporting polypeptide 1B1 [OATP1B1] drug transporter enzyme), and/or characteristics of concomitantly used drugs, predispose patients to simvastatin-associated pulmonary toxicity. METHODS: Characteristics of concomitantly used drugs and/or variations in the CYP or SLCO1B1 genes and drug-gene interactions were assessed. The outcome after withdrawal of simvastatin and/or switch to another statin was assessed after 6 months. RESULTS: Multiple drug use involving either substrates and/or inhibitors of CYP3A4 and/or three or more drugs with the potential to cause acidosis explained the simvastatin-associated toxicity in 70.5% (n = 24) of cases. Cases did not differ significantly from controls regarding CYP3A4, CYP2C9, or OATP1B1 phenotypes, and genetic variation explained only 20.6% (n = 7) of cases. Withdrawal of simvastatin without switching to another statin or with a switch to a hydrophilic statin led to improvement or stabilization in all NSIP cases, whereas all cases who were switched to the lipophilic atorvastatin progressed. CONCLUSION: Simvastatin-associated pulmonary toxicity is multifactorial. For patients with this drug-induced pulmonary toxicity who need to continue taking a statin, switching to a hydrophilic statin should be considered. CLINICALTRIALS. GOV IDENTIFIER: NCT00267800, registered in 2005.

Drug-induced interstitial lung disease: role of pharmacogenetics in predicting cytotoxic mechanisms and risks of side effects.

PURPOSE OF REVIEW: The diagnosis of drug-induced interstitial lung disease (DI-ILD) is challenging and mainly made by exclusion of other possible causes. Toxicity can occur as a cause of drug(s) or drug-drug interactions. In this review, we summarize the possible role of pharmacogenetics of metabolizing enzymes in DI-ILD. RECENT FINDINGS: Knowledge of the genetic predispositions of enzymes involved in drug metabolization and their relation with proposed cytotoxic mechanisms of DI-ILD, in particular direct cell toxicity and free oxygen radical production is increasing. The cytochrome P450 enzyme family and other enzymes play an important role in the metabolism of all sorts of ingested, injected, or inhaled xenobiotic substances. The liver is the major site for metabolism. Metabolic cytotoxic mechanisms have however also been detected in lung tissue. Polymorphisms in genes coding for enzymes that influence metabolic activity may lead to localized (toxic) reactions and tissue damage. This knowledge may be helpful in preventing the risk of DI-ILD. SUMMARY: Drug toxicity can be the consequence of absence or very poor enzyme activity, especially if no other metabolic route is available. In the case of reduced enzyme activity, it is recommended to reduce the dose or to prescribe an alternative drug, which is metabolized by a different, unaffected enzyme system to prevent toxic side effects. However, enhanced enzyme activity may lead to excessive formation of toxic and sometimes reactive metabolites. Therefore, knowing a patient's drug-metabolizing profile before drug prescription is a promising way to prevent or explain DI-ILD.

VKORC1 and CYP2C9 Polymorphisms: A Case Report in a Dutch Family with Pulmonary Fibrosis.

Here, we describe a Dutch family with idiopathic pulmonary fibrosis (IPF). We hypothesized that there might be an association between the presence of Vitamin K epoxide reductase complex 1 (VKORC1) and/or cytochrome P450 2C9 (CYP2C9) variant alleles and the early onset of IPF in the members of this family. VKORC1 (rs9923231 and rs9934438) and CYP2C9 (rs1799853 and rs1057910) were genotyped in this family, which includes a significant number of pulmonary fibrosis patients. In all family members, at least one of the variant alleles tested was present. The presence of the VKORC1 variant alleles in all of the IPF cases and CYP2C9 variants in all but one, which likely leads to a phenotype that is characterized by the early onset and progressive course of IPF. Our findings indicate a role of these allelic variants in (familial) IPF. Therefore, we suggest that the presence of these variants, in association with other pathogenic mutations, should be evaluated during genetic counselling. Our findings might have consequences for the lifestyle of patients with familial IPF in order to prevent the disease from becoming manifest.

Pharmacogenetic variants and vitamin K deficiency: a risk factor or trigger for fibrosing interstitial pneumonias?

PURPOSE OF REVIEW: Fibrosing interstitial pneumonias are associated with various stages of fibrosis. The cause of this group of syndromes remains largely unknown. For most of these diseases, a genetic basis, environmental factors and certain triggers have been suggested as possible risk factors. Various studies have found an association between genetic polymorphisms, or the presence of certain variant alleles, and the occurrence and/or progression of interstitial pneumonias of unknown origin. An acute exacerbation of idiopathic pulmonary fibrosis shows characteristics of diffuse alveolar haemorrhage (DAH). DAH can be aggravated by vitamin K deficiency. This review deals with pharmacogenetic factors underlying interindividual differences of vitamin K status in patients with interstitial pneumonias and the possibilities for a personalized approach to patient management. RECENT FINDINGS: DAH has been associated with the presence of variant alleles in vitamin K epoxide reductase complex 1, cytochrome P450 (CYP)2C9 and CYP2C19 genes. Vitamin K deficiency has been associated with an increased risk for the development of DAH and progression and/or deterioration of interstitial pneumonias. This is in line with plausible pathophysiological mechanisms. However, clinical use should be confirmed. SUMMARY: DAH has been associated with vitamin K deficiency and suggested as potential trigger of fibrosing interstitial pneumonias. Information on genetic variation might benefit ongoing/new clinical trials, design of which should reflect needs to address relevance of testing gene variants. Whether vitamin K supplementation may prevent exacerbations or progression of interstitial pneumonias needs to be explored in future studies.

Increased circulating desmosine and age-dependent elastinolysis in idiopathic pulmonary fibrosis.

Although chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) seem to be opposite entities from a clinical perspective, common initial pathogenic steps have been suggested in both lung diseases. Emphysema is caused by an elastase/anti-elastase imbalance leading to accelerated elastin degradation. Elastinolysis is however, also accelerated in the IPF patients' lungs. The amino acids desmosine and isodesmosine (DES) are unique to elastin. During the degradation process, elastases liberate DES from elastin fibers. Blood DES levels consequently reflect the rate of systemic elastinolysis and are increased in COPD. This is the first report describing elevated DES levels in IPF patients. We also demonstrated that the age-related increment of DES concentrations is enhanced in IPF. Our current study suggests that elastinolysis is a shared pathogenic step in both COPD and IPF. Further investigation is required to establish the relevance of accelerated elastin degradation in IPF and to determine whether decelerating this process leads to slower progression of lung fibrosis and better survival for patients with IPF.

Acute eosinophilic pneumonia associated with glyphosate-surfactant exposure.

We report a case of a female patient who developed acute eosinophilic pneumonia (AEP) after recent onset of smoking and exposure to glyphosate-surfactant.The additional exposure associated with the recent start of smoking may have contributed to the development and/or severity of AEP.A clinical relapse after re-challenge four years later both with smoking and glyphosate-surfactant made the association highly likely.Respiratory distress is a factor of poor outcome and mortality after ingestion of glyphosate-surfactant.This case highlights the importance of a thorough exposure history e.g., possible occupational and environmental exposures together with drug-intake.Genotyping should be considered in cases of severe unexplained pulmonary damage.

Extent of disease activity assessed by 18F-FDG PET/CT in a Dutch sarcoidosis population.

BACKGROUND: Sarcoidosis is characterized by a wide range of disease manifestations. In the management and follow-up of sarcoidosis patients, knowledge of extent of disease, activity and severity is crucial. Objectives The aim of this study was to assess the extent, distribution and consistency of inflammatory organ involvement using 18F-FDG PET/CT (PET) in sarcoidosis patients with persistent disabling symptoms. METHODS: Retrospectively, sarcoidosis patients who underwent a PET between 2005 and 2011 (n=158) were included. Clinical data were gathered from medical records and PET scans were evaluated. Positive findings were classified as thoracic and/or extrathoracic. RESULTS :Of the studied PET positive sarcoidosis patients (n=118/158; 75%), 93% had intrathoracic activity (79% mediastinal and 64% pulmonary activity, respectively) and 75% displayed extrathoracic activity (mainly peripheral lymph nodes, bone/bone marrow, and spleen). Hepatic positivity was always accompanied by splenic activity, whereas the majority of patients with parotid gland, splenic or bone/bone marrow activity showed lymph node activity. A substantial number of patients with PET positive pulmonary findings (86%) had signs of respiratory functional impairment. No obvious association between hepatic, splenic or bone/bone marrow activity and their corresponding laboratory abnormalities suggestive of specific organ involvement, was found. CONCLUSIONS: The majority of studied patients appeared to have PET positive findings (75%), of which a high proportion (75%) displayed extrathoracic activity. Hence, PET can be especially useful in the assessment of extent, distribution and consistency of inflammatory activity in sarcoidosis to provide an explanation for persistent disabling symptoms and/or to provide a suitable location for biopsy.

Association of the TNF-α G-308A polymorphism with TNF-inhibitor response in sarcoidosis.

Responsiveness to tumour necrosis factor (TNF) inhibitors has been associated with the TNF-α G-308A polymorphism in rheumatoid arthritis. The aim of this study was to examine the association between the presence of this polymorphism and the response to TNF inhibitors in patients with refractory sarcoidosis. Patients (n=111) who started TNF-inhibitor treatment (76 infliximab, 35 adalimumab) were followed for at least 1 year. The main symptoms in these patients were fatigue (n=100, 90.1%), small fibre neuropathy (n=91, 82.0%), pulmonary involvement (n=69, 62.2%), and/or uveitis (n=31, 27.9%). Patients were additionally genotyped for the presence of the TNF-α G-308A polymorphism. Treatment response was assessed using clinical outcome measures and questionnaires. Three-quarters (n=83, 74.8%) of the patients responded well. Of the patients without the variant A-allele 93.6% (73 out of 78, p<0.001) improved, while 30.3% (10 out of 33) of variant A-allele carriers responded favourably to TNF inhibitors. For patients with the GG-genotype, the probability of improving compared with remaining stable or deteriorating was three times higher (risk ratio 3.09, 95% CI 1.84-5.20). Sarcoidosis patients without the TNF-α -308A variant allele (GG-genotype) had a three-fold higher response to TNF inhibitors (adalimumab or infliximab). Further research is needed to evaluate the value of genotyping for the TNF-α G-308A polymorphism in order to tailor TNF-inhibitor treatment.

Body composition profiling in a Dutch sarcoidosis population.

UNLABELLED: Muscle atrophy is a common problem in many chronic inflammatory diseases. It may occur as part of a generalized wasting process (cachexia) or be hidden due to preservation of fatmass (sarcopenia, sarcopenic obesity). OBJECTIVES: The aim of this study was to assess the prevalence of cachexia and muscle atrophy in sarcoidosis and their association with disease activity and severity. METHODS: A cross-sectional study was performed in 423 sarcoidosis patients. Fat-free mass was assessed as an indirect measure of muscle mass by bioelectrical impedance analysis. Patients were stratified based on body mass index (BMI) and fat-free mass index (FFMI).Muscle atrophy was defined as FFMI <15 kg/m2 for women and <17 kg/m2 for men corresponding to <10th percentile of current reference values; cachexia as BMI <20 combined with muscle atrophy.Multivariate linear regression models were used to adjust for potential confounders. RESULTS: Of the patients examined, 58% were categorized as overweight (37%) or obese (21%), whereas 7% were underweight.Muscle atrophy was present in 25% and cachexia in 5%. Patients with muscle atrophy showed significantly worse lung function (DLCO, FEV1, FVC, all p-values <0.01) and impaired exercise capacity (VO2max, p<0.001). The associations were most pronounced in patients with cachexia. Associations remained significant after adjustment for potential confounders. CONCLUSIONS: Muscle atrophy was present in 25% of sarcoidosis patients and was associated with more severe pulmonary disease. Prospective studies with longitudinal design are needed to assess the association between muscle atrophy and disease severity in sarcoidosis.

Therapeutic approach of hepatic sarcoidosis.

PURPOSE OF REVIEW: Surveillance of hepatic involvement in sarcoidosis has not been standardized. Therefore, management of hepatic involvement is a clinical challenge. This review analyses published data on the pharmacological treatment of hepatic sarcoidosis. RECENT FINDINGS: Only 5-30% of patients with hepatic sarcoidosis display symptoms. Occasionally, it has a rapid progressive course with serious complications, stressing an appropriate and carefully timed therapeutic approach. Because symptomatic hepatic sarcoidosis is uncommon, therapeutic studies are scarce. Answers to the questions when to initiate which treatment are lacking. Case reports describe beneficial effects of prednisone and the augmentation of cytotoxic and anti-tumor necrotic factor-α (TNF-α) therapy. However, because of small sample sizes, no meaningful conclusions could be drawn. In symptomatic hepatic sarcoidosis patients, it is recommended to start to treat the sarcoidosis with prednisone, preceded by ursodeoxycholic acid when signs of cholestasis are present. In refractory cases or when prednisone weaning is impossible, cytotoxic drugs or anti-TNF-α therapy should be considered. SUMMARY: This review illustrates the importance of an appropriate therapeutic approach of sarcoidosis patients with hepatic involvement. It emphasizes the need for future studies to evaluate treatment options to avoid disease progression and hepatic complications.

Liver-test abnormalities in sarcoidosis.

BACKGROUND: Sarcoidosis is a multisystemic inflammatory granulomatous disease. The prevalence of hepatic involvement is not clear. AIM: The aim of this study was to establish the presence and severity of the liver-test abnormalities in sarcoidosis. METHODS: Retrospectively, patients with confirmed sarcoidosis (n=837) presented with the liver-test abnormalities [alkaline phosphatase, γ-glutamyl transaminase, alanine aminotransferase or aspartate aminotransferase >1.5 times the upper limit of normal (ULN)] who were classified according to severity into mild (zero liver tests ≥3×ULN), moderate (one or two liver tests ≥3×ULN) and severe (three or four liver tests ≥3×ULN) were evaluated. Moreover, the relationship between severity of liver tests and histology was examined. RESULTS: Liver-test abnormalities were found in 204 of 837 patients with chronic sarcoidosis (24.4%), among which 127 (15.2%) were suspected of having hepatic sarcoidosis (79 of 127 males, 111 Caucasian, eight African-American). In 22 of 127 patients (17.3%), a liver biopsy was obtained; 21 were compatible with hepatic sarcoidosis. In these 21 patients, severity of liver-test abnormalities was significantly associated with extensiveness of granulomatous inflammation (ρ=0.58, P=0.006) and degree of fibrosis (ρ=0.64, P=0.002). These results remained in the multiple regression analysis when controlled for treatment status, sex, genetics, ethnicity and age. CONCLUSION: Liver-test abnormalities were present in 24% of the studied patients; in 15% highly because of hepatic involvement of sarcoidosis. Moderate and severe liver-test abnormalities seemed to be associated with more advanced histopathological disease. Therefore, in the management of sarcoidosis, for patients with moderate or severe liver-test abnormalities a liver biopsy is recommended.

F-18 FDG PET/CT for detecting bone and bone marrow involvement in sarcoidosis patients.

BACKGROUND: The prevalence of bone involvement in sarcoidosis has been estimated to be 3% to 5%, mostly affecting the phalanges. The aim of this study was to assess the prevalence and distribution pattern of bone and bone marrow involvement as detected by positron emission tomography/computed tomography (PET/CT) in sarcoidosis patients. METHODS: Between June 2006 and September 2010, 122 patients suffering from severe sarcoidosis who underwent a PET/CT and met the inclusion criteria were studied. In 94 (77%) patients, the PET/CT demonstrated positive findings associated with sarcoidosis. The 94 PET/CTs were screened for the presence of bone/bone marrow localizations. Additionally, low-dose CT scans were screened for other causes of increased bone uptake. Relevant clinical data were gathered retrospectively. RESULTS: Evidence for bone/bone marrow localizations was found in 34% of the 94 patients with PET/CT-positive findings. Of these patients, 60% showed obvious focal bone lesions at various localizations: axial skeleton (47%), pelvis (40%), extremities (34%), and skull (2%). In 40% of patients, diffuse increased uptake in both axial and peripheral bone marrow, without focal lesions, was found. Both diffuse and focal uptake were seen in 34%, whereas only focal lesions were observed in 25%. In all but 2 (6%) patients, no bone abnormalities on low-dose CT were found. CONCLUSIONS: More than one-third of PET/CT-positive sarcoidosis patients had osseous abnormalities on PET/CT. The majority of these lesions (94%) could not be detected on low-dose CT. No single localization of preference was found. These preliminary results stress the value of PET/CT imaging in the assessment of bone/bone marrow involvement in sarcoidosis patients.

Everyday cognitive failure in sarcoidosis: the prevalence and the effect of anti-TNF-alpha treatment.

BACKGROUND: Cognitive symptoms, such as concentration problems, are frequently recorded by sarcoidosis patients. OBJECTIVES: The aim of this study was to assess the prevalence of perceived everyday cognitive failure in sarcoidosis patients and healthy controls. Furthermore, the effect of treatment on cognitive functioning was examined. METHODS: The study included 343 sarcoidosis patients (44.6% females; age 49.3 +/- 11.0 years). They completed the Cognitive Failure Questionnaire (CFQ) and Fatigue Assessment Scale (FAS) at baseline and the 6-month follow-up to evaluate the effect of treatment on cognitive functioning. The control group consisted of 343 age- and sex-matched healthy controls. RESULTS: The mean CFQ score was significantly higher in sarcoidosis patients (37.3 +/- 16.1) compared with the controls (31.3 +/- 10.1; p < 0.0001).A high CFQ sore (> or =43) was found in 35.0% of the patients and only 14.3% of the controls. No relation with disease severity and duration, or disease location was found. The proportion of patients receiving treatment did not differ among the groups with high and normal CFQ score. At the 6-month follow-up, only patients recently treated with anti-TNF-alpha therapy (n = 42) demonstrated a significant improvement in the CFQ score (Delta -7.07 +/- 7.23) compared with the untreated patients (Delta -0.08 +/- 9.35) and patients treated with prednisone with or without methotrexate (Delta 1.67 +/- 9.22; p < 0.0001). After adjustment for the concomitant decrease in fatigue, the effect of anti-TNF-alpha therapy remained high and significant. CONCLUSIONS: Subjective cognitive failure is a substantial problem in sarcoidosis patients regardless of disease severity. Anti-TNF-alpha therapy had a positive effect on cognition, fatigue and other symptoms of sarcoidosis.

Rapid genotyping of the OATP1B1 polymorphisms A388G and T521C with real-time PCR FRET assays.

The polymorphisms (OATP)1B1 A388G and T521C of the solute carrier organic anion-transporter family member 1B1 gene (SLCO1B1), previously known as OATP-C, have potential impacts on drug metabolism. In order to establish a fast and consistent assay for these polymorphisms, rapid speed polymerase chain reaction (PCR) fluorescence resonance energy transfer (FRET) assays on the LightCycler were developed for both OATP1B1 polymorphisms. A locked nucleic acid (LNA) on the polymorphic location within the sensor probe was necessary to discriminate both alleles of the OATP1B1 T521C polymorphism. To confirm the reliability of both real-time PCR FRET assays, these new methods were validated by genotyping 120 samples using a PCR restriction fragment length polymorphism (RFLP) assay and an allele-specific PCR. The results of the real-time PCR FRET assays were completely in line with conventional PCR methods, indicating that the real-time PCR FRET assays are appropriate for clinical settings.