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.

Tamsulosin Associated with Interstitial Lung Damage in CYP2D6 Variant Alleles Carriers.

Drugs are serious but underestimated causative agents of interstitial lung disease (ILD). Both cytotoxic and immune mechanisms may be involved in drug-induced ILD (DI-ILD). We aimed to investigate whether polymorphisms of relevant CYP enzymes involved in the metabolization of tamsulosin might explain the pathologic mechanism of the DI-ILD in the cases with suspected tamsulosin DI-ILD. We collected 22 tamsulosin-associated DI-ILD cases at two ILD Expertise Centers in the Netherlands between 2009 and 2020. CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 single nucleotide polymorphisms were genotyped and compared with a control group of 78 healthy Caucasian male volunteers. Nine cases were phenotyped as CYP2D6 poor metabolizers and 13 as CYP2D6 intermediate metabolizers. The phenotypes of the cases differed significantly from those of the healthy controls, with more poor metabolizers. After withdrawal of tamsulosin, the pulmonary condition of three cases had improved, six patients had stabilized, and one patient stabilized after reducing the tamsulosin dose. The described 22 cases suggest that an association between the presence of CYP2D6 allelic variants and tamsulosin-associated ILD is highly likely. These cases highlight the importance of both clinical and genetic risk stratification aimed to achieve a more accurate prevention of DI-ILD in the future and enhance the quality of life of patients.

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.

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.

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.

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.

Diffuse alveolar hemorrhage in coumarin users: a fibrosing interstitial pneumonia trigger?

BACKGROUND: Fibrosing interstitial pneumonias (IPs) include idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP). It has been suggested that oxidative damage plays a role in the pathophysiology of idiopathic interstitial pneumonias. Diffuse alveolar hemorrhage (DAH) can cause oxidative stress. Accordingly, we hypothesized that episodes of DAH might trigger fibrosing IP development. METHODS: Patients using coumarins with confirmed DAH were retrospectively gathered during a 9 year period and reviewed for the development of IPF or fibrosing NSIP. RESULTS: A total of 65 patients with DAH could finally be included, 31 (48 %) of whom subsequently developed a fibrosing IP. The majority of these 31 patients developed the fibrosing IP within 3 years after DAH confirmation. A total of 41 (63 %) patients died within 3.0 ± 0.9 (range 1.3-4.7) years after the DAH diagnosis had been confirmed. Twenty-two of the deceased (54 %) had finally developed fibrosing IP. CONCLUSIONS: Almost half of the patients with established episodes of DAH developed fibrosing IP; therefore it seems that DAH might be a trigger for the development of fibrosing IP. This observation warrants prospective studies to further evaluate the clinical impact of these findings.

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.

A predictive tool for an effective use of (18)F-FDG PET in assessing activity of sarcoidosis.

BACKGROUND: (18)F-FDG PET/CT (PET) is useful in assessing inflammatory activity in sarcoidosis. However, no appropriate indications are available. The aim of this study was to develop a prediction rule that can be used to identify symptomatic sarcoidosis patients who have a high probability of PET-positivity. METHODS: We retrospectively analyzed a cohort of sarcoidosis patients with non organ specific persistent disabling symptoms (n = 95). Results of soluble interleukin-2 receptor (sIL-2R) assessment and high-resolution computed tomography (HRCT) were included in the predefined model. HRCT scans were classified using a semi-quantitative scoring system and PET findings as positive or negative, respectively. A prediction model was derived based on logistic regression analysis. We quantified the model's performance using measures of discrimination and calibration. Finally, we constructed a prediction rule that should be easily applicable in clinical practice. RESULTS: The prediction rule showed good calibration and good overall performance (goodness-of-fit test, p = 0.78, Brier score 20.1%) and discriminated between patients with positive and negative PET findings (area under the receiver-operating characteristic curve, 0.83). If a positive predictive value for the presence of inflammatory activity of ≥90% is considered acceptable for clinical decision-making without referral to PET, PET would be indicated in only 29.5% of the patients. Using a positive predictive value of 98%, about half of the patients (46.3%) would require referral to PET. CONCLUSIONS: The derived and internally validated clinical prediction rule, based on sIL-2R levels and HRCT scoring results, appeared to be useful to identify sarcoidosis patients with a high probability of inflammatory activity. Using this rule may enable a more effective use of PET scan for assessment of inflammatory activity in sarcoidosis.

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.

Differential Impact of Cytochrome 2C19 Allelic Variants on Three Different Platelet Function Tests in Clopidogrel-Treated Patients.

On-treatment platelet reactivity in clopidogrel-treated patients can be measured with several platelet function tests (PFTs). However, the agreement between different PFTs is only slight to moderate. Polymorphisms of the CYP2C19 gene have an impact on the metabolization of clopidogrel and, thereby, have an impact on on-treatment platelet reactivity. The aim of the current study is to evaluate the differential effects of the CYP2C19 genotype on three different PFTs. METHODS: From a prospective cohort study, we included patients treated with clopidogrel following percutaneous coronary intervention (PCI). One month after PCI, we simultaneously performed three different PFTs; light transmission aggregometry (LTA), VerifyNow P2Y12, and Multiplate. In whole EDTA blood, genotyping of the CYP2C19 polymorphisms was performed. RESULTS: We included 308 patients treated with clopidogrel in combination with aspirin (69.5%) and/or anticoagulants (33.8%) and, based on CYP2C19 genotyping, classified them as either extensive (36.4%), rapid (34.7%), intermediate (26.0%), or poor metabolizers (2.9%). On-treatment platelet reactivity as measured by LTA and VerifyNow is significantly affected by CYP2C19 metabolizer status (p < 0.01); as metabolizer status changes from rapid, via extensive and intermediate, to poor, the mean platelet reactivity increases accordingly (p < 0.01). On the contrary, for Multiplate, no such ordering of metabolizer groups was found (p = 0.10). CONCLUSIONS: For VerifyNow and LTA, the on-treatment platelet reactivity in clopidogrel-treated patients correlates well with the underlying CYP2C19 polymorphism. For Multiplate, no major effect of genetic background could be shown, and effects of other (patient-related) variables prevail. Thus, besides differences in test principles and the influence of patient-related factors, the disagreement between PFTs is partly explained by differential effects of the CYP2C19 genotype.

Relationship between drug-induced interstitial lung diseases and cytochrome P450 polymorphisms.

PURPOSE OF REVIEW: Interstitial lung disease and especially drug-induced interstitial lung disease can occur as a cause of drug(s) or drug-drug interactions. In this review we summarize the possible role of cytochrome P450 (CYP) enzymes in drug-induced interstitial lung disease. RECENT FINDINGS: The CYP enzyme family plays an important role in the metabolism of all sorts of ingested, injected or inhaled xenobiotic substances. Although the liver is considered to be the major metabolism site of CYP enzymes, in recent years more CYP isoforms have been detected in lung tissue. Polymorphisms in these CYP genes can influence the metabolic activity of the subsequent enzymes, which in turn may lead to localized (toxic) reactions and tissue damage. SUMMARY: Drug toxicity can be the consequence of no or very poor enzyme activity, especially if no other metabolic route is available. In the case of reduced enzyme activity, dose reduction or prescribing an alternative drug metabolized by a different, unaffected CYP enzyme is recommended to prevent toxic side effects. Therefore, knowing a patient's CYP profile before drug prescription could be a way to prevent drug-induced interstitial lung disease. Moreover, it might be helpful in explaining serious adverse effects from inhaled, injected or ingested xenobiotic substances.

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.

Everyday cognitive failure in patients suffering from neurosarcoidosis.

BACKGROUND: Cognitive failure is associated with memory and concentration problems. Previously, a prevalence of one third was found in a general sarcoidosis population. The aim of this study was to assess if neurosarcoidosis patients are at higher risk for developing everyday cognitive failure using the Cognitive Failure Questionnaire (CFQ) and to determine what factors were associated with cognitive failure. METHODS: A cross-sectional web-based survey was conducted from April to May 2017 in a national sample of neurosarcoidosis patients. The survey asked about complaints and included 3 questionnaires (Fatigue Assessment Scale [FAS], Small Fiber Neuropathy Screening List [SFNSL] and CFQ. Data were compared to a general sarcoidosis population. RESULTS: Of the 152 patients who completed the survey, 131 had neurosarcoidosis. The mean CFQ score was significantly higher in the neurosarcoidosis (45.6±20.7) compared to the general sarcoidosis population (36.2±15.9; p< 0.0001). High CFQ scores (≥43) were found in 55.7% and 33.9%, respectively (p<0.0001). The FAS score (OR 21.4) and SFNSL score (OR 4.3) were the strongest positive predictors of a high CFQ score. CONCLUSION: Cognitive failure is a significant problem in neurosarcoidosis. More than half of the patients reported cognitive deficits, compared to one third of a general sarcoidosis population. Fatigue and small fiber neuropathy play a role in cognitive failure.

Role of cytochrome P450 polymorphisms in the development of pulmonary drug toxicity: a case-control study in the Netherlands.

BACKGROUND: Drug-induced pulmonary toxicity is a serious and expanding problem with often unknown aetiology. Many drugs are metabolized by cytochrome P450 (CYP) enzymes. OBJECTIVE: To establish whether allelic variation in CYP polymorphic genes contributes to variability in drug response and unexpected toxicity. METHODS: A case-control study was conducted. The cases consisted of patients with drug-induced interstitial lung disease (DI-ILD; n = 59). Two control groups were used: one group of healthy volunteers (n = 173) and one group of patients with idiopathic pulmonary fibrosis (IPF; n = 110). RESULTS: Of the patients with DI-ILD 91.5% (54/59) had at least one of the studied variant genes compared with 70.5% (122/173, p < 0.001) of the healthy volunteers and 69.1% (76/110, p < 0.001) of the IPF patients. The percentage of individuals with one or more variant CYP genes was higher in the DI-ILD group. Odds ratios were significantly increased and ranged from 3.25 to 40.8, indicating a significant association between the development of DI-ILD and the presence of one or more variant CYP genes. CONCLUSION: DI-ILD appeared to be associated with the presence of at least one variant CYP allele. This study supports the potential usefulness of personalized medicine by genotyping aiming to improve efficacy, tolerability and drug safety.

Genotyping with a dried blood spot method: a useful technique for application in pharmacogenetics.

Several commercial DNA isolation kits are available for extracting the genomic DNA from the ethylene diamine tetra-acetic acid (EDTA) whole blood samples. To obtain DNA from whole blood these DNA isolation procedures require quite some hands on time and are rather expensive. An alternative technique could be dried blood spot (DBS) sampling, with which DNA isolation is faster, cheaper and logistics are easier. We have developed a non-commercial DBS method and examined its performance in practice. DNA isolation from EDTA blood samples and made blood spots on filter paper from 106 renal transplant recipients were compared. Additionally, DNA isolation with a column method and two different DBS method was performed for 10 healthy volunteers and compared. Also DNA isolation with only capillary blood using both DBS methods from another 100 healthy volunteers has been investigated. Real-time PCR FRET assays for the CYP3A4 A-392G, CYP3A5 A6986G, ABCB1 C1236T, G2677T/A and C3435T polymorphisms were used and the melting curves of both DNA isolation methods were compared. In all cases DNA extracted with the column method corresponded completely with the results of the DNA isolated with the DBS procedure. Hence, DNA isolation from filter paper appears to be a useful alternative for the commercially available DNA isolation kits.

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.

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.

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.