Self-reported Gastrointestinal Side Effects of Antifibrotic Drugs in Dutch Idiopathic Pulmonary Fibrosis patients.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is an inexorably progressive disease, which has a great impact on patients' lives. Pirfenidone and nintedanib are approved and recommended antifibrotic drugs for patients with IPF. The aim of this study was to evaluate self-reported gastrointestinal side effects of antifibrotic drugs in 176 Dutch IPF patients. METHODS: A cross-sectional web-based anonymous survey about complaints and side effects was conducted among IPF patients in the Netherlands. Logistic regression was used to quantify whether pirfenidone and nintedanib caused complaints of nausea, vomiting, diarrhoea, appetite loss, weight loss or loss of taste or smell perception. RESULTS: The questionnaire was completed by 176 IPF patients, 71 of whom used pirfenidone and 85 nintedanib, while 20 patients did not use any antifibrotic drugs. Nintedanib users reported complaints of diarrhoea, vomiting, weight loss and loss of appetite (p < 0.01). Nausea was a significant adverse reaction (p < 0.05). Pirfenidone caused increased appetite loss (p < 0.01) and the risk of weight loss (p < 0.05). The increase in loss of appetite and weight loss did not differ significantly between the two drugs. CONCLUSION: The current study showed that nintedanib causes a significant increase in diarrhoea, vomiting, weight loss and loss of appetite, while pirfenidone led to loss of appetite. Our results suggest new avenues regarding dietary recommendations for IPF patients.

Sarcoidosis and Work Participation: The Need to Develop a Disease-Specific Core Set for Assessment of Work Ability.

OBJECTIVE: Sarcoidosis, an inflammatory multi-organ disease with a wide variety of clinical manifestations, affecting people of working age. Patients suffer from a broad spectrum of physical symptoms of varying severity that impact function including cognitive impairment and disabling fatigue. The Dutch Sarcoidosis Society identified a knowledge gap in various facets related to work ability. The aim of this study was to assess sarcoidosis patients' perceived problems related to work performance, employer, and disability evaluations. METHODS: A cross-sectional web-based anonymous survey was conducted among Dutch sarcoidosis patients recruited through sarcoidosis patient societies and outpatient sarcoidosis clinics. This investigation queried work performance, employer support, and disability evaluations. RESULTS: The study sample included 755 patients of whom 43% (n = 328) had undergone disability evaluation and were significantly more likely to experience extrapulmonary symptoms, severe fatigue, reduced exercise capacity along with memory problems and concentration problems with higher mean FAS and SFNSL-scores. Of these 328, 37% (n = 121) perceived they had not been listened to or taken seriously at assessments, and 38% (n = 124) disagreed with the outcome of disability assessments by benefits authorities; 75% (n = 93) appealed or requested re-assessment. DISCUSSION: A better understanding of sarcoidosis-related impact on work ability and quantification of disease burden is needed. Education for medical examiners and employers on sarcoidosis may improve quality of assessments and work accommodations. Development of guidelines for benefit authorities, which consider the broad impact of sarcoidosis beyond that of reduced pulmonary function, including extra-pulmonary assessment like fatigue, cognitive difficulties, as well as other organ involvement are needed.

Adalimumab successful in sarcoidosis patients with refractory chronic non-infectious uveitis.

INTRODUCTION: Adalimumab, a humanized monoclonal antibody targeted against TNF-α, has proved to be successful in the treatment of uveitis. Another anti-TNF-α agent, i.e., infliximab, has been reported of benefit in the treatment of refractory sarcoidosis. The aim of this prospective case series was to evaluate the effect of adalimumab on intraocular inflammatory signs and other relevant clinical manifestations (lung function, serological inflammatory parameters, and fatigue) of sarcoidosis. METHODS: Sarcoidosis patients with refractory posterior uveitis (n = 26, 17 females, 41 eyes in total) were systematically followed for 12 months after initiation of adalimumab 40 mg sc once a week. Inclusion criteria were non-responsiveness to prednisone and methotrexate (MTX) or intolerance to these drugs. Adjunctive therapy with prednisone and MTX was tapered during treatment with adalimumab. Localization and improvement, stabilization or deterioration of intraocular inflammatory signs was scored. Pulmonary function- and laboratory testing were performed and Fatigue Assessment Scale was completed. Results at baseline, 6 months, and 12 months were compared. RESULTS: Choroidal involvement resolved in 10/15 patients, five had partial improvement; vasculitis resolved in 1/1 patient; papillitis resolved in 7/8 patients, one had partial response; macular edema resolved in 5/8 patients, three had partial response; vitreous cleared completely in 5/5 patients. Overall outcome regarding intraocular inflammatory signs showed improvement in 22 patients (85%) and stabilization in four patients (15%). At 12 months, no recurrences were reported in those successfully treated. Laboratory parameters of inflammatory activity (C-reactive protein; serum angiotensin-converting enzyme and soluble interleukin-2 Receptor) improved (p < 0.01). Moreover, fatigue improved in 14/21 (67%) of the patients suffering from fatigue and the diffusion capacity for carbon monoxide (DLCO) improved in 7/8 (88%) of patients with a decreased DLCO (p < 0.01). The dosage of both prednisone and MTX could be tapered down significantly (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: Adalimumab appeared successful in sarcoidosis patients with refractory chronic non-infectious uveitis showing improvement in intraocular inflammatory signs as well as in other relevant clinical indicators of disease activity. Future randomized studies are needed to determine the optimal dosage, dose interval and duration of therapy in refractory multisystemic sarcoidosis.

Inflammatory activity assessment by F18 FDG-PET/CT in persistent symptomatic sarcoidosis.

BACKGROUND: Establishing inflammatory activity in sarcoidosis patients with persistent disabling symptoms is important. Whole body F(18)-FDG PET/CT (PET) appeared to be a sensitive method to detect inflammatory activity in newly diagnosed symptomatic sarcoidosis. The aim was to assess the presence of inflammatory activity using PET in sarcoidosis patients with unexplained persistent disabling symptoms and the association between PET findings and serological inflammatory markers. METHODS: Sarcoidosis patients who underwent a PET between June 2005 and June 2010 (n = 89), were retrospectively included. All PET scans were examined and positive findings were classified as thoracic and/or extrathoracic. As serological markers of inflammatory activity angiotensin-converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R), and neopterin were considered. RESULTS: In 65/89 (73%) of the studied patients PET was positive, 52 of them (80%) had serological signs of inflammatory activity. In 14/15 patients with a Chest X-ray stage IV PET was positive. In 80% of the PET positive patients extrathoracic inflammatory activity was found. Sensitivity of combined serological inflammatory markers for the presence of inflammatory activity as detected by PET was 80%, specificity 100%, positive predictive value 100%, negative predictive value 65%. CONCLUSIONS: The majority of sarcoidosis patients with persistent disabling symptoms, even those with radiological stage IV, had PET positive findings with remarkably 80% extrathoracic lesions. In 20% PET was positive without signs of serological inflammatory activity. PET appeared to be of additional value to assess inflammatory activity in patients with persistent symptoms in the absence of signs of serological inflammatory activity and to detect extrathoracic lesions.

Depressive effect of an antidepressant: therapeutic failure of venlafaxine in a case lacking CYP2D6 activity.

Understanding the mechanisms of drug metabolism and interactions can help to prevent side-effects. Not only drug interactions, environmental factors, disease processes and ageing are factors in the inter-individual metabolic capacity variance but also genetic factors probably play an important role, as is illustrated in the case presented. Besides therapeutic drug monitoring, genotyping some important cytochrome P450 (CYP450) enzymes was of additional value in explaining why the patient developed severe adverse effects and, moreover, did not experience any therapeutical effect of venlafaxine. Results indicated that the patient was a poor metabolizer for CYP2D6, the most important phase I enzyme to metabolize venlafaxine. This corroborates that polymorphisms in the CYP450 gene influence the metabolic activity of the corresponding enzymes, thus affecting the subsequent serum drug levels and their metabolites. This case highlights the potential benefit of both clinical and genetic risk stratification (pharmacogenetics) prior to treatment, either for setting the individual dose or for making a decision about using a particular drug.

Linkage between Toll-like receptor (TLR) 2 promotor and intron polymorphisms: functional effects and relevance to sarcoidosis.

The intracellular pathogens Propionibacterium acnes and Mycobacterium tuberculosis have been leading suspects as the cause of sarcoidosis, a systemic disorder characterized by the formation of non-caseating granulomas. Toll-like receptor (TLR) 2 is important in the innate immune response against both pathogens, and is therefore of interest in sarcoidosis research. In the present study, three single nucleotide polymorphisms and one dinucleotide repeat polymorphism in the TLR-2 gene were genotyped in 419 sarcoidosis patients, divided into a study cohort and a validation cohort, and 196 healthy controls. In the study cohort we found a significant increase in prevalence of the AA-genotype at promotor location -16934 in patients with chronic disease compared to patients with acute/self-remitting sarcoidosis (34.5% versus 15.9%, respectively, P = 0.006, P(c) = 0.019). These results could not be confirmed in our validation cohort, implicating a possible role for TLR-2 genetics in only a small percentage of sarcoidosis patients. Furthermore, linkage was found between the promotor polymorphism -16934 A/T and the number of GT repeats in intron 1 (P < 0.0001). After in vitro stimulation of peripheral blood mononuclear cells (PMBCs) with different TLR-2 agonists, a correlation between induction of TNF-alpha (P = 0.008), interleukin (IL)-12 (P = 0.008) as well as IL-6 (P = 0.02), and the number of GT repeats was observed. In conclusion, the data show that polymorphisms in TLR-2 might be important in a small group of sarcoidosis patients and that their functional consequences explain partly some of the variance in cytokine pattern observed in different clinical phenotypes of this disease.

Review article: The prevalence and clinical relevance of cytochrome P450 polymorphisms.

BACKGROUND: Most drugs currently used in clinical practice are effective in only 25% to 60% of patients, while adverse drug reactions (ADRs) as a consequence of treatment are estimated to cost billions of US dollars and tens of thousands of deaths. AIM: To review the prevalence and clinical significance of cytochrome P450 polymorphisms. RESULTS: The cytochrome P450 enzyme families 1-3 are responsible for 70 to 80% of all phase I dependent drug metabolisms. In 90% metabolic activity dependents on six enzymes: CYP1A2, CYP3A, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. Polymorphisms in the CYP450 gene can influence metabolic activity of the subsequent enzymes. A poor metabolizer (PM) has no or very poor enzyme activity. A consequence of PM is drug toxicity if no other metabolic route is available, or when multiple drugs are metabolized by the same cytochrome. In that case dose reduction is an option to prevent toxic effects. CONCLUSIONS: In the future genotyping should be considered to identify patients who might be at risk of severe toxic responses, in order to guide appropriate individual dosage. Medical therapy should be a close cooperation between clinicians, pharmacologists and laboratory specialists, leading to reduced therapeutic errors, ADRs and health care costs.