J. van der Schaft

The association between vitamin D and cognition: A systematic review

Vitamin D insufficiency and deficiency are a major health care problem. The association between vitamin D levels and cognitive function is still under debate. We conducted a systematic review to assess the association between levels of vitamin D and cognition. Therefore, the databases of Embase and Pubmed were searched through June 2012 for observational studies relating vitamin D levels to cognition. Our initial search yielded 2182 articles. After applying exclusion criteria, there were 28 studies eligible for inclusion: 25 cross-sectional and 6 prospective studies (3 studies show cross-sectional as well as prospective data). The main finding of the 25 cross-sectional studies was a statistically significant worse outcome on one or more cognitive function tests or a higher frequency of dementia with lower vitamin D levels or intake in 18 out of 25 (72%) studies, whereas 7 (28%) studies failed to show an association. Four out of 6 (66.7%) prospective studies showed a higher risk of cognitive decline after a follow-up period of 4-7 years in participants with lower vitamin D levels at baseline. In conclusion, this review supports the hypothesis that hypovitaminosis D is associated with worse outcome on one or more cognitive function tests or a higher frequency of dementia in cross-sectional as well as prospective studies. Further studies should focus on the role of vitamin D supplementation in the prevention of cognitive decline in participants with low vitamin D levels.

Ten years experience with oral immunosuppressive treatment in adult patients with atopic dermatitis in two academic centres

There is a lack of information on the use oral immunosuppressive drugs in atopic dermatitis (AD) daily practice.

Drug survival for ciclosporin A in a long-term daily practice cohort of adult patients with atopic dermatitis

Long‐term data of ciclosporin A (CsA) treatment in daily practice in patients with severe atopic dermatitis (AD) are lacking.

Drug survival for methotrexate in a daily practice cohort of adult patients with severe atopic dermatitis

DEAR EDITOR, Methotrexate is prescribed off-label for atopic dermatitis. Some clinical studies of methotrexate treatment in atopic dermatitis have demonstrated effectiveness, although the number of patients was small and the treatment and follow-up periods were relatively short. Therefore, we conducted an analysis of drug survival for methotrexate in a long-term daily practice cohort of patients with severe atopic dermatitis. This retrospective study was performed at the dermatology departments of the University Medical Center Groningen and the University Medical Center Utrecht. In both centres all patients are registered according to the 10th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). The patients for the study were identified using the morbidity atopic dermatitis (XII-L20) and laboratory monitoring in the same period. Laboratory monitoring is mandatory during treatment with systemic therapy and liver function parameters were used to identify subjects treated with methotrexate. Patients aged ≥ 18 years with atopic dermatitis according to the U.K. Working Party’s Diagnostic Criteria, who were treated between 1997 until data lock in February 2015, were included. Data were retrieved from medical charts that were prespecified for atopic dermatitis. Treatment with methotrexate was initiated with a dosage of 5–10 mg per week and gradually increased based on clinical signs with a maximum of 5 mg per visit (maximum total dosage 25 mg per week), according to a standard follow-up protocol in both centres. Some patients received concomitant prednisolone (10–30 mg per day) during the start-up phase, for crisis intervention or a low maintenance dose (5 mg per day) during their complete methotrexate treatment. A retrospective Physician’s Global Assessment (PGA) score was used to measure an overall treatment response at the moment of discontinuation or data lock. The improvement of lesions relative to the baseline (before starting methotrexate) was categorized into the following three groups: (i) PGA1, good effect of treatment; (ii) PGA2, moderate effect and (iii) PGA3, failure of treatment (no improvement or worse). Treatment episodes shorter than 8 weeks were not given a PGA score. Only the first methotrexate treatment episodes were analysed. Treatment interruptions up to 14 days were considered as a continuous treatment episode. Drug survival rates of methotrexate were analysed using Kaplan–Meier survival curves. Three events for drug survival were analysed separately: (i) discontinuation overall; (ii) discontinuation due to side-effects and (iii) discontinuation due to ineffectiveness. Patients were censored when lost to follow-up, still active at the moment of data lock or discontinued due to an event other than the event of interest. Possible determinants of drug survival for the events of interest (side-effects or ineffectiveness) were analysed by a univariate Cox regression model and assumptions of proportional hazards were checked and met. Determinants with a P-value < 0 2 were entered in a multivariate Cox regression model. A full model was created by backward selection and P-values < 0 05 were considered statistically significant. Data analyses were performed using SPSS Statistics 22.0 (IBM, Armonk, NY, U.S.A.). A total of 89 patients were included. The baseline characteristics are displayed in Table 1. The median treatment duration was 223 days (range 11–1387) with a total of 69 3 patientyears. At the moment of data lock 35 patients (39%) still used methotrexate; two of these patients used concomitant prednisolone. Overall, 49% of the patients showed a good response to methotrexate treatment (PGA1) at the moment of discontinuation or data lock (Table 1). Of 20 patients who used methotrexate for more than 1 year, a total of 16 patients (80%) had a PGA1 score. Side-effects and ineffectiveness were the main reasons for discontinuation of methotrexate in 25% and 15% of the patients, respectively. In cases of treatment failure, patients discontinued treatment due to side-effects or ineffectiveness in the first year only and not later in the treatment. The overall drug survival showed that 73%, 41% and 34% of the patients still used methotrexate after 6 months, 1 year and 2 years, respectively (Fig. 1). The median drug survival was 9 8 months [95% confidence interval (CI) 7 7–11 9]. After 6 months, 1 year and 2 years, the treatment was discontinued in 10%, 24% and 24%, respectively, of the patients owing to ineffectiveness. Side-effects were a reason for discontinuation in 17%, 33% and 33% of the patients after 6 months, 1 year and 2 years, respectively. Univariate Cox regression analysis demonstrated that a higher maintenance dose (dose in intervals of 5 mg kg ) was associated with a decreased drug survival related to ineffectiveness [hazard ratio (HR) 2 84, 95% CI 1 28–6 31; P = 0 01] and an increased drug survival related to side-effects (HR 0 42, 95% CI 0 22– 0 82; P = 0 01). Male sex, older age (age in 5-year intervals),

Drug survival for azathioprine and enteric-coated mycophenolate sodium in a long-term daily practice cohort of adult patients with atopic dermatitis

Results from clinical studies indicate that azathioprine and enteric-coated mycophenolate sodium (EC-MPS) are safe and potent drugs in the treatment of atopic dermatitis (AD).(1-5) However, published data from large groups of non-selected patients is non-existent to date which hampers generalization to daily practice. In addition, head-to-head trials in which azathioprine and EC-MPS are compared, have never been performed. The primary objective was to perform an analysis of drug survival for azathioprine and EC-MPS in a long-term daily practice cohort of patients with AD. The secondary objective was to identify determinants of drug survival. This article is protected by copyright. All rights reserved.

Drug survival of cyclosporine in the treatment of hand eczema: a multicentre, daily use study

Hand eczema is a common condition; it is often chronic and can be difficult to treat. Cyclosporine is used off‐label to treat severe hand eczema; however, the evidence for this treatment is scarce.

Predicting therapy response to mycophenolic acid using UGT1A9 genotyping: towards personalized medicine in atopic dermatitis

Abstract Atopic dermatitis (AD) is a very common chronic inflammatory skin disease requiring long-term treatment. Mycophenolic acid (MPA) is used off-label in treatment of patients with severe AD failing Cyclosporin A (CsA) treatment, however clinical efficacy is observed in only half of the AD patients. In blood, MPA levels are known to have a large interindividual variability. Low MPA exposure and increased enzyme activity correlates with the presence of UGT1A9 polymorphisms. In this retrospective study, 65 adult AD patients treated with MPA were classified as responder or non-responder to MPA treatment. UGT1A9 polymorphisms were determined using PCR. A significantly higher number of UGT1A9 polymorphisms was found in the group that did not respond to MPA treatment. Of the patients that carried a UGT1A9 polymorphism, 85.7% were non-responsive to MPA treatment. This implies that non-responsiveness in AD patients is more likely to occur in carriers of a UGT1A9 polymorphism. In a binary logistic regression analysis the odds ratio (OR) was 8.65 (95% confidence interval: 0.93–80.17). Our results show that UGT1A9 polymorphisms can be used to identify patients with non-responsiveness to MPA. Patients with UGT1A9 polymorphisms might benefit from higher MPA dosage.

Drug survival of methotrexate treatment in hand eczema patients: results from a retrospective daily practice study

for the negative result of CEA in the Bowenoid lesions (Fig. 2b). Therefore, to confirm the cell lineage of Bowenoid cells, Ber-EP4 and CK5/6 staining were added. EMPD has been reported to stain positive with Ber-EP4, whereas Bowen’s disease stains negative. CK5/6 are positive in Bowen’s disease, but negative in EMPD. The Bowenoid cells in our case demonstrated the characteristic immunohistochemical features of Paget cells (Fig. 2c, d). These results indicate that the Bowenoid cells in our case were not derived from keratinocytes. In summary, our detailed pathological examination, in addition to the literature review, has clarified the immunohistochemical profiles of EMPD with Bowenoid features. We propose that Ber-EP4 and CK5/6 staining can improve the diagnostic accuracy when the clinician suspects atypical cases of Bowenoid EMPD.

Thiopurine metabolite levels in patients with atopic dermatitis and/or chronic hand/foot eczema treated with azathioprine

Abstract Background: Azathioprine is frequently used in severe eczema. It is converted in the liver into active metabolites, including 6-thioguanine nucleotide (6-TGN) and methylated 6-methylmercaptopurine (6-MMP). In the past, the therapeutic potential of azathioprine may have not been fully utilized. Recent investigations on inflammatory bowel disease have led to a better understanding of azathioprine metabolism and optimizing treatment. Objective: To investigate whether measuring thiopurine metabolites in circulation can improve the effectiveness and safety of azathioprine treatment in patients with atopic dermatitis and/or chronic hand/foot eczema. Methods: Azathioprine metabolite levels were measured in eczema patients during maintenance treatment (Part I) and dose escalation (Part II). Clinical effectiveness, hepatotoxicity, and bone marrow suppression were analyzed and TPMT genotype was assessed. Results: A wide variation in metabolite levels in all dose groups was observed. In Part I (32 patients), there were no significant differences in 6-TGN levels between clinical responders and non-responders (p = .806). No hepatoxicity or myelotoxicity was observed. In Part II, all 6-TGN and 6-MMP levels increased during dose escalation. Hypermethylation was observed in 2/8 patients. Conclusion: For individual eczema patients treated with azathioprine, routinely measuring 6-TGN and 6-MMP can be helpful in optimizing azathioprine dose, improving clinical effectiveness, and preventing side effects.

Increased liver enzyme levels during azathioprine treatment; beware of concomitant use of proton pump inhibitors

Azathioprine (AZA) is a purine antagonist, which is frequently used off label in chronic inflammatory skin diseases. Genetic polymorphisms in thiopurine S-methyltransferase (TPMT) influence the metabolism of AZA. A reduced enzymatic activity of TMPT is associated with increased 6-thioguaninie nucleotide (6-TGN) levels which may cause severe leukopenia. High TPMT activity is associated with increased 6-methylmercaptopurine (6-MMP) levels (toxic 6-MMP >5700 pmol/8x10(8) RBCs), which is associated with liver toxicity.(1) Alanine transaminase (ALT) >3 upper limits of normal has been identified as a sensitive, but not necessarily specific signal of liver toxicity.(2) In daily practice AZA is often started with a test dose of 50 mg/day for 1-2 weeks. If laboratory tests show no abnormalities, the dose is increased to up to 150-200 mg/day. This article is protected by copyright. All rights reserved.