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Psoriasis is a common immune-mediated inflammatory skin disease that can elicit a significant high burden of disease on patients, theirs families, and society. In the last two decades significant advances have been made in the treatment of psoriasis, but psoriasis remains a challenging and difficult-to-treat disease. In this thesis, the focus was set on advancing psoriasis treatment by undertaking a clinical drug evaluation approach of two different systemic psoriasis treatments. The first studied therapy is fumaric acid esters (FAEs), which are an established classical systemic treatment for psoriasis, but important questions regarding their efficacy, safety, and mechanism of action remain unanswered. We undertook a systematic literature search to assess the evidence on the efficacy and safety of FAEs in psoriasis treatment (Chapter 2). In two randomized controlled trials, we assessed the therapeutic benefit of combining FAE treatment with the TNF-alpha antagonist etanercept (Chapter 3) and the histamine-1 receptor antagonist cetirizine (Chapter 4). Furthermore, we performed a descriptive case series of two rare but clinically important side effects associated with FAEs: first, progressive multifocal leuko-encephalopathy, an opportunistic viral infection of the central nervous system; and second, Fanconi syndrome, which is characterized by proximal renal tubular dysfunction (Chapter 5). In a gene expression profiling study using lesional psoriasis skin samples we identified several pathways and mechanisms affected by FAE treatment (Chapter 6). The second drug assessed in this thesis is a novel oligonucleotide-based antagonist of toll-like receptor (TLR) 7, 8 and 9, which is a potential targeted biologic treatment for psoriasis. Aberrant TLR 7, 8, and 9 activation by self-nucleic acids is implicated in the initiation of immune-mediated inflammatory diseases (IMIDs) such as psoriasis. In multiple IMID models, blockage of TLR-activation reduced disease severity. In ch

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of benign hamartomas in multiple organs. Most patients with TSC exhibit cutaneous manifestations. Methods: We report a 28-year-old patient with multiple pink papules at the proximal nail fold of several toes. Results: Histopathological analysis of a biopsy of a papule was consistent with an ungual fibroma. Histopathological analysis of a biopsy of an elevated skin-colored plaque at the lower back was diagnostic for a Shagreen patch. These findings were consistent with a clinical diagnosis of TSC. This patient was subsequently referred to a multidisciplinary TSC clinic for further screening, which revealed a giant cell astrocytoma and multiple subependymal tubers. Annual monitoring was recommended. The skin lesions were treated with topical rapamycin ointment. Conclusions: Recognizing dermatological manifestations of TSC is of importance to allow early diagnosis. TSC should be considered as a differential diagnosis in the case of ungual fibromas, even in older patients.

Background: Fumaric acid esters (FAEs), an oral immunomodulating treatment for psoriasis and multiple sclerosis, have been anecdotally associated with proximal renal tubular dysfunction due to a drug-induced Fanconi syndrome. Few data are available on clinical outcomes of FAE-induced Fanconi syndrome. Methods: Descriptive case series with two cases of Fanconi syndrome associated with FAE treatment diagnosed at two Dutch university nephrology departments, three cases reported at the Dutch and German national pharmacovigilance databases and six previously reported cases. Results: All 11 cases involved female patients with psoriasis. The median age at the time of onset was 38 years [interquartile range (IQR) 37-46]. Patients received long-term FAEs treatment with a median treatment duration of 60 months (IQR 28-111). Laboratory tests were typically significant for low serum levels of phosphate and uric acid, while urinalysis showed glycosuria and proteinuria. Eight (73%) patients had developed a hypophosphataemic osteomalacia and three (27%) had pathological bone fractures. All patients discontinued FAEs, while four (36%) patients were treated with supplementation of phosphate and/or vitamin D. Five (45%) patients had persisting symptoms despite FAEs discontinuation. Conclusions: FAEs treatment can cause drug-induced Fanconi syndrome, but the association has been reported infrequently. Female patients with psoriasis treated long term with FAEs seem to be particularly at risk. Physicians treating patients with FAEs should be vigilant and monitor for the potential occurrence of Fanconi syndrome. Measurement of the urinary albumin:total protein ratio is a suggested screening tool for tubular proteinuria in Fanconi syndrome.

Background: Keloids and atopic disorders share common inducing and maintaining inflammatory pathways that are characterized by T-helper cell 2 cytokines. Aims and Objectives: The objective of this study was to test for associations between keloids and atopic eczema, asthma and hay fever. Materials and Methods: This was a case-control study with 131 patients diagnosed with keloids at our dermatology outpatient clinic between 2000 and 2012. Controls were 258 partners of keloid or sarcoidosis patients. Patient who reported life time prevalences of atopic eczema, asthma and hay fever were assessed using a questionnaire based on The European Community Respiratory Health Survey (ECRHS) and The International Study of Asthma and Allergies in Children (ISAAC). Results: The prevalence of asthma was lower in keloid patients (19/131 vs. 20/258, P = 0.035), as was being diagnosed with asthma by a physician (18/131 vs. 19/258, P = 0.039) and using inhalators for asthma (13/131 vs. 7/258, P = 0.02). After adjusting for age and non-European descent the odds ratio for having a keloid was (adjusted OR = 4.44; 95% CI 1.59-12.40) in asthmatics using inhalators. There were no clear and consistent associations found for keloids with atopic eczema or with hay fever. Conclusion: In conclusion, our study shows that keloids may be strongly associated with atopic asthma. Atopic eczema and hay fever do not seem to be correlated with keloid. Further studies are warranted to assess the validity of atopic asthma as a risk factor for the development of keloid scars.

Motivation: Automatic tracking of cells in multidimensional time-lapse fluorescence microscopy is an important task in many biomedical applications. A novel framework for objective evaluation of cell tracking algorithms has been established under the auspices of the IEEE International Symposium on Biomedical Imaging 2013 Cell Tracking Challenge. In this article, we present the logistics, datasets, methods and results of the challenge and lay down the principles for future uses of this benchmark. Results: The main contributions of the challenge include the creation of a comprehensive video dataset repository and the definition of objective measures for comparison and ranking of the algorithms. With this benchmark, six algorithms covering a variety of segmentation and tracking paradigms have been compared and ranked based on their performance on both synthetic and real datasets. Given the diversity of the datasets, we do not declare a single winner of the challenge. Instead, we present and discuss the results for each individual dataset separately.

Carriers of haemophilia face difficult choices regarding prenatal diagnosis, but little is known about the determinants that influence their decisions. The aim of this study was to assess the incidence of prenatal diagnosis and potential determinants affecting the choice for prenatal diagnosis. A nationwide survey was performed among all women who underwent carriership testing for haemophilia in the Netherlands between 1992 and 2004. Prenatal diagnosis was assessed in

Glatiramer acetate and interferon-beta are approved first-line disease-modifying treatments (DMTs) for multiple sclerosis (MS). DMTs can be associated with cutaneous adverse events, which may influence treatment adherence and patient quality of life. In this systematic review, we aimed to provide an overview of the clinical spectrum and the incidence of skin reactions associated with DMTs. A systematic literature search was performed up to May 2011 in Medline, Embase, and Cochrane databases without applying restrictions in study design, language, or publishing date. Eligible for inclusion were articles describing any skin reaction related to DMTs in MS patients. Selection of articles and data extraction were performed by two authors independently. One hundred and six articles were included, of which 41 (39%) were randomized controlled trials or cohort studies reporting incidences of mainly local injection-site reactions. A large number of patients had experienced some form of localized injection-site reaction: up to 90% for those using subcutaneous formulations and up to 33% for those using an intramuscular formulation. Sixty-five case-reports involving 106 MS patients described a wide spectrum of cutaneous adverse events, the most frequently reported being lipoatrophy, cutaneous necrosis and ulcers, and various immune-mediated inflammatory skin diseases. DMTs for MS are frequently associated with local injection-site reactions and a wide spectrum of generalized cutaneous adverse events, in particular, the subcutaneous formulations. Although some of the skin reactions may be severe and persistent, most of them are mild and do not require cessation of DMT.