Siegfried Segaert

Vitamin D metabolism and action

Vitamin D3 is a secosteroid derived either from photosynthesis, whereby 7-dehydrocholesterol is transformed into previtamin D by short-wave ultraviolet (UVB) light, or from nutritional origin. Nutritional vitamin D3 (from most natural sources) or D 2 (mostly from pharmaceutical origin) in fact also originates from photosynthesis in living organisms. The vitamin D content of most food products is rather low (Table 1), with the exception of some fatty fish. Moreover, its stated content has not always been verified by accurate up-to-date measurements. Even food supplemented with vitamin D does not always contain the stated concentrations, as gross errors have been detected even in critical baby milk products [1]. The skin synthesis of vitamin D is therefore considered the common source of vitamin D in man and probably also in most vertebrates (from reptiles to mammals; see below). The photosynthesis requires the presence of 7-dehydrocholesterol, which requires de novo synthesis of cholesterol (Fig. 1) in the epidermis. If the enzyme 7-dehydrocholesterolD7-reductase is overactive, as seems to be the case in cats, UV light cannot activate vitamin D synthesis so that vitamin D 3 is a true vitamin for this species [2]. The congenital absence of a functional 7-dehydrocholesterolD7-reductase enzyme is responsible for a serious disease called Smith–Lemli– Opitz syndrome, in which deficiency of cholesterol and/ or excess 7-dehydrocholesterol causes abnormal brain development and other soft and hard tissue malformations (e.g. syndactyly and cleft palate) [3,4]. Previtamin D3 slowly equilibrates with vitamin D3, a process thought to be non-enzymatic and highly temperaturedependent. However, more recent indirect data support the idea that its thermal isomerization might be accelerated in vivo by entrapment in the lipid bilayers of the keratinocytes [5]. Additional or excess UV light can degrade (pre)vitamin D into lumisterol or tachysterol and other sterols that are largely devoid of vitamin D activity. This phenomenon is largely responsible for avoiding ‘natural’ vitamin D intoxication. Vitamin D from nutritional origin is transported via chylomicrons from the intestine via lymph veins to the liver, whereas skin-produced vitamin D is probably transported mainly via DBP, an albumin-like plasma carrier protein. The liver but also some other tissues metabolise vitamin D3 into 25-OHD, probably by the enzyme CYP27. This sterol-27-hydroxylase (EC 1.14.13.15) is a multifunctional enzyme responsible for 27-hydroxylation of cholesterol and bile acid precursors (e.g. 5b-cholestane-3 a,7a12a-triol) as main function (rate of metabolism) and 25or 24-hydroxylation of vitamin D3 or D2, respectively, as minor function [6]. The enzyme is encoded by a gene located on the human chromosome 2, but its regulation and promoter structure have not been studied in detail. The enzyme is, however, found in many tissues outside the liver (e.g. duodenum, adrenal gland, lung, macrophages). A mouse KO model is not yet available, but a human disease, cerebrotendinous xanthomatosis, is due to a genetic abnormality or deficiency of CYP27 [7]. The disease is mainly characterized by neurological abnormalities, believed to be due to cholestanol overloading, premature atherosclerosis and osteoporotic bone fractures (with Osteoporos Int (1998) Suppl. 8:S13–S19 ß 1998 European Foundation for Osteoporosis and National Osteoporosis Foundation Osteoporosis International

Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis : a randomized controlled trial with open-label extension

Background  In previous studies, etanercept 25 mg twice weekly (BIW) or 50 mg BIW significantly reduced disease severity in patients with plaque psoriasis and demonstrated a favourable safety profile.

Dermatological side effects of hepatitis C and its treatment: Patient management in the era of direct-acting antivirals

Dermatological adverse events (AEs) are an existing concern during hepatitis C virus (HCV) infection and peginterferon/ribavirin treatment. HCV infection leads to dermatological and muco-cutaneous manifestations including small-vessel vasculitis as part of the mixed cryoglobulinemic syndrome. Peginterferon/ribavirin treatment is associated with well-characterized dermatological AEs tending towards a uniform entity of dermatitis. New direct-acting antivirals have led to significant improvements in sustained virologic response rates, but several have led to an increase in dermatological AEs versus peginterferon/ribavirin alone. In telaprevir trials, approximately half of treated patients had rash. More than 90% of these events were Grade 1 or 2 (mild/moderate) and in the majority (92%) of cases, progression to a more severe grade did not occur. In a small number of cases (6%), rash led to telaprevir discontinuation, whereupon symptoms commonly resolved. Dermatological AEs with telaprevir-based triple therapy were generally similar to those observed with peginterferon/ribavirin (xerosis, pruritus, and eczema). A few cases were classified as severe cutaneous adverse reaction (SCAR), also referred to as serious skin reactions, a group of rare conditions that are potentially life-threatening. It is therefore important to distinguish between telaprevir-related dermatitis and SCAR. The telaprevir prescribing information does not require telaprevir discontinuation for Grade 1 or 2 (mild/moderate) rash, which can be treated using emollients/moisturizers and topical corticosteroids. For Grade 3 rash, the prescribing information mandates immediate telaprevir discontinuation, with ribavirin interruption (with or without peginterferon) within 7 days of stopping telaprevir if there is no improvement, or sooner if it worsens. In case of suspicion or confirmed diagnosis of SCAR, all study medication must be discontinued.

The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies

The use of epidermal growth factor receptor (EGFR) inhibitors for the treatment of solid tumours is increasing. However, the tolerability profile for EGFR‐inhibitors, such as the monoclonal antibody cetuximab and the tyrosine kinase inhibitor erlotinib, is characterised by a unique group of skin reactions dominated by an acneiform eruption, xerosis, eczema and changes in the hair and nails. The possibility that this skin toxicity correlates with anti‐tumour activity offers the potential to titrate dosing on a case‐by‐case basis. These skin effects may constitute a significant obstacle to treatment compliance. Accordingly, there is a need for consistent, multi‐disciplinary management strategies that will allow patients to receive the recommended dosages of such targeted therapies. The eruption responds well to some acne therapies and xerosis can be controlled by standard emollients. Here we present an overview of the treatment options for skin reactions that are available today, and evaluate some of the ways in which the treatment of such EGFR‐inhibitor‐related skin reactions may be improved in the future. Evidence‐based studies are needed to determine the best way to manage these effects.

A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group

BackgroundAccurate grading of dermatologic adverse events (AE) due to epidermal growth factor receptor (EGFR) inhibitors (EGFRIs) is necessary for drug toxicity determinations, interagent comparisons, and supportive care trials. The most widely used severity grading scale, the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0), was not designed specifically for this class of agents and may result in underreporting and poor grading of distinctive adverse events. We believe a class-specific grading scale is needed to help standardize assessment and improve reporting of EGFRI-associated dermatologic AEs.MethodsThe Multinational Association of Supportive Care in Cancer (MASCC) Skin Toxicity Study Group conducted an international multidisciplinary meeting that included 20 clinicians and researchers from academic centers and government agencies. Experts from different disciplines presented current information specific to EGFRI-induced dermatologic toxicities: grading scale development, pharmacovigilance safety reporting, health-related quality of life, patient reporting, and pharmacology. Group discussions, literature reviews, and professional expertise established the theoretical foundation for the proposed grading scale.ResultsA new grading system is proposed for the most common events associated with EGFRI-induced dermatologic AEs: papulopustular reaction or acneiform rash, nail changes, erythema, pruritus, xerosis, hair changes, telangiectasias, hyperpigmentation, mucositis, flushing, radiation dermatitis, hyposalivation, and taste changes. The proposed scale maintains consistency with the grading principles and language of the existing CTCAE version 4.0 and MedDRA terminology and includes relevant patient-reported health-related quality of life factors.ConclusionsA grading scale specific to EGFR inhibitor dermatologic AEs is presented for formal integration into future versions of CTCAE and for validation in clinical trial settings. The study group designed this scale to detect and report EGFRI-related toxicities with greater sensitivity, specificity, and range than the scales currently used. This scale should serve as a foundation for efforts to perform objective interdrug comparisons and assessments of supportive care treatment strategies more effectively than with current methods.

1,25‐dihydroxyvitamin D3 inhibits ultraviolet B‐induced apoptosis, Jun kinase activation, and interleukin‐6 production in primary human keratinocytes

We investigated the capacity of 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3] to protect human keratinocytes against the hazardous effects of ultraviolet B (UVB)‐irradiation, recognized as the most important etiological factor in the development of skin cancer. Cytoprotective effects of 1,25(OH)2D3 on UVB‐irradiated keratinocytes were seen morphologically and quantified using a colorimetric survival assay. Moreover, 1,25(OH)2D3 suppressed UVB‐induced apoptotic cell death. An ELISA, detecting DNA‐fragmentation, demonstrated that pretreatment of keratinocytes with 1,25(OH)2D3 1 μM for 24 h reduced UVB‐stimulated apoptosis by 55–70%. This suppression required pharmacological concentrations 1,25(OH)2D3 and a preincubation period of several hours. In addition, 1,25(OH)2D3 also inhibited mitochondrial cytochrome c release (90%), a hallmark event of UVB‐induced apoptosis. Furthermore, we demonstrated that 1,25(OH)2D3 reduced two important mediators of the UV‐response, namely, c‐Jun‐NH2‐terminal kinase (JNK) activation and interleukin‐6 (IL‐6) production. As shown by Western blotting, pretreatment of keratinocytes with 1,25(OH)2D3 1 μM diminished UVB‐stimulated JNK activation with more than 30%. 1,25(OH)2D3 treatment (1 μM) reduced UVB‐induced IL‐6 mRNA expression and secretion with 75–90%. Taken together, these findings suggest the existence of a photoprotective effect of active vitamin D3 and create new perspectives for the pharmacological use of active vitamin D compounds in the prevention of UVB‐induced skin damage and carcinogenesis. J. Cell. Biochem. 89: 663–673, 2003.

A new scalp formulation of calcipotriol plus betamethasone dipropionate compared with each of its active ingredients in the same vehicle for the treatment of scalp psoriasis: a randomized, double-blind, controlled trial

Background  There is a need for new treatments for scalp psoriasis, as many topical treatments are cosmetically unacceptable and difficult to apply, resulting in poor compliance.

Skin toxicities of targeted therapies

Over the last few years, EGFR inhibitors have successfully joined the armamentarium of anti-cancer drugs with an increasing number of indications such as colorectal cancer, head and neck cancer, nonsmall cell lung cancer and breast cancer [1]. EGFRtargeted drugs consist of monoclonal antibodies to EGFR (e.g. cetuximab, panitumumab), small-molecule tyrosine kinase inhibitors specific for EGFR (e.g. erlotinib, gefitinib), dual kinase inhibitors inhibiting EGFR and HER2 (lapatinib), pan-erbB inhibitors inhibiting EGFR and other erbB receptors (canertinib) and other less specific inhibitors such as vandetanib inhibiting EGFR, vascular endothelial growth factor receptor (VEGFR) and RET [1].

Efficacy and safety of calcipotriol plus betamethasone dipropionate scalp formulation compared with calcipotriol scalp solution in the treatment of scalp psoriasis: a randomized controlled trial

Background  Current topical therapies for scalp psoriasis are difficult or unpleasant to apply, resulting in decreased adherence and efficacy.

Vitamin D and regulation of gene expression

The function of 1,25-dihydroxyvitamin D3, the biologically active form of vitamin D, extends from bone and mineral homeostasis to the control of cell growth and differentiation in a variety of tissues. Most of these actions are mediated by activation of the nuclear vitamin D receptor, which regulates the transcription of vitamin D target genes. Considerable progress has been made in the understanding of vitamin D receptor function (especially regarding its interaction with coactivators), as well as in the identification of novel vitamin D responsive genes related to cell growth, differentiation and cytokine production.