Cem Griffiths

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10−8 and two loci with a combined P < 5 × 10−7). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10−6). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.

IL-1β-induced Langerhans' cell migration and TNF-α production in human skin: Regulation by lactoferrin

In mice, the roles of cytokines in the initiation of epidermal Langerhans’ cell (LC) migration are well documented; however, the mechanism of this response in humans is less well defined. The purpose of the present investigation was to examine the contribution of interleukin (IL)‐1β to human epidermal LC migration and to define further the mechanisms of this response. We demonstrate here that homologous recombinant IL‐1β administered intradermally to healthy human volunteers provides a stimulus for LC migration, with significant (P < 0·01) reductions in LC densities being observed at both 2 h and 4 h following treatment. At the later time‐point of 4 h, injection of IL‐1β was also accompanied by activation of those LC remaining in the epidermis. Analysis of fluid aspirated from suction blisters formed at injection sites revealed significant (P < 0·01) tumour necrosis factor (TNF)‐α production (2·99 ± 1·18 pg TNF‐α/mg protein; mean ± s.d. of n = 10) in response to IL‐1β treatment compared with saline control injections (0·90 ± 1·05 pg TNF‐α/mg protein). Prior topical application of human recombinant lactoferrin (LF), an iron‐binding protein found in exocrine secretions and skin, inhibited IL‐1β‐mediated LC migration and also compromised the production of TNF‐α protein as measured in suction blister fluids derived from each of the treatment sites. Taken together, these data demonstrate that IL‐1β is associated with both the stimulation of human epidermal LC migration and local TNF‐α production. Topical treatment with LF compromises both these responses. These data suggest that topical LF may potentially represent a novel therapeutic in the treatment of skin inflammation where TNF‐α is an important mediator.

Tumour necrosis factor‐α‐induced migration of human Langerhans cells: the influence of ageing

Summary Background  Langerhans cells (LCs) play essential roles in the initiation and regulation of cutaneous immune responses mediated through their successful migration from the epidermis to draining lymph nodes while carrying antigen. Tumour necrosis factor (TNF)‐α, a keratinocyte‐derived cytokine, has recently been shown to play an important role in the mobilization of LCs from human epidermis. Although it is known that with age the immune system changes, the influence of increasing age on the function of human LCs has not been defined clearly.

Tumour necrosis factor-alpha induces Langerhans cell migration in humans.

The role of tumour necrosis factor (TNF)‐α in the mobilization and migration of human epidermal Langerhans cells (LC) has been investigated. Intradermal injection of normal human volunteers with homologous recombinant TNF‐α was found to cause a dose‐dependent reduction in the frequency of LC within epidermal sheets 2 h later. Equivalent results were obtained when epidermal LC were identified on the basis of either CD1a or HLA‐DR expression. At the dose of TNF‐α used routinely (500 U), treatment resulted in an average reduction in LC density of approximately 24%. Treatment with TNF‐α was associated with a perivascular polymorphonuclear infiltration at 2 h, but the epidermis appeared normal with neither fibrinoid necrosis nor vasculitis, and LC morphology was not affected significantly. These results demonstrate that TNF‐α provides an important signal for LC migration in humans and is likely therefore to play a crucial part in the induction of cutaneous immune responses.

A cosmetic ‘anti-ageing’ product improves photoaged skin: a double-blind, randomized controlled trial

Summary Background Very few over‐the‐counter cosmetic ‘anti‐ageing’ products have been subjected to a rigorous double‐blind, vehicle‐controlled trial of efficacy. Previously we have shown that application of a cosmetic ‘anti‐ageing’ product to photoaged skin under occlusion for 12 days can stimulate the deposition of fibrillin‐1. This observation infers potential to repair and perhaps clinically improve photoaged skin.

Exogenous interleukin-1beta restores impaired Langerhans cell migration in aged skin.

As far as we know this response has not been previously reported. Nodular prurigo is characterized by reduplication of cutaneous peptidergic nerves. Topical tacrolimus reputedly elicits a tingling and burning sensation on topical application. The mechanism is not known but we speculate that there may be a direct capsaicin-like effect on the sensory afferent nerve fibres. Furthermore, this patient’s skin pretreatment showed increased S-100 staining of cutaneous nerves. The quantity and extent of the staining was considerably diminished in a skin biopsy taken after treatment with tacrolimus. However, nodular prurigo is an eczematous condition. Ciclosporin, another calcineurin inhibitor, has been reported to be successful in managing nodular prurigo when administered orally. Both ciclosporin and tacrolimus are known to be efficacious in suppressing proinflammatory cytokines in eczematous inflammatory processes.

Patterns of biologic therapy use in the management of psoriasis: cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR)

Treatment modifications, including dose escalations, dose reductions, switches, discontinuations and restarts of biologics may be necessary in the management of psoriasis but the patterns of usage are incompletely defined.

Iron status of patients with alopecia areata

1 Fine RM, Meitzer HD. Chronic erythema nodosum. Arch Dermatol 1969; 100: 33-8. 2 Fine RM. Meitzer HD. Erythema nodosum. A form of allergic cutaneous vasculitis. South MedJ 1968; 61: 680-6. 3 Auger C, Leclerc JL. Erytheme noueux chronique. Laval Med 1966; 37: 28-33 (Fre.). 4 Perry HO. Winkelmann RK. Subacute nodular migratory panniculitis. Arch Dermatol 1964; 89: 170-9. 5 Vilanova X. Subacute, nodular, migrans hypodermites. Arch Dermatol 1963; 87: 536-7. 6 Vilanova X, Pinol Aguade J. Subacute nodular migratory panniculitis. Br J Dermatol 1959; 71: 45-50. 7 Hannuksela M. Erythema nodosum migrans. Acta Derm Venereol (Stockh) 1973; 53: 313-17. 8 Bafverstedt B. Erythema nodosum migrans. Acta Derm Venereol (Stockh) 1968; 48: 381-4. 9 Bafverstedt B. Erythema nodosum migrans. Acta Derm Venereol (Stockh) 1954; 34: 181-93. 10 Horio T, Imamura S, Danno K, Ofuji S. Potassium iodide in the treatment of erythema nodosum and nodular vasculitis. Arch Dermatol 1981: 117: 29-31. 11 Lever WF, Shaumburg-Lever G. Histopathology of the Skin. Philadelphia; JB Uppincott Company, 1990; 270-2. 12 Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum 1993; 23 (Suppl. 1); 82-91. 13 Easterbrook M. The ocular safety of hydroxychloroquine. Semin Arthritis Rheum 1993; 23 (Suppl. 1); 62-7.

Danger signals and skin sensitization

SIR, The ichthyoses are a heterogeneous group of skin disorders of epidermal differentiation, with both inherited and acquired forms. This cornification disorder may be found isolated or in association with other genetic defects. In 1998, five siblings with congenital ichthyosis, follicular atrophoderma, hypotrichosis and hypohidrosis were described as a new genodermatosis by Lestringant et al. We report a 17-year-old Turkish patient with ichthyosis vulgaris, follicular atrophoderma, woolly hair and hypotrichosis as a second report on this syndrome. A 17-year-old-girl was admitted to our hospital because of woolly hair, sparse eyelashes and eyebrows, and a very dry skin. She was born at term after an uncomplicated pregnancy. Ichthyosis and baldness were present at birth, but there was no history of a collodion baby. She had almost no scalp hair until she was 4 months old. In the early childhood period, funnel-shaped round follicular depressions had appeared on the dorsal aspects of the hands. She stated that her scalp hair had improved and straightened with age. The patient was otherwise healthy and detailed ophthalmological, neurological and audiometric examinations were normal. There was no history of atopy. There was no family history of similar skin problems. Both her parents and paternal grandparents were first cousins. There was no maternal history of drug intake during pregnancy. On examination, there was diffuse ichthyosiform scaling sparing the major flexures and face as in ichthyosis vulgaris (Fig. 1). The ichthyotic skin was hypohydrotic but the axilla, palms and soles sweated normally. Follicular atrophoderma was observed on the backs of her hands (Fig. 2). She had diffuse and patchy non-scarring hypotrichosis with a receding frontal hairline. Her hair was normal in length, but was light brown in colour, coarse, curly and unruly, in contrast to the straight black hair of the rest of her family. Eyelashes and particularly eyebrows were sparse (Figs 3–4). Routine haematological, biochemical, immunological, thyroid and radiological investigations were normal. Osteopoikilosis was not present on the X-rays. Echocardiography and ECG were normal. Hair microscopy was normal apart from curling. Biopsy from ichthyotic skin showed orthokeratosis with focal hypogranulosis (Fig. 5). Electron microcopy showed normal tonofilaments. Based on clinical and laboratory findings a diagnosis of ichthyosis vulgaris associated with follicular atrophoderma, hypotrichosis and woolly hair was made. The patient was prescribed 10% urea cream and salicylic acid ointments. The ichthyotic lesions resolved within a few weeks. Ichthyosis is a feature of several genetic disorders. These are rare disorders and the associated ichthyosis may be mild. The following syndromes with ichthyosis may be considered

Calcium homeostasis remains unaffected after 12 weeks' therapy with calcitriol 3 microg/g ointment; no correlation with extent of psoriasis

OBJECTIVE: To assess the systemic safety of calcitriol 3 µg/g ointment (Silkis ® ointment) in relation to body surface area (BSA) affected by chronic plaque psoriasis. METHODS: In this open-label, multicentre study, patients were divided into three parallel groups: 5% to <15% ( n =23), 15% to <25% ( n =18), 25% to 35% ( n =18) based on BSA involvement. Ointment was applied topically twice daily for 12 weeks; patients were followed up for a further 8 weeks. RESULTS: There was no alteration of calcium homeostasis: the mean values of albumin-adjusted serum total calcium, as well as 24-hour urinary calcium and serum calcitriol levels, remained within normal ranges throughout treatment. No changes in calcium or phosphate homeostasis related to the area of psoriasis being treated with calcitriol ointment were detected. CONCLUSIONS: Reductions in the global severity score and BSA involvement, as well as results of the assessment of improvement, attested to the clinical efficacy of calcitriol 3 µg/g ointment in psoriasis. The study confirms the systemic safety of calcitriol 3 µg/g in psoriatic patients with 5-35% BSA involvement.