N.J. Reynolds

Necrolytic migratory erythema and zinc deficiency

Necrolytic migratory erythema (NME) is an uncommon condition classically associated with high plasma levels of circulating glucagon and a glucagonoma. We report a patient with cirrhosis who showed clinical and histological features of NME. Investigation revealed normal glucagon levels without evidence of glucagonoma. Serum zinc levels were below the normal range and zinc supplementation resulted in rapid and complete resolution of the eruption.

Demographics and disease characteristics of patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register

The British Association of Dermatologists Biologic Interventions Register (BADBIR) is a prospective, observational cohort designed to assess the long‐term safety of biologic and conventional systemic therapies used for adults with moderate‐to‐severe psoriasis in the U.K. and Republic of Ireland.

Hepatitis: a rare, but important, complication of infliximab therapy for psoriasis

healthy subjects (control) observed by Hamurku et al. are 2.2% and 0.77%, respectively, and these numbers are 7.9and 9.6-fold higher than those reported earlier in subjects of Turkish ethnicity. Very high levels of MN in exfoliated cells of studied subjects (both healthy controls and patients) could be due to the small number of cells studied (500); Hamurçu et al. used a DNA-specific stain, thus this could not be a source of bias. Recently I discussed the necessity of studying at least 2000 exfoliated cells to avoid errors. I completely agree with the authors that the number of samples may be too few for meaningful statistical analyses , but a high number of MN in the lymphocytes of healthy subjects of Turkish ethnicity in this study should be explained by the authors. It is questionable that MN levels in both types of cell are several-fold higher in this study than in the study by Karakaya et al. In addition, P 1⁄4 0.000 is given in the summary, the text on page 567, and Table 3, which is meaningless. In conclusion, Hamurçu et al. presented very interesting data about chronic multisystem disease occurences worldwide, especially in Turkey and Japan. The most intriguing circumstance is that this disease affected the skin. Hence, it is possible that increased MN frequency can be found in exfoliated epithelial cells, but the data presented by Hamurçu et al. are not convincing. Further investigations are certainly warranted to evaluate the level of cytogenetic disorders in exfoliated epithelial cells (at least 2000) and lymphocytes on a larger number of patients.

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.

Psoriasis occurring after myeloablative therapy and autologous stem cell transplantation

1 Kirtschig G, Chow ET, Venning VA et al. Acquired subepidermal bullous diseases associated with psoriasis: a clinical, immunopathological and immunogenetic study. Br J Dermatol 1996; 135:738–45. 2 Brun P, Baran R. Pemphigoide bulleuse induite par photochimiothérapie du psoriasis. Ann Dermatol Venereol 1982; 109:461–8. 3 Hashimoto T, Ogawa MM, Konohana A et al. Detection of pemphigus vulgaris and pemphigus foliaceus antigens by immunoblot analysis using different antigen sources. J Invest Dermatol 1990; 94:327–31. 4 Fujimoto W, Ohtsu T, Toi Y et al. Linear IgA disease with IgA antibodies directed against 200and 280-kDa epidermal antigens. Br J Dermatol 2000; 142:1213–18. 5 Chorzelski TP, Jablonska S, Bean SF et al. Linear IgA bullous dermatosis. In: Immunopathology of the Skin (Beutner EH, Chorzelski TP, Bean SF, eds), 2nd edn. New York: Wiley Medical, 1979; 315–19. 6 Chan LS, Traczyk T, Taylor TB et al. Linear IgA bullous dermatosis. Characterization of a subset of patients with concurrent IgA and IgG anti-basement membrane autoantibodies. Arch Dermatol 1995; 131:1432–7. 7 Takagi Y, Sawada S, Yamauchi M et al. Coexistence of psoriasis and linear IgA bullous dermatosis. Br J Dermatol 2000; 142:513–16. 8 Cox AJ. The dermal-epidermal junction in psoriasis. J Invest Dermatol 1969; 53:428–35.

Filaggrin mutations are a major predisposing factor in childhood-onset adult-persistent atopic dermatitis

The transfer of normal genes into somatic cells is one strategy to treat patients with genetic diseases. However, this strategy has still encounters technical problems including effi cacy of gene transfer rate and practical clinical safety. Thus, other strategies including pharmacological therapy or gene correction, are receiving increasing attention. Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the COL7A1 encoding type VII collagen. This study examined the feasibility of antisense oligoribonucleotide (AON) therapy for DEB. AON was designed to induce skipping of a targeted exon containing a premature termination codon mutation, resulting in restoration of the open reading frame. We targeted exon 70 of COL7A1 since a recurrent mutation 5818delC was localized to exon 70 in Japanese DEB patients. We initially designed and synthesized two AONs to modulate splicing of exon 70 and found that one AON induced effective skipping of normal exon 70 containing the 16 amino acids. Attachment and migration analyses showed that recombinant collagen without contribution of exon 70 had similar effect to normal type VII collagen. Next, we synthesized mutation-specifi c AON by deleting cytosine at 5818. Introduction of this AON into DEB keratinocytes harboring 5818delC without expression of type VII collagen showed that the AON induced skipping of exon 70 in the abnormal 5818delC allele. Furthermore, 6.2 % of the DEB keratinocytes started to express type VII collagen in vitro after application of the mutation-specifi c AON. Injection of the AON into rat model grafted the DEB keratinocytes and fi broblasts induced detectable of type VII collagen expression at the basement membrane zone. We conclude that skipping of targeted exons using mutation-specifi c AON may show potential for future gene therapy for DEB patients.We recently reported that ABCA12 works as an epidermal keratinocyte lipid transporter, and that defective ABCA12 results in a loss of the skin lipid barrier, leading to harlequin ichthyosis (HI), one of the most devastating genodermatoses. In the present study, precise expression pattern of ABCA12 was studied in human embryonic and fetal skin of 7-22 weeks estimated gestational age (EGA) and newborn skin samples. For controls, we also studied the expression of transglutaminase 1 (TGase1) that is known to cross-link several precursor proteins in the formation of the cornifi ed cell envelope during keratinocyte terminal differentiation. In twolayered epidermis (about 6-9 weeks EGA), both ABCA12 and TGase1 were only expressed in periderm cells. In three-layered epidermis (10-13 weeks EGA), ABCA12 staining was seen not only in periderm, but also throughout the entire epidermis, while TGase1 staining was restricted to the periderm. A similar pattern was observed during four- or more-layered epidermal development (14-22 weeks EGA). In newborn skin, ABCA12 and TGase1 were seen only in the upper epidermal layers, mainly the granular layer. These staining patterns were similar to those in normal adult skin. Next, we studied ABCA12 mRNA expression in extracts of the fetal skin (at 10, 14, 15 weeks EGA). In 15 weeks EGA, the expression level of ABCA12 mRNA was signifi cantly increased compared with that in the early development (10 and 14 weeks EGA). This increasing pattern of ABCA12 mRNA expression is consistent with ABCA12 immunofl uorescent staining during human epidermal development. The unique pattern of ABCA12 expression during human epidermal development might imply severe symptoms of HI patients with ABCA12 mutations around the birth. 2006 ESDR ABSTRACTS www.Mutations in ABCA12 lead to harlequin ichthyosis and lamellar ichthyosis. The keratinocyte lipid transporter ABCA12 is a member of the ATP-binding cassette transporter family, and members of the ABCA subfamily have closely related functions as lipid transporters. Previously, we reported that the pathomechanism of harlequin ichthyosis involves the defective function of the lipid transporter ABCA12.To further elucidate the precise distribution pattern and function of ABCA12, we performed double-labeling immunofl uorescence staining for ABCA12 and for Golgi-associated or lamellar granule-associated molecules both on normal human epidermis and cultured normal human keratinocytes. We studied the precise localization of ABCA12 and other molecules using confocal laser scanning microscope. In normal human epidermis, ABCA12 was observed mainly in the granular layers with glucosylceramide (one of the major lamellar granule contents) and transglutaminase 1 (a cornifi ed cell envelope-associated keratinization marker), but not always colocalized with GM130 and TGN46 (Golgi-related molecules) that were expressed from the lower epidermis. In normal human keratinocytes cultured in high Ca++ concentration medium, ABCA12 colocalized with GM130 (a cis-Golgi- associated molecule), TGN46 (a trans-Golgi-associated molecule) and glucosylceramide. Transglutaminase 1 was restricted to the cell membrane and ABCA12 localization was within the cytoplasm distinct from transglutaminase 1 localization. The present results suggest that ABCA12 is mainly expressed in differentiated, granular layer keratinocytes with glucosylceramide and transglutaminase 1, and, at the subcellular level, ABCA12 is distributed from the cisside of the Golgi apparatus to trans-Golgi network, lamellar granules at the cell periphery. Our results suggest that ABCA12 may play an important role in lipid transport from the cis-side of the Golgi apparatus through the trans-Golgi network, to the cell periphery via lamellar granules in human epidermal granular layer keratinocytesHarlequin ichthyosis (HI) is a devastating genodermatosis that is often fatal during the neonatal period. Until the identifi cation of ABCA12-encoding a keratinocyte lipid transporter, as the causative gene for HI, prenatal diagnosis (PNDx) had been performed for more than 20 years by electron microscopic examination of fetal skin biopsy samples. We report here the fi rst case of DNA-based PNDx for HI. The proband, the fi rst child of healthy non-consanguineous French parents, showed a typical HI phenotype and died soon after birth. ABCA12 immunostaining was markedly reduced in the proband’s skin. Direct sequence analysis of ABCA12 revealed that the proband was a compound heterozygote for two novel mutations: a maternal nonsense mutation p.Ser1249X in exon 26 and a paternal missense mutation p.Arg2479Lys occurring at the last codon of exon 50. p.Ser1249X leads to an approximate 52 % truncation of the ABCA12 protein losing both ATP-binding cassette active sites. p.Arg2479Lys involves a highly conserved codon among diverse species in the second ABCA12 ATP-binding cassette. For their third pregnancy, the parents requested PNDx. Direct sequence analysis using fetal genomic DNA from amniotic fl uid cells at 17 weeks of pregnancy revealed that the fetus was a compound heterozygote for both mutations. The fetus was predicted to be affected and the parents requested the pregnancy to be terminated. The aborted fetus showed typical signs of HI. Analysis of ABCA12 transcripts of cultured keratinocytes from the abortus showed the presence of six abnormally spliced products arising from the allele carrying the missense mutation. Four of them lead to premature termination codons while the two others produced deleted proteins missing 21 and 31 amino acids in the second ATP-binding cassette. These results indicated residual expression of ABCA12. The present report paves the way for molecular PNDx of HI in the earlier stages of pregnancy

Infliximab is associated with an increased risk of serious infection in patients with psoriasis in the United Kingdom and Republic of Ireland: results from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

Patients with psoriasis and clinicians are concerned that infliximab may be associated with a risk of serious infections.

Identifying demographic, social and clinical predictors of biologic therapy effectiveness in psoriasis: a multicentre longitudinal cohort study

Biologic therapies have revolutionized the treatment of moderate‐to‐severe psoriasis. However, for reasons largely unknown, many patients do not respond or lose response to these drugs.

Ustekinumab exposure during conception and pregnancy in patients with chronic plaque psoriasis: a case series of 10 pregnancies

Biologic drugs are increasingly being prescribed to treat moderate to severe psoriasis. This cohort includes a significant proportion of woman of child bearing potential. Regulatory authorities state that studies to evaluate drug safety during conception or pregnancy are inadequate and therefore advise against their use. This article is protected by copyright. All rights reserved.