Biologic drug survival rates in the era of anti-interleukin-17 antibodies: a time-period-adjusted registry analysis.

BACKGROUND: Drug survival rates reflect efficacy and safety and may be influenced by the availability of alternative treatment options. Little is known about time-dependent drug survival in psoriasis and the effect of increasing numbers of biologic treatment options. OBJECTIVES: To determine whether drug survival is influenced by the availability of treatment options and by factors such as gender, psoriatic arthritis or previous biologic treatment. METHODS: This observational, retrospective, multicentre cohort study analysed data from patients registered in the Austrian Psoriasis Registry (PsoRA) who were treated with biologics between 1 January 2015 and 30 November 2019. RESULTS: A total of 1572 patients who received 1848 treatment cycles were included in this analysis. The highest long-term Psoriasis Area and Severity Index improvement was observed after treatment with ixekizumab, followed by ustekinumab and secukinumab, adalimumab and etanercept. Overall, ustekinumab surpassed all other biologics in drug survival up to 48 months. However, when adjusted for biologic naïvety, its superiority vanished and drug survival rates were similar for ixekizumab (91·6%), secukinumab (90·2%) and ustekinumab (92·8%), all of them superior to adalimumab (76·5%) and etanercept (71·9%) at 12 months and beyond. Besides biologic non-naïvety (2·10, P < 0·001), the introduction of a new drug such as secukinumab or ixekizumab (relative hazard ratio 1·6, P = 0·001) and female gender (1·50, P = 0·019) increased the risk of treatment discontinuation overall, whereas psoriatic arthritis did not (1·12, P = 0·21). CONCLUSIONS: The time-dependent availability of drugs should be considered when analysing and comparing drug survival. Previous biologic exposure significantly influences drug survival. Women are more likely to stop treatment.

Management of congenital ichthyoses: European guidelines of care, part two.

These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016, and a consensus on the discussions. These guidelines summarize evidence and expert-based recommendations and intend to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part two, covering the management of complications and the particularities of some forms of congenital ichthyosis.

Management of congenital ichthyoses: European guidelines of care, part one.

These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016 and a consensus on the discussions. They summarize evidence and expert-based recommendations and are intended to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part one, covering topical therapies, systemic therapies, psychosocial management, communicating the diagnosis and genetic counselling.

Prosthetic rehabilitation of patients with hypohidrotic ectodermal dysplasia: A systematic review.

Hypohidrotic ectodermal dysplasia (HED) comprises a large group of inherited disorders of ectodermal structures, characterised by hypo- or anhidrosis, hypotrichosis and hypo- or oligo- or anodontia. We aimed to systematically assess the spectrum of prosthodontic approaches with regard to the patients' age and to provide clinical implications for practicing dentists. An electronic and manual search was conducted in four databases (Medline, LIVIVO, Cochrane Library, Web of Science Core Collection). Publications of multiple study designs written in English or German without data restrictions, reporting on prosthodontic treatment of patients diagnosed with HED and afflicted with oligo- or anodontia, were included. In total, 75 articles on 146 patients were analysed according to the patients' age. In children aged 2-17 years, removable full or partial (over)dentures represented standard treatment. In the mandible, implant-supported removable dentures on two interforaminal implants presented an alternative, already in young childhood. In cases with more than six teeth per jaw, also fixed (resin) bridges were used, frequently after orthodontic treatment. In adults, fixed or removable reconstructions with the help of up to eight implants per jaw, usually placed after bone augmentation procedures, were standard. Ten case reports/series with long-term follow-up illustrated the need for consistent maintenance including denture renewals. Prosthodontic rehabilitation should start in early childhood and needs to be revised in accordance with the patients' growth. Treatment should be carried out by a multidisciplinary team addressing variable demands in different age groups.

Morphological alterations in two siblings with autosomal recessive congenital ichthyosis associated with CYP4F22 mutations.

Autosomal recessive congenital ichthyosis (ARCI) caused by mutations in CYP4F22 is very rare. CyP4F22, a protein of the cytochrome-P450 family 4, encodes an epidermal ω-hydroxylase decisive in the formation of acylceramides, which is hypothesized to be crucial for skin-barrier function. We report a girl with consanguineous parents presenting as collodion baby with contractures of the great joints and palmoplantar hyperlinearity. In the course of the disease she developed fine scaling of the skin with erythroderma, the latter disappearing until the age of 6 months. Her sister showed a generalized fine-scaling phenotype, and, interestingly, was born without a collodion membrane. The analysis of all known candidate genes for ARCI in parallel with a next-generation sequencing approach using a newly designed dermatogenetics gene panel revealed a previously unknown homozygous splice-site mutation c.549+5G>C in CYP4F22 in both girls, confirming the diagnosis of ARCI. Ultrastructural analysis by transmission electron microscopy in both patients showed epidermal hyperplasia, orthohyperkeratosis with persistence of corneodesmosomes into the outer stratum corneum layers, fragmented and disorganized lamellar lipid bilayers, which could be ascribed to inhomogeneous lamellar body secretion, as well as lamellar body and lipid entombment in the corneocytes. These findings correlated with increased transepidermal water loss on the functional level. For the first time, we report a collodion baby phenotype and epidermal barrier impairment in CyP4F22-deficient epidermis at both the ultrastructural and functional level, and corroborate the importance of CyP4F22 for epidermal maturation and barrier function.

Epidermal barrier abnormalities in exfoliative ichthyosis with a novel homozygous loss-of-function mutation in CSTA.

Autosomal recessive exfoliative ichthyosis (AREI) results from mutations in CSTA, encoding cysteine protease inhibitor A (cystatin A). We present a 25-year-old man from Iran with consanguineous parents, who presented with congenital erythroderma, hyperhidrosis and diffuse hyperkeratosis with coarse palmoplantar peeling of the skin, aggravated by exposure to water and by occlusion. Candidate gene analysis revealed a previously unknown homozygous loss-of-function mutation c.172C>T (p.Arg58Ter) in CSTA, and immunostaining showed absence of epidermal cystatin A, confirming the diagnosis of AREI. Ultrastructural analysis by transmission electron microscopy showed normal degradation of corneodesmosomes, mild intercellular oedema in the spinous layer but not in the basal layer, normal-appearing desmosomes, and prominent keratin filaments within basal keratinocytes. Thickness of cornified envelopes was reduced, lamellar lipid bilayers were disturbed, lamellar body secretion occurred prematurely and processing of secreted lamellar body contents was delayed. These barrier abnormalities were reminiscent of (albeit less severe than in) Netherton syndrome, which results from a deficiency of the serine protease inhibitor LEKTI. This work describes ultrastructural findings with evidence of epidermal barrier abnormalities in AREI.

Premature newborns with fatal intrauterine herpes simplex virus-1 infection: first report of twins and review of the literature.

BACKGROUND: Neonates with blistering skin diseases are dermatologic emergencies. The pathologies involved can pose diagnostic difficulties and there exists a variety of potential life-threatening differential diagnoses. OBJECTIVE: description of the first case of intrauterine acquired herpes simplex virus (HSV) 1 infection in twins. METHODS: We present the case of two premature bicordial biamniotic twins (27th week of gestation) whose intrauterine growth retardation, fetal anaemia and cardiotocography abnormalities led to a caesarean emergency delivery. RESULTS: Accurate medical history revealed a maternal febrile gingivostomatitis at the 23rd week of gestation, which was neglected by the treating gynaecologist. Respiratory distress was present at delivery and intubation was necessary in both children. The whole skin showed extensive erosions and ulcerations and the mucosa of the eyes and genitals was also involved. Intrauterine Herpes simplex virus (HSV) 1 infection was confirmed by immunohistochemistry of skin Tzanck smear (HSV 1 positive, HSV 2 negative), real-time polymerase chain reaction of both serum and skin (HSV 1 positive; HSV 2 negative) and maternal serology positive for HSV 1 IgM and IgG. Siblings were immediately treated with high-dose endovenous acyclovir. Anaemia thrombocytopenia and hepatorenal values markedly deteriorated and both developed consequential hepatorenal failure. The third day live supportive measures were terminated after parental informed consent and both siblings deceased shortly after on their mother's breast. DISCUSSION: Intrauterine HSV infection is rare and accounts only for 5% of neonatal HSV infections. Literature reports only 64 cases and 90% of those are related to HSV-2. Transplacental viral transmission is highest during the first 20 weeks of gestation and has been observed in pregnant women with disseminated HSV infection. Mortality and morbidity of intrauterine herpetic infection are extremely high. CONCLUSION: Despite transplacental HSV transmission remains a rare event, the potential devastating outcome justifies immediate adequate antiviral treatment in a pregnant woman affected by primary HSV infection.

Increased pachyonychia congenita severity in patients with concurrent keratin and filaggrin mutations.

Pachyonychia congenita (PC), a rare autosomal-dominant keratin disorder caused by mutations in keratin genes KRT6A/B, KRT16 or KRT17, is characterized by painful plantar keratoderma and hypertrophic nail dystrophy. Loss-of-function mutations in the filaggrin (FLG) gene underlie the most prevalent skin disorder of cornification, ichthyosis vulgaris (IV), which presents with generalized scaling and is also associated with atopic dermatitis. Recently, FLG mutations have been reported to increase phenotype severity of X-linked ichthyosis and alopecia areata. We report a parent-child trio in which the mother and the son have PC and the father has IV. Both the mother and the son are carriers for the KRT16 mutation p.Leu132Pro. The son, who is much more severely affected than his mother, in addition carries the heterozygous FLG mutation p.R2447X, which was inherited from the father. This observation suggests that coinheritance of mutations in KRT16 and FLG may aggravate the PC phenotype and that FLG could serve as a genetic modifier in PC.

Pili annulati: refinement of the locus on chromosome 12q24.33 to a 2.9-Mb interval and candidate gene analysis.

BACKGROUND: Pili annulati is an autosomal dominant hair shaft disorder characterized by alternating light and dark bands in hairs of affected individuals. Recently, a locus for pili annulati was mapped to chromosome 12q24.32-24.33 and recombination events defined a critical region of 9.2 cM (3.9 Mb). OBJECTIVES: The aim of the current study was to narrow the size of the candidate region and to identify the pathogenic mutation for pili annulati by analysing the candidate genes. METHODS: In three families with 90 individuals, including 40 affected subjects, linkage analysis was performed with 13 microsatellite markers in the candidate region on chromosome 12. Candidate genes were analysed for their expression in hair follicles and other tissues by reverse transcriptase-polymerase chain reaction (RT-PCR) and mutation analysis. RESULTS: Multipoint LOD score analysis for all three families confirmed the locus on the long arm of chromosome 12 with a maximum LOD score of 12.26 at marker D12S357. In two families, recombinations were identified which narrowed the region to 2.9 Mb containing 36 genes. We analysed the candidate genes in this region by RT-PCR and found that 24 were expressed in human hair follicles. Based on the result of the expression analysis, DNA sequencing of the coding region of the candidate genes was performed; this did not result in the discovery of a causal mutation. CONCLUSION: We reduced the critical interval of pili annulati to 2.9 Mb and excluded mutations in the coding region of all 36 possible candidate genes by sequence analysis.

Sézary syndrome is a unique cutaneous T-cell lymphoma as identified by an expanded gene signature including diagnostic marker molecules CDO1 and DNM3.

Sezary syndrome (SS) is a rare, aggressive CD4+ cutaneous T-cell lymphoma (CTCL); molecular traits differentiating SS from nonleukemic mycosis fungoides (MF) and from inflammatory skin diseases (ID) are not sufficiently characterized. Peripheral blood mononuclear cells (PBMC) of 10 SS patients and 10 healthy donors (HD) were screened by Affymetrix U133Plus2.0 chips for differential gene expression. Ten candidate genes were confirmed by qRT-PCR to be significantly overexpressed in CD4+ T cells of SS versus HD/ID. For easier clinical use, these genes were re-analyzed in PBMC; qRT-PCR confirmed five novel (DNM3, IGFL2, CDO1, NEDD4L, KLHDC5) and two known genes (PLS3, TNFSF11) to be significantly overexpressed in SS. Multiple logistic regression analysis revealed that CDO1 and DNM3 had the highest discriminative power in combination. Upon comparison of PBMC and skin samples of SS versus MF, CDO1 and DNM3 were found upregulated only in SS. Using anti-CDO1 antisera, differential expression of CDO1 protein was confirmed in SS CD4+ T cells. Interestingly, DNM3 and CDO1 are known to be regulated by SS-associated transcription factors TWIST1 and c-myb, respectively. Furthermore, CDO1 catalyzes taurine synthesis and taurine inhibits apoptosis and promotes chemoprotection. In summary, CDO1 and DNM3 may improve the diagnosis of SS and open novel clues to its pathogenesis.

Nuclear hormone receptors in human skin.

Nuclear hormone receptors are of critical importance for skin homeostasis where they modulate cellular metabolism, proliferation, differentiation, cell death, and inflammation. The cutaneous role of the glucocorticoid, androgen, and estrogen receptors was explored initially. In recent years, sequence homology comparisons have uncovered the complete superfamily of related receptors, many of which are also implicated in cutaneous homeostasis. A subgroup of these receptors acts in concert with the retinoid X receptor by heterodimerization and has been successfully targeted for dermatologic therapy; i.e., the retinoic acid receptor and the vitamin D receptor. Ongoing research is aimed at delineating the cutaneous effects of additional members of this subgroup including the peroxisome proliferator-activated receptors and the liver X receptors. The various receptors exert differential effects in skin and can be rationally chosen as drug targets for the treatment of cutaneous pathologies.

Topical corticosteroid therapy for acute radiation dermatitis: a prospective, randomized, double-blind study.

BACKGROUND: Radiation dermatitis is a common side-effect of radiation therapy, but there is no current consensus about its appropriate therapy. OBJECTIVES: To compare treatment with topical 0.1% methylprednisolone vs. 0.5% dexpanthenol in a cohort of patients undergoing fractionated radiation therapy for breast cancer. METHODS: In a randomized, double-blind design, treatment was initiated at the beginning of radiation therapy and continued for 2 weeks after termination of radiation. Outcomes were compared by three different measures: clinical (symptom score), functional (transepidermal water loss, TEWL) and subjective (quality of life, QOL). RESULTS: In a preliminary cohort of untreated patients undergoing radiation therapy, clinical signs and TEWL levels increased progressively during radiation therapy, reaching highest values at 5 and 4 weeks, respectively. Although neither topical treatment reduced the incidence of radiation dermatitis, both delayed the emergence of greatest clinical and TEWL scores until approximately 6 and 5 weeks, respectively. With topical corticosteroids, clinical symptoms and TEWL were less pronounced than with dexpanthenol. Whereas general QOL improved after completion of radiation therapy, skin-related QOL declined. However, the skin-related QOL decline could be at least in part reversed by use of topical corticosteroid vs. dexpanthenol-containing emollient. CONCLUSIONS: We provide evidence that prophylactic and ongoing use of topical therapy with either topical corticosteroid or a dexpanthenol-containing emollient ameliorates, but does not prevent radiation dermatitis. Our data suggest, but do not prove, a benefit of a topical corticosteroid vs. a dexpanthenol-containing emollient. Further controlled studies with larger cohorts will be needed to determine optimal forms of topical therapy for radiation dermatitis.

Expression of the C-C chemokine MIP-3 alpha/CCL20 in human epidermis with impaired permeability barrier function.

External assault to the skin is followed by an epidermal response including synthesis of DNA, lipids, cytokines and migration of antigen presenting cells. MIP-3 alpha (CCL20, LARC, Exodus-1, Scya20) is a recently described C-C chemokine, predominantly expressed in extralymphoid tissue, which is known to direct migration of dendritic cell precursors and memory lymphocytes to sites of antigen invasion. We assessed the expression of MIP-3 alpha in human skin using semi-quantitative polymerase chain reaction. In vivo, MIP-3 alpha mRNA was constitutively expressed at low levels in untreated human epidermis. After acute disruption of the epidermal permeability barrier MIP-3 alpha mRNA was upregulated in the epidermal fraction, whereas dermal MIP-3 alpha mRNA levels remained unchanged. In vitro, MIP-3 alpha was increased in cultured keratinocytes treated with IL-1 alpha and TNF-alpha and was present in immature and mature dendritic cells, THP-1 monocytic cells and activated T cells. Finally, skin biopsies from patients with psoriasis, contact dermatitis and mycosis fungoides showed abundant expression. In biopsies from atopic dermatitis and graft vs. host disease a weak signal was present, whereas no expression was found in scleroderma and toxic epidermal necrolysis. We conclude that regulation of MIP-3 alpha mRNA is part of the epidermal response to external assault. Its upregulation may represent a danger signal for increased immunosurveillance in barrier disrupted skin and inflammatory skin conditions with impaired barrier function to counteract potential antigen invasion.