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Background: Behçet disease (BD) presents with lymphocytic and neutrophilic vasculitis of unknown aetiology. HLA-B*51, the endoplasmic reticulum aminopeptidase 1 (ERAP1), and interleukin 23 receptor (IL23R)/IL12R are genetic risk factors. IL-23 regulates IL-17A, which controls the recruitment and activation of neutrophils., Objectives: To determine pathological changes in BD skin lesions related to the complex genetic predisposition., Methods: We characterized the expression of IL-17A and IL-23A in various cell types by immunohistological double staining of sections from papulopustular skin lesions of acute attacks of BD and psoriasis vulgaris lesions, another HLA-class I-associated T-cell-mediated autoimmune disease in which excessive T-cell-derived IL-17A production promotes neutrophil activation., Results: We found that in BD lesions, as in psoriasis, actively expanding CD8 + T cells were the predominant source of IL-17A. IL-17A + CD8 + T (T c 17) cells outnumbered infiltrating IL-17A + CD4 + T cells. Unlike the epidermal localization of CD8 + T cells in psoriasis, T c 17 cells in BD lesions mainly infiltrated the perivascular tissue and the blood vessel walls of dermis and subcutaneous tissue. They co-localised with a marked IL-23A expression by CD11c + dendritic cells and CD68 + macrophages. IL-17A expression was associated with extensive recruitment of neutrophils around blood vessels that formed neutrophil extracellular traps (NETs)., Conclusions: In BD, the genetic predisposition may mediate antigen-specific activation and differentiation of a T c 17 response, possibly targeting endothelial (auto)antigens. Neutrophils recruited by IL-17A in this process may enhance tissue damage by extensive NET formation (NETosis). Thus, the IL-23/IL-17 axis presumably controls neutrophilic inflammation in BD vasculitis in the context of a predominant antigen-specific CD8 + T-cell response., (© 2021 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP)., Objectives: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN., Methods: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort., Results: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers., Conclusions: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN., (© 2017 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, demonstrated efficacy and safety in moderate-to-severe plaque psoriasis when administered via subcutaneous injection. Self-administration by pre-filled syringe (PFS) can offer patients clinical benefits of a drug, with increased convenience., Objectives: To assess efficacy, safety and usability of secukinumab administration via PFS in subjects with moderate-to-severe plaque psoriasis., Materials and Methods: Subjects in this phase 3 trial were randomized 1 : 1 : 1 to secukinumab 300 or 150 mg or matching placebo. Results to week 12 are presented here. Each treatment was delivered using a PFS once weekly to week 4, and again at week 8. Co-primary endpoints were secukinumab superiority over placebo for week 12 PASI 75 (≥ 75% reduction in Psoriasis Area and Severity Index) and IGA mod 2011 (2011 modified Investigator's Global Assessment) 0/1 response rates. Secondary endpoints included PFS usability, determined by observer rating of successful, hazard-free self-injection and subject rating of acceptability by the Self-Injection Assessment Questionnaire (SIAQ)., Results: Co-primary endpoints were met, with demonstration of superiority for each secukinumab dose vs. placebo at week 12 (PASI 75: 75·9%, 69·5% and 0% for secukinumab 300 mg, 150 mg and placebo; IGA mod 2011 0/1: 69·0%, 52·5% and 0%, respectively; P < 0·0001 for all comparisons vs. placebo). PFS usability was high: 100% of subjects successfully self-administered treatment at week 1, and subjects reported high SIAQ-assessed acceptability of the PFS throughout the trial. No new/unexpected safety signals were observed., Conclusions: Secukinumab administration by PFS was effective, with an acceptable safety profile and high usability. The PFS provides a reliable, convenient form of secukinumab administration in subjects with moderate-to-severe plaque psoriasis., (© 2014 British Association of Dermatologists.)

Background: Evaluation of the dosing flexibility and long-term efficacy of biological agents is limited., Objectives: To evaluate the long-term efficacy and safety of ustekinumab with and without dosing adjustment in the 5-year PHOENIX 2 study., Methods: Patients were randomized to placebo or ustekinumab (45 or 90 mg) at weeks 0, 4, then every 12 weeks; patients receiving placebo crossed-over at week 12. Dosing adjustments were permitted at/beyond week 28 for early adjusters (weeks 28 or 40 per response); late adjusters (during long-term extension per investigator judgement); and nonadjusters (maintained randomized treatment throughout the study). Efficacy and safety were evaluated through weeks 244 and 264, respectively., Results: In the overall population, 70% (849 of 1212) of ustekinumab-treated patients completed treatment through week 244, with high proportions of patients responding to the 45-mg and 90-mg doses, respectively: 75% improvement in Psoriasis Area and Severity Index (PASI 75) (76·5% and 78·6%) and PASI 90 (50·0% and 55·5%). Approximately 20% of patients were early adjusters, 30% were late adjusters and 50% were nonadjusters. Approximately half of the late adjusters initiated adjustments after already achieving PASI 75. Improved response was generally observed following dosing adjustments. Through week 264, safety event rates did not increase and event rates were generally comparable between dose groups and between patients with and without dosing adjustment., Conclusions: Treatment with ustekinumab for up to 5 years was safe and effective. Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify actual incremental benefits. The results also suggest that some patients may desire treatment goals beyond PASI 75., (© 2014 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: The pathogenesis of chronic hand eczema (CHE) is multifactorial and involves both endogenous predisposition and environmental triggers., Objectives: Filaggrin is a structural protein of the cornified envelope and important for the formation of the epidermal skin barrier. The aim of this investigation was to evaluate the role of mutations in the filaggrin gene (FLG) in the development of CHE., Methods: In total, 122 German patients with clearly defined CHE subtypes were screened for the FLG variants R501X and 2282del4 by polymerase chain reaction and restriction enzyme digest analysis. The prevalence of these variants in CHE patients was compared with that in 95 healthy individuals., Results: Overall, allele frequency and the number of mutation carriers were similar in both the CHE and control groups. When classified according to clearly defined CHE subtypes, however, the nonfunctional FLG variants showed an association with CHE involving an aetiological combination of contact allergy and irritant factors [P = 0.04; P (exact test) = 0.06; P (difference in rates) = 0.09; 95% confidence interval (CI) 0-56.8)], or with excessive daily exposure to water and irritants [P = 0.003; P (difference in rates) < 0.001; 95% CI 29.3-67.9]., Conclusion: Heterozygosity for nonfunctional mutations in the FLG gene may contribute to the manifestation and maintenance of a particular CHE subtype that is characterized by the combination of allergic and irritant contact dermatitis.

Borrelia burgdorferi is a major cause of morbidity in wooded area in western Europe and the eastern seaboard of the U.S.A. Diagnosis of late stage infection and associated disorders may be difficult and often requires an array of different diagnostic procedures. Here we report an 11-year-old girl with acrodermatitis chronica atrophicans affecting all four limbs and parts of the trunk. The diagnosis was made on the basis of clinical appearance, serological and histopathological findings, and the lesional detection of B. burgdorferi-specific gene segments by polymerase chain reaction. This very unusual, severe case illustrates that despite being a late manifestation of tick-borne B.burgdorferi infection, usually occurring in adults, acrodermatitis chronica atrophicans may already appear at a young age and may be characterized by extensive skin involvement.