Common variants in FOXP1 are associated with generalized vitiligo

In a recent genome-wide association study of generalized vitiligo, we identified ten confirmed susceptibility loci. By testing additional loci that showed suggestive association in the genome-wide study, using two replication cohorts of European descent, we observed replicated association of generalized vitiligo with variants at 3p13 encompassing FOXP1 (rs17008723, combined P = 1.04 × 10−8) and with variants at 6q27 encompassing CCR6 (rs6902119, combined P = 3.94 × 10−7)

Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo.

BACKGROUND Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases. METHODS To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families. RESULTS We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05×10−23) and class II molecules (P=4.50×10−34), PTPN22 (P=1.31×10−7), LPP (P=1.01×10−11), IL2RA (P=2.78×10−9), UBASH3A (P=1.26×10−9), and C1QTNF6 (P=2.21×10−16). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07×10−15) and GZMB (P=3.44×10−8), and in a locus containing TYR (P=1.60×10−18), encoding tyrosinase. CONCLUSIONS We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma

Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo

We previously reported a genome-wide association study (GWAS) identifying 14 susceptibility loci for generalized vitiligo. We report here a second GWAS (450 individuals with vitiligo (cases) and 3,182 controls), an independent replication study (1,440 cases and 1,316 controls) and a meta-analysis (3,187 cases and 6,723 controls) identifying 13 additional vitiligo-associated loci. These include OCA2-HERC2 (combined P = 3.80 × 10 ), MC1R (P = 1.82 × 10 ), a region near TYR (P = 1.57 × 10 ), IFIH1 (P = 4.91 × 10 ), CD80 (P = 3.78 × 10 ), CLNK (P = 1.56 × 10 ), BACH2 (P = 2.53 × 10 ), SLA (P = 1.58 × 10 ), CASP7 (P = 3.56 × 10 ), CD44 (P = 1.78 × 10 ), IKZF4 (P = 2.75 × 10 ), SH2B3 (P = 3.54 × 10 ) and TOB2 (P = 6.81 × 10 ). Most vitiligo susceptibility loci encode immunoregulatory proteins or melanocyte components that likely mediate immune targeting and the relationships among vitiligo, melanoma, and eye, skin and hair coloration

The contribution of metal allergy to the failure of metal alloy implants, with special reference to titanium: current knowledge and controversies

After almost three-quarters of a century during which contact dermatologists have often struggled to comprehend the relationship between metal allergy and failure of metal-alloy containing implant, it is possible to say that a relationship does exist, particularly for cobalt and chromium, but also for nickel. There is still debate as to whether allergy develops as a consequent of failure but thenceforth contributes to it, or whether sensitisation starts first and induces failure secondarily—opinion probably favours the first. Metal-on-polypropylene articulations were associated with few metal allergic problems but now are less favoured by orthopaedists due to plastic wear products causing osteolysis and pseudotumour formation through local inflammation. New metal alloys are regularly being introduced such that interested dermatologists need to stay on top of the situation. The jury is still out as to whether the recent favouring of titanium-containing alloys will confirm them to be more inert allergenically. Case reports do show some clinical reactions to titanium-containing implants and patch test series have inferred sometimes quite a high background rate of allergy, but interpretation must be tempered by the awareness that titanium salts on patch testing have a tendency to cause irritant reactions. Blood monitoring of metal ion values is now recommended in certain situations after joint replacement and increasing levels may be an indication that allergy with joint failure can develop, in which case patch testing is indicated, and suggested series are available. Predictive patch testing, whilst generally not recommended in the past, has been introduced into some protocols often by non-dermatologists, such that it is now needed for temporo-mandibular joint and Nuss bar insertion, and it can be anticipated that this may become more commonplace in the future. One of the major current deficits for patch testers is standardised guidance on which preparation or preparations to use for suspected titanium allergy. One suggestion is 0.5% titanium sulphate in petrolatum, though experience in at least one centre suggests the use of a battery of titanium salts might be desirable

Sodium benzoate as an emerging but problematic allergen: retrospective analysis of patch test results in 3198 cases underlines the need for an improved test preparation, as even dubious reactions may be clinically relevant

Background Sodium benzoate is increasingly used as a preservative in personal care products and in foods. Recently published experience of patch testing sodium benzoate at 5% in pet shows it to be an allergen that may be assuming increasing clinical relevance. Objectives We set out to define the prevalence of clinically relevant reactions to sodium benzoate, to delineate problems with the interpretation of patch test readings to this allergen and to identify whether its inclusion in various series offers additional diagnostic benefit beyond those offered by commonly tested allergens, for example benzoic acid and Myroxylon pereirae, with which it may show some cross reactivity. Methods From 2008 to 2023, 3198 patients were patch tested to 5% sodium benzoate in pet, which has been included in our bakery/cheilitis, fragrance and facial series. Types of reaction, clinical relevance and cross-reactivities were noted. Results Of 3198 subjects tested to 5% sodium benzoate in pet, 57 (1.8%) had an allergic positive reaction (+/++), 53 (1.6%) had a doubtful reaction (?+) and 133 (4.1%) had an irritant reaction (IR) – meaning that ?+ or irritant reactions were more than three times more common than allergic responses. Clinical relevance was identified in 67% (38 of 57) of + or ++ reactors to sodium benzoate, and in 36% (19 of 53) of those with doubtful (?+) reactions. Co-reactivity to benzoic acid was seen in 15.4% of cases + or ++ to sodium benzoate. The positivity ratio (the proportion of + reactions compared to ++ and +++) was 96.5% and the reaction index (number of allergic positives compared to ?+ or IR) was −0.53. Both indices indicate a problematic allergen. Conclusions This series reaffirms that sodium benzoate is an important allergen which should be included in bakery/cheilitis, fragrance and facial series in addition to benzoic acid and Myroxylon pereirae, with which it occasionally cross-reacts. However, it is tricky to test and its reactions are difficult to interpret—underlining the need to refine the preparation used for patch testing

Patho-immunological mechanisms of vitiligo: the role of the innate and adaptive immunities and environmental stress factors.

Epidermal melanocyte loss in vitiligo, triggered by stresses ranging from trauma to emotional stress, chemical exposure or metabolite imbalance, to the unknown, can stimulate oxidative stress in pigment cells, which secrete damage-associated molecular patterns that then initiate innate immune responses. Antigen presentation to melanocytes leads to stimulation of autoreactive T-cell responses, with further targeting of pigment cells. Studies show a pathogenic basis for cellular stress, innate immune responses and adaptive immunity in vitiligo. Improved understanding of the aetiological mechanisms in vitiligo has already resulted in successful use of the Jak inhibitors in vitiligo. In this review, we outline the current understanding of the pathological mechanisms in vitiligo and locate loci to which therapeutic attack might be directed

Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic non-inferiority randomised controlled trial

Background: Bullous pemphigoid (BP) is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline conveys acceptable short-term blister control whilst conferring long-term safety advantages over starting treatment with oral corticosteroids. Methods: Pragmatic multi-centre parallel-group randomised controlled trial of adults with BP (≥3 blisters ≥2 sites and linear basement membrane IgG/C3) plus economic evaluation. Participants were randomised to doxycycline (200 mg/day) or prednisolone (0·5 mg/kg/day). Localised adjuvant potent topical corticosteroids (<30 g/week) was permitted weeks 1-3. The non-inferiority primary effectiveness outcome was the proportion of participants with ≤3 blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of noninferiority. The primary safety outcome was the proportion with severe, life-threatening or fatal treatment-related adverse events by 52 weeks. Analysis used a regression model adjusting for baseline disease severity, age and Karnofsky score, with missing data imputed. Results: 132 patients were randomised to doxycycline and 121 to prednisolone from 54 UK and 7 German dermatology centres. Mean age was 77·7 years and 68.4% had moderate to severe baseline disease. For those starting doxycycline, 83/112 (74·1%) had ≤3 blisters at 6 weeks compared with 92/101 (91·1%) for prednisolone, a difference of 18·6% favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening and fatal events at 52 weeks were 18·5% for those starting doxycycline and 36·6% for prednisolone (mITT analysis), an adjusted difference of 19·0% (95% CI, 7·9%, 30·1%, p=0·001). Conclusions: A strategy of starting BP patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control and significantly safer long-term

Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants

Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes1, with epidemiological association with other autoimmune diseases2. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some of which corresponds to expression quantitative trait loci (eQTLs) at these loci. Together, the identified genes provide a framework for the genetic architecture and pathobiology of vitiligo, highlight relationships with other autoimmune diseases and melanoma, and offer potential targets for treatment