Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove.

Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6-36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.

Treatment of paediatric eczema with narrowband ultraviolet light B therapy.

BACKGROUND: Narrowband ultraviolet B phototherapy (nbUVB) is a well-established, well-tolerated and efficacious treatment for eczema. There is a distinct lack of literature surrounding the therapeutic use of nbUVB in eczema in children and especially in children with higher skin phototypes (III to VI). METHODS: We undertook a retrospective review of children aged 18 years and under with eczema who had undergone nbUVB in our department between 1 January 2011 and 31 December 2017. Abstracted data included sex, age, skin phototype, severity as graded by a paediatric dermatologist, cumulative dose, response to treatment and subsequent remission. RESULTS: In total, 60 children had nbUVB. Of those, 56 had more than 10 nbUVB exposures. Complete or near-complete clearance was achieved in 31 children (52%). Of those, 24 (77%) had a skin phototype of III or greater. Clinical remission rates of these patients were 100%, 87%, 57% and 52% at 0, 3, 6 and 12 months, respectively. Seventeen patients (28%) suffered side effects. Most commonly these were mild side effects such as erythema and xerosis. CONCLUSION: We have demonstrated that nbUVB is a safe, well-tolerated and efficacious form of treatment for children with atopic eczema. We have shown it to be effective in those with skin phototypes greater than III and shown that they are a group that may derive greater long-term efficacy. In clinical practice, preference for nbUVB as second-line treatment, over oral systemics, should always be considered.

Exacerbation of X-linked ichthyosis phenotype in a female by inheritance of filaggrin and steroid sulfatase mutations.

BACKGROUND: X-linked ichthyosis (XLI) is a relatively common, recessive condition caused by mutations in the steroid sulfatase (STS) gene. Common loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and predispose individuals to atopic eczema. OBJECTIVE: To test the hypothesis that co-inheritance of FLG mutations can act as a genetic modifier in XLI. METHODS: An unusually severe XLI phenotype in addition to eczema and mild childhood asthma was investigated in a female Indian patient by fluorescent in situ hybridization (FISH) for the common STS gene deletion. Direct sequencing of the entire FLG gene was also performed. RESULTS: FISH analysis revealed that the proband was homozygous for the common STS genomic deletion mutation. Further investigation revealed a frame-shift mutation 3672del4 in the gene encoding filaggrin (FLG), leading to premature termination of profilaggrin translation. Interestingly, her father, who had a very typical mild presentation of XLI, did not carry this FLG mutation in addition to his STS deletion. Her mother was a heterozygous carrier of the FLG mutation and consistent with this, had mild symptoms of ichthyosis vulgaris; she was also a heterozygous carrier of the STS deletion. CONCLUSION: This is the second reported case of the modifying effects of FLG null alleles on XLI and strengthens the hypothesis that filaggrin defects can synergize with STS deficiency to exacerbate the ichthyosis phenotype.