Severe, refractory epidermolysis bullosa acquisita complicated by an oesophageal stricture responding to intravenous immune globulin

SIR, Despite the enormous literature detailing associations between particular polymorphisms of the human leucocyte antigen (HLA) genes and predisposition to a large number of benign, immune system-mediated diseases, until comparatively recently there has been much less interest in HLA genetic polymorphism and predisposition to malignant diseases. Therefore, the recent report by Long et al. suggesting that in individuals of Celtic ancestry, HLA phenotype may be a risk factor for skin cancer, independent of paler skin type, is of considerable interest. Results from this study of 736 Welsh subjects indicated that the HLA class II DR4 phenotype was present at a significantly higher frequency among subjects of Celtic ancestry compared with non-Celts (44% vs. 32%; P<0·05). In particular, DR4 was found at the highest frequency in ‘High Scoring Celts’, as defined in the paper (53% vs. 32% in controls; P<0·01), although these comparative differences were not significant after correcting for comparisons made. Other associations between HLA phenotype and Celtic ancestry were also reported in this study, although most of the observations made and hypotheses raised by the authors concern HLA-DR4 and the fact that in the studies they quote, DR4 is the only HLA phenotype associated with both malignant melanoma (MM) and non-malignant melanoma skin cancer (NMSC). Based on these data, the authors suggest that the increased frequency of DR4 in Celts may be an independent risk factor for both MM and NMSC, in addition to skin type. While this remains to be proven, Long et al. are selective in the studies they quote concerning increases in the HLA-DR4 phenotype and MM. In particular, they do not quote the most recent U.S.-based studies which suggest that HLADQB1*0301 is strongly associated with cutaneous MM and may also be associated with more advanced disease, including metastasis. The same group has also shown that the DQB1*0301 genotype is also associated with an increased risk of recurrence. These studies provide no evidence for an increased incidence of HLA-DR4 in cutaneous MM, nor does another recent U.S. study. A further study in the Italian population fails to find DR4 associations with MM, but does report an increased incidence of the DRB1*11, DQA1*0501, DQB1*0301 haplotype. Data from our laboratory also indicate associations between the DQB1*0303 and *0301 alleles and susceptibility to and prognosis in cutaneous MM. Therefore, if there is any consensus in the HLA class II data and cutaneous MM it is that the DQB1*0301 genotype influences either susceptibility to and/or severity of this form of skin cancer. This conclusion is not necessarily at odds with that of Long et al. as DQB1*0301 and *0302 alleles occur in linkage disequilibrium with DRB1*04 (DR4), although DQB1*0301 is also found in linkage disequilibrium with other groups of DRB1 alleles, including DRB1*11. Therefore an apparent HLA-DR4 association, in the absence of DQB1 typing data, may in fact reflect a primary DQB1*0301 (or *0302) association with skin type or disease. However, despite performing ‘low resolution’ molecular DQB1 typing, Long et al. do not report any significant DQB1 associations with Celtic ancestry, although the data from which this conclusion is drawn are not presented in the paper. Irrespective of whether the same HLA class II phenotypes influence susceptibility to both MM and NMSC, HLA class II phenotype and genotype in patients with skin cancer from different racial groups merit further investigation.