The Relationship between Autoimmune Bullous Disease and Systemic Disorders

The mystery of the association of skin disease with systemic disease has been a matter of fascination to dermatologists for hundreds of years. There are a myriad of articles and case reports linking various cutaneous findings to internal disease. The implication has always been that some soluble or cellular factor is being produced that results in a cutaneous disease. Immunobullous disease associates a particular antibody with a cutaneous disease and so the responsible factor for associating an immunobullous disease with a systemic disease is production of an antibody. We will review the milestones in immunobullous disease that have refined our understanding of these associations and consider possible pathogenic mechanisms. Dermatitis herpetiformis (DH) is a papulovesicular skin disease with gluten-sensitive enteropathy (celiac disease, CD) and a unique HLA type (HLADQ2 and DQ8) associated in virtually all cases. Granular deposition of IgA is the immunopathological hallmark. Marks et al. (1966) are generally credited with describing the association of CD with DH. Marks, Fry, and others established that the skin disease with its IgA deposition as well as the intestinal disorder responded to gluten restriction and recurred with the reinstitution of a gluten-containing diet culminating in a landmark paper on gluten challenge in 1983 (Leonard et al., 1983). Katz and Strober (1978) clarified the association of HLA B8/DR3 with the entire spectrum of CD with DH. Kumar et al. (1987) established the presence of IgA endomysial antibodies in DH and CD patients. The endomysial antigen was found to be tissue transglutaminase, and now testing for IgA tissue transglutaminase antibody has become the standard for the serological diagnosis of CD. The link between the intestine and the skin in genetically predisposed individuals is twofold. First, Hall et al. (2007) have established that cytokines elaborated at the site of intestinal inflammation are likely critical to the inflammatory process in the skin. Second, Sardy et al. (2002) have shown that epidermal transglutaminase is the antigen bound to the IgA stimulated by the intestinal inflammatory process. The association between DH and thyroid disease is even more intricate. In 1983, Cunningham and Zone (Cunningham and Zone, 1985) closely evaluated 50 DH patients, and showed that these patients had a high incidence of thyroid autoantibodies as well as hyperthyroidism, hypothyroidism, and thyroid enlargement. Gaspari et al., 1990. showed that this association was not related to the underlying HLA B8/DR3 genotype but was likely related to a high prevalence of Hashimoto’s thyroiditis manifested by thyroid autoantibodies and was independently associated with DH. Whether or not the intestinal inflammation in DH patients is responsible for stimulating the thyroid autoimmune process by a cellular or humoral mechanism remains to be determined (Gaspari et al., 1990). Since the 1980s, several immunobullous disorders have been linked to inflammatory bowel disease including bullous pemphigoid, epidermolysis bullosa acquisita (EBA), and linear IgA bullous disease in case reports and case series. Of these, EBA appears to have the strongest association with inflammatory bowel disease. EBA, an immunobullous disorder is characterized by autoantibodies to type VII collagen, the major structural protein of anchoring fibrils, and clinical presentations resembling bullous pemphigoid, cicatricial pemphigoid, or epidermolysis bullosa. EBA has been described in patients with both Crohn’s disease and UC, with Crohn’s disease being the predominant association. In a study of 51 EBA patients, Chen et al. (2002) found that 25% (13 of 51) had inflammatory bowel disease: 12 had Crohn’s disease and 1 had UC. They also demonstrated full-length (290 kDa) type VII collagen in normal colonic extracts from four patients and type VII collagen immunoreactivity in the colonic basement membrane. Of 19 patients, 13 patients with Crohn’s disease and 4 of 31 patients with UC were found to have elevated levels of circulating antibodies to the immunodominant NC1 domain of type VII collagen by ELISA. Despite these findings, there is no evidence linking an autoantibody to the pathogenesis of inflammatory bowel disease. The presence of type VII collagen antibodies is thought to represent epitope spreading, resulting from exposure of type VII collagen epitopes due to damage to the overlying colonic mucosa. Immunobullous diseases have also been linked to malignancies. The quintessential disorder is paraneoplastic pemphigus (PNP), described by Anhalt et al. (1990). PNP is characterized by painful mucosal erosions and polymorphous