Treatment of oral pemphigoid with intravenous immunoglobulin as monotherapy. Long-term follow-up: influence of treatment on antibody titres to human alpha6 integrin

Abstract

Oral pemphigoid (OP) is a chronic autoimmune disease, involving the oral cavity, characterized by a homogenous linear deposition of immunoglobulins, complement, or both along the basement membrane zone (BMZ) and a subepithelial blister formation. The alpha6/beta4 heterodimer is an integrin family of adhesion receptors, which mediates basal cell to matrix interactions. Recent evidence suggests a pathophysiologic role for antibodies against human alpha6 integrin in blister formation in OP, in organ culture studies. Fifty percent of OP patients have been reported to experience disease progression to involve other mucosal tissues, including the eye and larynx. To prevent this extension of disease, systemic therapy with systemic corticosteroids, dapsone, and immunosuppressive agents has been recommended. The use of intravenous immunoglobulin (IVIg) in the treatment of pemphigoid has been recently described. In this study, we present the use of IVIg, in a group of seven patients, with severe OP, in whom systemic conventional treatment was contraindicated. To determine the influence of treatment on antibodies to human alpha6 integrin in OP, seven patients with OP treated with IVIg therapy and a comparable control group of seven patients with OP, treated with conventional therapy, were evaluated at monthly intervals, for a 12 consecutive month treatment period. An effective clinical response was observed in all seven patients treated with IVIg therapy, after a mean treatment period of 4.5 months. IVIg therapy induced a prolonged and sustained clinical remission in all seven patients after a mean treatment period of 26.9 months. A statistically significant difference was observed in the quality of life pre- and post-IVIg therapy (P < 0.001). Both the study and the control groups had a very similar initial serological response to treatment. A statistically significant reduction in the antibody titres was observed after four months of treatment, in both groups (P = 0.015). Thereafter, patients treated with IVIg therapy had a faster rate of decline in the antibody titres, and the difference in the rate of decline between the study and control groups became statistically significant after six months of treatment (P = 0.03). The use of IVIg therapy resulted in reduction of antialpha6 antibody titres and in inducing and maintaining both a sustained, clinical and serological remission.

Fig. 1

Specificity of immunoblot assay; binding pattern of test sera on an immunoblot assay, using bovine gingival lysate as substrate. Lane 1: Immunoblot of sera from a patient with oral pemphigoid. Note binding to a 120-kD protein. Lane 2: Immunoblot performed with a monoclonal antibody to human α6 integrin. Note binding to a 120-kD protein. Lane 3: Immunoblot of serum from a patient with pemphigus vulgaris. Note binding to a 130-kD protein. Lane 4: Immunoblot of serum from a patient with mucous membrane pemphigoid. Note binding to a 205-kD protein. Lane 5: Immunoblot of serum from a patient with bullous pemphigoid. Note binding to both 230 kD (BP Ag1) and 180 kD (BP Ag2) proteins. Lanes 6 & 7: Immunoblots with serum from a normal healthy individual and a patient with oral erosive lichen planus, used as negative controls. Note absence of binding.

Fig. 2

Comparison of antibody titres to human α6 integrin in OP patients treated with IVIg (✦) and conventional therapy (○).

Fig. 3

Correlation between disease activity and serum levels ofantibodies to human α6 integrin. A direct relationship between antibody titres to human α6 integrin and disease activity is observed in 27 patients with active disease. Antibody titres to human α6 integrin are nondetectable in patients in 12 patients who are in remission and 25 normal healthy individuals.