Treatment of epidermolysis bullosa acquisita with intravenous immunoglobulin in patients non-responsive to conventional therapy: clinical outcome and post-treatment long-term follow-up.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a chronic subepidermal blistering disease that is caused by antibodies binding to type VII collagen within anchoring fibrils. It is rare disease with an incidence of 0.25 cases per 1,000,000 population. OBJECTIVE: The objective of this study is to report the treatment outcomes with intravenous immunoglobulin (IVIg) therapy in 10 patients with severe and widespread EBA non-responsive to conventional therapy. METHODS: Patients were treated according to a protocol published in a Consensus Statement to treat autoimmune mucocutaneous blistering diseases, including EBA with IVIg. A dose of 2 g/kg/cycle was used. RESULTS: Ten patients: four males and six females, all were North American Caucasian. The age at onset varied from 37 to 75 years (mean 57.4). A satisfactory clinical response was observed in all 10 patients. The patients received 16-31 cycles (mean 23.1) of IVIg over a period of 30-52 months (mean 38.8). Once IVIg was initiated, earlier drugs (prednisone, dapsone and others) were gradually withdrawn over a 5-9 month period (mean 7.2). Thereafter, IVIg was used as monotherapy. No serious side-effects were observed. The follow-up period since discontinuation of IVIg varied from 29 to 123 months (mean 53.9). During this follow-up period, recurrence of disease was not observed. CONCLUSION: The data suggest that IVIg can produce a long-term sustained clinical remission in patients with EBA. In the patients, of this study concomitant therapy could be discontinued and IVIg was used as monotherapy.

Use of intravenous immunoglobulin therapy during pregnancy in patients with pemphigus vulgaris.

BACKGROUND: Pemphigus vulgaris (PV) is a potentially fatal autoimmune disease characterized by the presence of in vivo deposition of antibodies against cell surface antigens desmoglein 1 and desmoglein 2 in the epidermis. OBJECTIVES: To report the treatment outcomes in pregnant PV patients treated with intravenous immunoglobulin (IVIg) therapy. METHODS: Eight patients with active disease during pregnancy were treated. Patients were treated with a dose of 2 g/kg/cycle. Seven patients were treated for 2 months on post-partum basis. Main outcome measures were as follows: (i) pregnancy outcome; (ii) presence of neonatal pemphigus; (iii) post-partum flare; (iv) effect of IVIg on present and future pregnancies; (v) immediate and long-term side-effects in the mother and child. RESULTS: Patients ages ranged from 20 to 43 years (mean 29.6). All patients had severe and widespread disease involving the skin and multiple mucous membranes. Patients one to seven responded to IVIg therapy and did not have a post-partum flare. Patient eight could not tolerate IVIg because of intense headaches and significant post-partum flare. None of the neonates had pemphigus. Three patients who completed the IVIg protocol had normal second pregnancies. One patient who did not complete the protocol had a miscarriage during the second pregnancy. Since last observation, none of the patients have had a recurrence of the disease or another pregnancy. CONCLUSIONS: The data suggests that IVIg can be useful and safe in treating pregnant patients with PV. No long-term adverse effects of IVIg in the mother or in the child were observed based on a long-term follow-up.

Coexistence of mucous membrane pemphigoid and connective-tissue disease.

Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease that predominantly affects the mucosa. We report eight patients with MMP who also had systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), or both. Eight women (six white, two Hispanic; mean age of onset 53.5 years [range 44-68]) were studied. In four patients, both diseases were detected simultaneously, and in the other four patients, MMP preceded SLE or MCTD. MMP was widespread and resistant to conventional immunosuppressive therapy, but responded to intravenous immunoglobulin (IVIg). During a mean follow-up of 10.25 years (range 6-18), three patients had stable SLE/MCTD, whereas in the other five patients the SLE/MCTD required systemic corticosteroids either with or without immunosuppressive agents. Renal, serosal, pulmonary and neurological features were not observed in any patient. At the time of reporting, the MMP was in a prolonged sustained remission in all eight patients. The SLE/MCTD remained mild, did not involve vital organs and had continued with low-grade activity. In summary, we report the simultaneous occurrence of two rare diseases in a group of patients.

Analysis of current data on the use of methotrexate in the treatment of pemphigus and pemphigoid.

Methotrexate (MTX) is primarily used in the treatment of malignancies. It has also been used as an immunosuppressive agent in the treatment of pemphigus and pemphigoid. The objective of this study was to determine the role of MTX in the treatment of pemphigus and pemphigoid based on an analysis of the available literature. A retrospective analysis of the English language literature was conducted. The studies included in this analysis were required to fulfil the following inclusion criteria: English language; diagnosis based on histology and immunopathology; minimum of five patients in each series; and data for efficacy, spectrum of responses and follow-up. A total of 136 patients with pemphigus were reported in seven studies. One hundred and eleven of the 136 patients (82%) showed clinical improvement with MTX. A total of 79 patients with pemphigoid were reported in six studies. Overall, 74 of the 79 patients (94%) showed clinical improvement. Nausea and infection were the most common side-effects. Death due to MTX resulted in seven of 215 patients (3%). There is a lack of randomized controlled trials. In many studies in this review there was insufficient information on clinical follow-up post-therapy and on serological correlations. Analysis of the data suggests that MTX may be useful and effective in patients with pemphigus vulgaris, who are corticosteroid dependent or who develop significant complications in relation to corticosteroids. MTX is likely to be more beneficial in patients with pemphigoid, particularly in bullous pemphigoid, than in patients with pemphigus. Given the limitations of the available data, it appears that when there is a need for adjuvant therapy, MTX may be considered early in the management of moderate to moderately severe disease.

Intravenous immunoglobulin treatment in laryngeal pemphigoid.

We report a 29-year-old white woman who presented with oral involvement and subsequently developed severe and extensive laryngeal involvement with mucous membrane pemphigoid. She could not tolerate systemic corticosteroids due to side-effects. Dapsone improved only the oral disease, but the laryngeal disease remained active and progressive. She refused immunosuppressive agents, because she wanted to conceive. The acute severe widespread laryngeal pemphigoid was accompanied by severe relentless coughing and dysphonia. The patient was treated with intravenous immunoglobulin (IVIg) as monotherapy, which led to complete resolution of the symptoms and the laryngeal lesions, as seen on repeated direct laryngoscopies. The normal anatomy and function of the larynx was restored, and scarring did not occur. The patient did not develop any side-effects to the IVIg treatment, which led to disease remission. While on IVIg treatment, she delivered a healthy child. She remained in remission after 5 years of follow-up.

Relative risk for cancer in mucous membrane pemphigoid associated with antibodies to the beta4 integrin subunit.

BACKGROUND: Mucous membrane pemphigoid (MMP) is a mucocutaneous vesiculobullous autoimmune disease characterized by autoantibodies to components of the basement membrane zone (BMZ). Recently, it has been reported that patients with MMP who have autoantibodies to laminin 5, known as anti-epiligrin cicatricial pemphigoid (AECP) have a high incidence of malignancy. OBJECTIVE: The purpose of this study was to determine the association between malignancy and MMP in patients with antibodies to beta4 integrin. METHODS: The incidence of cancer was studied in 79 patients with MMP and/or ocular cicatricial pemphigoid (OCP) who had antibodies to human beta4 integrin subunit. In each patient, the diagnosis was made by histology and confirmed by immunopathology of affected tissues. It was compared to the expected incidence, for age- and gender-matched individuals, in the National Cancer Institute's Surveillance, Epidemiology and End Results (NCISEER) database. RESULTS: Of 79 patients, 3 had cancer. The relative risk (RR) for cancer in patients with MMP and/or OCP, with autoantibodies to human beta4 integrin subunit was 0.29 (95% CI 0.62-8.77). The expected number in the NCISEER database was 10.37. This difference was statistically significant (P < 0.01). CONCLUSION: This incidence of cancer in MMP/OCP patients, with antibodies to human beta4 integrin subunit is considerably lower than expected. Preliminary observations in this and other studies suggest that serological subsets of MMP, based on antigen reactivity, have a different clinical course, prognosis and associations with cancer.