Monoclonal anti-CD20 Antibody Therapy in Cicatrical Pemphigoid with Oral and Hypopharyngeal Involvement and Related Conditions

Abstract

Mucous membrane pemphigoid is a rare blistering autoimmune disorder that can lead to significant disability. Recently, the monoclonal anti-CD20 antibody rituximab has shown efficacy in pemphigus and pemphigoid, but the data for pemphigoid are relatively sparse. The authors report a series of four patients with severe cicatrical pemphigoid treated with rituximab. All of these patients responded and two of them had a complete remission. Rituximab is a second-line treatment for severe and recalcitrant cicatrical pemphigoid.

Cicatrical pemphigoid (CP) is a rare autoimmune disease with subepithelial blisters. CP primarily affects mucous membranes, but occasionally also involves skin. On mucous membranes, blisters are unstable and often only erosions can be seen. Since the disease has a propensity for scar formation, this may lead to functional impairment.1

Direct immunofluorescence of perilesional skin shows immune deposits of immunoglobulin(s) and complement. The majority of patients also have circulating autoantibodies directed against bullous pemphigoid antigen-2 (BPAG2), laminin-5 (epiligrin).2

CP mainly affects elderly people with an annual incidence of about 0.9 per million of the population in Germany.3 Oral mucosa is often affected with desquamative gingivitis, aphthous lesions, and bullae. Ocular involvement is seen in one-third of CP patients with the potential threat of blindness. A later symptom of the disease is the formation of symblepharon and ankyloblepharon. Nasopharyngeal involvement is characterized by epistaxis, discharge, or crusting.1

Fortunately, laryngeal, hypopharyngeal, and esophageal involvement are seen infrequently. The calculated prevalence of laryngeal CP is 1 in 10 million persons in the general population.4 Esophageal involvement occurs in about five percent of CP patients.5 However, these sites of involvement can potentially result in serious complications, mainly due to scarring. Typical symptoms are hoarseness, dysphagia, swallowing, or chronic reflux disease.6

Treating CP patients aggressively is very important in order to prevent scarring and blindness. Standard treatment comprises systemic corticosteroids alone or in addition to immunosuppressants, such as azathioprine, cyclosporine A, or cyclophosphamide. Dapsone often demonstrates a mixed response. Intravenous immuno-globulins have also been used as second-line immunomodulatory treatment or as a possible first-line treatment during pregnancy.6,7

Recently, the chimeric anti-CD20 monoclonal antibody rituximab has been used successfully in autoimmune blistering diseases.8,9 In contrast to pemphigus, the reports on CP treated by rituximab are less frequent. Only recently, an uncontrolled, multicenter trial was published in France.10”13

CASE SERIES

The authors report a series of four cases treated second-or third-line by rituximab. They focus on mucous membrane involvement and response. Two cases (Cases 3 and 4) have been published before, but with a different focus.10

Case 1. A 79-year-old woman was diagnosed four years ago with CP by histology, immunofluorescence, and serum antibodies. Her medical history was unremarkable except for breast cancer in 1981.

She came to the authors’ hospital after various pretreatments elsewhere, including dapsone, cortico-steroids, azathioprine, mycophenolate mofetil, metho-trexate, and intravenous immunoglobulins (IVIG, for >1 year). Anemia and gastrointestinal adverse effects were seen with the first five systemic drugs. IVIG were well-tolerated, but the symptoms were not controlled and progressed. The patient suffered from painful oral erosions and dysphagia. She had severe problems with coughing and swallowing. She was only capable of eating mushy food and fluids, leading her to lose more than 10kg of weight.

On examination, the patient presented with oral erosions and bullae on the buccal sites and hard palate. Erythematous lesions were seen in her larynx and hypopharynx mucous membranes. There was a dorsal triangular hypopharynx stenosis as well as a stenosis of the proximal esophageal opening. The remaining lumen measured only 5mm explaining the severe dysphagia the patient reported (Figure 1). Her vocal cords showed a normal endoscopic appearance although she had a hoarse voice. Cardiac and pulmonary functions were in the normal range. Laboratory results included leukocytosis 14.1Gpt/L (normal range: 3.8-11.0), glucose 11.8 mmol/L (normal range: 3.5-5.5), immunoglobulins normal range, T-spot negative, and pemphigoid antibodies 1:320 positive.

Figure 1.

Case 1 before therapy with rituximab: Desquamative and erythemathous lesions of the laryngo-hypopharyngeal mucosa with edema of the postcricoid area

The authors used an interdisciplinary treatment approach. They put her on medical high-calorie drinks to improve her energy balance, began dysphagia therapy to enable her to overcome swallowing problems, and administered monoclonal anti-CD20 therapy with rituximab 375mg/m² given as a slow intravenous infusion plus 20mg prednisolone per day orally to control inflammation.

The patient experienced no adverse effects, and treatment was well-tolerated. Erythematous lesions partially disappeared, inflammatory signs of the pharyngeal mucosa diminished, and dysphagia improved remarkably (Figure 2).

Figure 2.

Case 1 after therapy with rituximab: Mucosal lesions and edema are reduced clearly, followed by a remarkable improvement of swallowing function

Case 2. A 48-year-old man with a two-year history of pemphigus vulgaris confirmed by histology, immunofluorescence, and autoantibody analysis presented with painful aphthous lesions of the oral mucosa unresponsive to topical and systemic corticosteroids. His medical history was otherwise unremarkable.

On admission, he had cutaneous erosive lesions and bullae on the trunk and widespread painful erosions of the buccal mucosa. Eating and talking was impaired. Laboratory results included pemphigus antibodies 1:160 positive and hepatitis A antibodies >1500IU/L (normal range: 0-20). Dual energy x-ray of the thorax and abdominal sonography were without abnormalities.

The patient was treated with rituximab 375mg/kg body weight four times from December 2011 to March 2012. After two infusions, his health status improved significantly. He showed a complete response with only scar residues in the oral mucosa. Pemphigus antibodies could no longer be detected. Methylprednisolone was tapered down from 32mg/d to 4mg/d. The treatment was well-tolerated except a mild temporary tachycardia during the first infusion.

Case 3. A 41-year-old man with mucous membrane pemphigoid confirmed by histology but negative for auto-antibodies was treated since 2003 with immunosuppressive drugs including systemic corticosteroids, dapsone, cyclophosphamide, mycophenolic acid, and topical cyclosporine A, ofloxacine, and dexamethasone. Despite continuous therapy, his eyes worsened. He developed severe symblepharon, vascularization, and scar formation (Figure 3). In 2007, the patient was started on rituxumab therapy (375mg/kg body weight) once a week for one month. The treatment was well-tolerated and his eye involvement stabilized without any systemic immunosuppression necessary (Figure 4).

Figure 3.

Case 3 with severe ocular involvement

Figure 4.

Case 3 one year after rituximab therapy without any immunosuppressant

Case 4. A 79-year-old woman with cardiac disease was referred to the authors’ hospital in 2008 for severe relapse of a pemphigus vulgaris with mucosal involvement first diagnosed two years before. She was on prednisolone and azathioprine since then.

On admission, bullae and crusted lesions were all over the trunk with more than 80-percent body surface involvement. Mucosal lesions were seen on buccal mucosa, tongue, and conjunctiva. There was cutaneous superinfection with staphylococci and mucosal superinfection by Candida species. Laboratory findings included pemphigus vulgaris antibodies 1:320 positive.

The patient was started on prednisolone 120mg/day, mycophenolate mofetil 720mg/g twice/day, and antibotics/antimycotics, but achieved only a minor response. Therefore, rituximab (375mg/kg body weight) therapy was given once a week for one month. The authors achieved an almost complete response with less than one-percent body surface involvement. Pemphigus antibodies decreased to 1:40. The patient was released from the hospital with mycophenolate mofetil 720mg twice per day and prednisolone 15mg/day. There has been no relapse since then.

DISCUSSION

Autoimmune blistering diseases, such as pemphigus or pemphigoid, may affect mucous membranes severely. This can result in significant disabilities, such as blindness,14,15 stenosis of upper airways with the need of tracheostomy,16,17 and esophageal strictures.18

These complications do not only have a strong negative impact on quality of life, but also limit therapeutic options. The best way to improve the outcome of such patients is an interdisciplinary approach.

Rituximab—a CD20-depleting monoclonal antibody— has shown efficacy in uncontrolled trials of recalcitrant pemphigoid with complete responses in 50 to 68 percent of cases, which is in the same range observed herein.12,13 Since severe infections may occur as an unwanted adverse effect, close monitoring of patients is a necessity.12 The results obtained in the authors’ series of mucous membrane pemphigoid, however, are promising, even for patients with severe complications. When the drug is given in a very late stage, complete remission is sometimes impossible, but significant improvements can be seen even then.