Randomized Clinical Trial Comparing the Safety and Efficacy of Rituximab Versus Oral Cyclophosphamide in Severe Forms of Mucous Membrane Pemphigoid

Inclusion Criteria: 1. Male or female patients aged ≥18 years old and ≤ 80 years old with a newly diagnosed or previously diagnosed severe MMP diagnosed according to the International MMP Consensus (Chan 2002) on the following criteria: Clinical features: Blisters or erosions predominantly affecting any or all mucous membranes (oral, nasal, pharyngeal, laryngeal, anal, genital, or esophageal,) with or without clinically observable scarring. Ocular involvement includes conjunctival inflammation, shortening of fornices, symblepharon, ankyloblepharon, entropion, trichiasis and corneal neovascularisation. Patients with skin involvement must not have more than 2 out of the 4 clinical criteria for bullous pemphigoid (BP) proposed by the French group (Vaillant L et al,1998; Joly P et al. 2004) Direct Immunofluorescence (DIF): Linear deposits of IgG, IgA and/or C3 on the BMZ by DIF of patient's skin or mucous membrane Histology: Sub epithelial blister with or without significant leukocyte infiltrate by standard histology of skin or mucosal lesions, when the skin or mucosal biopsy is possible and appropriate. 2. MMP is defined as "severe" in patients with: Sight-threatening ocular disease, and/or Potentially life-threatening laryngeal, tracheal or oesophageal stenosis, and/or Involvement of a mucosal site where there is a risk of scarring stenosis (larynx, trachea, esophagus, anus, foreskin, vagina…) and/or More than one mucosal site involved and/or Mucosal involvement (including exclusive but severe oral involvement defined as an oral MMP DAI score \> 10), and/or Skin involvement, which have not achieved control of disease activity despite a one month treatment with dapsone at the maximum dose tolerated or for patients with sight-threatening ocular disease, and/or potentially life-threatening laryngeal, tracheal or oesophageal stenosis, without previous treatment by dapsone 3. Patient having read and understood the information letter and signed the Informed Consent Form 4. Patient with updated vaccinations. It is recommended that a patient's vaccination record and the need for immunization prior to study entry be carefully investigated. 5. For women who are not postmenopausal (≥12 months of non-therapy-induced amenorrhoea) or surgically sterile (absence of ovaries and/or uterus) and who do not plan on having children anymore: agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of \<1% per year, during the treatment period and for at least 12 months after the last dose of study treatment. Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Barrier methods must always be supplemented with the use of a spermicide. For men: Surgical sterility or agreement to remain abstinent or use a condom during the treatment period and for at least 12 months after the last dose of study treatment and agreement to refrain from donating sperm during this same period. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. 6. Patient agreement to avoid excessive exposure to sunlight during study participation 7. Patient able to comply with the study protocol, in the investigator's judgment 8. Patient affiliated with, or beneficiary of a social security category Exclusion Criteria: 1. Patient \< 18 years old or \> 80 years old 2. Non-consenting patient or patient who cannot be followed regularly 3. Patients with only MMP sequelae (stenosis, fibrosis, without inflammation or disease activity) 4. Patients with Brunsting Perry pemphigoid and exclusive skin lesions without mucosal involvement 5. Karnofsky index \< 50% (see Appendix 3) 6. Unstable angina or advanced ischemic cardiopathy (extensive myocardial infarction within the last 3 months or post-infarction heart failure) 7. Severe heart failure (NYHA Class III or IV) or severe uncontrolled cardiac disease 8. Uncontrolled cardiac rhythm disorders 9. Severe bronchial obstruction 10. Past history of malignant disease in the previous 10 years, or current progressive malignant disease, except basal cell carcinoma, and squamous cell carcinoma of the skin that have been treated or excised and cured, in situ cervix carcinoma, or any situation in which the oncologist in charge of the patient considers that risk of evolution of severe localisation(s) of MMP is higher than oncologic risk of cyclophosphamide and rituximab. 11. Anemia (haemoglobin \< 10 g/ dL ), neutropenia (\<1000/mm3), lymphopenia (\<900/mm3), thrombopenia (\<100 000/mm3) 12. Positive test results for hepatitis B surface antigen (HBsAg), hepatitis B core, antibody (HBcAb), or hepatitis C virus (HCV) serology at screening 13. Liver insufficiency, major renal insufficiency (creatinin clearance ≤ 30 ml/min) 14. Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24 weeks prior to screening 15. Patients with positive blood test for HIV 16. Inherited or acquired severe immune deficiency 17. Known active infection of any kind (excluding fungal infections of nail), or recent episode of infection, which has required oral antibiotic treatment within 2 weeks prior to enrollment in the trial 18. Infection having required hospitalization, or IV antibiotic treatment within 4 weeks prior to enrollment 19. Past history of severe infection such as fasciitis, osteomyelitis septic arthritis during the year prior to enrollment. Entry into this study may be reconsidered once the infection has fully resolved 20. Evidence of any new or uncontrolled concomitant disease that, in the investigator's judgment, would preclude patient participation, including but not limited to nervous system, renal, hepatic, endocrine, malignant, or gastrointestinal disorders 21. Any concomitant condition that required treatment with oral or systemic corticosteroids within 12 weeks prior to randomization 22. Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery. 23. Patients having received immunosuppressive treatment (such as cyclosporine, mycophenolate mofetil, azathioprine), or any other treatment that might potentially be active on MMP lesions (anti-TNF) within 4 weeks prior to baseline. 24. Treatment with intravenous immunoglobulins, plasmapheresis, or other similar procedure within 8 weeks prior to randomization 25. Previous treatment of MMP with one of the test products: cyclophosphamide or rituximab 26. Previous treatment with a B cell-targeted therapy other than rituximab (e.g., anti-CD20, anti-CD22, or anti-BLyS) 27. Treatment with a live or attenuated vaccine within 28 days prior to randomization 28. Contraindication to MABTHERA 500 mg concentrate for solution for infusion 29. Contraindication to ENDOXAN 50 mg, tablets 30. Contraindication to methylprednisolone marketed as 120 mg powder for injectable solution pharmaceutical form 31. Contraindication to paracetamol marketed as 10 mg/ml solution for infusion pharmaceutical form 32. Contraindication to hydroxyzine marketed as 100 mg / 2 ml injectable solution pharmaceutical form 33. Contraindication to sodium chloride marketed as 0,9% sodium chloride solution for infusion pharmaceutical form 34. Contraindication to glucose marketed as 5% glucose solution for infusion pharmaceutical form 35. Lactose intolerance 36. Lack of peripheral venous access 37. Women pregnant or lactating, or intending to become pregnant during and for 12 months following the study. Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative result from a serum pregnancy test within 1 week prior to randomization. 38. Patients who plan on having children (due to the risk of amenorrhoea/azoospermia related to cyclophosphamide) and due to the long retention time of rituximab in B cells depleted patients, women of childbearing potential should use effective contraceptive methods during and for 12 months following treatment with MABTHERA 39. Participation in another interventional clinical trial within 28 days prior to randomization and during the study 40. Person deprived of liberty by administrative or judicial decision or placed under judicial protection (guardianship or supervision)