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 diagnosedor previously diagnosed severe MMP diagnosed according to the International MMPConsensus (Chan 2002) on the following criteria: Clinical features: Blisters or erosions predominantly affecting any or all mucousmembranes (oral, nasal, pharyngeal, laryngeal, anal, genital, or esophageal,) withor without clinically observable scarring. Ocular involvement includes conjunctivalinflammation, shortening of fornices, symblepharon, ankyloblepharon, entropion,trichiasis and corneal neovascularisation. Patients with skin involvement must not have more than 2 out of the 4 clinicalcriteria for bullous pemphigoid (BP) proposed by the French group (Vaillant L etal,1998; Joly P et al. 2004) Direct Immunofluorescence (DIF): Linear deposits ofIgG, 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 standardhistology of skin or mucosal lesions, when the skin or mucosal biopsy is possibleand 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 thereis a risk of scarring stenosis (larynx, trachea, esophagus, anus, foreskin, vagina…)and/or More than one mucosal site involved and/or Mucosal involvement (includingexclusive but severe oral involvement defined as an oral MMP DAI score > 10), and/orSkin involvement, which have not achieved control of disease activity despite a onemonth treatment with dapsone at the maximum dose tolerated or for patients withsight-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 InformedConsent Form

4. Patient with updated vaccinations. It is recommended that a patient's vaccinationrecord 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 onhaving children anymore: agreement to remain abstinent or use two adequate methodsof 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 studytreatment. Abstinence is acceptable only if it is in line with the preferred and usuallifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulationmethods) 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 duringthe treatment period and for at least 12 months after the last dose of studytreatment and agreement to refrain from donating sperm during this same period. Abstinence is only acceptable if it is in line with the preferred and usuallifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulationmethods) 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 diseaseactivity)

4. Patients with Brunsting Perry pemphigoid and exclusive skin lesions without mucosalinvolvement

5. Karnofsky index < 50% (see Appendix 3)

6. Unstable angina or advanced ischemic cardiopathy (extensive myocardial infarctionwithin 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 progressivemalignant disease, except basal cell carcinoma, and squamous cell carcinoma of theskin that have been treated or excised and cured, in situ cervix carcinoma, or anysituation in which the oncologist in charge of the patient considers that risk ofevolution of severe localisation(s) of MMP is higher than oncologic risk ofcyclophosphamide 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 recentepisode of infection, which has required oral antibiotic treatment within 2 weeksprior to enrollment in the trial

18. Infection having required hospitalization, or IV antibiotic treatment within 4 weeksprior to enrollment

19. Past history of severe infection such as fasciitis, osteomyelitis septic arthritisduring the year prior to enrollment. Entry into this study may be reconsidered oncethe infection has fully resolved

20. Evidence of any new or uncontrolled concomitant disease that, in the investigator'sjudgment, would preclude patient participation, including but not limited to nervoussystem, renal, hepatic, endocrine, malignant, or gastrointestinal disorders

21. Any concomitant condition that required treatment with oral or systemiccorticosteroids 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 potentiallybe active on MMP lesions (anti-TNF) within 4 weeks prior to baseline.

24. Treatment with intravenous immunoglobulins, plasmapheresis, or other similarprocedure within 8 weeks prior to randomization

25. Previous treatment of MMP with one of the test products: cyclophosphamide orrituximab

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 injectablesolution pharmaceutical form

31. Contraindication to paracetamol marketed as 10 mg/ml solution for infusionpharmaceutical form

32. Contraindication to hydroxyzine marketed as 100 mg / 2 ml injectable solutionpharmaceutical form

33. Contraindication to sodium chloride marketed as 0,9% sodium chloride solution forinfusion pharmaceutical form

34. Contraindication to glucose marketed as 5% glucose solution for infusionpharmaceutical form

35. Lactose intolerance

36. Lack of peripheral venous access

37. Women pregnant or lactating, or intending to become pregnant during and for 12months following the study. Women who are not postmenopausal (≥ 12 months ofnon-therapy-induced amenorrhea) or surgically sterile must have a negative resultfrom a serum pregnancy test within 1 week prior to randomization.

38. Patients who plan on having children (due to the risk of amenorrhoea/azoospermiarelated to cyclophosphamide) and due to the long retention time of rituximab in Bcells depleted patients, women of childbearing potential should use effectivecontraceptive methods during and for 12 months following treatment with MABTHERA

39. Participation in another interventional clinical trial within 28 days prior torandomization and during the study

40. Person deprived of liberty by administrative or judicial decision or placed underjudicial protection (guardianship or supervision)