Pemphigus diseases are life-threatening chronic autoimmune blistering diseases characterized by split formation within the epidermis and surface-close epithelia accompanied by acantholysis. Autoantibodies (Abs) are mainly directed against two structural proteins of the epidermal/epithelial desmosome, desmoglein (Dsg) 1 and Dsg3. Two main pemphigus variants can be differentiated, pemphigus vulgaris (PV), and pemphigus foliaceus (PF). Diagnosis of PV and PF is based on the combination of the clinical picture, histological picture of acantholysis, direct immunofluorescence microscopy (DIF) of a perilesional biopsy and serology.

The present "Ritux 4" trial is the fourth academic study with the French study group on auto immune bullous skin diseases (Groupe Bulle) to assess the use of rituximab in auto immune bullous skin diseases, in particular pemphigus. The 3 previous trials have been published in outstanding Journals (N Engl J Med 2007, Science Transl Med 2013, The Lancet 2017 and 2020), and have led to the approval of rituximab in pemphigus by the FDA in 2018 and EMA in 2019. In addition, an industry-sponsored trial testing rituximab versus mycophenolate mofetil in pemphigus, that the investigators have largely contributed to design has been very recently accepted for publication in the N Engl J Med (2021).

The investigator hypothesize that a maintenance therapy using an infusion of 1g of rituximab at Month 6 in patients whose anti-Dsg Abs have not sufficiently decreased at Month 3 after the initial cycle of rituximab (persistence of anti-Dsg1 Abs> 20 UI/ml and/or anti-Dsg3 Abs> 130 UI/ml), and or had an initial PDAI score >45 ( first year of follow-up), and the re-treatment with 1g of rituximab of patients whose anti Dsg Abs re-increase during the evolution of pemphigus after the initial cycle of rituximab (anti-Dsg1 Abs> 20 IU/ml, anti-Dsg3 Abs> 50 UI/ml), could be effective in preventing the occurrence of relapses, thus avoiding to restart a CS treatment, and would provide benefit as compared with the current treatment strategy of retreating patients with 2 g of rituximab (1g at Day0 and Day14) combined with oral CS patients, once a clinical relapse occurs.

Inclusion Criteria:

• Age ≥ 18 and ≤ 80 years
• Signed Informed Consent Form (or from the family in case of impossibility of patient's consent).
• Confirmed newly diagnosed PV or PF, based on the presence of the following: histological features of acantholysis on skin or mucosal biopsy, and deposition of IgG, complement component 3, or both on the keratinocyte membrane detected by direct immunofluorescence on affected skin or mucosa
• Presence of moderate-to-severely active disease, defined by an overall PDAI score> 1554
• Patient able to receive the standard-of-care consisting of corticosteroids (prednisone 1 mg/kg/day PO) and rituximab
• Patients must be vaccinated against Covid-19 before study entry. It is recommended that patients are vaccinated against influenza and Streptococcus pneumoniae and have their first injection (Prevenar 13) before study entry.
• For women who are not postmenopausal (menopausal: ≥ 12 months of non-therapy-induced amenorrhoea) or surgically sterile (absence of ovaries and/or uterus + bilateral salphingectomy) 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. They must have a negative result from a blood beta-HCG test within 1 week prior to randomization 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.

• Able to comply with the study protocol, in the investigator's judgment
• Patient affiliated with, or beneficiary of a social security (national health insurance) plan

Exclusion Criteria:

• Non-consenting patient or patient who cannot be followed regularly.
• Diagnosis of paraneoplastic pemphigus or evidence of other non-PV or PF autoimmune blistering disease
• Contraindication to rituximab marketed as 500 mg concentrate for solution for infusion
• Contraindication to prednisone marketed as 20 mg, scored tablet pharmaceutical form
• Contraindication to methylprednisolone marketed as 120 mg powder for injectable solution pharmaceutical form
• Contraindication to paracetamol marketed as 10 mg/mL solution for infusion pharmaceutical form
• Contraindication to dexchlorpheniramine maleate marketed as 5 mg/1mL injectable solution pharmaceutical form
• Lack of peripheral venous access
• Pregnant or lactating
• Significant cardiovascular or pulmonary disease (including obstructive pulmonary disease)
• 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
• Any concomitant condition that required treatment with oral or systemic corticosteroids within 12 weeks prior to randomization- excluding transitory treatments (such as a corticosteroid therapy prescribed for a few days for an acute infection), and chronic corticosteroid treatments with a prednisone / prednisolone dose ≤20 mg/day, (these latter patients remain eligible for study entry)
• Treatment with IV Ig, plasmapheresis, or other similar procedure within 8 weeks prior to randomization
• Patients having received immunosuppressive treatment (such as cyclosporine, mycophenolate mofetil, azathioprine given at an effective dose for any other condition than Pemphigus, or any other treatment that might potentially be active on Pemphigus lesions (anti-TNF) within 4 weeks prior to baseline
• Treatment with cyclophosphamide within 12 weeks prior to randomization
• Patients with positive blood test for HIV
• Inherited or acquired severe immune deficiency
• Known active infection of any kind (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV anti-infectives within 4 weeks prior to screening, or completion of oral anti-infectives within 2 weeks prior to randomization. Entry into this study may be reconsidered once the infection has fully resolved.
• Patients with a currently treated cancer, including solid tumors, hematologic malignancies, and carcinoma (except basal cell of the skin and squamous cell carcinoma of the skin which can be easily cured with a standard excision )
• Patients with a past history ( < 5 years) of cancer, including solid tumors, hematologic malignancies, and carcinoma (except complete excision of basal cell of the skin and squamous cell carcinoma of the skin that have been excised and cured) NB: Patients whose cancer is cured and do not have anti-cancer treatment anymore must be referred to an oncologist before entry in the study
• Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24 weeks prior to screening
• Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery
• Treatment with rituximab or a B cell-targeted therapy (e.g., anti-CD20, anti-CD22, or anti-BLyS) within 12 months prior to randomization
• Treatment with a live or attenuated vaccine within 28 days prior to randomization. It is recommended that a patient's vaccination record and the need for immunization prior to study entry be carefully investigated.
• Major biological abnormality which in the investigator's judgment, would preclude patient participation,
• Positive test results for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) serology at screening
• Participation in another interventional clinical trial within 28 days prior to randomization and during the study
• Person deprived of liberty by administrative or judicial decision or placed under judicial protection (guardianship or supervision)