Dapsone is an effective drug and can be used as a single agent to control mild to moderate MMP. No placebo-controlled clinical trial has demonstrated the efficacy of dapsone in MMP. However, this drug has been evaluated in a small randomized study comparing dapsone versus CYC in patients with MMP affecting the eyes and an ocular response was observed in 70 % of patients [4]. In a study of Rogers III et al., 20 out of 24 patients (83 %) with ocular MMP treated with dapsone had partial or complete control. Control was obtained within 4 weeks in 11 out of 20 patients. Initial treatment was dapsone 100–150 mg per day during 3–6 months followed by a maintenance therapy of variable duration [5]. Efficacy of dapsone is better on buccal involvement than ocular inflammation.

The most prominent side effects associated with dapsone are hemolytic anemia and methemoglobinemia, which are dose dependent. In the case of glucose-6-phosphate dehydrogenase deficiency, hemolysis is more severe and such a deficiency has to be excluded before prescribing this drug. Other adverse effects include agranulocytosis, toxic hepatitis, hypersensitivity reaction, and peripheral neuropathy. In our experience of MMP, we prefer an initial dose of 2 mg/kg per day dapsone and maintenance therapy of 1 mg/kg per day. Dose escalation from 1 mg/kg/day initially by 25 mg per week is recommended to have a better tolerance of anemia, and careful monitoring by regular full blood counts, reticulocyte counts, and methemoglobin level after the beginning of dapsone is mandatory. A fall in hemoglobin of 2 g/dl is expected to control disease and does not require the cessation of dapsone except in case of poor tolerance of anemia.

Sulfasalazine has been used in MMP in case of intolerance of dapsone. Based on a previous study showing efficacy of sulfapyridine in a series of 20 MMP, 3 g per day of sulfasalazine, an oral precursor of sulfapyridine, has been used in a retrospective study of nine patients with ocular MMP [6]. Four of these patients were controlled with sulfasalazine alone, two with the combination of sulfasalazine and CYC, and three had to stop because of side effects.

Tetracyclines have been proposed as a treatment in MMP [1], but few studies have reported their efficacy. Combination therapy with nicotinamide 3 g per day and minocycline 100 mg per day gave subjective or clinical improvement in five out of eight MMP patients but worsening with development of laryngeal involvement in one patient [7]. Minocycline alone induced a reduction of oral symptoms in six out of seven MMP patients but did not prevent disease progression [8]. In another study of nine patients with oral MMP, minocycline induced a major response in three patients, a minor response in four, and no response in two; five patients stopped the drug because of side effects, such as vertigo and gastric pain [9].

Corticosteroids have been proposed either in mild form of the disease at a dose of 0.5 mg/kg per day to wait for the efficacy of dapsone or immunosuppressants or either at a dose of 1–1.5 mg/kg per day to treat life-threatening locations of the disease (laryngeal or esophageal involvement). Historically, patients with severe progressive MMP have been treated with systemic corticosteroids, such as prednisone 1–2 mg/kg per day often combined with an immunosuppressant drug. In our experience systemic corticosteroids are not a treatment of choice in MMP because they are less effective than cytotoxic drugs and have unacceptable long-term side effects as previously reported by Foster [4].

CYC is the reference treatment for severe ocular MMP or recalcitrant MMP with harmful mucosal involvement. It can be used orally at a dose of 2 mg/kg per day or intravenously at a dose of 10 mg/kg per month. Intravenous pulsed CYC is associated with less adverse effects than is low-dose oral administration but time to disease control is often longer. The oral formulation achieves rapid remission induction and is easy to use but can have severe side effects including serious infections due to lymphopenia and hemorrhagic cystitis. To minimize infections the CYC dose has to be adjusted to achieve a lymphocyte count above 700/μL. In the clinical trial by Foster, all the 20 patients with ocular MMP treated with CYC responded, and in his experience 91 % of patients with this treatment showed cessation of conjunctival inflammation and of progressive fibrosis [4]. In a study of nine patients with severe and resistant MMP treated with CYC pulses at a dose of 10 mg/kg per month, all patients responded after an average of 24 weeks and seven had complete resolution [10]. Munyangango et al. recently reported the efficacy of oral CYC 2 mg/kg per day without corticosteroids in 13 patients with severe refractory MMP [11]. After 52 weeks of follow-up, the overall response rate was 69 % with a decrease of active scores as early as week 4 of treatment and a median time to disease control of 8 weeks. Seven patients (54 %) achieved complete remission with a time to achieve it of 24 weeks.

Mycophenolate mofetil has been proposed to patients with mild MMP. It has been used at a dose of 2 g per day as a steroid-sparing agent in association with oral prednisolone [12], in combination with minocycline [13], or with dapsone [14]. It is difficult to draw conclusions from these nonrandomized studies. Mycophenolate mofetil seems not to be efficacious alone nor in allowing a decrease of dapsone doses [14]. In ocular MMP, mycophenolate mofetil in association with oral corticosteroids is effective, with control of inflammation achieved in 70 % by 1 year, but seems less successful than CYC [15]. Low dose of mycophenolate mofetil (1 g per day) in combination with 50 mg per day dapsone and 0.5 mg/kg per day prednisolone has been used in a retrospective study of 6 MMP patients with a control of oral lesions [16].

Recently, case reports and a small series have described the successful use of TNF-α[alpha] blockade in addition to immunosuppressive drugs in refractory MMP. The TNF-α[alpha] antagonist used was always etanercept at a dose of 50 mg per week except infliximab in one patient [17]. Patients with oral [18–20], ocular [21, 22], or pharyngeal MMP [23, 24] received etanercept, and improvement of inflammation started after 1 month of treatment, leading to remission. Surprisingly, a decrease of ocular fibrosis was observed in parallel in one patient [22] and no side effects from this treatment were reported. An open retrospective series of 17 patients with ocular (n = 15) and buccal (n = 11) involvement of MMP reported 7 infections leading to cessation of etanercept in 3 patients and a less dramatic efficacy since complete and partial remission of inflammation occurred in 10 and 4 patients respectively, but interestingly stabilization of fibrosis arose in 11 patients [25].

Rituximab, an anti-CD20 monoclonal antibody targeting B lymphocytes, was tested in some patients with refractory MMP with some benefits (reported in [3]). Complete or partial remissions were obtained within 2–7 months after one rituximab cycle. Most often improvement was observed as early as the first month after the start of rituximab infusion. Recently, Foster et al. reported the benefit of combining rituximab (12 infusions in 6 month) and intravenous immunoglobulin (2 g/kg per month), which halted disease progression in six patients with severe ocular pemphigoid, in contrast to a group of six patients who became totally blind despite maximal immunosuppressive regimens [26]. Le Roux-Villet et al. treated 25 patients with severe or refractory MMP using one or two cycles of rituximab (each cycle consisting of rituximab, 4 × 375 mg/m² administered intravenously at weekly intervals). After the first cycle, 68 % of patients experienced complete remission within 12 weeks, while an additional 20 % of patients required a second cycle to achieve clinical remission. Serious infectious side effects developed in 12 % of patients including two deaths attributed to the concomitant association of rituximab with immunosuppressants and high-dose corticosteroids in hypogammaglobulinemic patients [3].