Rituximab for Severe Mucous Membrane Pemphigoid: Title and subTitle BreakSafe Enough to Be Drug of First Choice?

In this issue of the Archives, Le Roux-Villet et al¹ describe 25 patients with mucous membrane pemphigoid (MMP) who had either extensive disease for a mean of 32 months, ie, progressive eye and/or oral/tracheal involvement or were refractory to the initially applied immunosuppressive or immunomodulatory drugs. The cohort of patients with MMP had either ocular (n  =  10) and/or extraocular involvement (n  =  15) and received 1 or 2 cycles of rituximab (each cycle consisting of rituximab, 4   ×  375 mg/m² administered intravenously at weekly intervals). After the first rituximab cycle, a total of 68% (17 of 25) of patients with MMP experienced complete clinical remission within 12 weeks, while an additional 5 of 25 patients required a second cycle of rituximab to achieve clinical remission. Overall, only 3 of 25 patients (12%) did not experience clinical remission with rituximab treatment. Most of the patients did not continue adjuvant immunosuppressive drugs and received only concomitant immunomodulatory treatment with dapsone or sulfasalazine during rituximab treatment. Of the 22 patients in complete remission, 10 developed a clinical relapse within 4 months, suggesting a short-lived effect of rituximab. Of note, 3 of 25 patients (12%) developed severe infections within 4 months after rituximab treatment and 2 patients died.

Mucous membrane pemphigoid is a heterogeneous group of autoimmune bullous diseases that encompasses chronic subepidermal/subepithelial blistering disorders that predominantly affect mucous membranes and lead to scarring.^{2 - 4} Based on the 2002 international consensus, MMP now includes the former clinical entities cicatricial pemphigoid, mucous membrane –dominant epidermolysis bullosa acquisita, and linear IgA bullous dermatosis with preferential mucous membrane involvement.² Immunologically, MMP is characterized by linear deposits of immunoglobulins and/or complement at the dermal-epidermal basement membrane zone (BMZ). Because the major autoantigens of MMP (either the ectodomain or the shed domain of bullous pemphigoid [BP] 180 and laminin 332) reach into the lamina densa of the BMZ or are components of the dermal anchor fibrils (collagen VII), scarring is the major sequela leading to disability or even death.^{3 - 4}

Mucous membrane pemphigoid poses 2 major challenges: prompt diagnosis and therapeutic management. First, it is not unusual that patients with MMP, particularly those with predominant ocular, nasal, pharyngeal, laryngeal, or esophageal involvement, frequently consult many physicians, such as general practitioners, ophthalmologists, otorhinolaryngologists, and gastroenterologists. Because many of these physicians may be unfamiliar with MMP, they do not carry out the immunopathological studies essential and critical for diagnosis of MMP, that is, direct immunofluorescence microscopy studies and analysis for circulating autoantibodies. This results in diagnostic delay and, most importantly, in the development of complications. Second, once the diagnosis is made, one has to face the therapeutic challenge related to acute or chronic inflammation that ultimately leads to rapid or gradual postinflammatory scarring. The therapeutic algorithm is primarily dictated by the site(s) of mucous membrane involvement and its severity and by the presence or lack of severe or even life-threatening ocular, laryngeal, pharyngeal, or esophageal complications. Because large controlled studies are lacking, available recommendations are solely based on smaller patients' cohorts or case series. Treatment options include systemic corticosteroids and immunosuppressive adjuvants such as cyclophosphamide, azathioprine, mycophenolate mofetil, or cyclosporine.^{4 - 5} Moreover, immunomodulatory drugs, such as high-dose immunoglobulins, dapsone, or sulfasalazine have also been successfully tried. More recently, rituximab has been used in various adjuvant settings as a rescue drug, such as in a small case series of refractory MMP or epidermolysis bullosa acquisita.⁶

Rituximab is a chimeric monoclonal IgG₁ antibody that specifically binds CD20 antigen expressed on B lymphocytes from the pre –B-cell stage to the pre –plasma cell stage but not on hemopoietic stem cells or on plasma blasts leading to depletion of B cells via different mechanisms, including complement induced lysis and apoptosis.^{7 - 8} Rituximab was originally approved for the treatment of CD20⁺ B-cell non-Hodgkin lymphoma and, later, for the treatment of refractory rheumatoid arthritis.⁸ In autoimmune blistering diseases of the skin and mucosae, rituximab was first used in paraneoplastic pemphigus^{7 ,9} and later in pemphigus, in which it was shown to have a remarkable efficacy in treatment-resistant cases, even as single therapy.^{10 - 11} In this context, the results have been so impressive that the question was raised as to whether it should be used as a first-line agent.¹²

Rituximab is given in 2 treatment options, ie, 4 consecutive intravenous treatments at 375 mg/m² over 4 weeks (derived from the original oncological protocol) or at 2   ×  1 g at a biweekly interval (based on the treatment protocol in rheumatoid arthritis) with similar efficacy.^{7 - 8} Complete depletion of peripheral B cells occurs as early as after the first rituximab infusion and usually lasts 8 to 12 months. Rituximab does not fully erase the previous B cell repertoire, as recently shown in a cohort of patients with pemphigus who showed the identical autoantibody profile when they experienced a clinical relapse after rituximab treatment.^{13 - 14}

Apart from B-cell depletion, rituximab has been shown to exert pleiotropic effects such as down-regulation of autoaggressive T cells in pemphigus (presumably via depletion of antigen-presenting B cells) and the induction of B-cell activating factor, which has a stimulatory effect on long-lived (but presumably not autoreactive) plasma cells.¹⁵ Thus, titers of protective IgG antibodies to pathogens such as pneumococcal capsular polysaccharides or tetanus toxoid did not change significantly in patients with pemphigus following rituximab treatment, while the titers of IgG autoantibodies against desmoglein 3 and 1 decreased.^{13 ,15} Moreover, rituximab has been shown to induce T-regulatory cells in lupus erythematosus, a finding that has not yet been reproduced in autoimmune bullous skin diseases. Thus, the impressive clinical efficacy of rituximab is presumably based on its inhibitory effects on several targets such as IgG autoantibodies but also autoaggressive T cells, which have been previously linked to the immune pathogenesis of cicatricial pemphigoid.¹⁶

So far, rituximab has been mainly used in a strictly adjuvant setting in MMP and epidermolysis bullosa acquisita.^{6 ,17} The optimal combination with additional immunosuppressive drugs or other immunomodulatory agents such as high-dose intravenous immunoglobulins or immunoadsorption needs to be defined by prospective clinical trials.^{4 ,6}

Despite all the optimism regarding the advent of a novel, highly effective drug in MMP, major attention should focus also on the immediate or delayed adverse effects of rituximab treatment.¹⁸ The major caveat of rituximab treatment is severe bacterial infections that may be lethal as observed in 3 of the 25 patients with MMP in the study by Le Roux-Villet et al¹ ; thus, even though MMP is very rarely a life-threatening disease by itself, the complication of treatment with rituximab may be lethal. Severe viral infections, such as chronic hepatitis B and C and human immunodeficiency viral infection, are contraindications for the use of rituximab.⁷

Although rare and not yet observed in autoimmune bullous skin diseases, progressive multifocal leukoencephalopathy is a potentially lethal adverse effect of rituximab.^{7 - 8} Again, the relative risk of acquiring progressive multifocal leukoencephalopathy with rituximab treatment is hard to assess because it is not directly linked to the cumulative dose of the adjuvant immunosuppressive treatment.

Rituximab is a highly promising treatment option in MMP and may help to avoid major devastating adverse effects of this chronic inflammatory skin disorder. Clinical efficacy and safety issues need to be elucidated in more detail in controlled prospective clinical trials. Nevertheless, these trials will only be possible through joining the forces of several groups interested in reducing morbidity and complications of MMP.