Search

Mucous membrane pemphigoid (MMP) is a heterogeneous group of rare, chronic, subepithelial autoimmune blistering diseases (AIBDs) with predominant involvement of mucous membranes that can be sight-threatening and life-threatening. Rituximab (RTX) has demonstrated its efficacy in severe MMP refractory to conventional immunosuppressants in small series that differed in RTX scheme, concomitant therapies, and outcome definitions. In a meta-analysis involving 112 patients with MMP treated with RTX, complete remission (CR) was reported in 70.5% of cases. Herein, we report the largest retrospective monocentric study on RTX efficacy in a series of 109 severe and/or refractory patients with MMP treated with RTX with a median follow-up period of 51.4 months. RTX was administered in association with immunomodulatory drugs (dapsone, salazopyrine) without any other systemic immunosuppressant in 104 patients. The RTX schedule comprised two injections (1 g, 2 weeks apart), repeated every 6 months until CR or failure, with a unique consolidation injection (1 g) after CR. The median survival times to disease control and to CR were 7.1 months and 12.2 months, respectively. The median number of RTX cycles required to achieve CR in 85.3% of patients was two. The larynx was the lesional site that took the longest time to achieve disease control. One year after RTX weaning, CR off RTX was obtained in 68.7% of cases. CR off RTX with only minimum doses of immunomodulatory drugs was achieved in 22.0% of patients. Further, 10.1% of patients were partial responders and 4.6% were non-responders to RTX. Relapse occurred in 38.7% of cases, of whom 91.7% had achieved CR again at the last follow-up. In MMP, CR was achieved in a longer time and after more rituximab cycles than in pemphigus, especially for patients with MMP with anti-type VII collagen reactivity. RTX with concomitant immunomodulatory drugs was not responsible for an unusual proportion of adverse events. This large study confirms that RTX is an effective therapy in patients with severe and/or refractory MMP, corroborating previous findings regarding the effects of RTX on AIBDs such as pemphigus., Competing Interests: GB, MA, CL-V, FC, CP-P, and PM were investigators in the “Ritux 3” study (NCT00784589) and the “Pemphix” trial (NCT02383589) conducted by Roche Laboratories. MA, CL-V, FC, CP-P, and PM are investigators in “RTX-MMP” study (NCT03295383). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bohelay, Alexandre, Le Roux-Villet, Sitbon, Doan, Soued, Shourick, Rousset, Mellottee, Heller, Lièvre, Zumelzu, Morin, Grootenboer-Mignot, Gabison, Caux, Prost-Squarcioni and Musette.)

The role of IgE autoantibodies has been demonstrated in the pathogenesis of bullous pemphigoid for many years. Recently, omalizumab (OMZ), a humanized monoclonal anti-IgE antibody that depletes total serum IgE, has been used off-label in a few case series of bullous pemphigoids demonstrating a rapid efficacy and allowing significant improvements or complete remission as add-on therapy in first-line treatment-resistant patients. Herein, we report the largest retrospective study to evaluate OMZ effectiveness in patients with subepidermal autoimmune blistering diseases. Our series included 13 patients from a single center with bullous pemphigoid or mucous membrane pemphigoid, of whom 7 had mucous membrane involvement. OMZ was added to the unchanged immunosuppressive therapies. Detailed clinical and immunological data during the first year were collected, notably for specific anti-BP180-NC16A IgE and IgG, and the median total follow-up was 30 months (range: 3-81). Our series demonstrated that OMZ induced a significant improvement in pruritus, urticarial score, and daily blister count on day 15, allowing disease control to be achieved in a 1-month median time and complete remission (CR) in a 3-month median time in 85% of these patients previously in therapeutic impasse. At the end of the follow-up, 31% of patients achieved CR on minimal therapy after OMZ weaning without relapses, and 54% achieved CR on OMZ continuation with a minimal dose of concomitant treatment. Two patients experienced therapeutic failure (15%). At baseline, clinical variables reflecting activity were significantly positively correlated with eosinophil blood count, total IgE serum level, specific anti-BP180 IgE and IgG. While baseline anti-BP180 IgG and specific anti-BP180 IgE were significantly positively correlated, only the two patients who experienced a therapeutic failure with OMZ did not fit with this correlation, demonstrating elevated levels of anti-BP180 IgG with no measurable BP180-specific IgE. Follow-up of immunological variables demonstrated a rapid decrease of eosinophilia towards normalization, whereas a slower decline towards negativation was observed over 1 year for anti-BP180 IgG and anti BP180 IgE in patients who responded to OMZ. This case series demonstrated that OMZ is a rapidly effective biologic therapy for refractory bullous pemphigoid and mucous membrane pemphigoid, permitting rapid disease control and reduction of concomitant therapeutics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alexandre, Bohelay, Gille, Le Roux-Villet, Soued, Morin, Caux, Grootenboer-Mignot and Prost-Squarcioni.)

Mucous membrane pemphigoids (MMPs) and bullous pemphigoid (BP) are autoimmune bullous diseases that share physiopathological features: both can result from autoantibodies directed against BP180 or BP230 antigens. An association has been reported between BP and intake of gliptins, which are dipeptidyl peptidase-IV inhibitors used to treat type 2 diabetes mellitus. Clinical and immunological differences have been reported between gliptin-induced BPs and classical BPs: mucosal involvement, non-inflammatory lesions, and target BP180 epitopes other than the NC16A domain. Those findings accorded gliptins extrinsic accountability in triggering MMP onset. Therefore, we examined gliptin intrinsic accountability in a cohort of 313 MMP patients. To do so, we (1) identified MMP patients with gliptin-treated (challenge) diabetes; (2) selected those whose interval between starting gliptin and MMP onset was suggestive or compatible with gliptin-induced MMP; (3) compared the follow-ups of patients who did not stop (no dechallenge), stopped (dechallenge) or repeated gliptin intake (rechallenge); (4) compared the clinical and immunological characteristics of suggestive-or-compatible-challenge patients to 121 never-gliptin-treated MMP patients serving as controls; and (5) individually scored gliptin accountability as the trigger of each patient's MMP using the World Health Organization-Uppsala Monitoring Center, Naranjo- and Begaud-scoring systems. 17 out of 24 gliptin-treated diabetic MMP patients had suggestive (≤12 weeks) or compatible challenges. Complete remission at 1 year of follow-up was more frequent in the 11 dechallenged patients. One rechallenged patient's MMP relapsed. These 17 gliptin-treated diabetic MMP patients differed significantly from the MMP controls by more cutaneous, less buccal, and less severe involvements and no direct immunofluorescence IgA labeling of the basement membrane zone. Multiple autoantibody-target antigens/epitopes (BP180-NC16A, BP180 mid- and C-terminal parts, integrin α6β4) could be detected, but not laminin 332. Last, among the 24 gliptin-treated diabetic MMP patients, five had high (I4-I3), 12 had low (I2-I1) and 7 had I0 Begaud intrinsic accountability scores. These results strongly suggest that gliptins are probably responsible for some MMPs. Consequently, gliptins should immediately be discontinued for patients with a positive accountability score. Moreover, pharmacovigilance centers should be notified of these events.

Background: Oesophageal involvement of mucous membrane pemphigoid (MMP) has not yet been thoroughly described., Objectives: To characterize systematically the endoscopic lesions of a series of patients with oesophageal symptoms seen at a referral centre for autoimmune bullous diseases., Methods: Clinical, endoscopic and immunological findings of consecutively referred patients with MMP with oesophageal involvement, systemic and endoscopic treatments, and follow-up are described., Results: Of 477 consecutive patients with MMP consulting between 2002 and 2012, 26 (5·4%) had symptomatic oesophageal involvement. Dysphagia, observed in 23 (88%) patients, was the most frequent symptom. Oesophageal symptoms could be the first sign of MMP. Patients with oesophageal involvement had a mean of three other involved sites. At initial oesophageal endoscopy, 17 of 26 patients had active lesions (intact bullae, erosions and/or erythema), 15 had stricture(s) and 12 had other cicatricial lesions. Systemic therapy alone achieved oesophageal symptom relief for five patients. Dilatation was combined with systemic therapy for 12 patients and was successful in nine; one perforation occurred., Conclusions: Symptomatic oesophageal involvement affected 5·4% of patients with MMP. Dermatologists and gastroenterologists should be aware of these mucocutaneous diseases and their oesophageal involvement, as it could lead to earlier diagnosis and better care. Oesophageal dilatation could be a therapeutic option for symptomatic stricture not relieved by optimized systemic therapy alone., (© 2017 British Association of Dermatologists.)

Importance: A rare variant of mucous membrane pemphigoid (MMP) is characterized by circulating anti-laminin 332 (Lam332) autoantibodies and seems to be associated with concurrent malignant neoplasms., Objective: To determine the prevalence and clinical significance of anti-Lam332 autoantibody detection from a large series of patients with MMP., Design: Multicenter retrospective study., Setting: Four French national centers for autoimmune bullous diseases., Participants: One hundred fifty-four patients with MMP and 89 individuals serving as controls were included., Interventions: Serum samples were analyzed by a new Lam332 enzyme-linked immunosorbent assay (ELISA); clinical and immunopathologic data were obtained from the patients' medical records., Main Outcome Measures: The Lam332 ELISA scores were evaluated with respect to clinical characteristics, standard and salt-split indirect immunofluorescence, and bullous pemphigoid (BP) 230 and BP180-NC16A ELISAs., Results: The Lam332 ELISA score was positive (≥9 U/mL) in 20.1% of serum samples from patients with MMP, 1 of 50 patients with bullous pemphigoid (BP), none of 7 with pemphigus, and 3 of 32 other controls. No relationship was evidenced between a positive ELISA Lam332 score and age; sex ratio; oral, ocular, genital, skin, or esophageal/laryngeal involvement; internal malignant neoplasm; or BP180 ELISA score. Salt-split skin indirect immunofluorescence and ELISA BP230 results were more frequently positive when Lam332 ELISA results were positive (P = .04 and .02, respectively). Patients with a positive Lam332 ELISA score frequently had more severe MMP (67.8% vs 47.2%; P = .04)., Conclusions and Relevance: Results of this novel ELISA showed that serum anti-Lam332 autoantibodies are detected in 20.1% of patients with MMP. Anti-Lam332 autoantibodies are mainly detected in patients with severe MMP but not preferentially in those with a malignant neoplasm. The association between anti-Lam332 and anti-BP230 autoantibodies might arise from an epitope-spreading phenomenon.

Background: Mucous membrane pemphigoid (MMP) still represents a potentially life- and sight-threatening disease. Immunosuppressants, such as cyclophosphamide (CYC), are indicated for patients with severe and/or refractory MMP., Objectives: To evaluate the efficacy and safety of daily oral CYC without corticosteroids as therapy for severe MMP., Methods: Thirteen patients with severe refractory MMP, who received oral CYC at an initial dose of 2 mg kg(-1) without corticosteroids, were retained. Previous treatments, for example dapsone, sulfasalazine or topical agents, were maintained during CYC treatment. Initial clinical severity and response to treatment were assessed by scoring. CYC was stopped after complete remission (CR), or when MMP progressed or lymphopenia (< 0·7 × 10(9) cells L(-1) ) occurred., Results: After 52 weeks of CYC treatment, the overall response rate was 69% (9/13 patients) with a median time to disease control of 8 weeks (range 4-52 weeks). Seven patients (54%) entered CR with a median time to CR of 24 weeks (range 16-52 weeks), all remaining in CR at week 52. The mean duration of CYC administration was 12 weeks (range 2-52 weeks). The most common side effect was lymphopenia (10/13 patients), which led to CYC withdrawal for six patients. No sepsis was observed., Conclusions: CYC without corticosteroids had rapid efficacy in patients with severe refractory MMP and was safe., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

Background: Mucous membrane pemphigoid (MMP) still represents a potentially life- and sight-threatening disease. In a subset of patients with severe MMP, conventional immunosuppressants are ineffective or contraindicated., Observations: Twenty-five patients with severe refractory MMP, including 5 with mucous membrane-dominant epidermolysis bullosa acquisita, received 1 or 2 cycles of rituximab (375 mg/m(2) weekly for 4 weeks). Twenty-one of the patients were receiving concomitant therapy with dapsone and/or sulfasalazine therapy, which was maintained during rituximab cycles. Complete responses in all affected sites (ocular and/or extraocular) were obtained in 17 patients (68%) by a median time of 12 weeks after the first cycle, and 5 additional patients responded completely after a second cycle, yielding an 88% complete response rate. In all but 1 of the 10 patients with ocular lesions, their eyes became noninflammatory within a mean of 10 weeks. Among the 3 patients (12%) who developed severe infectious complications, 2 (8%) died; they had been receiving concomitant conventional immunosuppressants and high-dose corticosteroids and were hypogammaglobulinemic. Treatment with immunosuppressants was discontinued for all other patients, and no other infection was observed. Ten patients experienced relapse after a mean of 4 (range, 1-16) months after achieving complete responses., Conclusions: Rituximab appears to have rapid and dramatic efficacy in patients with severe, refractory MMP. The occurrence of severe infections in patients receiving concomitant conventional immunosuppressants supports using rituximab without other immunosuppressants. Controlled prospective studies are warranted to define an optimal treatment protocol.

We conducted a prospective study between 1995 and 2002 to investigate nose and throat (NT) manifestations of mucous membrane pemphigoid (MMP). One hundred ten consecutive patients with clinical, histologic, and immunologic criteria of MMP were seen in 2 referral centers for bullous diseases. They were systematically asked about the existence of persistent NT symptoms. Patients who had any were examined with a flexible nasopharyngolaryngoscope by the same otorhinolaryngologist. When possible, NT mucous membrane (MM) biopsies were taken for direct immunofluorescence (IF) assays to determine lesion specificity. Thirty-eight (35%) patients (23 F/15 M; mean age, 58.5 yr) had the following NT symptoms: 35 (92%) nasal, 19 (50%) pharyngeal, and 10 (26%) laryngeal. Five (13%) had acute dyspnea. Thirty-three (87%) of the 38 symptomatic patients had lesions at physical examination: 30 (79%) nasal, 6 (16%) pharyngeal, and 19 (50%) laryngeal. Laryngeal involvement was asymptomatic in 11 patients. Lesions were mainly atrophic rhinitis and oropharyngeal and epiglottal erosions. Nasal valves, choanae, pharynx, and/or larynx were severely scarred in 7 (18%) patients, causing the death of 3. Direct IF showed malpighian epithelium associated with linear immune deposits (IgG, IgA, or C3) along the chorioepithelial junction in all 18 biopsies performed, including those of 4 symptomatic patients without lesions at physical examination. The presence of severe ophthalmologic lesions (p = 0.02) and > or =3 sites involved other than NT (p = 0.02) were predictive of laryngeal involvement. In contrast, laryngeal symptoms, disease duration, HLA DQB1*0301, and smoking were not significantly associated with laryngeal lesions. In conclusion, at least 35% of MMP patients had NT involvement. Atrophic rhinitis was the most frequent lesion. The most severe were the laryngeal lesions that were significantly associated with severe ocular involvement and disseminated disease, and could be fatal. Our results highlight the necessity of a multidisciplinary approach to MMP management to assure early diagnosis of NT involvement, to guide therapeutic choices, and to improve patient survival and functional outcomes.

Background: The severity of cicatricial pemphigoid (CP) varies. First-intent treatment of mild or moderate cases is dapsone. In life or sight-threatening cases, intravenous cyclophosphamide pulses are efficient but may have digestive side effects and imply repeated hospitalizations. Mycophenolate mofetil (MMF) is an oral and well tolerated immunosuppressant agent which has proved its efficacy in pemphigus and some bullous pemphigoid. In CP, encouraging case reports have been previously published. We report herein a retrospective study about 14 patients who have received MMF since 2000., Patients and Methods: There were 5 men and 9 women, with a mean age of 69 years. MMF was introduced in 3 different clinical situations: immediately in relay to cyclophosphamide in 7 patients with severe CP (group I); in case of a mild-severe relapse at distance from with dranal of cyclophosphamide in 3 patients (group II); as first-intent immunosuppressant agent in 4 patients whose disease was not under control with high-dose dapsone, but not life - or sight-threatening (group III). In all these patients, the disease was invalidating and not controlled by dapsone +/- sulfasalazine, but did not threaten life or sight. The aim was to achieve satisfying control of the disease with an oral and well tolerated immunosuppressant agent, and to maintain good quality of life. The dose of MMF was 1.5 or 2 g per day. The criteria of MMF efficacy was the healing of previous lesions and the absence of new progressive lesions., Results: MMF was efficient in obtaining or maintaining a good control of the disease in 10/14 patients, as long as the underlying treatment with dapsone (2 mg/kg/d) was maintained. In 7/10 cases, it was possible to decrease the dapsone dose in order to improve hematological tolerance. In the 3 other cases, a relapse occurred when the dose of dapsone was decreased. MMF was inefficient in controling the disease in 4/14 patients (29 p. 100). Clinical and biological tolerance of MMF was good in 13/14 patients., Discussion: In this series, MMF was proposed to heterogenous patients, who presented at that time a mild-moderate disease and for whom we wanted in improve the quality of life. MMF seems to be an interesting drug, capable of obtaining or maintaining satisfactory control of the disease and permitting the decrease of dapsone doses in some mild-severe CP. However MMF must not replace cyclophosphamide in severe sight or life-threatening forms of CP.

Objective: We aimed to develop consensus-based recommendations for streamlining medical communication among various health care professionals, to improve accuracy of diagnosis and treatment, and to facilitate future investigations for mucous membrane pemphigoid., Participants: Because of the highly specific nature of this group of diseases, the 26 invited participants included either international scholars in the field of mucous membrane pemphigoid or experts in cutaneous pharmacology representing the 3 medical disciplines ophthalmology, oral medicine, and dermatology., Evidence: The first author (L.S.C.) conducted a literature search. Based on the information obtained, international experts who had contributed to the literature in the clinical care, diagnosis, and laboratory investigation for mucous membrane pemphigoid were invited to participate in a consensus meeting aimed at developing a consensus statement., Consensus Process: A consensus meeting was convened and conducted on May 10, 1999, in Chicago, Ill, to discuss the relevant issues. The first author drafted the statement based on the consensus developed at the meeting and the participants' written comments. The draft was submitted to all participants for 3 separate rounds of review, and disagreements were reconciled based on literature evidence. The third and final statement incorporated all relevant evidence obtained in the literature search and the consensus developed by the participants. The final statement was approved and endorsed by all 26 participants., Conclusions: Specific consensus-based recommendations were made regarding the definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators for mucous membrane pemphigoid. A system of standard reporting for these patients was proposed to facilitate a uniform data collection.