Oral mucous membrane pemphigoid: updates in diagnosis and management.

Mucous membrane pemphigoid (MMP) is a rare, immune-mediated, vesiculobullous disease that predominantly affects the oral cavity and conjunctiva. In MMP, autoantibodies are directed against hemidesmosomal proteins in the basement membrane zone, most commonly BP180. Clinical signs and symptoms include gingival desquamation, erosions, and ulcerations. Differential diagnoses include other immune-mediated blistering diseases, such as bullous pemphigoid. Definitive diagnosis is reached through history taking, physical examination, tissue biopsy and/or serology testing. MMP, although not curable, is typically managed with topical or systemic corticosteroids, in addition to immunosuppressive therapies and biologic agents in recalcitrant cases. Untreated MMP can lead to life-threatening complications, such as blindness. As a condition that affects the oral cavity, it is important that dentists understand how to recognise, diagnose and manage the disease.

Topical applications of heterologous platelet rich plasma (PRP) for refractory gingival lesions in autoimmune blistering diseases.

BACKGROUND: Recalcitrant gingival erosions, blisters and desquamative gingivitis are common features in oral autoimmune blistering diseases (AIBD). First line treatments include high-dosage corticosteroids and other immunosuppressive drugs, with several side effects and elevated number of recurrences. Autologous platelet-rich plasma (PRP) has been recently introduced as an alternative treatment and its use seems to be promising and safe. METHODS: In this study we describe the use of topical application of heterologous PRP in nine patients affected by mucous membrane pemphigoid, with gingival lesions refractory to previous treatments. Topical applications of PRP were performed once a week for 2 months and the endpoint for clinical evaluation was set 3 months after the last session. Oral disease severity score (ODSS) and VAS scores for pain measurement were recorded before and after treatment. RESULTS: The procedure was painless, well accepted, and free from adverse reactions. All patients (100%) reported a reduction in VAS whereas reduction in ODSS was observed in 89% of patients. CONCLUSIONS: Within the limits of the study, topical heterologous PRP is a safe and promising procedure to be studied in future controlled randomized trials as adjuvant treatment for refractory gingival lesions in patients with AIBDs.

Concurrence of Ocular Cicatricial Pemphigoid in Chronic Ocular Graft-Versus-Host Disease.

PURPOSE: The aim of this study was to report a series of 3 patients with ocular graft-versus-host disease (oGVHD) with progressive cicatricial conjunctival changes who were diagnosed with ocular cicatricial pemphigoid (OCP) after conjunctival biopsy. METHODS: This study was a retrospective case series. RESULTS: Three patients who received hematopoietic stem cell transplantation for hematologic malignancies developed oGVHD and subsequently were diagnosed with OCP. Case 1 was a 73-year-old woman with oGVHD who developed symblepharon and showed positive IgA, IgG, and C3 staining of the basement membrane zone (BMZ) on conjunctival biopsy, consistent with OCP. She was systemically treated with tacrolimus and prednisone with resolution of conjunctival inflammation. Case 2 was a 68-year-old man with oGVHD who developed symblepharon, severe dry eye, and corneal epithelial defect. An initial conjunctival biopsy was negative, but a repeat biopsy performed 10 years later showed positive BMZ IgA and IgG staining. Healing of the epithelial defect was achieved after treatment with high-dose systemic cyclosporine. Case 3 was a 75-year-old woman with oGVHD who had a nonhealing corneal epithelial defect and symblepharon with positive IgA BMZ staining on conjunctival biopsy, consistent with OCP. The patient responded well to methotrexate with healing of the epithelial defect. CONCLUSIONS: Although low-grade conjunctival fibrotic changes may be observed in chronic oGVHD, development of severe and progressive cicatricial changes, including symblepharon formation, should prompt consideration of biopsy to rule out concurrent OCP, the management of which differs from that of oGVHD.

Ocular involvement in autoimmune bullous diseases.

Autoimmune bullous diseases represent a heterogenous group of disorders caused by autoantibodies against adhesion molecules; the location of the target protein determines the level of cleft formation. The spectrum of ocular lesions in autoimmune bullous diseases can range from mild symptoms to severe involvement with sight impairment and even, in some cases, blindness. In pemphigus vulgaris, the prevalence of ocular involvement has been reported to be between 7% and 26%. The most common clinical sign of ocular pemphigus vulgaris is bilateral conjunctivitis with hyperemia. Ocular involvement also occurs in 41% to 70% of patients with paraneoplastic pemphigus. The main ocular manifestations are bilateral cicatrizing conjunctivitis with symblepharon formation, and shortening of the fornices. In mucous membrane pemphigoid, ocular involvement is seen in 61% to 70% of patients; the most frequent ocular finding is cicatricial conjunctivitis. Patients with autoimmune bullous diseases having common ocular involvement should be assessed by an ophthalmologist to avoid serious complications. Diagnostic procedures and treatment require multidisciplinary care based on the close cooperation between dermatologists and ophthalmologists.

Retrospective analysis of the long-term therapeutic effectiveness and safety profile of rituximab in the treatment of mucous membrane pemphigoid in a German university center between 2008 and 2019.

Background: The B-cell-depleting anti-CD20 antibody rituximab (RTX) is often used as an adjuvant drug for the treatment of refractory cases of mucous membrane pemphigoid (MMP). Objective: This study aims to determine the therapeutic effectiveness and the safety profile of RTX in MMP. Methods: The medical records of all cases of MMP treated with RTX between 2008 and 2019 in our university medical center located in northern Germany, which specialized in autoimmune blistering skin diseases, were retrieved and systemically analyzed for treatment responses and potential adverse events over a median period of 27 months. Results: We identified 18 MMP patients who received at least one cycle of RTX to treat MMP. RTX was always used as an adjuvant treatment, and its application did not change concomitant treatments. Under treatment with RTX, 67% of the patients achieved an improvement in their disease activity within 6 months. This was also reflected in a statistically significant reduction in the Mucous Membrane Pemphigoid Disease Index (MMPDAI) activity score. The frequency of infections under RTX treatment increased only slightly. Conclusions: The use of RTX is associated with an attenuation of MMP in a large proportion of MMP patients in our study. At the same time, its application was not found to further increase the susceptibility of the most strongly immunocompromised population of MMP patients to opportunistic infections. Collectively, our results suggest that the potential benefits of RTX outweigh its risks in patients with refractory MMP.

[Immunopathogenesis of mucous membrane pemphigoid]. / Immunpathogenese des Schleimhautpemphigoids.

A detailed understanding of the immunopathogenesis of mucous membrane pemphigoid (MMP) is of particular importance in view of the mostly difficult diagnostics and treatment of this blistering autoimmune dermatosis. A still unknown disturbance of the body's own immune tolerance leads to the formation of autoreactive cells. As the disease progresses these produce autoantibodies which are directed against structural proteins in the basement membrane zone (BMZ). After they bind to the target antigen, complement factors are deposited along the BMZ and inflammatory cells invade the underlying tissue and produce the characteristic subepithelial blistering. This inflammatory response is associated with fibrosis and scarring in many affected tissues. Most phases of MMP pathogenesis are poorly understood; however, the last few years have shed more light on this processes. These advances are mostly the result of animal and cell culture models. Typical clinical and immunopathological characteristics of MMP, such as oral, conjunctival and skin lesions, are reflected, for example, in an antibody transfer-induced mouse model for anti-laminin 332 MMP in adult mice. Dapsone, as first-line treatment for MMP patients, significantly reduced the severity of these symptoms, and fibrosis in the skin and mucous membranes was also found histologically, which makes the model well-suited for testing new therapeutic approaches for MMP patients and might be of help for further elucidation of the immunopathogenesis of MMP.

Clinical Approach to Ocular Cicatricial Pemphigoid.

Objectives: To evaluate the demographic data, ocular and systemic findings, clinical management, and outcomes of patients with ocular cicatricial pemphigoid (OCP). Materials and Methods: The medical records of 11 patients diagnosed as having OCP in the ophthalmology department of Ege University between 2008 and 2021 were evaluated retrospectively. Results: The patients' mean follow-up time was 14±5.76 months. All eyes (100%) had conjunctival involvement and 18 (81.81%) had corneal involvement. According to the Tauber staging system, 7 (31.81%), 8 (36.36%), and 7 (31.81%) of the eyes were stage 2, 3, and 4, respectively. The diagnosis was confirmed in 6 (66.66%) of 9 patients who underwent biopsy. Amniotic membrane transplantation was performed in 7 eyes, entropion surgery in 2 eyes, and electrocauterization for trichiasis in 5 eyes. Systemic involvement was observed in 45.45% (5/11) of patients, most commonly oral mucosal involvement (18.18%). Review of medical records showed that alkylating agents, steroids, and dapsone were used in patients treated before 2020. Mycophenolate mofetil was preferred to be used in combination with corticosteroids. Although treatment responses before mycophenolate mofetil usage could not be evaluated well because of loss to follow-up, 4 (66.66%) of 6 patients who received steroid treatment combined with mycophenolate mofetil showed partial or complete clinical remission. No serious side effects and drug withdrawal were observed. Conclusion: OCP is a sight-threatening autoimmune disease that affects older adults. Although positive biopsy results are valuable for diagnosis, negative results do not exclude the diagnosis. The main treatment is systemic immunosuppressives. Disease activity can be suppressed, especially with early initiation of drug therapy. These patients require a multidisciplinary approach. Especially in the presence of isolated ocular findings, ophthalmologists should be able to make the decision to start immunosuppressive treatment, and systemic treatment should not be delayed.

A 10-Year Review of the Management of Ocular Mucous Membrane Pemphigoid: A Private Practice Experience.

PURPOSE: Ocular mucous membrane pemphigoid (OcMMP) is a rare and potentially blinding condition for which consensus treatment guidelines do not exist. The purpose of this study was to assess the effectiveness and safety of various immunomodulatory agents in the treatment of OcMMP in a private practice setting. METHODS: We conducted a 10-year retrospective chart review of patients managed with OcMMP (n = 22). The median age at diagnosis was 73 (range: 35-91) years, and 59% (13/22) of patients were female. Visual acuity, Foster stage, and adverse effects (AEs) were documented. Treatment outcomes for each treatment episode were qualified at 3 months as complete response (CR), response (R), or failure (F). After 3 months, CR was then further subqualified as sustained CR, reactivation after initial CR, or AE after initial CR. The Fisher exact test P values were calculated for each outcome in comparison with mycophenolate. RESULTS: Twenty patients were treated with an immunomodulatory agent for a total of 55 treatment episodes. In comparison to dapsone, mycophenolate was more likely to achieve sustained CR (50% vs. 0%, P = 0.022) and R (100% vs. 50%, P = 0.007), and less likely to fail (0% vs. 50%, P = 0.007). Dapsone was also more likely to be discontinued because of AEs than mycophenolate (40% vs. 6%, P = 0.041). CONCLUSIONS: Mycophenolate is a superior first-line agent to dapsone in the treatment of OcMMP. Although not statistically significant, mycophenolate trends toward superiority over methotrexate as well. Mycophenolate is very effective when used in combination with rituximab. Azathioprine remains a reasonable second-line agent.

Ocular Cicatricial Pemphigoid With IgM-Positive Biopsy.

PURPOSE: The aim of this study was to investigate the prevalence of IgM along the basement membrane zone (BMZ) of patients with ocular cicatricial pemphigoid (OCP) and the outcomes of these patients with immunomodulatory therapy. METHODS: This study is a retrospective chart review of patients with conjunctival biopsy-proven OCP. Clinical data, including the presence of linear IgM deposition along the BMZ on either direct immunofluorescence or avidin-biotin complex immunohistochemistry, were recorded. Response to IMT was also recorded. RESULTS: A total of 817 patients with documented conjunctival biopsies were identified, with 93 (11.4%) positive for OCP with linear IgM deposition along the BMZ. Forty-six patients with sufficient follow-up were evaluated for clinical outcomes, with 35 (76.1%) able to achieve durable remission an average of 24.3 months after initiation of IMT. Most of these patients, 82.9%, were able to achieve durable remission with first-line antimetabolite therapy. Three patients were identified with solely IgM-positive conjunctival biopsies. CONCLUSIONS: Our study suggests that IgM positivity is seen in a minority of patients with OCP and that outcomes are comparable for these patients to the general OCP patient population.

Characteristics Associated With Refractory Course, Blindness, and Treatment Strategy-Related Outcomes in Patients With Mucous Membrane Pemphigoid.

Importance: Mucous membrane pemphigoid (MMP) is a rare and heterogeneous subepithelial autoimmune bullous disease with predominant mucosal involvement. Characteristics associated with the disease course and complications are yet to be delineated. Objectives: To evaluate characteristics associated with refractory disease course and blindness among patients with MMP and to estimate the association of different treatment strategies with the prognostic outcome. Design, Setting, and Participants: A retrospective cohort study of consecutive patients diagnosed with MMP and followed up for more than 1 year from 2007 to 2020 in 2 tertiary referral centers. Data were analyzed from January 1, 2009, to June 30, 2020. Main Outcomes and Measures: Characteristics associated with refractory disease course and blindness were evaluated using multivariable logistic regression model. Results: The study encompassed 121 patients with MMP (mean [SD] age, 66.0 [14.0] years; 78 (64.5%) were women), of whom 56 (46.3%) followed a refractory course and 13 (10.7%) developed blindness. Anti-LAD-1 IgA (odds ratio [OR], 3.42; 95% CI, 1.11-10.52; P = .03) and anti-dermal-epidermal/epithelial junction (DEJ) IgG (by indirect immunofluorescence on human salt-split skin; OR, 2.92; 95% CI, 1.26-6.78; P = .01) were significantly associated with refractory course. Development of blindness was associated with older age (≥68 years; OR, 6.38; 95% CI, 1.35-30.16; P = .009), initial presentation with bilateral ocular involvement (OR, 7.92; 95% CI, 2.04-30.68; P = .001), and scarring ocular lesions (OR, 5.11; 95% CI, 1.47-17.79; P = .006). However, 4 (30.8%) and 2 (15.4%) of those experiencing blindness had no ocular scarring lesions and unilateral ocular involvement at the onset of their disease, respectively. Patients progressing to blindness were more likely to be treated by 3 or more immunosuppressive/immunomodulatory drugs (OR, 4.07; 95% CI, 1.17-14.14; P = .02) and by cyclophosphamide (OR, 7.64; 95% CI, 2.24-26.09; P < .001). Patients developing blindness and refractory course were more frequently managed by intravenous immunoglobulin (OR, 7.64; 95% CI, 2.24-26.09; P < .001 and OR, 3.47; 95% CI, 1.42-8.45; P = .005, respectively). Conclusions and Relevance: Findings of this cohort study support that patients with MMP with anti-LAD-1 IgA and anti-DEJ IgG reactivity should be carefully monitored. While initial bilateral ocular disease and scarring ocular lesions were associated with blindness, patients initially presenting with unilateral and nonscarring ocular disease may still develop severe vision impairment.

Management of bilateral conjunctival squamous carcinoma following ocular cicatricial pemphigoid: A case report and review of literature.

The purpose of this study is to report a case of bilateral highly locally invasive conjunctival squamous neoplasia in the clinical setting of ocular cicatricial pemphigoid (OCP), and to review the available literature about this rare association.Case description: A man presented with chronic bilateral conjunctivitis and forniceal foreshortening. He had been previously diagnosed with OCP, and received proper therapy with systemic Dapsone and local steroids. After six months from treatment initiation, the patient complained of worsening symptoms and underwent two more biopsies, revealing a bilateral conjunctival squamous neoplasia. Conclusion: In rare cases, OCP can be associated with conjunctival squamous neoplasia. In case of suspected clinical modifications, it is important to make an early diagnosis by repeating several conjunctival biopsies or by performing less invasive diagnostic techniques (e.g. impression cytology of the ocular surface epithelium) to avoid unnecessary surgical damages.

On the Current Care Situation and Treatment of Ocular Mucous Membrane Pemphigoid in Germany. / Zur Versorgungssituation und konservativen Therapie des okulären vernarbenden Schleimhautpemphigoids in Deutschland.

BACKGROUND: Ocular involvement in mucous membrane pemphigoid (MMP) is relatively rare, with a prevalence of 25 cases per million population, equating to approx. 2,100 patients throughout Germany. Diagnosis can be difficult - especially in cases of isolated ocular involvement - and treatment can be complex and lengthy. Immunosuppressants or immunomodulatory drugs are often used. Due to the complexity of diagnosis and treatment, MMP patients are usually referred to specialized centers. The aim of this project was to evaluate the current care situation of patients with ocular MMP in Germany. METHODS: A paper-based survey was designed and sent to all university eye clinics and other specialized centers in Germany in April 2020. The survey asked about the existence of a specialized outpatient service, the total annual number of patients with MMP, the annual number of newly diagnosed patients, any interdisciplinary collaboration for diagnostic or therapeutic purposes, as well as the local and systemic therapy used. RESULTS: Of a total of 44 clinics, 28 (64%) responded, reporting a total average of 27 ± 42 (0 - 200) patients and 3.6 ± 2.2 (0 - 10) new cases per year. This corresponds to a total of 741 patients. Only nine (32%) of the responding clinics offer specialized MMP clinics. 93% of the centers collaborate with the local dermatology department. 79% perform serological and histological diagnostics in-house. About half of the centers (n = 16) apply a standardized treatment regime. Systemic glucocorticoids (66.7%) are most commonly used, followed by mycophenolate mofetil and dapsone (57.1%), rituximab (33.3%), azathioprine and cyclophosphamide (28.6%), as well as methotrexate (19.0%). The least frequently used treatment is intravenous immunoglobulin (14.3%). CONCLUSION: This survey of German ophthalmology departments obtained data from about one third of the estimated total cohort of all patients with MMP in Germany. These are presumed to be exclusively patients with at least one ocular involvement. The complex care of these patients is usually provided in collaboration with a dermatologist and with the use of systemic anti-inflammatory medication. Currently, an ophthalmological MMP register is being established to better record the epidemiology and care situation of this rare disease in Germany and to improve it in the long term.

Mucous Membrane Pemphigoid: A Case Report with Oral and Ocular Presentation.

AIM: To describe the diagnosis and management of mucous membrane pemphigoid (MMP) with oral and ocular presentation. BACKGROUND: Mucous membrane pemphigoid constitutes a heterogeneous group of chronic, autoimmune vesiculobullous diseases characterized by blister formation that has a propensity to affect different mucous membranes of the body. The most commonly affected areas include the oral cavity, mucous membranes of the eyes, throat, genitalia, and nose. This disease usually affects elderly women with a peak incidence at around 50-70 years of age; however, rare cases have been diagnosed in children. The symptoms of MMP include recurrent blistering lesions which eventually rupture and occasionally heal with scarring that may lead to certain complications involving the eyes and throat regions. CASE DESCRIPTION: In this report, we describe a 66-year-old female patient who complained of oral and ocular lesions for a period of 2 years. Pain, burning mouth, and gingival inflammation were present. Ocular examination showed mild conjunctivitis with scar formation at the lateral canthus of the left eye. The patient also noticed periods of water-filled balloon-like formation in the gingiva that rupture spontaneously leaving sore spots. A biopsy was obtained from perilesional tissue and sent for histopathological examination, correlation of clinical and histological features directed us toward the diagnosis of MMP. The patient was treated for both oral and ocular lesions using topical corticosteroid therapy in conjunction with antifungal and antibacterial drugs. The response to local treatment was augmented via effective periodontal therapy to control the concurrent plaque-induced gingival inflammation and via using a customized application tray to sustain the drug efficacy. CONCLUSION: A multidisciplinary approach is often necessary in order to treat MMP lesions efficaciously. CLINICAL SIGNIFICANCE: Early diagnosis and effective treatment protocol using systemic or topical corticosteroid therapy along with other therapeutic means including periodontal therapy, good oral hygiene practice, and timely follow-up are very useful in preventing long-term complications due to this disease.

Anti-laminin 332 mucous membrane pemphigoid in a young woman treated with rituximab.

Mucous membrane pemphigoid, formerly known as cicatricial pemphigoid, is a rare and difficult-to-treat bullous disorder that occurs most commonly in older adults. We describe a 32-year-old woman who was diagnosed with anti-laminin 332 mucous membrane pemphigoid through indirect immunofluorescence for laminin 332 following nonspecific histologic and direct immunofluorescence findings. At 16 weeks following completion of her first cycle of with rituximab 375mg/m2 weekly for four weeks, her mucosal erosions had resolved. Although not widely available, this case highlights the utility of anti-laminin 332 immunofluorescence for diagnostic confirmation of this entity and the efficacy of rituximab in obtaining disease control.

Management of mucous membrane pemphigoid: a literature review and update

Mucous membrane pemphigoid (MMP) is a rare group of heterogeneous chronic autoimmune diseases that predominantly manifest as blistering of the mucous membranes. MMP lesions often heal with scarring, which may result in impaired organ function and significant morbidity. The exact pathogenic mechanisms of MMP are still largely unknown while the diagnosis is based on a combination of clinical, histological and immuno-pathological findings. Several treatment modalities of MMP are available and are reported in the literature, however, such treatment options are principally guided by expert opinions and descriptive reports. Non-specific immunosuppression, especially corticosteroids, remains the mainstay of treatment, which often leads to severe adverse effects. Therefore, safer and more effective therapeutic modalities are required. This comprehensive literature review outlines the current knowledge and recent advances in the field of MMP management, with particular emphasis on the oral variant of MMP.