Ocular Cicatricial Pemphigoid in Young Patients.

PURPOSE: The purpose of this study is to report ocular cicatricial pemphigoid (OCP) occurring in young patients. Relevant literature is also reviewed. METHODS: Medical records of patients aged 30 years or younger who were treated for OCP between August 2021 and May 2023 at a tertiary care eye institute were reviewed. The most common differential diagnoses of cicatrizing conjunctivitis, such as Stevens-Johnson syndrome sequelae, chemical injury, chronic topical/systemic drug use, autoimmune connective tissue disorders, or allergic eye diseases, were ruled out based on clinical history, examination, and the Cicatrizing Conjunctivitis Score described by Shanbhag et al. The diagnosis of OCP was confirmed by positive direct immunofluorescence of oral mucosal and/or conjunctival biopsy in a majority of the patients. RESULTS: Seven patients fulfilled the criteria for a diagnosis of OCP. The mean age at presentation was 21.86 ± 5.25 years (13-28 years). Some of the patients presented with relatively atypical features for OCP such as corneal immune ring infiltrate and bilateral corneal perforation. Six patients exhibited systemic mucosal lesions, and the direct immunofluorescence yield was 85.71%. All patients required aggressive immunosuppressive treatment. CONCLUSIONS: OCP is classically described as a rare disease that occurs in old age. This case series highlights the importance of a higher index of suspicion for diagnosing OCP at a younger age. Early administration of immunosuppressive agents can potentially control severe ocular surface inflammation and its sequelae.

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.

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.

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.

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.

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.

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.

Use of rituximab in the treatment of mucous membrane pemphigoid: An analytic review.

Mucous Membrane Pemphigoid (MMP) is a potentially fatal mucocutaneous autoimmune blistering disease. Autoantibodies are produced against various components of the dermo-epidermal or mucosal-submucosal junction are referred to as basement membrane zone (BMZ). The hallmark is deposition of of Ig and C3 on the perilesional tissues and in some patients detection of anti-BMZ autoantibodies. A unique characteristic of MMP is that as the blisters or erosions heal, they leave irreversible scarring. This scarring results in serious and catastrophic sequelae that affect the quality of life. Conventional therapy consists of anti-inflammatory and immunosuppressive agents (ISA). In patients who fail conventional therapy or develop significant side effects to them, rituximab (RTX) has been used off label. In this review, the clinical outcomes of patients with MMP treated with RTX were studied. 124 patients were identified, 47.58% being male. 72 patients were treated by the Lymphoma Protocol and 51 by Rheumatoid Arthritis (RA) protocol. Follow up for the entire cohort was 36 months (range 0.5-72). On follow-up 64 patients (51.61%) achieved complete clinical remission (CR) off therapy, 25 patients (20.16%) were in CR on therapy, 5 patients (4.03%) were non-responders, and 9 patients (7.25%) were failures. 52 patients (41.93%) experienced a relapse, after 36 months follow-up. Duration between last RTX infusion and relapse was 10.5 months (range 1-30). Most patients with relapses were treated with additional RTX. A statistically significant better outcome was observed in patients treated with RTX as monotherapy compared to those who received RTX with ISA. Clinical outcomes in patients treated with Lymphoma protocol were better than RA protocol at a statistically significant level. Data on CD20+ B cell depletion and repopulation was limited. Interestingly relapses were seen in patients with CD20+ B cell depletion and after repopulation. In the final analysis, 89 patients (71.77%) were in complete remission. Data in this review indicated that RTX was a useful agent to treat MMP. While a randomized control trial may not be practically possible, better and disease specific protocols need to be developed. When publishing, authors should attempt to provide complete and detailed information. In doing so, they will benefit their colleagues and the patients with MMP they treat with RTX.

Perioperative Management and Long-Term Outcomes in Ocular Cicatricial Pemphigoid Patients Undergoing Cataract Surgery.

Objective: To observe the outcomes of cataract surgery in ocular cicatricial pemphigoid (OCP) patients and explore routine perioperative medical treatments. Design: Retrospective case series. Methods: Fourteen eyes of 8 patients were included in the study. Foster's stage 1-4 OCP patients were given human intravenous immunoglobulin, whereas patients with active inflammation were treated with prednisone tablets and methotrexate. Those who were intolerant to methotrexate and had severe inflammatory symptoms were treated with cyclophosphamide. Cataract surgery was performed for all patients after three months of systemic treatment under stable conditions. The conjunctival biopsy was evaluated by immunofluorescence microscopy. Then, patients were divided into individuals with or without ankyloblepharon. Records were reviewed for OCP stage, type of surgery, best-corrected visual acuity (BCVA), Schirmer I test, corneal fluorescein sodium staining, meibomian gland coloboma range, and ocular surface disease index (OSDI) scores. Follow-up was for the duration of taking topical and systemic medication. Results: Nine female (64.29%) and 4 male (35.71%) eyes were diagnosed with OCP by biopsy. The mean follow-up time was 60.64 ± 35.62 months. Thirteen eyes (92.86%) of 7 patients underwent phacoemulsification. One eye underwent phacoemulsification combined with amniotic membrane transplantation. The intracapsular extraction of cataract was applied to one eye. The BCVA improved significantly in all the patients, which remained stable until the last follow-up. The Schirmer I test was higher than that before the surgery. Corneal fluorescein sodium staining after surgery showed a decrease in score compared to the preoperative score. The BCVA of the patients after surgery increased significantly. The OSDI scores of patients with ankyloblepharon were significantly higher than for those without it. Postoperative symblepharon showed no significant difference compared to the preoperative symblepharon. Conclusions: In this series, OCP patients with cataracts were able to undergo phacoemulsification surgery, whereas routine use of immunosuppression and closed postoperative follow-up were necessary.

Ocular paraneoplastic pemphigoid / Szemészeti érintettséggel járó paraneoplasiás pemphigoid

Paraneoplastic mucous membrane pemphigoid, a rare pemphigoid variant is associated with primary malignancy, and characterised by fulminant progression and frequent ineffectivity of classical systemic immunosuppression. In this paper, the clinical features, diagnostic and therapeutical challenges are presented through three cases. Detailed history and analysis of the immunofluorescent samples help the diagnosis. The therapeutic goal is to prevent the progression with systemic immunosuppressive treatment, which can be contraindicated during the ongoing oncological therapy. In absence of consent in the exact diagnostic criteria and management protocol of this rare condition, consultation with other specialists (ophthalmologist, dermatologist, dentist, ear-nose-throat specialist, immunologist) has high importance in early diagnosis and treatment.

Biologic treatment outcomes in mucous membrane pemphigoid: A systematic review.

BACKGROUND: Mucous membrane pemphigoid (MMP) is an autoimmune disease that can lead to fibrosis of mucous membranes and functional impairment. Biologic agents should be explored as alternative treatment options to improve outcomes. OBJECTIVE: To conduct a systematic review of biologic treatment outcomes in patients with MMP. METHODS: A MEDLINE and Embase search was conducted on July 23, 2020, to include 63 studies using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: Use of intravenous immunoglobulin (n = 154), rituximab (n = 112), tumor necrosis factor α inhibitors (n = 7), and combination treatments (n = 58) were reported in 331 patients with MMP. Intravenous immunoglobulin led to complete resolution in 61.7% (n = 95/154) of patients within 26.0 months, with a recurrence rate of 22.7% (n = 35/154) and headache as the most common adverse effect (8.4%, n = 13/154). Rituximab led to complete resolution in 70.5% (n = 79/112) of patients within 8.7 months, with a recurrence rate of 35.7% (n = 40/112). The most commonly reported adverse effects were urinary tract infections (4.5%, n = 5/112), leukocytopenia (2.7%, n = 3/112), and death due to severe infections (1.8%, n = 2/112). Tumor necrosis factor α inhibitors led to complete resolution in 71.4% (n = 5/7) of patients within 3.9 months of treatment without reported adverse events. CONCLUSIONS: Randomized clinical trials with long-term follow-up are required to conclude the promising safety and efficacy of biologic agents in patients with MMP.

Insights into clinical and diagnostic findings as well as treatment responses in patients with mucous membrane pemphigoid: A retrospective cohort study.

BACKGROUND: The variable clinical severity of mucous membrane pemphigoid (MMP) often leads to diagnostic and therapeutic delays. OBJECTIVE: To describe the characteristics of a large cohort of patients with MMP. METHODS: A retrospective review of clinical and diagnostic characteristics as well as treatment responses in 145 patients with MMP. RESULTS: Monosite involvement was seen in 41.4% and multisite involvement in 58.6% of the patients. The oral mucosa was affected in 86.9% of the patients, followed by the ocular mucosa (30.3%), skin (26.2%), genital mucosa (25.5%), nasal mucosa (23.4%), and pharyngeal and/or laryngeal mucosa (17.2%). Ocular disease developed during the disease course in 41.7% of patients with initially other mucosal site involvement. The malignancy rate was significantly higher in patients with autoantibodies against laminin-332 than in patients with MMP without laminin-332 autoantibodies (35.3% vs 10.9%, respectively; P = .007). Systemic immunosuppressive or immunomodulatory therapy was administered to 77.1% of the patients, mainly to patients with multisite (P < .001), ocular (P < .001), and pharyngeal and laryngeal involvement (P = .002). The remaining patients (22.9%) received topical therapy. Adverse events were frequently reported. LIMITATIONS: Retrospective design. CONCLUSION: Patients with MMP present with a heterogeneous clinical presentation, and new symptoms may develop during the disease course. Cancer screening should be considered for patients with MMP and, in particular, for those with autoantibodies against laminin-332.

Childhood Vulvar Mucous Membrane Pemphigoid.

BACKGROUND: Autoimmune bullous diseases in childhood are a diagnostic challenge. CASE: We present the case of an 11-year-old girl with recurrent vulvar erosions since early childhood. She had been referred to a child abuse unit under the suspicion of sexual abuse. She responded well to dapsone and topical corticosteroids. SUMMARY AND CONCLUSION: Our review focuses on previously reported cases of pemphigoid (bullous or mucous membrane) in childhood with exclusively genital involvement. We also summarize mucous membrane pemphigoid cases diagnosed during childhood. There seems to be a differentiated form of pemphigoid predominantly affecting girls with exclusively vulvar involvement and with good prognosis. Dermatologic evaluation and a skin biopsy with direct immunofluorescence are key to diagnosing a mucous membrane pemphigoid. Further antigenic studies are needed to nosologically classify the disease properly.

Repository Corticotropin Injection as an Alternative Treatment for Refractory Ocular Mucous Membrane Pemphigoid.

PURPOSE: The purpose of this study was to report the clinical course and outcome of patients with refractory ocular mucous membrane pemphigoid (MMP) treated by repository corticotropin injection (RCI). METHODS: Patients with biopsy-proven ocular MMP treated with RCI from 3 tertiary medical centers were evaluated. Medical records between January 2013 and January 2021 were reviewed and deidentified to retrieve relevant disease-related data. Primary outcome measures included conjunctival inflammatory activity, change in Foster clinical conjunctival scarring staging after RCI treatment, and the development of ocular and systemic complications. RESULTS: Included were 15 patients (10 women and 5 men; 36-95 yrs of age) with a mean follow-up of 4.5 years. Most of the patients (80%) had Foster stage 3 at presentation, and all patients had active MMP. Each patient had failed to respond to at least 1 immunomodulatory drug during the follow-up, and 9 (60%) patients had treatment failure of at least 2 other agents before the use of RCI. The mean duration of RCI treatment was 21 months (range, 3-54 mo). Foster stage did not change in any of the 15 patients at the last follow-up. Nine patients continued RCI therapy at the last follow-up, and in all of them, the disease activity of MMP was well controlled. No serious adverse events because of RCI were documented during the follow-up in any treated patient. CONCLUSIONS: RCI may serve as an alternative or an adjunctive treatment in patients with severe and refractory ocular MMP. Treatment with RCI seems to be safe and well-tolerated.

Surgical Management of Ocular Cicatricial Pemphigoid in a Pediatric Patient.

PURPOSE: The purpose of the report was to describe the first successful tarsal fracture surgery in a 1-year-old boy diagnosed with cicatricial ocular pemphigoid whose visual and psychomotor development were notably limited. METHODS: We present the case of a 1-year-old boy diagnosed with mucous membrane pemphigoid by biopsy who was treated with rituximab (375 mg/m 2 intravenous infusion at 2-week interval administered twice) and stable with oral dapsone (2 mg·kg -1 ·d -1 ). His eyelid cicatricial entropion and trichiasis in both eyes prevented him from opening his eyes, impeding visual development. After 1 year of clinical stability, we performed a tarsal fracture procedure in both eyes to restore eyelid anatomy and functionality, with the aim to prevent an inflammatory reaction, administrating intravenous dexamethasone before and after surgery. RESULTS: The intervention was successfully performed without postoperative complications. Excellent anatomic and functional results allowed him to develop normally in his daily life the first week after surgery. He is currently taking oral dapsone (2 mg·kg -1 ·d -1 ) as a maintenance treatment to stop the progression of the disease. CONCLUSIONS: Tarsal fracture surgery may be considered part of the treatment in pediatric patients with stable ocular cicatricial pemphigoid presenting with severe entropion and trichiasis.

Ocular Cicatricial Pemphigoid, Sjögren's Syndrome, and Hashimoto's Thyroiditis as a Multiple Autoimmune Syndrome: A case report.

PURPOSE: To present a rare and novel association of Ocular Cicatricial Pemphigoid, Sjögren's Syndrome, and Hashimoto's Thyroiditis as a Multiple Autoimmune Syndrome. CASE REPORT: A 43-year-old Colombian female, presented with corneal ulcers, associated with trichiasis. At the ophthalmological examination forniceal shortening OU and symblepharon OD was found. Conjunctival biopsy was performed, evidencing linear deposition of IgG and IgA antibodies along the basement membrane of the conjunctiva, confirming Ocular Cicatricial Pemphigoid diagnosis. After 12 years, the patient presented constitutional symptoms, xerostomia, and worsening of xerophthalmia. Laboratory tests showed positive Anti-TG, Anti-TPO, Anti-Ro, and Anti-La antibodies, and salivary gland biopsy was consistent with Sjögren's Syndrome. Due to these findings, Hashimoto's Thyroiditis and Sjögren's Syndrome were diagnosed, defining a Multiple Autoimmune Syndrome. CONCLUSION: A novel association of Multiple Autoimmune Syndrome is presented in this case. Ophthalmologists and other specialists involved in the evaluation and treatment of patients with autoimmune diseases, should be aware of this clinical presentation. A multidisciplinary approach in this condition is important for optimum treatment instauration and follow-up, in order to prevent complications.

Symmetrical Skin Lesions on the Gluteal Region in a Patient with Anti-Laminin-332 Mucous Membrane Pemphigoid.

Mucous membrane pemphigoid (MMP), previously called cicatricial pemphigoid, is a rare subepidermal immunobullous disorder that primarily affects the mucous membranes (1,2). MMP is divided into two major subtypes, anti-BP180-type MMP and anti-laminin-332 (previously called laminin 5 or epiligrin) MMP. Anti-laminin-332 MMP is known to be associated with malignant tumors (3), which may cause overexpression of autoantibodies and induce autoimmunity to laminin-332 (4). MMP primarily affects the mucous membranes, and widespread skin lesions are rare. In MMP, circumscribed skin lesions have been previously reported as occurring on the head, neck, and upper trunk (5). We report a case of anti-laminin-332 MMP presenting with symmetrical skin lesions characteristic of MMP on the weight-bearing areas of the gluteal region. A 66-year-old Japanese man presented with a month-long history of multiple erosions and blisters on the mucous membranes and skin, with conjunctival hyperemia, nasal obstruction, oral pain, and hoarseness of voice. Three days before the first visit, he was diagnosed with gastric cancer with liver metastasis by gastrointestinal endoscopy and abdominal ultrasound examination for tarry stool. Physical examination demonstrated erosions and tense bullae on the conjunctivae, tongue, and lips (Figure 1, a,b), as well as erosive erythematous skin lesions on the nape, right index finger, both legs, and symmetric lesions on the gluteal region (Figure 1, c). His body weight was 86 kg. Laboratory examinations showed slight liver dysfunction and elevation of C-reactive protein levels. Histopathologic examination of the skin lesions demonstrated subepidermal blisters with lymphocytic and eosinophilic infiltrates (Figure 1, d,e). Direct immunofluorescence (IF) revealed linear deposits of IgG and C3, but not IgA, along the basement membrane zone (BMZ) (Figure 1, f,g). An IgG subclass study showed IgG1 and IgG4 deposits. Indirect IF on normal human skin revealed weak positivity for IgA anti-keratinocyte cell surface antibodies and IgG anti-BMZ antibodies, which were bound to the dermal side of 1 mol/L NaCl-split skin (Figure 1, h). IgG immunoblot analyses of both normal human epidermal and dermal extracts showed negative results (including BP230, BP180, 290 kDa type VII collagen, and 200 kDa laminin-γ1). Immunoprecipitation using radio-labeled cultured keratinocyte lysate demonstrated positive reactivity with laminin-332 (Figure 1, i). We established the diagnosis of anti-laminin-332 MMP. We started treatment with oral minocycline (200 mg/day) and niacinamide (900 mg/day) with topical corticosteroids without any effect after 2 weeks of therapy. Administration of oral prednisolone (40 mg/day) with topical corticosteroids and alprostadil ointment on the skin lesions, as well as beclometasone dipropionate powder on the oral lesions resulted in significant improvement of mucocutaneous lesions within 10 days. Although the gastric cancer and liver metastasis initially responded to chemotherapy with fluorouracil and cisplatin, the patient succumbed to multiple organ failure 9 months after the initial visit. Anti-laminin-332 antibodies were originally detected by immunoprecipitation, as in our case. Immunoblotting of purified human laminin-332 have been subsequently developed, which detects the 165/145 kDa α3, 140 kDa ß3, and 105 kDa γ2 subunits of laminin-332 in various patterns (6). Today, the ELISA system uses laminin-332 preparations as adjunct diagnostic tools in MMP (7). Occasionally, a wide spectrum of autoantibodies is detected in MMP, for example, MMP with IgG antibodies to both BP180 and laminin-332, which were considered to be developed via epitope spreading. Detection of circulating IgA autoantibodies against the skin have also been reported in MMP (8). However, the pathogenic significance and mechanisms of coexistence of IgG anti-laminin-332 antibodies and IgA anti-keratinocyte cell surface antibodies found in our case are currently unknown. It is generally considered that IgG1 antibodies activate complements and are pathogenic in MMP, while IgG4 antibodies behave as blocking antibodies and are protective. In our case, direct IF revealed IgG1 and IgG4 deposits; the same was reported in a previous case report (9). The pathogenic roles of autoantibodies with different IgG subclasses need to be analyzed in further studies. Conjunctival mucosal lesions in MMP may occur by rubbing of the eyes due to irritation. Blinking subjects the conjunctivae to repeated friction. Vocal cords vibrate during breathing and speaking. The tongue moves while eating and drinking; in particular, the tip of the tongue gets into frequent contact with the inner sides of the incisor teeth. In the present case, characteristic symmetrical skin lesions were seen on the weight-bearing areas of the gluteal region on bony prominences which receive mechanical stresses in the sitting position. These skin lesions were subjected to repeated stretch and pressure stresses, but no ischemic changes were observed, such as decubitus ulcers. Therefore, the symmetrical skin lesions in the gluteal region as well as the ocular and oral mucosal lesions seen in our patient might have resulted from the same mechanism of pathogenesis. We reported a case of anti-laminin-332 MMP presenting with symmetrical gluteal skin lesions, probably induced by mechanical stress. MMP primarily affects the mucous membranes, and widespread skin lesions are rare. Our case emphasizes that clinicians need to specifically check for the presence of skin lesions on weight-bearing parts of the body during examination of patients with suspected MMP.

European Guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part II.

This guideline has been initiated by the task force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology, including physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline that systematically reviewed the literature on mucous membrane pemphigoid (MMP) in the MEDLINE and EMBASE databases until June 2019, with no limitations on language. While the first part of this guideline addressed methodology, as well as epidemiology, terminology, aetiology, clinical presentation and outcome measures in MMP, the second part presents the diagnostics and management of MMP. MMP should be suspected in cases with predominant mucosal lesions. Direct immunofluorescence microscopy to detect tissue-bound IgG, IgA and/or complement C3, combined with serological testing for circulating autoantibodies are recommended. In most patients, serum autoantibodies are present only in low levels and in variable proportions, depending on the clinical sites involved. Circulating autoantibodies are determined by indirect IF assays using tissue substrates, or ELISA using different recombinant forms of the target antigens or immunoblotting using different substrates. The major target antigen in MMP is type XVII collagen (BP180), although in 10-25% of patients laminin 332 is recognized. In 25-30% of MMP patients with anti-laminin 332 reactivity, malignancies have been associated. As first-line treatment of mild/moderate MMP, dapsone, methotrexate or tetracyclines and/or topical corticosteroids are recommended. For severe MMP, dapsone and oral or intravenous cyclophosphamide and/or oral corticosteroids are recommended as first-line regimens. Additional recommendations are given, tailored to treatment of single-site MMP such as oral, ocular, laryngeal, oesophageal and genital MMP, as well as the diagnosis of ocular MMP. Treatment recommendations are limited by the complete lack of high-quality randomized controlled trials.