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To describe the diagnosis and management of mucous membrane pemphigoid (MMP) with oral and ocular presentation.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.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.A multidisciplinary approach is often necessary in order to treat MMP lesions efficaciously.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.

The variable clinical severity of mucous membrane pemphigoid (MMP) often leads to diagnostic and therapeutic delays.To describe the characteristics of a large cohort of patients with MMP.A retrospective review of clinical and diagnostic characteristics as well as treatment responses in 145 patients with MMP.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.Retrospective design.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.

Összefoglaló. A nyálkahártya-pemphigoid különleges formája a paraneoplasiás pemphigoid, amely primer malignus betegséghez társul; lefolyása szokatlanul gyors, és a klasszikus immunszuppresszív terápiákkal szemben rezisztens lehet. Közleményünkben három eseten keresztül mutatjuk be a paraneoplasiás pemphigoid megjelenését, diagnosztikáját és a terápiás kihívásokat. A diagnózist a kórelőzményi adatok és az immunfluoreszcens vizsgálatok segítik. A terápiás célkitűzés a progresszió lassítása immunszuppresszív kezeléssel, amely a zajló onkológiai kezelés mellett kontraindikált lehet. Tekintettel arra, hogy jelenleg nincs konszenzus ennek a ritka kórképnek a diagnosztikájában és kezelésében, különösen fontos, hogy a társszakmák (szemészet, bőrgyógyászat, fogászat, fül-orr-gégészet, onkológia, immunológia) együttműködésével a betegség minél hamarabb felismerhető legyen, és a kezelést ezáltal minél korábban el lehessen kezdeni. Orv Hetil. 2022; 163(18): 720–725. Summary. 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. Orv Hetil. 2022; 163(18): 720–725.

Mucous membrane pemphigoid (MMP) is an autoimmune condition characterized by subepithelial separation and deposition of autoantibodies and complement along the basement membrane zone. The disease results in the development of vesiculobullous lesions of the mucous membranes and skin. This report discusses the surgical treatment and management and the prosthetic implant rehabilitation of a patient with mucous membrane pemphigoid. The rationale for this treatment was to fabricate a prosthesis that was stable and did not rub against the gingival tissues and that was easily cleaned. The overdenture attachment system used provides more stability than other attachment systems while allowing the prosthesis and abutments to be easily cleaned.

Summary Mucous membrane pemphigoid (MMP) is a pemphigoid disease with predominant mucous membrane involvement. It mainly affects the mucous membranes of the mouth, eyes, nose and pharynx, but also the larynx, trachea, esophagus, genital and perianal regions. The manifestation of the disease covers a wide spectrum from gingival erythema and single oral lesions to severe tracheal strictures that obstruct breathing and conjunctival scarring with marked visual impairment and, not infrequently, blindness. In addition to a clinical picture of predominant mucosal involvement, diagnosis is based on direct immunofluorescence of a peri‐lesional biopsy and serology. The main target antigen is BP180 (collagen XVII), and reactivity with laminin 332 is associated with malignancy in approximately 25 % of MMP patients. The treatment of MMP is challenging. On the one hand, due to the involvement of different mucous membranes, good interdisciplinary cooperation is required; on the other hand, due to the rarity of the disease, no randomized controlled clinical trials are available. The aim of this guideline is to present the clinical picture, including severity and scoring systems, and to give guidance for diagnosing and treating this complex disease. In MMP, interdisciplinary cooperation plays an essential role as well as the prompt diagnosis and initiation of adequate therapy in order to avoid irreversible damage to the mucous membranes with serious complications.

Purpose: Many diseases of the cornea and ocular surface are manifestations of an underlying autoimmune process and require systemic immunosuppression for their management. These cases often present to a general ophthalmologist before being referred to an ocular immunologist or rheumatologist. However, the patients do need to be followed by the ophthalmologist to assess disease progression or for management of ocular co-morbidities and for taking care of ocular complications of the disease. Undeniably, there is a certain hesitance to promptly initiate them on systemic therapy because the literature regarding the indications, dosages, and side effects of this group of drugs is vast and dispersed.The aim of this review is to provide a source of ready reference for the general ophthalmologist as well as trainees and residents, on systemic immunosuppression for corneal and ocular surface disease. Methods: This review included 153 studies which were published as randomized controlled trials, systematic reviews, or as nonrandomized comparative studies (cohort or case-control series) on the topic of systemic immunosuppression in cornea and ocular surface disorders.Results: This review provides a concise summary of both the types of drugs and the common indications where they would be indicated, along with treatment and monitoring algorithms for each specific disease condition. The most used group of drugs are corticosteroids, which have significant side effects, particularly when administered systemically or for longer periods of time. To overcome this, steroid-sparing immunosuppressants are recommended. The four main classes of immunosuppressants used today are antimetabolites, T-cell inhibitors, alkylating agents and biologic agents. This review details the use of these drugs in ocular surface inflammation, including the dosing schedule, side effects and monitoring in allergic conjunctivitis, mucous membrane pemphigoid, peripheral ulcerative keratitis, immunological rejection against corneal allografts, anterior scleritis and aqueous deficiency dry eyes. Conclusions: This review provides an uncluttered and wholesome understanding of systemic immunosuppression in cornea and ocular surface diseases, with the hope that this will serve as a ready reckoner and help bridge the gap between ophthalmology and rheumatology for the betterment of our patients.

Dipeptidyl peptidase 4 inhibitors (DPP-4i) are associated with an increased risk of developing bullous pemphigoid (BP) in patients with diabetes. Autoantibodies targeting epitopes on the processed BP180, 120-kDa (LAD-1), and 97-kDa (LABD97) linear immunoglobulin (Ig)A dermatosis antigens are the major autoantibodies in DPP-4i-associated BP. However, no case of mucous membrane pemphigoid (MMP) developing during treatment with DPP-4i has been reported. We report a case of MMP associated with DPP-4i. A man in his late 70s presented with oral mucous membrane erosion and a few blisters on his upper chest and back. He had used linagliptin for diabetes for over 1 year when he presented. The immunological characteristics were similar to DPP4i-associated BP: higher reactivity to LAD-1 and LABD97 than to the full-length BP180. The aphthae achieved remission after oral linagliptin was replaced with sitagliptin. However, 6 months later, the aphthae relapsed and any DPP-4i was discontinued. The aphthae disappeared, and now he is completely free from lesions associated with MMP. This case suggests that the DPP-4i may have shared roles in the production of IgG antibodies to LAD-1 or to LABD97 in the pathogenesis of DPP-4i-associated BP and MMP. Our case highlights the possibility of overlooking the mild MMP in DPP-4i-treated diabetes patients with mucosal lesions.

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.

*Correspondence - Saaeha Rauz: s.rauz@bham.ac.uk OBJECTIVES: Mucous Membrane Pemphigoid is an orphan multi-system autoimmune scarring disease involving mucosal sites, including the ocular surface (OcMMP) and gut. The gut microbiome plays a critical role in the development of the immune system. This study examines the relationship between gut microbiome diversity and ocular inflammation in patients with OcMMP.Gut microbiome profiles between OcMMP patients (n=49) and healthy controls (n=40) were compared by extracting DNA from faecal samples and amplified for the V4 region of the 16S rRNA gene followed by Illumina Miseq platform sequencing. Sequencing reads were processed using the bioinformatics pipeline available in the mothur v.1.44.1 software.Using multivariable model and adjustment for participant factors, OcMMP cohort was found to be associated with lower number of operational taxonomic units (OTUs) and Shannon Diversity Index when compared to healthy controls. OcMMP OTUs were found to be significantly correlated with both the bulbar conjunctival inflammation score (p=0.03) and the current use of systemic immunotherapy (p=0.02). Linear discriminant analysis effect size scores found Streptococcus and Lachnoclostridium enriched in OcMMP. By contrast, healthy controls were enriched with Oxalobacter, Clostridia uncultured genus-level group (UCG) 014, Christensenellaceae R-7 group and butyrate-producing bacteria such as Ruminococcus, Lachnospiraceae, Coprococcus, Roseburia, Oscillospiraceae UCG 003, 005, NK4A214 group (Log10 LDA score2, FDR-adjusted p0.05).In conclusion, OcMMP patients have gut dysbiosis that correlated with bulbar conjunctival inflammation and the use of systemic immunotherapies. This provides a framework for future longitudinal deep phenotyping studies on the role of the gut microbiome in the pathogenesis of OcMMP.Low L, Suleiman K, Shamdas M, Bassilious K, Poonit N, Rossiter AE, Acharjee A, Loman N, Murray PI, Wallace GR, Rauz S. Gut dysbiosis in ocular mucous membrane pemphigoid.

Dear Editor, Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by erosive mucosal lesions mainly on the oral and ocular mucosae (1). We report a case of oral and ocular anti-BP180-type MMP with variable IgG and IgA reactivities and underlying dementia. An 84-year-old Japanese man presented with a 4-year history of erosions in the oral cavity and on the conjunctivae, with progressive vision impairment. The medical history included benign prostatic hyperplasia, cataract, sinusitis, and dementia. Physical examination revealed erosions and white atrophic scars along the gingival mucosa and on the hard palate (Figure 1, a, b). Conjunctival inflammation and corneal scarring were also observed only on the left eye (Figure 1, c, d). No lesions were observed on the skin or on any other mucosae. A skin biopsy from the patient's oral mucosa showed lymphocytic infiltration in the superficial dermis without apparent subepithelial blister. Direct immunofluorescence showed linear depositions of IgG, IgA, and C3 at the epithelial basement membrane zone (Figure 1, e-g). Circulating IgG and IgA autoantibodies were not detected by indirect immunofluorescence of normal human skin, while circulating IgA, but not IgG, autoantibodies were bound to the epidermal side of 1M NaCl-split normal human skin at 1:10 serum dilution (Figure 1, h, i). Commercially available IgG enzyme-linked immunosorbent assays (ELISAs) of BP180 NC16a domain, BP230, and type VII collagen (MBL, Nagoya, Japan) showed negative results. IgG and IgA immunoblotting analyses of six different antigen sources, including BP180 C-terminal domain recombinant protein, were all negative. However, ELISA of full-length BP180 was slightly positive for IgG antibodies (index = 5.79; cut-off4.64). Immunoblotting analysis of full-length BP180 was negative for both IgG and IgA antibodies (Figure 1, j, k). Immunoblotting analysis of hemidesmosome-rich fraction was negative for both IgG and IgA antibodies to integrin β4 (Figure 1, l). Based mainly on the clinical and immunological findings, we established a diagnosis of MMP with IgG and IgA autoantibodies, likely reactive with BP180. Because the patient refused systemic treatments, we prescribed a mouth rinse sodium gualenate hydrate and eyedrops of fluorometholone and purified sodium hyaluronate, which did not improve the oral and ocular mucosal symptoms during the 8 month follow-up period (Figure 1, m, n). Both IgG and IgA autoantibodies in anti-BP180-type MMP tend to react with the C-terminal domain of BP180 (2), and IgG autoantibodies in 39.7% of MMP patients reactive with the epidermal side of split skin were reported to be positive with BP180 C-terminal domain (3). The full-length BP180 ELISA shows excellent sensitivity for diagnosing BP180-type MMP (4). The different IgG and IgA reactivities among various methods used in the present study may be attributed either to different methodologies (i.e., immunoblotting or ELISA) or to the different substrates, since BP180-type MMP targets various regions of BP180, including the NC16a domain, the C-terminal domain, and the intracytoplasmic region (5). Precise diagnosis for MMP by various immunological methods is critical, because urgent and extensive treatments are necessary for the ocular and laryngeal lesions, which may result in loss of eyesight and airway obstruction, respectively. Acknowledgments: We express our gratitude to Ms. Mako Mine and Dr. Daisuke Hayashi, Department of Dermatology, Osaka City University Graduate School of Medicine in Osaka, Japan for the HD-rich fraction immunoblotting analysis, and Dr. Yoshiaki Hirako, Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan for the preparation of the HD-rich fraction sample. This work was supported by JSPS KAKENHI Grant Number JP20k08684 and the Hirosaki University Research Support System.

Anti-laminin (LM) 332-type mucous membrane pemphigoid (MMP) is a rare autoimmune bullous disease and was originally discovered as anti-epiligrin cicatricial pemphigoid. Anti-LM332-type MMP has clinical manifestations similar to those of other types of MMP and can only be distinguished through the detection of circulating autoantibodies against LM332. Our group and others have established a number of immunological methods with varying sensitivity and specificity for detection of anti-LM332 autoantibodies; however, none of the established methods has been widely used for clinical diagnosis. There is currently no unified standard treatment, and it is very difficult to completely cure anti-LM332-type MMP. In addition, an increasing body of evidence suggests that there may be a strong correlation between anti-LM332-type MMP and tumors. In this article, we review the current progression of diagnosis and treatment of anti-LM332-type MMP, as well as the possible correlation between anti-LM332-type MMP and tumors.

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.

Background/aimsTo investigate the long-term outcomes of cultivated oral mucosal epithelial transplantation (COMET) for fornix reconstruction in eyes with chronic cicatrising disease.MethodsThis retrospective cohort study involved 16 eyes of 15 patients who underwent COMET for symblepharon release and fornix reconstruction between June 2002 and December 2008. The mean postoperative follow-up period was 102.1±46.0 months (range: 32–183 months). The treated cicatrising disorders included ocular cicatricial pemphigoid (OCP, five eyes), thermal/chemical injury (three eyes) and other chronic diseases (seven eyes; including recurrent pterygium (two eyes), Stevens-Johnson syndrome (one eye) and graft-versus-host disease (one eye)). Ocular-surface appearance was evaluated before surgery, at 1, 4, 12 and 24 weeks postoperative, and then annually based on the previously reported scoring system. Main outcome measures included overall and disease-specific fornix-reconstruction success probabilities analysed by the Kaplan-Meier survival curve. Symblepharon/fornix-shortening recurrence at 24 weeks postoperative, and its relationship to long-term surgical success was also examined.ResultsAt 5 years postoperative, the mean±SD overall fornix-reconstruction success probability was 79.6%±10.7%, and success probability for thermal/chemical injury and OCP was 100% and 53.3%±24.8%, respectively (p=0.53, log-rank test). The 3-year success probability was significantly higher in the no-disease-recurrence group at 24 weeks postoperative (13 eyes) than in the disease-recurrence group (three eyes) (100% and 33.3%±27.2%, respectively) (p=0.0073, log-rank test).ConclusionCOMET was found to be safe and effective for symblepharon release and long-term fornix reconstruction in eyes with chronic cicatrisation. Although the 5-year success probability differed depend on the underlying disease, ocular-surface appearance at 24 weeks postoperative is a factor for predicting long-term outcome.

Aim: To report a case of ocular cicatricial pemphigoid caused by levamisole-adulterated cocaine. Methods: Case report. Results: A 54-year-old woman with multi-systemic levamisole-induced vasculitis which triggered bilateral cicatrizing conjunctivitis refractory to conventional immunosuppressants due to continued cocaine misuse. Conclusion: Levamisole-induced vasculitis is a significant public health issue due to its popularity as an adulterant to cocaine. Our report suggests that levamisole caused vasculitis and ocular cicatricial pemphigoid in this case. Ocular manifestation of this syndrome is rare.

Pemphigoid is a heterogeneous group of rare and chronic autoimmune subepidermal bullous diseases, characterized by circulating autoantibodies against structural proteins in the hemidesmosomes. Long-term therapy with systemic oral prednisone and immunosuppressants are often required and associated with severe adverse reactions.

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/m2 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.

To quantitate the risk of relapse of ocular and extraocular disease among patients with mucous membrane pemphigoid (MMP) who had undergone drug-free remission.Retrospective, comparative, interventional case series.There were 167 patients with biopsy-proven MMP who were seen at the Wilmer Eye Institute between November 1984 and December 2019. Among the 167 patients, 119 patients had ocular involvement and 103 of those patients received systemic treatment for MMP. The main outcome measures were the incidence of ocular remission, incidence rate of disease relapse after remission, and risk factors for disease relapse.Over a median follow-up time of 7 years, 74 of 103 treated patients (71.8%) experienced drug-free remission (incidence rate = 0.28/person-year [PY], 95% confidence interval [CI] 0.22-0.35/PY). Most patients (80/103, 77.7%) received cyclophosphamide therapy. Thirteen of the 74 patients (17.6%) had disease relapse after remission: 4 with ocular disease only, 4 with extraocular disease only, and 5 with both. The rate relapse of ocular MMP was 0.020/PY (95% CI 0.009-0.038/PY), and the rate of relapse of MMP at any site (ocular or extraocular site) was 0.029/PY (95% CI 0.015-0.050/PY). The use of cyclophosphamide was associated with a greater chance of remission (hazard ratio [HR] = 3.84, P.0001) and a lower risk of relapse (HR = 0.32, P = .05) compared with other immunosuppressive drugs except for rituximab. Five patients experienced drug-free remission after rituximab therapy and none of them had relapse (median follow-up after remission = 3.6 years). When use of cyclophosphamide or rituximab was compared with all other treatments, the risk of MMP relapse at any site (HR = 0.17, P = .02) and of ocular MMP (HR = 0.11, P = .007) were significantly lower.Rates of relapse of MMP after drug-free remission are low but not zero; therefore, monitoring of patients remains necessary. Relapses were not observed among those patients treated with rituximab who had remission; however, follow-up duration in those patients was shorter than the whole MMP cohort and the sample size was small.

PURPOSE Ocular cicatricial pemphigoid (OCP) can lead to devastating ocular complications without prompt treatment. A number of immunomodulatory agents have been attempted with varying success. The objective of this study was to evaluate the use of rituximab as an adjuvant to immunomodulatory treatments (IMTs) in refractory OCP. METHODS The clinical records of 14 patients with treatment refractory OCP treated with rituximab as monotherapy or in combination with IMTs were retrospectively reviewed, with a focus on demographics, treatments prerituximab and postrituximab, total number of rituximab infusions, response to treatment, and ocular outcomes including staging and best-corrected visual acuity. RESULTS Thirteen patients (92.9%) achieved a complete response with rituximab over a mean period of 4.3 months. The average sustained complete response time in those without relapse was 29.7 months. Five patients relapsed over a mean period of 15 months, 2 of whom were able to regain control over a mean of 2.5 months with additional rituximab treatments. At the final evaluation, rituximab-based therapy improved ocular outcomes in OCP by stabilizing Foster staging and preventing the deterioration of best-corrected visual acuity in 72% of eyes. In total, 90% of eyes with Foster stages 3 or less did not progress. All patients were able to decrease IMT dosage and/or transition to less potent adjuvant treatments. CONCLUSIONS The consideration of rituximab earlier in treatment of OCP as a rescue and/or maintenance therapy could result in an earlier arrest of disease progression, resulting in preservation of patients' vision, and enable tapering of adjuvant IMT.

*Correspondence, Jesse Panthagani: j.panthagani@bham.ac.uk OBJECTIVE: Ocular Mucous Membrane Pemphigoid (OcMMP) is a rare disease characterised by chronic autoimmune-driven conjunctival inflammation leading to progressive scarring, and blinding sequelae. The purpose of this study was to characterise the conjunctival gene 'fingerprint' involved in the fibrosis signalling pathways in the pathogenesis of OcMMP.Ocular surface gene expression studies were undertaken on conjunctival swabs from OcMMP and age-matched control patients. The NanoString nCounter Human Fibrosis panel (NanoString Technologies Inc.) quantified RNA expression from 770 genes. Differentially expressed genes (DEG) and pathway analysis were determined using HyperScale architecture designed by ROSALIND, Inc. with normalisation, fold changes (≥+1.5-fold or ≤-1.5-fold) and p-values adjustment (0.05) using the Benjamini-Hochberg method. Significantly identified genes were aligned to the aldehyde dehydrogenase (ALDH)/retinoic acid fibroblast autoregulation conjunctival scarring signalling pathway, known to be central to immune-mediated mucosal scarring in OcMMP.6 OcMMP patients (8 eyes, mean age 76.5 (±7.0 SD) years, 6 (66%) male, 3 (50%) biopsy-positive) and 8 age-matched cataract patients (15 eyes; age 73.1 (±9.3) years, 3 (37%) male), serving as controls were analysed. Ninety-three DEGs were observed between OcMMP and controls (48 upregulated and 45 downregulated). Of these, the top 10 upregulated DEGs were COL3A1, COL1A1, FN1, TPSAB1/B2, THBS1, SERPINE1, SPP1, COL5A1, OASL and IL1B. 44 pathways that had a global significance score greater or equal to 2, the most significant representing extracellular matrix (ECM) remodelling, synthesis, and degradation.The conjunctival genetic 'fingerprint' predominantly suggests an activated fibroblastic phenotype in the OcMMP patients and could represent (i) novel targets for drug discovery and (ii) surrogate outcomes/novel biomarkers for the monitoring of disease progression.

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.

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.

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.

To determine the rate of positivity of immunofluorescence studies in buccal biopsies in patients with cicatrizing conjunctivitis undergoing workup for ocular mucous membrane pemphigoid (MMP)/ocular cicatricial pemphigoid (OCP).Retrospective cohort review.Forty-one patients with cicatrizing conjunctivitis undergoing workup for OCP.A retrospective chart review of direct immunofluorescence (DIF) studies in buccal mucosal biopsies was performed.The primary outcome measure was the rate of positivity of direct and indirect immunofluorescence studies on buccal mucosal biopsies.Twenty-two patients (54%) had a positive buccal mucosal biopsy; 64% of patients (14/22) demonstrated +DIF on initial biopsy and an additional 36% of patients (8/22) on the second biopsy. Eighteen patients underwent conjunctival biopsy. In the 6 patients with a negative conjunctival biopsy, 4 (67%) had a positive buccal biopsy.Buccal mucosal immunofluorescence studies may be positive in patients with OCP even in the absence of extraocular disease. Buccal mucosal biopsy may be considered as an alternative to or attempted before conjunctival biopsy for the diagnosis of OCP, particularly in patients in whom conjunctival biopsy may be difficult or imminently visually threatening.