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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.

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.

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.

Dipeptidyl peptidase-4 (DPP4) is a multifunctional, transmembrane glycoprotein present on the cell surface of various tissues. It is present in multiple molecular forms including cell surface and soluble. The role of DPP4 and its inhibition in cutaneous dermatoses have been a recent point of investigation. DPP4 exerts a notable influence on T-cell biology, the induction of skin-specific lymphocytes, and the homeostasis between regulatory and effector T cells. Moreover, DPP4 interacts with a broad range of molecules, including adenosine deaminase, caveolin-1, CXCR4 receptor, M6P/insulin-like growth factor II-receptor and fibroblast activation protein-α, triggering downstream effects that modulate the immune response, cell adhesion and chemokine activity. DPP4 expression on melanocytes, keratinocytes and fibroblasts further alters cell function and, thus, has crucial implications in cutaneous pathology. As a result, DPP4 plays a significant role in bullous pemphigoid, T helper type 1-like reactions, cutaneous lymphoma, melanoma, wound healing and fibrotic disorders. This review illustrates the multifactorial role of DPP4 expression, regulation, and inhibition in cutaneous diseases.

Stevens-Johnson syndrome, ocular cicatricial pemphigoid, and severe thermal or chemical injury are considered severe ocular surface disorders (OSDs) because they affect the entire ocular surface, including corneal and conjunctival epithelial stem cells. In patients with severe OSDs, the long-term prognosis for limbal transplantation is poor, and the related corneal opacity and cicatrization lead to devastating visual impairment. To date, there is no standardized treatment to improve vision in cases with severe OSD. Investigating novel treatment methods for severe OSDs, our group began cultivated oral mucosal epithelial transplantation in 2002 and developed a limbal-supported rigid-type contact lens that can be applied as a nonsurgical treatment. When used in combination, these treatment methods make it possible to successfully restore vision in cases with severe OSDs.

Background Mucous membrane pemphigoid (MMP) is an uncommon bullous disease typically involving the oral cavity. The most commonly used laboratory test for the diagnosis of MMP is direct immunofluorescence (DIF) on fresh perilesional tissue; however, the sensitivity of this test may be hampered by technical difficulties. Immune-serological investigations can also be employed to render a diagnosis. The purpose of this paper was to present an evaluation of diagnostic testing for MMP within an Oral Medicine Unit in UK. Methods A retrospective analysis of the medical records was undertaken for patients who had undergone biopsy and DIF testing from January 2016 to December 2018. Parameters analysed included clinical presentation, histopathological features, DIF, salt-split skin indirect immunofluorescence, ELISA anti-BP180 and BP 230 and HLA-DQB1*03:01 findings. Results Thirty patients (23 females and 7 males, mean age 66.8 years old) were diagnosed with MMP through a combination of histopathology and serological testing. Sixteen patients (53%) were DIF positive, whereas in 14 (47%), MMP diagnosis was achieved using immune-serologic tests. HLA DQB1*03:01 status was undertaken in 15 DIF-positive and 12 DIF-negative patients, and HLA DQB1*03:01 was found in 73% and 58% of the cases, respectively. Conclusions This service evaluation has shown that when DIF is informative, it remains the gold standard technique for diagnosis of MMP. However, we have also highlighted the value of serological testing for increasing diagnostic yield for patients with suspected MMP and the potential for HLA DQB1*03:01 as an adjunctive test for the evaluation of MMP.

Rituximab is a monoclonal antibody targeting CD20 on B cells with proven efficacy for pemphigus vulgaris, now an FDA-approved indication. Other autoimmune bullous diseases can be challenging to treat and have significant associated morbidity and mortality, but data supporting the use of rituximab in pemphigoid group diseases remain limited. Although rituximab demonstrates efficacy for clinical improvement and remission in pemphigoid, concern for adverse events may also limit the use of this medication. We review the current evidence fo rthe use of rituximab in pemphigoid diseases, pertinent dosing schedules and laboratory monitoring, and the associated common and rare adverse events. Review of the literature to date not only supports consideration of rituximab for treatment of refractory pemphigoid group diseases but also reflects tolerability and an acceptable safety profile.

Purpose: To demonstrate the reliability of conjunctival biopsy analyzed by direct immunofluorescence (DIF) and supplemented with avidin-biotin complex immunoperoxidase (ABC) in diagnosing oMMP, and...

Summary Background Antilaminin‐332 mucous membrane pemphigoid is a chronic severe pemphigoid disease characterized by autoantibodies to laminin‐332. At present no commercial assay is available to demonstrate antilaminin‐332 antibodies, and diagnosis relies on in‐house techniques with limited sensitivities. Objectives In order to move, keratinocytes cultured in vitro secrete laminin‐332 to attach to the culture dish. In that way, they leave behind a unique footprint trail of laminin‐332. We aimed to develop a sensitive and specific laboratory assay to determine antilaminin‐332 autoantibodies in patient serum based on binding of patient IgG to these unique footprints. Methods Normal human keratinocytes were grown on glass coverslips and incubated with patient or control serum for 1 h. The binding of IgG was then investigated by immunofluorescence. After validating the test for its ability to identify antilaminin‐332 autoantibodies it was converted into a daily available test based on binding of IgG to dried coverslips that can be stored frozen. The staining patterns of sera from patients with antilaminin‐332 pemphigoid were then compared with those of sera from patients with other autoimmune bullous diseases and normal human sera. Results IgG of all antilaminin‐332 pemphigoid sera (n = 16) bound to laminin‐332 footprints, while all normal human controls (n = 55) were negative. From the sera of patients with other diseases (n = 72) four sera tested positive. The footprint assay was also positive for sera that were negative by salt‐split skin analysis, demonstrating that it is a very sensitive technique. Conclusions The keratinocyte footprint assay is a fast and specific assay to confirm or rule out the presence of antilaminin‐332 autoantibodies. What's already known about this topic? Antilaminin‐332 mucous membrane pemphigoid is a severe form of pemphigoid, and patients may have an increased risk of malignancies.The diagnosis of antilaminin‐332 mucous membrane pemphigoid is complicated by the lack of specific commercial tests for antilaminin‐332 antibodies and can be confirmed only in specialized laboratories.Keratinocytes in culture need laminin‐332 for adhesion and migration and therefore deposit it on the bottom of the culture dish. What does this study add? The keratinocyte footprint assay detects antilaminin‐332 autoantibodies in patient serum using the native laminin‐332 produced by cultured keratinocytes. What is the translational message? The keratinocyte footprint assay is a fast and specific assay to confirm or rule out the presence of antilaminin‐332 autoantibodies., Linked Comment: https://doi.org/10.1111/bjd.18372. https://doi.org/10.1111/bjd.18761 available online

Purpose To characterize the clinical features of patients with direct immunofluorescence (DIF)-negative mucous membrane pemphigoid (MMP). Design Retrospective case series. Methods Thirty-six patients who underwent a conjunctival biopsy for suspected MMP were included. Demographic and clinical information was collected. Main outcome measures included visual acuity, Foster stages, presence of extraocular involvement, history of autoimmune disease, and durations of follow-up. Results Thirty-two patients had a negative DIF. Of those, 2 had a positive DIF on repeat biopsy. Eleven showed progression of conjunctival scarring during a median follow-up of 42 months (range, 8-100 months) and were diagnosed with biopsy-negative MMP. Another 11 patients with a median follow-up of 54 months (range, 15-138 months) were diagnosed with cicatrizing conjunctivitis of other causes. The median visual acuity of patients with biopsy-negative MMP at presentation was significantly lower compared to patients with cicatrizing conjunctivitis of other causes (20/400 vs 20/40, P = .02). Conjunctival scarring score at presentation in both biopsy-positive and biopsy-negative MMP groups was significantly higher compared to patients with cicatrizing conjunctivitis of other causes (median Foster stage, 3 vs 1, P = .009; and 3 vs 1, P = .01, respectively). Conclusions Patients with progressive cicatrizing conjunctivitis likely have MMP in the absence of alternate diagnoses. Our findings emphasize that suspicion for MMP must remain high for patients who have Foster stage 3 conjunctival scarring on presentation or worsening of scarring during follow-up, even in the setting of negative DIF.

Cicatrizing conjunctivitis constitutes a group of chronic local and systemic disorders that cause conjunctival scarring. A systematic approach is required to sift through the clinical history, examination, and laboratory investigations of patients to arrive at the correct diagnosis of the underlying cause. Establishing the etiology is critical, as the therapeutic approach changes based on the cause of conjunctival inflammation. Effective management of patients with the condition requires knowledge of multiple modalities such as systemic immunosuppressive therapy, use of scleral contact lenses, and surgery for ocular surface and vision improvement. We review the clinical features of this condition and present diagnostic and treatment algorithms to help simplify the complexities in its management. This review attempts to place all the relevant information on chronic cicatrizing conjunctivitis together in one place for the benefit of cornea and ocular surface specialists, general ophthalmologists, and ophthalmology residents.

Mucous membrane pemphigoid (MMP) is a heterogeneous group of subepidermal autoimmune bullous skin disease (AIBD), which affects mainly various mucous membranes and occasionally skin.1-3 Although oral mucosa is most commonly affected, ocular, nasal, pharyngeal, laryngeal, esophageal and genital mucosae are also involved.2.

Laminin-332 pemphigoid is a rare and severe autoimmune blistering disease, caused by IgG autoantibodies targeting laminin-332 in the dermal-epidermal basement zone. Laminin-332 pemphigoid is characterized by variable inflammatory infiltrate and the predominance of non-complement-fixing antibodies. Given these findings, we hypothesized that IgG autoantibodies to laminin-332 directly resulted in keratinocyte expression of inflammatory factors. We performed RNA-seq on primary human keratinocytes treated with IgG from patients with laminin-332 pemphigoid. Genes for numerous cytokines and chemokines were upregulated, including CSF2, CSF3, CXCL1, CXCL5, CXCL3, CXCL8, CXCL10, CXCL1, IL6, IL7, IL15, IL23, IL32, IL37, TGFB2 as well as metalloproteases. Considering the pro-inflammatory and proteolytic effect of autoantibodies from patients with laminin-332 pemphigoid identified in our initial experiment, we next questioned whether the reactivity against specific laminin subunits dictates the inflammatory and proteolytic keratinocyte response. Then, we treated keratinocytes with IgG from a separate cohort of patients with reactivity against individual subunits of laminin-332. We identified upregulation of IL-1α, IL-6, IL-8, CXCL1, MMP9, TSLP, and GM-CSF at the protein level, most notably in keratinocytes treated with IgG from laminin β3-reactive patients. We for the first time demonstrated a pro-inflammatory response, similar to that described in keratinocytes treated with IgG autoantibodies from patients with bullous pemphigoid, providing novel insight into the pathogenesis of laminin-332 pemphigoid and laminin-332 biology.

Anti-laminin 332 mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by predominant mucosal lesions and autoantibodies against laminin 332. The exact diagnosis of anti-laminin 332 MMP is important since nearly 30% of patients develop solid cancers. This study compared two independently developed diagnostic indirect immunofluorescence (IF) tests based on recombinant laminin 332 expressed in HEK239 cells (biochip mosaic assay) and the migration trails of cultured keratinocytes rich in laminin 332 (footprint assay). The sera of 54 anti-laminin 332 MMP, 35 non-anti-laminin 332 MMP, and 30 pemphigus vulgaris patients as well as 20 healthy blood donors were analyzed blindly and independently. Fifty-two of 54 and 54/54 anti-laminin 332 MMP sera were positive in the biochip mosaic and the footprint assay, respectively. In the 35 non-anti-laminin 332 MMP sera, 3 were positive in both tests and 4 others showed weak reactivity in the footprint assay. In conclusion, both assays are easy to perform, highly sensitive, and specific, which will further facilitate the diagnosis of anti-laminin 332 MMP.

BackgroundRecently, we published an article retrospectively summarizing the results in 55 anti-laminin 332 (LM332)-type mucous membrane pemphigoid (MMP) cases examined at Kurume University, which were diagnosed by strict inclusion criteria, including positive reactivity in direct immunofluorescence and absence of antibodies to non-LM332 autoantigens. However, indirect immunofluorescence using 1M-NaCl-split normal human skin (ssIIF) is also valuable for diagnosis of anti-LM332-type MMP.MethodsIn this second study, we selected 133 anti-LM332-type MMP cases, which were diagnosed by our different inclusion criteria: (i) immunoglobulin G (IgG) deposition to basement membrane zone (BMZ) by direct immunofluorescence or IgG reactivity with dermal side of split skin by ssIIF, (ii) positivity for at least one of the three subunits of LM332 by immunoblotting of purified human LM332, and (iii) the presence of mucosal lesions. Clinical, histopathological, and immunological findings were summarized and analyzed statistically. Although these cases included the 55 previous cases, the more detailed study for larger scale of patients was conducted for further characterization.ResultsClinically, among the 133 patients, 89% and 43% patients had oral and ocular mucosal lesions, respectively, 71% had cutaneous lesions, and 17% had associated malignancies. Histopathologically, 93% patients showed subepidermal blisters. The sensitivities of ssIIF and direct immunofluorescence are similar but are significantly higher than indirect immunofluorescence using non-split human skin (both p < 0.001). In immunoblotting of purified LM332, patient IgG antibodies most frequently reacted with LMγ2 subunit (58%), followed by LMα3 (49%) and LMβ3 (36%). Thirty-four percent patients recognized additional non-LM332 autoantigens. Statistical analysis revealed that autoantibodies against non-LM332 autoantigens might stimulate the production of anti-LMγ2 antibodies.ConclusionsThis retrospective study further characterized in more detail the clinical and immunological features of 133 cases of anti-LM332-type MMP, in which the new diagnostic criteria without positive direct immunofluorescence reactivity were useful for the diagnosis. Higher frequency with anti-LMγ2 antibodies suggested more significant pathogenic role of this subunit. Additional autoantibodies to non-LM332 autoantigens detected in one-third of the patients may contribute to complexity in anti-LM332-type MMP, including the induction of anti-LMγ2 antibodies.

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.

Ocular cicatricial pemphigoid (OCP) represents an insidious, autoimmune-mediated disease of the conjunctiva, initially presenting as chronic conjunctivitis and progressing to fibrosis, cicatrization, and eventually blindness secondary to corneal keratinization. This series reports 3 cases presenting with chronic conjunctivitis lasting an average of 10 years without cicatrix formation, ultimately diagnosed as OCP based on direct immunofluorescence of conjunctival biopsy samples. This chronic conjunctivitis without fibrosis suggests the possibility of an OCP subtype with a prolonged early stage or prodrome prior to cicatrization, which may benefit from early diagnosis and treatment to prevent complications of this disease.

Purpose of review To describe current treatments of ocular mucous membrane pemphigoid (OMMP), including conventional systemic immunosuppression (CIST) and novel biologic agents. Recent findings CIST remains the main stay therapy for the management of OMMP. The choice of agents is tailored to disease severity - mild disease is treated with dapsone, whereas moderately severe cases are often treated with mycophenolate mofetil or sulfa-based drugs and severe cases are treated with cyclophosphamide. In recalcitrant disease newer biologics such as Rituximab, intravenous immunoglobins and tumour necrosis alpha antagonists have proven to be effective in disease control. Control of inflammation with topical therapy and halting conjunctival fibrosis remain as areas of unmet clinical needs. Summary OMMP is largely treated with CIST. The recent introduction of new biologic agents could shape the way the disease is treated in the near future.

IMPORTANCE: An accurate diagnosis of mucous membrane pemphigoid (MMP) is essential to reduce diagnostic and therapeutic delay.OBJECTIVE: To assess the diagnostic accuracy of direct immunofluorescence microscopy on mucosal biopsy specimens and immunoserology in a large cohort of patients with suspected MMP.DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was carried out in a single tertiary care center for blistering diseases between January 2002 and March 2019. Eligible participants were patients with suspected MMP and paired data on at least a mucosal biopsy specimen for direct immunofluorescence microscopy (DIF) and indirect immunofluorescence microscopy (IIF) on a human salt-split skin substrate (SSS). In addition, an optional DIF test on a skin biopsy specimen and one or more performed routine immunoserologic tests were analyzed. Data analysis was conducted from April 2019, to June 2020.MAIN OUTCOMES AND MEASURES: Diagnostic accuracy of DIF, IIF SSS, and immunoblot for BP180 and BP230.RESULTS: Of the 787 participants, 121 (15.4%) received the diagnosis of MMP (50 men [41.3%], 71 women [58.7%]; mean [SD] age at diagnosis, 60.1 [17.7] years). Sixty-seven of the patients with MMP (55.4%) had monosite involvement, of which oral site was the most frequently affected (51 [42.1%]). No significant difference was found between the sensitivity of DIF on a perilesional buccal biopsy and a normal buccal biopsy (89.3% vs 76.7%). Three patients with solitary ocular involvement showed a positive DIF of only the oral mucosa. In 6 patients with a negative mucosal DIF, a skin biopsy confirmed diagnosis of MMP. Overall, IIF SSS was less sensitive (44.6%), but highly specific (98.9%). The sensitivity of immunoblot (66.1%) was higher compared to SSS, but with lower specificity (91.3%).CONCLUSIONS AND RELEVANCE: This comparative diagnostic accuracy study of a cohort of 787 patients found a high sensitivity of a mucosal DIF biopsy for diagnosis of MMP, and lower sensitivity of serologic analysis. A biopsy can be taken from either perilesional or normal buccal mucosa. An additional DIF biopsy of another mucosal site or of affected or unaffected skin may increase the diagnostic yield and is recommended in patients with negative DIF results and high clinical suspicion.

PURPOSE To describe a novel surgical technique using the Boston Keratoprosthesis (KPro) type I in a patient with advanced ocular cicatricial pemphigoid (OCP) using oral mucosa for covering the prosthesis. METHODS We present the case of an 85-year-old man previously diagnosed with type 2 diabetes and advanced OCP nonresponsive to immunosuppressive treatment, whose best-corrected visual acuity was light perception and projection in both eyes. After examination, Boston KPro type I in the right eye was contemplated because osteo-odonto KPro and Tibial bone KPro were not feasible because of the patient's osteoporosis and edentulism. Reconstruction of the ocular surface was first performed using oral mucosa to release the symblepharon and try to deep the fornices. Three months later, the oral mucosa was lifted, and the Boston KPro type I was implanted using the patient's own cornea. Then, a modification of the standard surgical technique was carried out, replacing the use of contact lens for covering the prosthesis with an oral mucosa graft with a central trephination as an alternative option in fornix foreshortening cases. RESULTS After 11 months, visual acuity was stable to 0.2 decimal. No postoperative complications have been encountered, and prosthesis was in place. CONCLUSIONS The surgical technique of transmucosal Boston KPro type I may be considered a surgical alternative in patients with advanced OCP who present with severe fornix foreshortening, where osteo-odonto KPro or Tibial bone KPro cannot be performed due to osteoporosis or edentulism or when the Boston KPro type II is not readily available.

Ocular cicatricial pemphigoid (OCP) is a rare systemic autoimmune disease and a potentially blinding subepithelial blistering disorder. The purpose of this study was to describe the clinical spectrum of the disease and to assess the efficacy and safety of immunosuppressive agents in a cohort of patients with OCP.We conducted a monocentric retrospective cross-sectional cohort study of all unselected consecutive patients diagnosed with progressive OCP. Ocular and extra ophthalmological involvement as well as histological findings were gathered. Other outcomes were exposures to immunosuppressive agents defined by the use of a particular treatment. For each exposure, success in controlling ocular inflammation was graded as a complete response, response, or failure. Relapses and adverse events (AE) were also recorded.Seventeen patients (34 affected eyes), 35% of whom were women, were included, with an age at diagnosis of 75 ± 11 years. Corneal involvement was diagnosed in 30 of 34 eyes, and 22 of 34 eyes had progressive fibrosing conjunctival involvement. Sixty-two exposures to immunosuppressive agents or biologics were recorded: dapsone, n = 26; mycophenolate mofetil, n = 6; azathioprine, n = 4; cyclophosphamide, n = 10; rituximab, n = 14; and intravenous immunoglobulin, n = 2. Rates of response and of complete response achievement during the first 3 months were 84% and 45%, respectively. Response rates were 100%, 100%, 86%, 85%, and 80% for intravenous immunoglobulin, mycophenolate mofetil, rituximab, dapsone, and cyclophosphamide, respectively. Thirteen percent of those drugs were discontinued because of an adverse event in 4 patients.This study describes the efficacy of immunosuppressants or biologics with an acceptable safety profile for OCP.

Ectodermal dysplasia (ED) is a group of several genetic conditions with absence or dysgenesis of at least two ectodermal derivatives: teeth, skin and its appendages including hair, nails, eccrine and sebaceous glands. The most important clinical findings in patients with ED are hypodontia, hypotrichosis, and hypohidrosis, which can lead to episodes of hyperthermia. Few reports have focused on the progressive keratopathy in ED. Cicatrizing conjunctivitis associated with anti-basement membrane autoantibodies has been described. We report a series of three ectodermal dysplasia patients with an ocular phenotype typically seen in ocular mucous membrane pemphigoid; conjunctival immunohistopathology revealed anti-basement membrane autoantibodies in all of them, and systemic immunosuppression proved to be effective in improving symptoms and helping to stabilize ocular surface disease.

BACKGROUND Autoimmune blistering diseases are a group of severe mucocutaneous conditions that typically require the use of prolonged corticosteroids and immunosuppression. Properly managing associated comorbidities is an integral part of these patients' care. The frequency of gastrointestinal symptoms, particularly gastrointestinal bleeding in these patients, is not known. Likewise, the effect of diet on disease is unknown. OBJECTIVE To determine the incidence of gastrointestinal comorbidities and the role of diet in patients with autoimmune blistering disease. METHODS We distributed an e-survey to patients with autoimmune blistering disease utilizing the International Pemphigus and Pemphigoid Foundation's listserv. The incidence of gastrointestinal symptoms and gastrointestinal bleeding were recorded, as were foods avoided and those noted to be beneficial in patients' disease. Historical incidences in the general population were used as controls. RESULTS A total of 200 responses were collected. 30.3% of patients experienced gastroesophageal reflux following treatment of their autoimmune blistering disease, with 51.7% utilizing some form of gastrointestinal symptomatic treatment. The incidence of gastrointestinal bleeding following an autoimmune blistering diagnosis was 2.1%, which remained significant despite correction for non-steroidal anti-inflammatory use (NSAID), but not corticosteroid use. 65.2% of patients reported dietary limitations because of their autoimmune blistering disease. Significant intolerances after correction for multiple comparisons included alcohol, citrus and spicy foods. Greater than 10% of patients reported improvements in their disease with vegetables and dairy. CONCLUSIONS Gastrointestinal comorbidities are common in patients with autoimmune blistering diseases, with gastrointestinal bleeding occurring in 2.1% of patients following a diagnosis of autoimmune blistering disease. While further work is needed to determine the relative risk of routine gastrointestinal prophylaxis in this population, gastrointestinal bleeding prophylaxis should be considered in patients receiving corticosteroids, particularly those taking NSAIDs. Dietary limitations are additionally frequent in this population. Patients should be cautious of alcohol, citrus and spicy foods.

Mucocutaneous blistering autoimmune diseases are a group of systemic, rare, chronic disorders characterized by humoral-mediated immunologic mechanisms against epithelial, basement membrane, and subepithelial tissues. Morbidity and mortality can be completely different among these diseases, with outcome being dependent on an early and accurate diagnosis, systemic comorbidities, and the patient's response to treatment. Definitive diagnosis is based on clinical and histopathologic findings. Because clinical presentations among these diseases are often similar, different immunofluorescence tests and ELISAs are used to confirm the specific diagnosis. Oral mucosa may often be the first site of clinical manifestation from which the disease spreads to other mucosal surfaces and skin. Thus, often dentists and oral medicine specialists may be the first to encounter patients with such diseases. In this review we discuss the most frequent autoimmune vesicobullous disorders, namely pemphigus vulgaris, mucous membrane pemphigoid, bullous pemphigoid, and linear IgA disease.

Purpose: To present five cases of lower eyelid cicatricial entropion secondary to ocular cicatricial pemphigoid (OCP) successfully repaired with a conjunctival-sparing surgical technique.Me...

High levels of proinflammatory cytokines have been associated with a loss of tissue function in ocular autoimmune diseases, but the basis for this relationship remains poorly understood. Here we investigate a new role for tumor necrosis factor α in promoting N-glycan-processing deficiency at the surface of the eye through inhibition of N-acetylglucosaminyltransferase expression in the Golgi. Using mass spectrometry, complex-type biantennary oligosaccharides were identified as major N-glycan structures in differentiated human corneal epithelial cells. Remarkably, significant differences were detected between the efficacies of cytokines in regulating the expression of glycogenes involved in the biosynthesis of N-glycans. Tumor necrosis factor α but not IL-1β had a profound effect in suppressing the expression of enzymes involved in the Golgi branching pathway, including N-acetylglucosaminyltransferases 1 and 2, which are required for the formation of biantennary structures. This decrease in gene expression was correlated with a reduction in enzymatic activity and impaired N-glycan branching. Moreover, patients with ocular mucous membrane pemphigoid were characterized by marginal N-acetylglucosaminyltransferase expression and decreased N-glycan branching in the conjunctiva. Together, these data indicate that proinflammatory cytokines differentially influence the expression of N-glycan-processing enzymes in the Golgi and set the stage for future studies to explore the pathophysiology of ocular autoimmune diseases.

Immunoglobulins (Igs) consist of two antigen-binding regions (Fab) and one constant region (Fc). Protein A and protein G are bacterial proteins used for the purification of IgG by virtue of their high affinities for the Fc fragment. Rheumatoid factors are autoantibodies against IgG Fc fragments, which are present in the body under physiological conditions. Little is known about the influence of Fc-binding proteins on the pathogenicity of antibody-induced autoimmune diseases. Pemphigoid diseases are a group of autoimmune subepidermal blistering disorders that includes bullous pemphigoid and mucous membrane pemphigoid. IgGs targeting the non-collagenous NC16A domain of the 180-kDa bullous pemphigoid antigen (BP180) are known to induce skin fragility in mice and the depletion of BP180 in keratinocytes. In this study, mAb against NC16A in combination with Fc-binding proteins was found to enhance BP180 depletion. Although mAb against the C-terminus of BP180 does not show pathogenicity in vivo or in vitro, mAb treatment with Fc-binding proteins clearly induced skin fragility in mice and BP180 depletion in keratinocytes. Anti-BP180 mAbs and Fc-binding proteins were colocalized in the cytoplasm and at the basement membrane zone. Cell adhesion strengths were decreased in parallel with BP180 amounts. Clinically, bullous pemphigoid patients had higher rheumatoid factor titers than controls. Anti-BP180 mAb in combination with high-titer rheumatoid factor serum was found to enhance BP180 depletion. Furthermore, saliva from mucous membrane pemphigoid patients contained larger quantities of bacteria and Fc-binding proteins than controls. Our results suggest that Fc-binding proteins (rheumatoid factor or protein G) may enhance the pathogenicity of autoantibodies in pemphigoid diseases. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Objective The objective of this study was to evaluate the frequency of upper aerodigestive tract involvement in patients with mucous membrane pemphigoid associated with desquamative gingivitis. Subjects and methods Data from 25 patients were collected by retrospective chart review. Their upper aerodigestive had been evaluated using a conventional flexible fiberscope. Oral disease activity was quantified on the basis of the Mucous Membrane Pemphigoid Disease Area Index activity score. Results Lesions of the upper aerodigestive tract were confirmed in nine symptomatic patients (9/25, 36%), of which five (5/25, 20%) had laryngeal involvement. No lesions were seen in the asymptomatic patients on fiberscope examination. There was a statistically significant difference in the symptoms, high oral disease activity score, and linear IgA deposition on direct immunofluorescence between patients with and without upper aerodigestive tract lesions (p = .001, .001, .002, respectively). Conclusion The high frequency of considerable complications highlights the importance of confirming the presence of upper aerodigestive tract involvement in patients with mucous membrane pemphigoid having desquamative gingivitis. Signs including the presence of symptoms, high oral disease activity score, or linear IgA deposition on direct immunofluorescence might indicate a higher risk of upper aerodigestive tract involvement.

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.

Mucous membrane pemphigoid (MMP) rarely coexists with another autoimmune bullous disease (AIBD). Herein, we report an extremely rare MMP case who sequentially developed pemphigus foliaceus (PF). A 72-year-old man had been treated by azathioprine monotherapy for anti-BP180 MMP for 1.5 years. Clinical findings suggestive of PF, represented by scaly erythema and erosions, started to appear approximately 1 month after the episode of diarrhea. Serological and immunohistochemical examinations confirmed the diagnosis of PF. The mucocutaneous lesions were controlled by oral azathioprine and topical corticosteroids. To our knowledge, this is a previously unreported case of PF coexistent with MMP. A literature review of MMP cases associated with AIBD elucidated that 16 out of 18 cases simultaneously developed MMP and AIBD, while only two cases were diagnosed sequentially by the changes in clinical symptoms similar to our case. The titer of anti-desmoglein 1 antibodies lineally correlated with the changes in the severity of scaly erythema. Mild but noticeable exacerbation of mucosal erosion prior to the gradual increase in anti-BP180-NC16a antibodies was also noted. Unlike in other cases where MMP/AIBD coexisted, sequential development of autoantibodies in our case cannot be explained by the epitope-spreading theory as autoantigens are micro-anatomically isolated from one other. The preceding viral infection and/or continuous moderate inflammation due to azathioprine monotherapy for MMP might have contributed to the development of PF in our case.

BACKGROUND Mucous membrane pemphigoid (MMP) is an autoimmune disease characterized by scarring lesions at mucosal sites. Although the pathogenic role of specific IgG and/or IgA has been already demonstrated and the detection of these immunoglobulins is a criterion in the diagnosis of MMP, little is known about IgE role in this disease. Therefore, the main purpose of this study was to assess the presence of circulating and tissue bound IgE in patients with MMP and their possible correlations with clinical presentation and disease course. METHODS We conducted a retrospective study on 29 patients affected by MMP, recruited from a single center. Direct and indirect immunofluorescence studies were assessed to analyze the presence of specific IgE directed against the basal membrane zone. For each patient, fluorescence data were compared to clinical features. RESULTS Linear deposits of C3, IgG and IgA were present in 86.2%, 62% and 37.9% of cases respectively, while IgE linear deposits were detected in 17 out of 29 patients (58.6%) including one case with isolated IgE positivity. Circulating IgE and IgA anti-BMZ were present in 7 (24.1%) and 5 (17.2%) patients, respectively. Both the presence of circulating IgA and of tissue bound IgE deposits correlated with disease activity index (P

A 45-year-old man with a background of mucous membrane pemphigoid (MMP) was referred to ENT (Ear,Nose and Throat) clinic with a 7-month history of progressive sore throat and dysphonia. He had been under the care of Dermatology and Ophthalmology for management of his disease which was diagnosed 7

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.

ObjectivesAutoimmune bullous diseases vary in their clinico-epidemiological features and burden across populations. Data about these diseases was lacking in Sudan. We aimed to describe the epidemiological profile and to estimate the burden of autoimmune bullous diseases in Sudan.MethodsThis was a retrospective cross-sectional study conducted at Khartoum Dermatological and Venereal Diseases Teaching Hospital. We used routinely collected health care data, and included all patients with an autoimmune bullous disease who presented to the hospital between 2001 and 2016.ResultsOut of the 4736 patients who were admitted to the hospital during the study period, 923 (19.5%) had an autoimmune bullous disease. The average rate of patients at the hospital was 57.7 per year representing 1.3 per 100,000 population per year. After exclusion of patients where the final diagnosis was missing, 585 were included in the further analysis. Pemphigus vulgaris was the most common disease (50.9%), followed by bullous pemphigoid (28.2%), linear IgA disease/chronic bullous disease of childhood (8.4%), and pemphigus foliaceous (8.2%). Pemphigoid gestationis and IgA pemphigus constituted 1.4% and 1.2% of the cohort, respectively. Paraneoplastic pemphigus, mucous membrane pemphigoid, lichen planus pemphigoidis, bullous systemic lupus erythematosus, and dermatitis herpetiformis were rare. None of the patients had epidermolysis bullosa acquisita.ConclusionsThe clinico-epidemiological characteristics vary among the types of autoimmune bullous diseases. Females were more predominant in most of them. Sudanese patients tended in general to present at a younger age than other populations. The pool of Sudanese patients with autoimmune bullous diseases is large which requires investigation for the local risk factors and presents a field for future trials.

Intravenous immunoglobulins are an effective and well-tolerated treatment option for immune dermatological diseases. However, they are primarily used to treat diseases with a severe course and are mostly used off-label. Therefore, it is important to document case series on the use of intravenous immunoglobulins in rare immune dermatological diseases. We present here 32 patients who were treated with intravenous immunoglobulins in our clinic between 2015 and 2020. The indications were dermatomyositis, including amyopathic and paraneoplastic forms, as well as overlap-syndromes (n = 18), pemphigus vulgaris (n = 2), mucous membrane pemphigoid (n = 2), linear IgA dermatosis (n = 1), necrotizing vasculitis (n = 1), urticarial vasculitis (n = 1), systemic scleroderma (n = 1), Stevens-Johnson syndrome (n = 1), pyoderma gangrenosum (n = 3), and livedoid vasculopathy (n = 2). The data from this case series confirm the efficacy and tolerability of intravenous immunoglobulins as an adjuvant treatment option for rare therapy-resistant immune dermatoses.