The Role of Serology in the Diagnosis of Ocular Predominant Mucous Membrane Pemphigoid and the Search for an Ocular-Specific Autoantigen.

Ocular predominant mucous membrane pemphigoid (oMMP) is a severe subtype of MMP that can lead to scarring and blindness. While conjunctival biopsy for direct immunofluorescence (DIF) is considered the gold standard for diagnosis, limited sensitivity results in a false-negative rate upwards of 40%. Likewise, it remains unclear to what extent a negative biopsy, whether false-negative or true-negative, results in a different prognosis, with patients previously termed "pseudopemphigoid" demonstrating comparable disease progression. Serologic testing allows for a less invasive means to demonstrate circulating autoantibodies against known autoantigens in pemphigoid diseases. Patients with MMP, particularly oMMP, however, typically demonstrate low titers of circulating autoantibodies, limiting the diagnostic utility of these tests. The autoantigen integrin ß4 has been previously reported to be a specific marker of pure ocular MMP, while in the majority of patients with oMMP, the identified target antigens are BP180 (type XVII collagen) and laminin 332. Recent studies have, however, demonstrated inconsistent reactivity and specificity for integrin ß4 as an ocular-specific marker in MMP. Herein, we review the role of serologic testing in the diagnosis and prognosis of oMMP, as well as the current understanding of autoantigens in oMMP.Abbreviations: BMZ - basement membrane zone, DIF - direct immunofluorescence, IIF - indirect immunofluorescence, MMP - mucous membrane pemphigoid, oMMP - ocular predominant mucous membrane pemphigoid.

Clinical Characteristics of Ocular Mucous Membrane Pemphigoid: A Systematic Review and Meta-Analysis.

PURPOSE: To synthesize the evidence and generate a combined weighted measure on the frequency of ocular manifestations of mucous membrane pemphigoid (OMMP). METHODS: Systematic literature review and meta-analysis, searching PubMed, Embase, VHL, and Google Scholar. Articles reporting patients with mucous membrane pemphigoid and ocular involvement were included. At least, two reviewers independently and in parallel participated in all the following phases; preliminary screening, full-text review, risk of bias assessment by validated tools, and data extraction. Qualitative analysis and meta-analysis were conducted. This study was previously registered in PROSPERO (CRD42023451844). RESULTS: Thirty-five studies met the inclusion criteria, comprising 1,439 patients and 1,040 eyes summarized in qualitative analysis. Twenty-eight studies were included in the meta-analysis. Ages included ranged from 60.4 to 75 years. Women were reported with more frequency. The mean time for diagnosis was 55.1 months, usually with bilateral ocular disease in 90% (95% CI 78%; 96%). Trichiasis and entropion were the most frequent manifestations in up to 92%, followed by symblepharon and punctate keratitis. Ankyloblepharon, persistent epithelial defects, and visual impairment were less frequent complications. Direct immunofluorescence positivity in conjunctival biopsies was 54% (95% CI 43%; 64%). Extraocular involvement was highly frequent, being oral and skin involvement the most frequently reported. CONCLUSIONS: Our systematic review and meta-analysis evidenced that patients around 60 years of age are the most affected population with a female preponderance, usually with bilateral ocular involvement. Trichiasis and entropion were the most frequent findings; although visual impairment and persistent epithelial defects were less reported, they should not be overlooked in suspected OMMP.

Ocular cicatricial pemphigoid: is there an association with autoimmune diseases?

PURPOSE: To assess the prevalence of autoimmune diseases (ADs) associated with ocular cicatricial pemphigoid (OCP) and analyze clinical, laboratory, and treatment associations between these entities. METHODS: A multicentre cross-sectional study of patients with an OCP diagnosis. The population was divided into two groups according to their association with other ADs or not. Clinical, laboratory and treatment variables were described and compared between groups. A multivariable logistic regression analysis was performed to identify variables that could suggest the association between OCP and ADs. RESULTS: Eighty-eight patients were recruited, with a mean age at diagnosis of 64.3 years (SD 11.9). Biopsy was performed in 86.8% of the patients. There was a median delay of 2 years from the onset of symptoms to diagnosis. Extraocular involvement was evidenced in 11.5%. The group associated with ADs included 24 patients (27.3%). The most prevalent diagnosis was Sjögren´s syndrome. Hypergammaglobulinemia was associated with ADs and OCP, adjusted for age, sex, smoking, skin and mucosal involvement, and erythrocyte sedimentation rate (OR 8.7; 95%CI 1.6-46.8; p = 0.012). CONCLUSIONS: Due to OCP's autoimmune nature, it could coexist with other ADs. This study observed that more than a quarter of the population presented with this association, and hypergammaglobulinemia could suggest it.

Ocular cicatricial pemphigoid following Dipeptidyl Peptidase-4 inhibitor use: A case report.

Purpose: To report a rare Ocular Cicatricial Pemphigoid (OCP) case in a patient taking a Dipeptidyl Peptidase-4 Inhibitor (DPP-4 inhibitor), a medication used for the management of type 2 diabetes, for at least six years. Observations: A 64-year-old male presented with refractory bilateral conjunctival inflammation and ocular discharge that had persisted for two months, despite multiple prior therapies for presumed bacterial conjunctivitis. Upon initial examination, clinical findings strongly suggested OCP, and he had elevated levels of anti-BP180 antibodies. Despite receiving systemic treatments such as steroid pulse therapy and therapeutic plasma exchange after discontinuing DPP-4 inhibitors, his condition progressively worsened, with manifestations such as forniceal shortening in his left eye. Consequently, the patient required keratoepithelioplasty, amniotic membrane transplantation in his left eye, and bilateral eyelid entropion surgery. His condition initially worsened for a time after discontinuing the DPP-4 inhibitor, but it gradually improved over time, and ocular surface surgical intervention was not required in the right eye. Conclusions and Importance: The findings in this study demonstrate that severe refractory OCP may occur while taking the DPP-4 inhibitor, thus indicating that a detailed interview regarding medications is essential for patients with ocular pemphigoid, especially those with type 2 diabetes.

Clinical Approach to Ocular Cicatricial Pemphigoid.

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

Cataract surgery in ocular surface disease.

Cataract surgery, which is the most widely performed ophthalmic procedure, is usually done in the elderly population, who are also prone to ocular surface disorders. Ocular surface diseases are multifactorial in nature and associated with symptoms and signs such as foreign body sensation, burning, fatigue, photophobia, red or watery eyes, or reduced visual acuity. These include a spectrum of conditions that may be immune or non-immune in nature. Cataract surgery in itself is known to alter the normal ocular surface milieu and cause tear film disturbances which can last up to 6 months post-operatively. These symptoms can be exaggerated in patients with ocular surface diseases. The planning and execution of cataract surgery can also be difficult in patients with associated ocular surface diseases. In this review, we discuss the various aspects of planning and intraoperative modifications to optimize the outcomes of cataract surgery in patients with ocular surface diseases.

Ab Interno Goniotomy with the Kahook Dual Blade in a Monocular Patient with Mucous Membrane Pemphigoid and Refractory Open Angle Glaucoma: A Case Report.

Purpose: To describe the case of a monocular patient with ocular mucous membrane pemphigoid (MMP) and open angle glaucoma refractory to medical treatment, who was successfully managed with ab interno goniotomy at the time of cataract surgery. Methods: A 63-year-old woman with a history of severe MMP presented with exacerbation of the disease in both eyes. Vision was 20/80 in the right eye and light perception in the left eye. Symblepharon formation, trichiasis and forniceal foreshortening were present in the right eye, while the cornea of the left eye was completely conjunctivalized. Following aggressive systemic immunosuppressive therapy with corticosteroids and cyclophosphamide, the disease was brought under control. However, the patient developed a mature cataract and high intraocular pressure (IOP) of 28 mmHg on maximal medical therapy. Due to the high risk of ocular MMP exacerbation with glaucoma filtration surgery, the decision was made to proceed with cataract extraction combined with ab interno goniotomy with the Kahook Dual Blade. Results: There were no intraoperative complications. The IOP has remained in the 12-14 mmHg range without any topical glaucoma medications over a total follow up of 3.5 years. Conclusion: Ab interno goniotomy using the Kahook Dual Blade can significantly reduce IOP and medication burden in MMP cases, where any type of conjunctival incisional surgery could induce disease flare up. In this case, it represented a safe and effective surgical procedure for ocular MMP with concomitant refractory open angle glaucoma.

Drug induced cicatrizing conjunctivitis: A case series with review of etiopathogenesis, diagnosis and management.

Drug induced cicatrizing conjunctivitis (DICC) is defined as a disease in which conjunctival cicatrization develops as a response to the chronic use of inciting topical and, rarely, systemic medications. DICC accounts for up to one third of cases of pseudopemphigoid, a large group of cicatrizing conjunctival diseases sharing similar clinical features to those of mucous membrane pemphigoid (MMP) but generally without the morbidity of progressive scarring or the need for systemic immunosuppression. The preservatives in topical anti-glaucoma medications (AGM) are the most frequently implicated inciting causes of DICC although topical antivirals, vasoconstrictors and mydriatics and some systemic drugs have been implicated. The literature review summarizes the classification, epidemiology, etiopathogenesis, histopathology, clinical presentation, diagnosis, management, and treatment outcomes of DICC in the context of a case series of 23 patients (42 eyes) with AGM induced DICC, from India and the UK. In this series all subjects reacted to preserved AGM with one exception, who also reacted to non-preserved AGM. At diagnosis >70% of eyes showed punctal scarring, inflammation, and forniceal shortening. Pemphigoid studies were negative in the 19/23 patients in whom they were carried out. DICC can be classified as non-progressive, progressive with positive pemphigoid immunopathology or progressive with negative pemphigoid immunopathology. It is unclear whether progressive DICC is a stand-alone disease, or concurrent (or drug induced) ocular MMP. Progressive cases should currently be treated as ocular MMP. The diagnosis can be made clinically when there is rapid resolution of symptoms and inflammation, usually within 1-16 weeks, after withdrawal of suspected inciting medications, ideally by temporary substitution of oral carbonic anhydrase inhibitors. If the response to withdrawal is uncertain, or the progression of inflammation and scarring continues then patients must be evaluated to exclude concurrent (or drug induced) MMP, and other potential causes of CC, for which the treatment and prognosis is different. Management, in addition to withdrawing inciting medications, may require short-term treatment of conjunctival inflammation with steroids, treatment of associated corneal disease with contact lenses or surface reconstructive surgery, control of intra-ocular pressure with non-preserved AGM and, in some, surgery for glaucoma or for trichiasis and entropion.

Ocular cicatricial pemphigoid. From a rheumatology and ophthalmology point of view / Penfigoide ocular cicatrizal, enfoque diagnóstico y terapéutico integral entre el oftalmólogo y el reumatólogo

ABSTRACT Ocular cicatricial pemphigoid (OCP) is a chronic, immune-mediated, bullous, cicatricial disease within the spectrum of mucocutaneous membranous pemphigoids (MMP). Although the diagnosis is often ophthalmological, due to the autoimmune nature of the pathology, it requires a joint approach with rheumatologists and immunologists. The objective of this narrative review was to explore the evidence available in the literature from 2000 to 2020 with respect to clinical manifestations, diagnosis, and treatment. The clinical presentation varies widely, from mild cases with slow progression of years of progression, to severe cases with a torpid and rapidly progressive evolution to fibrosis, refractory to multiple treatments. A com plete evaluation of the patient will help guide the diagnosis. The gold standard for diagnosis is conjunctival biopsy with direct immunofluorescence, although on occasions it can be reached if the symptoms are characteristic. Treatment is local and systemic according to its severity and evolution. The evidence on topical and systemic therapeutics is obtained mainly from uncontrolled observational and experimental studies. Immunomodulatory therapy has made it possible to preserve vision and, in many cases, prevent sequelae. The evolu tion is linked to the early diagnosis and immunosuppressive treatment, so it is essential to be aware of this disease, the diagnostic methods, as well as the immunomodulating and immunosuppressive therapies available.

RESUMEN El penfigoide ocular cicatrizal (POC) es una enfermedad crónica, inmunomediada ampollar, mucosinequiante, comprendida dentro del espectro de penfigoides membranosos mucocutáneos (PMM). El diagnóstico es, con frecuencia, oftalmológico, pero debido al carácter autoinmune de la patología, requiere el abordaje en conjunto con reumatólogos e inmunólogos. El objetivo de esta revisión narrativa fue explorar la evidencia disponible en la literatura, desde el año 2000 hasta el 2020, en lo que respecta a sus manifestaciones clínicas, diagnóstico y tratamiento. La presentación clínica varía ampliamente, desde casos leves con progresión lenta de años de evolución hasta casos severos con evolución tórpida y rápidamente progresiva a la fibrosis, refractarios a múltiples tratamientos. Una evaluación completa del paciente ayudará a guiar el diagnóstico. El estándar de oro diagnóstico es la biopsia conjuntival con inmunofluorescencia directa, si bien en ocasiones puede diagnosticarse por la clínica característica. El tratamiento es local y sistêmico de acuerdo con su severidad y evolución. En los últimos 20 anos, la evidencia sobre los tratamientos tópicos y sistêmicos corresponde en su mayoría a estudios observacionales y experimentales no controlados. Los métodos de tratamiento inmunomoduladores han permitido preservar la visión y, en muchos casos, prevenir secuelas. La evolución está ligada al diagnóstico temprano y a los tratamientos disponibles, por lo que es fundamental el conocimiento de esta patología, los métodos diagnósticos y los tratamientos inmunomoduladores e inmunosupresores.

Single Center Retrospective Study of Patients with Ocular Mucous Membrane Pemphigoid (MMP).

PURPOSE: Mucous membrane pemphigoid (MMP) with ocular involvement often leads to devastating vision loss from ocular surface disease. This study sought to better characterize presenting symptoms, clinical characteristics, important factors in clinical progression, and visual acuity over time. METHODS: A retrospective chart review was performed on 88 patients seen at the Emory Eye Center between January 1, 2012 and July 1, 2017 for ocular MMP. RESULTS: A large percentage of patients with MMP presented at later stages. Partial or complete loss of the fornices and symblepharon were the most common initial disease complications. The time to clinical stabilization usually occurred 1 year after initial presentation. CONCLUSIONS: Ocular MMP is a devastating disease that often presents to tertiary care hospitals at late stages and leads to numerous eyelid and ocular surface changes. This study demonstrated that presenting clinical signs are broad and that stabilization of visual acuity takes months.

Ocular cicatricial pemphigoid: Methotrexate as an initial treatment?

OBJECTIVE: To analyse the clinical/epidemiological data, the management and the treatments established in patients with Ocular Cicatricial Pemphigoid (OCP) in a Rheumatology Service. MATERIAL AND METHODS: Review of clinical histories of patients with OCP referred by ophthalmology between 2008 and 2019. RESULTS: In our series of 27 patients, 67% were diagnosed and referred in the last 2 years. Most in Foster stage 1. Of the patients, 18.5% presented associated Sjogren's syndrome, with poor progression: 88.8% received Methotrexate, 74% used it as monotherapy and 66% continued with said treatment up to the end. Eighteen point five percent had to combine or rotate therapies, the drugs used were mycophenolate, azathioprine, cyclophosphamide, sirolimus, etanercept, rituximab: 29% used steroids. Only in 2 eyes was stage progression observed. There were no serious adverse events, and 37% had mild adverse events. CONCLUSION: Starting immunosuppressive therapy early is essential, methotrexate being a good initial alternative in our experience, and treatment must be escalated in line with disease progression.

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

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

Association Between Skin Findings and Ocular Signs in Rosacea.

OBJECTIVES: To report the most frequent signs in ocular rosacea and evaluate their association with skin findings. MATERIALS AND METHODS: Fifty-one patients diagnosed with rosacea by a trained dermatologist were evaluated by an ocular surface specialist. A complete ophthalmological examination was performed. RESULTS: In our study, the prevalence of ocular signs in patients with rosacea was 74.5%. The average age at presentation was 50 years and women were more affected than men. The most common findings were lid margin erythema, meibomian gland dysfunction, and blepharitis. Fifteen patients had decreased visual acuity due to complications related to rosacea such as leukoma and corneal neovascularization. Interestingly, patients that had the lowest visual acuity presented with dermatological signs of papules and pustules (p=0.001) and rhinophyma (p=0.023). Two patients who showed subepithelial fibrosis and fornix foreshortening were diagnosed as having ocular cicatricial pemphigoid (OCP) by immunohistopathological analysis of conjunctival specimens. CONCLUSION: Ocular compromise is common in rosacea. Our study shows that there might be a relationship between the severity of ocular involvement and certain subtypes of cutaneous disease. Rosacea and OCP may coexist. In cases that present with conjunctival fibrotic changes, a diagnostic biopsy is mandatory.

Incidence, prevalence, and demographic characteristics of ocular cicatricial pemphigoid in Colombia: data from the National Health Registry 2009-2019.

AIM: To provide an epidemiological characterization of ocular cicatricial pemphigoid (OCP) in Colombia. METHODS: We conducted a cross-sectional study using SISPRO. We applied the specific code of the International Classification of Diseases for Ocular Pemphigoid, from 2009-2019 to estimate prevalence, incidence, and the demographic status of the disease in Colombia. RESULTS: The estimated average prevalence was 0.22 per 1 000 000 inhabitants, and the estimated average incidence was 0.24 per 1 000 000 inhabitants. With a female predominance of 62.5%, and a male/female ratio of 1:1.6. The group of patients diagnosed with the disease after the age of 80 presented the highest prevalence. The departments with the highest prevalence were Antioquia, Bogotá, and Santander. CONCLUSION: There are important differences between worldwide and Colombian prevalence and incidence data, which may be related to genetic and epigenetic factors, and the possible underdiagnosis of the disease. According to the results, OCP is an extremely rare disease in Colombia. Nevertheless, it is important to encourage awareness of the disease due to its devastating consequences.

Tofacitinib for refractory ocular mucous membrane pemphigoid.

PURPOSE: To report the successful use of tofacitinib in the treatment of refractory ocular mucous membrane pemphigoid (MMP). OBSERVATIONS: Two patients with ocular MMP presented with refractory disease after failure of multiple therapies. Treatment with tofacitinib led to durable control of conjunctival inflammation within 8 weeks and no apparent progression of sub-conjunctival fibrosis. One patient maintained absence of apparent disease activity over 16 months of follow-up. Cessation of tofacitinib in the other patient led to disease relapse which was reversed by re-initiation of therapy. CONCLUSIONS AND IMPORTANCE: Small molecule inhibitors of Janus kinases, such as tofacitinib, may offer an effective treatment option for refractory ocular MMP.

A novel case of ocular cicatricial pemphigoid induced by levamisole-adulterated cocaine.

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.

Ocular Cicatricial Pemphigoid: Methotrexate as an Initial Treatment? / Penfigoide ocular cicatricial: ¿metotrexato como tratamiento de inicio?

OBJECTIVE: To analyse the clinical / epidemiological data, the management and the treatments established in patients with ocular cicatricial pemphigoid in a Rheumatology Service. MATERIAL AND METHODS: Review of clinical histories of patients with ocular cicatricial pemphigoid referred by ophthalmology between 2008 and 2019. RESULTS: In our series of 27 patients, 67% were diagnosed and referred in the last 2 years. Most in Foster stage 1. Of the patients, 18.5% presented associated Sjogren's syndrome, with poor progression: 88.8% received Methotrexate, 74% used it as monotherapy and 66% continued with said treatment up to the end. Eighteen point five percent had to combine or rotate therapies, the drugs used were mycophenolate, azathioprine, cyclophosphamide, sirolimus, etanercept, rituximab: 29% used steroids. Only in 2 eyes was stage progression observed. There were no serious adverse events, and 37% had mild adverse events. CONCLUSION: Starting immunosuppressive therapy early is essential, methotrexate being a good initial alternative in our experience, and treatment must be escalated in line with disease progression.