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.

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

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

Ocular involvement in autoimmune bullous diseases.

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

Clinical Approach to Ocular Cicatricial Pemphigoid.

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

[Refractory esophageal stricture of esophageal mucous membrane pemphigoid after allogeneic hematopoietic stem cell transplantation].

Haploidentical allogeneic hematopoietic stem cell transplantation from her brother was performed on a 41-year-old lady with no prior history of pemphigoid to treat recurrent AML. On day 59 following transplantation, she experienced esophageal stenosis. During immunosuppressive therapy for graft vs. host disease, this condition was controlled with periodic esophageal dilatation (GVHD). Her esophageal stricture, which required periodic dilatation, grew worse after she stopped immunosuppressive therapy because of recurrent AML. The esophageal mucosa was easily hemorrhagic and desquamative. Histologic analysis revealed that the squamous cell layers had been divided. Indirect immunofluorescence was negative for IgG and positive for IgA on the epidermal layers, while direct immunofluorescence showed a linear deposition of IgG on the basement membrane zone. It was determined through immunoblotting utilizing recombinant protein of BP180 C-terminal domain that both IgG and IgA antibodies were present, supporting the diagnosis of mucous membrane pemphigoid with anti-BP180. After allogeneic transplantation, basal epidermal cell destruction by GVHD may result in autoimmune blistering disorders, which expose basement membrane proteins and antigen presentation. A similar mechanism could apply to our situation. For rare GVHD cases, a thorough histological diagnosis is required.

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

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

Ocular Mucus Membrane Pemphigoid: A Primary Versus Secondary Entity.

PURPOSE: The purpose of this review was to investigate the idea that inflammatory events of the conjunctiva and ocular surface may act as triggering events for the onset of ocular mucus membrane pemphigoid (oMMP). METHODS: A retrospective chart review of patients with biopsy-proven oMMP and no systemic pemphigoid disease. The presence, or absence, of the following inflammatory conditions at the time of OMMP diagnosis was noted: significant eyelid disease, significant atopic eye disease, Stevens-Johnson syndrome, graft-versus-host disease, viral keratitis, sarcoidosis with ocular involvement, chemical burns, medicamentosa, Sjogren syndrome, systemic lupus erythematosus with ocular involvement, and epidemic keratoconjunctivitis. Response to immunomodulatory therapy (IMT) was also recorded. RESULTS: A total of 779 patient records were identified. Conjunctival biopsy was present in 724 patients, with 646 (89.2%) being positive. One hundred thirty-nine patients (21.5%) with positive biopsies had extraocular pemphigoid disease and were excluded from further analysis. Of the 507 included patients, 154 (30.4%) had at least one of the specified inflammatory conditions present at the time of OMMP diagnosis. One hundred eighteen patients (23.3%) had only 1 such condition, 35 (6.9%) had 2, and 1 patient had 3. In patients with at least one of these conditions present, response to IMT was seen in 84.9% of patients with sufficient follow-up. CONCLUSIONS: Our study suggests that oMMP may arise as a secondary pathology to acute inflammatory events or chronic inflammatory states of the conjunctiva and ocular surface.

Long-term outcome of cultivated oral mucosal epithelial transplantation for fornix reconstruction in chronic cicatrising diseases.

BACKGROUND/AIMS: To investigate the long-term outcomes of cultivated oral mucosal epithelial transplantation (COMET) for fornix reconstruction in eyes with chronic cicatrising disease. METHODS: This 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. RESULTS: At 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). CONCLUSION: COMET 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.

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.

Surgical Management of Ocular Cicatricial Pemphigoid in a Pediatric Patient.

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

A case series of ocular involvement in bullous pemphigoid: clinical features, management, and outcomes.

Ocular involvement in cases of bullous pemphigoid is rare and when present, the signs are usually subtle and in the form of fine tarsal scarring and dry eye disease. The current report aims to describe the clinical features and management protocols in a series of cases with aggressive ocular manifestations at presentation. All cases of bullous pemphigoid seen between 2017 and 2020 were included in this retrospective case series. Data regarding the clinical features, treatment administered, and outcomes was collected. Five cases (n=10 eyes) of bullous pemphigoid disease with ocular involvement were included. All eyes had significant cicatricial conjunctival changes in the form of symblephara, inferior forniceal shortening, and tarsal conjunctival scarring. Conjunctival granulomas were present in 3/10 eyes. Corneal involvement in the form of punctate keratitis was present in all eyes while 4/10 eyes had an epithelial defect as well. The management of these cases involved topical therapy with corticosteroids and lubricants (n=10 eyes) while pulse doses of intravenous methyl prednisolone were administered in 5/5 cases. Pulse intravenous cyclophosphamide was supplemented in 2/5 cases. Adequate control of the disease was noted in 3/5 cases while one case had a recalcitrant form of the disease and developed a dermalised ocular surface in both eyes. The last patient was lost to follow up during the course of therapy. Bullous pemphigoid can present with an aggressive form of cicatrizing conjunctivitis similar to other variants of autoimmune blistering disorders and must be considered as a differential in cases presenting with ocular cicatricial disease. Long-term intensive immunosuppression is required for the management of these cases to preserve the visual function and the integrity of the globe.

Direct Injection of 5-Fluorouracil Improves Outcomes in Cicatrizing Conjunctival Disorders Secondary to Systemic Disease.

PURPOSE: Conjunctival cicatrizing conditions are vision threatening, with poor outcomes despite aggressive systemic therapy. This study tests the utility of serial injections of 5-fluorouracil (5-FU) into the fornices to treat conjunctival scarring in patients with ocular cicatricial pemphigoid or Stevens-Johnson syndrome/toxic epidermal necrolysis. METHODS: Retrospective cohort study. Fisher exact test and multivariable logistic regression analyses were used to compare clinical outcomes of patients who were administered 5-FU injections versus patients who were not injected. Model fit was examined for multivariable regression. RESULTS: One hundred twelve eyes (56 patients) met the inclusion criteria. Thirty-eight eyes (34%) had Stevens-Johnson syndrome/toxic epidermal necrolysis, and 74 eyes (66%) were diagnosed with ocular cicatricial pemphigoid. Twenty-five eyes received ≥1 injection of 5-FU. Sixteen eyes received 1-4 injections, while 9 received ≥5. Median follow-up until last encounter was 18 months. Analysis of each disease entity alone and in combination revealed that 5-FU injections were associated with improvement in final visual acuity, corneal scarring, trichiasis, need for/number of mucous membrane graft surgeries, and severity of symblephara. CONCLUSIONS: Serial injection of 5-FU in the affected fornices is a promising treatment for severe vision-threatening conjunctival scarring from ocular cicatricial pemphigoid and Stevens-Johnson syndrome/toxic epidermal necrolysis. Given the excellent safety profile of 5-FU around the eye, the solid biologic foundation for using 5-FU in this setting, and the severe risk of vision loss from these disorders, the authors suggest that serial 5-FU injections be adopted as therapy for conjunctival scarring from ocular cicatricial pemphigoid or Stevens-Johnson syndrome/toxic epidermal necrolysis despite the limitations of this retrospective study.

Report of two cases of mucous membrane pemphigoid with frontal fibrosing alopecia: a variant of lichen planus pemphigoides or an incidental finding?

Lichen planus pemphigoides (LPP) is a rare autoimmune subepidermal blistering disease characterized by the coexistence of both lichen planus and either bullous pemphigoid or mucous membrane pemphigoid (MMP) features. Frontal fibrosing alopecia (FFA) is a scarring alopecia, generally considered a form of lichen planopilaris. We report two patients with concomitant FFA and MPP. Patient 1 was a 73-year-old woman with the clinical and histological diagnosis of oral lichen planus. In addition, she presented alopecic plaques in the parietal area with blisters, immunohistologically compatible with Brunsting-Perry pemphigoid, a variant of MMP. During follow-up, the patient also developed FFA. Patient 2 was a 70-year-old woman with a history of ocular inflammation and desquamative gingivitis, who was diagnosed with MMP based on a conjunctival biopsy. She also had clinical features of FFA. ELISA and frontal biopsy confirmed the diagnoses of MMP and FFA. In conclusion, we report two patients with MMP associated with FFA, and discuss whether this association is a new variant of LPP or an incidental finding.

Mucous membrane pemphigoid-otorhinolaryngological manifestations: a retrospective cohort study.

INTRODUCTION: Mucous membrane pemphigoid (MMP) refers to a heterogeneous group of rare, chronic, inflammatory, mucous membrane-dominated, sub-epithelial blistering diseases that manifest with a varying constellation of oral, ocular, cutaneous, genital, nasopharyngeal, esophageal, and laryngeal lesions. MMP can progress to scarring in affected areas, which may lead to devastating complications including ocular involvement leading to blindness as well as laryngeal involvement leading to airway obstruction. MATERIALS AND METHODS: A retrospective chart review was conducted for patients that were followed in two tertiary academic centers between 2009 through 2017 for upper aerodigestive tract manifestations of MMP. Patients with significant underlying skin involvement suggestive of bullous pemphigoid as well as MMP with isolated ocular involvement were excluded. RESULTS: Twenty-seven patients were diagnosed with MMP and followed in two tertiary referral medical centers. The most common site of initial presentation was the oral cavity, and all patients had oral cavity involvement at some point. Two-thirds of our patients had complete remission or remission with intermittent relapses disease. Patients with mild to moderate disease showed excellent response to topical steroid treatment. For more severe disease, high-dose prednisone was insufficient, as in most cases relapse occurred at some point of time during tapering down. CONCLUSIONS: MMP is a rare autoimmune disorder that may present with a wide spectrum of head and neck manifestations and, potentially, catastrophic sequelae. This work highlights the experience of two tertiary centers with MMP in an attempt to draw attention to this unusual disorder.

A conjunctival-sparing surgical technique for lower eyelid cicatricial entropion repair in ocular cicatricial pemphigoid.

Purpose: To present five cases of lower eyelid cicatricial entropion secondary to ocular cicatricial pemphigoid (OCP) successfully repaired with a conjunctival-sparing surgical technique.Methods: The records of one surgeon (SKF) were reviewed to identify patients with lower eyelid cicatricial entropion secondary to OCP who underwent repair with a conjunctival-sparing technique between September 1, 2016 and October 18, 2017. The medical records were reviewed and extracted data included: age, gender, past medical history, current medical and OCP status, clinical examination, details of entropion repair surgery, and outcome.Results: Five patients (three female, two male) were included with ages ranging from 44 to 93 years. All had biopsy proven OCP, which was in remission at the time of surgery, and all were currently receiving immunomodulatory medications. All patients were symptomatic from cicatricial entropion secondary to OCP and underwent successful lower eyelid entropion repair with a conjunctival-sparing technique described herein, involving infraciliary rotation with suture fixation of the orbicularis muscle to the tarsus. Other contributing mechanisms of eyelid malposition including horizontal eyelid laxity and orbicularis oculi override were addressed simultaneously with lateral tarsal plication or orbicularis muscle debulking, resulting in 100% anatomic success and relief of symptoms with no cases of OCP reactivation, and with good durability with an average 13.9 months follow up (range 6.5-22 months).Conclusions: Successful repair of lower eyelid cicatricial entropion in immunomodulated patients with OCP can be achieved without disease reactivation using a surgical technique that spares the conjunctiva and lower eyelid retractors.

Ectodermal Dysplasia: Association with Anti-Basement Membrane Autoantibodies.

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.