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.

Characteristics Associated With Refractory Course, Blindness, and Treatment Strategy-Related Outcomes in Patients With Mucous Membrane Pemphigoid.

Importance: Mucous membrane pemphigoid (MMP) is a rare and heterogeneous subepithelial autoimmune bullous disease with predominant mucosal involvement. Characteristics associated with the disease course and complications are yet to be delineated. Objectives: To evaluate characteristics associated with refractory disease course and blindness among patients with MMP and to estimate the association of different treatment strategies with the prognostic outcome. Design, Setting, and Participants: A retrospective cohort study of consecutive patients diagnosed with MMP and followed up for more than 1 year from 2007 to 2020 in 2 tertiary referral centers. Data were analyzed from January 1, 2009, to June 30, 2020. Main Outcomes and Measures: Characteristics associated with refractory disease course and blindness were evaluated using multivariable logistic regression model. Results: The study encompassed 121 patients with MMP (mean [SD] age, 66.0 [14.0] years; 78 (64.5%) were women), of whom 56 (46.3%) followed a refractory course and 13 (10.7%) developed blindness. Anti-LAD-1 IgA (odds ratio [OR], 3.42; 95% CI, 1.11-10.52; P = .03) and anti-dermal-epidermal/epithelial junction (DEJ) IgG (by indirect immunofluorescence on human salt-split skin; OR, 2.92; 95% CI, 1.26-6.78; P = .01) were significantly associated with refractory course. Development of blindness was associated with older age (≥68 years; OR, 6.38; 95% CI, 1.35-30.16; P = .009), initial presentation with bilateral ocular involvement (OR, 7.92; 95% CI, 2.04-30.68; P = .001), and scarring ocular lesions (OR, 5.11; 95% CI, 1.47-17.79; P = .006). However, 4 (30.8%) and 2 (15.4%) of those experiencing blindness had no ocular scarring lesions and unilateral ocular involvement at the onset of their disease, respectively. Patients progressing to blindness were more likely to be treated by 3 or more immunosuppressive/immunomodulatory drugs (OR, 4.07; 95% CI, 1.17-14.14; P = .02) and by cyclophosphamide (OR, 7.64; 95% CI, 2.24-26.09; P < .001). Patients developing blindness and refractory course were more frequently managed by intravenous immunoglobulin (OR, 7.64; 95% CI, 2.24-26.09; P < .001 and OR, 3.47; 95% CI, 1.42-8.45; P = .005, respectively). Conclusions and Relevance: Findings of this cohort study support that patients with MMP with anti-LAD-1 IgA and anti-DEJ IgG reactivity should be carefully monitored. While initial bilateral ocular disease and scarring ocular lesions were associated with blindness, patients initially presenting with unilateral and nonscarring ocular disease may still develop severe vision impairment.

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.

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.

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.

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.

Corneal perforation in ocular cicatricial pemphigoid: A CARE-compliant case report.

RATIONALE: Ocular cicatricial pemphigoid (OCP) is a potentially blinding, rare systemic autoimmune disease. The definite etiology of OCP remains under debate, early diagnosis is important to prevent rapid deterioration. The majority of the discussion has been focused on its medical therapeutic strategy, while little effort has been made to study the role of amniotic membrane transplantation (AMT). We describe the first case of OCP with minimal immunosuppressant and initial ocular surface reconstruction procedure using double layer AMT. PATIENT CONCERNS: A 66-year-old female patient presented to our outpatient department with right eye pain for several days. DIAGNOSIS: Slit lamp examination revealed the right eye cornea perforation with iris incarceration and total collapse of anterior chamber. Symblepharon formation and severe fornix shortening was also noted. While bulbi phthisis with ankyloblepharon and ocular surface keratinization was observed in the left eye. The final diagnosis was right eye stage III ocular cicatricial pemphigoid complicated with corneal perforation and iris prolapsed. INTERVENTIONS: The patient underwent ocular surface reconstruction with the aid of amniotic membrane. The first layer of the amniotic membrane was attached with tissue adhesive and fibrin glue while the second layer amniotic membrane came with a conformer ring which supported the fornix space that was recreated. Postoperative care included topical medications for inflammation alleviation. Systemic immunosuppressive agents were not administered except for oral prednisolone. OUTCOMES: No recurrence of symblepharon was noted during the one year follow-up. LESSONS: We aim at highlighting the possible important role of AMT in advance OCP. Further investigation is still needed for providing evidence to incorporate the procedure into treatment protocol.

Development of pemphigus foliaceus in a mucous membrane pemphigoid patient: An insight into possible mechanism eliciting a distinct autoimmune bullous disease in a rare anti-basement membrane autoimmunity.

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.