Discoid lupus erythematosus and cicatrizing conjunctivitis: clinicopathologic study of two cases

Background: Discoid lupus erythematosus (DLE) demonstrates both cutaneous and mucosal manifestations. Mucosal involvement is typically limited to the oral and anogenital mucosa. Conjunctival involvement in DLE is rare, especially in the absence of accompanying cutaneous disease. Objective: We describe the clinical and immunopathologic features of two cases of cicatrizing conjunctivitis due to DLE. Methods: In each patient, the clinical, immunopathologic, and serologic features were reviewed and the results recorded. Results: Both patients presented with cicatrizing conjunctivitis suggestive of mucous membrane pemphigoid. Patient 1 had no history of typical DLE skin lesions. Patient 2 had a history of cutaneous and oral DLE prior to presentation. Histologic, electron microscopic, and direct immunofluorescence examination confirmed the diagnosis DLE in both patients. Conclusion: In patients presenting with cicatrizing conjunctivitis, DLE should be considered in the differential diagnosis. Performing appropriate investigations to distinguish conjunctival DLE from other autoimmune diseases with conjunctival involvement such as mucous membrane pemphigoid is critical in selecting an appropriate treatment regimen, in offering an accurate prognosis, and in monitoring for signs and symptoms of disease progression.     

Immunoelectron microscopic study of the conjunctiva in cicatricial pemphigoid

· Background: Immune deposits can be found on the conjunctival basement membrane zone of patients affected by cicatricial pemphigoid using immunofluorescence technique. The purpose of this study was to perform direct immunoelectron microscopy on the conjunctiva of patients with scarring conjunctivitis associated with cicatricial pemphigoid · Methods: Conjunctival and skin biopsies were performed in six patients who presented with presumed autoimmune cicatrizing conjunctivitis associated with cicatricial pemphigoid. Specimens were processed for direct immunofluorescence and direct immunoelectron microscopy. · Results: Direct immunofluorescence was positive in all skin samples and in three of six conjunctival samples. Direct immunoelectron microscopy showed immune deposits in the lamina lucida and the lamina densa of all skin and conjunctival samples. · Conclusions: Direct immunoelectron microscopy can be performed on the conjunctiva. It shows the precise localization of cicatricial pemphigoid target antigens within the conjunctival basement membrane zone. Received: 29 April 1997 Revised version received: 16 February 1998 Accepted: 9 March 1998     

Patient with lichen planus and conjunctival immunopathologic features of lupus erythematosus.

PURPOSE: To report a case of severe cicatricial conjunctivitis in a patient with lichen planus, which is known to affect the skin and mucous membranes. The conjunctival immunopathologic features were consistent with lupus erythematosus rather than with lichen planus. METHOD: Oral mucosal and skin biopsies were performed with histopathologic and immunofluorescent studies consistent with lichen planus. The patient later had a biopsy of cicatrized conjunctiva with histopathologic and immunofluorescent findings consistent with lupus erythematosus. Evaluation by rheumatology and dermatology consultants demonstrated no evidence of active systemic lupus erythematosus or discoid lupus erythematosus. RESULTS: The patient was treated with topical and systemic immunosuppressives and her disease eventually stabilized. CONCLUSION: The case demonstrates two coexisting autoimmune disease entities: lichen planus of the skin and oral mucosa and a cicatricial conjunctivitis consistent with lupus erythematosus.     

Cicatrizing conjunctivitis associated with paraneoplastic lichen planus

PURPOSE: To report two cases of cicatrizing conjunctivitis associated with paraneoplastic lichen planus. METHODS: Case reports. RESULTS: Two patients were examined because of redness and discomfort in both eyes. A 63-year-old woman with follicular, small-cleaved cell lymphoma had cicatrizing conjunctivitis, stomatitis, vulvitis, and skin lesions. A 25-year-old man with malignant thymoma had cicatrizing conjunctivitis, erosive stomatitis, and penile papules. Histopathologic studies of conjunctiva and skin biopsy specimens in the first patient and labial biopsy specimens in the second revealed lichen planus. CONCLUSION: Paraneoplastic lichen planus is a possible cause of cicatrizing conjunctivitis associated with inflammatory skin and mucous membrane disease.     

A case of lichen planus-lupus erythematosus overlap syndrome with eyelid involvement

PURPOSE: To report a case of lichen planus-lupus erythematosus overlap syndrome with eyelid involvement. Lichen planus and lupus erythematosus infrequently coexist in the same patients. Ocular involvement has rarely been reported for both diseases. CASE REPORT: We describe a case of lichen planus-lupus erythematosus overlap syndrome with eyelid involvement. Histopathologic and immunofluorescent studies were done on buccal, lip, left conjunctival, malar, auricular and scalp lesions. The immunopathologic features of the conjunctiva, buccal mucosa and lip were consistent with lichen planus, while those of the malar, auricular and scalp lesions favoured lupus erythematosus. RESULTS: The patient was successfully treated with hydroxychloroquine 200 mg/day and all lesions responded to therapy within weeks. CONCLUSIONS: This is a rare example of two coexisting autoimmune disease entities: lichen planus of the oral mucosa, lip, eyelid and discoid lupus erythematosus of the skin. To our knowledge, this is the first reported case of lichen planus-lupus erythematosus overlap syndrome with eyelid involvement.     

Pure ocular cicatricial pemphigoid: A distinct immunopathologic subset of cicatricial pemphigoid

ObjectiveTo determine whether ocular cicatricial pemphigoid (OCP) may represent a distinct immunopathologic disease when it is pure ocular cicatricial pemphigoid (POCP) (e.g., only confined to the conjunctiva) or when it is associated with skin or extraocular mucous membrane lesions or both (OCP⁺).DesignProspective, immunologic, and immunopathologic study with special emphasis on direct immunoelectron microscopy.ParticipantsSix patients with POCP and seven patients with OCP⁺.InterventionAfter informed consent was obtained, a conjunctival biopsy was performed in all patients. Skin and extraocular mucosa biopsy specimens were harvested in selected cases only.Main outcome measuresResults of direct immunofluorescence and direct immunoelectron microscopy without freezing on conjunctival and skin biopsy specimens, indirect immunofluorescence, and Western immunoblotting analysis were analyzed.ResultsResults of direct immunoelectron microscopic examination of the conjunctiva showed the presence of immune deposits in the upper lamina lucida of the basement membrane zone in the six patients with POCP, whereas the immune reactants were located in the lower part of the lamina lucida and in the lamina densa of the basement membrane zone (conjunctiva, buccal mucosa, and skin) in the seven patients with OCP⁺. Direct immunofluorescence was positive in the biopsy specimens of three patients with POCP (50%) and the seven patients with OCP⁺ (100%). Results of indirect immunofluorescence study showed circulating autoantibody levels only in two patients with OCP⁺, and results of Western immunoblot analysis were negative.ConclusionsResults of direct immunoelectron microscopic examination of the conjunctiva support the hypothesis that POCP may be a disease entity distinct from mucocutaneous cicatricial pemphigoid.     

Episodic conjunctival inflammation after Stevens-Johnson syndrome

The authors studied the histopathologic, ultrastructural, and immunopathologic characteristics of conjunctiva from patients with Stevens-Johnson syndrome (SJS). A small subset of SJS patients with recurrent conjunctival inflammation unassociated with external factors such as lid margin keratinization, sicca syndrome, trichiasis, or entropion was identified. The ultrastructural and immunopathologic characteristics of the conjunctiva from these patients were distinctly different from those of the conjunctiva from SJS patients without recurrent conjunctivitis, and suggested an active, immunologically mediated inflammation. Vasculitis or perivasculitis, immunoreactant deposition in vessel walls, vascular basement membrane disruption, thickening, and reduplication, and a preponderance of helper T-lymphocytes, macrophages, and Langerhans' cells were the notable distinguishing features in those patients with recurrent conjunctival inflammation. This rare clinical syndrome may represent the ocular counterpart to recurrent dermal or oral mucosal erythema multiforme.     

Conjunctival cicatrizing disease presenting with lacrimal obstruction

Patients with conjunctival cicatrizing disease may develop lacrimal obstruction. Little is published on lacrimal obstruction as the presenting feature of otherwise asymptomatic cicatrizing conjunctival disease. The records of all patients presenting between 1994 and 2015 with lacrimal obstruction found to have cicatrizing conjunctival disease were reviewed. Demographic details, clinical findings, disease progression and treatment were analyzed. Thirty-five patients (25 female), aged 43–91 years (median 74, mean 71.3 years) had epiphora and a mild conjunctival cicatrizing process. Nine patients had onset of epiphora after cataract surgery. All except one patient had obstruction of the proximal lacrimal system (punctum and/or canaliculus). In 14 cases, the obstruction was unilateral (both puncta or canaliculi), with one progressing to bilateral obstruction after 11 years. In 19, all 4 puncta or canaliculi were obstructed. Two patients had unilateral nasolacrimal duct obstruction; one developed contralateral canalicular obstruction 2 years later. Conjunctival biopsies were obtained in 19 of 35 cases (54%), and OCP immunohistochemistry was positive in 7/19 (37%). All other biopsies showed chronic inflammation. Two patients had lichen planus. In follow-up (range 0.1–11 years, mean 3.2 years), 2 patients’ conjunctival disease progressed mildly, and 3 progressed moderately, with 2 of these 5 having positive OCP immunohistochemistry, and 1 having lichen planus. Patients with conjunctival cicatrization may present with lacrimal obstruction, usually punctal or canalicular. Conjunctival disease is usually mild and non-progressive, but patients should be monitored for disease progression.     

Ocular Cicatricial Pemphigoid

The characteristic feature of ocular cicatricial pemphigoid (OCP) is progressive shrinkage of the conjunctiva. In our series of 78 patients with OCP, 21% had cutaneous involvement and 50% had involvement of the oral mucosa. Immunoglobulins and the third component of complement are found bound to the conjunctival epithelium and basement membrane of patients with OCP. Circulating antibodies which bind to the conjunctival and corneal epithelium but not to the conjunctival basement membrane have also been demonstrated. OCP is associated with an increased prevalence of HLA-B12. The lids and conjunctiva of patients with OCP demonstrate an increased incidence of potential pathogens when compared with age- and sex-matched controls. When followed for a period averaging 22 months, the majority of patients not treated with systemic immunosuppressives or topical corticosteroids progress. However, OCP has a variable course because there were patients in all stages who did not progress. The acute manifestations of OCP may cause rapid shrinkage of the conjunctiva and may be suppressed with systemic corticosteroids.     

Preliminary serological studies comparing immunofluorescence assay with radioimmunoassay

We assayed serum from 12 patients with untreated cicatricial pemphigoid affecting the conjunctiva for circulating autoantibodies directed against the epithelial basement membrane zone. We employed a conventional indirect immunofluorescence assay, with monkey esophagus and human conjunctiva as substrates, and compared the results with those obtained employing a radioimmunoassay measuring antibasement membrane zone antibody binding to COLO-16 and to SCaBER tumor cell lines. The indirect immunofluorescence assay on normal human conjunctival substrate detected circulating antibodies to conjunctival epithelium in 6 of 12 CP patient serum specimens. Monkey esophagus failed to detect antibodies to the epithelial basement membrane zone. In contrast, autoantibodies were detected in all 12 specimens by the radioimmunoassay. Specificity, as demonstrated by appropriate controls and assay of normal human serum, was 100%. These results demonstrate that radioimmunoassay employing COLO-16 or SCaBER cells is an exquisitely sensitive and specific assay for detection of circulating antibasement membrane antibodies in patients with cicatricial pemphigoid affecting the conjunctiva.     

Chronic cicatrizing conjunctivitis in a patient with ocular cicatricial pemphigoid and fatal Wegener granulomatosis

PURPOSE: To describe a case of chronic cicatrizing conjunctivitis in a patient with ocular cicatricial pemphigoid and Wegener granulomatosis. METHODS: Observational case report. A retrospective study. RESULTS: An 80-year-old man presented with chronic cicatrizing conjunctivitis, peripheral corneal thinning, and Wegener granulomatosis, which were diagnosed by his referring physician based on clinical (recurrent epistaxis, sinus congestion) and histopathologic features of nasal mucosa (granulomatous inflammation, vasculitis). A conjunctival biopsy performed by us disclosed features of active Wegener granulomatosis and ocular cicatricial pemphigoid, which indicate lack of control of both diseases with methotrexate treatment. The patient died of pulmonary complications from Wegener granulomatosis 1 week after our evaluation. CONCLUSION: Ocular cicatricial pemphigoid and Wegener granulomatosis are both potentially fatal autoimmune diseases. Ocular involvement in Wegener granulomatosis indicates poor control of the underlying systemic condition and is a marker for active vasculitis, which indicates the need for treatment with cyclophosphamide.     

Conjunctival involvement in cicatricial and bullous pemphigoid: a clinical and immunopathological study.

Patients with bullous pemphigoid were found to have significant ocular abnormalities. In a group of 18 patients one had conjunctival shrinkage, and 11 of 15 (73%) had positive linear direct immunofluorescence on conjunctival biopsy from a clinically uninvolved site. Our ocular findings in a group of 14 with cicatricial pemphigoid are also reported and compared with those from a control group of 20. Our findings suggest there is overlap between the pemphigoid groups and raise further questions about the pathogenicity of immunoreactants within the basement membrane zone. Bulbar conjunctival biopsy was simple and well tolerated, and the rate of immunofluorescence positivity of conjunctiva was twice that of skin in both pemphigoid groups.     

The role of antibody to human beta4 integrin in conjunctival basement membrane separation: possible in vitro model for ocular cicatricial pemphigoid.

PURPOSE: To demonstrate the specific binding of autoantibodies present in the sera of patients with ocular cicatricial pemphigoid (OCP) to human beta4 integrin present in the normal human conjunctiva (NHC) and to study the role of OCP autoantibodies and antibody to human beta4 integrin in the pathogenesis of subepithelial lesion formation in OCP. METHODS: Indirect immunofluorescence assay and in vitro organ culture method using NHC were used. Sera and IgG fractions from 10 patients with OCP; immunoaffinity-purified OCP autoantibody; antibodies to human beta4, beta1, alpha6, and alpha5 integrins; and sera from patients with pemphigus vulgaris, bullous pemphigoid (BP), and chronic atopic and chronic ocular rosacea cicatrizing conjunctivitis; and normal human serum (NHS) were used. RESULTS: Nine of 10 OCP sera or IgG fractions, immunoaffinity-purified OCP autoantibody, antibodies to human beta4 and alpha6 integrins, and sera from patients with BP showed homogenous, smooth linear binding along the basement membrane zone (BMZ) of the NHC. NHS, antibodies to other integrins, and sera from patients with chronic cicatrizing conjunctivitis from other causes showed no such binding. When NHC was first absorbed with OCP sera and then reacted with anti-beta4 antibodies or vice versa, the intensity of the BMZ binding was dramatically reduced or completely eliminated, indicating that there were autoantibodies in OCP sera specific for the beta4 integrin. BMZ separation developed 48 to 72 hours after addition of total OCP sera, IgG fractions from OCP sera, immunoaffinity-purified autoantibodies from sera of patients with OCP, or anti-beta4 antibodies to the NHC cultures, but not after addition of normal control sera, sera from patients with chronic cicatrizing conjunctivitis from causes other than OCP, or sera from patients with OCP in clinical remission. CONCLUSION: Circulating anti-beta4 integrin antibody may have an important role in the pathogenesis of OCP.     

Linear IgA disease

PURPOSE: A case of linear IgA disease is reported to alert ophthalmologists and physicians to this unusual cause of chronic cicatrizing conjunctivitis. METHODS: Clinical records of a patient suffering from linear IgA disease were reviewed. RESULTS: A 65-year-old woman with a complicated medical history experienced rapidly progressive chronic cicatrizing conjunctivitis leading to corneal perforation. Undiagnosed gingivitis and palatal ulceration had been present for 5 years prior to the onset of ocular symptoms and vitamin C deficiency had followed the consequent dietary restrictions. A diagnosis of linear IgA disease was made on conjunctival biopsy, which demonstrated linear deposits of IgA along the epithelial basement membrane. The perforation was managed successfully with a conjunctival pediculate flap. Control of the inflammation was achieved with systemic prednisolone and cyclophosphamide but at the expense of serious systemic side-effects. CONCLUSIONS: Linear IgA disease causes progressive conjunctival cicatrization in many affected individuals.Although dapsone generally controls the inflammation, heavier systemic immunosuppression was required in this case. Involvement of skin or other mucosal surfaces may become symptomatic before the conjunctivitis, and physicians must be educated to refer patients for ophthalmological review on diagnosis. Conversely, ophthalmologists encountering ocular linear IgA disease should be aware of the possibility of other mucosal involvement requiring physician intervention.     

Linear IgA disease

Purpose: A case of linear IgA disease is reported to alert ophthalmologists and physicians to this unusual cause of chronic cicatrizing conjunctivitis. Methods: Clinical records of a patient suffering from linear IgA disease were reviewed. Results: A 65-year-old woman with a complicated medical history experienced rapidly progressive chronic cicatrizing conjunctivitis leading to corneal perforation. Undiagnosed gingivitis and palatal ulceration had been present for 5 years prior to the onset of ocular symptoms and vitamin C deficiency had followed the consequent dietary restrictions. A diagnosis of linear IgA disease was made on conjunctival biopsy, which demonstrated linear deposits of IgA along the epithelial basement membrane. The perforation was managed successfully with a conjunctival pediculate flap. Control of the inflammation was achieved with systemic prednisolone and cyclophosphamide but at the expense of serious systemic side-effects. Conclusions: Linear IgA disease causes progressive conjunctival cicatrization in many affected individuals. Although dapsone generally controls the inflammation, heavier systemic immunosuppression was required in this case. Involvement of skin or other mucosal surfaces may become symptomatic before the conjunctivitis, and physicians must be educated to refer patients for ophthalmological review on diagnosis. Conversely, ophthalmologists encountering ocular linear IgA disease should be aware of the possibility of other mucosal involvement requiring physician intervention.     

Two cases of cicatricial pemphigoid showing atypical immunofluorescent findings.

We describe two patients with the clinical symptoms of cicatricial pemphigoid (CP). Biopsy specimens of the conjunctiva were taken. Histologic examination revealed subepidermal bullae and infiltration of inflammatory mononuclear cells. Direct immunofluorescent study showed immunoglobulins bound to the basement membrane zone (BMZ) in these patients. The patients also had intercellular immunoglobulin deposition in the conjunctival epithelium. No circulating anti-BMZ antibodies were detected, but one patient had a circulating antiintercellular antibody. Rare cases of CP with atypical immunofluorescent findings are reported.     

In vivo confocal microscopy of normal conjunctiva and conjunctivitis

PURPOSE: To analyze the appearance of normal conjunctiva and conjunctival inflammation by in vivo confocal microscopy. METHODS: Conjunctiva of 15 normal patients and 21 patients with conjunctivitis including bacterial, papillary, follicular, granulomatous, and cicatrizing disease were analyzed by the Heidelberg retina tomograph (HRTII)/Rostock cornea modul (RCM). RESULTS: Scans of normal bulbar and tarsal conjunctiva corresponded well to the established anatomy except for a prominent, thickened epithelial basement membrane observed by in vivo microscopy. Presumed goblet cells were visible throughout the conjunctival epithelium. Adenoid structures and hair follicles were discernible in the tarsal conjunctiva in vivo. Conjunctival perfusion could be observed directly. Acute and chronic inflammatory cells, conjunctival papillary, and follicular reactions, as well as conjunctival cicatrization, could be discriminated. In a patient with conjunctival granuloma, in vivo confocal microscopy disclosed suture material inside the lesion. CONCLUSION: Confocal microscopy using near-infrared laser light is a useful new tool in the analysis of conjunctival tissue in vivo. It is a valuable aid in the differential diagnosis of conjunctival inflammation and thus may guide therapeutical decisions.     

Antibasement membrane antibody-mediated experimental conjunctivitis

In ocular cicatricial pemphigoid, the binding of circulating antibodies to conjunctiva is believed to initiate an antibody-mediated cytotoxic response that results in inflammation and tissue damage. To develop a model of antibody-mediated conjunctival inflammation, we examined the effect on conjunctiva of local or systemic administration of a murine monoclonal antibody against basement membrane of stratified squamous epithelium. Neonatal rabbits were given either a single subconjunctival or intraperitoneal injection of the antibody. Eyes were graded clinically for inflammation and conjunctival biopsies were performed. After subconjunctival injection, clinical and histologic inflammation as well as murine antibody and rabbit complement binding to conjunctival basement membrane were detected. With systemic administration there was post-injection clinical inflammation, and conjunctival basement membrane-bound murine antibody was detected. There was no difference observed in conjunctival mitotic rate or goblet cell frequency between treatment groups and controls, following either route of administration. We have created, therefore, a model for antibody-mediated conjunctivitis in rabbits by local or systemic administration of a monoclonal antibody against a component of stratified squamous epithelial basement membrane.     

Bilateral keratoconjunctivitis associated with lichen planus

PURPOSE: To describe a case of bilateral keratoconjunctivitis in a patient with lichen planus. METHODS: Case report and review of the English literature. RESULTS: To our knowledge, this is the fourth reported case of keratoconjunctivitis associated with lichen planus. A 33-year-old Navajo man with lichen planus had recurrent and progressive keratoconjunctivitis that failed to improve on multiple topical medications. Tapered oral prednisone, 2% topical cyclosporin, and amniotic membrane transplantation pacified the acute exacerbation. CONCLUSIONS: Our patient with lichen planus developed an ocular surface disease with cicatricial conjunctivitis, keratouveitis, keratoconjunctivitis sicca, punctate epithelial erosions, and persistent epithelial defects leading to noninfectious or infectious corneal ulceration. Amniotic membrane transplantation may play an adjunctive role in refractory cases of lichen planus-related keratoconjunctivitis. Topical cyclosporin may stabilize the ocular surface when combined with systemic immunosuppression in severe cases.     

Ocular Ferning Test: A Qualitative Test for Mucus Deficiency

A new qualitative test for the study of conjunctival mucus has been developed. Conjunctival scrapings were obtained from 196 patients. Microscopic mucus ferning (arborization) was observed in 148 (91%) patients with various forms of acute conjunctivitis. Six patients (18%) with cicatrizing conjunctivitis (diffuse conjunctival cicatrization, ocular pemphigoid, Stevens-Johnson syndrome) had mucus ferning in their conjunctival scrapings specimens. Mucus ferning was significantly absent (P < 0.005) in patients with diffuse conjunctival cicatrization when compared to mucus ferning in other forms of conjunctivitis. Ocular mucus ferning test is a simple inexpensive office test for the evaluation of patients with mucus deficiency.