Linear IgA dermatosis mimicking ocular cicatricial pemphigoid.

PURPOSE: To describe an unusual case of cicatrizing conjunctivitis. METHODS AND RESULTS: A 59 year old male presented in July 1997 with a complaint of intermittent redness and discharge of the right eye. Medical history was significant for a buccal mucosal lesion biopsy taken two years earlier that revealed subepidermal fibrosis. Conjunctival biopsy, performed to rule out ocular cicatricial pemphigoid, yielded a diagnosis of linear IgA dermatosis, an unusual diagnosis not often considered by ophthalmologists. CONCLUSIONS: The diagnosis of cicatrizing conjunctivitis is often overlooked. Its importance as it pertains to the life threatening disease of ocular cicatricial pemphigoid is clear.     

Treatment of ocular cicatricial pemphigoid with sulfasalazine]

PURPOSE: To report on three patients with biopsy-proven ocular cicatricial pemphigoid successfully treated with sulphasalazine. METHODS: Three case reports. RESULTS: A 71-year-old man, treated with dapsone for ocular cicatricial pemphigoid stopped his treatment because of an allergy to this drug. Oral sulphasalazine, 2.5 grams daily was successfully used as an alternative treatment (3 month follow-up). Two patients, aged 71 and 84 year old, were treated with dapsone for ocular cicatricial pemphigoid. Both patients stopped their treatment because of drug induced hemolytic anemia. They then received oral sulphasalazine, 4 grams daily. The disease was successfully controlled. In the first patient, sulphasalazine was discontinued after 13 months; and in the second patient no relapse was seen after a 16 month follow-up period. No adverse side effect of sulphasalazine occurred. CONCLUSION: Sulphasalazine, that has already been proven to be effective for Crohn's disease, also can be used in ocular cicatricial pemphigoid. However, further studies including a larger series of patients along with a longer follow-up are necessary to confirm the efficacy of sulphasalazine in this disease.     

Mucous membrane pemphigoid: an update

PURPOSE OF REVIEW: To review articles on mucous membrane pemphigoid, published between June 2004-May 2005. RECENT FINDINGS: Decreased glycosylation of mucin was found in patients with ocular cicatricial pemphigoid. A unique antigen in oral mucous membrane pemphigoid has not yet been identified. Increased vascular cell adhesion molecule and intercellular adhesion molecule 1 expression was found in skin of patients affected by mucous membrane pemphigoid. Autoreactive T cells to an epitope of bullous pemphigoid antigen 180 kilodaltons were identified in the blood of some patients with mucous membrane pemphigoid. Circulating IgA against an antigen in mucous membrane pemphigoid was found in about 20% of patients, without prognostic significance. Enhanced sensitivity for direct immunofluorescence was reported if skin biopsy specimens were stored for 24 hours in saline. An enzyme-linked immunosorbent assay for detection of circulating autoantibodies against laminin-5 was developed. Sensitivity was higher than indirect immunofluorescence on salt-split skin and immunoblotting. Patients with younger onset (<60 years) of ocular cicatricial pemphigoid were found to have disease evolution similar to that of an older group (>70 years) but were visually impaired earlier in life. Intravenous immunoglobulin as treatment of ocular cicatricial pemphigoid was found to be superior to conventional immunosuppressants, with fewer side effects and better long-term outcome for halting disease activity. Intraoperative adjunction of mitomycin C during fornix reconstruction with amniotic membrane resulted in achieving a deeper fornix in 83% of patients with various cicatrizing conjunctivitis. Transplantation of cultured epithelial cells of oral mucosa in corneal limbal stem cell deficiency was successful in improving visual acuity and reestablishing corneal transparency in mid- to advanced ocular cicatricial pemphigoid. SUMMARY: Further advances have been achieved in the field of mucous membrane pemphigoid.     

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     

Porphyria cutanea tarda presenting as cicatricial conjunctivitis

PURPOSE: To report a case of porphyria cutanea tarda presenting as cicatricial conjunctivitis.DESIGN: Observational study.METHODS: A 31-year-old man presented with bilateral inferior symblepharon, superior tarsal conjunctival scarring and concretions, and recurrent conjunctival and episcleral injection.RESULTS: Four years after initial presentation, the patient developed hepatitis C, and 2 years later blisters on his scalp and hands. Direct immunofluorescence studies of biopsies taken from the palpebral conjunctiva of the right lower lid were negative for cicatricial pemphigoid. A twenty-four hour urine specimen analysis revealed elevated levels of uroporphyrins and polycarboxylated porphyrins, confirming the diagnosis of porphyria cutanea tarda. The patient was treated with repeated phlebotomies and oral hydroxychloroquine, which resulted in a significant decrease in the skin lesions, conjunctival injection, and concretions under the upper lids.CONCLUSIONS: Cicatricial conjunctivitis may be a manifestation of porphyria cutanea tarda.     

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.     

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.     

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.     

Exacerbation of undiagnosed ocular cicatricial pemphigoid after repair of involutional entropion

We report a case of exacerbation of undiagnosed ocular cicatricial pemphigoid after repair of involutional entropion. A lateral tarsal strip was performed to address entropion in the setting of eyelid laxity. No evidence of ocular cicatricial pemphigoid was observed before surgery. Postoperatively the patient developed intense conjunctival inflammation and diffuse symblepharon formation. Conjunctival biopsy demonstrated immunoglobulin and complement deposition at the basement membrane consistent with ocular cicatricial pemphigoid. Clinicians should be aware of the possibility of underlying ocular cicatricial pemphigoid in all patients with entropion, including those without a cicatricial component.     

Ocular cicatricial pemphigoid

Ocular cicatricial pemphigoid is a chronic progressive immunological disease, although acute inflammatory episodes may occur. Typically, it leads to fornix foreshortening, symblepharon and dry eye problems. In the end stage, the cornea is severely affected, resulting in serious vision loss. We report on the diagnosis and management of a patient with ocular cicatricial pemphigoid and comment on the differential diagnosis, complications and treatment options.     

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.     

HLA antigens in ocular cicatricial pemphigoid.

HLA antigen frequencies were studied in 20 patients with ocular cicatricial pemphigoid and 245 normal persons. HLA-B12 demonstrated an increased frequency of 45% in patients with ocular cicatricial pemphigoid which was statistically significant when compared to a frequency of 19.6% in the general population (P less than 0.02). In patients with ocular cicatricial pemphigoid the prevalance of HLA-A3 was increased to 35% when compared to 22.9% in the general population, but this was not statistically significant. The frequency of finding either HLA-A3 or B12 in patients with ocular cicatricial pemphigoid was increased to 75% in comparison with 38.8% in the general population (P less than 0.005). The present study suggests that HLA-B12 and possibly HLA-A3 are genetic markers for ocular cicatricial pemphigoid.     

Ocular manifestations in a case of childhood cicatricial pemphigoid

PURPOSE: Cicatricial pemphigoid is a rare chronic autoimmune disease, characterized by progressive alterations on the skin and mucous membranes. Ocular lesions consists of chronic conjunctivitis, progressive subepithelial fibrosis on the conjunctival fornix together with symblepharon formation, obstruction of the Meibomian ducts, sicca syndrome, and occasionally, entropion associated with consequent trichiasis and corneal ulcers. METHODS: A 9-year-old patient with cicatricial pemphigoid with severe eye involvement came to our observation. A complete anamnesis, ophthalmologic examination, and systemic evaluation, including serum antibody levels evaluation and biopsies of mouth, vulva, parotid, and intestine mucosa, were performed. RESULTS: Ocular examination showed blepharospasm, conjunctival hyperemia, symblepharon, total cicatricial corneal leucoma, severe dryness, trichiasis, and eyelid edema. The results of medical and surgical treatment are reported. CONCLUSIONS: Given the serious clinical picture, possibly due to a late diagnosis, it was not possible to avoid relapse and appearance of new cicatricial adherences for which we considered wait and see the most appropriate approach, protecting the anterior segment of both eyes, sacrificing their function. Further follow-up was not possible as the patient died. An early diagnosis would have had a significant influence on the clinical course and on the response to therapy.     

Scanning electron microscopy of conjunctival surfaces in patients with ocular cicatricial pemphigoid

The conjunctival surfaces of ten patients with active, ocular cicatricial pemphigoid, three patients with drug-controlled ocular cicatricial pemphigoid, and six patients with normal conjunctivas were studied using scanning electron microscopy. A homogeneous granular sheet of amorphous mucin-like material was observed covering extensive areas of the conjunctiva in eight of ten patients with active ocular cicatricial pemphigoid. This sheet of amorphous material was absent on drug-controlled ocular cicatricial pemphigoid and normal conjunctival specimens. Our study demonstrates that patients with active ocular cicatricial pemphigoid possess ocular surface mucus that appears thicker and more continuous than normal ocular mucus when observed with scanning electron microscopy. This observation is in agreement with clinical observations of thick mucus strands in the inferior fornix of patients with active ocular cicatricial pemphigoid.     

A case of suspected drug-induced ocular pemphigoid

BACKGROUND: Lacrimal obstruction can occur as a complication of ocular cicatricial pemphigoid. We report a patient who was diagnosed as having drug-induced ocular cicatricial pemphigoid associated with acquired lacrimal canalicular obstruction in spite of relatively mild subconjunctival scar formation. CASE: The patient was a 69-year-old woman. She had been treated for glaucoma, blepharoconjunctivitis, dacryocystitis, and lacrimal canalicular obstruction for two years with topical administration including 0.5% timolol maleate, 0.1% dipivefrine hydrocholoride, 0.1% fluorometholone, and 0.3% ofloxacin. The patient had moderate conjunctival hyperemia without shortening of the inferior conjunctival sac, corneal ulceration, neovascularization, and keratinization. Lacrimal canalicular obstruction progressed further as topical ocular medications were continued. Topical anti-glaucoma medications were stopped after dacryocystorhinostomy. Although the blepharoconjunctivitis was improved, left inferior conjunctival symblepharon, and medical canthal keratinization was progressive despite the use of topical corticosteroids. The conjunctival biopsy specimen showed the lacrimal punctum covered with proliferated conjunctival epithelium. There was a moderate stromal infiltration of small lymphocytes and plasma cells. We diagnosed this patient as having drug-induced ocular cicatricial pemphigoid caused by topical anti-glaucoma medications. CONCLUSION: Lacrimal canalicular obstructions may occur with the topical anti-glaucoma medications even when subconjunctival scarring is mild.     

Mucous membrane pemphigoid in a patient with chronic lymphocytic leukemia

PURPOSE: To describe a case of mucous membrane pemphigoid (MMP) with ocular manifestations in a patient subsequently diagnosed with B-cell chronic lymphocytic leukemia (CLL). METHODS: Case report and literature review. RESULTS: A 64-year-old man presented with redness and irritation of both eyes. The patient also had blistering lesions on the roof of his mouth, trunk, and buttocks as well as bilateral conjunctival ulceration and symblepharon formation. A complete blood count performed before initiating treatment of presumed mucous membrane pemphigoid revealed a markedly increased white blood cell count (83,920) with a predominance of lymphocytes. Hematologic evaluation including immunophenotyping flow cytometry resulted in the diagnosis of B-cell chronic lymphocytic leukemia. Cyclophosphamide treatment improved his MMP and decreased the white blood cell count. CONCLUSIONS: Mucous membrane pemphigoid has been reported in association with a variety of nonhematologic malignancies. This case suggests that mucous membrane pemphigoid may also occur in B-cell CLL and supports the concept that autoantibodies play a role in the pathogenesis of this cicatricial conjunctival disease.     

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.     

Diagnostics and pharmacological treatment of ocular cicatrical pemphigoid

Ocular cicatricial pemphigoid (OCP) is an autoimmune disease characterize by mucous membrane fibrosis and skin changes resulting with scarring. The pathogenic mechanisms of ocular cicatricial pemphigoid are incompletely understood. Antibasement membrane antibodies which lead to subepithelial blistering, granulation tissue and inflammatory infiltrate formation in the substantia propria are thought to be the main pathophysiological mechanisms in cicatricial pemphigoid. It has been found eosinophils and increased collagen type I and III. Human leukocyte antigen HLA-DR2, HLA-DR4 and DQw7 genotypes have been identified as conferring increased susceptibility to the development of this disease. Ocular cicatrical pemphigoid (OCP) is one of the forms of bullous pemphigoid. Initial symptoms of ocular pemfigoid are not characteristic. Conjunctival fibrosis may cause severe entropion, trichiasis, symblepharon, dry eye syndrome, corneal epithelial erosions or ulceration. Secondary glaucoma is one of the most frequent complications. Ocular cicatricial pemphigoid may be chronic, acute, or subacute disease with periodic exacerbation of conjunctival inflammation. The treatment in this disease are topical drops or ointment (lubricants, corticosteroids, antibiotics, antiglaucomatous). Oral dapsone and corticosteroids may control the activity of the disease. In other progressive cases immunosuppressive drugs must be used (azathioprine, cyclophosphamide, methotrexate, mycophenolan mofetil, daclizumab, intravenous immunoglobulin therapy). To make an early diagnosis of ocular cicatricial pemphigoid, biopsy and immunohistochemical analysis of conjunctiva should be performed in every case of persistent conjunctival inflammation.     

Intravenous immunoglobulin therapy for ocular cicatricial pemphigoid: a preliminary study

OBJECTIVE: To report the effects of intravenous immunoglobulin treatment of ten patients with progressive ocular cicatricial pemphigoid who did not respond to conventional immunomodulatory regimens. DESIGN: Noncomparative, interventional case series. PARTICIPANTS: Ten patients with biopsy-proven progressive cicatricial pemphigoid affecting the eyes who did not respond adequately to other local and systemic immunosuppressive treatment regimens. INTERVENTION: Intravenous infusions of pooled human immunoglobulin, 2 to 3 g/kg body weight/cycle, divided over 3 days, and repeated every 2 to 6 weeks. MAIN OUTCOME MEASURES: Reduction in conjunctival inflammation, prevention of progression of subepithelial conjunctival fibrosis, improvement in ocular symptoms (discomfort, photophobia), improved visual acuity, reduction in extraocular mucosal lesions. RESULTS: Clinical deterioration was arrested and resolution of chronic conjunctivitis was documented in all ten patients. Maximum therapeutic effect was observed and maintained after a minimum of 4 cycles of therapy; three patients required 12 cycles before disease control. The duration of therapy in these ten patients has been 16 to 23 months (mean, 19.3 months) with no treatment-induced side effects. Extraocular mucosal lesion resolution has occurred in all but one patient, Visual acuity has stabilized or improved in all ten patients, and subjective complaints of discomfort and photophobia have decreased in all patients. CONCLUSIONS: Intravenous immunoglobulin immunomodulatory therapy can be a safe and effective therapy for otherwise treatment-resistant ocular cicatricial pemphigoid.     

Okuläres vernarbendes Pemphigoid Retrospektive Analyse von Risikofaktoren und Komplikationen

Cicatricial pemphigoid (CP) is a rare autoimmune disease characterized by subepidermal blistering and progressive cicatrization affecting the skin and mucosa. Ocular involvement occurs in approximately 70% of the patients. METHODS: The course of the disease, complications and putative risk factors in patients with ocular cicatricial pemphigoid (OCP) treated at the Departments of Ophthalmology and Dermatology were analyzed retrospectively from 1986 to 1998. RESULTS: Eighteen of 28 patients (64%) with CP demonstrated ocular involvement. The mean age of patients with OCP was 73 years; 61% were female. At the time of referral to our hospital, all patients had reached advanced stage III (83%) or IV (17%) of OCP. In 38% of patients vision was already reduced to < 20/200 at first presentation. Twenty-eight percent of patients additionally suffered from glaucoma. Two patients exhibited life-threatening extraocular manifestations of CP (larynx stricture, esophagus stricture). Conjunctival or mucosal biopsies were performed in 15 patients with OCP and showed typical immuno-deposits at the basement membrane zone in 12/15 patients. Therapy with dapsone (12 patients), oral steroids (11 patients), azathioprine (5 patients), cyclophosphamide (4 patients), colchicine (2 patients) and methotrexate (1 patient) was used concomitantly or consecutively. Complications of OCP including entropion, recurrent epithelial erosions, corneal ulcers, keratitis, and corneal perforations required multiple surgical interventions such as entropion surgery (8 patients), tarsorrhaphy (3 patients), mucous membrane grafting (1 patient), amniotic membrane transplantation (1 patient), tectonic keratoplasty (1 patient), keratoprosthesis (1 patient) and enucleation (1 patient). Despite control of the inflammatory process, further visual loss occurred in 53% of eyes. Reading visual acuity could only be maintained in 35% of eyes. DISCUSSION: Early diagnosis and therapy can prevent ocular complications of OCP. This study indicates that advanced stages of the disease often result in irreversible visual loss despite institution of immunosuppressive therapy. Whether or not the high association of OCP with glaucoma and/or anti-glaucomatous treatment in our patients represents part of the underlying disease process or plays a role in the pathogenesis of OCP must still be clarified.