Penetrating keratoplasty in ocular cicatricial pemphigoid

PURPOSE: Ocular cicatricial pemphigoid (OCP) is a chronic progressive disease characterised by exacerbations of immunologically driven conjunctival inflammation. In the advanced stages of the disease, severe xerosis with mechanical factors may contribute to the development of blinding keratopathy. The authors report two cases of penetrating keratoplasty (PK) in patients with OCP and discuss the modalities of the surgical procedure for this particular disease. METHODS: Two patients with stage III OCP according to Foster's classification, underwent PK. Initial and final visual acuity, indications of PK, surgical procedure, postoperative therapy, and complications were recorded. RESULTS: For the first patient, after 3 months of follow-up, the graft is still clear, with a remarkable improvement in vision (3/10). For the second patient, however, graft rejection developed 15 days after the operation, complicated later by endophthalmitis, which was controlled with an antibiotic. DISCUSSION: The progression of ocular pemphigoid involves the filling of the conjunctival fornices, formation of symblepharon with lagophthalmos, and dry eye, from which blinding keratopathy can originate. A corticosteroid-based or immunosuppressant treatment blocks the progression of the fibrosis but does not get rid of palpebrale or corneal anomalies, making surgery necessary. This surgery generally gives disappointing results and should be planned when the disease is perfectly under control, during a lull in the disease so as to avoid reactivation of the fibrosis process. Reconstruction of the conjunctival fornices should also precede any corneal transplantation. CONCLUSION: These results indicate that PK may be performed to restore of sight in patients with advanced OCP after controlling the primary immunological process and aggressive treatment of the mechanical factors damaging the ocular surface.     

Long term results of systemic chemotherapy for ocular cicatricial pemphigoid

Ocular cicatricial pemphigoid (OCP) is a chronic, progressive, blinding, autoimmune disease that scars mucous membranes. We studied the long-term outcome in 104 consecutive patients (average follow-up: 4 years) to determine whether complete remission could be achieved following a course of treatment with immunosuppressive drugs. We found that prolonged periods of remission off therapy are maintained in about one third of OCP patients. Follow-up must be continued for life as relapse occurs in approximately one third of cases. Those who relapsed regained disease control readily upon reinstitution of therapy and did not deteriorate to more advanced cicatrization. Sex, age, initial degree of inflammation and the incidence of extraocular involvement did not bear a prognostic significance. The mechanism which underlies the differing responses to therapy is not yet known.Abbreviations BMZ basement membrane zone - CP cicatricial pemphigoid - OCP ocular cicatricial pemphigoid - OD right eye - OS left eye     

Chronic cicatrizing conjunctivitis

Conjunctival fibrosis may result from chronic inflammation and may lead to alterations of conjunctival architecture. This results in ocular dryness, entropion and trichiasis, and corneal complications. Causes of conjunctival cicatrization are not limited to autoimmune diseases, such as ocular cicatricial pemphigoid, a severe disease associated with poor ocular prognosis. Other well-known causes include thermal and chemical burns, postinfectious conjunctivitis, and Stevens-Johnson syndrome. Ocular rosacea and atopic keratoconjunctivitis often are underdiagnosed causes of conjunctival fibrosis. Medical history, physical exam, and laboratory tests often allow for diagnosis of the underlying disease. Medical management varies according to specific causes, and many surgical strategies are available to restore corneal transparency and normal palpebral architecture.     

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.     

眼瘢痕性类天疱疮机制及治疗研究进展

眼瘢痕性类天疱疮(ocular cicatricial pemphigoid,OCP)是黏膜类天疱疮(mucous membrane pemphigoid,MMP)在眼部的一种特殊表现形式,目前发病机制尚不明确,可由抗原抗体反应、炎细胞浸润、细胞因子作用、钙离子水平升高、易感基因等多种因素导致。病变早期表现为慢性进行性的结膜纤维化性炎症,晚期可见角膜混浊及新生血管形成,最终导致视力严重丧失。因此,及时对OCP患者进行规范的临床治疗尤为重要。例如氨苯砜、免疫球蛋白(intravenous immunoglobulin,IVIG)、利妥昔单抗(rituximab,RTX)、肿瘤坏死因子拮抗剂、肾上腺皮质激素类药物,可以有效控制炎症反应、延缓疾病进展。手术治疗可在OCP患者并发严重倒睫、角膜病变及白内障时酌情考虑。     

Mast cells in conjunctiva affected by cicatricial pemphigoid

Ocular cicatricial pemphigoid (OCP) is characterized by progressive conjunctival subepithelial fibrosis often leading ultimately to corneal blindness. Mast cells have been shown to play a role in several fibrotic disorders, but the role of mast cells in OCP is unknown. The authors compared the mast cell population in conjunctival biopsy specimens from 14 OCP patients and from six controls by using specific histochemical stains for mast cell subsets. The total mast cell number and the ratio of connective tissue mast cells to mucosal mast cells (MMCs) were significantly higher in OCP than in normal conjunctiva (P less than 0.05). This report is the first analysis of mast cell subsets in human ocular tissue. The results suggest that connective tissue mast cells (CTMCs) may play an important role in OCP and that therapy directed toward mast cells and their mediators may be an appropriate avenue for further exploration.     

Ocular cicatricial pemphigoid.

Cicatricial pemphigoid is an inflammatory disease of presumed autoimmune etiology. It most commonly affects the conjunctiva and oral mucosa and less commonly the skin. The ocular manifestations of the disease include bilateral conjunctival shrinkage, xerosis, and corneal opacification. The progression of cicatricial pemphigoid is variable and can be interrupted by periods of remission or by periods of rapid exacerbation. Ocular surgery and topical pharmaceuticals may contribute to the exacerbation of this disease. Current treatment consists of systemic immunosuppressants and systemic corticosteroids.     

Amniotic membrane transplantation elicits goblet cell repopulation after conjunctival reconstruction in a case of severe ocular cicatricial pemphigoid

PURPOSE: The surgical procedures used until now to rebuild the conjunctiva in patients affected by ocular cicatricial pemphigoid (OCP) have not demonstrated appreciable anatomical and functional success. This study reports the postoperative clinical and cytological outcomes of a human amniotic membrane transplantation (AMT) to rebuild the conjunctiva in a case of late stage OCP. METHODS: We present a 75-year-old woman with a severe form of pemphigoid with entropion, trichiasis, symblepharon and blunting of the fornices, who underwent excision of the scarred and inflamed tissue covering the ocular surface and AMT. RESULTS: Our data show an improvement of the ocular surface condition, with reacquired fornix depth, reduced inflammation and presence of goblet cells at each follow-up. CONCLUSION: Amniotic membrane transplantation was successful as a first step procedure to reduce inflammation and to rebuild a physiological conjunctival epithelium in late stage OCP.     

Role of cyclophosphamide and high dose steroid in ocular cicatricial pemphigoid.

AIMS/BACKGROUND--Ocular cicatricial pemphigoid (OCP) can present with severe conjunctival inflammation that requires systemic immunosuppression to avoid serious ocular morbidity. This study aimed to assess the clinical response to cyclophosphamide and short term, high dose prednisolone in this group of patients. METHODS--A prospective, unmasked study assessed patients presenting with either 'severe' ocular inflammation (n = 4) or 'marked' or 'severe' ocular inflammation that had failed to respond to other systemic immunosuppression (n = 6). Nineteen inflamed eyes of 10 consecutive patients were enrolled. RESULTS--The ocular inflammation resolved in 15 eyes in a mean time of 2.4 months. Two eyes perforated despite treatment and one patient was unable to tolerate the medication. Progressive cicatrisation occurred in 21%. CONCLUSION--Cyclophosphamide and short term, high dose prednisolone are effective in severe inflammation caused by OCP but may not completely prevent cicatrisation.     

Cataract surgery in ocular cicatricial pemphigoid

The authors report the results of their experience with cataract surgery in 20 patients (26 eyes) with biopsy-proven cicatricial pemphigoid. All patients were on systemic immunosuppression at the time of surgery (dapsone, azathioprine, cyclophosphamide, or combinations) and were treated with perioperative oral corticosteroids. Patients were evaluated pre- and postoperatively for conjunctival inflammation, conjunctival cicatrization, degree of keratopathy, and disease stage. No patient progressed in disease stage. Vision improved an average of 3.5 Snellen lines (-3 to +8). Worse outcome was associated with chemotherapy intolerance or the presence of any preoperative conjunctival inflammation. Thirteen patients remained on immunosuppressives for the entire study. Corneal ulcers developed postoperatively in three patients in whom continued immunosuppression was not tolerated. Possible mechanisms for inflammatory exacerbation after surgery are discussed. Results indicate that after successful abolition of all conjunctival inflammation through chemotherapy, cataract surgery may be safely performed in patients with cicatricial pemphigoid.     

眼瘢痕性类天疱疮的治疗策略

眼瘢痕性类天疱疮（ OCP）是一种罕见的累及眼结膜的自身免疫病,常由于其早期的非特异性临床表现导致误诊或延误治疗,最终造成眼表结构功能损害及失明。 OCP治疗主要通过全身免疫抑制控制炎症反应及瘢痕进展,经过多年的临床探索及众多新药问世,目前治疗期前景乐观。现全身免疫抑制治疗主要包括传统免疫抑制治疗（CIST）及新型免疫抑制治疗。 CIST现主要为治疗OCP的一线用药,但由于其副作用较多、对顽固性OCP疗效不佳而有一定缺陷;新型免疫抑制药物如IVIg、抗TNF-α药及单克隆抗体等,凭借强力的免疫抑制作用及较少副反应逐渐受到重视,在今后可能可作为一线用药的更优选择。中晚期OCP患者因并发眼表畸形及角膜浑浊等严重影响生活质量,在全身炎症情况控制稳定的前提下可行手术治疗。局部治疗主要针对不同的眼表并发症行相应处理,以改善局部症状。经过科学合理的药物及手术治疗,大部分OCP患者预后良好,但仍有少量反复发作者需进一步研究,寻找最为合适的治疗策略。     

Eosinophil granule proteins expressed in ocular cicatricial pemphigoid

BACKGROUND—Blister formation and tissue damage in bullous pemphigoid have been attributed to the release of eosinophil granule proteins—namely, to eosinophil derived cationic protein (ECP) and major basic protein (MBP). In the present investigation these eosinophil granule proteins were studied in the conjunctiva of patients with ocular cicatricial pemphigoid (OCP).
METHODS—Conjunctival biopsy specimens obtained from patients with subacute (n=8) or chronic conjunctival disease (n=13) were analysed histologically and immunohistochemically using antibodies directed against EG1 (stored and secreted ECP), EG2 (secreted ECP), MBP, CD45 (common leucocyte antigen), CD3 (pan T cell marker), and HLA-DR (class II antigen).
RESULTS—Subepithelial mononuclear cells, mast cells, and neutrophils were detected in all specimens. The number of mononuclear cells, neutrophils, CD45+ cells, CD3+ cells, and the HLA-DR expression were significantly higher in the subacute than in the chronic disease group. Some eosinophils were found in specimens from five of eight patients with subacute OCP, but in none of the patients with chronic disease. The eosinophil granule proteins (ECP and MBP) were found in the epithelium and substantia propria in patients with subacute conjunctivitis.
CONCLUSIONS—Subepithelial cell infiltration in the conjunctiva greatly differs between subacute and chronic ocular cicatricial pemphigoid specimens. The findings suggest that eosinophil granule proteins may participate in tissue damage in acute phase of inflammation in OCP.

     

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.     

Progression of disease in ocular cicatricial pemphigoid.

BACKGROUND: Ocular cicatricial pemphigoid (OCP) is a sight threatening autoimmune disease that can lead to severe conjunctival cicatrisation and keratopathy. It has a variable course and little is known about the factors that determine disease progression. This study analysed the factors that have prognostic significance regarding disease outcome, progression, and keratopathy. METHODS: Sixty six patients with OCP were monitored prospectively at Moorfields Eye Hospital. The influence of ocular features, the systemic disease, and the management were analysed to identify factors that influence the outcomes and disease progression. RESULTS: The mean age at presentation was 67 years; 56% were men. The binocular visual acuities were 6/24 or worse in 25%. Extensive cicatrisation at presentation was common but correlated only weakly with the visual prognosis. Systemic manifestations included lesions of the mouth in 44%, pharynx in 30%, oesophagus in 27%, nose/sinus in 18%, and skin in 17%. There was no association between the ocular and systemic manifestations. Persistent corneal epithelial defects and limbitis occurred in 18% and 32%, respectively, and both were associated with a worse visual prognosis. Systemic immunosuppression was ultimately prescribed in 74%, mainly in patients with advanced stages of conjunctival cicatrisation. Of patients with more than 24 months follow up, progression of cicatrisation occurred in 35% of eyes (16/46) all but one of which were associated with episodes of conjunctival inflammation. CONCLUSIONS: Persistent epithelial defects, limbal inflammation, and ongoing conjunctival inflammation are important factors that lead to keratopathy and visual handicap. These require aggressive management, often with systemic immunosuppressive treatment. Close follow up is required in cases with extensive cicatrisation.     

Schleimhautpemphigoid mit okulärer Beteiligung

Treatment of mucous membrane pemphigoid (MMP) aims at reduction of conjunctival inflammation by means of systemic immunosuppression. In addition, cicatricial progression and management of the resulting ocular surface disease requires topical conservative or surgical measures. The former includes systemic immunosuppression with steroids and other immunosuppressive agents: dapsone in mild to moderate disease and cyclophosphamide in severe cases have been established in two randomized trials. Other agents such as methotrexate, azathioprine, mycophenolate mofetil or monoclonal antibodies including daclizumab or rituximab were found to be effective in uncontrolled small studies. Surgery is primarily focused on eyelid problems such as entropium and trichiasis. Ocular surface disease and secondary complications, e.g. cataract formation and glaucoma, may need surgical treatment. Any surgery is associated with the risk of a relapse of inflammation and should be postponed until inflammation is controlled by systemic therapy. Management of MMP patients requires close collaboration of a specialized ophthalmologist with specialists from dermatology and internal medicine.     

The acute manifestations of ocular cicatricial pemphigoid: diagnosis and treatment

Seven patients with ocular cicatricial pemphigoid displayed acute inflammatory activity that could not be attributed to secondary bacterial infections, trichiasis, or lagophthalmos secondary to symblepharon. This acute inflammatory activity was manifested either as a localized conjunctival mound that was ulcerated and intensely hyperemic or as diffuse and intense conjunctival hyperemia and chemosis. Acute disease activity developed shortly after conjunctival biopsy in three patients and appeared spontaneously in the other four patients. Conjunctival biopsy specmens disclosed a heavy infiltrate of polymorphonuclear leucocytes within and beneath the conjunctival epithelium in addition to the chronic inflammatory cells typically found in this condition. The acute manifestations of ocular cicatricial pemphigoid cause rapid shrinkage and scarring of the conjunctiva. Systemic corticosteroids suppressed the acute disease activity and prevented additional scarring in all five patients treated.     

Management and outcome of cataract surgery in ocular cicatricial pemphigoid

· Background: Patients with ocular cicatricial pemphigoid (OCP) lose vision due to corneal disease or cataract, which may be senile, drug induced or complex. The success of cataract surgery in these patients may be limited by an increased risk of surgical complications due to difficult access and visualisation, exacerbation of the cicatrising disease following surgery or later progression of the corneal disease. We report our experience on cataract surgery in OCP. · Methods: Cataract surgery was performed on 15 eyes of 13 patients. In the pre- and postoperative examinations the stage of the condition (according Foster’s classification), the degree of conjunctival hyperaemia and the visual acuity (VA) were evaluated and topical and systemic medication recorded. All procedures used a corneal incision. The technique was intracapsular (ICCE) in 1, extracapsular (ECCE) in 4 and phacoemulsification in 10 eyes. In 13 of 15 cases an intraocular lens was implanted. The unoperated fellow eyes constituted a control group. Duration of postoperative follow-up was 35.8±39.1 months. · Results: 10 of 15 eyes had stage III disease or worse before surgery. Two eyes following ECCE showed early postoperative progression of the disease. Postoperative visual acuity improved in 14 eyes by 2 or more lines. Preoperatively 5 eyes met the criteria for blind registration, whereas postoperatively all eyes achieved a VA of at least 0.1. In 6 eyes the VA was sufficient to allow driving. However, by the 22nd postoperative month progressive cicatricial and ocular surface disease resulted in a regression of the achieved visual rehabilitation in 8 eyes. · Conclusion: OCP does not prevent successful cataract surgery if appropriate techniques are used and precautions taken. Systemic perioperative immunosuppression is necessary in patients with active conjunctival inflammation. The use of small clear corneal incision surgery is recommended to reduce the risk of an acute exacerbation of conjunctival inflammation. Although visual rehabilitation may be only temporary due to progression of the conjunctival or corneal disease in OCP, cataract surgery can provide some benefit, in severely disabled patients, without precipitating an acute exacerbation of OCP. Received: 25 February 1999 Revised: 23 August 1999 Accepted: 24 August 1999     

Corneal ulcer as an atypical presentation of ocular cicatricial pemphigoid

PURPOSE: To describe three patients, each presenting noninfective corneal epithelial damage as first manifestation of ocular cicatricial pemphigoid (OCP). METHODS: Case report. RESULTS: Patients 1 and 2 were referred to the authors' clinic for corneal ulcer while Patient 3 for relapsed epithelial defects. All patients had negative history for systemic diseases and microbiological tests were negative. Topical steroid treatment induced the complete resolution of corneal damage. During the follow-up period, the onset of mild conjunctival fibrosis in the lower fornix allowed the authors to suspect OCP, confirmed by conjunctival biopsy. CONCLUSIONS: In the three patients corneal damage was an early sign of OCP, in the absence of typical signs of conjunctival fibrosis. The authors thus suggest considering conjunctival biopsy as a useful additional test in the management of idiopathic corneal ulcers.     

Inferior retractor plication surgery for lower lid entropion with trichiasis in ocular cicatricial pemphigoid.

AIMS--To assess the outcome of inferior retractor plication surgery for lower lid entropion in patients with ocular cicatricial pemphigoid (OCP). This technique avoids surgery on the conjunctiva that can result in exacerbations of disease activity. METHODS--This prospective study assessed the outcomes of a standard 'Jones' type plication in 14 lids of 10 patients with OCP. Seven patients were taking systemic immunosuppression and no patients had conjunctival inflammation for the 4 months before surgery. RESULTS--Life table analysis showed a 77% chance of anatomical success at 2 years and a 54% chance of completely preventing lash-globe touch. The surgery did not cause clinical activation of conjunctival inflammation or other complications. Anatomical failure was primary (n = 2) and due to late cicatrisation (n = 1). Three further cases had restoration of normal anatomy but the patients had persistently misdirected lashes that touched the globe. CONCLUSION--This technique gives good anatomical success over long periods and is particularly safe when there is no conjunctival inflammation present before surgery.     

Sulphapyridine--a new agent for the treatment of ocular cicatricial pemphigoid.

AIMS--Ocular cicatricial pemphigoid (OCP) is a severe, potentially sight threatening systemic disease that sometimes requires systemic immunosuppression. This study assessed the clinical outcome of patients with OCP treated with sulphapyridine, a sulphonamide with an anti-inflammatory and immunosuppressive action but few side effects. METHODS--A prospective, single armed, unmasked clinical trial was undertaken at Moorfields Eye Hospital. Twenty consecutive patients with moderate or marked conjunctival inflammation due to OCP were treated with oral sulphapyridine 500 mg twice daily. The degree of ocular inflammation was assessed as nil, mild, moderate, marked, or severe. Success was defined as resolution to mild or less. Ocular limbitis, systemic features of the disease, and side effects of the drug were also monitored. RESULTS--Follow up was a mean of 12.3 (SD 4.0) months and ranged from 7 to 17 months. A successful reduction in inflammation was recorded in 22/39 eyes (56%) and 10/20 patients (50%). This improvement occurred within 1 month in 64% and in all by 2 months. Three patients developed allergy. Other side effects included nausea (n = 3), headache (n = 1), urinary hesitancy (n = 1), and mild lymphocytopenia (n = 1). These were dose dependent. Progression of cicatrisation was observed in 1/22 eyes. Success was less likely if there were systemic features of OCP or ocular limbitis. CONCLUSIONS--Sulphapyridine was clinically effective in 50% of patients with moderate marked inflammation and had few side effects. It is a good alternative to dapsone.