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This book is the product of a unique symposium on the immunology of mucous membranes, which convened at Lake Tahoe, Nev, in September 1979 under the sponsorship of the Alta California Eye Research Foundation. In essence, it is a collection of 18 well-written and well-referenced articles that bring the reader up to date on this important continuing frontier in ocular immunology. As one would expect from a text authored for the most part by ophthalmologists, the mucosal surface that receives the most attention is the conjunctiva. One major objective of this symposium was to get input from other specialties on the immunology of mucous membranes. For example, Daniels' article concerning bullous diseases of the mouth complements the conjunctival-oriented papers of Friedlaender, Franklin, and Rice to put cicatricial pemphigoid into total perspective. Four of the papers address themselves to specific aspects of microbial—mucous membrane relationships. The contributors, Caldwell, Oh, O'Connor, and

• Three patients are described with cicatricial pemphigoid and positive immunofluorescence findings in the basement membrane zone of mucous glands of the pharynx, mouth, and nose. These findings appear to be unique to cicatricial pemphigoid. (Arch Dermatol1988;124:1407-1410)

• We describe clinical and immunofluorescence findings of a patient with Brunsting-Perry-type cicatricial pemphigoid. Direct immunofluorescence showed tissue-fixed basement membrane zone antibodies similar to those characteristic of bullous pemphigoid. Circulating antibodies to the basement membrane zone were not found. Brunsting-Perry-type cicatricial pemphigoid probably represents a clinical variation midway in the cicatricial pemphigoid-bullous pemphigoid spectrum of disease. Management with intralesional corticosteroids was successful in controlling the skin lesions. (Arch Dermatol114:779-781, 1978)

• Three years after the onset of lupus erythematosus, blisters, erosions, and erythema of the gingivae developed in a 31-year-old man. A diagnosis of cicatricial pemphigoid was established by routine and immunofluorescence microscopy studies. An association between cicatricial pemphigoid and other autoimmune disorders seems to be rare. This case demonstrates the importance of performing immunofluorescence microscopy studies, as well as routine histologic assessments, of conditions that resemble desquamative gingivitis. ( Arch Dermatol 117:109-110, 1981)

In Reply.— I must disagree with Dr Callen with regard to the diagnosis of rheumatoid arthritis in three of the four patients in our recent report. On the basis of history, clinical findings, and laboratory and roentgenographic data, the three cases fit the criteria for definite rheumatoid arthritis. 1 Callen implies in his letter that because only two of the four patients had a positive rheumatoid factor, a diagnosis of rheumatoid arthritis can not be made. He does not seem to take into consideration the other data provided. I am sure that I do not need to point out that a positive rheumatoid factor is only one of 11 criteria used to make the diagnosis in the ARA's list. In addition, the fourth patient, who also happened to have a positive rheumatoid factor, did not have rheumatoid arthritis. He had ankylosing spondylitis as well, and this is clearly stated in

• Antibodies against conjunctival basement membrane zone (BMZ) were found in the serum of six of 12 patients with cicatricial pemphigoid. The ability to detect antibodies correlated with the degree of clinical activity. Each of four patients with active manifestations of the disease was found to have antibodies against BMZ, while only two of the remaining eight patients in a less active stage of the disease demonstrated specific antibodies. Specific circulating serum antibodies are a manifestation of cicatricial pemphigoid, but such antibodies are more easily detected during active disease. Antibodies against BMZ are frequently observed in patients with bullous pemphigoid, a nonocular bullous disease in which circulating antibodies react with a specific skin antigen localized to the lamina lucida, a portion of the BMZ. Therefore, cicatricial pemphigoid and bullous pemphigoid may have a similar pathogenesis.

The characteristic conjunctival scarring in cicatricial pemphigoid is a consequence of subepithelial fibrosis. The fibroblast is the cellular element responsible for fibrosis. To increase the understanding of the pathogenesis of abnormal fibrosis in cicatricial pemphigoid, the growth characteristics of conjunctival fibroblasts, from untreated patients with cicatricial pemphigoid (n = 9) and normal controls (n = 6), were studied in tissue culture. The latent period until fibroblast outgrowth began from the conjunctival explant was determined, as were the plating efficiency and doubling time of cells from first-passage cultures. Outgrowths of fibroblasts from patients with cicatricial pemphigoid appeared significantly sooner than from controls, 8.1 +/- 3.8 vs 19.3 +/- 6.4 (mean +/- SD) days. While there was no significant difference in the plating efficiency between fibroblasts from cicatricial pemphigoid (mean +/- SD, 116.4% +/- 44.6%) and those from controls (71.0% +/- 39.4%), the doubling time was significantly faster for cicatricial pemphigoid than for controls, 26.5 +/- 8.5 vs 50.7 +/- 7.8 hours. Thus, conjunctival fibroblasts from patients with cicatricial pemphigoid are hyperproliferative in tissue culture when compared with normal controls. Therefore, scarring, which characterizes cicatricial pemphigoid, may be due, in part, to excessive fibroblast proliferation.

A patient has an acquired, scarring, bullous eruption. The severity of the cutaneous, ocular, esophageal, and laryngeal scarring was suggestive of cicatricial pemphigoid or the severely dystrophic forms of epidermolysis bullosa. Clinical features and histologic and immunofluorescence and electron microscopic study led to the diagnosis of epidermolysis bullosa acquisita. The spectrum of epidermolysis bullosa acquisita includes cases that closely approximate the severity of disease previously recognized only for the recessive form of epidermolysis bullosa dystrophica. ( Arch Dermatol 115:1325-1328, 1979)

• A review of our experience with cicatricial pemphigoid revealed three patients with cicatricial pemphigoid and rheumatoid arthritis and one patient with ankylosing spondylitis who had a high titer of rheumatoid factor. A comparison of these four patients with patients who had bullous pemphigoid and rheumatoid arthritis shows similarities between cicatricial pemphigoid and bullous pemphigoid in relation to the development of rheumatoid arthritis. ( Arch Dermatol 114:415-417, 1978)

• Six patients with a vesiculobullous eruption of the type described by Brunsting and Perry as benign pemphigoid were studied by direct and indirect immunofluorescence. All six showed linear deposits of IgG but not IgM or IgA at the epidermal-dermal junction. One case also showed C3 deposition and one patient had circulating antibasement membrane zone antibodies in a titer of 1280. These data provide strong evidence that this condition belongs to the cicatricial pemphigoid-bullous pemphigoid spectrum of disease. ( Arch Dermatol 113:1403-1405, 1977)

To the Editor —D-penicillamine is a heavy metal chelator used in the treatment of Wilson's disease, heavy metal poisoning, cystinuria, rheumatoid arthritis, primary biliary cirrhosis, and scleroderma. The administration ofD-penicillamine in the treatment of these diseases has been shown to be effective, but numerous side effects have been observed, among which are the induction of autoimmune diseases of the skin, such as pemphigus, disseminated lupus erythematosus, and dermatomyositis. More autoimmune skin diseases appear to be induced byD-penicillamine when it is used in the treatment of rheumatoid arthritis than when it is used in the treatment of other nonautoimmune diseases. A 54-year-old woman diagnosed in December 1967 to have rheumatoid arthritis developed xerostomia and nonspecific ocular discomfort in 1981, diagnosed as Sjogren's syndrome. Beginning in May 1984, she received treatment with 125 mg/d of indomethacin and 250 mg/d ofD-penicillamine. In April 1985, she

• Normal skin was transplanted into a cicatricial plaque in a patient affected with localized, benign pemphigoid of the Brunsting-Perry type. Eight weeks later, the transplanted tissue was removed and found to have IgG at the basement membrane zone on immunofluorescence microscopy. Subepidermal bullae developed at the graft-donor site. Local factors and trauma may be important in the pathogenesis of this variant of cicatricial pemphigoid. (Arch Dermatol1984;120:932-935)

IN 1964, Beutner and Jordon reported that serum specimens of patients with pemphigus contained antibodies against the epidermal cell surface, the site of earliest histopathologic change. This finding stimulated subsequent studies that improved the therapeutic approaches to these diseases. In this section the following vesiculobullous disorders are discussed: pemphigus vulgaris, bullous pemphigoid, cicatricial pemphigoid, herpes gestationis, dermatitis herpetiformis, and benign chronic bullous dermatosis of childhood. PEMPHIGUS VULGARIS Pemphigus vulgaris is a chronic bullous disease that occurs in all races and ethnic groups. It has been reported in association with thymoma, myasthenia gravis, and systemic lupus erythematosus. Before the availability of corticosteroid and antibiotic drugs, the disease was often fatal because of fluid and electrolyte abnormalities, cachexia, and sepsis secondary to the denudation of large areas of skin. The disorder is characterized by thin, flaccid bullae on normal-appearing skin. The mucous membranes are commonly involved and are often the sites where

Benign mucous membrane pemphigoid, also called cicatricial pemphigoid, is a chronic vesiculobullous disease of the mucosa and skin that results in permanent scarring of the affected areas, often causing blindness. Reports of treatment for this disorder have been scanty and quite variable in presentation. To our knowledge, this is the first case report of an initially recalcitrant patient treated successfully with cyclophosphamide. Report of a Case A 49-year-old man was in good health until June 1975 when he noted injection of the right conjunctiva accompanied by photophobia. The diagnosis was staphylococcal keratoconjunctivitis, and he was treated accordingly with antibiotics and topical steroid combinations with minimal response and progression to the left eye in September of 1975. Several months later an

To the Editor.— Spigel and Winkelmann have recently reported the association of cicatricial pemphigoid with rheumatoid arthritis (Archives114:415-417, 1978). They have suggested that this association supports the concept that cicatricial pemphigoid and bullous pemphigoid are identical in their pathogenesis. My associates and I1have reported a case of bullous pemphigoid that was associated with classical rheumatoid arthritis, as defined by the criteria of the American Rheumatism Association (ARA).2To date, this is the only case, to our knowledge, of bullous pemphigoid associated with documented rheumatoid arthritis. In our report we stressed the importance of using diagnostic criteria. Drs Spigel and Winkelmann have not provided enough information to support the diagnosis of rheumatoid arthritis in any of the patients they presented. Only two of their four patients had positive rheumatoid factors, and both of these patients were elderly (67 and 78 years old). Svec and Veit3have

• A 5½ girl with a blistering disease involving the skin and the oral, ocular, and anogenital mucosa is described. The initial clinical, histologic, and immunofluorescence findings suggested a diagnosis of cicatricial pemphigoid. However, immunoelectron microscopy demonstrated linear deposits of several immunoreactants within the sub-lamina densa region of the dermoepidermal junction, consistent with the diagnosis of epidermolysis bullosa acquisita. Although epidermolysis bullosa acquisita is considered a disease of adult onset, it should be included in the differential diagnosis of blistering diseases in children. (Arch Dermatol1987;123:772-776)

To the Editor.— I was pleased to read of Dr. Sams' interest in my article that appeared in theArchivesand would like to reply to his questions about the diagnosis in this patient. I believe there is little question that this patient has cicatricial pemphigoid. She has a chronic bullous, erosive disease that has lasted nine years and resulted in involvement and scarring of skin, oral mucosa, vaginal and cervical mucosa, pharynx, larynx, and esophagus. In the differential diagnosis of oral cicatricial pemphigoid, there are five diseases 1 : (1) pemphigus vulgarus, (2) erythema multiforme, (3) lichen planus, (4) bullous pemphigoid, and (5) desquamative gingivitis. The first three are easily eliminated from consideration in this case by clinical presentation and histopathologic findings. Dr. Sams implies that this patient might have bullous pemphigoid. However, bullous pemphigoid rarely lasts nine years; rarely involves cervix, larynx, or esophagus; does not cause severe

Cicatricial pemphigoid is a rare disease affecting the skin and mucous membranes. It is a disorder characterized by sub-epidermal blisters which heal with fibrosis and scarring. The diagnosis is confirmed by demonstration of immunoglobulins along the basement membrane of perilesional tissue using immunofluorescence. Ten patients with cicatricial pemphigoid who complained of dysphagia were investigated by barium swallow. An upper oesophageal stricture was demonstrated in eight of these. In the remaining two patients indirect laryngoscopy showed hypopharyngeal ulcers which could account for the dysphagia. A benign stricture of the upper third of the oesophagus is a rare finding and cicatricial pemphigoid should be recognized as a possible cause. The other clinical manifestations of cicatricial pemphigoid may be subtle. However, they can be seen on careful examination of the skin and mucous membranes which will enable the diagnosis to be made.

• Recent studies have shown an orderly sequence of expression of structural antigens within the skin basement-membrane zone of the human fetus. Interestingly, these findings differ from those reported following splitthickness wound induction in Yorkshire pigs. To readdress this apparent disparity, as well as to further extend such studies to include other basement-membrane antigens more recently identified, we produced split-thickness wounds in a primate species and serially examined the wounds by immunofluorescence technique for the expression of seven antigens normally found in intact primate skin basement membrane. By the fourth day following wounding, laminin, type-IV collagen, and fibronectin were all detectable along the dermoepidermal junction. In contrast, bullous pemphigoid antigen, epidermolysis bullosa acquisita antigen, cicatricial pemphigoid antigen, and KF-1 antigen were undetectable until days 6, 8, 10, and 11, respectively. These latter findings are in complete agreement with those previously reported in the developing human fetus. On the basis of the results of this study, we would suggest that primate rather than pig skin may be a more appropriate animal model for wound-healing studies. These data are consistent with previous reports suggesting that the basement-membrane antigens recognized by bullous pemphigoid and cicatricial pemphigoid autoantibodies are indeed distinct. Finally, these data bring into question the functional role of bullous pemphigoid antigen during the early phase of wound healing in humans. ( Arch Dermatol 1987;123:1174-1178)

A slowly progressive disease characterized clinically by a noninflammatory process, produced over many years unique annular atrophic disfiguring plaques of the face in two patients. The histopathological findings of many lesions revealed sclerosis and fibrosis of the upper and middle dermis, mild lymphocytic inflammation, and atrophy of the epidermis and hair follicles. Severe solar elastosis was a prominent feature in most biopsies and may be an important factor. No evidence of photosensitivity, porphyria, cicatricial pemphigoid, lichen planus, or any significant systemic disease was present. The disease did not respond to corticosteroids, antimalarials, or many other forms of therapy. Many consultants in pathology suggested various diagnoses: morphea, lichen sclerosus et atrophicus, and discoid lupus erythematosus.

The clinical and laboratory data on 81 patients with benign mucous membrane pemphigoid (BMMP) seen during the years 1950 through 1968 were reviewed. Mucous-membrane and cutaneous involvements were variable, but the oral mucosa and conjunctivae were eventually involved in approximately 75% of the cases. Scarring was a common complication of mucosal and cutaneous lesions. The most severe sequela was blindness. Of the 81 patients in this series 21 became blind, 17 in both eyes. Systemic administration of corticosteroids, used in 33 cases, was the single treatment of greatest benefit. Daily doses equivalent to 40 mg of prednisone were required initially to retard or arrest the disease. Of the various corticosteroid preparations employed, triamcinolone was the most effective. There were no deaths attributed to BMMP, but one patient died from the side effects of corticosteroid therapy.

Bullous Pemphigoid. Presented by Irving D. Ehrenfeld, MD. The patient, a 73-year-old woman, first became aware of blisters on her left breast four months ago. There are several bullae on a non-erythematous base overlying the lower half of the areola and extending to the adjacent skin of the left breast. Histopathologic examination was interpreted as showing "bullous pemphigoid." Neither topical application of 0.5% triamcinolone acetonide cream nor intralesional injection of triamcinolone has had any effect. Grenz ray therapy (200 rads) has been given five times at weekly intervals without any noticeable response. Discussion Samuel B. Frank, MD: I think that this is a case of cicatricial pemphigoid. Indirect immunofluorescent studies can help differentiate the two processes in that results of such studies usually are abnormal in bullous pemphigoid and are normal in cicatricial pemphigoid. Harvey J. Cohen, MD: There is atrophic scarring in the involved site, further supporting the diagnosis

Lever (1951, 1953) first clearly differentiated ocular pemphigus, which he renamed benign mucous membrane pemphigoid and, more recently, cicatricial pemphigoid, from pemphigus vulgaris. He pointed out the benign course, the subepidermal position of the bullae, and, most important of all, the tendency for the bullae to form scars on mucosae and skin. Church and I (1953) drew attention to the lesions on mucous membranes other than the conjunctiva and confirmed (1956) Lever's observations that there were 2 types of skin lesions. The most common is a generalized bullous eruption of short duration which is similar to the bullous eruption of pemphigoid. The second is a localized erythematous plaque, the site of recurring bullae, which may become scarred or ulcerated. Such ulceration is superficial, moist, and with little evidence of epithelialization. The localized skin lesions occur near affected mucous surfaces and are not unusual on the scalp. Lortat-Jacob (1958) stressed that

Two unusual, striking, and puzzling cases of persistent denudation of the scalp have been followed for 5 and 10 years respectively by 2 of us (A. H. S. and J. W. B.). The first patient was presented before the Chicago Dermatological Society in February, 1955, as: "A Case for Diagnosis— Pemphigus Vulgaris?" 1 This led to the comparative study of the second such extraordinary clinical manifestation. The diagnosis of pemphigus is often made only after enough time has elapsed to complete the characteristic picture. Senear 2 has pointed out the effectiveness of certain well-accepted criteria for diagnosis in certain cases. When the disorders of the pemphigoid group are added to the differential problem, however, the dilemma becomes compounded. The present report concerns 2 cases of cicatricial pemphigoid. Both patients displayed massive nonhealing erosive lesions affecting the major portions of the scalp. Report of Cases Case 1.— A 56-year-old white woman

Direct immunofluorescent staining of specimens from the conjunctiva, buccal mucosa, and skin of four patients with cicatricial pemphigoid revealed the presence of tissue-fixed, basement membrane zone antibodies similar to the basement membrane zone fluorescent staining characteristic of bullous pemphigoid. No circulating basement membrane zone antibodies could be detected in the sera of these patients. These findings suggest a relationship between cicatricial pemphigoid and bullous pemphigoid and that cicatricial pemphigoid may represent a forme fruste of bullous pemphigoid with predilection for mucous membrane and a tendency to scarring.

Sight, surgical outcomes and, ultimately, patient satisfaction critically depend on the health of the ocular surface. The extraordinary complexity of the ocular surface is maintained by intricate homeostasis; destabilization of this equilibrium may result in devastating consequences. Eyelid disorders can instigate a deleterious cascade of events, effacing the integrity and functions of the ocular surface epithelia. In many disease processes (e.g., Stevens-Johnson syndrome, cicatricial pemphigoid, collagen vascular diseases, burns, or even chronic blepharitis), the fundamental pathophysiology produces dysfunctional tear film, anomalous ocular surface epithelia, and disfigured lids. Disruption of the tear film progresses to keratoconjunctivitis sicca. Potentially devastating consequences, such as corneal scarring, infection and blindness, may ensue. Similarly, a healthy ocular surface is an important prognostic factor for surgical outcome. Accordingly, in this special edition on dry eye and ocular surface disease (OSD), we endeavor to provide the anterior segment surgeons with information to manage OSD and ensure optimal eyesight, surgical outcome, and patient satisfaction. Current literature indicates that the outcome of cataract surgeries, especially premium IOL implantation, is governed by OSD. Preexisting OSD is associated with suboptimal visual outcomes and higher risks of postoperative complications. In this issue, Movahedan and colleagues1 reviewed the salient observation between OSD and cataract surgeries. The authors presented strategies to diagnose and manage these conditions pre- and post-operatively to ensure optimal outcome. Amniotic membrane is a versatile tool for ocular surface reconstruction. Katzman and Jeng2 discussed different management modalities for persistent epithelial defects. Nguyen et al.3 investigated the role of amniotic membrane as an adjuvant therapy in high-risk penetrating keratoplasty. The authors aimed to leverage the anti-inflammatory properties of amniotic membrane to rehabilitate the ocular surface and reduce graft rejection; however, no correlation was determined in this retrospective series. In severe ocular surface disorders, the loss of limbal epithelial stem cells, or limbal stem cell deficiency (LSCD), has many deleterious complications, e.g. LSCD is a leading cause of corneal blindness. The diminished regenerative capacity seen in LSCD is characterized by persistent epithelial defects, erosion and ulceration, conjunctivalization and neovascularization, and chronic inflammation. Lin and Yiu4 provided excellent review diagnostic approaches and treatment for dry eye disease. Tu5 performed a comprehensive review of the toxicity of current ophthalmic eye drops. He and Yiu6 reviewed various stem cell based approaches for treating LSCD as well as discussing future direction and challenges. A recent innovation, the prosthetic replacement of the ocular surface ecosystem (PROSE) scleral lens has been instrumental in restoring vision and improving patient satisfaction for a wide range of OSD, e.g. severe dry eye, graft versus host disease, exposure keratopathy, limbal stem cell deficiency, as well as corneal ectasia. In this issue, Chiu et al.7 presented that PROSE can improve vision in patients with Salzmann’s nodular degeneration. OSD is a challenging adversity for the ophthalmologists. Successful outcome and patient satisfaction require thorough evaluation utilizing appropriate clinical tools and comprehensive medical management. Surgical patients necessitate attentive pre- and post-operative management. Evolution in the field will continue to arm the surgeons with tools to manage this chronic devastating condition.