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Mucous membrane pemphigoid presenting with isolated esophageal involvement: A case report
Mucous membrane pemphigoid with isolated esophageal involvement
Mucous membrane pemphigoid presenting with isolated esophageal involvement: a case report Hisham Sallout, MD, Grant J. Anhalt, MD, Firas H. Al-Kawas, MD, FACP
Mucous membrane pemphigoid is a rare autoimmune bullous disease that most frequently involves the mucous membranes of the eye or the mouth. Esophageal involvement does occur, but usually in patients with established oral or conjunctival disease. Herein we report a case of isolated esophageal involvement in a patient with mucous membrane pemphigoid and no evidence of oral or ocular disease. VOLUME 52, NO. 3, 2000
H Sallout, G Anhalt, F Al-Kawas
CASE REPORT A 57-year-old woman was referred with a 1-year history of progressively worsening dysphagia for solid food despite multiple sessions of esophageal dilation. In the From the Division of Gastroenterology, Georgetown University Medical Center, Washington, DC; Department of Dermatology, Johns Hopkins University, Baltimore, Maryland. Presented in part at the American College of Gastroenterology National Fellows Meeting, Colorado Springs, Colorado, August 1997. Reprints requests: Firas H. Al-Kawas, MD, FACP, Division of Gastroenterology, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Suite M2122, Washington, DC 20007-2197; fax 202-784 3957; e-mail: [email protected]. Copyright © 2000 by the American Society for Gastrointestinal Endoscopy 0016-5107/2000/$12.00 + 0 37/4/108295 doi:10.1067/mge.2000.108295 GASTROINTESTINAL ENDOSCOPY
429
H Sallout, G Anhalt, F Al-Kawas
A
B Figure 1. A, Endoscopic view of esophageal stricture covered with exudate at 29 cm from incisors. B, Esophageal webs in distal esophagus.
past, barium swallow and upper endoscopy had shown a proximal esophageal stricture. Biopsies of the stricture and CT of the chest have not been revealing. She denied any oral or ocular symptoms. There was no history of any cutaneous lesions, although there was a history of vaginal stenosis. Physical examination showed a mildly obese woman. There were no oral ulcers or scars, no evidence of conjunctival inflammation or scarring, and no skin lesions. Upper endoscopy showed two esophageal strictures, one at 20 and the other at 29 cm from the incisors (Fig. 1A). A 9 mm diameter endoscope (Pentax Precision Instrument Corp., Orangeburg, N.Y.) could not be passed through the distal stricture. Therefore, careful over-thewire dilation using Savary bougies (Wilson-Cook Medical Inc., Winston-Salem, N.C.) was performed using 30, 33, and 36F dilators; passage met with minimal resistance. Endoscopic examination after dilation revealed multiple distal esophageal webs (Fig. 1B); in addition it was noticed that the mucosa peeled away when probed with the forceps (Fig. 2). Esophageal biopsies were taken. On with430
GASTROINTESTINAL ENDOSCOPY
Mucous membrane pemphigoid with isolated esophageal involvement
Figure 2. Endoscopic view of peeling esophageal mucosa. drawal of the endoscope, a deep “tear” was noted at the level of the distal stricture and a small perforation was suspected. A barium study revealed a small, contained esophageal perforation in the middle esophagus. The patient was asymptomatic; however, because of the x-ray finding, she was kept NPO and treatment was started with intravenous antibiotics. A barium swallow 3 days later showed no evidence of a leak, and subsequently oral intake of food was resumed. Biopsies were consistent with nonspecific chronic inflammation with basilar cell hyperplasia. The patient had only minimal improvement in her dysphagia. Repeated upper endoscopies were performed with similar findings noted 2, 3, and 4 weeks later. Dilations with Savary bougies were also performed. In addition, 0.5 mL of triamcinolone (Kenalog–40; Apothecon-Bristol-Myers Squibb Co., Princeton, N.J.) was injected repeatedly in all four quadrants of the distal stricture using a sclerotherapy needle. Mild improvement in dysphagia was noted. Additional esophageal biopsies were obtained for both histopathology and direct immunofluorescence studies. The latter failed to show any specific immunoglobulin deposition. Therefore, biopsies of the peeling mucosal sheaths were sent for direct immunofluorescence studies to a different laboratory (G.J.A.). In this specimen there was linear deposition of IgG, IgA, and C3 on the basilar poles of the basal epithelial cells. These findings were diagnostic for mucous membrane pemphigoid. After the biopsy results, the patient was treated with prednisolone 30 mg/day and cyclophosphamide 100 mg/day with marked initial symptomatic response. Upper endoscopy 2 months later showed significant endoscopic improvement with a few esophageal webs and a mild esophageal stricture at 23 cm that did not require dilation. Evaluation by a consulting gynecologist revealed vaginal stenosis again. Multiple biopsies were obtained and revealed a bandlike lymphocytic infiltration in the upper dermis, while immunofluorescence examination showed a weak linear fibrinogen deposition along basement membrane, which was negative for IgG, IgM, and C3. These findings were consistent with a lichenoid eruption. VOLUME 52, NO. 3, 2000
Mucous membrane pemphigoid with isolated esophageal involvement
DISCUSSION Esophageal strictures associated with multiple webs have been described in patients with chronic graft-versus-host disease, congenital esophageal stenosis, and bullous autoimmune diseases of the skin (pemphigus vulgaris, mucous membrane pemphigoid, and epidermolysis bullosa dystrophica). Mucous membrane pemphigoid is a rare systemic autoimmune subepidermal bullous disease primarily involving mucous membranes.1 Oral, ocular, anal, and genital mucous membranes are most frequently involved. Its nomenclature can be confusing, for it also has been referred to as essential shrinkage of the conjunctiva, chronic pemphigus, ocular pemphigus, and cicatricial pemphigoid. A recent consensus conference has concluded that the most appropriate name should be mucous membrane pemphigoid (MMP) (Ahmed et al. Unpublished data. 2000). Histologically, MMP is defined by (1) blisters and erosions that heal with scarring and primarily affect mucosal surfaces, (2) subepidermal blistering, and (3) the presence of IgG and/or IgA autoantibodies that bind the basement membrane in a linear pattern. Blistering occurs after binding of the autoantibodies to the mucosal antigens with subsequent activation of the complement pathway.2-5 MMP prevalence varies from 1:15,000 to 1:40,0006 and is a disease of the elderly with a high female predominance. There is no known racial or geographic predilection. The immunopathology of MMP and bullous pemphigoid (BP) is markedly similar. The histologic and direct immunofluorescence patterns are highly similar in both diseases. Distinction between these two entities is made on clinical grounds because MMP is a mucosal disease with rare skin involvement, whereas BP is primarily a skin disease affecting cornified epithelial surfaces. In addition, MMP has the unique ability to heal with scar formation, which is the major factor contributing to morbidity and mortality in this disease.2,3 Oropharyngeal involvement in the form of desquamative gingivitis or chronic buccal ulceration is the most common presentation of mucous membrane pemphigoid.7 Ocular involvement is also common and may manifest as chronic cicatrizing conjunctivitis, entropion, and symblepharon and can lead to eventual blindness.1 Skin involvement is seen in only 20% of patients with MMP and is usually transient and trivial.8 Esophageal involvement in patients with MMP is rare and is usually seen in patients with widespread disease.9-13 Multiple esophageal webs or esophageal strictures are the usual manifestations. Esophageal webs are thought to represent an early stage of the disease, whereas esophageal strictures are more VOLUME 52, NO. 3, 2000
H Sallout, G Anhalt, F Al-Kawas
likely to represent a more advanced stage secondary to scarring and fibrosis.10 In a cohort study of 197 MMP patients, esophageal involvement was demonstrated on barium swallow (stricture or web) in 5% of patients.9 Endoscopic findings in MMP include bullae, ulcerations, webs, and strictures.12 Evidence of associated involvement of the skin, oral cavity, or conjunctiva was present in all previously documented cases of esophageal mucous membrane pemphigoid.7,10-12 Rarely, laryngeal involvement has been described as a potentially life-threatening complication of MMP.14 Vulvar involvement is uncommon and usually presents with chronic excoriation or frank ulceration, which may progress to stricture formation and eventual scarring.12 Immunologically, MMP is a member of a heterogeneous group of subepidermal blistering autoimmune diseases that can be distinguished using salt split-skin immunofluorescence, immunoelectron microscopy, or immunochemical techniques such as immunoblotting, antigen-specific enzyme-linked immunosorbent assay, or immunoprecipitation.4 The clinical phenotype of MMP can be caused by autoantibodies against several distinct antigens of the epithelial basement membrane.4 The most commonly targeted antigen in this structure is the minor bullous-pemphigoid antigen, BP 180 (BPAG2). The C terminal end region of BPAG2, which extends deep into the lamina densa, is a unique target epitope limited to mucous membrane pemphigoid.5 Another target antigen in a subset of MMP patients is Laminin 5.5 The diagnosis of mucous membrane pemphigoid requires a high index of the suspicion. Histologic examination may show subepithelial blisters with an intact basal cell layer. Direct immunofluorescence examination will demonstrate IgG, often IgA and complement deposition along the basement membrane. Direct immunofluorescence is the most sensitive and specific test for MMP, but a false-negative result can occur and repeated biopsies may be required to demonstrate diagnostic findings. It is also recommended that the specimens be examined at a laboratory with experience in interpretation of these specimens. Immunoelectron microscopy can further determine the exact location of the targeted antigen at the level of basement membrane, but is not a practical alternative diagnostic technique due to limited availability, cost, and a lack of expert laboratories that can perform this study. Indirect immunofluorescence for circulating antibodies is an insensitive method to diagnose MMP because it is positive only in a minority of patients.3 Immunochemical techniques are most definitive but can be performed only in the minority of cases in GASTROINTESTINAL ENDOSCOPY
431
H Sallout, G Anhalt, F Al-Kawas
which serum autoantibodies are present, for these techniques all rely on the use of circulating autoantibodies. As reported previously and demonstrated by our patient, histologic confirmation of esophageal involvement may be difficult and additional biopsies may be required to establish the diagnosis.3,12 Our patient presented with dysphagia and esophageal strictures. After multiple attempts, positive direct immunofluorescence was obtained from her esophageal tissue samples. The diagnosis of MMP was based on clinical and immunologic findings. There was no evidence for disease involvement in other organs. Vaginal stenosis was initially suspected to be secondary to MMP in view of previous reports of cases of vulval MMP mistaken for lichen sclerosis.15 However, multiple and repeated vaginal biopsies were obtained and were consistently negative for any immunofluorescence pattern suggestive of MMP. The treatment of mucous membrane pemphigoid should be guided by the clinical presentation. The location of the involved organ and the severity of the inflammation will determine treatment choices. Disease limited to the oropharyngeal mucosa can be treated using a number of options, including topical corticosteroids or tetracycline.16-18 Skin involvement is more likely to require a more potent corticosteroid such as clobetasol propionate. Intralesional corticosteroid injection may be useful in localized disease and may have been helpful in our patient. Diaminodiphenylsulfone (Dapsone-Jacobus Pharmaceutical Co., Inc., Princeton, N.J.) and tetracyclines with or without nicotinamide were also reported to be an effective treatment in mild cutaneous and oropharyngeal disease.17,18 However, if the eye, esophagus, or larynx is involved, definitive systemic treatment using a combined regimen of corticosteroids and an alkylating agent is essential to prevent catastrophic sequela.19 Systemic corticosteroids alone may provide symptomatic improvement but would not significantly delay the progression of the disease and the eventual scarring and fibrosis. The addition of cyclophosphamide, 2 to 2.5 mg/kg daily, has been shown to prevent progression and induce a clinical remission that may last for many years. More recent reports suggest that pulse intravenous cyclophosphamide in combination with oral cyclophosphamide and corticosteroids may allow a prolonged clinical remission using a significantly lower total dose of cyclophosphamide, but pulse cyclophosphamide is generally not as effective as daily oral administration.20 As in our patient, esophageal bouginage without first inducing a clinical remission of the autoimmune disease is frequently unsuccessful and may be 432
GASTROINTESTINAL ENDOSCOPY
Mucous membrane pemphigoid with isolated esophageal involvement
hazardous. In fact, some reports have suggested that mucosal trauma may perpetuate the disease and may be associated with an increased risk of perforation.12 In conclusion, this is a description of a patient with MMP manifested by isolated esophageal involvement. MMP should be considered in patients with multiple esophageal webs and esophageal strictures resistant to esophageal dilation. Additional ocular and/or oropharyngeal involvement should be searched for. Treatment should be initiated using a combination of corticosteroids and an alkylating immunosuppressive agent to prevent further progression of disease. If possible, esophageal dilation should be avoided until the disease is in clinical remission. The role of intralesional corticosteroids is not clear. To our knowledge, this is the first reported case of isolated esophageal involvement in a patient with MMP diagnosed by positive esophageal immunofluorescence examination. REFERENCES 1. Nguyen Q, Foster CS. Cicatricial pemphigoid: diagnosis and treatment. Int Ophthalmol Clin 1996;36:41-60. 2. Anhalt GJ. Pemphigoid. bullous and cicatricial. Dermatol Clin 1990;8:701-16. 3. Anhalt GJ. Bullous diseases. In: Rakel RE, editor. Conn’s current therapy. Philadelphia: Saunders; 1995. p. 766-75. 4. Chan LS. Human basement membrane in health and in autoimmune diseases. Frontiers Biosci 1997;2:343-52. 5. Moll R, Moll I. Epidermal adhesion molecules and basement membrane components as target structures of autoimmunity. Virchows Arch 1998;432:487-504. 6. Foster CS. Immunological disorders of the conjunctiva, cornea and sclera. In: Albert DM, Jakobiec FA, editors. Principles and practice of ophthalmology. Vol. 1. Philadelphia: WB Saunders; 1993. p. 196-9. 7. Hanson RD, Olsen KD, Rogers RS 3d. Upper aerodigestive tract manifestations of cicatricial pemphigoid. Ann Otol Phinol Laryngol 1988;97:493-9. 8. Ahmed AR, Kurgis BS, Rogers RS 3rd. Cicatricial pemphigoid. J Am Acad Dermatol 1991;24:987-1001. 9. Naylor MF, MacCarty RL, Rogers RS 3rd. Barium studies in esophageal cicatricial pemphigoid. Abdom Imaging 1995;20:97100. 10. Ostlere LS, Mallet RB, Howard PJ, Holden CA. Oesophageal webs associated with cicatricial pemphigoid. Clin Exp Dermatol 1995;20:176-8. 11. Isenberg SF. Esophageal presentation of cicatricial pemphigoid. Otolaryngol Head Neck Surg 1998;118:845-7. 12. Stallmach A, Weg-Remers S, Moser C, Bonkoff H, Feifel G, Zeitz M. Esophageal involvement in cicatricial pemphigoid. Endoscopy 1998;30:657-61. 13. Watkinson AF, Vretenar DF, Morrison MD, Burhenne HJ. Benign mucous membrane pemphigoid: treatment of esophageal stricture. J Can Assoc Radiol 1994;45:140-2. 14. Lazor JB, Varvares MA, Montgomery W, Goodman ML, Mackool BT. Management of airway obstruction in cicatricial pemphigoid. Laryngoscope 1996;106:1014-7. 15. Marren P, Walkden V, Mallon E, Wojnarowska F. Vulva cicaVOLUME 52, NO. 3, 2000
tricial pemphigoid may mimic lichen sclerosus. Br J Dermatol 1996;134:522-4. 16. Mallon E, Wojnarowska F. Cicatricial pemphigoid presenting with unusual palmer involvement, successfully treated with a combination of nicotinamide and tetracycline. Clin Exp Dermatol 1994;19:526-30. 17. Poskitt L, Wojnarowska F. Treatment of cicatricial pemphigoid with tetracycline and nicotinamide. Clin Exp Dermatol 1995;20:258-9.
VOLUME 52, NO. 3, 2000
18. Bauco van der Wal V, Jonkman MF. Topical tetracycline in cicatricial pemphigoid. J Am Acad Dermatol 1997;36:492-3. 19. Elder MJ, Lightman S, Dart JK. Role of cyclophosphamide and high dose steroids inocular cicatricial pemphigoid. Br J Ophthalmol 1995;79:264-6. 20. Pandya AG, Warren KJ, Bergstresser PR. Cicatricial pemphigoid successfully treated with pulse intravenous cyclophosphamide. Arch Dermatol 1997;133:245-7.
GASTROINTESTINAL ENDOSCOPY
433
Mucous membrane pemphigoid presenting with isolated esophageal involvement: a case report Hisham Sallout, MD, Grant J. Anhalt, MD, Firas H. Al-Kawas, MD, FACP
Mucous membrane pemphigoid is a rare autoimmune bullous disease that most frequently involves the mucous membranes of the eye or the mouth. Esophageal involvement does occur, but usually in patients with established oral or conjunctival disease. Herein we report a case of isolated esophageal involvement in a patient with mucous membrane pemphigoid and no evidence of oral or ocular disease. VOLUME 52, NO. 3, 2000
H Sallout, G Anhalt, F Al-Kawas
CASE REPORT A 57-year-old woman was referred with a 1-year history of progressively worsening dysphagia for solid food despite multiple sessions of esophageal dilation. In the From the Division of Gastroenterology, Georgetown University Medical Center, Washington, DC; Department of Dermatology, Johns Hopkins University, Baltimore, Maryland. Presented in part at the American College of Gastroenterology National Fellows Meeting, Colorado Springs, Colorado, August 1997. Reprints requests: Firas H. Al-Kawas, MD, FACP, Division of Gastroenterology, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Suite M2122, Washington, DC 20007-2197; fax 202-784 3957; e-mail: [email protected]. Copyright © 2000 by the American Society for Gastrointestinal Endoscopy 0016-5107/2000/$12.00 + 0 37/4/108295 doi:10.1067/mge.2000.108295 GASTROINTESTINAL ENDOSCOPY
429
H Sallout, G Anhalt, F Al-Kawas
A
B Figure 1. A, Endoscopic view of esophageal stricture covered with exudate at 29 cm from incisors. B, Esophageal webs in distal esophagus.
past, barium swallow and upper endoscopy had shown a proximal esophageal stricture. Biopsies of the stricture and CT of the chest have not been revealing. She denied any oral or ocular symptoms. There was no history of any cutaneous lesions, although there was a history of vaginal stenosis. Physical examination showed a mildly obese woman. There were no oral ulcers or scars, no evidence of conjunctival inflammation or scarring, and no skin lesions. Upper endoscopy showed two esophageal strictures, one at 20 and the other at 29 cm from the incisors (Fig. 1A). A 9 mm diameter endoscope (Pentax Precision Instrument Corp., Orangeburg, N.Y.) could not be passed through the distal stricture. Therefore, careful over-thewire dilation using Savary bougies (Wilson-Cook Medical Inc., Winston-Salem, N.C.) was performed using 30, 33, and 36F dilators; passage met with minimal resistance. Endoscopic examination after dilation revealed multiple distal esophageal webs (Fig. 1B); in addition it was noticed that the mucosa peeled away when probed with the forceps (Fig. 2). Esophageal biopsies were taken. On with430
GASTROINTESTINAL ENDOSCOPY
Mucous membrane pemphigoid with isolated esophageal involvement
Figure 2. Endoscopic view of peeling esophageal mucosa. drawal of the endoscope, a deep “tear” was noted at the level of the distal stricture and a small perforation was suspected. A barium study revealed a small, contained esophageal perforation in the middle esophagus. The patient was asymptomatic; however, because of the x-ray finding, she was kept NPO and treatment was started with intravenous antibiotics. A barium swallow 3 days later showed no evidence of a leak, and subsequently oral intake of food was resumed. Biopsies were consistent with nonspecific chronic inflammation with basilar cell hyperplasia. The patient had only minimal improvement in her dysphagia. Repeated upper endoscopies were performed with similar findings noted 2, 3, and 4 weeks later. Dilations with Savary bougies were also performed. In addition, 0.5 mL of triamcinolone (Kenalog–40; Apothecon-Bristol-Myers Squibb Co., Princeton, N.J.) was injected repeatedly in all four quadrants of the distal stricture using a sclerotherapy needle. Mild improvement in dysphagia was noted. Additional esophageal biopsies were obtained for both histopathology and direct immunofluorescence studies. The latter failed to show any specific immunoglobulin deposition. Therefore, biopsies of the peeling mucosal sheaths were sent for direct immunofluorescence studies to a different laboratory (G.J.A.). In this specimen there was linear deposition of IgG, IgA, and C3 on the basilar poles of the basal epithelial cells. These findings were diagnostic for mucous membrane pemphigoid. After the biopsy results, the patient was treated with prednisolone 30 mg/day and cyclophosphamide 100 mg/day with marked initial symptomatic response. Upper endoscopy 2 months later showed significant endoscopic improvement with a few esophageal webs and a mild esophageal stricture at 23 cm that did not require dilation. Evaluation by a consulting gynecologist revealed vaginal stenosis again. Multiple biopsies were obtained and revealed a bandlike lymphocytic infiltration in the upper dermis, while immunofluorescence examination showed a weak linear fibrinogen deposition along basement membrane, which was negative for IgG, IgM, and C3. These findings were consistent with a lichenoid eruption. VOLUME 52, NO. 3, 2000
Mucous membrane pemphigoid with isolated esophageal involvement
DISCUSSION Esophageal strictures associated with multiple webs have been described in patients with chronic graft-versus-host disease, congenital esophageal stenosis, and bullous autoimmune diseases of the skin (pemphigus vulgaris, mucous membrane pemphigoid, and epidermolysis bullosa dystrophica). Mucous membrane pemphigoid is a rare systemic autoimmune subepidermal bullous disease primarily involving mucous membranes.1 Oral, ocular, anal, and genital mucous membranes are most frequently involved. Its nomenclature can be confusing, for it also has been referred to as essential shrinkage of the conjunctiva, chronic pemphigus, ocular pemphigus, and cicatricial pemphigoid. A recent consensus conference has concluded that the most appropriate name should be mucous membrane pemphigoid (MMP) (Ahmed et al. Unpublished data. 2000). Histologically, MMP is defined by (1) blisters and erosions that heal with scarring and primarily affect mucosal surfaces, (2) subepidermal blistering, and (3) the presence of IgG and/or IgA autoantibodies that bind the basement membrane in a linear pattern. Blistering occurs after binding of the autoantibodies to the mucosal antigens with subsequent activation of the complement pathway.2-5 MMP prevalence varies from 1:15,000 to 1:40,0006 and is a disease of the elderly with a high female predominance. There is no known racial or geographic predilection. The immunopathology of MMP and bullous pemphigoid (BP) is markedly similar. The histologic and direct immunofluorescence patterns are highly similar in both diseases. Distinction between these two entities is made on clinical grounds because MMP is a mucosal disease with rare skin involvement, whereas BP is primarily a skin disease affecting cornified epithelial surfaces. In addition, MMP has the unique ability to heal with scar formation, which is the major factor contributing to morbidity and mortality in this disease.2,3 Oropharyngeal involvement in the form of desquamative gingivitis or chronic buccal ulceration is the most common presentation of mucous membrane pemphigoid.7 Ocular involvement is also common and may manifest as chronic cicatrizing conjunctivitis, entropion, and symblepharon and can lead to eventual blindness.1 Skin involvement is seen in only 20% of patients with MMP and is usually transient and trivial.8 Esophageal involvement in patients with MMP is rare and is usually seen in patients with widespread disease.9-13 Multiple esophageal webs or esophageal strictures are the usual manifestations. Esophageal webs are thought to represent an early stage of the disease, whereas esophageal strictures are more VOLUME 52, NO. 3, 2000
H Sallout, G Anhalt, F Al-Kawas
likely to represent a more advanced stage secondary to scarring and fibrosis.10 In a cohort study of 197 MMP patients, esophageal involvement was demonstrated on barium swallow (stricture or web) in 5% of patients.9 Endoscopic findings in MMP include bullae, ulcerations, webs, and strictures.12 Evidence of associated involvement of the skin, oral cavity, or conjunctiva was present in all previously documented cases of esophageal mucous membrane pemphigoid.7,10-12 Rarely, laryngeal involvement has been described as a potentially life-threatening complication of MMP.14 Vulvar involvement is uncommon and usually presents with chronic excoriation or frank ulceration, which may progress to stricture formation and eventual scarring.12 Immunologically, MMP is a member of a heterogeneous group of subepidermal blistering autoimmune diseases that can be distinguished using salt split-skin immunofluorescence, immunoelectron microscopy, or immunochemical techniques such as immunoblotting, antigen-specific enzyme-linked immunosorbent assay, or immunoprecipitation.4 The clinical phenotype of MMP can be caused by autoantibodies against several distinct antigens of the epithelial basement membrane.4 The most commonly targeted antigen in this structure is the minor bullous-pemphigoid antigen, BP 180 (BPAG2). The C terminal end region of BPAG2, which extends deep into the lamina densa, is a unique target epitope limited to mucous membrane pemphigoid.5 Another target antigen in a subset of MMP patients is Laminin 5.5 The diagnosis of mucous membrane pemphigoid requires a high index of the suspicion. Histologic examination may show subepithelial blisters with an intact basal cell layer. Direct immunofluorescence examination will demonstrate IgG, often IgA and complement deposition along the basement membrane. Direct immunofluorescence is the most sensitive and specific test for MMP, but a false-negative result can occur and repeated biopsies may be required to demonstrate diagnostic findings. It is also recommended that the specimens be examined at a laboratory with experience in interpretation of these specimens. Immunoelectron microscopy can further determine the exact location of the targeted antigen at the level of basement membrane, but is not a practical alternative diagnostic technique due to limited availability, cost, and a lack of expert laboratories that can perform this study. Indirect immunofluorescence for circulating antibodies is an insensitive method to diagnose MMP because it is positive only in a minority of patients.3 Immunochemical techniques are most definitive but can be performed only in the minority of cases in GASTROINTESTINAL ENDOSCOPY
431
H Sallout, G Anhalt, F Al-Kawas
which serum autoantibodies are present, for these techniques all rely on the use of circulating autoantibodies. As reported previously and demonstrated by our patient, histologic confirmation of esophageal involvement may be difficult and additional biopsies may be required to establish the diagnosis.3,12 Our patient presented with dysphagia and esophageal strictures. After multiple attempts, positive direct immunofluorescence was obtained from her esophageal tissue samples. The diagnosis of MMP was based on clinical and immunologic findings. There was no evidence for disease involvement in other organs. Vaginal stenosis was initially suspected to be secondary to MMP in view of previous reports of cases of vulval MMP mistaken for lichen sclerosis.15 However, multiple and repeated vaginal biopsies were obtained and were consistently negative for any immunofluorescence pattern suggestive of MMP. The treatment of mucous membrane pemphigoid should be guided by the clinical presentation. The location of the involved organ and the severity of the inflammation will determine treatment choices. Disease limited to the oropharyngeal mucosa can be treated using a number of options, including topical corticosteroids or tetracycline.16-18 Skin involvement is more likely to require a more potent corticosteroid such as clobetasol propionate. Intralesional corticosteroid injection may be useful in localized disease and may have been helpful in our patient. Diaminodiphenylsulfone (Dapsone-Jacobus Pharmaceutical Co., Inc., Princeton, N.J.) and tetracyclines with or without nicotinamide were also reported to be an effective treatment in mild cutaneous and oropharyngeal disease.17,18 However, if the eye, esophagus, or larynx is involved, definitive systemic treatment using a combined regimen of corticosteroids and an alkylating agent is essential to prevent catastrophic sequela.19 Systemic corticosteroids alone may provide symptomatic improvement but would not significantly delay the progression of the disease and the eventual scarring and fibrosis. The addition of cyclophosphamide, 2 to 2.5 mg/kg daily, has been shown to prevent progression and induce a clinical remission that may last for many years. More recent reports suggest that pulse intravenous cyclophosphamide in combination with oral cyclophosphamide and corticosteroids may allow a prolonged clinical remission using a significantly lower total dose of cyclophosphamide, but pulse cyclophosphamide is generally not as effective as daily oral administration.20 As in our patient, esophageal bouginage without first inducing a clinical remission of the autoimmune disease is frequently unsuccessful and may be 432
GASTROINTESTINAL ENDOSCOPY
Mucous membrane pemphigoid with isolated esophageal involvement
hazardous. In fact, some reports have suggested that mucosal trauma may perpetuate the disease and may be associated with an increased risk of perforation.12 In conclusion, this is a description of a patient with MMP manifested by isolated esophageal involvement. MMP should be considered in patients with multiple esophageal webs and esophageal strictures resistant to esophageal dilation. Additional ocular and/or oropharyngeal involvement should be searched for. Treatment should be initiated using a combination of corticosteroids and an alkylating immunosuppressive agent to prevent further progression of disease. If possible, esophageal dilation should be avoided until the disease is in clinical remission. The role of intralesional corticosteroids is not clear. To our knowledge, this is the first reported case of isolated esophageal involvement in a patient with MMP diagnosed by positive esophageal immunofluorescence examination. REFERENCES 1. Nguyen Q, Foster CS. Cicatricial pemphigoid: diagnosis and treatment. Int Ophthalmol Clin 1996;36:41-60. 2. Anhalt GJ. Pemphigoid. bullous and cicatricial. Dermatol Clin 1990;8:701-16. 3. Anhalt GJ. Bullous diseases. In: Rakel RE, editor. Conn’s current therapy. Philadelphia: Saunders; 1995. p. 766-75. 4. Chan LS. Human basement membrane in health and in autoimmune diseases. Frontiers Biosci 1997;2:343-52. 5. Moll R, Moll I. Epidermal adhesion molecules and basement membrane components as target structures of autoimmunity. Virchows Arch 1998;432:487-504. 6. Foster CS. Immunological disorders of the conjunctiva, cornea and sclera. In: Albert DM, Jakobiec FA, editors. Principles and practice of ophthalmology. Vol. 1. Philadelphia: WB Saunders; 1993. p. 196-9. 7. Hanson RD, Olsen KD, Rogers RS 3d. Upper aerodigestive tract manifestations of cicatricial pemphigoid. Ann Otol Phinol Laryngol 1988;97:493-9. 8. Ahmed AR, Kurgis BS, Rogers RS 3rd. Cicatricial pemphigoid. J Am Acad Dermatol 1991;24:987-1001. 9. Naylor MF, MacCarty RL, Rogers RS 3rd. Barium studies in esophageal cicatricial pemphigoid. Abdom Imaging 1995;20:97100. 10. Ostlere LS, Mallet RB, Howard PJ, Holden CA. Oesophageal webs associated with cicatricial pemphigoid. Clin Exp Dermatol 1995;20:176-8. 11. Isenberg SF. Esophageal presentation of cicatricial pemphigoid. Otolaryngol Head Neck Surg 1998;118:845-7. 12. Stallmach A, Weg-Remers S, Moser C, Bonkoff H, Feifel G, Zeitz M. Esophageal involvement in cicatricial pemphigoid. Endoscopy 1998;30:657-61. 13. Watkinson AF, Vretenar DF, Morrison MD, Burhenne HJ. Benign mucous membrane pemphigoid: treatment of esophageal stricture. J Can Assoc Radiol 1994;45:140-2. 14. Lazor JB, Varvares MA, Montgomery W, Goodman ML, Mackool BT. Management of airway obstruction in cicatricial pemphigoid. Laryngoscope 1996;106:1014-7. 15. Marren P, Walkden V, Mallon E, Wojnarowska F. Vulva cicaVOLUME 52, NO. 3, 2000
tricial pemphigoid may mimic lichen sclerosus. Br J Dermatol 1996;134:522-4. 16. Mallon E, Wojnarowska F. Cicatricial pemphigoid presenting with unusual palmer involvement, successfully treated with a combination of nicotinamide and tetracycline. Clin Exp Dermatol 1994;19:526-30. 17. Poskitt L, Wojnarowska F. Treatment of cicatricial pemphigoid with tetracycline and nicotinamide. Clin Exp Dermatol 1995;20:258-9.
VOLUME 52, NO. 3, 2000
18. Bauco van der Wal V, Jonkman MF. Topical tetracycline in cicatricial pemphigoid. J Am Acad Dermatol 1997;36:492-3. 19. Elder MJ, Lightman S, Dart JK. Role of cyclophosphamide and high dose steroids inocular cicatricial pemphigoid. Br J Ophthalmol 1995;79:264-6. 20. Pandya AG, Warren KJ, Bergstresser PR. Cicatricial pemphigoid successfully treated with pulse intravenous cyclophosphamide. Arch Dermatol 1997;133:245-7.
GASTROINTESTINAL ENDOSCOPY
433