Case : A 51-Year-Old Woman with Epistaxis and Oral Mucosal Ulcers

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1 T h e n e w e ngl a nd j o u r na l o f m e dic i n e case records of the massachusetts general hospital Founded by Richard C. Cabot Eric S. Rosenberg, m.d., Editor Jo-Anne O. Shepard, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Nancy Lee Harris, m.d., Editor Alice M. Cort, m.d., Associate Editor Emily K. McDonald, Assistant Editor Case : A 51-Year-Old Woman with Epistaxis and Oral Mucosal Ulcers Sook-Bin Woo, D.M.D., John H. Stone, M.D., M.P.H., and Stefan Kraft, M.D. Pr esen tation of C a se Dr. Luis A. Arias-Urdaneta (Medicine): A 51-year-old woman was seen in the rheumatology clinic of this hospital because of recurrent bloody nasal discharge and oral ulcers. The patient had been well until 3.3 years before this ation, when episodic bilateral epistaxis developed, associated with intermittent sore throat, bloodtinged sputum, and nasal crusting, without rhinorrhea. Two months after the onset of symptoms, examination by an otolaryngologist at Massachusetts Eye and Ear Infirmary revealed a straight septum, with active bleeding bilaterally. Cauterization with silver nitrate was performed, followed by packing; nasal dryness and intermittent bleeding persisted. Six months after the onset of symptoms, fiberoptic nasal endoscopic examination revealed crusting in the nose, mucosal inflammation, and synechiae in the left nasal cavity, without masses or polyps. Amoxicillin with clavulanate was prescribed. Three months later, surgical repair of bilateral nasal vestibular stenosis, with polymeric-silicone splints, and biopsies were performed. Pathological examination of the biopsy specimens showed superficial fragments of squamous mucosa with mild atypia, hyperkeratosis, a prominent granular layer, and no evidence of cancer. A tapering course of prednisone (starting at 40 mg daily) and topical triamcinolone acetonide cream were administered, with partial improvement. During the next year, symptoms persisted despite multiple fiberoptic nasal endoscopic examinations, débridement of the crusted tissue, the application of topical antibiotic unguent, and nasal rinses. Approximately 20 months after the onset of symptoms, examination revealed complete obstruction of the nasal passages, with scab formation and no polyps or discharge; nasal cultures grew normal flora. Additional débridement was followed by the application of mupirocin ointment. Follow-up cultures grew moderate anaerobes and few Staphylococcus aureus. A 2-week course of clindamycin was prescribed. Approximately 1 year before this evaluation, painful ulcers developed on the buccal mucosa and tongue. Multiple courses of prednisone (up to 40 mg daily, rapidly tapering over a period of 1 week) were administered, with transient improvement during each course. Testing for antineutrophil cytoplasmic antibodies (ANCA) and antinuclear antibodies was negative. A chest radiograph and results of computed tomography (CT) of the sinuses were normal. During the next 4 months, episodes of epistaxis increased in frequency, in association with nasal crusting and sinus congestion. From the Departments of Surgery and Pathology, Brigham and Women s Hospital (S.-B.W.); the Departments of Medicine (J.H.S.) and Pathology (S.K.), Massachusetts General Hospital; the Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine (S.-B.W.); and the Departments of Medicine (J.H.S.) and Pathology (S.K.), Harvard Medical School all in Boston. N Engl J Med 2013;369: DOI: /NEJMcpc Copyright 2013 Massachusetts Medical Society. n engl j med 369;3 nejm.org july 18,

2 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Eight months before this evaluation, on evaluation by a rheumatologist at this hospital, the patient reported dyspnea, cough, fatigue, ear fullness, and weight loss of 7 kg. Examination revealed normal vital signs and an ulceration on the tip of the tongue; the remainder of the examination was normal. The blood level of thyroid peroxidase antibody was IU per milliliter (reference range, <35.0), and antibodies to doublestranded DNA were positive at 1:40 dilution (reference, negative at 1:10). The complete blood count was normal, as were the levels of electrolytes, calcium, glucose, total protein, albumin, globulin, creatine kinase, C-reactive protein, and immunoglobulins (IgG, IgA, and IgM); results of tests of renal and liver function and serum protein electrophoresis were normal. Testing for syphilis (with the use of rapid plasma reagin), rheumatoid factor, antinuclear antibody, and ANCA was negative, as was testing for antibodies to Ro, La, Sm, and ribonuclear protein. Colchicine, 0.6 mg twice daily, was administered for 1 week but was stopped because of diarrhea. The patient began to use dexamethasone elixir mouthwash, with improvement in the oral lesions. CT of the chest revealed a hiatal hernia. Approximately 5 months before this evaluation, intermittent rectal bleeding developed. Colonoscopic examination performed at another hospital reportedly showed two ulcers, 25 cm from the anal verge, without surrounding inflammation. Pathological examination of biopsy specimens of the lesions showed no evidence of ulceration or vasculitis; there were mild nonspecific findings of focal acute cryptitis and rare lymphoid aggregates. Serologic evaluation for inflammatory bowel disease was reportedly negative except for the presence of IgG antibodies to Saccharomyces cerevisiae (34.9 ELISA [enzyme-linked immunosorbent assay] units per milliliter; reference range, <17.8). Omeprazole, colchicine, and vitamin B were prescribed, without improvement. The patient was referred to the rheumatology clinic of this hospital. The patient rated the pain of the oral ulcers at 8 on a scale of 0 to 10, with 10 indicating the most severe pain, and reported recurrent epistaxis, lower gastrointestinal bleeding, fatigue, nonrestorative sleep, arthralgias, and intermittent pain in the elbows and legs, without swelling, erythema, or increased warmth. She did not have alopecia, uveitis, rash (malar or other), genital ulcers, or anal or perianal fistulas. She had a history of Hashimoto s thyroiditis, hyperlipidemia, and migraines. A transient ischemic attack had occurred 3.5 years before this evaluation, associated with tinnitus in the right ear, numbness and weakness on the left side, and possible aphasia; the symptoms had resolved after several hours. Daily medications included atenolol, cyclobenzaprine hydrochloride, levothyroxine, prednisone (20 mg, tapering from 40 mg over a period of 7 days), simvastatin, and aspirin (81 mg). She was allergic to trimethoprim sulfamethoxazole, amoxicillin with clavulanate, erythromycin, and tetracycline (which had caused rashes), and ciprofloxacin. The patient was married, had two grown children, and worked in an office. She drank alcohol occasionally and did not smoke or use illicit drugs. Her mother and sister had celiac disease, and her sister also had scleroderma. On examination, the blood pressure was 140/91 mm Hg and other vital signs were normal. The weight was 76.2 kg. The oropharynx was pink, with numerous erosions of the mucous membranes of the mouth, including the tongue, soft palate, and inner buccal mucosa, without bleeding (Fig. 1). The remainder of the examination was normal. The erythrocyte sedimentation rate and level of C-reactive protein were normal. A diagnostic procedure was performed. Differ en ti a l Di agnosis Dr. Sook-Bin Woo: The salient features in this case are the following: middle-aged woman with a 3-year history of epistaxis, sore throat, fullness in the ears, lower gastrointestinal tract ulcers, and painful multifocal oral ulcers that responded to moderate doses of prednisone and topical glucocorticoids, specifically triamcinolone acetonide and dexamethasone. Specimens from nasal-vestibule biopsies showed nonspecific inflammatory and reactive changes, but it is important to note that the specimens were from superficial biopsies. Chronic, persistent multifocal ulcers in the oral cavity are seen in the following three broad categories of conditions: infections, immune-mediated disorders, and autoimmune blistering disorders. Some important differentiating features include the size and appearance of lesions, involvement of keratinized versus nonkeratinized sites (especially the gingiva), complete healing of lesions between outbreaks, and involvement of skin. 266 n engl j med 369;3 nejm.org july 18, 2013

3 case records of the massachusetts general hospital Viral infections Many viral infections (e.g., hand, foot, and mouth disease and herpangina, caused by coxsackieviruses or enteroviruses) give rise to acute multifocal ulcerations in the oral cavity that are self-limiting; the persistent nature of this patient s ulcers eliminates most of these. Viruses of the herpesvirus family establish latency and may cause recurrent oral or oropharyngeal ulcers. The most common culprit is herpes simplex virus (HSV). Recrudescent HSV infections frequently as herpes labialis and, in immunocompetent patients, as ulcers on the keratinized mucosa of the gingiva, hard palate, and dorsum of the tongue. In the immunocompromised host, recrudescence of HSV infection may occur on any oral mucosal site and may resemble oral aphthae. 1 However, this patient s ulcers responded to prednisone, which would have exacerbated an HSV infection. Immune-mediated disorders Granulomatosis with Polyangiitis Granulomatosis with polyangiitis (formerly known as Wegener s granulomatosis) is a necrotizing and granulomatous vasculitic disorder with involvement of the upper airways, lungs, and kidneys; patients with this and other ANCA-associated vasculitides may with oral ulcers. 2,3 Patients with a variant of granulomatosis with polyangiitis may with limited involvement of the upper airways and oral cavity. However, the oral ulcers tend to be large and necrotic, and the gingiva typically shows hyperplasia with petechial hemorrhages ( strawberry gingivitis ). 4 ANCAs with specificity for serine proteinase 3 (more common) or myeloperoxidase (less common) are almost always positive. 3 In this case, the clinical and laboratory findings (including results of renalfunction tests and chest radiographs) do not support this diagnosis. Aphthous and Aphthous-like Ulcers So-called idiopathic recurrent aphthous ulcers are most likely immune-mediated, 5 are generally first noted in patients in the second and third decades of life, and tend to appear during periods of stress and after local trauma. Ulcers are covered by a yellow membrane composed of coagulated fibrin, are surrounded by an erythematous halo, and are confined to the nonkeratinized, movable (nonmasticatory) mucosa (i.e., the buccal and lip mucosa and the mucosa of the ventral tongue, A B C Figure 1. Clinical Photographs of the Patient. Oral ulcers are on the upper labial mucosa (Panel A), lower labial mucosa (Panel B), and ventral surface of the tongue (Panel C). floor of the mouth, and soft palate). There are three clinical forms. Aphthous minor, the most common, is associated with ulcers less than 1 cm in n engl j med 369;3 nejm.org july 18,

4 T h e n e w e ngl a nd j o u r na l o f m e dic i n e greatest dimension that heal within 5 to 10 days without scarring. Aphthous major is associated with ulcers greater than 1 cm that take weeks or months to heal and may scar. In aphthous herpetiformis, there are more than 10 ulcers, measuring 0.1 to 0.5 cm, per episode. The ulcers in this patient are fairly large but do not show evidence of scarring; therefore, they are unlikely to re aphthous major. Aphthous-like ulcers are seen in patients with systemic disorders, such as hematinic deficiencies, Crohn s disease, gluten-sensitive enteropathy, food sensitivities, sensitivity to sodium lauryl sulfate (a detergent found in most toothpastes), adverse reaction to medications, infection with the human immunodeficiency virus acquired immunodeficiency syndrome, the PFAPA (periodic fever, adenopathy, pharyngitis, and aphthae) syndrome, other complex aphthosis syndromes, and Behçet s disease. An accurate patient history, elimination of suspected offending agents, and simple blood tests would rule out most of these conditions. This patient s gastrointestinal-biopsy specimen showed cryptitis and no granulomas; there were antibodies to S. cerevisiae associated with Crohn s disease and Behçet s disease but the C-reactive protein level was normal. I believe it is unlikely that her oral ulcers are related to inflammatory bowel disease. Behçet s disease, a chronic multisystem inflammatory and vasculitic disorder, is characterized by oral aphtheiform ulcers in all patients, genital ulcers, eye lesions (often uveitis or retinal vasculitis), skin lesions (e.g., erythema nodosum), and often a positive pathergy test. 6,7 The disease tends to affect young Turkish and Japanese men and women, with a strong association with the HLA-B51 allele. Gastrointestinal involvement tends to localize around the ileocecal area and usually spares the rectum. This patient did not have genital or eye disease, making a diagnosis of Behçet s disease unlikely. Erythema Multiforme Erythema multiforme occurs in the oral cavity as recurrent acute bouts of coalescent ulcers on a diffusely erythematous mucosa (keratinized or nonkeratinized), usually 1 or 2 weeks after reactivated or recrudescent HSV infection. 8 Some cases are associated with exposure to food preservatives, such as benzoates. 9 Skin lesions are often but not always seen in erythema multiforme. 10 The chronic nature of this patient s ulcers makes this diagnosis unlikely. Lichen Planus Oral lichen planus typically results in bilaterally symmetric white striations on the buccal mucosa, lip mucosa, tongue, and attached gingiva. Areas of erythema and erosion are common (particularly on the gingiva), as are areas of ulceration. 11 However, ulcers in oral lichen planus almost always occur concomitantly with reticular and erythematous lesions, which were absent in this patient. Autoimmune blistering diseases For several reasons, the most likely diagnosis for this patient is an autoimmune blistering disorder, such as pemphigus vulgaris or mucous-membrane pemphigoid (also referred to as cicatricial pemphigoid). First, the appearance of the lesion as a membrane overlying the mucosa is more suggestive of a collapsed blister than of a true ulcer, although distinguishing between the two may be difficult. Second, epistaxis and hoarseness suggest multifocal mucosal involvement, which is common in blistering diseases, and nasal synechiae suggest pemphigoid in particular. Third, the age and sex of the patient are typical of patients who have one of these two conditions. Mucous-membrane pemphigoid is a subepithelial blistering disorder. Patients typically with bright red, painful denudation on the gingiva (desquamative gingivitis) or with ulcers on the palate. 12 Bleeding on tooth brushing is common. Collapsed bullae and erosions may also occur in other mucosal sites, although they are almost always accompanied by involvement of the gingiva or palate or both. Scarring is common in ocular pemphigoid but not in oral pemphigoid, and erosive lesions of the larynx, pharynx, and nasal mucosa occur in approximately 35% of cases. 13 Erosive lesions may lead to scarring, stenosis, synechiae, obstruction, and dyspnea. This patient s ulcers are consistent with a diagnosis of mucous-membrane pemphigoid, although there was apparently no gingival involvement. She did not have elevated IgG levels, which is consistent with the diagnosis; however, ulcers in the colon are unusual. Pemphigus vulgaris is an intraepithelial blistering disorder. Lesions begin in the oral cavity in up to 60% of patients, with skin lesions developing months or years later. 14,15 The soft palate and the 268 n engl j med 369;3 nejm.org july 18, 2013

5 case records of the massachusetts general hospital mucosa of the hard palate are commonly involved because of trauma from swallowing. Gingival manifestations are similar to those of mucousmembrane pemphigoid. Laryngeal or pharyngeal involvement is in up to 80% of patients, nasal crusting and erosions are found in up to 60%, and the ears are involved in 20%. 16 This patient s oral ulcers are consistent with this diagnosis. In a patient with only oral mucosal involvement, I would not expect the IgG levels to be elevated; ulcers in the colon are unusual in pemphigus vulgaris. The paraneoplastic autoimmune multiorgan syndrome (paraneoplastic pemphigus), linear IgA disease, lupus erythematosus, and epidermolysis bullosa are other autoimmune blistering diseases; patients may with ulcers in the oral cavity and other mucous membranes but always with concomitant involvement of the skin, serologic abnormalities, or both. These diseases are unlikely in this case. It is difficult to distinguish clinically between oral mucous-membrane pemphigoid and oral pemphigus vulgaris; in each condition, there is involvement of the laryngeal and nasal mucosa, as seen in this patient. The presence of nasal synechiae in this patient is more suggestive of mucous-membrane pemphigoid. The diagnostic procedure should be another biopsy of perilesional, clinically noninvolved mucosa, both for routine histopathological examination and for direct immunofluorescence studies of the specimen. Dr. John H. Stone: The rheumatology service considered Behçet s disease, other forms of systemic vasculitis, and several autoimmune conditions, including lupus. Because some of the oral lesions had the appearance of a membrane overlying the ulcer beneath a collapsed blister, rather than a classic aphthous ulcer, we suspected an autoimmune blistering disorder. Clinic a l Di agnosis Autoimmune blistering disorder, either pemphigus vulgaris or mucous-membrane pemphigoid. DR. SOOK-BIN WO O S DI AGNOSIS Autoimmune blistering disorder, either pemphigus vulgaris or mucous-membrane pemphigoid. Pathol o gic a l Discussion Dr. Stefan Kraft: The first diagnostic procedures were biopsies of the nasal vestibule. The specimens showed lichen simplex chronicus, which is a nonspecific histologic pattern that can be seen in ongoing mechanical trauma. The initial trigger can be an eczematous dermatitis or other underlying process. No diagnostic evidence of an autoimmune bullous disorder was seen. However, direct immunofluorescence studies would have been helpful for further evaluation. The biopsy was too superficial to completely assess scarring. The rectalbiopsy specimen also showed nonspecific findings. The diagnostic procedure consisted of oralmucosal biopsies. Specimens were submitted for routine histologic processing and direct immunofluorescence. Routine examination showed epidermal ulceration and subepithelial clefting. The inflammatory infiltrate consisted of lymphocytes, neutrophils, and scattered eosinophils (Fig. 2A, 2B, and 2C). These changes open a broad differential diagnosis (Table 1). Recurrent aphthous ulcers and Behçet s disease typically have nonspecific histologic features and do not show subepithelial clefting. Herpesvirus infection shows viral nuclear changes in keratinocytes, which were not seen here. Because of the presence of subepithelial cleft formation, the differential diagnosis includes the following two major groups of conditions: conditions involving interface mucositis (lichen planus, erythema multiforme, and lupus erythematosus) and autoimmune bullous disorders (pemphigus vulgaris, bullous pemphigoid, mucous-membrane pemphigoid, and paraneoplastic pemphigus). Although routine histologic examination can provide subtle clues to allow a distinction to be made between the two groups, direct immunofluorescence is essential for an accurate diagnosis (Fig. 3). Interface mucositis Interface mucositis is an inflammatory process of the epithelial subepithelial junction and leads to vacuolar degeneration of basal keratinocytes. Apoptotic keratinocytes (colloid bodies) are often seen. These degenerative changes can lead to cleft formation and ulceration, as seen in the biopsy specimen from this patient; however, apoptotic keratinocytes were not seen in this specimen. In addition, eosinophils around the basement-mem- n engl j med 369;3 nejm.org july 18,

6 T h e n e w e ngl a nd j o u r na l o f m e dic i n e A B C D Figure 2. Biopsy Specimens of the Oral Mucosa. Panel A (hematoxylin and eosin) shows partial ulceration of the mucosa. Panel B (hematoxylin and eosin) shows subepithelial cleft formation and an associated lymphocytic infiltrate containing neutrophils and eosinophils. Panel C (hematoxylin and eosin) shows eosinophils focally clustering around the basement-membrane zone. Panel D shows linear staining for IgG at the basement membrane with direct immunofluorescence. brane zone, as seen in this case, are not a typical feature of interface mucositis. Direct immunofluorescence reveals nonspecific findings in lichen planus (Table 1). Drug reactions are often associated with interface changes involving prominent eosinophils and no findings on direct immunofluorescence. Lupus erythematosus is probably the leading entity in this group in the differential diagnosis for this case, but eosinophils are usually not. Autoimmune bullous disorders The pemphigus and pemphigoid groups are the most important diagnostic considerations in this case. Disorders of the pemphigus group show acantholysis and intraepithelial vesicle formation due to the binding of autoantibodies to antigens in desmosomes, which provide attachment between keratinocytes. 17 In this case, the cleft is subepithelial, making pemphigus unlikely. Disorders of the pemphigoid group are caused by antibodies against basement-membrane proteins, leading to subepithelial clefting and bulla formation, as seen in this case (Table 1 and Fig. 2B). In bullous pemphigoid, the main antigens are located within hemidesmosomes that mediate attachment of keratinocytes to the basement membrane. 18 Mucous-membrane pemphigoid is a heterogeneous disease 18,19 involving autoantibodies that bind to various hemidesmosomal antigens and antigens in the lamina lucida of the basement membrane (most commonly bullous pemphigoid antigen 2 [BPAG2], but also α 6 β 4 integrin, laminins 5 and 6, and others) (Table 1 and Fig. 3). 20 Similar to bullous pemphigoid, this translates into linear staining at the basement membrane with direct immunofluorescence, commonly for IgG and complement (C3). The presence of eosinophils scattered around the basement-membrane zone, 270 n engl j med 369;3 nejm.org july 18, 2013

7 case records of the massachusetts general hospital Table 1. Histologic Differential Diagnosis.* Diagnosis HSV infection Histologic Pattern Acantholysis, intraepithelial vesicles Subepithelial Clefting Prominent Histologic Features Eosinophils Absent Nuclear changes May be Aphthous ulcers Nonspecific ulceration Absent Nonspecific May be Behçet s disease Nonspecific ulceration Absent Nonspecific May be Erythema multiforme Interface mucositis May be Erosive lichen planus Interface mucositis May be Lupus erythematosus Interface mucositis May be Drug reactions Mucous-membrane pemphigoid Various patterns, interface mucositis May be Apoptotic keratinocytes Apoptotic keratinocytes Vacuolar degeneration, apoptotic keratinocytes Various patterns May be May be Absent Often Bullous Present Subepithelial vesicles Often (BMZ) Bullous pemphigoid Bullous Present Subepithelial vesicles Present (BMZ) Pemphigus Paraneoplastic pemphigus Acantholysis, intraepithelial vesicles Acantholysis, intraepithelial vesicles, bullous Absent May be Intraepithelial vesicles, erosions Intraepithelial and subepithelial vesicles, erosions Often May be Other Histologic Features Ulceration, mixed inflammation Mixed inflammation Possible vasculitis Mixed inflammation Bandlike infiltrate, atrophy, ulceration Epithelial atrophy, superficial and deep infiltrate Secondary ulceration, lymphocytes, neutrophils, and uncommonly, oral scarring Secondary ulceration, lymphocytes, neutrophils, no scarring Mixed inflammation Mixed patterns of pemphigus and pemphigoid Findings on Direct Immunofluorescence Fibrin at BMZ, immunoglobulins in apoptotic cells + (BMZ) + (BMZ) + (BMZ) + (intraepithelial) + (BMZ, intraepithelial) * BMZ denotes basement-membrane zone, and HSV herpes simplex virus. Minus signs indicate no staining, and plus signs positive staining. as seen in this case, is a typical feature of both bullous pemphigoid and mucous-membrane pemphigoid. On a substrate of this patient s skin, direct immunofluorescence and subsequent incubation with fluorescein-conjugated antibodies against immunoglobulins and C3 showed linear staining for IgG and linear and partially granular staining for C3 at the basement membrane. These findings are seen in both mucous-membrane pemphigoid and bullous pemphigoid (Fig. 2D). The distinction between bullous pemphigoid and mucous-membrane pemphigoid cannot be made on the basis of histology and direct immunofluorescence alone. Clinical correlation (or serologic characterization of the autoantibodies) is necessary. In view of the clinical features of this case, the biopsy findings are consistent with mucous-membrane pemphigoid. Discussion of M a nagemen t Dr. Stone: According to the 2002 international consensus, mucous-membrane pemphigoid now includes the former clinical entities cicatricial pemphigoid, mucous-membrane dominant epidermolysis bullosa acquisita, and linear IgA bullous dermatosis. 21 The severity of the disease varies, but treatment-resistant cases are common. Clinically significant symptoms and even death can result from the scarring process associated with this condition or from infections that result from ex- n engl j med 369;3 nejm.org july 18,

8 T h e n e w e ngl a nd j o u r na l o f m e dic i n e A Pemphigus Anti desmoglein 3 antibodies Anti desmoglein n 1 antibodies Superficial layer Desmosomes Desmosome Desmoglein 3 Desmoglein 1 Anti desmoglein 3 Desmosomal plaque Intermediate layer Anti desmoglein 1 Keratinocyte Intercellular staining between keratinocytes Basal layer Basement membrane Keratin filaments Cell membranes B Bullous Pemphigoid Dermis Basement-Membrane Zone Hemidesmosome Anti-BPAG1 Plaques Anti-BPAG2 Linear staining at basementmembrane zone Anti α 6 β 4 integrin BPAG1 Integrin α 6 β 4 BPAG2 Cell membrane Lamina lucida Anti-BPAG2 Anti-BPAG1 Hemidesmosome Anti laminin 5 and 6 Laminin n 5 Anti collagen type VII Lamina densa Laminin 6 Anchoring fibrils (collagen type VII) Collagen type IV C Mucous-Membrane Pemphigoid D Lupus Erythematosus Linear staining at basementmembrane zone Anti α 6 β 4 integrin Anti-BPAG1 Anti-BPAG2 Granular and linear staining at basementmembrane zone Anti laminins nin 5 and 6 Anti collagen n type VII (anchoring fibrils) 272 n engl j med 369;3 nejm.org july 18, 2013

9 case records of the massachusetts general hospital Figure 3 (facing page). Pathogenetic Mechanisms and Antibody Deposition in Blistering Disorders. In pemphigus (Panel A), autoantibodies target desmosomal antigens (desmoglein 1 and desmoglein 3). Desmosomes connect epithelial keratinocytes, resulting in intercellular staining in a network pattern on direct immunofluorescence and acantholysis with intraepithelial vesicle formation. In bullous pemphigoid (Panel B), autoantibodies bind to hemidesmosomal antigens (bullous pemphigoid antigens 1 and 2 [BPAG1 and BPAG2]). Hemidesmosomes mediate attachment of keratinocytes to the basement membrane. Thus, linear staining at the basement membrane with direct immunofluorescence and a subepithelial blister are seen. In mucous-membrane pemphigoid (Panel C), antibodies are most commonly detected against BPAG2 and the beta-chain of α 6 β 4 integrin, which extends from hemidesmosomes to the lamina lucida. In addition, antibodies directed against laminin 5 (epiligrin, a lamina lucida component) and against BPAG1 and laminin 6 are seen. The anti laminin 5 subtype shows an association with internal malignant conditions. Linear staining at the basement membrane with direct immunofluorescence and a subepithelial blister are seen, similar to those seen in bullous pemphigoid. In lupus erythematosus (Panel D), antibodies against collagen type VII within anchoring fibrils lead to a granular (and sometimes linear) staining pattern at the basement membrane with direct immunofluorescence and possible subepithelial clefting. tensive ulcerations. Treatment-associated side effects are frequent, and the regimen selected must therefore strike a balance between the prevention of disease-related complications and the avoidance of serious adverse effects of therapy. We did not direct this patient s initial treatment, but she had shown an excellent response to high-dose glucocorticoids, beginning with prednisone at 60 mg per day. Unfortunately, over the next 2 months, we were unable to taper the prednisone dose below 15 to 20 mg per day without the recurrence of painful oral lesions. At the same time, multiple side effects developed in association with the glucocorticoids, particularly insomnia, a cushingoid facies, and substantial weight gain. The addition of methotrexate (25 mg per week), followed by a tumor necrosis factor α inhibitor (etanercept, 50 mg weekly), did not provide any additional disease control and did not have a glucocorticoid-sparing effect. Rituximab in Mucous-Membrane Pemphigoid Although anecdotal evidence would have supported trials of cyclophosphamide, mycophenolate mofetil, intravenous immune globulin, and other agents, we chose to treat this patient with rituximab (1 g intravenously twice, separated by 15 days). Our rationale for B-cell depletion by means of rituximab was the reports of the striking success of treatment with B-cell depletion for refractory cases of pemphigus vulgaris and pemphigus foliaceus and a small number of cases of mucous-membrane pemphigoid Furthermore, the primary autoantibody in both pemphigus vulgaris and pemphigus foliaceus is of the IgG4 subclass, and swift efficacy of this treatment approach in patients with glucocorticoid-resistant IgG4- related disease has been observed. 25,26 Mucousmembrane pemphigoid is associated with a variety of antibodies, as noted by Dr. Kraft, but to our knowledge, systematic reports of the specific IgG subclasses involved in these conditions have not been made. The patient is here with us today. Would you please tell us how you are doing now? The Patient: I had been dealing with very uncomfortable symptoms for some time, which significantly affected my quality of life. In my search for answers, I was occasionally treated with a dismissive attitude and made to feel that my problems really weren t that bad. When I came to Massachusetts General Hospital, I was treated with professionalism, care, and concern. My symptoms were validated, and there seemed to be a real urgency to try to find out exactly what was wrong. I cannot express how important I was made to feel. My questions and concerns were answered promptly, no matter whom I was speaking with the secretarial staff, the medical assistants, and of course the providers. I am overwhelmed by the dignity and respect I have been shown. Within a month after my second infusion of rituximab, I was already getting back to being myself again. It was a very long journey getting here. I was absolutely miserable I was in so much pain. Only now that I feel so well can I think, gosh, that was really miserable. I couldn t even drink water out of a straw at one point. I can now drink juice again, even orange juice and tomato juice. Now that I am on this side of it, I am very grateful. Dr. Stone: We have all been extremely gratified by the patient s response to treatment. After she received the rituximab infusions, we tapered the prednisone dose steadily and discontinued the glucocorticoids over a period of 3 months. During that time, the patient had only one mild ulcer, n engl j med 369;3 nejm.org july 18,

10 case records of the massachusetts general hospital which disappeared after 2 days. Previously, she had not been able to taper prednisone below 10 mg per day, despite the other concurrent immunosuppressive medications. She remained off prednisone entirely for 5 months, until the peripheral B cells began to reconstitute, whereupon she began to have recurrent oral ulcerations. We recently retreated her with a second course of rituximab. She continues to have occasional blood in the stools but overall remains well and does not require prednisone. A nat omic a l Di agnosis Mucous-membrane pemphigoid. This case was discussed at Rheumatology Grand Rounds. Dr. Stone reports receiving consulting fees from Genentech and Roche, grant support through his institution from Genentech and Roche, and travel support through his institution from Genentech, Biogen Idec, and Genzyme. No other potential conflict of interest relevant to this article was reported. 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Rituximab for the treatment of IgG4- related disease: lessons from 10 consecutive patients. Medicine (Baltimore) 2012;91: Copyright 2013 Massachusetts Medical Society. Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends, shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens, and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced, averaging slides per set. 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