Clinical phenotype and anti-desmoglein autoantibody profile in paraneoplastic pemphigus

Clinical phenotype and anti-desmoglein autoantibody profile in paraneoplastic pemphigus Manabu Ohyama, MD,a Masayuki Amagai, MD,a Takashi Hashimoto, MD,b Hossein C. Nousari, MD,c Grant J. Anhalt, MD,c and Takeji Nishikawa, MDa Tokyo and Fukuoka, Japan, and Baltimore, Maryland Background: Paraneoplastic pemphigus (PNP) has similar features to pemphigus vulgaris (PV), including circulating anti-desmoglein (Dsg) IgG as pathogenic autoantibodies. When PV is divided into mucosal dominant type and mucocutaneous type, mucosal dominant type has only anti-Dsg3 IgG, whereas the mucocutaneous type has both anti-Dsg3 and anti-Dsg1 IgG. Objective: The purpose of this study was to determine whether there is a difference in anti-Dsg autoantibody profile between mucosal dominant PNP and mucocutaneous PNP. Methods: Twenty-one patients with PNP were categorized as mucosal dominant and mucocutaneous types based on clinical information. Antibody titers against Dsg3 and Dsg1 were measured by enzyme-linked immunosorbent assay by means of recombinant Dsg1 and Dsg3. Results: There were 9 cases of mucosal dominant type and 12 cases of mucocutaneous type. Eight of 9 cases of mucosal dominant type were positive for anti-Dsg3 IgG, but 3 of them were also positive for antiDsg1 IgG. All 12 cases of mucocutaneous type were positive for anti-Dsg3 IgG, whereas only 6 of them were positive for anti-Dsg1 IgG. Conclusion: There was no clear association between the clinical phenotype and anti-Dsg antibody profile in PNP as seen in PV. This finding suggests that besides anti-Dsg IgG other pathologic mechanisms such as lichenoid reaction or interface dermatitis may be involved in the blister formation in PNP. (J Am Acad Dermatol 2001;44:593-8.)

P

emphigus is a group of autoimmune blistering diseases of the skin and mucous membranes characterized by intraepidermal blisters caused by autoantibodies against desmosomal cadherins, desmoglein (Dsg) 1 and Dsg3.1-3 Classically, there are two subtypes of pemphigus described: pemphigus From the Department of Dermatology, Keio University School of Medicine, Tokyoa; the Department of Dermatology, Kurume University School of Medicine, Fukuokab; and the Department of Dermatology and Pathology, Johns Hopkins University, School of Medicine, Baltimore.c Supported in part by Health Sciences Research Grants for Research on Specific Diseases from Ministry of Health and Welfare and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan. Accepted for publication Aug 30, 2000. Reprint requests: Masayuki Amagai, MD, Assistant Professor, Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/1/112222 doi:10.1067/mjd.2001.112222

vulgaris (PV) and pemphigus foliaceus (PF). Recently, it was demonstrated that the clinical phenotype of classic pemphigus is defined by the anti-Dsg autoantibody profile.4,5 Patients with the mucosal dominant type of PV have only anti-Dsg3 IgG autoantibodies. Patients with the mucocutaneous type of PV have both anti-Dsg3 and anti-Dsg1 IgG autoantibodies. Patients with PF, which has lesions on the skin but shows no apparent mucosal involvement, have only anti-Dsg1 IgG autoantibodies. Furthermore, gross and microscopic distributions of blister formation in these different types of classic pemphigus were explained by the anti-Dsg antibody profile and expression pattern of Dsg1 and Dsg3 in the epidermis and mucous membranes.6 Paraneoplastic pemphigus (PNP) is a recently described autoimmune blistering disease that occurs in association with underlying neoplasm, especially with hematologic disorders such as nonHodgkin’s lymphoma, chronic lymphocytic leukemia, and Castleman’s disease, or with poorly 593

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Table I. PNP patient profile and ELISA score Mucosal lesion Patient No.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Age (y)

66 18 17 36 39 46 56 56 40 62 67 70 56 52 56 34 54 65 65? 53 57

Cutaneous lesion

Sex

Oral lesion

Ocular lesion

Genital lesion

Blister and erosion

Non-blister lesion

Subtype*

M F F F M F M M M F M F M M M F M F F F M

3 3 3 3 2 3 3 3 3 3 3 3 3 3 3 3 3 3 2 3 3

1 2 1 1 3 2 2 1 2 2 0 0 3 2 0 1 3 2 3 0 2

2 1 UN 2 2 2 1 2 0 1 0 0 2 2 0 0 UN 2 UN 2 0

1 0 1 1 1 0 0 1 1 2 5 5 2 4 2 2 2 2 2 2 5

0 0 1 1 0 2 0 1 1 1 0 0 1 4 0 1 1 2 2 0 0

M M M M M M M M M MC MC MC MC MC MC MC MC MC MC MC MC

CLL, Chronic lymphocytic leukemia; ID, interface dermatitis; UN, unknown. *M, Mucosal type: patients whose score of blister and erosion is 0 or 1. MC, Mucocutaneous type: patients whose score of blister and erosion is 2 or greater. †Cervical adenosquamous carcinoma.

differentiated sarcomas.7 Patients with PNP raise antibodies against multiple antigens, including members of the plakin family (desmoplakin I, II, BPAG1, envoplakin, periplakin, and HD1/plectin)712 as well as desmogleins.13 In PNP, anti-Dsg IgG autoantibodies are considered to be involved in pathogenesis in the initiation of blister formation based on the following observations with a neonatal mouse model for pemphigus: (1) Passive transfer of whole IgG from PNP sera caused blisters with histology of suprabasilar acantholysis, which is a typical finding of PV.7 (2) Essentially all patients with PNP have circulating anti-Dsg3 IgG as determined by enzyme-linked immunosorbent assay (ELISA).13 (3) Immunoadsorption of anti-Dsg3 and anti-Dsg1 IgG with recombinant Dsg3 and Dsg1 from PNP sera prevented blister formation in neonatal mice.13 (4) Anti-Dsg3 IgG, which was affinity-purified from PNP sera, caused suprabasilar acantholysis.13 In this study, we determined whether similar association to PV between clinical phenotype and antiDsg antibody profile is observed in PNP.

MATERIAL AND METHODS Human sera Sera were obtained from 21 patients diagnosed as having PNP according to diagnostic criteria proposed by Anhalt14 as follows: (1) mucosal ulcerations and blisters, polymorphous skin lesions in the context of an underlying neoplasm; (2) histologic findings of vacuolar interface change, keratinocyte necrosis, and intraepidermal acantholysis; (3) deposition of IgG and C3 on epidermal cell surfaces and variably also along the basement membrane zone; (4) serum autoantibodies that bind to the cell surfaces of monkey esophagus and also to urinary bladder epithelium; and (5) serum autoantibodies that recognize antigens of 250, 230, 210, 190, and 170 kd by immunochemical techniques such as immunoprecipitation. All patients satisfied at least 4 of these criteria. All patients’ sera were confirmed to have the characteristic autoantibodies against several antigens of 250, 230, 210, 190, and 170 kd by immunoprecipitation. Sera were basically collected in clinically active disease stage. However, at least in 2 patients (patients 2 and 10 in Table I), sera were obtained after immunosup-

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ELISA index Dsg1

Dsg3

Underlying neoplasm

0 0.4 0.9 2.4 4.6 4.7 15.4 25.5 110 0 1.8 3.8 4.5 7.5 8.5 11 11.6 14.6 35.8 55.5 80.6

13.9 0.5 18.5 45.4 105 16.6 262.8 108 101.8 28.5 117.4 102.1 49.9 40.1 174 149 124 99.9 150 64.9 112.2

Malignant lymphoma Castleman’s disease Thymoma Malignant lymphoma Malignant lymphoma Uterine cancer† CLL Castleman’s tumor Malignant lymphoma Not found CLL Malignant lymphoma CLL Malignant lymphoma CLL Malignant lymphoma Malignant lymphoma Lymphoma? Castleman’s tumor Castleman’s tumor Macroglobulinemia

pressive therapy was initiated. Most sera were sent to us for immunologic investigation from doctors in charge of treatment for each patient with PNP. ELISA against Dsg1 and Dsg3 ELISA scores against Dsg1 and Dsg3 were obtained by the method described previously.4,15 In brief, ELISA plates coated with recombinant Dsg1 and Dsg3 were incubated for 1 hour at room temperature with sera diluted 200-fold, washed twice, and incubated with 1000-fold diluted peroxidase-conjugated mouse antihuman IgG monoclonal antibody (MBL, Nagoya, Japan) for 1 hour. After the second wash, color was developed with 1.6 mmol/L tetramethylbenzidine (Sigma Chemical Co, St Louis, Mo) in 10 mmol/L sodium citrate, 1.25% polyethylene glycol 4000, and 10 mmol/L hydrogen peroxide, and was terminated with H2SO4. One each of PV serum and PF serum was selected as the standard for each ELISA. The index value was calculated according to the formula: Index value = (ODsample – ODnegative/ODpositive – ODnegative)*100

Main pathologic features

Lichenoid tissue reaction Suprabasilar acantholysis ID ID ID ID Acantholysis, ID Subepidermal blister Acantholysis Suprabasilar acantholysis, ID Acantholysis, ID Acantholysis, subepidermal blister Suprabasilar acantholysis Suprabasilar acantholysis Suprabasilar acantholysis Suprabasilar acantholysis Subepidermal blister Suprabasilar acantholysis UN Suprabasilar acantholysis Suprabasilar acantholysis

Reference No.

21

22

27 28

A cut-off index value was defined to be 11.0 for Dsg1 and 10.0 for Dsg3 ELISA as described previously.16 Subtyping of PNP patients based on clinical information To obtain clinical information, questionnaires were sent out to the doctors in charge. The questionnaire was focused on the extent of mucosal and cutaneous involvement as follows. • Mucosal findings: We evaluated oral, ocular, and genital mucosal involvement separately. Involvement was scored as follows. For oral lesions, 0: no involvement; 1: involvement of less than 10% of total oral mucosal area; 2: involvement of less than 30% of total oral mucosal area; 3: involvement of more than 30% of total oral mucosal area. For ocular lesions, 0: no involvement; 1: congestion of palpebral conjunctiva; 2: congestion of bulbar conjunctiva; 3: erosion of palpebral conjunctiva. For genital lesions, 0: no involvement; 1: only erythema; 2: erosion of less than 30% of total genital area; 3: erosion of more than 30% of total genital area.

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Fig 1. Antibody titer against Dsg1 and Dsg3 for different subtypes of PNP; mucosal type PNP (M) and mucocutaneous type PNP (MC). Antibody titer was determined by ELISA against recombinant Dsg1 and Dsg3. Line indicates cut-off index value of ELISA (11.0 for Dsg1, 10.0 for Dsg3). Bar indicates means of index value for each subtype.

• Cutaneous findings: We divided cutaneous findings into two subtypes: blister/erosion and erythema/lichenoid eruption. Then, we scored the degree of involvement as follows: for blister/erosion, 0: no involvement; 1: no more than 5 blisters or erosions with sizes of no larger than 5 cm in diameter; 2: involvement of less than 10% of total skin body surface area; 3: involvement of less than 30% of total skin surface area; 4: involvement of more than 30% of total skin surface area; 5: almost whole body involvement. For non-blister lesions (erythema/lichenoid eruption), 0: no involvement; 1: involvement of less than 10% of total skin body surface area; 2: involvement of less than 30% of total skin surface area; 3: involvement of more than 30% of total skin surface area; 4: almost whole body involvement. • Pathology: Pathologic findings, when available, were categorized into 4 major patterns: (1) suprabasilar acantholysis; (2) interface dermatitis (vacuolization of the basal layer, lymphocytic infiltration along the dermoepidermal junction with apoptotic keratinocytes); (3) lichenoid tissue reaction (dense bandlike infiltrate of lymphocytes along the dermoepidermal junction); and (4) subepidermal blister. On the basis of the above information, patients with PNP were subdivided into mucosal dominant

type and mucocutaneous type. Because all the patients had extensive oral mucosal involvement (the scores for the oral lesion were all 2 or 3), we defined patients with a cutaneous score for blister/erosion of 0 or 1 as having the mucosal dominant type and patients with a cutaneous score of 2 or greater as having the mucocutaneous type.

RESULTS The association between clinical phenotype and anti-desmoglein autoantibody profile in PNP is not as clear as that in classic pemphigus. Our questionnaire delineated the clinical features of the 21 patients with PNP (11 male/10 female) (Table I). Mean age was 50 years (range, 17-70 years). Eight patients had malignant lymphoma, 4 had chronic lymphocytic leukemia, and 4 had Castleman’s disease. Thus most of the patients had lymphoproliferative disorders as an underlying neoplasm. However, patient 6 had cervical adenosquamous carcinoma, and patient 10 had no apparent underlying malignancy. A possibility of undetected underlying lymphoproliferative disorders was not excluded because of limitation of clinical information. As to the scores of involved lesions, all patients had scores of 2 or 3 in oral lesions, which is consistent with the previous observation that severe oral involvement is characteristic of PNP. Among 21

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patients, 9 had scores of 0 or 1 for cutaneous lesions for blister/erosion and were defined as having mucosal dominant type disease, whereas 12 cases had scores of 2 or greater and were defined as having mucocutaneous type disease. We plotted individual ELISA scores for two PNP subtypes (Fig 1). Three of 9 patients with mucosal dominant disease were positive for anti-Dsg1 IgG (mean index value, 18.2), whereas 6 of 12 patients with mucocutaneous disease were positive for antiDsg1 IgG (mean index value, 19.6). Eight of 9 patients with mucosal dominant type disease were positive for anti-Dsg3 IgG (mean index value, 74.7), whereas all of the 12 patients with mucocutaneous type disease were positive for anti-Dsg3 (mean index value, 101.0). When we applied the finding of classic pemphigus,4,5,15 6 of 9 patients with mucosal dominant disease were negative for anti-Dsg1 IgG and 6 of 12 with mucocutaneous disease were positive for antiDsg1 IgG. Therefore only 12 of 21 patients with PNP showed the correlation between clinical phenotype and antibody profile that was found in classic pemphigus.

anti-Dsg IgG is acantholysis. There are several PNP cases reported that showed indistinguishable pathologic findings from PV for their cutaneous blisters or erosions.17-20 However, because the histologic findings of diagnostic criteria for PNP consist of various pathologic patterns,14 many cases showed bandlike cell infiltration and individual cell necrosis or vacuolization of basal cells besides suprabasilar acantholysis, including patients 7, 10, and 11 in this study.20-25 Other patients with PNP, including patients 1 and 3 through 6, showed minimal or no apparent acantholysis,26-28 and predominant lichenoid tissue reaction29 or interface dermatitis with exocytosis.30 Moreover, 3 cases of anti-Dsg1 IgG negative mucocutaneous type (patients 10, 11, and 12) showed interface dermatitis or subepidermal blister pattern along with acantholysis. These findings suggest that skin blisters observed in these patients with mucocutaneous type PNP can be caused not only by anti-Dsg IgG autoantibodies but also by other pathologic mechanisms such as lichenoid reaction or interface dermatitis. Thus the pathophysiologic mechanism of blister formation is more complex in PNP than in classic pemphigus.

DISCUSSION

We are grateful to Dr Michiyo Takahashi, Dr Kyo-ichi Kimura, Dr Naoto Otake, Dr Seiichi Izaki, Dr Yayoi Niimi, Dr Takao Uchihira, Dr Hiroshi Hosokawa, Dr Shigeru Yanagawa, and Dr Yasuyuki Sugita for answering our questionnaire. We thank Mrs Minae Suzuki for help with the ELISA work.

According to the desmoglein compensation theory6 and previous findings in classic pemphigus,4,5,15 anti-Dsg3 IgG alone can induce no or only limited skin blisters, whereas anti-Dsg1 IgG in addition to anti-Dsg3 IgG can cause extensive skin blisters. Because Dsg is the only cell surface target antigen identified at this point and because the pathogenic function of anti-Dsg IgG was demonstrated by using neonatal mouse model for pemphigus,13 we attempted to correlate the clinical phenotype and anti-Dsg antibody profile in PNP, as found in classic pemphigus. However, we observed this correlation in only 12 of 21 cases with PNP. A weakness of our study is that we had to collect clinical information by questionnaires from several doctors who might use different scales to evaluate the extent of skin involvement because PNP is a rare disease. In addition, in some patients (patients 2 and 10), sera were available only after immunosuppressive treatment was initiated. Patient 2 was negative against both Dsg3 and Dsg1; patient 10, who had mucocutaneous type disease, was positive against Dsg3 but negative against Dsg1. These could be part of the reasons why the correlation between the clinical phenotype and the antibody profile in PNP was not as clear as that in PV. Apart from this, 6 of 12 patients with mucocutaneous type disease were negative for anti-Dsg1 IgG. A histologic finding that reflects the pathogenicity of

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