Epitope spreading in PAMS: A ClinicalImmunopathologic Basis

Valeria Aoki MD., PhD.Associate Professor

Department of DermatologyUniversity of São Paulo School of Medicine

São Paulo, Brazil

Symposium 060: Recent Advances in AIBD

N Engl J Med 1990; 323:1279-35

Aoki V- FMUSP-AAD 2019

• n=5, 45-67yo• extensive blisters/erosions mucosa• polymorphic skin lesions• underlying neoplasms: lymphoma, leukemia, thymoma, sarcoma

(N Engl J Med 1990; 323:1279-35)

(N Engl J Med 1990; 323:1279-35)

• Desmoplakin I (250kD)

• BP230Ag, Ags 210, 190, 170KDa

• Animal models:

• Blisters, +Nikolsky

• H&E: IE blisters,

• acantholysis (skin/esophagus)

• EM: loss cell-cell adhesion

Paraneoplastic Pemphigus

• acantholysis

• apoptotic keratinocytes

• interface dermatitis with vacuolization

• DIF: IgG and C3-intraepidermal intercellular

deposits and/or deposits at the BMZ

• IIF: IgG intercellular deposits

Ø squamous epithelium

Ø columnar epithelium (rodent bladder)

Aoki V- FMUSP-AAD 2019

Aoki V- AAD 2019

(N Engl J Med 1999; May 6;340(18):1406-10)

• 2 patients: 13 and 39 yo• Castleman’s disease / B cell non-Hodgkin lymphoma• Dyspnea evolving to fatal bronchiolitis obliterans (> 1y PNP)

PNP 1 PNP 2

S SR R

PV

R

Plakins• DPI• BP230 Ag• DPII• Envoplakin• Periplakin• Ag 170 kDa

Paraneoplastic Pemphigus endobronchial biopsy

PNP: n=84; 30% BO

Hematologic-related-84%• Non-Hodgkin lymphoma: 38.6%• Chronic lymphocytic leucemia: 18.4%• Castleman’s disease: 18.4%• Thymoma:5.5%• Waldenstrom’s macroglobulinemia: 1.2%• Hodgkin’s lymphoma: 0.6%• Monoclonal gammopathy: 0.6%

Non hematologic-16%• Carcinomas: 8.6%Adenocarcinomas

(prostate, colon, breast, pancreas)

• Sarcomas: 6.2%• Melanoma 0.6%

PNP/PAMS

(Amber KT et al. Autoimmunity rev 17 (2018):1002-10; Czernik A et al. Int j Dermatol 2011; 50:905-14; Kaplan I, et al. Oral Oncol 2004;40:553-62; Frew JW et al. Dermatol Clin 2011; 29(3):419-25)

Associated Neoplasms

• males > females; 45-70 yo, children reported• 3-5% of all pemphigus; 68-90% mortality• HLA class II DRBI*03 (Caucasian)/ Cw14 (Chinese)• Bronchiolitis Obliterans (BO): 30-40%

Aoki V- FMUSP-AAD 2019

PNP/PAMS

EM-likeBP-likePNP GVHD-like LP-like

B cell response T-cell response

• painful mucosal involvement: erosive stomatitis (100%)• conjunctiva (41%), GI tract• bronchiolitis obliterans (30-40%): ectopic expression of

Dsg3 in the lungs (squamous metaplasia?)• neurological involvement (myasthenia gravis:35%)• kidney involvement

Aoki V- FMUSP-AAD 2019

PNP/PAMS:clinical-pathological

features

(Amber KT et al. Autoimmunity rev 17 (2018):1002-10 ; Wang R et al, Brit J Dermatol 2015, 172:968-75); Hata T et al. J Immunol 2013;191:83-90)(Czernik A et al. Int j Dermatol 2011, 50:905-14; Nguyen VT et al. Arch Dermatol 2001 Feb;137(2):193-206); Leger S et al Arch Dermatol 2012:148:1165-72; Santi CG et al. J Dermatol 2005, 32: 1014–1020)

Poor prognostic factor

PNP/PAMS: Autoantibody Profile

Technique Sensitivity Specificity

IP-IB 100 86R-IP 95 100IB 89 100

IIF ratbladder

74 100

EnvoplakinELISA

63 98

(Poots A et al. Brit J Dermatol 2013; 169:1016-24)

(Anhalt GJ et al. N Engl J Med 1990; 323:1279-35; Amber et al. Autoimmunity Rev2018;17:1002-10)

DPI

EP/DPII

PPBP2Ag

A2ML1

• Epiplakin: expressed by culture keratinocytes (IF)• 48 PNP sera: 72.6% + IP-IB for epiplakin (KU extract)

• correlation with bronchiolitis obliterans (BO) in Japanese• no correlation with BO in Europeans• serological marker for BO?

(Tsuchisaka A, et al. J Investig Dermatol

2016; 136, 399-408)

Aoki V- FMUSP-AAD 2019

Plakins

Dsg 3Dsg1

• AChR• AChE• BP180• DSC1-3• MUSK• PK3• Plectin

Decreased recognition of paraneoplasticpemphigus in patients previously treated with anti-CD 20 monoclonal antibodies

patients with lymphocytic malignancies treated with anti-CD20

chronic lichenoid /interface dermatitis

rule out PNP/PAMS

(DOI: 10.1111/bjd.17577 ; Kwatra et al 2019)

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PNP/PAMS - Diagnostic Criteria Features

Clinical features • persistent mucositis (stomatitis), conjunctivitis (41%)• polymorphic lesions (PV-BP-EP-GVHD-LP like)• associated neoplasm (hematologic:84%; non-hematologic:16%)

Extracutaneous involvement • bronchiolitis obliterans (30-40%)• myastenia gravis (35%)

Histopathology • acantholysis• dyskeratosis-keratinocyte necrosis• interface dermatitis with vacuolization

Immunofluorescence • DIF: IgG and C3: intraepidermal intercellular deposits and/or deposits at the BMZ• IIF: Intercellular intraepidermal IgG deposits Ø squamous and transitional epithelium (rat bladder)

Immunochemistry(main autoantigens)

• 250kDa Desmoplakin I• 230KDa BPAg2• 210kD Desmoplakin II• 210kD Envoplakin• 190kD Periplakin• 170kD a2 macroglobulin-like protein• Desmogleins 3/1, Desmocolins 1-3, BP180, Epiplakin (BO marker?)

Aoki V- FMUSP-AAD 2019

(Amber KT et al. Autoimmunity rev 17 (2018):1002-10 ; Wang R et al,. Brit J Dermatol 2015, 172:968-75); Czernik A et al. Int j Dermatol 2011, 50:905-14; Nguyen VT et al. Arch Dermatol 2001 Feb;137(2):193-206)