Immunobullous Diseases: Review and Update. May P. Chan, MD Associate Professor of Pathology and Dermatology University of Michigan

Transcription

1 Immunobullous Diseases: Review and Update May P. Chan, MD Associate Professor of Pathology and Dermatology University of Michigan

2 Diagnosis of Immunobullous Diseases Clinical H&E DIF DIAGNOSIS IIF ELISA Immunoblot

3 Direct IF Indirect IF Anti-IgG/A/M FITC Anti-IgG/A/M FITC IgG/A/M Anti-C3 C3 Pt s IgG/A/M Anti-C3 Pt s C3 Patient s Biopsy Control Substrate

4 Enzyme-Linked Immunosorbent Assay (ELISA) 2 Antibody Enzyme Patient s Ig (Serum) Recombinant protein (Antigen)

5 Immunoblot

6 Subepidermal Bullous pemphigoid (BP) Mucous membrane pemphigoid (MMP) / Cicatricial pemphigoid (CP) Anti-p200 pemphigoid Bullous lupus erythematosus (BLE) Lichen planus pemphigoides (LPP) Herpes gestationis Dermatitis herpetiformis (DH) Linear IgA bullous dermatosis (LABD) Epidermolysis bullosa acquisita (EBA) Intraepidermal Pemphigus vulgaris (PV) Pemphigus foliaceus (PF) Pemphigus erythematosus (PE) Pemphigus vegetans (PVeg) Pemphigus herpetiformis IgA Pemphigus Paraneoplastic pemphigus (PNP) IgG/IgA pemphigus

7 Case 1 76-year-old woman Tense blisters on abdomen, upper and lower extremities

8 Dx: Bullous Pemphigoid

9 Bullous Pemphigoid (BP) Most common blistering disease Elderly (7 th decade) May be induced by UV light, drugs, vaccines Severe pruritus Tense blisters on erythematous or normal skin Abdomen, groin, extremities (flexor) 10-40% patients with mild oral involvement

10 BP: Clinical Variants Pemphigoid nodularis Pemphigoid vegetans Ecthyma gangrenosum-like pemphigoid Erythrodermic BP Dyshidrosiform BP Seborrheic BP Localized BP

11 BP: Autoantigens BP230 (BPAg1) BP180 (BPAg2)

12 BP: H&E Clean subepidermal split Numerous eosinophils Variable number of neutrophils

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15 Neutrophilic BP Predominance of neutrophils Rare eosinophils Histologic DDx: Dermatitis herpetiformis (DH) Linear IgA bullous dermatosis (LABD) Bullous lupus erythematosus (BLE)

16 Urticarial BP Eosinophilic spongiosis Eosinophils tagging along BMZ Dermal edema

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20 BP: DIF IgG Linear IgG (90-95%) and C3 (~100%) along BMZ SSS: Roof (epidermal) side IgG (SSS) C3

21 BP: n-serrated Pattern

22 Linear BMZ Pattern Terra JB et al. Br J Dermatol 2013.

23 Salt-Split Skin (SSS) Salt split

24 Linear BMZ Pattern: SSS Roof (+ floor) Floor only Courtesy of Dr. Mary Jane Zimarowski

25 BP: ELISA BP180 NC16A domain Sensitivity 75-90% Level correlates with disease activity BP230 C-terminal domain Sensitivity 80%

26 Case 2 75-year-old woman Symblepharon

27 IgG IgA Dx: Mucous Membrane Pemphigoid

28 Mucous Membrane Pemphigoid (MMP) Cicatricial Pemphigoid (CP) Elderly, female predilection Variant of BP Oral (85%), conjunctiva (65%), skin (25%), nasopharynx (20%), genitalia (20%), larynx (8%), esophagus (4%), anus (3%) Heals with scarring

29 MMP: Clinical Desquamative gingivitis often resembles erosive lichen planus Chronic conjunctivitis symblepharon Brunsting-Perry CP affects only skin on head and neck, heals with atrophic scar

30 MMP: Autoantigens BP180 BP230 α6 integrin (oral) β4 integrin (ocular) Laminin-332 Collagen VII

31 MMP: H&E Clean subepidermal split Subepithelial fibrosis Cells???

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33 Brunsting-Perry CP CP involving scalp blister scarring alopecia Mucosal lesions may be present BP180 > Laminin-332

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36 MMP: DIF IgG Linear IgG, C3: % Linear IgA: 50% IgA C3

37 MMP: IIF on SSS Lam-332 BP180 Hayakawa 2014 BP180 + Lam-332

38 MMP: Post-SJS Rare cases of MMP preceded by Stevens-Johnson syndrome Few months to 31 years Autoimmunization with epidermal antigens not normally presented to the immune system ( epitope spreading ) Chan 1991

39 Case 3 40-year-old man History of psoriasis Tense bullae on hands, feet, and abdomen DDx: Dyshidrotic BP? Meijer 2016

40 IgG Dx: Anti-p200 Pemphigoid C3 ELISA: (-) BP180, BP230, collagen VII, laminin-332

41 Anti-p200 Pemphigoid Slightly younger age of onset than BP Hands and feet most common Mucosal involvement in half of patients May mimic BP, DH, LABD clinically Tends to run a milder clinical course and be more responsive to treatment than BP, MMP, and EBA

42 Anti-p200 Pemphigoid: Autoantigen Autoantibodies target laminin- γ1 in 90% cases Laminins are heterotrimeric glycoproteins: α chain (400 kda) β chain (200 kda) γ chain (200 kda)

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44 Anti-p200 Pemphigoid: H&E Subepidermal bullae with neutrophils > eosinophils May mimic BP, inflammatory EBA, DH, LABD Monshi 2012 Rose 2007

45 Anti-p200 Pemphigoid: DIF Linear IgG and C3 with n-serration Floor (dermal) pattern on SSS SSS IgG C3 Monshi 2012

46 Anti-p200 Pemphigoid: ELISA Recombinant C-terminal fragment of laminin γ1 Anti-laminin γ1 levels correlate with disease activity -N -C Groth 2011 Monshi 2012

47 Case 4 50-year-old man History of lichen planus (LP) Abrupt development of tense blisters, some of which are superimposed on LP lesions

48 IgG Dx: Lichen Planus C3 Pemphigoides

49 Lichen Planus Pemphigoides (LPP) Originally thought to be coexisting LP and BP Epitope spreading : Autoimmune response to endogenous epitope secondary to release and exposure of self-protein during an inflammatory process Damage of basal cells in LP leads to formation of autoantibodies to hemidesmosome (BP)

50 LPP: Autoantigens BP180 BP230 Uncharacterized 200-kDa antigen Uncharacterized 130-kDa antigen Dsg1?

51 LPP: Clinical Lichen planus Violaceous flat-topped papules White reticulated oral lesions Tense bullae Within LP papules or normal skin Abrupt onset Extremities Ilknur 2011

52 LPP: H&E LP lesions: Lichenoid interface dermatitis BP lesions: Subepidermal split, eosinophils, neutrophils

53 LPP: DIF Linear IgG, C3 at BMZ (BP pattern) Shaggy fibrin, cytoid bodies (LP pattern) IgG Fibrin C3 IgM

54 BP180: LPP vs. BP NH2 NC16A COOH Both LPP and BP target the C-terminal NC16A domain of BP180 antigen (by immunoblot and ELISA) LPP: region 4 (besides regions 2 and 3) BP: regions 1-3 TM

55 Case 5 45-year-old man Flaccid bullae on thigh

56 IgG Dx: Pemphigus Vulgaris

57 PV: Clinical Most prevalent 4 th to 6 th decades Oral erosions Flaccid bullae on scalp, face, chest, axilla, groin, extremities Mucocutaneous or mucosal dominant

58 PV: Autoantigen Dsg3 ± Dsg1 (50%)

59 PV: H&E Suprabasilar acantholysis Row of tombstones Perivascular lymphocytes, eosinophils, neutrophils

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61 PV: DIF Intercellular, net-like deposition of IgG and C3 IgG C3

62 Skin Mucosa Mucosal-dominant PV (anti-dsg3): Dsg1 Dsg3 Mucocutaneous PV (anti-dsg3 + anti-dsg1): PF (anti-dsg1): Amagai 2003

63 Pemphigus Foliaceus (PF) Flaccid bullae on skin more prone to erosion and crusting No oral involvement

64 PF: H&E Subcorneal split stratum corneum often lost Acantholytic dyskeratosis Involvement of follicular epithelium May have superficial neutrophils

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66 PF: DIF Intercellular, net-like deposition of IgG and C3 IgG C3

67 Neonatal PV Dsg3 expressed in the entire epidermis in neonatal skin Passive transfer of maternal anti-dsg3 antibodies result in neonatal PV Passive transfer of maternal anti-dsg1 antibodies does not result in neonatal PF Itsukaichi 2013

68 Case 6 47 yo woman with odynophagia Upper endoscopy showed esophageal ulcers Esophageal biopsy

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70 IgG IgA Dx: IgG/IgA Pemphigus C3

71 IgG/IgA Pemphigus ~40 reported cases Clinically similar to PV > PF > IgA pemphigus Mucosal involvement in >60% Subset of patients had underlying malignancy IgG and IgA autoantibodies targeting desmogleins ± desmocollins

72 IgG/IgA Pemphigus: H&E Intraepithelial (suprabasilar/subcorneal) acantholysis Rodriguez-Vivian 2018 Toosi 2016

73 IgG/IgA Pemphigus: DIF Intercellular IgG, IgA, ± C3 deposits

74 Case 7 45 yo man History of non-hodgkin lymphoma Cutaneous flaccid blisters Oral ulcers and stomatitis

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76 IgG IIF on rat bladder (+) Dx: Paraneoplastic IgM Pemphigus

77 Paraneoplastic Pemphigus (PNP) Mucocutaneous acantholytic disease Underlying neoplasia A more encompassing term paraneoplastic autoimmune multiorgan syndrome (PAMS) proposed by Nguyen et al. (2001): Skin, conjunctiva, oral mucosa, respiratory tract (bronchiolitis obliterans), upper GI tract, kidney, bladder, thyroid, smooth and striated muscles

78 PNP: Associated Neoplasms Waldenstrom Hodgkin lymphoma Monoclonal gammopathy Melanoma Non-Hodgkin Lymphoma 38.6% Thymoma 5.5% Sarcoma 6.2% Carcinoma 8.6% Castleman 18.4% CLL 18.4% Kaplan 2004

79 PNP: Pathogenesis Autoreactive Cells CD8+ cytotoxic T cells CD56+ NK cells CD68+ macrophages Lichenoid inflammation Dyskeratoses Autoantibodies Envoplakin Desmoglein 1 Periplakin Desmoglein 3 Desmoplakin Plectin A2ML1 BP230 BP180 Suprabasilar acantholysis Subepidermal split (+) DIF

80 PNP: Autoantigens

81 PNP: Autoantigens

82 Antibody mediated BP-like EM-like PV/PFlike GVHDlike LP-like Cell mediated Subtype Clinical Histopathology Pemphiguslike BP-like EM-like GVHD-like LP-like Flaccid blisters, crusted erosions Scaling erythematous papules ± tense blisters Polymorphic, annular papules or plaques Widespread dusky red scaly papules Small violaceous flat-topped scaly papules Intraepidermal acantholysis ± subepidermal split Subepidermal split with dyskeratosis Dyskeratosis ± subepidermal split Vacuolar interface dermatitis with hyperkeratosis; no split Lichenoid interface dermatitis with hyperkeratosis; no split

83 EM-like PV-like BP-like LP-like PF-like Choi 2012; Tsuchisaka 2014

84 PNP: H&E Suprabasilar acanthosis Dyskeratoses

85 PNP: H&E PV-like GVHD-like

86 IgG PNP: DIF Intercellular ± linear BMZ deposition of IgG and C3 Some cases also show IgA deposition C3 Tsuchisaka 2014

87 PNP: IIF Rat bladder: Envoplakin, periplakin present Desmogleins absent A2ML1 absent Sensitivity 74%; specificity 100% Poot 2013

88 PNP: Immunoblot (IB) IB: Sensitivity 89%; specificity 100% IB + IIF: Sensitivity and specificity 100% Poot 2013 Tsuchisaka 2014

89 PNP: Immunoprecipitation (IP) Human keratinocyte proteins IP d by PNP sera Recombinant A2ML1 IP d by PNP sera Schepens 2010

90 A2ML1 Alpha-2-macroglobulin-like-1 protein 170-kDa protease inhibitor expressed by human keratinocytes Anti-A2ML2 antibody inhibits A2ML1 plasmin activation cellular adhesion Anti-A2ML1 autoantibodies detected in 69% of PNP sera IB/IP shows higher sensitivity than IF

91 Anti-A2ML1 Presence of anti-a2ml1 autoantibodies is associated with early disease onset and absence of ocular lesions Numata 2013

92 PNP: ELISA Limited utility in PNP Recombinant proteins Envoplakin (sensitivity 82%, specificity 98%) Dsg3 Dsg1

93 PNP: Laboratory Diagnostic Algorithm Suspicion for PNP IIF (rat bladder) and/or immunoblot Positive Negative Immunoprecipitation (+) EP and PP (+) A2ML1 Negative PNP confirmed PNP possible but r/o TEN PNP unlikely (seroreversion?) Poot 2013

94 THANK YOU!