Intra-Epidermal blistering disorders

Dr.Preethi chekuriMD Dermatology

India

Types :

Pemphigus vulgaris

Pemphigus foliaceus

Paraneoplastic pemphigus

Intoduction

Term ‘pemphigus’ refers to a group of autoimmune blistering disorders of skin and mucous membrane that are characterised histologically by intraepidermal blisters due to acantholysis and immunopathologically by in vivo bound and circulating immunoglobulins directed against the cell surface of keratinocyte

Pemphigus vulgaris

Introduction

Supra basal acantholysis

The patients PV may present with more localised disease, one form of which is called pemphigus vegetans of hallopeau and a slightly more extensive form called called pemphigus vegetans of neumann

Epidemiology

Depends on the geographic location as well as the ethnic population in that area

PV is more common in jews and also in people from mediterranean and middle east decent

Ratio of PV:PF ~ Iran – 12 :1

Finland – 0.5 :1

male : female ~ 1 : 1.33 or 2.25

Mean age of onset being 40 yrs

EtiopathogenesisPemphigus antigens are desmogleins,

transmembrane glycoproteins of desmosomes

Desmogleins are part of the cadherin superfamily of calcium- dependent cell adhesion molecules.

The PF antigen (as well as the fogo selvagem antigen) is desmoglein 1, a 160-kDa protein. The PV antigen is desmoglein 3, a 130-kDa protein

All patients with PV have antidesmoglein 3 antibodies, and some of these patients also have antidesmoglein 1 antibodies

PF patients typically have antibodies against only desmoglein 1

Clinical findings

Cutaneous lesions

Vegetating lesions

Mucous membrane lesions

Cutaneous lesionsPrimary lesion – flaccid blister

Blisters are fragile resulting in erosions

May occur anywhere on the skin surface

NIKOLSKY SIGN – erosions can be extended into visibly normal skin by pulling the remnant of the blister wall or rubbing at the periphery of active lesions and erosions can be induced in normal-appearing skin distant from active lesions by pressure or mechanical shear force

Vegetating lesions

In certain patients, erosions have a tendency to develop excessive granulation tissue and crusting, referred to as vegetating lesions

Intertriginous areas, scalp and face

Mucous membrane lesions

Oropharynx

Gastro – intestinal tract ~ oesophagus, stomach, duodenum and anus

Vulvovaginal ,nasal, laryngeal and conjunctival mucosa can also get involved

Rare case reports of corneal erosions are also present

Oral erosions are painful and makes the patient unable to eat or drink

Painful mucous membrane lesions may be the presenting sign for 32% of the cases

These patients progress to a more generalised from in 5 months to 1 year period

Skin involvement without mucous membrane lesions is less common

Laboratory tests

Skin biopsy

Immunofluorescence – direct

indirect

ELISA

Histology The characteristic histopathologic finding in PV is a

suprabasal blister with acantholysis

The basal cells stay attached to the basement membrane, but may lose the contact with their neighbors; as a result, they may appear to be a “row of tombstones”

Usually, the upper epidermis remains intact

Pemphigus vegetans shows not only suprabasilar acantholysis, but also papillomatosis of the dermal papillae and downward growth of epidermal stands into the dermis, with hyperkeratosis and scale-crust formation

In addition, pemphigus vegetans lesions may show intraepidermal abscesses composed of eosinophils or neutrophils.

Early PV lesions may show eosinophilic spongiosis

Direct immunofluorescenceIgG auto-antibodies against the cell surface of

keratinocytes in perilesional skin

It is important that the biopsy for DIF be performed on normal-appearing perilesional skin, as the immune reactants can be difficult to detect in blistered inflamed epidermis (leading to a false negative result)

This is a nonquantitative test (either negative or positive)

Indirect immunoflourescencePerformed by incubating serial dilutions of

patients sera with epithelial substrates.

It is reported as a semiquantitative titer (indicating the last dilution at which the serum demonstrates a positive cell surface staining pattern)

Pemphigus patients have circulating antiepithelial cell surface IgG

ELISAmore sensitive and specific

than immunofluorescence

ELISAs are easier toperform and less subjective

Use desmogleins 1,3 bound to plates, which are then incubated with patient sera and developed with antihuman IgG reagents

help differentiate between PV and PF due to the different autoantigen profiles

Pemphigus foliaceus

Introduction

Subcorneal acantholysis

Patients with PF may present with a more localised disease called PEMPHIGUS ERYTHEMATOSUS

Epidemiology

Dependent on location

Endemic foci – brazil, colombia and tunisia

FOLO SELVAGEM (wild fire)

Fogo selvagem occurs often in children and young adults, unlike sporadic PF, which is a disease of mostly middle-aged and older patients

Clinical findingsThe characteristic clinical lesions of

PF are scaly, crusted erosions, often on an erythematous base

In more localized and early disease, these lesions are usually well demarcated and scattered in a seborrheic distribution, including the face, scalp, and upper trunk

In contrast to patients with PV, those with PF very rarely, if ever, have mucous membrane involvement, even with widespread disease.

Histology Acantholysis just below the stratum corneum and in

the granular layer

The epidermis, below the granular layer, remains intact.

Another frequent finding is subcorneal pustules, with neutrophils and acantholytic epidermal cells in the blister cavity

Drug induced pemphigus

Association with penicillamine and captopril is the most significant

PF is more common than PV

Both penicillamine and captopril contain sulfhydryl groups that are postulated to interact with the sulfhydryl groups in desmoglein 1, 3

Treatment

Corticosteroids

Immunosuppressive agents - azathioprine

mycophenolate mofetil

cyclophosphamide

dapsone

Additional therapies - rituximab, plasmapheresis, intravenous immunoglobulin

Corticosteroids

1 to 1.5 mg/kg/ day of prednisolone equivalent used singly or in combination with adjuvant immunosuppressive therapy

Some recommend controlling initial phase with high doses ( upto 240mg/day)

Topical - used to help heal new lesions

- mucosal disease benefitted from swish and spit method

DCP pulse therapy

Day 1 : Iv administration of 100mg dexamethasone with 500mg cyclophosphamide in 500ml of 5% dextrose over 1-2 hrs

Day 2 and day 3 : 100mg dexamethasone

Pulses repeated every 4 weeks

On remaining days, 50 mg of cyclophosphamide given orally

4 phases

Immunosuppressive agents

Azathioprine - 2.5mg/kg/day

Due to its toxicity it is reasonable to start with 50-100mg daily

Mycophenolate mofetil - 30-40 mg/kg/day twice daily

Cyclophosphamide - 1- 2.5mg/kg/day or daily oral therapy of 50 mg

Additional therapy

Rituximab - monoclonal anti CD20 antibody, targets B cells, the precursors of antibody producing cells

IV dose of 375mg/m2 once every 4 weeks

Intravenous immunoglobulins - gamma globulin in high doses is given

Paraneoplastic pemphigus

Introduction

It is an autoimmune mucocutaneous blistering disorder characterized by an associated neoplasm and the presence of unique antibodies directed at desmosomal plakins

HLA-DRB1*03

Etiopathogenesis 3 mechanisms postulates :

Molecular mimicry - an immune response against tumor antigens cross reacts with normal epithelium

Tumor may cause cytokine dysregulation leading to synthesis of antibodies to pemphigus autoantigen Dsg 3, with a subsequent secondary autoimmune reaction to intercellular proteins of plakins

Epitope spreading - tumor induces a cell mediated lichenoid interface dermatitis that uncovers previously hidden antigens

Clinical featuresAge - 45 to 70 yrs

Recalcitrant stomatitis - painful erosions of oropharynx and vermilion border of lips

Polymorphous and pruritic

Mucocutaneous lesions

Palmoplantar target lesions

Bronchiolitis obliterans

malignancies

Malignancies associated are :

Non - hodgskin lymphoma

Chronic lymphocytic leukemia

Castleman disease

Retro peritoneal sarcoma

thymoma

Waldenstom’s macroglobulinemia

HistologySupra basal acantholysis, individual cell necrosis,

vacuolar interface dermatitis, lichenoid inflammation and lymphocytic exocytosis

The spectrum of changes can include:

(1) individual keratinocyte necrosis with lymphocytic infiltration into the epidermis, reminiscent of that seen in EMF or GVHD

(2) vacuolar interface change with sparse lymphocytic infiltrate of the basilar epithelium, resembling LE and DM

(3) a thick lichenoid band along the DEJ

DIF

the most characteristic changes are those of deposition of IgG and complement components (C3) on both the surface of basilar and suprabasilar keratinocytes and along the epidermal basement membrane zone

IIF and ELISA

Identical to pemphigus vulgaris with staining of the epidermal cell surface

Demonstration of characteristic combination of anti plakin and anti desmoglein auto antibodies by ELISA

Special tests

CT

MRI

Positron emission tomography/ computer tomog-raphy (PET/CT) using fluorodeoxyglucose (FDG) as abiologically active molecule can be more specific

Diagnosis (Anhalt et al criteria)

1.Painful stomatitis and a polymorphous cutaneous eruption with lesions that may be blistering, lichenoid, or resemble EMF .

2.Histologic findings that reflect the variability of the cutaneous lesions, showing acantholysis, lichenoid, or interface change.

3.DIF findings of IgG and C3 deposition in the epidermal intercellular spaces and granular/linear C3 deposition along the epidermal BMZ

4.Serum autoantibodies that bind to the cell surface of skin and mucosae in a pattern typical of pemphigus, but in addition, bind to simple, columnar, and transitional epithelia.

5.The serum autoantibodies identify Dsg 1 and 3 in addition to members of the plakin family of epithelial proteins, such as desmoplakins, envoplakin, and periplakin

Differential diagnosis

Treatment

Thank you