pemphigus - intra epidermal blistering disorders
TRANSCRIPT
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
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