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Pemphigus Flashcards

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1
Q

Pemphigus classification

A
  • Pemphigus vulgaris (deeper)
    • Vegetans
  • Pemphigus foliaceus (more superficial)
    • Pemphigus erythematosus
    • Fogo selvagem
  • Herpetiform pemphigus
  • Drug-induced pemphigus
  • Paraneoplastic pemphigus (humoral and cellular autoimmune reactions)
  • IgA pemphigus
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2
Q

What is fogo selvagem?

A
  • Clinically, histo and immunopath the same as pemphigus foliaceous
  • Endemic in Brazil, thought to be caused by environmental factors
  • Affects young adults and children
  • Any race exposed to local ecology
  • Patients often live close to rivers, and within 10-15 km flying range of black flies
  • History of bed bugs and kissing bugs
  • In related family members
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3
Q

What is the pathogenesis of pemphigus?

A
  • IgG autoantobidoes against the cell surface of keratinocytes
    • Can be transient in neonates from the placenta
  • Antibodies to desmosomes: prominent cell-cell adhesion junctions in stratified squamous epithelia
  • We don’t know why the develop the antibodies, there is some genetic component, and it is thought T cells are involved
  • Vulgaris is 130 kDa and foliaceus is 160 kDa
  • Autoantibodies inhibit the adhesive function of desmogleins and lead to the loss of the cell-cell adhesion of keratinocytes, resulting in blister formation
  • Cadherins:
    • Classic
    • Desmosomal - desmogleins and desmocollins
  • Desmoglein 1 and 3 compensate for each other when they are coexpressed in the same cell:
    • anti-Dsg1 positive - blisters appear only in the superficial epidermis of the skin because that is the only area in which Dsg1 is present without coexpression of Dsg3
      • In unaffected deep dermis, the presence of Dsg3 compensates for the loss of Dsg 1
      • therefore, anti-Dsg1 only causes superficial blisters in the skin without mucosal involvement –> PF
    • anti-DsG3 only:
      • no cutaneous blisters because the Dsg1 compensates
      • however no Dsg1 in mucous membranes –> results in blistering here
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4
Q

What autoantibodies does pemphigus vulgaris have?

A

Mucosal dominant: IgG to DsG 3

Mucocutaneous IgG to Dsg# and 1

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5
Q

What autoantibodies does pemphigus foliaceous have?

A

IgG to DsG1

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6
Q

What autoantibodies does IgA pemphigus have?

A

SCPD type: IgA to desmocollin

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7
Q

What can PV clinically look like

A
  • Can be mucosal (Dsg3) and mucocutaneous (Dsg1 and 3)
  • Oral:
    • painful erosions
    • intact blisters are rare as too fragile/break easily
    • Most common site: buccal and palatine mucosa
    • Different sized erosions with irregular and ill-defined border
    • diagnosis tends to be delayed in mucosal pemphigus
    • can lead out onto the vermillion lip and lead to thick, fissured haemorrhagic crusts
    • Hoarseness and difficulty swallowing
    • Oesophagus can be involved
    • Other sites: conjunctivae, nasal mucosa, vagina, labia, penis and anus
  • Cutaneous
    • Flaccid, thin walled, easily ruptured blisters
    • Fluid within bullae is initially clear, but may become haemorrhagic, turbid or seropurulent
    • Painful erosions when rupture
    • Healing: hyperpigmentation
    • Pruritus
    • appear anywhere on the skin
    • Nikolksy positive, Asboe-Hansen positive
  • Unusual presentations:
    • Isolated crusted plaque on face or scalp
    • Paronychia and/or onychomadesis
    • Foot ulcers
    • Dyshidrotic eczema or pompholyx
    • Macroglossia
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8
Q

What are the types of pemphigus vegetans and what does it look like

A
  • rare variant of PV –> thought to be a reactive pattern of the skin to the autoimmune insult of pemphigus vulgaris
  • Flaccid blisters that become erosions and then form fungoid vegetans or papillomatous proliferations
  • Intertriginous areas and scalp/face
  • Pustules characterize early lesions –> then progress to vegetative plaques
  • Tongue: cerebriform changes
  • Two subtypes:
      1. Severe Neumann
      1. Mild Hallopeau
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9
Q

What is herpetiform pemphigus?

A

Characterized by:

  1. Erythematous urticarial plaques and tense vesicles in a herpetiform arrangement
  2. Eosinophilic spongiosis and subcorneal pustules with minimal acantholysis
  3. IgG autoantibodies against cell surfaces of keratinocytes
    - Mostly have pemphigus foliaceus, some have PV
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10
Q

What drugs cause pemphigus and why?

A
  • PV? More liky PC: penicillamine and captopril
  • Penicillamine: pemphigus foliaceus more commonly
  • P & C contain suflhydryl groups that interact with the sulfhydryl groups on Dsg1 and 3
  • Most go into remission once drug is stopped
  • In the JAAD they say: penicillamines, ACEI, ARBs, cephalosporins
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11
Q

What cancers cause paraneoplastic pemphigus?

A
  • NHL + CLL –> account for 2/3
  • Castleman disease –> third most common, and most common in kids
  • Malignant and benign thyomomas
  • Sarcomas
  • Waldenstrom macroglobulinaemia
  • Not associated with adenocarcinomas
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12
Q

What does paraneoplastic pemphigus look like?

A
  • Mucosal:
    • Intractable stomatitis –> usually the earliest presenting sign
    • Erosions and ulcerations that affect all surfaces of the oropharynx and characteristically extend onto the vermilion lip
  • Ocular: pseudomembranous conjunctivitis –> scarring and obliteration
  • Nasopharyngeal, oeosphageal, vaginal, labial, penile and perianal lesions may also be seen
  • Cutaneous
    • Polymorphic: erythematous macules, flaccid blisters, erosions
    • Tense blisters looking like BP
    • EM like lesions
    • Lichenoid eruption –> seen in chronic form
    • Palm and sole involvement helps differentiate from PV
  • Extracutaneous:
    • Bronchiolitis obliterans –> resp failure. CXR and CT often normal at the beginning, but PFT show small airway disease
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13
Q

What are the types of IgA pemphigus

A
  1. Subcorneal pustular dermatosis type
    1. IgA tends to react against the upper epidermal surfaces
  2. Intraepidermal neutrophilic type
    1. Sunflower-liker configuration characteristic of this type
    2. IgA found throughout the entire epidermis
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14
Q

What does IgA pemphigus look like

A
  • autoimmune intraepidermal blistering disease: neutrophilic infiltrate, IgA to keratinocytes, no IgG
  • Middle-aged to elderly patients
  • Vesiculopustular eruption
  • both present with flaccid vesicles or pustules on erythematous or normal skin
  • pustules coalesce to form an annular or circinate pattern with crusts in the centre of the lesion
  • Axilla and groin, but lesions can also develop on trunk and proximal extremities
  • No MM involvement, can be itchy
  • Only thing to differentiate from SCPD is immunologic evaluation
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15
Q

Histo and IF for pemphigus vulgaris

A
  • Intra-epidermal blister formation due to loss of cell-cell adhesion of keratinocytes: acantholysis without keratinocyte necrosis
  • Sometimes the acantholysis is a bit more superficial, but usually suprabasilar
  • Tombstones: basal cells maintain their attachment to the basement membrane
  • Dermal papillae may protrude into the blister cavity
  • Blister cavity may have inflammatory cells (eosinophils)
  • Dermis: moderate perivascular mononuclear cell infiltrate with conspicuous eosinophils
  • Very early: eosinophilic spongiosis

IgG deposition in 100% usually
‘Chickenwire or honeycomb or fishnet like’

Occasional IgA seen with an epithelial cell surface pattern

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16
Q

Histo and IF for pemphigus foliaceous, fogo selvagem and pemphigus erythematosus

A
  • Acantholysis is sometimes difficult to detect as the roof is taken off given so fragile
  • Split is in the upper spinous layer
  • Acantholytic keratinocytes can be found attached to the roof or floor of the blister
  • Deeper dermis usually remains in tact, but secondary clefts may develop leading to detachment of the epidermis in its midlevel
  • Looks like staph scalded skin or bullous impetigo because Dsg1
  • Sometimes contains acute inflammatory cells - neutrophils
  • Can see eosinophilic spongiosis in early phase

IgG deposition in 100% usually

17
Q

Histo and IF for paraneoplastic pemphigus

A
  • Variable given polymorphic
  • EM like, PV like, LP like
  • Intact blisters: suprabasilar acantholysis and individual keratinocyte necrosis as well as lymphocytes in the epidermis
  • Interface dermatitis
  • Dense band-like lymphocytic infiltrate in the upper dermis
  • Eos are rare

IgG and C3 on epidermal cell surfaces

18
Q

Histo and IF for IgA pemphigus

A
  • Intra-epidermal pustule or vesicle
  • Consist predominantly of neutrophils
  • If pustule is subcorneal –> then subcorneal type
  • If lower or entire epidermis –> intraepidermal

IgA but not IgG on keratinocyte cell surfaces

19
Q

For IIF, what is usually recommended to be used for substrate?

A 
PV - monkey skin oesophagus
PF - human skin or guinea pig eosopahgus
PNP - monkey and guinea pig, rat bladder
BP and LABD: human skin, salt split
MMP: human skin, salt split
20
Q

What autoantigens involved in PNP?

A

DsG1 , 3, laminin 332, envoplakin, periplakin

21
Q

EBA has which autoantigen

A

Type 7 collagen

22
Q

MMP has which autoantigen

A

BP 180, 230, laminin 332, type 7 collagen

23
Q

Differentials for pemphigus vegetans

A 
Hailey Hailey
Pemphigoid vegetans
Blastomycosis-like pyoderma
Pyodermatitis-pyostomatitis
Halogenoderma
Infections
Bacterial - granuloma ingunala, condylomata lata
Fungal - chromomycosis
Viral
Parasitic
Extramammary Paget disease
24
Q

All the possible treatments for pemphigus

A
  • systemic steroids are the mainstay of treatment - start at 1 mg/kg/day as an initial dose
  • once clinical remission is obtained, changes in the titre of circulating autoantibodies gauges how helpful the prednisone has been
  • if there is no response in 3-7 days, then use something else
  • IV pulse of methylprednisone 1 g/day for 3-5 days is an alternative choice
  • Aggressive treatments: Immunosuppressive agents in combination with oral prednisone:
    • Azathioprine - 2-4 mg/kg/day
    • MMF - 2-3 g/day
    • Cyclophosphamide - 1-3 mg/kg/day
    • Cyclosporine - 3-5 mg/kg/day
    • Pulse methylprednisone - 1g/day over a period of 2-3 hours for 3-5 days
    • MTX - 7.5 mg - 20 mg a week
    • Pulse cyclophosphamide - 500-1000 mg/m^2 every 4 weeks
    • Plasmapharesis - 1-2 times a weeka t the onset
    • High dose IVIG - 400 mg/kg/day for 5 consecutive days, may need to be repeated monthly –> has a double blind randomized trial supporting it
    • Rituximab - 375 mg/m^2 once weekly for 4 weeks, or 1 g initially then at 2 weeks, either regimen may need to be repeated every 3-6 months
      • reduces CD20 B cells and a decline in IgG, but also decreases desmoglein-specific T cells
    • ECP - 2 days per month
  • If complete remission is achieved with a combined therapy, the dosage of the immunosuppressive drug is maintained whilst the prednisone is tapered
  • Gold therapy on the back burner now
  • Watch this space: veltuzumab - humanized CD20 antibody
25
Q

The recommended lines of treatment from the JAAD

A
  • First line:
    • steroids - 0.5-1.5 mg/kg/day
      • treat with the smallest dose for the shortest time period
      • uncertain if pulsing is helpful
    • anti-CD20 (rituximab)
      • Ofatumumab is available as well, but there are no published trials on it like rituximab
      • First line in new onset moderate-severe pemphigus or those who do not achieve clinical remission with systemic steroids
      • Suggest either 2 X 1 g 2 weeks apart, of 4 X 375 mg/m^2 1 week apart
      • Treatment can be repeated in cases of clinical relapse or as early as 6 months after treatmnet
      • Combine with short term steroids (<4 m) and long term (>12 m) immunosuppressive
      • Unforseen fatal infections such as progressive multifocal leukoencephalopathy cannot be estimated due to rarity of pemphigus
  • First line steroid sparing:
    • azathioprine 1-3 mg/kg/day
      • Start 50 mg/day for the first week to detect idiosyncractic reactions- sudden onset fevers, oral ulcers, elevated LFTs
      • Do TPMT: if high TPMT activity then give normal dose, but intermediate or low give 0.5-1.5 mg/kg/day
    • MMF 30 mg/kg- 45 mg/kg/day or mycophenolic acid 1440 mg/d
  • Other steroid sparing agents:
    • IVIG 2 g/kg over 2-5 d/month
      • Aseptic meningitis rare but important side effect of IVIG
      • If IgA deficiency then give IgA depleted IVIG
    • Immunoadsorption
      • Extracorporeal technique to remove antibodies and molecules from the blood
      • First line treatment option in emergency situation
      • Contraindications: sever cardiovascular diseases, hypersensitivity against components of the immunoadsorption column, treatment with ACEI and extensive haemorrhagic diathesis
    • Cyclophosphamide
      • Severe cases that have not resonded to other treatments
26
Q

Supportive treatment for pemphigus

A
  • Dental care
  • IL-steroids
  • Topical treatments: steroids, calcineurin inhibitors (triamcinolone acetonide gel)
  • Antiseptic baths
  • Covering erosive lesions with low adhesive wound dressings or local emollients and compresses
  • Analgesics
  • Gels containing local anaesthetics
  • Nutritional management
27
Q

Monitoring pemphigus

A
  • Level of disease control
  • A/E: DM, BP, etc
  • Serologic:
    • ELISA: Dsg1 with ELISA indicates skin relapses, but Dsg 3 does not, but both correlate with disease activity
    • If ELISA not available use IIF with monkey oesophagus
28
Q

Tapering prednisone for pemphigus

A
  • Start tapering steroids as soon as disease control is reached really
  • Decrease pred by 25% every 2 weeks until you hit 20 mg/day
  • Once at 20 mg, drop by 2.5 mg a week, then when you hit 10 mg, drop by 1 mg a week
  • If more than 3 lesions reappear, then go back to last dose
  • If relapse: increase the steroids by going back to second to last dose until control is achieved within 2 weeks, then resume taper
  • If disease control still not reached –> go back to initial dose
  • If using steroid monotherapy and not working, add an immunosuppressant

Derm (57 decks)

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