Pemphigus

Question 1

Pemphigus classification

Answer 1

• 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

Question 2

What is fogo selvagem?

Answer 2

• 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

Question 3

What is the pathogenesis of pemphigus?

Answer 3

• 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

Question 4

What autoantibodies does pemphigus vulgaris have?

Answer 4

Mucosal dominant: IgG to DsG 3

Mucocutaneous IgG to Dsg# and 1

Question 5

What autoantibodies does pemphigus foliaceous have?

Answer 5

IgG to DsG1

Question 6

What autoantibodies does IgA pemphigus have?

Answer 6

SCPD type: IgA to desmocollin

Question 7

What can PV clinically look like

Answer 7

• 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

Question 8

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

Answer 8

• 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
  • 2. Mild Hallopeau

Question 9

What is herpetiform pemphigus?

Answer 9

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

Question 10

What drugs cause pemphigus and why?

Answer 10

• 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

Question 11

What cancers cause paraneoplastic pemphigus?

Answer 11

• 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

Question 12

What does paraneoplastic pemphigus look like?

Answer 12

• 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

Question 13

What are the types of IgA pemphigus

Answer 13

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

Question 14

What does IgA pemphigus look like

Answer 14

• 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

Question 15

Histo and IF for pemphigus vulgaris

Answer 15

• 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

Question 16

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

Answer 16

• 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

Question 17

Histo and IF for paraneoplastic pemphigus

Answer 17

• 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

Question 18

Histo and IF for IgA pemphigus

Answer 18

• 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

Question 19

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

Answer 19

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

Question 20

What autoantigens involved in PNP?

Answer 20

DsG1 , 3, laminin 332, envoplakin, periplakin

Question 21

EBA has which autoantigen

Answer 21

Type 7 collagen

Question 22

MMP has which autoantigen

Answer 22

BP 180, 230, laminin 332, type 7 collagen

Question 23

Differentials for pemphigus vegetans

Answer 23

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

Question 24

All the possible treatments for pemphigus

Answer 24

• 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

Question 25

The recommended lines of treatment from the JAAD

Answer 25

- 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

Question 26

Supportive treatment for pemphigus

Answer 26

- 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

Question 27

Monitoring pemphigus

Answer 27

- 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

Question 28

Tapering prednisone for pemphigus

Answer 28

- 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