This document provides information on pemphigus, an autoimmune blistering disease of the skin and mucous membranes. It discusses the various subtypes of pemphigus, including pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, paraneoplastic pemphigus, and drug-induced pemphigus. It covers the clinical presentation, pathogenesis, histopathology, diagnosis and management of pemphigus. Key points include that pemphigus vulgaris presents with oral blisters/erosions in 50-70% of patients, while pemphigus foliaceus presents with superficial blisters that rupture and form scaly crust

1. Dr. Kriti Maheshwari
1st year Resident
M.D. Skin & V.D.

2.  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 cells.
 It can broadly be categorize into 5 types :
Pemphigus vulgaris (PV), Pemphigus foliaceus (PF),
Pemphigus vegetans, Paraneoplastic pemphigus(PNP)
and drug induced pemphigus.

3.  The incidence of pemphigus worldwide varied widely
0.09% to 2%.
 Pemphigus is more common in Jews and in people of
Mediterranean descent and from Middle East.
 In India Pemphigus occurs in younger age group (<45
years) as compared to western country.
 Male to female ratio is almost equal with few studies
showing female predominance.

4.  Genetic Determinants
– Susceptibility to pemphigus has been linked to
HLA-DRB1 and HLA-DQB1.
– Jews are affected > non-Jews.
– Circulating PV-IgG antibodies have been detected in
40%–70% of sera of first-degree relatives of PV.

5.  Environmetal factors:
– Thiols are present in garlic and onion.
– Phenols and tannins are present in high
concentration in foods like nuts, mangoes,
bananas and tomatoes.
– The earlier age of onset in Indians may be related to
greater consumption of such foods.
– Sunlight exposure can worsen PV and Endemic PF.

6.  Immunological factors:
- Pemphigus 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

8. 1. Steric hindrance:
Binding of auto-antibodies to their specific antigens
can disrupt adhesion of the bound antigens by
causing steric hindrance.

9. 2. Basal Cell Shrinkage Theory :
- PV IgG-induced phosphorylation of adhesion
molecules and structural proteins leads to
weakening of intercellular junction and collapse of
cytoskeleton respectively.
- This leads to reorganization of the Keratinocyte
cytoskeleton leading to cellular shrinkage and
separation of keratinocytes.
- Desmosomes do not split and disappear until late
in acantholysis.

10. 3. Apoptolysis Hypothesis:
• The apoptolysis hypothesis links the basal cell
shrinkage to suprabasal acantholysis and cell death
and emphasizes that apoptotic enzymes contribute
to acantholysis in terms of both molecular events
and chronologic sequence.
• Pathogenic auto antibodies bind to keratinocytes and
leads to elevation of intracellular Calcium which
initiates cell death enzymatic caspases.

11. 4. Multiple Hit hypothesis:
• Involvement of multiple autoantibody specificities in
pemphigus pathogenesis is explained through the
“multiple hit hypothesis”.
• Anti-AChR antibodies trigger acantholysis by
weakening cohesion between keratinocytes causing
them to shrink and desmosomes to slough into
intercellular spaces.
• The sloughed desmosomes stimulate production of
antibodies that saturate epidermis and prevent
desmosome formation by steric hindrance.

12. 5. Role of T cells:
• The role of T lymphocytes in the pathogenesis of
pemphigus vulgaris is not clear, but auto reactive T
cell responses to Dsg3 may be critical in its
pathogenesis.
• These auto reactive CD4+ T cells preferentially
produce Th2 cytokines such as IL-4 and IL-10.
• A disturbance in the regulatory mechanisms of Dsg3-
specific T cells that leads to loss of tolerance at the B
cell level leading to the production of auto
antibodies.

13. • The most common subtype, pemphigus vulgaris (PV)
presents with oral blisters and erosions in 50%–70% of
patients.
• Skin lesions may appear after a period of several
weeks to a year or more.
• The cutaneous lesions are vesicles and bullae on
apparently normal or erythematous skin.

14. • They may be localized or generalized. The sites most
commonly involved are the scalp, face, axillae and the
oral cavity.
• The bullae are initially tense and clear, but become
flaccid and turbid in two to three days.
• Blisters rupture easily to leave behind painful areas
of oozing and denuded skin that continue to
extend showing little tendency to heal.
• Erosions are a/w pain and lesions often become
crusted.

17. • It is a rare and more benign variant of PV.
• Two forms of Pemphigus vegetans
– Neumann (an early type with vesiculopustules)
– Hallopeau types (later vegetating type)
• Pemphigus vegetations may resolve as such or may
turn into classical PV lesions prior to resolution.

18. • Tumid, vegetating, papillomatous and hypertrophic
plaques are formed in the intertriginous area and the
flexural surfaces.
• Local moisture, heat and friction are important factors
in their development.
• Characteristic glossal changes termed “cerebriform
Tongue” may be seen.
• Exuberant vegetating granules occur in the oral cavity
as well.

20. • Pemphigus foliaceus (PF) is characterized by small
flaccid bullae with crusting and scaling.
• The initial lesions are scaly papules or superficial
flaccid bullae on normal or erythematous skin.
• The bullae readily rupture, resulting in moist erosions
and corn flake-like crusts.
• Lesions are usually sharply demarcated, as opposed
to the extending erosions of pemphigus vulgaris.
• The seborrheic areas (i.e. face, scalp and upper trunk)
are initially involved, but later the disease may become
generalized and can present as erythroderma.

21. • There is a characteristic musty odor.
• Small vesicles may be present along the borders of the
lesions.
• Nikolsky’s sign is positive

22. • It is a localized variant of PF characterized by
erythematous scaly plaques, thin walled bulla and
denuded areas, mostly on the butterfly area of the
face, upper part of back, chest and intertriginous areas.
• Exacerbation of lesions on exposure to sunlight.
• The disease resembles pemphigus foliaceus in its lack
of oral involvement.
• Patients have immuno-pathologic features of both
pemphigus and lupus erythematosus (LE).
• PE is a distinct disorder that represents the
concomitant presence of immunological abnormalities
resembling those of LE.

24. • Endemic pemphigus foliaceus (EPF) is a distinctive form of
pemphigus that is clinically, histologically and immuno-
pathologically identical to PF.
• A striking distribution of lesions on skin that is
exposed to the sun.
• It occurs endemically in densely forested areas of South
America, most commonly in Brazil, but disappears when
the jungle is cleared.
• It is called name ‘fogo selvagem’ (Portuguese for ‘wild
fire’).
• it is believed that endemic pemphigus foliaceus may be an
infectious disease caused by a virus transmitted by a black
fly.

25. • The target antigen is Dsg1 in most cases, followed by
Dsg3 in the remainder cases.
• It is characterized by herpetiform arrangement of tense
vesicles and occurrence of pruritus (resembling DH).
• There may be erythematous or urticarial plaques with
central healing and peripheral papulovesicles.
• Not severe as Pemphigus vulgaris but follows a
chronic course.
• Treated with dapsone and low dose of prednisolone.

26. • Rare disease with neutrophilic infiltration and
occasional acantholysis.
• k/a Intraepidermal neutrophilic (IEN) IgA
dermatosis, Sub-corneal pustular dermatosis
type, IgA PF, IgA Herpetiform pemphigus.
• Flaccid bullae or pustules are seen on normal or
erythemtous skin.

27. • The pustules tend to coalesce in an annular or
circinate pattern with central crusting, though a “sun-
flower” configuration is more characteristic for IEN
type.
• Dapsone is the drug of choice.
• Acitretin, topical steroid, PUVA therapy and
colchicine have been used.

28. • PNP is a rare autoimmune mucocutaneous blistering disorder
characterized by an associated neoplasm and the presence of
unique antibodies directed at desmosomal plakins.
• HLA-DRB1 allele was found in 61.5% of
patients.
• Both humoral and cellular autoimmunity responses are
involved in the pathogenesis.
• The antibodies are predominantly of the IgG1 subclass and
directed at multiple auto antigens including members of the
plakin family of cytoplasmic proteins as well as desmoglein 1
and desmoglein 3.

29. • The majority of patients are between the ages of 45 and 70
years.
• The commonest clinical feature, which is also usually the
earliest presenting sign, is recalcitrant stomatitis, seen as
painful erosions and ulcerations of the oropharynx and
vermilion border of the lips .

30. • The different disorders associated with PNP
include lymphoproliferative neoplasms like
– Non-Hodgkin’s lymphoma
– Chronic lymphocytic leukemia
– Castleman tumor (growth of lymphoid tissue,
usually in the mediastinum or retroperitoneum)
– Waldenström’s macroglobulinemia,
– Thymoma (malignant and benign)
– Retroperitoneal sarcomas.

31. • The causes of drug-induced pemphigus can be
divided into two groups:
1. Thiol drugs (SH)drugs, whose molecules contain a
sulfhydryl or thiol group in their chemical structure
(e.g. penicllamine, captopril, pyritinol, piroxicam and
thiopronine).
2. Non-thiol drugs (e.g. penicillin, ampicillin, amoxicillin,
cefadroxil, rifampicin, propranolol, phenytoin and
phenobarbitone).

32. • Pemphigus vulgaris is the commonest form induced
and PF seen in only 15%.
• The drugs appear to have stimulated the disease in
those with a predisposition to develop pemphigus
(“triggered pemphigus”)
• Possible mechanism could be a direct toxic effect of
the drug or an allergic mechanism where pemphigus is
induced by contact with plants containing
polyphenolic compounds.
• Contact causes alteration in skin structure that leads o
formation of neoantigens, which then provoke
pemphigus auto antibodies. (thus called contact
pemphigus)

33. • Pregnancy may aggravate pemphigus. Adverse events
such as preterm births or IUD can occur.
• A mother with pemphigus may passively transfer the
antibodies to the fetus, leading to pemphigus in the
newborn.
• The physiological variation in Dsg distribution in
neonatal skin (both Dsg1 and Dsg3 are present in the
upper layers, while Dsg3 is predominant in the
suprabasal layer) as compared to adult skin accounts
for a greater chance of a pregnant woman with PV
(anti-Dsg3) antibodies delivering an affected child than
a pregnant woman with PF (anti-Dsg1 antibodies).

34. • Myasthenia gravis
• Thymoma
• Polymyositis
• Sjögren’s syndrome
• Rheumatoid arthritis
• Lupus erythematosus
• Pernicious anemia

35.  Nikolsky’s Sign:
• The sign is elicited by applying tangential pressure with a
finger or thumb to the affected skin, peri-lesional skin, or
normal skin in patients with suspected pemphigus.
• It is termed positive if there is extension of the blister and/or
removal of epidermis in the rubbed area.
• “Marginal Nikolsky's sign” describes the extension of the
erosion on the surrounding normal-appearing skin by rubbing
the skin surrounding existing lesions.
• “Direct Nikolsky's sign” is the induction of an erosion on
normal-appearing skin, distant from the lesions.

37. • A positive direct Nikolsky’s sign indicates disease severity.
• Pseudo-Nikolsky’s sign is positive in Stevens-Johnson
syndrome, toxic epidermal necrolysis and in some cases of
burns and bullous ichthyosiform erythroderma. (the sign is
positive due to necrolyis of cells and NOT acantholysis)
• False Nikolsky’s sign or Sheklakov’s sign is positive in sub-
epidermal blistering disorders. It involves pulling the
peripheral remnant roof of a ruptured blister, thereby
extending the erosion on the surrounding normal skin.

38. • It is considered positive when unidirectional pressure
applied by a finger causes peripheral extension of the
bulla beyond marked margin.
• Asboe-Hansen sign is a variation of bulla spread sign
where the pressure is applied to the centre of the
lesion (when the bulla is small)
• Bulla spread sign is positive in all varieties of
pemphigus.
• In PV, the blister extension has a sharp angle, whereas
in BP,the advanced border is rounded.

39. • The base of an unroofed blister is gently scraped; the
material obtained is gently smeared onto a clean glass
slide, allowed to air dry and stained with Giemsa.
• Tzanck cell is a rounded keratinocyte with a
hypertrophic or dysmorphic nucleus, hazy or absent
nucleoli, with increased N:C ratio and a rim of
eosinophilic cytoplasm.
• The staining is more intensely basophilic near the cell
membrane (‘mourning edge’) because of cytoplasmic
condensation at the periphery, resulting in a
perinuclear halo.

41. • Pemphigus Vulgaris:
1. The earliest change seen is eosinophilic
spongiosis.
2. Loss of coherence between epidermal cells
(acantholysis) leads to the formation of clefts and
then of bullae in the suprabasal zone.
3. The basal cells remain attached to the dermis,
producing a ‘tombstone’ appearance
4. Superficial dermis shows scant perivascular
lymphocytic infiltrate.

43. – shows a suprabasal cleft similar to that in PV.
– but it is dominated by papillomatosis and
acanthosis with occasional formation of
intraepidermal eosinophilic abscesses.
– Villi formation and downward proliferation of
epithelial strands are more marked.
– The papillary and reticular dermal infiltrate is
mainly of eosinophils.

44. – The cleft in pemphigus foliaceus is superficial,
usually in the granular layer or right beneath it.
– It may develop into a bulla with acantholysis.
– Old lesion shows acanthosis and a mild degree of
hyperkeratosis and papillomatosis.
– Dyskeratotic changes in the cells of the granular
layer are diagnostic and is a frequently observed
feature in old lesions.

46. • The biopsy specimen is treated with fluorescein-
labeled antibodies to human immunoglobulin.
• When the section is viewed under a fluorescence
microscope, Fluorescence is seen at sites where the
antibodies are bound
• Intercellular fluorescence is observed.
• DIF testing is best performed on biopsy specimens of
apparently normal peri-lesional skin.

47. When seen under fluorescein microscope, antibodies are
bound at the intercellular area which is similar in both
PV and PF

48. • In PV, IgG antibodies are predominantly seen in the
intercellular space giving a green coloured FISH-NET
appearance.
• In PF, fluorescence predominantly present in the
superficial layers of epidermis

49. • Indirect immunofluorescence (IIF) is a two-stage
procedure for in vitro demonstration of circulating
antibodies in the patient’s serum.
• The serum is added to a substrate, resulting in fixation
of circulating antibodies to the antigen in the
substrate.
• IIF testing of serum demonstrates circulating IgG
antibodies directed against cell surface of keratinocytes
in 90% of patients.

50. • Enzyme-linked immunosorbent assays (ELISA) that
detect IgG autoantibodies to Dsg1 and Dsg3 have also
been developed.
• These assays are highly sensitive and specific for the
diagnosis of both PF and PV, and simpler and more
quantifiable than immunofluorescence.
• They are useful for distinguishing subtypes of PV and
PF and for monitoring disease activity as well.

51.  It helps to detect the location of antibody and
complement deposits in the epidermis

52.  Early PV lesions may resemble:
1. Aphthous ulcers
2. Erythema multiforme
3. primary herpetic gingivostomatitis
4. Oral Candidiasis
5. Erosive LP
 PF may resemble :
1. Seborrheic dermatitis
2. Pustular psoriasis
 PE has to be differentiated from SD or LE.

53. • The most common causes of death are septicemia(d/t
S. aureus) and pulmonary embolism.
• Various prognostic factors I course of pemphigus are :
1. Type of pemphigus - PV & PNP have worst prognosis.
2. Age – elder patients have poorer prognosis than
younger ones.
3. Disease progression before starting therapy –
patients with minimal disease activity for longer
periods have better prognosis.
4. Involvement of mucosa or skin – patients with only
cutaneous lesions have better prognosis than those
with mucosal involvement

55.  Mild cases of pemphigus can sometimes be treated by
topical therapy alone.
 Topical clobetasol proprionate can be used. It is
particularly useful in treating localize relapses after
controlling the disease.
 Topical tacrolimus has also been found to be effective
in such localized and refractory lesions.
 Topical EGF significantly reduces the healing time of
skin lesions in patients with PV
 Intralesional triamcinolone acetonide (5-10 mg/ml) is
helpful for intractable oral ulcers and cutaneous lesions
respectively.

56. • It is mainstay of treatment of pemphigus and prednisolone is
the preferred drug.
• For mild to moderate disease, the starting dose of
prednisolone is 60–80 mg/day, for severe disease treatment is
started with 80–120 mg/day and can be up to 180-
240mg/day.
• The dose can be stepped up in increments of 50% every 4–7
days until the disease activity is controlled (i.e. no new lesions)
• Tapering off by 50% every 2 weeks is started only after
80%–90% of the lesions have healed.
• Concomitant immunosuppressive or other adjuvants
are advocated if there are relative contraindications to
the use of corticosteroids

57. • Day 1 - IV administration of 100 mg of dexamethasone
(equivalent to 667 mg of prednisolone) in 500 ml of 5%
dextrose over 3 hours.
• Day 2 - 500 mg of cyclophosphamide is dissolved in the
same infusion on the second day.
• Day 3 - 100 mg of dexamethasone in 500 ml of 5%
dextrose.
• These pulses are repeated every 28 days.
• Also patient recieves 50 mg of cyclophosphamide
orally every day.

58. Azathioprine:
• most commonly used adjuvants for Pemphigus.
• Less effective than Cyclophosphamide.
• It is less toxic, lower risk of infertility and lower lifetime risk of
malignancy, making it suitable for the younger populations.
• The usual dose is 2-4mg/kg/day.
Cyclophosphamide:
• Apart from DCP regime, Cyclophosphamide pulse can be
given at the interval of 28 days.
• Cyclophosphamide 15mg/kg is dissolved in 200ml of 5%
Dextrose and infused over one hour.
• It is followed by hydration with 500ml of 5% dextrose given
intravenously over 4 to 5 hours.

59. Mycophenolate Mofetil: (MMF)
• MMF is an antimetabolite that inhibits the de novo pathway
of purine synthesis in T and B cells by selectively inhibiting
inosine monophosphate dehydrogenase enzyme.
• It is usually given along with corticosteroid. Patients shows
faster response.
• Dose - 1gm BD, taken orally.
Cyclosporine:
• Cyclosporine (3–6 mg/kg body weight per day) has been used
in combination with steroids in patients otherwise
unresponsive to moderate doses (1 mg/kg per day) of
prednisolone.
• Cyclosporine suppresses cellular immunity resulting in
reduced expression of several lymphokines.

60.  Methotrexate
• MTX can be used as a adjuvant drug along with
corticosteroid.
• Unresponsive to DCP showed good response when patients
were treated with DMP pulse. (C is susbstituted with weekly
dose of MTX)
• Dapsone
Although dapsone alone in the dose of 100–300 mg per day
has been tried, there are no studies to support the claim that
it is truly effective when administered alone.
• However, it has been found very useful as a steroid- sparing
agent.
• The maintenance dose of corticosteroids could be reduced
by 50%.

61.  Rituximab
 IV Ig
 Plasmapheresis
 Pulsed IV high dose Glucocorticoids
 Immunoadsorption
 Extracorporeal photochemotherapy
 TNF α antagonists
 Cholinergic agents