All blistering disorders of the skin in all age groups

1. Pemphigus
Dr Nikhil Ranjan Das

2. CONTENTS
• Introduction
• Definition
• Epidemiology
• Etiology and Pathogenesis
• Clinical Features
• Bedside Test
• Laboratory Findings
• Treatment

3. Bullous Disease

4. Introduction
• The word Pemphigus is derived from Greek word
“pemphix” meaning blister or bubble.
• Until the early twentieth century, all blistering
diseases were grouped under this name.
• In 1953, Lever distinguished pemphigus vulgaris and
bullous pemphigoid on the basis of clinical and
histopathological features and their natural course.

5. Defination
• A group of chronic autoimmune bullous dermatoses
that are characterized histologically by
intraepidermal blister formation and
immunopathologically by the presence of bound and
circulating autoantibodies directed against the
intercellular adhesion structures of the epithelial
cells.

6. Epidemiology

7. Epidemiology
• The incidence of pemphigus worldwide varied widely
0.09% to 2%.
• Incidence of various type of Pemphigus in decreasing
order
– Pemphigus Vulgaris
– Pemphigus Foliaceous
– Pemphigus Eryhematousus
– Pemphigus vegetans

8. Epidemiologycont.
• Others are
– Neonatal pemphigus
– Drug-induced pemphigus
– Paraneoplastic pemphigus
– IgA pemphigus
– Pemphigus Herpetiformis
– Endemic Pemphigus Foliaceous

9. Epidemiologycont.
• 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.

10. Etiology and Pathogenesis

11. Etiology and Pathogenesis
• The discovery of Pemphigus as an organ-specific,
auto-anti-body mediated disease of desmosomes
highlites the synergy between the clinical care and
basic science research.
• Patient serum IgG served as the key reagent to help
identify both the PF and PV antigen.

12. Etiology and Pathogenesiscont.
• Genetic Determinants
– Susceptibility to pemphigus has been linked to
HLA-DRB1.
– Jews are more commonly affected than non-Jews.
• Circulating PV-IgG antibodies have been detected in
40%–70% of sera of first-degree relatives of PV.

13. Etiology and Pathogenesiscont.
Environmental Factors
– Thiols are present in vegetables like 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.

14. Desmosomes

15. Desmosomes
• Desmosomes contain desmosomal cadherins
(desmogleins and desmocollins) as transmembrane
components, and desmoplakin and plakoglobin as
cytoplasmic components.
• Cadherins are calcium ion dependent cell adhesion
molecules that show homophilic adhesion.
• other desmosomal proteins have been identified:
plakophilins, envoplakin, periplakin and plectin.

16. Desmosomescont.
• Desmoglein(Dsg) exists in four isoform named
desmogleins 1,2,3 and 4.
• Antigen Dsg1 and Dsg3 are predominant in PF and PV
respectively.
• Dsg1- 160kD glycoprotein- expressed in upper dermis
• Dsg3- 130kD glycoprotein- expressed in basal and
parabasal layers of epidermis.

17. Desmosomescont.
• Dsg4- expressed in developing hair cortex and
superficial epidermis is a target of pemphigus
antibodies.
• Desmocollins have 3 isoforms (1,2 and 3).
• Dsc-1 is an autoantigen for the subcorneal pustular
dermatosis(SCPD) type of IgA pemphigus.

18. Desmosomes

19. Varoius concept of Acantholysis

20. Steric Hinderance
• Binding of auto-antibodies to their specific
antigens can disrupt adhesion of the bound
antigens by causing stearic hinderance.

21. Basal shrinkage theory
• It appers that PV IgG-induced phosphorylation
of adhesion molecules and structural proteins
leads to weakening of intercellular junction
and collapse of cytoskeleton.
• This leads to reorganization of the
keratinocyte cytoskeleton leading to cellular
shrinkage and separation of keratinocytes.

22. 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.
• Death enzymes caspase helps in this process.

23. Multiple hit hypothesis
• Involvement of multiple autoantibody
specificities in pemphigus pathogenesis is
explained through the “multiple hit
hypothesis”.
• Anti-AChR antibodies plays a role in this
pathogenesis.

24. Role of T cell
• The role of T lymphocytes in the pathogenesis of
pemphigus vulgaris is not clear, but autoreactive
T cell responses to Dsg3 may be critical in its
pathogenesis.
• These autoreactive CD4+ T cells preferentially
produce Th2 cytokines such as IL-4 and IL-10.
• 30 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
autoantibodies has been recently demonstrated

25. Clinical Features

26. Pemphigus Vulgaris
• 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.

27. Pemphigus Vulgaris

28. Pemphigus Vulgaris
• 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.
• The blisters rupture easily to leave behind painful
areas of oozing and denuded skin that continue to
extend, showing little tendency to heal.

29. Pemphigus Vulgaris
• The oesophagus may be involved & sloughing of
entire lining in the form of cast which is called
“Esophagitis Dissecans Superficialis”.
• It is because the entire epithelium is dependent on
Dsg-3

30. Pemphigus Vulgaris
• The lesions often become crusted
• The erosions may be associated with pain.

31. Pemphigus Vulgaris

32. Pemphigus Vulgaris

33. Pemphigus Vegetans

34. Pemphigus Vegetans
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.

35. Pemphigus Vegetans
• Tumid, vegetating, papillomatous and hypertrophic
plaques are formed in the intertriginous area and the
flexural surfaces.
• Characteristic glossal changes termed “cerebriform
Tongue” may be seen.

36. Pemphigus Foliaceus

37. Pemphigus Foliaceus
• 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.

38. Pemphigus Foliaceus
• 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.

39. Pemphigus Erythematosus

40. Pemphigus Erythematosus
• Pemphigus erythematosus (PE), a localized variant of
PF, is typified by the appearance of erythematous
scaly plaques, thin walled bullae and denuded areas,
predominantly on the butterfly area of the face,
upper part of the back, chest, and intertriginous
area.

41. Pemphigus Erythematosus
• Exacerbations on exposure to sunlight are common.
• The disease resembles pemphigus foliaceus in its lack
of oral involvement.

42. Pemphigus Erythematosus
• Pemphigus Eythematous is also called Senar-Ushar
Syndrome.
• Patients have immunopathologic 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 rather than a
mere combination of pemphigus and LE.

43. Endemic Pemphigus Foliaceus

44. Endemic Pemphigus Foliaceus
• 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.

45. Endemic Pemphigus Foliaceus
• 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 (Simulium prurinosum)

46. Pemphigus Herpetiformis

47. Pemphigus Herpetiformis
• 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).
• Not severe as Pemphigus vulgaris but follows a
chronic course.
• Treated with dapsone and low dose of prednisolone.

48. IgA Pemphigus

49. IgA Pemphigus
• Rare disease with neutrophiclic infiltration and
occasional acantholysis.
• Two subtypes.
– Intraepidermal neutrophilic (IEA) IgA dermatosis
– Sub-corneal pustular dermatosis type
(Sneddon-Wilkinson Disease)
• Both the subtypes have similar clinical features.
• Flaccid bullae or pustules are seen on normal or
erythemtous skin.

50. IgA Pemphigus
• 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.

51. Paraneoplastic Pemphigus

52. Paraneoplastic Pemphigus
• 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
paraneoplastic patients.

53. Paraneoplastic Pemphigus
• The different disorders associated with PNP include
lymphoproliferative neoplasms, that is
– Non-Hodgkin’s lymphoma
– Chronic lymphocytic leukemia
– Castleman tumor (which is characterized by the
growth of lymphoid tissue, usually in the mediastinum
or retroperitoneum)
– Waldenström’s macroglobulinemia,
– Thymoma (malignant and benign) retroperitoneal
sarcomas.

54. Paraneoplastic Pemphigus
• Both humoral and cellular autoimmunity responses
are involved in the pathogenesis.
• The antibodies are predominantly of the IgG1
subclass and directed at multiple autoantigens
including members of the plakin family of
cytoplasmic proteins (desmoplakins I and II,
envoplakin, periplakin, bullous pemphigoid antigen)
as well as desmoglein 1 and desmoglein 3.

55. Paraneoplastic Pemphigus
• 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 .

56. Paraneoplastic Pemphigus

57. Paraneoplastic Pemphigus
• Treatment is generally ineffective.
• In patients with malignant tumors, chemotherapy
occasionally results in complete resolution of the
malignancy and a slow resolution of the skin lesions.

58. Neonatal Pemphigus

59. Neonatal Pemphigus
• 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).

60. Neonatal Pemphigus
• Neonatal pemphigus is self limited and the condition
regresses within 3–4 weeks of birth as maternal
antibodies are catabolized.

61. Drug-Induced Pemphigus

62. Drug-Induced Pemphigus
• The causes of drug-induced pemphigus can be
divided into two groups according to their
chemical structure:
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).
D-Penicillamine is the commonest causative drug. Up to
7% of patients treated with D-penicillamine for more
than 6 months acquire pemphigus.

63. Drug-Induced Pemphigus
2. Non-thiol drugs (e.g. penicillin, ampicillin,
amoxicillin, cefadroxil, rifampicin, propranolol,
phenytoin and phenobarbitone).
• 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”)

64. Clinical Associations
• Myasthenia gravis
• Thymoma
• Polymyositis
• Sjögren’s syndrome
• Rheumatoid arthritis
• Lupus erythematosus
• pernicious anemia

65. Bedside Tests

66. Nikolsky's sign
• The Russian dermatologist Pyotr Vasiliyevich
Nikolskiy first described this 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.

67. Nikolsky's sign
• “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.

68. Nikolsky's sign

69. Nikolsky's sign
• “Wet” Nikolsky’s in which a moist, glistening, eroded
base is seen after pressure is exerted on the skin.
• “Dry” Nikolsky’s, in which the base of eroded skin is
dry.
• In active PV, a wet sign is expected, whereas the dry
sign indicates re-epithelialization beneath a PV blister
or may suggest PF and hence a higher level of blister
formation.
• In “Nikolsky’s phenomenon,” the superficial
epidermis is felt to move over the deeper layers, and
instead of immediate erosion formation.

70. Nikolsky's sign
• 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.
• The erosions thus induced are limited in size, lack the
tendency to extend spontaneously, and heal rapidly.
• Pseudo-Nikolsky’s sign is positive in Stevens-Johnson
syndrome, toxic epidermal necrolysis and in some
cases of burns and bullous ichthyosiform
erythroderma.

71. Tzanck Test

72. Tzanck Test
• It was introduced by Arnault Tzanck, this is a simple
technique to analyze vesiculobullous diseases.
• 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.

73. Tzanck Test

74. Tzanck Test
• Tzanck cell is a rounded keratinocyte with a
hypertrophic or dysmorphic nucleus, hazy or absent
nucleoli,
• Increased nuclear to cytoplasmic ratio due to the loss
of normalintercellular cohesion and abundant
eosinophilic tobasophilic 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.

75. Tzanck Test
• Other findings, not pathognomonic to pemphigus
but frequently detectable, are Sertoli’s rosettes and
‘streptocytes.’
• Sertoli’s rosettes are composed of a central
necrobiotic keratinocyte with a surrounding
leukocyte rosette.
• A ‘streptocyte’ is a chain of leukocytes, joined by a
filamentous, glue-like substance.
• Sertoli’s rosettes and ‘streptocytes’ can be observed
in herpes zoster and the pemphigoid group
respectively.

76. Bulla spread sign (Asboe-Hansen sign)
• It was described originally by Wilhelm Lutz,
• It is the enlargement of an intact blister by the
application of mechanical pressure on its roof.
• If one carefully presses upon the blister, it enlarges
towards its periphery due to the mechanical pressure
of the blister fluid.
• In PV, the blister extension has a sharp
angle,whereas in BP, the advanced border is
rounded.

77. Laboratory Findings

78. Histopathology
Pemphigus Vulgaris
– The earliest changes are intercellular edema and
disappearance of the intercellular bridges in the
lowermost epidermis.
– Loss of coherence between epidermal cells
(acantholysis) leads to the formation of clefts and
then of bullae in the suprabasal zone.
– The basal cells remain attached to the dermis,
producing a ‘tombstone’ appearance

79. Rows of Tombstone

80. Rows of Tombstone

81. Histopathology
• Pemphigus Vegetans
– Histopathologically the disease shows a
suprabasal cleft similar to that in PV,
– but it is dominated by papillomatosis and
acanthosis with occasional formation of
intraepidermal eosinophilic abscesses.
– The papillary and reticular dermal infiltrate is
composed predominantly of eosinophils.

82. Histopathology
• Pemphigus Foliaceus
– 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.

83. Pemphigus Foliaceus

84. Histopathology
• Pemphigus Erythematosus
– The histopathologic picture is identical to that of
pemphigus foliaceus.
– In old lesions, follicular hyperkeratosis with
acantholysis and dyskeratosis of the granular layer
is often pronounced.

85. Direct Immunofluorescence
• 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 perilesional skin.

86. Direct Immunofluorescence
• Patients with pemphigus foliaceus may show
fluorescence solely or predominantly in the
superficial layers of the epidermis.

87. Direct Immunofluorescence

88. Direct Immunofluorescence
• DIF demonstrate “Chicken wire” pattern of
intercellular IgG in perilesional skin/Plucked
hair.

89. Indirect Immunofluorescence
• 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.
• The best single substrate for detection of these
antibodies is monkey esophagus,
• When both monkey esophagus (which is rich in Dsg3)
and normal human skin (which is rich in Dsg1) are
used as substrates the sensitivity increases to 100%.

90. ELISA
• Recently, enzyme-linked immunosorbent assays
(ELISA) that detect IgG autoantibodies to Dsg1 and
Dsg3 have been developed.
• These assays are highly sensitive and specific for the
diagnosis of both PF and PV, and simpler and more
quantifiable than immunofluorescence.

91. ELISA

92. Immunoelectron Microscopy
• It helps to detect the location of antibody and
complement deposits in the epidermis.

93. Treatment

94. Treatment
• General Measures
– Before initiating specific treatment measures, it is
important to assess the general condition and
extent and severity of the disease.
– Particular attention should be paid to general
nursing care, nutrition and control of secondary
infection.
– There may be loss of fluid and electrolytes from
denuded areas, especially in severe and extensive
disease, and efforts should be made to maintain
adequate fluid and electrolyte balance.

95. Treatment
• Adequate nutrition may require oral
supplementation with proteins and high calorie
fluids.
• A soft, easily chewable diet is preferable in the
presence of oral lesions.
• In case the patient is not able to take enough
nutrition orally, a feeding tube or even parenteral
nutrition may be needed.

96. Treatment
• Prolonged Daily bathing is helpful in removing crusting
which may be a source for the bacterial infection.
• Topical bland ointments reduce the pain from lesions.
• Measures should be taken to prevent formation of
bedsores in moribund patients.
• Cleaning of teeth and maintenance of proper oral
hygiene is important in the presence of oral disease.

97. Treatment
• Mild examples of pemphigus can sometimes be
controlled by topical therapy alone.
• Topical clobetasol propionate was reported to induce
remission in mild pemphigus foliaceus and
pemphigus vulgaris.
• Topical tacrolimus has been recently found to be
effective in healing such localized and refractory
erosions.

98. Treatment
• Patients with painful oral ulcers can be encouraged
to mix hydrogen peroxide with warm water (1:1) and
swish and spit out 4 times a day to remove necrotic
tissue.
• After each meal, gargling of this mixture is carried
out and a corticosteroid gel can be applied.
• Triamcinolone acetonide oral paste can be applied to
a small piece of gauze and kept on the affected area
for 10 minutes 3 times daily.

99. Treatment
• Intralesional triamcinolone acetonide (2.5–5 mg/ml)
is helpful for intractable oral ulcers.
• Oral candidiasis should be treated with clotrimazole
mouth paint four times a day and with oral
fluconazole 200mg stat then 100mg daily for 2
weeks.

100. Systemic Corticosteroids
• Systemic corticosteroids remain the 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, whereas for severe
disease treatment is started with 80–120 mg/day
and can be up to 180-240mg/kg/day.

101. Systemic Corticosteroids
• 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 appearing).
• Tapering off by 50% every 2 weeks is started only
after 80%–90% of the lesions have healed.
• Concomitant immunosuppressives or other
adjuvants are advocated if there are relative
contraindications to the use of corticosteroids

102. Antimetabolites
• Azathioprine and cyclophosphamide are generally
ineffective when given alone, and hence either one is
given in addition to steroids.
• Their effect takes 4–8 weeks to manifest.
• Adverse reactions like nonmelanoma skin cancer,
infection, gastric upsets and microscopic hematuria
were seen but none required discontinuation of
cyclophosphamide.

103. Dexamethasone–
Cyclophosphamide Pulse Therapy
• Pasricha et al pioneered and persevered to evolve a
curative treatment for pemphigus and investigated
the efficacy of dexamethasone–cyclophosphamide
pulse (DCP) therapy in this disease.
• Treatment is arbitrarily divided into four phases.
• Phase 1
• Phase 2
• Phase 3
• Phase 4

104. • DCP therapy involves the intravenous administration
of 100 mg of dexamethasone (equivalent to 667 mg
of prednisolone) with 500 mg of cyclophosphamide
in 500 ml of 5% dextrose over 1–2 hours on day 1,
followed by daily administration of 100 mg of
dexamethasone for the next 2 days.
• These pulses are repeated every 4 weeks. On the
balance days, 50 mg of cyclophosphamide is
administered orally every day.
Dexamethasone–Cyclophosphamide Pulse
Therapy

105. ADVERSE EFFECT
Immediate Late
Flushing Secondary Infection
Palpitation Oral candidiasis
Hiccup Reactivation of TB
Asthenia Eczema Herpeticum
Muscular weakness Diabetes Mellitus
Numbness in feet Hypertension
Altered taste Peptic Ulcer
Hair loss Weight gain
Electrolyte Imbalance Cataract
Avascular necrosis of Bone
Dexamethasone–
Cyclophosphamide Pulse Therapy

106. Adjuvant
Immunosuppressants

107. Cyclophosphamide
• Oral cyclophosphamide (1-1.5 mg/kg body weight
per day) has been recommended as the adjuvant
therapy of choice.
• Patients of PV and PF who failed to respond to a
combination of prednisolone with azathioprine or
MMF respond to cyclophosphamide with
prednisolone.

108. 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.
• Mesna (50% of dose of Cyclophosphamide)may be
added to avoid bladder toxicity.

109. Azathioprine
• Azathioprine is one of the most commonly used
adjuvants for Pemphigus.
• Less effective than Cyclophosphamide.
• Azathioprine 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.
• It should be cousinly used in patients deficient in
Thiopurine methyl transferase.

110. Mycophenolate Mofetil
• 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.
• MMF treated patients shows faster response.
• But later it was found that it is no way superior than
only corticosteroid pulse therapy.

111. 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.
• Side effects occur in most patients (e.g.
nephrotoxicity, hypertension, abnormal LFTs,
neurologic complications) and may require cessation
of therapy

112. 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.

113. Dapsone
• Although dapsone alone in the dose of 100–300 mg
per day has been tried in the management of PV,
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%.

114. Tetracycline and Nicotinamide
• A combination of nicotinamide (1.5 g/day)
and tetracycline (2 g/day) has been reported
to control pemphigus in 2 of 6 patients with
PV and 3 of 6 with PF/PE in an uncontrolled
trial.
• Minocycline and tetracycline have also been
used as adjuvants with steroids.

115. Gold
• It is advocated as an adjuvant in refractory
pemphigus vulgaris.
• Auranofin, an oral formulation of gold, is
easier to use and less toxic than parenteral
formulations (gold sodium thiomalate and
aurothioglucose).
• Adverse effect like bone marrow suppression,
renal toxicity and cutaneous allergic reactions
may occur.

116. Rituximab
• Rituximab, an anti-CD20 monoclonal antibody
that targets B lymphocytes,
• Lymphoma Protocol
– Rituximab is administered at dose of 375 mg/m2
intravenously once weekly for 4 consecutive weeks.
• Rheumatoid Arthritis protocol
– Two doses of Rituximab 1gm is administered at an
interval of 15 days.
• Combination therapy
– Rituximab has been used in combination with
intravenous Ig, immunoadaorption and
dexamethasone pulse therapy.

117. Rituximab
• Long term Rituximab treatment with regular
infusions every 4 to 12 weeks following an induction
cycle infusions every week.
• Its high costs and the limited knowledge of long-term
adverse effects limit its use to selected patients with
treatment-resistant or life-threatening disease.

118. Intravenous Immunoglobulin G
• Intravenous immunoglobulin G (IVIG) is purified IgG
obtained from pooled.
• The usual dose is 2 g/kg body weight per cycle
divided over 3–5 days.
• The cycles are repeated every 3–4 weeks.

119. Intravenous Immunoglobulin G
• IVIG given for a minimum of 3 cycles produced
beneficial
• But cost was a limiting factor.
• IVIG has been associated with pulmonary emboli,
deep vein thrombosis, myocardial infarctions, and
other thrombotic events, as well as aseptic
meningitis and acute renal failure.

120. Plasmapheresis
• Plasmapheresis has been used for severe examples
of pemphigus unresponsive to conventional therapy.
• Its major limitation is that improvement is short-
lived.
• Because a feedback mechanism regulates the level of
antibodies in the serum, after cessation of
plasmapheresis titers rebound and the disease flares
up.
• Hence, immunosuppressive drugs (generally cyclo-
phosphamide) are concomitantly administered to
suppress antibody formation

121. Extracorporeal photo chemotherapy
• It is also known as photopheresis, in which
leukapheresis is done and WBC are exposed to 8-
methoxypsoralen, irradiated with UVA light and
reinfused into the patient.
• No adequate data avaliable & procedure is not
feasible in low resourse locations.

122. TNF-alpha Antagonists
 TNF-alpha antagonists such as infliximab and
etanercept may be useful in the treatment of PV.
 No adequate data avaliable & procedure is not
feasible in low resourse locations.

123. Cholinergic Agonist
• Actylcholine and its receptors are involved in the
acantholytic process of pemphigus.
• 4% pilocarpine gel has been used with few success.

124. Under Trial Therapies
• High dose of intravenous desmoglein 3 peptides was
developed to supress the production of anti-
desmoglein 3 antibodies through inactivation or
deletation of disease associated CD4+ T lymphocyte.
• KC706 is an oral allosteric p38 mitogen-activated
protein kinase (p38MAPK) inhibitor in murine model
of pemphigus.

125. References
• 1. Wu H, Schapiro B, Harrist TJ. Noninfectious
vesiculobullous and vesiculopustular diseases. In:
Elder DE, editor. Lever’s histopathology of the skin.
Philadelphia: Lippincott, Williams and Wilkins; 2005.
p. 243–3.
• 2. James WD, Berger TG, Elston DM. Andrews’
diseases of the skin. Clinical dermatology. 10th
edition. Philadelphia: Saunders Elsevier; 2005. p. 1–
15.
• 3. Crosby DL, Diaz LA. Introduction. Dermatol Clin
1993;11:373–7.

126. References
• 4. Rico MJ. Differential diagnosis of vesiculobullous
lesions. In: Harper J, Oranje A, Prose N, editors.
Textbook of pediatric dermatology. Oxford: Blackwell
Publishing; 2006. p. 823–830.
• 5. Diaz LA, Giudice GJ. End of the century overview
of skin blisters. Arch Dermatol. 2000;136:106–112.
• 6. Miyagawa S, Higashimine I, Tida T, et al. HLA-
DRB1*04 and DRB1*14 alleles are associated with
susceptibility to pemphigus among Japanese. J Invest
Dermatol. 1997;109:615–8

127. References
• 7. Delgado JC, Hameed A, Yunis JJ, et al. Pemphigus
vulgaris autoantibody response is linked to HLA-
DQB1*0503 in Pakistani patients. Hum Immunol.
1997;57:110–9.
• 8. Delgado JC, Yunis DE, Bozon MV, et al. MHC class
II alleles and haplotypes in patients with pemphigus
vulgaris from India. Tissue Antigens. 1996;46:668–
72.
• 9. Loiseau P, Lecleach L, Prost C, et al. HLA class II
derived polymorphism contributes to specify
desmoglein-derived peptides in pemphigus vulgaris
and pemphigus foliaceus. J Autoimmun. 2000;15:67–
73

128. THANK
YOU