pemphigus disorders of skin

Pemphigus

Dr Nikhil Ranjan Das

CONTENTS

• Introduction

• Definition

• Epidemiology

• Etiology and Pathogenesis

• Clinical Features

• Bedside Test

• Laboratory Findings

• Treatment

Bullous Disease

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.

Defination

• A group of chronic autoimmune bullous dermatosesthat 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.

Epidemiology

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

Epidemiologycont.

• Others are

– Neonatal pemphigus

– Drug-induced pemphigus

– Paraneoplastic pemphigus

– IgA pemphigus

– Pemphigus Herpetiformis

– Endemic Pemphigus Foliaceous

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.

Etiology and Pathogenesis

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.

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.

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.

Desmosomes

Desmosomes

• Desmosomes contain desmosomal cadherins(desmogleins and desmocollins) as transmembranecomponents, 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.

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.

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 pustulardermatosis(SCPD) type of IgA pemphigus.

Desmosomes

Varoius concept of Acantholysis

Steric Hinderance

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

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.

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.

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.

Role of T cell

• The role of T lymphocytes in the pathogenesis of pemphigus vulgaris is not clear, but autoreactiveT 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

Clinical Features

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.

Pemphigus Vulgaris

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.

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

Pemphigus Vulgaris

• The lesions often become crusted

• The erosions may be associated with pain.

Pemphigus Vulgaris

Pemphigus Vulgaris

Pemphigus Vegetans

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.

Pemphigus Vegetans

• Tumid, vegetating, papillomatous and hypertrophic plaques are formed in the intertriginous area and the flexural surfaces.

• Characteristic glossal changes termed “cerebriformTongue” may be seen.

Pemphigus Foliaceus

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.

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.

Pemphigus Erythematosus

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 intertriginousarea.

Pemphigus Erythematosus

• Exacerbations on exposure to sunlight are common.

• The disease resembles pemphigus foliaceus in its lack of oral involvement.

Pemphigus Erythematosus

• Pemphigus Eythematous is also called Senar-UsharSyndrome.

• 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.

Endemic Pemphigus Foliaceus

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.

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)

Pemphigus Herpetiformis

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.

IgA Pemphigus

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.

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.

Paraneoplastic Pemphigus

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.

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.

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 autoantigensincluding 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.

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 .

Paraneoplastic Pemphigus

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.

Neonatal Pemphigus

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).

Neonatal Pemphigus

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

Drug-Induced Pemphigus

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.

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”)

Clinical Associations

• Myasthenia gravis

• Thymoma

• Polymyositis

• Sjögren’s syndrome

• Rheumatoid arthritis

• Lupus erythematosus

• pernicious anemia

Bedside Tests

Nikolsky's sign

• The Russian dermatologist Pyotr VasiliyevichNikolskiy 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.

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.

Nikolsky's sign

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.

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 ichthyosiformerythroderma.

Tzanck Test

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.

Tzanck Test

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.

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.

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.

Laboratory Findings

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

Rows of Tombstone

Rows of Tombstone

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.

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.

Pemphigus Foliaceus

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.

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.

Direct Immunofluorescence

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

Direct Immunofluorescence

Direct Immunofluorescence

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

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%.

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.

ELISA

Immunoelectron Microscopy

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

Treatment

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.

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.

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.

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.

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.

Treatment

• Intralesional triamcinolone acetonide (2.5–5 mg/ml) is helpful for intractable oral ulcers.

• Oral candidiasis should be treated with clotrimazolemouth paint four times a day and with oral fluconazole 200mg stat then 100mg daily for 2 weeks.

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.

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

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.

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

• 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

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

Adjuvant Immunosuppressants

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.

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.

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.

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.

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

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.

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%.

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.

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.

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.

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.

Intravenous Immunoglobulin G

• Intravenous immunoglobulin G (IVIG) is purified IgGobtained 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.

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.

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

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.

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.

Cholinergic Agonist

• Actylcholine and its receptors are involved in the acantholytic process of pemphigus.

• 4% pilocarpine gel has been used with few success.

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.

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 Clin1993;11:373–7.

References

• 4. Rico MJ. Differential diagnosis of vesiculobullouslesions. 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

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

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