Pemphigus is a chronic autoimmune blistering disease characterized by antibodies against desmosomal proteins. It is usually seen in the 4th-6th decades and has a variable worldwide incidence. Diagnosis involves clinical examination showing Nikolsky's sign and histopathology/direct immunofluorescence confirming acantholysis. Treatment aims to heal lesions and prevent recurrences with minimal side effects. Initial treatment is high-dose corticosteroids, with immunosuppressants like azathioprine or mycophenolate added if high steroid doses are needed long-term to limit side effects. Intralesional steroids or topical therapies may help localized lesions.

1. MANAGEMENT OF
PEMPHIGUS
Presenter: Dr Sunil
Moderator: Dr Puneet Agarwal Sir

2. Introduction:
• Pemphigus is a group of chronic autoimmune blistering diseases characterized by
the presence of antibodies against desmosomal adhesion proteins.
• The term ‘pemphigus’ derives from the Greek ‘pemphix’ meaning blister or
bubble .
• Incidence of pemphigus is low but variable worldwide, ranging from 0.05 to
2.7/100 000/year.
• Usually seen between the fourth and sixth decades of life .

3. Management-Objectives:
Confirmation of diagnosis (detailed history,examination,HPE,DIF).
 To search for risk factors, severity factors and potential comorbidities based
on history and initial clinical evaluation.
 Extent and distribution of lesions( mucosal /cutaneous /both)severity
assessment(ABSIS,PDAI).
 Fluid and nutrition management and wound care with all precautions to
prevent sepsis.
 Therapeutic management.

4. DIAGNOSIS
Bed side sign & tests :
 Nikolsky’s sign :
• Tangential pressure with a finger or thumb to the affected skin, perilesional skin or
normal skin in patients with suspected pemphigus.
• Positive – extension of the blister and/or
Removal of epidermis in the rubbed area.
• First sign to disappear as the disease responds to therapy.

5. Variants of nikolsky’s sign
• Marginal nikolsky: Ability to split the epidermis of the skin far beyond the preexisting
erosion, by pulling the remnant of a ruptured blister or rubbing at the periphery of
existing lesions. MORE SENSITIVE ˜ 69%
• Direct nikolsky sign: Ability to split the epidermis on skin areas distant from the
lesions by a lateral pressure with a finger. MORE SPECIFIC ˜ 100%
Others:
• Modified nikolsky’s sign
• Sheklakov/ false nikolsky sign
• Pseudo nikolsky sign
• Wet nikolsky’s sign
• Dry nikolsky’s sign
 Nikolsky’s sign is moderately sensitive & highly specific in the diagnosis of pemphigus.

6.  Bulla spread sign:
• Enlargement of an intact blister by the application of mechanical pressure on its
roof.
• Positive in all type pemphigus & pemphigoid.
• Irregular angulated border in PV and rounded border in BP.
.

7.  Tzanck smear:To demonstrate acantholytic cell
• A smear is taken from the underside of the roof and from the base of an early,
freshly opened bulla.
• The commercially available Giemsa stain solution is diluted 1:10 with distilled
water, and the diluted solution is poured over the smear and kept for 15
minutes, washed with water and examined under the microscope.
• The stained nuclei may vary in color from reddish blue to purple to pink. The
cytoplasm stains bluish.
• SENSITIVITY –(PV) ˜ 100% ´
• SPECIFICITY- 43.4%

8. Typical tzanck cell:
• Rounded keratinocyte
• Hypertrophic or dysmorphic nucleus
• Hazy or absent nucleoli
• Increased nuclear to cytoplasmic ratio
• Abundant eosinophilic to basophilic cytoplasm.

9. Specific investigations :
Histopathology :
• A biopsy should be taken from a recent (<24hr) small vesicle or 1/3rd of the peripheral
portion of a blister and 2/3rd perilesional skin.
• In PV -Earliest histological changes consist of intercellular oedema with loss of
intercellular attachments in the basal layers.
-Suprabasal epidermal cells separate from the basal cells to form clefts
and blisters.
- Basal cells remain attached to the basement membrane but
separate from one another and stand like a ‘row of tombstones’
on the floor the blister.

10. -Clefting may extend into the walls of adnexae.
- The superficial dermis has a mild, superficial, mixed inflammatory
infiltrate may include eosinophils.
-Blister cavities contain rounded‐up acantholytic cells.
• In PF – Acantholysis at the granular layer or immediate below the stratum
corneum.
• In IgA Pemphigus : A subcorneal blister filled with fluid and numerous neutrophils
(SCPD type),in IEN type the neutrophils are in the suprabasal and
stratum spinosum.

12. Direct immunofluorescence :
• It is a one step procedure for detection of in vivo bound antibody ,complement
component and fibrinogen in the pt ‘s skin .
• Biopsy should be taken from perilesional normal skin (upto 1cm) or mucous membrane.
• Essentially all patients with active PV or PF have a positive DIF.
• IgG and/or C3 deposits at the surface of epidermal keratinocytes. (PV, PF)
• Granular IgG and C3 at BMZ, Intercellular IgG and C3 in the epidermis (PE).
• IgA deposits with an epithelial cell surface pattern (IgA pemphigus).
• Linear or granular deposits of IgG or C3 along the D-E junction along with intercellular
fish net pattern (PNP).

13. Figure: Direct immunofluorescence
for IgG of perilesional skin from a
patient with PV.
Cell surface staining is observed
throughout the epidermis with
slight basal predominance.

14. Indirect immunofluorescence :
• This is two step procedure for in vitro demonstration of circulating antibodies in the pt’s serum.
• IIF test on monkey oesophagus or human skin to search for autoantibodies against surface
proteins of epidermal keratinocytes.
• Circulating pemphigus autoantibodies are detected in over 80% of patients.
• Esophageal mucosal substrates being preferable for the detection of antibodies to Dsg 3.
• Whereas normal human skin shows higher sensitivity for the detection of antibodies against
Dsg 1.
• Rat bladder is used for paraneoplastic pemphigus.
• The use of more than one substrate improves sensitivity.
•

15. ELISA :
• Recombinant Dsg 1 and 3 have been used to develop a sensitive and specific
ELISA assays for the serological diagnosis of pemphigus.
• Using ELISA, over 95% of PV patients have detectable Dsg 3 antibodies and
around 50% have Dsg 1 antibodies.
• Desmoglein ELISA has 96 – 100% sensitivity and specificity.
• Anti desmoglein 1 antibody titres - show a correlation with the course of the
disease.
• Disease activity compared with anti desmoglein 3 antibody titres.

16. Immunoelectron microscopy:
• Helps to detect location of antibody and complement in the epidermis.
Immunoblot and immunoprecipitation:
• The anti-plakin autoantibodies of PNP can be detected.
• Gold standard for PNP.
ANA, Abs to Ro,La and dsDNA:
• Supplementary test for PE.
• 30-80% of patients of PE may have circulating ANA with a speckled pattern.

17. Treatment:
Therapeutics-goals:
Healing of the bullous eruption/erosions and disappearance of the functional
impairment associated with the disease.
 Prevent/strictly limit the appearance of recurrences.
 Improve the quality of life of the patients.
 Limit/minimize treatment related side effects.

18. General nursing care:
• In patients with widespread blistering, intensive nursing care is mandatory.
• Meticulous oral hygiene is imported to keep the oral mucosa clean and allow the
epithelium to regenerate.
• Betadine mouth gargles can be used as an antiseptic.
• Eating bland, soft foods and avoid hard foods like chips, chunky peanut butter,
nuts, crisp vegetables like raw carrots and fruits.

19. • Avoid foods that can cause new sore like spicy foods, steaming hot foods and
acidic foods like tomatoes and citrus fruits.
• Avoid orange juice, hot tea, coffee and spicy drinks. It can irritate mouth and
causing new sores.
• Banana leaf with coconut oil spread over the bed sheet for patient since the
leaf does not adhere to the loose skin and decrease friction.
• The patient with painful and extensive lesions should be premedicated with
analgesics before skin care is initiated.

20. • Cool wet dressing are protective and soothing.
• Gentian violet (1:2 or 1:3) paint has antifungal and some antibacterial activity
apply on exudative lesion to drying and prevent excessive water loss.
• KMNO4 solution (1:10000) is oxidising agent, it has disinfection and astringent
effects apply on exudative lesions.
• Removed crusts by Saline compression for faster healing.
• Antimicrobial agents are administered as culture & sensitivity reports and
response to treatment is assessed.
• Hypothermia is common and measures to keep the patient warm and
comfortable are priority nursing activities.

21. • Health care personnel must perform effective hand hygiene and wear gloves.
• In the hospitalised patient, environmental contamination is reduced as much as
possible.
• The patient is encouraged to maintain adequate oral fluid intake.
• Small, frequent meals or snacks of high protein, high calorie foods help maintain
nutritional status.
• Parenteral nutrition is considered if the patient cannot eat adequate diet.

22. Baseline investigations : Workup before corticosteroid or immunosuppressive
therapy.
▪ CBC
▪ KFT
▪ LFT
▪ fasting serum glucose
▪ Hepatitis B,C and HIV
▪ chest X- Ray
 Mantoux test
▪ BP

23. Definitive treatment
TOPICAL THERAPY:
• Mild cases of pemphigus can sometimes be treated by topical therapy alone.
• Topical clobetasol useful in mild pemphigus and treating localise relapses after
controlling the disease.
• Topical cyclosporine mouth wash helpful in severe oral pemphigus.
• Topical tacrolimus found to be effective in localized and refractory erosions.
.

24. • Triamcinolone acetonide oral paste can be applied and left on the affected
area for 10 min 3 times daily.
• Intralesional triamcinolone acetonide (2.5 to 5mg /ml) is helpful for
intractable oral ulcers.
• Clotrimazole mouth paste or oral fluconazole 150mg-200mg for oral
candidiasis.

25. Intralesional steroid:
• Triamcinolone acetonide (5–10 mg/ml and 10–20 mg/ml for cutaneous and
mucosal lesions respectively) has been used intralesionally to hasten the
resolution of individual lesions.
• Lesions are injected with 0.05–0.1 ml per site every 1–2 weeks until healing
occurs.
• This modality may be useful: (a) to control mild pemphigus presenting with only
a few lesions,
(b) to treat recalcitrant lesions such as oral ones
(c) to treat new lesions in patients whose systemic
therapy is being tapered off.

26. Systemic Corticosteroids:
• CS producing anti inflammatory, immunosuppressive and antiproliferative effects.
• Increased transcription of desmogleins and other cell adhesion molecules which
counteracts the antibody induced interference with desmoglein adhesive
function.
• The advent of systemic corticosteroids in the 1950s led to a dramatic reduction in
mortality from 75% to 30% among patients with pemphigus.
• Control of disease activity is usually achieved within several weeks, whereas
complete remission on minimal treatment (≤10 mg/day prednisolone) requires
months.

27. Recommendations
• The guidelines of the EDF[European Dermatology forum] and BAD[British Association of
Dermatologists] define systemic corticosteroids as the first-line treatment of PV.
• Initial treatment with prednisolone at a dose of 0.5–1.5 mg/kg/day (EDF) and 1.0
mg/kg/day (BAD).
• If control of the disease is not achieved within 1–2 weeks, higher prednisolone doses (up
to 2 mg/kg) may be administered.
• Stepped tapering of prednisolone by a 25% reduction biweekly (or over a more extended
time period if <20 mg/day) is recommended.
• If the reappearance of >3 lesions occurs during tapering of oral corticosteroid therapy,
the recommendation is to readminister the last dose.
• At relapse, oral corticosteroid therapy should be increased until two steps back at the
previous dose to lead to disease control..

28. • Combined with an immunosuppressive agent, particularly when
complications due to prolonged use (>4 months), such as hypertension,
diabetes mellitus, and osteoporosis, are expected.
• In cases where doses of prednisolone exceeding 100 mg/day are required,
pulse treatment with either oral or intravenous steroids may be considered.
• There is no evidence that pulsed corticosteroids are superior to conventional
oral corticosteroids for maintenance of most cases of PV.
• However, short-term pulsed corticosteroids could be considered in recalcitrant
PV to induce remission, especially if there has been no response to oral high
doses.

29. Pulsed therapies:
• In pemphigus, it refers to intravenous (IV) infusion of high doses of steroids for one or more
days for quicker, better efficacy, and to decrease the side effects of long-term steroids.
A) Methylprednisolone plus therapy:
• It's biological half-life is 12-36 h, potency 1.25 times compared with prednisolone.
• Dosage- Methylprednisolone is administered at a dose of 20-30 mg/kg (500-1000 mg/m 2 ) per
pulse up to a maximum dose of 1 g.
• Potential side effects eg. Seizures
Electrolytes imbalance
MI
Arrhythmias and
Hypertension
• Results only in a short term remission.

30. B)Dexamethasone-Cyclophosphamide pulse therapy: Divided into four phases
1st phase:
• IV 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
• F/b daily administration of 100 mg of dexamethasone for the next 2 days.
• Repeated every 4 weeks.
• On the balance days, 50 mg of cyclophosphamide is administered orally every
day.
• DCP is continued till remission is achieved.
2nd phase: Monthly DCP continued for 9 more months despite the absence of
clinical lesions.

31. 3rd Phase: Monthly DCP stopped and cyclophosphamide 50mg daily is
continued for another 9 months and then stopped.
4th Phase: Observation period without medication and under follow up.
Modification of DCP therapy:
C) Dexamethasone- azathioprine pulse therapy:
• Cyclophosphamide is replaced by daily oral azathioprine.
• Recommended for unmarried patients who have not completed their family.
D) Dexamethasone-Methotrexate pulse (DMP):
• Cyclophosphamide is replaced by 7.5 mg of oral weekly methotrexate (three
doses of 2.5 mg at 12 h apart), during the three phases of pulse therapy.

32. Immunosuppressives:
Azathioprine:
• MECHANISM OF ACTION: antagonizes purine metabolism and blocks the
synthesis of DNA, RNA, and proteins. It may also impede cellular metabolism
and inhibit mitosis.
Recommendation:
• First-line adjuvant immunosuppressant.
• Dose of azathioprine is determined according to the activity of the
TPMT[Thiopurine methyltransferase ] enzyme involved in the metabolism of
the drug.
• In patients with normal TPMT enzymatic activity, 2.0–2.5 mg/kg/day of
azathioprine is usually administered, whereas 1 mg/kg/day is recommended for
patients with intermediate or reduced TPMT activity.

33. • The combination of prednisolone and azathioprine is more effective than
prednisolone alone both in terms of mortality and remission.
• Potential adverse effects - Bone marrow suppression
Nausea
liver dysfunction
• However, myelosuppression may occur despite normal TPMT
• Therefore, despite normal TPMT activity, a routine complete blood count
including liver enzymes throughout the treatment period should be performed.

34. Mycophenolate mofetil:
• MMF is a prodrug that converts to mycophenolic acid (MPA) upon oral administration.
• MPA downregulates the immune system by selective impairment of inosine monophosphate
dehydrogenase, leading to a blockade of the de novo pathway of purine synthesis in T and B
cells, affecting both cellular and humoral immunity.
RECOMMENDATIONS:
• first-line adjuvant immunosuppressant, based on both the EDF and BAD guidelines.
• prescribed in divided doses amounting to a total dose of 2–3 g/day, with reduced dosages in
patients with renal impairment.
• Improvement is usually observed within 2 months of initiation.
• Adverse effects: bone marrow suppression
gastrointestinal symptoms
• MMF is not recommended in pregnancy and breastfeeding, because of an increased risk of
spontaneous abortion and congenital malformations.

35. Cyclophosphamide:
• Synthetic alkylating agent.
• Converted to the active metabolites phosphoramide mustard and aldophosphamide, which bind
to DNA and inhibit DNA replication and induce cell death, predominantly in rapidly dividing cells.
• Dose: 1-3mg/kg/day.
• Its use is limited by significant adverse including
gonadal failure,
haemorrhagic cystitis,
bone marrow suppression
increased risk of bladder cancer.
• Urinalysis with cytologic examination: Indicated when the cumulative dose of
cyclophosphamide exceeds 50g and every 6 month thereafter or any occasion of hemorrhagic
cystitis.

36. Methotrexate:
• Mechanism of action: antimetabolite, inhibits dihydrofolate reductase, which
results in decreased methionine, purine, and thymidylate synthesis and thus
DNA synthesis.
• Recommendations: Methotrexate at a dosage of 10–20 mg/week is currently
under consideration.
• Adjunctive therapy in moderate to serious cases of pemphigus.
• It may have a steroid‐sparing effect and moderate doses of methotrexate may
permit withdrawal of prednisolone in steroid‐ dependent patients.

37. Cyclosporine:
• It is calcineurin inhibitor and suppresses cellular immunity resulting in reduced
expression of several lymphokines.
• Recommendations :3–5 mg/kg/day is infrequently added to systemic
corticosteroids.
• Current data are insufficient to support cyclosporine use in PV, and it is not
recommended by the EDF or BAD guidelines.

38. Dapsone:
• Mechanism of action: antimicrobial/antiprotozoal properties and anti-inflammatory
effects, inhibit tumor necrosis factor (TNF)-α and IL-8 production.
• Recommendations : in combination with systemic corticosteroids at a dose of
100 mg/day (or ≤1.5 mg/kg/day).
• Lack of evidence in regard to its efficacy in pemphigus.
• Evaluation of serum G6PD activity is mandatory before administration.
• Dapsone may be of particular utility in pemphigus herpetiformis.

39. Rituximab:
• The human CD 20 (B-cell restricted differentiation antigen)is expressed on the surface of B cells from
pre-B-cell through memory B-cell stages but not on stem cells, pro B cells & plasma cells.
• Rituximab is a chimeric monoclonal antibody directed against CD20 and acts by causing death of CD 20
positive cells by complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity.
• First biologic to be approved for pemphigus.
• Indications:1. Preferred in patients with extensive disease in whom immediate control of disease
activity is required.
2. When systemic corticosteroids and/or other immunosuppressants are contraindicated or
cause severe adverse effects requiring its discontinuation.
3. In patients who fail to respond adequately to conventional treatment modality. ´
4. Few authors in recent studies have recommended rituximab to be the first line
treatment.
5. It can also be safely used in patients in sepsis or those who are at risk of infection.

40. • Dose: 375mg/m2 weekly for 4 weeks(Lymphoma protocol).
Two infusion of 1g , 2weeks apart(RA protocol).
• IV infusion over 4-5 hrs.
• Premedication- PCM, diphenhydramine, iv hydrocortisone 100mg(1 hr before
infusion).
• Onset of action of rituximab is typically 8–16 weeks following the first infusion,
though it may take longer.
• Improvement may persist for 12–18 months.
• Rituximab may be combined with conventional steroid therapy and adjuvant
immunosuppressive, though care needs to be taken to avoid excessive
immunosuppression and increased infection risk.

41. • Caution: Immunosupressive drugs are not given concomitantly.
-Live vaccines C/I
- Non live vaccine can be given 4 weeks before RTX. After
RTX, vaccination not recommended sooner then 6 months d/o lack of
efficacy.
-Pregnancy cat C
Adverse effects:
• Infusion related- transient fever, headache, nausea, chills, orthostatic
hypotension, thrombocytopenia, skin rashes.
• Severe cytokine release syndrome- during first infusion
• Infections
• Progressive multifocal encephalopathy
• Anemia, neutropenia
• Cardiac arrhythmias

42. Acetretin:
• Used in conjunction with prednisolone in pemphigus vegetans.
Gold:
• It is advocated as an adjuvant in refractory pemphigus vulgaris.
• Though toxic effects limit its utility.

43. IVIG:
• IVIg consist of human plasma-derived IgG, sugars, salts and solvents.
• Exerts various anti-inflammatory effects, including Fc receptor blockade, stimulation of
antibodies production against different subclasses of T lymphocytes, inhibition of different T-
cell functions.
• However, the main mode of action is an increased catabolism of immunoglobulins via binding
to the neonatal Fc receptor (FcRn).
• It is generally used at a dose of 2 g/kg split over 3–5 days and treatment may need to be
continued monthly for prolonged periods.
• S/e: Headache, flu like symptoms and hypotension.
• Anaphylaxis may occur in patients with complete IgA deficiency and this should be excluded
prior to treatment.

44. Plasmapheresis:
MECHANSIM OF ACTION: Plasmapheresis is an extracorporeal blood purification
procedure in which plasma proteins are non-selectively removed from the
circulation which is replaced with another fluid – often, albumin or fresh-frozen
plasma.
• The rationale behind plasmapheresis is based on the correlation observed
between the titers of circulating anti- autoantibodies and disease activity.
• Following procedure there is rebound increase in autoantibodies which can be
managed with immunosuppresive agents given prior to the procedure.

45. • RECOMMENDATIONS: No standardized protocol, four or five plasma
exchanges – each consisting of 1–1.5 plasma volumes over a period of 7–10
days.
• ADVERSE EVENTS: Thrombocytopenia, hypogammaglobulinemia, fluid
overload leading to hypertension and pulmonary edema in patients with
underlying congestive heart failure, hypoproteinemia, anemia, leukopenia,
and hypocalcemia.

46. Immunoadsorption:
• MECHANISM OF ACTION: extracorporeal blood purification procedure which is more specific, where
only IgGs and immune complexes are attracted to the adsorber and removed from the circulation.
• In IA, the blood is passed through adsorber columns, in which molecules with high affinity for IgG, i.g.
protein A (Immunosorba ) or the synthetic peptide PGAM146 (Globaffin ), function as a ligand.
Recommendations : four treatments of immunoadsorption on four consecutive days (2.5-fold plasma
volume per day), repeated after 4 weeks, if needed.
• Indications: Reliable first-line treatment in pemphigus patients, in whom
lesions cover
(1) > 30% of the body surface or
(2) > 25% of oral or genital mucous membranes or involve
(3) the conjunctiva or
(4) the esophagus;
(5) it can be also recommended in refractory patients with more than 3
months of active disease despite at least two immunosuppressive therapies

47. • Other therapies that have been used in resistant cases of pemphigus include
Extracorporeal photophoresis.
Tumor necrosis factor (TNF) inhibitors: infliximab and adalimumab
• Tetracycline antibiotics with or without nicotinamide may be helpful as
steroid‐sparing agents in some patients.

48. PERSPECTIVES FOR FUTURE THERAPEUTIC STRATEGIES:
CHIMERIC ANTIGENIC RECEPTOR THERAPY:
• Human T cells were engineered to express a chimeric autoantibody receptor
(CAAR) consisting of Dsg3.
• In the murine model, Dsg3 CAAR-T cells exhibit specific cytotoxicity against B
cells bearing anti-Dsg3 B-cell receptors in vitro and specifically eliminate Dsg3-
specific B cells in vivo;
• Effective strategy for specific targeting of autoreactive B cells in PV without
inducing general immunosuppression.

49. T CELL IMMUNOTHERAPY:
• Antigen-specific T and B cells must interact via the molecules CD154 and
CD40, respectively, in order to produce autoantibodies;
• Altered peptide ligands (APLs) may be utilized in an immune-based treatment
strategy targeting the T-cell level.
BAFF and APRIL inhibitors:
• Both belong to a class of TNF alpha family, lead to the promotion of Ig
switching to the IgG, IgE, and IgA subclasses and B cell proliferation and
differentiation.
• Although BAFF and APRIL were not established as dominant players in the
immunopathogenesis of PV, further studies are warranted to clarify their role
in this disease.

50. P38MAPK signaling pathway inhibitor:
• IgG-induced phosphorylation has been demonstrated to activate p38
mitogen-activated protein kinase (p38MAPK) and heat shock protein (HSP) 27
• causes downstream remodeling of the actin cytoskeleton and retraction of
keratin and contributes to the loss of cell–cell adhesion.
• This signaling pathway is initiated following the binding of IgG autoantibody
to keratinocytes and may be involved in the induction of acantholysis.

51. Bruton’s tyrosine kinase inhibitor:
• Target several pathways
• Modulation of B-cell receptor-mediated B-cell pathways
• Inhibition of FcR-induced cytokine release from monocytes and macrophages.
• FcR-induced mast cell degranulation and granulocyte migration as well as
mediator release.

52. THANK YOU