Krishan Mehra

VESICOBULLOUS DISORDER

Surg Capt J SridharSr Adv

Dr Krishan MehraPGT-I

Dept of Dermatology

May 1, 2023 2

Patient particulars

32 years old serving solider

National handball player

Resident of Maharashtra

Admitted in Jan 2016

May 1, 2023 3

Presenting complaints

Mouth ulcers - 5 months

Fluid filled lesions/erosions over upper body including head, face, neck, upper chest and back - 5months

May 1, 2023 4

History of present illness

Five months ago the patient developed raw areas in mouth, associated with burning pain while eating food

Oral lesions increased in number and size with little tendency to heal

May 1, 2023 5

History of present illness ( Contd…) Patient developed multiple, painless clear fluid

filled lesions within three to four days of the appearance of mouth lesions - over scalp, face, neck, upper chest and upper back

Blisters burst on their own to form raw areas within two to three days with little tendency to heal

Gradual increase in number and size of blisters

May 1, 2023 6

History of present illness ( Contd…) No history of

itching prior to the onset of skin lesions contact with topical drugs or chemicals lesions over other mucosae - eyes/ genitals drug intake palm and sole involvement loose stools, weight loss fever, malaise skin lesions over trauma prone areas photosensitivity/ joint pain

May 1, 2023 7

History of present illness ( Contd…)

No history ofseasonal variation/ exacerbation on sun exposurepalpitations, breathlessness or chest painhigh risk behavior, IV drug abuse, blood transfusion

May 1, 2023 8

Relevance of the negative history?

May 1, 2023 9

Relevance of the negative history

History DiseaseItching prior to skin lesions Dermatitis herpetiformis, Bullous

pemphigoidPalm and sole involvement Erythema MultiformeLesions on trauma prone area Epidermolysis bullosa acquisitaJoint pain SLEDrug intake SJS-TEN

Contact with topical drugs or chemicals

Irritant contact dermatitis, Bullous pemphigoid

Weight loss, anorexia Malignancies, Paraneoplastic PemphigusPhotosensitivity / joint pain Bullous SLE, Porphyria cutanea tarda,

Pemphigus erythematosus, Hydroa vacciniforme

High risk sexual behavior HIV with recurrent HSV

May 1, 2023 10

Past history

No h/o diabetes mellitus, hypertension, coronary artery disease, tuberculosis, jaundice and epilepsy

No h/o similar illness in the past

No h/o any major surgical or medical illness in the past

May 1, 2023 11

Drugs implicated in vesiculobullous disorders?

May 1, 2023 12

Drugs implicated in Vesiculobullous disorder

Offending drugs EruptionThiol groups - Penicillamine, Thiamazole, Captopril, Lisnopril, Piroxicam, Phenylbutazone,

Non thiol group - Penicillin group, Rifampicin, Propranolol, Phenytoin,

Pemphigus

Carbamazepine, Phenytoin, Valproic acid, Barbiturates, Sulfonamides, NSAIDS, Penicillin, Rifampicin, Isoniazid, Pyrazinamide

Erythema Multiforme

Psoralens, Thiazides, Furosemides, Doxycycline, Fluroquinolone, Sulfonamides

Phototoxic drugs eruptions

Allopurinol, Anticonvusants, Barbiturates, Sulfonamides, Piroxicam, Phenylbutazone, Nevirapine, Quinolones

SJS-TEN

Tetracycline, Furosemide, NSAIDS, Captopril, Penicillamine, Penicillin group antibiotics

Bullous pemphigoid

May 1, 2023 13

Personal history

Graduate Married Vegetarian Teetotaller No h/o substance abuse Normal appetite, sleep Normal bowel and bladder habits

May 1, 2023 14

Family history

No h/o similar illness among family members

May 1, 2023 15

Treatment history

Under treatment from previous military centre with monthly IV infusions and daily oral tablets since four months

May 1, 2023 16

Summary?

May 1, 2023 17

Summary

32 years serving soldier, hailing from Maharashtra, married, with no comorbidities with h/o non healing ulcers in the mouth and painless fluid filled skin lesions/ erosions over the upper part of body with little tendency to heal for the last five months

May 1, 2023 18

Causes of blistering?

May 1, 2023 19

Causes of blistering (Adults) S

No.Causes Diseases

1 Infections Viral – Herpes simplex, Varicella, Hand foot mouth disease, Dermatophytosis

2 Inflammations Pustular psoriasis, Subcorneal pustular dermatosis, Bullous lichen planus

3 Genetic Hailey-Hailey disease, Darier’s disease

4 Antibody mediated Pemphigus,Llinear IgA bullous dermatoses, Paraneoplastic pemphigus, Bullous pemphigoid, Dermatitis herpetiformis, Epidermolysis bullosa acquisita

5 Metabolic Porphyria cutanea tarda, Diabetic bullae

6 Allergic Atopic dermatitis

7 Mechanical Friction blisters

8 Drugs Bullous drugs reaction, SJS-TEN, Erythema multiforme

9 Environmental Phototoxic reactions, Burns

May 1, 2023 20

Causes of blistering (Children) S No.

Casues Diseases

1 Infections Viral – Herpes simplex, Varicella, Hand foot mouth disease,Fungal – CandidiasisBacterial – Congenital syphilis, Bullous impetigo, SSSS,

2 Inflammations Bullous mastocytosis, Miliaria, Erythema toxicarum neonatorum, Suction blisters

3 Genodermatoses Epidermolysis bullosa, Incontinentia pigmenti, Bullous congenital ichthyosiform erythroderma

4 Antibody mediated

Pemphigus, IgA dermatoses, Paraneoplastic pemphigus

5 Metabolic Acrodermatitis enteropathica

6 Allergic Atopic dermatitis

May 1, 2023 21

Possibilities on History

Pemphigus Vulgaris Bullous Pemphigoid Linear IgA bullous disease Recurrent erythema multiforme Paraneoplastic Pemphigus Lupus erythematosus

May 1, 2023 22

EXAMINATION

May 1, 2023 23

General physical examination• General condition - fair• Ht- 171 cm ; Wt – 75 kg• BMI –25.65 Kg/m2 • Waist circumference – 88 cm• Temp- 98.80 F• Pulse- 94/min• BP- 110/74 mmHg• RR- 16/min• No pedal edema • No lymphadenopathy • No pallor, icterus, cyanosis, clubbing

May 1, 2023 24

Systemic examination

CVS

S1, S2 heard. No murmur

Respiratory

B/L equal air entry No adventitious sounds heard

May 1, 2023 25

Systemic examination (contd…)

Per abdomen

Soft, non tender No hepatosplenomegaly

CNS

Higher mental functions normal No focal neurological deficit

May 1, 2023 26

Dermatological examination Multiple erosions, covered with crusts

(corn flake like), on erythematous base, B/L symmetrical, involving face, scalp, neck, upper chest, upper back, sparing the axillary area with a musty smell, of various sizes (diameter of 1 to 3 cm) with multiple hyperpigmented macules.

May 1, 2023 27

May 1, 2023 28

May 1, 2023 29

Dermatological examination (contd…) Nikolsky's sign – not elicitable Nails, Hair - Normal Palms, soles, flexures - Normal

Genital & conjunctival mucosa – Normal

External genitalia, perianal region – Normal

Joint- WNL

May 1, 2023 30

Nikolsky's sign ?

May 1, 2023 31

Nikolsky's sign ?

Shearing or tangential force dislodges the upper layer of epidermis from lower epidermis

Nikolsky’s signBulla spread sign of Asboe-Hansen

May 1, 2023 33

video

May 1, 2023 34

Types of Nikolsky’s sign ?

May 1, 2023 35

Types of Nikolsky’s sign Direct Nikolsky’s sign-

When sign is elicited in normal skin away from the blister Indicates severe disease activity.

Marginal Nikolsky’s sign- When sign is elicited in normal skin near blister.

Pseudo Nikolsky’s sign- Shearing or tangential force cause peeling of skin which

is due to necrosis of the cells in contrast to acantholysis in pemphigus. Seen in Stevens-Johnson syndrome, Toxic epidermal necrolysis, burns.

May 1, 2023 36

Types of Nikolsky’s sign cont….. Microscopic Nikolsky’s sign-

Sign is elicited by rubbing normal appearing skin with an eraser around the blister to cause a microscopic blister.

Useful for taking a biopsy for histopathology.

False Nikolsky’s sign- This involves pulling of the peripheral remnants of

ruptured blister, thereby extending the erosion on the surrounding skin. Sign is positive in sub epidermal blistering disorders such bullous pemphigoid, JEB, mucous membrane pemphigoid.

May 1, 2023 37

Investigations• Hb - 15.4 gm%• TLC - 9600/cmm• DLC -P68, L29 ,M01, E03

• Pl Count- 2,20,000/ mm3

• ESR - 08 mm 1st hr• CRP - 0.15 mg/L• Urine RE/ME -NAD• S. bilirubin-0.7mg/dl• SGOT- 24 IU/L• SGPT- 28 IU/L• Total protein - 7.0 gm/L• Alb - 4.1 gm/L• Glob - 2.9gm/L• Blood urea- 29mg/dl

• S. creatinine- 0.9mg/dl• Na - 140 meq/L• K -4.2 meq/L• S. Ca -9.6 mg/dl• S. uric acid -5.5 mg/dl• ANA -ve• RA -ve• Blood sugar : F - 72mg/dl PP-120mg/dl• Lipid profile-

• TC – 253 mg/dl • TG – 173 mg/dl• LDL -184 mg/dl• HDL – 39 mg/dl

May 1, 2023 38

Investigations• ELISA for HIV - Neg• VDRL - Neg• HBV - Neg• HCV - Neg• ECG - WNL• CXR PA view - NAD• USG abdomen - NAD• Mantoux - Neg• Echocardigraphy - Normal• Tzank smear - Acantholytic cells seen• Skin Biopsy - Consistent with Pemphigus vulgaris• Indirect Immunofluorescence –

Dsg-1 207.3 U/ml (<20 u/ml) Dsg-3 92.7 U/ml (<20 U/ml)

May 1, 2023 39

Tzanck cells in pemphigus vulgaris (Giemsa stain, 40X )

Rounded keratinocyte with: perinuclear halo Hypertrophic/ dysmorphic

nucleus hazy or absent nucleoli increased N:C ratio abundant eosinophilic to

basophilic cytoplasm

May 1, 2023 40

Tzanck Smear ?

May 1, 2023 41

Tzanck Smear It is a bedside procedure done in blistering

disorders

The roof of the intact blister is opened along one side and floor is gently scraped with blunt edge of blade and material obtained is smeared on a glass slide and allowed to air dry.

Stained with Giemsa stain

May 1, 2023 42

Tzanck smear in cytodiagnosis ?

May 1, 2023 43

Skin biopsy

Epidermis : Suprabasal split with group of

acantholytic cells in the split. Basal layer shows loss of

adhesion with adjacent keratinoctye but attached to the basement membrane giving appearance of “row of tombstones”

Dermis: Superficial dermis shows scanty

perivascular lymphocytic infiltrate.

May 1, 2023 44

Pemphigus vs Pemphigoid?

May 1, 2023 45

May 1, 2023 46

Summary?

May 1, 2023 47

Summary

32 years serving solider , hailing from Maharashtra, married with no co-morbidities with h/o non healing ulcers in mouth and fluid filled skin lesions/erosions over upper body with little tendency to heal for the last five months.

Dermatological examination revealed multiple raw area over scalp , face, neck, chest and back.

Tzanck smear, Skin biopsy, IF studies s/o Pemphigus Vulgaris

May 1, 2023 48

Diagnosis

Pemphigus Vulgaris

May 1, 2023 49

Pemphigus ?

May 1, 2023 50

Pemphigus

Autoimmune blistering disease characterized by blisters and erosions on the skin or mucosal membranes or both

Characterized by intraepidermal split

May 1, 2023 51

Classification Pemphigus vulgaris

- Pemphigus vegetans • Pemphigus vegetans of Neumann • Pemphigus vegetans of Hallopeau

Pemphigus foliaceus - Pemphigus erythematosus - Endemic pemphigus

Paraneoplastic pemphigus Drug induced pemphigusIgA pemphigus

- Subcorneal pustular dermatosis - Intraepidermal neutrophilic IgA dermatosis

May 1, 2023 52

Epidemiology Prevalence 0.09% to 6.8% ( India 0.09 to 1.8 %)

Both sex equally affected

Average age fourth and fifth decades( third and fourth in India)

Pemphigus vulgaris is commonest type

Most common in North India, Gujarat, Maharashtra and Assam

May 1, 2023 53

Etiology Genetic Determinants

Pemphigus vulgaris is linked to HLA DRB1 *0402, HLA DQB1*0503.

Environmental Factors Exposure to ultraviolet light Pesticides and foods (nuts, mangoes, bananas, tomatoes,

garlic, onion) having thiol, phenols, polyphenolic compound, drugs

Immunological Factors Autoimmune disease and autoantibodies against antigens

located in the epidermis ○ Desmogleins (Dsg-1, Dsg-3)○ Acetylcholine receptors (AChR alfa 9)○ Pemphexin

Pathogenesis

Antibodies to epidermal Desmoglein 1&3 (cell-cell adhesion molecule)

Immune complexes deposited b/w keratinocytes - intraepidermal clefting

Acantholytic cells

‘Row of tombstones’ Fishnet pattern on DIF

May 1, 2023 55

Clinical features Oral ulcers- 50-70% patient present with oral

lesions only Painful Little tendency to heal

Skin blisters- Flaccid on normal appearing skin Easily rupture its own Usually painless without itching Little tendency to heal Characteristic musty offensive odour Head, face, neck, upper trunk, axilla, groin and pressure

points are common area involved

May 1, 2023 56

Course and prognosis Average mortality without treatment is about 100% in severe

disease

With the use of steroids mortality is about 23%

With early diagnosis, use of steroids, immunosuppressants and improved treatment of complications mortality is about 5 – 15%

Most common cause of deaths Septicemia Pulmonary embolism Complication of steroids and immunosuppressants

May 1, 2023 57

Management Aim of treatment :

Decrease blister formation

Promote healing of blisters and erosions

Determine minimal dose of medication necessary to control the disease process

May 1, 2023 58

Contd…..

Therapy must be tailored for each patient, taking into account severity, preexisting and coexisting conditions

Evaluation by Physician For any comorbidities

Evaluation by Ophthalmologist Those patients requiring prolonged high-dose steroids for ocular

involvement i.e Intraocular pressure, cataract.

Evaluation by a Rheumatologist Patients requiring long term systemic corticosteroids/ ‘mabs

May 1, 2023 59

Contd…

Adequate nutrition Nursing care Control of secondary infections Fluid and electrolyte monitoring

May 1, 2023 60

Treatment Topical (mild cases)

Topical potent steroid Topical tacrolimus Topical epidermal growth factor(EGF)

Intralesional steroids (to hasten remission) Triamcinolone acetonide (5-10mg/ml for mucosal) (10-20mg/ml for cutaneous

lesions) every weekly

Systemic steroids: Mainstay of treatment Daily dosing Pulse therapy

Oral steroids + Immunosuppressants Cyclophosphamide, Azathioprine, Cyclosporine, Mycophenolate mofetil,

Methotrexate Dexamethasone cyclophosphamide pulse

May 1, 2023 61

BiologicsRituximab with or without Immunosuppressants

IVIG

Plasmapheresis

Immunoadsorption

Extracorporeal photochemotherapy

Definitive Management – this patient

• Monthly Dexamethasone Cyclophosphamide Pulse

• Interval Prednisolone 15mg daily

• Interval oral Cyclophosphamide 50mg daily

Five cycles of DCP given with moderate control of blisters

62May 1, 2023

May 1, 2023 63

Management (contd)….. In view of:

Moderate control of the disease Long course of DCP therapy Long term side effect of systemic steroids Sports career of the patient Family not complete

Patient given Rituximab after thorough work up

RA protocol- Two does o f 1gm 15 days apart, slow IV infusion.

1st dose given and patient tolerated therapy well

Oral Cyclophosphamide 50mg daily continuing

In remission without daily steroids

May 1, 2023 64

THANK YOU