Pemphigus and Pemphigoid

Vesiculobullous Lesions - Pemphigus and Pemphigoid
Classification, Terminologies, Subsets of Pemphigus, Difference between pemphigus and pemphigoid, oral manifestations, differential diagnosis, Histopathology, Investigations and Management given in detail.

1. PEMPHIGUS and PEMPHIGOID DR. YUNUS AHMED BANGALORE INSTITUTE OF DENTAL SCIENCES & HOSPITAL RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

2. CLASSIFICATION OF SKIN LESIONS VESICULOBULLOUS GENODERMATOSIS MUCOCUTANEOUS DISEASE CHARACTERIZED HEREDITARY DISORDERS ACCOMPANIED BY VESCICLES AND BULLAE BY SYSTEMIC MANIFESTATIONS OF DIFFERENT ALTERED ENZYME FUNCTIONS GENOKERATOSIS ALTERATION IN NORMAL KERATINIZATION PROCESS

3. VESICLE A VESICLE IS A FLUID FILLED, ELEVATED, SAC, CYST OR VACUOLE IN OR BENEATH THE SKIN WHICH IS LESS THAN 1CM IN DIAMETER. BULLA A BULLA IS A CLEAR, FLUID FILLED, ELEVATED BLISTER GREATER THAN 1cm IN DIAMETER PUSTULE PUSTULES ARE VESICLES THAT CONTAIN PUS ACANTHOSIS THICKENING OF SKIN( MAINLY STRATUM BASALE & STRATUM SPINOSUM ) TERMINOLOGIES IN VESICULOBULLOUS LESIONS

4. ACANTHOLYSIS LOSS OF ADHESION B/W ONE CELL AND ANOTHER CELL DESQUAMATION SHEDDING OR SCRAPING OF OUTERMOST LAYER OF THE SKIN

5. CLASSIFICATION OF VESICULOBULLOUS LESIONS ACUTE DURATION – SHORT AGE – YOUNG ETIOLOGY – ALLERGY, BURNS, VIRUSES Eg . HERPES SIMPLEX INFECTION HERPES ZOSTER CHICKEN POX ERYTHEMA MULTIFORME CHRONIC LONG MIDDLE AGE – OLDER AUTOIMMUNE PEMPHIGUS BULLOUS PEMPHIGOID CICATRICIAL BULLOUS LICHEN PLANUS BASED ON CLINICAL PRESENTATION PREDOMINENTLY VESICULAR PREDOMINENTLY BULLOUS HSV INFECTION P EMPHIGUS BULLOUS PEMPHIGOID BULLOUS LICHENPLANUS

6. INTRA-EPITHELIAL VESICULOBULLOUS LESION HSV INFECTION PEMPHIGUS MUCOSAL ERYTHEMA MULTIFORME SUB-EPITHELIAL VESICULOBULLOUS LESION BULLOUS PEMPHIGOID CICATRICIAL DERMAL ERYTHEMA MULTIFORME HISTOPATHOLOGICAL INFECTIOUS NON INFECTIOUS HSV INFECTION PEMPHIGOUS PEMPHIGOID ERYTHEMA MULTIFORME

7. PEMPHIGOID IS A CHRONIC AUTOIMMUNE PREDOMINENTLY BULLOUS SUB-EPITHELIAL NON-INFECTIOUS LESION IN SHORT , PEMPHIGUS IS A CHRONIC (LONG STANDING) AUTOIMMUNE PREDOMINENTLY BULLOUS INTRA-EPITHELIAL NON-INFECTIOUS LESION

8. PEMPHIGUS IS A CHRONIC SKIN DISEASE CHARACTERIZED BY APPEARANCE OF VESCICLES & BULLAE THAT DEVELOP IN CYCLES. IT IS A DESQUAMATING CONDITION OF ORAL MUCOSA AND SKIN, IN WHICH ANTIBODIES DESTROY ANTIGENIC COMPONENTS OF DESMOSOMES, OF IMMEDIATE CELLS ABOVE BASAL CELLS PRODUCING EPITHELIAL CELL SEPERATION ABOVE BASAL CELL LAYER. PEMPHIGUS IS DERIVED FROM THE GREEK WORD ‘PEMPHIX’ MEANING BUBBLE/ BLISTER. WICHMAN IN 1971 CHARACTERIZED, HISTOLOGICALLY - BY INTRADERMAL BLISTERS IMMUNOLOGICALLY - BY FINDINGS OF CIRCULATING IgG ANTIBODIES DIRECTED AGAINST CELL SURFACES OF KERATINOCYTES. PEMPHIGUS

9. ORAL LESIONS FIRST TO SHOW & LAST TO GO 4 PRIMARY SUBSETS OF PEMPHIGUS PEMPHIGUS VULGARIS PEMPHIGUS VEGETANS PEMPHIGUS FOLIACEUS PARA-NEOPLASTIC PEMPHIGUS OTHER TYPES - PEMPHIGUS ERYTHEMATOSUS BRAZILIAN PEMPHIGUS

10. PEMPHGUS IS DERIVED FROM GREEK WORD PEMPHIX MEANING BUBBLE/BLISTER VULGARIS IS A LATIN WORD MEANING COMMON. IT IS A AUTOIMMUNE, INTRA-EPITHELIAL BLISTERING DISEASE AFFECTING SKIN AND MUCOUS MEMBRANE & IS MEDIATED BY CIRCULATING AUTO ANTIBODIES DIRECTED AGAINST KERATINOCYTE CELL SURFACE. PEMPHIGUS VULGARIS

11. THESE AUTOANTIBODIES ARE PATHOGENIC. THEY GET DEPOSITED IN THE SKIN AND MUCOUS MEMBRANE WHERE THEY INITIATE AN IMMUNE REACTION. BINDING OF SPECIFIC IgG AUTO ANTIBODIES TO THE ANTIGEN( DESMOGLEIN 1 AND 3 PROTEINS WHICH FORM THE ‘GLUE’ THAT ATTACHES EPITHELIAL CELLS TOGETHER VIA ATTACHMENT POINTS CALLED ‘DESMOSOMES’. THIS LEADS TO EPITHELIAL CELL SEPERATION BY TRIGERRING COMPLEMENT ACTIVITY THEREBY INHIBITING THE MOLECULAR REACTION RESPONSIBLE FOR CELL-CELL BINDING IN THE EPITHILIUM.

12. WHEN AUTO ANTIBODIES ATTACK DESMOGLEINS THESE CELLS BECOME SEPERATED(SPLIT IN THE EPITHILIUM) FROM EACH OTHER A PHENOMENON CALLED AS ‘ACANTHOLYSIS’ DUE TO LOSS OF CELL TO CELL ADHESION, THIS CAUSES BLISTERS THAT EVENTUALLY TURN INTO ULCERS. BLISTERS ULCERS

13. GENETIC VULNERABILITY OR SUSCEPTIBILITY PATIENTS WITH SPECIFIC MHC(CLASS 1)Ag ON SKIN AND MUCOSAL KERATINOCYTES . DIET – GARLIC DRUGS – PENICILLAMINE CAPTOPRIL RIFAMPICIN DICLOFENAC PREDIPOSING FACTORS

14. AGE OF ONSET – 50 TO 60 YRS EQUAL GENDER DISTRIBUTION (COMMON IN JEWS) RAPID APPEARANCE OF VESICLES & BULLAE IN ORAL CAVITY , SPREAD RAPIDLY TO EYES AND SKIN. MAY TURN LESION CONTAINS THIN,WATERY FLUID PURULENT AND SANGUINEOUS CLINICAL FEATURES

15. WHEN BULLA RUPTURES, THEY LEAVE RAW, ERODED SURFACE. WHEN GENTLE, OBLIQUE PRESSURE IS APPLIED ON THE UNAFFECTED AREAS AROUND THE LESION , IT CAUSES DENUDATION / STRIPPING OF NORMAL SKIN OR MUCOUS MEMBRANE. THIS PHENOMENON IS CALLED NIKOLSKY’S SIGN. IT IS CAUSED BY PERIVASCULAR EDEMA WHICH DISRUPTS THE DERMAL-EPIDERMAL JUNCTION. IT IS A CHARACTERISTIC FEATURE OF PEMPHIGUS . NIKOLSKYS’S SIGN

16. ILL DEFINED, IRREGULARLY SHAPED, GINGIVAL, BUCCAL AND PALATAL EROSIONS. PAINFUL AND SLOW TO HEAL RUPTURED VESICLES IN ORAL CAVITY LEAVE EXTREMELY PAINFUL AND SUPERFICIAL ERYTHEMATOUS ULCERS WITH RAGGED BORDERS. ORAL MUCOSAL LOCATIONS INVOLVED ARE - ORAL MANIFESTATIONS

17. OTHER SITES OF INVOLVEMENT ARE – PHARYNX LARYNX CONJUNCTIVA – OCULAR CERVIX URETHRA

18. UNCOMMON VARIANT OF PEMPHIGUS CHARACTERISTIC FEATURE – CEREBRIFORM TONGUE (PATTERN OF SULCI AND GYRI ON DORSUM OF TONGUE) PEMPHIGUS VEGETANS

19. BOTH ARE RARE FORMS OF PEMPHIGUS LESIONS. HERE BULLAE FORMATION IS ASSOCIATED WITH MARKED ERYTHEMA OF INVOLVED SKIN. BOTH THESE LESIONS RESEMBLE EXFOLIATIVE DERMATITIS & THERE ARE RARELY ANY ORAL MANIFESTATIONS PEMPHIGUS FOLIACEUS AND PEMPHIGUS ERYTHEMATOSUS PARANEOPLASTIC PEMPHIGUS (PNP) RARE VESICULOBULLOUS DISORDER THAT AFFECTS PATIENTS WHO HAVE A NEOPLASM USUALLY A NON-HODGEKINS LYMPHOMA, CHRONIC LYMPHOCYTIC LEUKEMIA OR CASTLEMAN’S TUMOUR.

20. HISTOPATHOLOGY OF PEMPHIGUS VULGARIS SEPERATION OF EPITHILIAL CELLS OCCURS ABOVE THE BASAL CELLS, FORMING A SPACE KNOWN AS ‘SUPRA BASILAR’ SPLIT . THE SPLIT PRODUCES A HISTOLOGIC CHARACTERISTIC PATTERN CALLED AS ‘ROW OF TOMBSTONES ’ REFERRING TO THE BASAL CELLS THAT PROJECT INTO THE BLISTER CAVITY.

21. DUE TO ACANTHOLYSIS CLUMPS OF EPITHILIAL CELLS ARE OFTEN FOUND LYING FREE WITHIN THE VESICULAR SPACE. THESE CELLS ARE CALLED AS ‘TZANK CELLS’ (RESEMBLE FRIED EGGS) TZANK CELLS ARE ROUND CELLS WITH HYPERCHROMATIC NUCLEI WITH A THIN RIM OF CYTOPLASM. MILD – MODERATE CHRONIC INFLAMMATORY CELL INFILTRATION IS SEEN. (PMNL’S,LYMOPHOCYTES )

22. IMMUNOFLUORESCENT TESTING DIRECT IMMUNOFLUORESCENCE TO DEMONSTRATE PRESENCE OF IMMUNOGLOBULIN IgG. ANTIBODY BINDS TO THE ANTIGEN IN INTERCELLULAR SUBSTANCE AND EXHIBITS POSITIVE FLUORESCENCE UNDER FLUORESCENT MICROSCOPE. INVESTIGATIONS TZANK TEST (CYTOLOGICAL TEST) SCRAPINGS OF ULCER BASE TO LOOK FOR TZANK CELLS

23. ERYTHEMA MULTIFORME PEMPHIGOID EPIDERMOLYSIS BULLOSA THE HISTOLOGICAL PRESENCE OF 1) SUPRA BASAL SPLIT , 2) INTRA EPIDERMAL BULLA , WITH 3) ACANTHOLYSIS IS A CHARACTERISTIC FEATURE OF PEMPHIGUS AND USUALLY DIFFERENCIATES IT FROM OTHER SIMILAR DISEASES . DIFFERENTIAL DIAGNOSIS MANAGEMENT TOPICAL – 0.01% POTASSIUM PERMANGANATE SOLUTION 0.5% SILVER NITRATE SOLUTION SYSTEMIC – HIGH DOSE OF CORTICOSTEROIDS – PREDNISONE IMMUNOSUPPRESSIVE AGENTS – AZATHIOPRINE ANTIOBIOTICS TO PREVENT SECONDARY INFECTION MAINTAINING FLUID AND ELECTROLYTE BALANCE

24. PEMPHIGOID IS A GROUP OF RELATIVELY UNCOMMON AUTOIMMUNE VESICULOBULLOUS LESION. CHARACTERIZED HISTOLOGICALLY BY SUB – EPITHELIAL BULLAE FORMATION IN THE BASEMENT MEMBRANE ZONE(BMZ) OF SKIN AND EPITHILIUM . PEMPHIGOID TYPES BULLOUS PEMPHIGOID CICATRICIAL PEMPHIGOID

25. FORMATION OF AUTOANTIBODIES IgG IN THE BODY AGAINST THE ANTIGENIC COMPONENTS OF THE BASEMENT MEMBRANE ZONE BINDING OF AUTOANTIBODIES IgG TO HEMIDESMOSOMES ASSOCIATED ANTGENS IN THE BASEMENT MEMBRANE BP230 AND BP180 – IN BULLOUS PEMPHIGOID BP180 AND EPILEGRIN(LAMININ-5 ) – IN CICATRICIAL PEMPHIGOID ACTIVATION OF COMPLEMENT SYSTEM, WHICH ATTRACTS INFLAMMATORY CELLS SYNTHESIS OF CHEMOTACTIC FACTORS AND RELEASE OF PROTEASE BY INFLAMMATORY CELLS PROTEASE CAUSES DESTRUCTION OF HEMIDESOMOSOMAL JUNCTIONS OF BASEMENT MEMBRANE ZONE FORMATION OF SUBEPITHELIAL VESICLES OR BULLAE PATHOGENESIS

26. IT IS AN AUTOIMMUNE, CHRONIC, INFLAMMATORY DISORDER CHARACTERIZED BY SUB-EPITHILIAL BLISTERING . AFFECTS SKIN, ORAL MUCOSA AND OCULAR MUCOSA. CICATRICIAL MUCOSA IS ATTRIBUTED TO SCARRING OF CONJUNCTIVAL MUCOSA . CICATRICIAL PEMPHIGOID ( BENIGN MUCOUS MEMBRANE PEMPHIGOID, OCULAR PEMPHIGUS ) ETIOLOGY – UNKNOWN

27. FREQUENTLY AFFECTS MIDDLE AGE OR ELDERLY FEMALES ORAL LESIONS DESQUAMATION OF GINGIVAL TISSUE (DESQUAMATIVE GINGIVITIS) GINGIVAL LESIONS SHOW EROSIONS AFTER RUPTURE OF BULLAE LEAVING A RAW, ERODED BLEEDING SURFACE FOR WEEKS/MONTHS. MUCOSAL BULLAE ARE OFTEN TENSE AND RELATIVELY TOUGH BECAUSE THEY ARE COVERED BY FULL THICKNESS EPITHILIUM. DEEPER LESIONS , BASE OF THE ULCER IS LOCATED DEEPER, BULLAE ARE LARGER AND MORE PAINFUL COMPARED TO PEMPHIGUS WHICH HAS SUPERFICIAL LESIONS WHICH ARE LESS EASILY HEALED. ORAL ULCERS OR EROSIONS HAVE DISTINCT MARGINS CLINICAL FEATURES

28. EYE LESIONS OCULAR INVOLVEMENT IN 25% OF THE CASES WITH ORAL LESIONS CONJUNCTIVITIS BLISTER FORMATION IN THE EYE

29. OCCURS MORE COMMONLY ON SKIN , RARELY AFFECTS ORAL MUCOSA. CHARACTERIZED BY PRESENCE OF IgG AUTO-ANTIBODIES SPECIFIC FOR HEMIDESMOSOMAL BULLOUS PEMPHIGOID Ag BP230 AND BP180 . BULLOUS PEMPHIGOID (PARAPEMPHIGUS) CLINICAL FEATURES 60-80 YEARS – EQUAL GENDER DISTRIBUTION NON SPECIFIC RASH COMMONLY ON LIMBS, WHICH PERSISTS FOR SEVERAL WEEKS BEFORE APPEARANCE OF VESICULOBULLOUS LESION. PRURITIS

30. ORAL LESIONS ARE LESS FREQUENT IN BULLOUS PEMPHIGOID THAN IN CICATRICIAL PEMPHIGOID BULLOUS PEMPHIGOID MAY CO-EXIST WITH LICHEN PLANUS AND IS REFERRED TO AS LICHEN PLANUS PEMPHIGOIDES

31. SUB-EPITHELIAL BULLAE FORMATION INTACT BASAL CELLS AND SUB-BASAL SEPERATION IS SEEN. (CAUSES SEPERATION OF FULL THICKNESS EPITHELIUM FROM THE UNDERLYING LAMINA PROPRIA AND THUS EPITHELIUM FORMS ROOF OF INTACT BULLAE TILL IT IS RUPTURED) INFLAMMATORY CELL INFILTRATION (BY LYMPHOCYTES, MACROPHAGES AND EOSINOPHILS) HISTOPATHOLOGY

32. SYSTEMIC STEROID THERAPY IS THE CHOICE OF TREATMENT IN BOTH FORMS OF THE DISEASE. PREDNISONE – DRUG OF CHOICE TREATMENT (Rx)

33. DIFFERENCES PEMPHIGUS INTRAEPITHELIAL SUPERFICIAL BLISTERS SUPRA-BASAL SPLIT MORE FRAGILE EASILY HEALED IMMUNOFLOURESCENCE TEST LACE LIKE OUTLINING OF EPIDERMAL CELLS (NET LIKE IgG) PEMPHIGOID B/W THE OUTER EPIDERMIS AND DERMIS.(SUB-EPITHELIAL) DEEPER LESIONS(LARGER, MORE PAINFUL AREA) SUB-BASAL SPLIT LESS FRAGILE LESS EASILY HEALED IMMUNOFLOURESCENCE TEST LINE SEEN AT THE BASE OF EPIDERMIS(LINEAR IgG)

34. PEMPHIGUS COMMONLY RELATED TO MUCOUS MEMBRANE AUTOANTIBODIES ARE DIRECTED AGAINST DESMOGLEINS WHICH ARE ATTACHED VIA DESMOSOMES (DEMOGLEIN 1 AND 3) PATIENT PRESENTS WITH BUNCH OF RUPTURED BULLAE COVERED WITH SCABS YOUNGER PATIENTS PEMPHIGOID SKIN AUTOANTIBODIES ARE DIRECTED AGAINST HEMIDESMOSOMES (INTERCELLULAR JUNCTIONS THAT ATTACH EPITHILIAL CELLS TO BASEMENT MEMBRANE) Ag BP230 AND BP180. PATIENT WITH INTACT, TENSE BULLAE ELDERLY PATIENTS (LESS SERIOUS DISEASE SINCE BULLAE OFTEN DON’T REPTURE, SO THERE IS LESS CHANCE OF INFECTION AND SCARRING)