Oral pemphigus vulgaris

1. ORAL PEMPHIGUS VULGARIS: A CASE REPORT WITH DIRECT IMMUNOFLUORESCENCE STUDY LEKSHMY JAYAN I MDS, ORAL AND MAXILLOFACIAL PATHOLOGY SRM DENTAL COLLEGE, CHENNAI

2. INTRODUCTION Named by Wichman (1791) name derived from the Greek word ‘PEMPHIX’ - bubble or blister DEFINITION : Pemphigus refers to autoimmune disorders, mucocutaneous blistering disease, in which the keratinocyte antigens are targets of autoantibodies leading to acantholysis and blister formation.

3. TYPES

4. PREDISPOSING FACTORS DRUGS DIET RADIATION STRESS SURGERY PREGANANCY VIRUS PESTICIDES Shamimul Hasan et al : Pemphigus vulgaris – a case report and detailed review of literature(2011)

5. EPIDEMIOLOGY INCIDENCE: 0.5 to 3.2 per year per 1,00,000 population Male: Female = 1:2 Ashkenazi Jews and people in Mediterranean origin 80-90% patients develop oral lesions, 60% develop oral lesions as first symptom. Occasionally associated with other autoimmune disorders, Herpes simplex infection, internal malignancies [Rai Arpita et al, 2015, ORAL PEMPHIGUS VULGARIS : A CASE REPORT ]

6. ST18- gene regulating apoptosis and inflammation, identified in predisposing individuals Genetic predisposition to HLA [ Frank.A.Santoro et al : Pemphigus 2013 October]

7. ` INTERCELLULAR JUNCTIONS OCCLUDING JUNCTION COMMUNICATING JUNCTION ANCHORING JUNCTION

8. DESMOSOMES(Macula adherens ) ( Giulio Bizzagero ) Small disk shaped- spot welds between adjacent cells Link cytoskeletal structure of two cells Resist shearing force and prevent mechanical stress Desmosomes are found in many tissues especially abundant in skin, heart, muscle, the neck of the uterus.

9. EXTRACELLULAR PART (DESMOGLEA) Transmembrane proteins Cadherin superfamily - Desmoglein and Desmocollin INTRACELLULAR PART (DESMOSOMAL PLAQUES) Two protein groups 1st group- Plakin family desmoplakin , envoplakin, periplakin 2 nd group- Plakoglobin and plakophilin DESMOGLEIN 1- Pemphigus Foliaceus DESMOGLEIN 3- Pemphigus Vulgaris

10. THEORIES OF PATHOGENESIS DESMOGLEIN COMPENSATION THEORY MULTIPLE HIT HYPOTHESIS ANTIBODY- INDUCED APOPTOSIS THEORY BASAL CELL SHRINKAGE THEORY AND APOPTOLYSIS THEORY

11. DESMOGLEIN COMPENSATION THEORY ( Amgai & Stanley,1999 ) Based on the distribution of Dsg1 and Dsg 3 in the skin and mucosa Existence of anyone type of Dsg is sufficient to maintain the integrity of epithelium and mucosa.

12. DRAWBACKS: 1) Assumption that the integrity of stratified squamous epithelium of skin and oral mucosa relies entirely on Dsg 1 and Dsg 3 molecules. 2) Ignores complex interactions of chromosomal cadherins for integrity of epidermis. [ Sergei.A.Grande , 2011, PEMPHIGUS AUTOIMMUNITY: HYPOTHESIS AND REALITY ]

13. MULTIPLE HITS HYPOTHESIS

14. ANTIBODY INDUCED APOPTOSIS THEORY Apoptosis may be responsible for the underlying mechanism of acantholysis . IgG and anti- Fas receptor antibody activate apoptosis

15. BASAL CELL SHRINKAGE HYPOTHESIS AND APOPTOLYSIS THEORY Acantholysis occurs in the suprabasal layers – tombstone like transformation of the basal layers Shrinkage of keratinocytes Apoptolysis [GRANDE ET AL,2009] links acantholysis and cell death pathways to cell shrinkage

16. MAIN DIFFERENCE BETWEEN APOPTOSIS AND APOPTOLYSIS IN PEMPHIGUS :

17. PEMPHIGUS VULGARIS Present with oral lesions and then develop cutaneous lesions Often misdiagnosed as aphthous ulcer COMMON SITES : Oral mucosa, Skin, Nose, Pharynx, Larynx, Oesophagus, Genital area

18. CLINICAL FEATURES : AGE- 40-60 years approximately Rapid appearance of multiple large flaccid bullae Fragile, ruptures easily- painful haemorrhagic erosion Early lesion- watery fluid and later purulent or sanguineous fluid

19. COURSE IS VARIABLE : 1) Acute fulminating (days to weeks) 2) Slow, prolonged (months to years) VESICLE V/S BULLAE

20. NIKOLSKY’S SIGN ( Pyotr Vasilyevich Nikolsky , 1896) lateral pressure to the border of intact bullae peripheral extension of the bullae. Positive upper dermis separates from basal layer Differentiate intraepidermal from subepidermal bullae Also seen in FAMILIAL BENIGN CHRONIC PEMPHIGUS, EPIDERMOLYSIS BULLOSA

21. Asboe- Hansen sign or Indirect Nickolsky’s sign ( Gustav Asboe-Hansen)   Extension of a blister to adjacent unblistered skin when pressure is put on the top of the bulla NIKOLSKY’S PHENOMENON When superficial layer of the epidermis is felt to move over the deeper layer- new bullae develops within 24 hours

22. ORAL MANIFESTATIONS : Intact bullae rare due to fragility Patchy erosions are seen- painful on chewing Desquamative gingivitis (2-3%) Common sites- Buccal mucosa Tongue Palate Lips Supriya.s.Venugopal et al, 2012,[DIAGNOSIS AND CLINICAL FEATURES OF PEMPHIGUS VULGARIS ]

23. HISTOLOGICAL FEATURES Acantholysis Formation of bullae above the basal cell layer Split is characteristically suprabasilar and cells remain attached to the basal lamina- tombstone appearance Presence of tzanck cells Vesicular fluid and connective tissue- scanty to dense inflammatory cell infiltration Spongiosis and acantholysis of adjacent epithelium

24. epithelium exhibiting spongiosis , tombstone appearance, suprabasilar split and dense inflammatory infiltrate 

25. Suprabasilar cleft showing acantholysis of the keratinocytes, Tzanck cells, red blood cells and inflammatory cells

26. DIAGNOSIS Clinical examination Biopsy Tzanck smear Compressed air test Immunofluorescence study ELISA

27. TZANCK CELLS Multinucleated giant cell formed by the fusion of acanthoytic keratinocytes Seen in – Pemphigus vulgaris, Chicken pox, Herpes simplex, Herpes zoster TZANCK TEST : (ARNAULT TZANCK, 1947) Simple diagnostic cytological method for mucocutaneous lesion Stains- Giemsa stain, H&E, Methylene blue, Papanicolaou, Toluidine blue

28. CYTODIAGNOSIS BY TZANCK SMEAR DISEASE CYTODIAGNOSIS BY TZANCK SMEAR Pemphigus Vulgaris Multiple tzanck cells Mourning edged cells Sertoli rosette Streptocytes Bullous Pemphigoid, Steven Johnson Syndrome and Erosive Lichen Planus Non-specific No acantholytic Rules out Pemphigus Vulgaris Herpes simplex, Varicella, Herpes zoster Rapid and reliable Multinucleated syncytial giant cells (tadpole, teardrop shape) & acantholytic cells Ballooning degeneration Nuclear molding Basal cell epithelioma Highly reliable Cluster of basaloid cells Cytoplasm is scant, poorly defined and basophilic Squamous cell carcinoma (nodular, ulcerated, non keratotic) Isolated cells , pleomorphism Nuclear alteration

29. IMMUNOFLUORESCENCE Technique allowing visualisation of specific protein or antigen by finding specific antibody chemically conjugated with a fluorescent dye. Specific antibodies labelled with Fluorescein Isothiocyanate[FITC] - apple green under polarised light

30. DIRECT IMMUNOFLUORESCENCE INDIRECT IMMUNOFLUORESCENCE

31. IMMUNOFLUORESCENCE IN PEMPHIGUS VULGARIS DIRECT IMMUNOFLUORESCENCE IN PEMPHIGUS VULGARIS INDIRECT IMMUNOFLUORESCENCE IN PEMPHIGUS VULGARIS

32. DIFFERENTIAL DIAGNOSIS Bullous pemphigoid Cicatricial pemphigoid Dermatitis herpetiformis Erythema multiforme Erosive lichen planus Allergic stomatitis

33. TREATMENT AIM OF TREATMENT 1)Decrease bullae formation 2)Promote healing of bullae and erosions 3)Determine minimal dose of medication necessary to control the disease process .

34. PERIODONTAL THERAPY CORTICOSTEROID THERAPY PLASMAPHERESIS [ Shamimul Hasan et al- Pemphigus vulgaris- A case report and detailed review of the literature,2011]

35. ORAL PEMPHIGUS VULGARIS: A CASE REPORT WITH DIRECT FLOURESCENCE STUDY BY, SANGEETHA JEEVAN KUMAR, SP NEHRU ANAND, NANDHINI GUNASEKARAN, RAJKUMAR KRISHNAN DEPARTMENT OF ORAL PATHOLOGY AND ORAL MEDICINE, SRM DENTAL COLLEGE, RAMAPUARAM

36. BIBLIOGRAPHY Sergei. A. Grando - Pemphigus autoimmunity: /Hypothesis and realities(2011) Frank. A. Satoro et al- Pemphigus (2013) Sreeshyla.H.S et al – Oral Pemphigus Vulgaris- Report of a case and review of the etiopathogenesis (2011) A.Rocher et al – Revaluating Tzanck Test: A comparative study with direct immunofluorescence for Herpes virus (2016) Atiya Yaheen et al- Diagnostic value of Tzanck smear in various erosive, vesicular and bullous skin lesions (2015) Supriya.S . Venugopal et al- Diagnosis and clinical features of Pemphigus vulgaris (2012)

37. Shamimul Hasan et al- Pemphigus vulgaris- A case report and detailed review of literature (2011) Yasuo Kitajima - New insights into desmosome regulation and pemphigus blistering as a desmosome-remodelling disease(2013)