Bullous disorders in dermatology post graduate ppt

Bullous disorders dermatology

1. Bullous Disorders Dr Ajithkumar K Addl Professor of D&V Government Medical College, Kozhikode 11/9/2018 Vizag

2. Learning Objective To review the clinical and theoretical knowledge on Bullous disorders with special reference to Immuno bullous disorders Acknowledgement: Dr Aparna vidya MD Some of the slides and pictures are borrowed/ modified from open source material available online 11/9/2018 Vizag

3. History of present illness Site Easily rupturing blisters Flaccid/tense fluid filled lesions Clear or hemorrhagic fluid Healing or spreading lesions Distribution –extent of skin lesions Purities Other mucosa involved Associated illness(of underlying malignancy) Systemic symptoms – fever , joint pain, malaise Drug intake/ Topical application Photosensitivity/ joint pain – ( bullous LE, Pemphigus erythematosus , PCT) Diarrhea(DH) History of IBR H/o aggravating factors – sun exposure, drugs, trauma, reduction of steroids, wheat etc h/o of relieving factors – diet avoidance of wheat, avoidance of trauma 11/9/2018 Vizag

4. Pemphigus Vulgaris Oral Mucosa, Scalp P. Foliaceus Scalp, Chest Bullous pemphigoid Extremities LAD Peri oral, Peri genital DH Trunk MMP Oral/Other Mucosa Pemphegoid gestationis Periumbelical , extremities EBA Extremities Haily Haily disease Friction sites Initial Sites 11/9/2018 Vizag

5. Mucosal Involvement Mucosal Involvement Always ---- Pemphigus Vulgaris,Para neoplastic pemphigus,MMP , Not Rare—BP (1040%),LAD(80%),EBA(50%), Un common--- Ig A pemphigus,PG,DH 11/9/2018 Vizag

6. PV Scalp, face,flexures,trunk PF Seborrheic distribution IgA pemphigus Axila , Groin, face, scalp, PNP Palmo plantar, Oral, Upper trunk BP Trunk, Limbs, flexures MMP Head , neck, upper trunk, Mucosa Distribution 11/9/2018 Vizag

7. 11/9/2018 Vizag

8. 11/9/2018 Vizag

9. Past history— simillar diseases ,Oral Ulcer, scalp lesions, vegetative lesions etc / Urticaria /child hood blisters Personal history--? Food habits Family history- DH/ Haily Haily / EB/ Porphyria etc Treatment history- steroid/ Dapsone /NSAIDS/ sulfas/ Rifampicine / Malignancy Socioeconomic history Menstrual history Marital history 11/9/2018 Vizag

10. Dermatological examination o Site o Size Tense/ flaccid o Flaccid/tense fluid filled lesions o On a clear base or erythematous base o Clear or hemorrhagic fluid o Healing or spreading lesions o Other mucosa involved o Wheals o Crusted lesions o Distribution Scarring o Mousy odour o o Nikolsky sign – marginal and direct o Bulla spread sign( Modified nikolsky sign orNikolsky II Asboe Hansen sign) o Nikolsky phenomenon o Sheklakov / False Nikolsky sign o Pseudo Nikolsky /Epidermal peeling sign o Pear sign 11/9/2018 Vizag

11. Scalp Hair Nails Palms and soles Genitalia Other mucosa 11/9/2018 Vizag

12. Nikolsky sign 11/9/2018 Vizag

13. 11/9/2018 Vizag

14. Nikolsky's sign Definition: Nikolsky's sign refers to the ability to induce peripheral extension of a blister as a consequence of applying lateral pressure to the border of an intact blister . • Indication to perform . To differentiate intraepidermal from sub epidermal blister . Method to elicit: • elicited by applying lateral pressure with the thumb or finger pad on skin over a bony prominence. • This results in a shearing force that dislodges the upper layers of epidermis from the lower epidermis. • The sign is said to be positive if the upper epidermis separates from the lower. 11/9/2018 Vizag

15. Variants of nikolsky’s sign Marginal nikolsky : nikolsky sign elicited over the normal looking skin of a pemphigus patient close to existing lesions. Direct nikolsky sign : nikolsky sign elicited over the normal looking skin at a distant site. • Positive direct nikolsky sign indicates severe activity of the disease in pemphigus . it is the peripheral extension of blisters on applying pressure to their surface. • Modified nikosky’s sign • This is helpful in patients in whom a new vesicle or bulla is not available for biopsy. • The advantage here is that artificially extended blister does not show epithelial regeneration, which may some times be seen in floor of older subepidermal blisters making them appear as intraepidermal   • Sheklakov sign/ false- nikolsky sign: • This is elicited by pulling the peripheral remnant of a roof of a ruptured blister, thereby extending the erosion on the surrounding normal skin. • It is called false nikolsky because it is a sub epidermal cleavage occurring in the perilesional skin. • This is positive in sub epidermal blistering disorders like 1. Bullous pemphigoid , 2. Cicatricial pemphigoid , 3. Pemphigoid gestationis , 4. Dermatitis herpetiformis , 5. Linear IgA bullous dermatosis , 6. Epidermolysis bullosa acquisita , 7. Junctional & dystrophic epidermolysis bullosa , 8. Porphyrias and 9. Bullous SLE.   11/9/2018 Vizag

16. • Pseudo nikolsky sign/epidermal peeling sign: • This is positive in 1. Steven johnson syndrome 2. Toxic epidermal necrolysis 3. Burns 4. Bullous icthyosiform erythroderma . • The method of eliciting is same as that for nikolsky sign. • It can be elicited only on the involved or erythematous skin. • Here the underlying mechanism is necrosis of epidermal cells and not acantholysis as in true nikolsky .   • “Wet” nikolsky’s sign : in which a moist, glistening base of eroded skin is seen after pressure is exerted on the skin • “Dry” nikolsky’s sign : in which a dry base of eroded skin is seen after pressure is exerted on the skin.   Implications of nikolsky’s sign oDiagnostic value of Nikolsky’s sign • Nikolsky’s sign is moderately sensitive & highly specific in the diagnosis of pemphigus . • Marginal Nikolsky’s sign is more sensitive (69%). • Direct Nikolsky’s sign is more specific (100%). The  Asboe - Hansen sign  (also known as "indirect Nikolsky   sign " or " Nikolsky II  sign ") refers to the extension of a blister to adjacent unblistered skin when pressure is put on the top of the bulla. This  sign is named for Gustav  Asboe - Hansen  (1917–1989), Danish physician. 11/9/2018 Vizag

17. Diagnosis PEMPHIGUS Bedside test – Tzanck test Biopsy Direct immunoflourescence Indirect immunofluorescence Immunoblotting Enzyme-linked immunosorbent assay (ELISA). PEMPHIGOID Bedside test – Tzanck test Biopsy Direct immunoflourescence Indirect immunofluorescence Salt split skin immunoflouresence Flourescent overlay antigen mapping Immune electron microscopy Immunoblotting Enzyme-linked immunosorbent assay (ELISA). 11/9/2018 Vizag

18. TZANKSmear Bed side test Open fresh blister Detach roof Scrape the floor with scalpel Make a smear Stain with Gimsa 11/9/2018 Vizag

19. Bedside test – Tzanck test Pemphigus Acantholytic cells Methodology Staining Other uses of cytology Classification of acantholysis Subepidermal Blisters Eosinophil —BP and EM Neutrophil –DH and LE 11/9/2018 Vizag

20. Histopathology Vesiculobullous disorder Biopsy Pemphigus vulgaris (PV) Intra epidermal bullae, Row of tomb stones, acantholytic cells Pemphigus foliaceous (PF) (a) eosinophilic spongiosis (b) a subcorneal blister, often with few acantholytic keratinocytes (c) a subcorneal blister with dyskeratotic granular keratinocytes Pemphigus erythematosus The light microscopic features are identical to those of pemphigus foliaceu . Interface dermatitis may also be apparent in rare cases, making distinction from lupus erythematosus difficult. Pemphigus herpetiformis Eosinophilic spongiosis with or without acantholysis . Neutrophilic spongiosis or subcorneal pustules with both eosinophils and neutrophils IgA pemphigus SPD type: subcorneal vesicopustules or pustules with minimal acantholysis . IEN type: intraepidermal vesicopustules or pustules containing small to moderate numbers of neutrophils . Drug induced pemphigus Early lesion: Nonspecific, consisting of spongiosis , parakeratosis , and a variable dermal infiltrate. Well-developed lesions: are identical to those of pemphigus foliaceus or pemphigus vulgaris . Eosinophilic spongiosis may be prominent Paraneoplastic pemphigus The lesions show a unique combination of EM-like, lichen planus like, pemphigus vulgaris like, and pemphigoid -like features. The principal findings are suprabasal acantholysis with basal apoptosis in association with vacuolar interface dermatitis (EM-like) with or without lichenoid inflammation (lichen planus like) In pemphigoid -like lesions, a subepidermal blister is present 11/9/2018 Vizag

21. Pemphigus vegetans Neumann type: Early lesion - histologic picture resembles pemphigus vulgaris . Older lesions - formation of villi and epidermal hyperplasia . Numerous eosinophils are present within the epidermis and dermis, producing both eosinophilic spongiosis and eosinophilic pustules Acantholysis may not be present in older lesions. Hallopeau type: Early lesions consist of pustules arising on normal skin with acantholysis and formation of small clefts, with many in a suprabasal location . The clefts are filled with numerous eosinophils and degenerated acantholytic epidermal cells . Bullous pemphigoid(BP) Subepidermal blister with a dense eosinophil rich infiltrate Mucous membrane pemphigoid (MMP) Subepithelial or subepidermal blister formation, Fewer eosinophils than in BP. MMP cannot be differentiated from other pemphigoid diseases based on histopathology Later stage - fibrosis, the distinctive feature of MMP, may develop. Linear IgA bullous disorder(LAD) subepidermal splitting and an infiltrate with neutrophils Epidermolysis bullosa aquisita subepidermal blistering, scarce inflammatory infiltrate in the mechanobullous variant and dense with predominant neutrophils , eosinophils , monocytes and lymphocytes reminiscent of BP in the inflammatory subtype Dermatitis Herpetiformis (DH) subepidermal blister formation with neutrophils located at the tips of the dermal papillae. Papillary tip Micro abcesses Anti-p200 antibody( only 50 cases reported ) subepidermal split accompanied by the accumulation of neutrophils in the upper dermis 11/9/2018 Vizag

22. Hailey hailey disease(HHD) Widespread partial loss of cohesion ( keratinocytes may still be linked together) between suprabasal keratinocytes with an appearance likened to a dilapidated brick wall. Clusters of loosely coherent cells float in suprabasal clefts or bullae . Dyskeratosis , when present, is usually mild, but changes may resemble those in DD. Darier’s disease Suprabasal acantholysis with suprabasal clefts (lacunae) Dyskeratosis (premature and abnormal keratinization ), Hyperkeratosis. Apoptosis results in rounded eosinophilic dyskeratotic cells in the epidermis ( corps ronds ) and flattened parakeratotic cells in the horny layer ( grains) . Bullous LE Resemble dermatitis herpetiformis with subepidermal splitting, dense neutrophil ‐ dominated infiltrate in the upper dermis sometimes accumulating in microabscesses of the papillary tips , and dermal oedema. Mucin depositions in the reticular dermis sometimes signs of leukocytoclastic vasculitis . Basal layer vacuolization characteristic for cutaneous LE is not present. 11/9/2018 Vizag

23. 11/9/2018 Vizag

24. 11/9/2018 Vizag

25. Dermatosis Principal immunoreactant Site Pattern Pemphigus all variants except : IgA pemphigus Paraneoplastic pemphigus IgG ICS Basket weave /fish netLike , IgA pemphigus IgA ICS Basket weave /fish net LikeLace like, dot like Paraneoplastic pemphigus IgG C3,IgG C3,IgG ICS BMZ BMZ Lace like, dot like Linear Granular Bullous pemphigoid C3,IgG BMZ Linear Cicatricial pemphigoid C3,IgG BMZ Granular anti p200 pemphigoid C3,IgG BMZ Linear Herpes gestationis C3,IgG BMZ Linear EBA C3,IgG BMZ Linear BUllous SLE C3,IgG C3,IgG BMZ BMZ Linear Granular Dermatitis herpetiformis IgA BMZ Granular LAD IgA BMZ Linear EM C3,IgM C3,IgM BMZ Vessels Granular Granular Porphyria/ pseudoporphyria/ bullous dermatosis of hemolysis IgG BMZ Vessels Glassy broad Glassy broad DIF 11/9/2018 Vizag

26. Pemphigus Bullous pemphigoid 11/9/2018 Vizag

27. Roof only Roof and base Base only Bullous pemphigoid (80%) herpes gestationis Bullous pemphigoid (15%) herpes gestationis Anti p200 pemphigoid Cicatritial pemphigoid Cicatritial pemphigoid Anti epiligrin Cicatricial pemphigoid EBA Bullous SLE Porphyria cutanea tarda LAD LAD IgA EBA salt split IF 11/9/2018 Vizag

28. Diseases Autoantibodies Antigens Location of antigens Pemphigus vulgaris . mucosal mainly . mucocutaneous IgG IgG Desmoglein 3 Desmoglein 3 Desmoglein 1 Desmosomes Pemphigus foliaceous IgG Desmoglein 1 Desmosomes Paraneoplastic pemphigus IgG Desmoglein 1&3 Desmoplakin Ienvoplakin , Periplakin , Plectin BPAg1 , Plakoglobin Desmosomes or hemidesmosomes Drug induced pemphigus (autoimmune variant) IgG Desmoglein 3 Desmoglein 1 Desmosomes IgA pemphigus SPD type IEN type IgA IgA Desmocollin 1 Desmoglein1,Desmoglein3 Desmosomes Target antigens 11/9/2018 Vizag

29. Autoimmune disease Protein target Structural target Genetic disease BP BPAg1(BP230) HD None identified BP,Pemphigoid gestationis , cicatricial pemphigoid , LABD BPAg2(BP180) HD anchoring filament complexes Generalised atrophic benign epidermolysis bullosa Ocular cicatricial pemphigoid  6  4 integrin, subunit  4 HD anchoring filament complexes Junctional EB with pyloric atresia Antiepiligrin cicatricial pemphigoid Laminin 5(epiligrin) Lamina lucida- lamina densa interface Junctional EB herlitz Anti p200 pemphigoid P200 Lower lamina lucida None identified EBA Bullous SLE typeVII collagen Anchoring fibrils Dystrophic EB Target antigens 11/9/2018 Vizag

30. Treatment Pemphigus Steroid steroid sparing agents – Cyclophosphamide Azathioprine Cyclosporine MMF Dapsone Methotrexate 11/9/2018 Vizag

31. Pulse Therapy DCP Pulse : Pulse100 mg dexamethasone dissolved in 500 mL of 5% glucose given as an intravenous infusion over approximately two hours, repeated on three consecutive days. On the second day, the patients also received 500 mg of cyclophosphamide added to the dexamethasone infusion. ( pulses ) Phase 1, 2 and 3 DAP DP / Methyl pred Others IVIG, tetra cycine , 11/9/2018 Vizag

32. Ritoximab Rhumatod arthritis regimen Two-1000 mg intravenous infusions separated by 2 weeksX 2 doses Lymphoma regimen The recommended dose is 375 mg/m 2  as an intravenous infusion 4 weekly pulse x 4 weeks Pemphigus regimen (Jolly etal ) 1000 mg of intravenous rituximab on days 0 and 14, and 500 mg at months 12 and 18, combined with a short-term prednisone regimen, 0·5 or 1·0 mg/kg per day tapered over 3 or 6 months Ultra Low dose regimen : Two doses of 100 mg every 3 months 11/9/2018 Vizag

33. Bullous Pemphgoid Steroid steroid sparing agents – Cyclophosphamide Azathioprine Cyclosporine MMF Dapsone Methotrexate Nicotinic acid Tetra cycline 11/9/2018 Vizag

34. Treatment Dermatitis Herpetiformis – Dapsone Ig A pemhigus / LAD – Bullous SLE : Dapsone /steroid EBA – steroid/ Cyclophosphamide / Azathioprine /Cyclosporine/MMF Treat Primary problem 11/9/2018 Vizag

35. Thank You 11/9/2018 Vizag