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Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
Immunologically mediated skin diseases
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Immunologically mediated skin diseases

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Immunologically mediated skin diseases …

Immunologically mediated skin diseases

Presented by Wat Mitthamsiri, MD.

October11, 2013

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  • 1. Immunologically Mediated Skin Diseases Wat Mitthamsiri, M.D. Allergy and Clinical Immunology Unit Department of Medicine King Chulalongkorn Memorial Hospital
  • 2. Outline  Epidermal and epidermal-dermal cohesion  Differential Dx of vesicles/bullae  Pemphigus vulgaris  Pemphigus foliaceus  Bullous pemphigoid  Gestational pemphigoid  Cicatricial pemphigoid  Dermatitis herpetiformis  Linear IgA bullous dermatosis  Epidermolysis bullosa acquisita  Paraneoplastic pemphigus
  • 3. Epidermal and epidermal-dermal cohesion  Desmosome  Hemidesmosome  Epidermal basement membrane S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 4. Epidermal and epidermal-dermal cohesion  Desmosome’s main components  Plakins  Armadillo proteins  Desmosomal cadherins S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 5. Epidermal and epidermal-dermal cohesion  Hemidesmosome’s main components  Plakins homologues  Integrins  Collageneous transmembrane protein S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 6. Epidermal and epidermal-dermal cohesion  Epidermal basement membrane  Collagen type IV  Laminins  Nidogens  Perlecan S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 7. Epidermal and epidermal-dermal cohesion  Proteins in desmosomes, hemidesmosomes and epidermal basement membranes are targeted by autoimmune in skin blistering diseases S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 8.  PF; Pemphigus foliaceus, PNP; Paraneoplasic pemphigus, PV; Pemphigus vulgaris, SPD; Subcorneal pustular dermatosis S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 9.  BP; Bullous pemphigoid, CP; Cicatricial pemphigoid, LAD; Linear IgA dermatosis, PG; Pemphigoid gestationis, EBA; Epidermolysis bullosa aquisita S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 10. Differential Dx of vesicles/bullae
  • 11. Primary mucocutaneous diseases  Primary blistering diseases (autoimmune)  Pemphigus vulgaris  Pemphigus foliaceus  Bullous pemphigoid  Gestational pemphigoid  Cicatricial pemphigoid  Dermatitis herpetiformis  Linear IgA bullous dermatosis  Epidermolysis bullosa acquisita DL Longo, et al., Harrison’s Principle of Internal Medicine, 18th edition , 2012.
  • 12. Primary mucocutaneous diseases  Secondary blistering diseases  Contact dermatitis  Erythema multiforme  Stevens-Johnson syndrome  Toxic epidermal necrolysis  Infections  Varicella/zoster virus  Herpes simplex virus  Enteroviruses, e.g., hand-foot-and-mouth disease  Staphylococcal scalded-skin syndrome  Bullous impetigo DL Longo, et al., Harrison’s Principle of Internal Medicine, 18th edition , 2012.
  • 13. Primary mucocutaneous diseases  Secondary blistering diseases  Contact dermatitis  Erythema multiforme  Stevens-Johnson syndrome  Toxic epidermal necrolysis  Infections  Varicella/zoster virus  Herpes simplex virus  Enteroviruses, e.g., hand-foot-and-mouth disease  Staphylococcal scalded-skin syndrome  Bullous impetigo DL Longo, et al., Harrison’s Principle of Internal Medicine, 18th edition , 2012.
  • 14. Systemic diseases  Autoimmune  Paraneoplastic pemphigus  Infections  Cutaneous emboli  Metabolic  Diabetic bullae  Porphyria cutanea tarda  Porphyria variegata  Pseudoporphyria  Bullous dermatosis of hemodialysis  Ischemia  Coma bullae DL Longo, et al., Harrison’s Principle of Internal Medicine, 18th edition , 2012.
  • 15. Systemic diseases  Autoimmune  Paraneoplastic pemphigus  Infections  Cutaneous emboli  Metabolic  Diabetic bullae  Porphyria cutanea tarda  Porphyria variegata  Pseudoporphyria  Bullous dermatosis of hemodialysis  Ischemia  Coma bullae DL Longo, et al., Harrison’s Principle of Internal Medicine, 18th edition , 2012.
  • 16. Pemphigus
  • 17. Pemphigus classification Type Pemphigus vulgaris Pemphigus foliaceus Paraneoplastic pemphigus IgA pemphigus Form Pemphigus vegetans; Localized Drug-induced Pemphigus erythematosus; Localized Fugo selvagem; Endemic Drug-induced Subcorneal pustular dermatosis Intraepidermal neutrophilic IgA dermatosis S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 18. Pemphigus vulgaris
  • 19. Pemphigus vulgaris  Epidemiology  Men = Women, except for some countries  Mean age 40-60 years, but range is broad  Incidence can be 7.6-100/1 million population/year (depends on ethnic group) S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 20. Pemphigus vulgaris  Etiology  Genetic predisposition: HLA-DRB1*0402, - DQB1*0503.  Ab against desmoglein 3 (Dsg3) and later desmoglein 1 (Dsg1)  The bound Ab activate proteases that damage the desmosome  Acantholysis  Drugs, esp. without sulfhydryl groups  Beta-blockers, cephalosporins, penicillin, and rifampicin Sterry, et al., Dermatology , 2006. DL Longo, et al., Harrison’s Principle of Internal Medicine, 18th edition , 2012.
  • 21. Pemphigus vulgaris  Clinical presentation  Typically begins on mucosal surfaces (mostly oral) and progresses to involve the skin  Fragile, flaccid blisters that rupture to produce extensive denudation of mucous membranes and skin  Involved areas: mouth, scalp, face, neck, trunk, genitalia, mechanically stressed areas, nail fold, intertriginous areas (eg. axilla, groin)  May be associated with severe pain and pruritus Sterry, et al., Dermatology , 2006 DL Longo, et al., Harrison’s Principle of Internal Medicine, 18th edition , 2012.
  • 22. Pemphigus vulgaris A: PV with marked erosions, B: PV with oral ulceration Sterry, et al., Dermatology , 2006
  • 23. Pemphigus vulgaris DL Longo, et al., Harrison’s Principle of Internal Medicine, 18th edition , 2012.
  • 24. Pemphigus vulgaris DL Longo, et al., Harrison’s Principle of Internal Medicine, 18th edition , 2012.
  • 25. Pemphigus vulgaris S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 26. Pemphigus vulgaris  Clinical presentation  Nikolsky sign:  True Nikolsky sign: Gentle rubbing allows one to separate upper layer of epidermis from lower, producing blister or erosion  Fairly specific for pemphigus  Pseudo-Nikolsky sign (Asboe–Hansen sign):  Pressure at edge of blister makes it spread  Less specific, seen with many blisters eg. TENS, SJS Sterry, et al., Dermatology , 2006. DL Longo, et al., Harrison’s Principle of Internal Medicine, 18th edition , 2012.
  • 27. Pemphigus vulgaris  Histopathology S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 28. Pemphigus vulgaris  Immunopathology  Direct immunofluorescence of perilesional skin  Deposition of IgG (100%), C3 (80%) or IgA (20%), as well C1q in early lesions  Hallmark: Abs surround the surface of individual keratinocytes  Indirect immunofluorescence: Using monkey esophagus  90% of sera show positive reaction; titer can be used to monitor disease course. Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 29. P. vulgaris vs P. foliaceus S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 30. Pemphigus vulgaris  Immunopathology  ELISA:  More sensitive and specific than immunofluorescence for DDx PV from PF  Can be used to identify:  Anti-Dsg3 only: patient with predominantly mucosal disease  Anti-Dsg1and anti-Dsg3: patient with widespread disease Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 31. Pemphigus vulgaris S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 32. Pemphigus vulgaris  Treatment  Systemic corticosteroids  Main cause of morbidity and mortality is corticosteroid side-effects  always combined with steroid-sparing agents  Screen for osteoporosis and latent tuberculosis  Treatment of choice.  Pulse of prednisolone 1 g/day q 3-4 wk  Plus single dose of cyclophosphamide 7.5–15 mg/kg divided into 1–2 mg/kg/day Sterry, et al., Dermatology , 2006
  • 33. Pemphigus vulgaris  Treatment  Prednisolone-azathioprine therapy:  prednisolone 1.5–2.0mg/kg and azathioprine 2.5mg/kg  If blister formation is not suppressed within 1 week, double the prednisolone dose  Once blister formation is suppressed, taper to maintenance dose of prednisolone 8mg daily and azathioprine 1.5mg/kg daily Sterry, et al., Dermatology , 2006
  • 34. Pemphigus vulgaris  Treatment  Alternative immunosuppressive agents:  Chlorambucil 0.1–0.2mg/kg daily  Cyclosporine 5.0–7.5mg/kg daily  Mycophenolate mofetil 2.0g daily  Topical measures  Local anesthetic gels in the mouth before meals  Antiseptics and anticandidal measures may also be useful  Therapy-resistant course  Drastic measures include high-dose IVIG or column immune absorption of autoantibodies  Immunosuppressive therapy must be continued or a rebound invariably occurs Sterry, et al., Dermatology , 2006
  • 35. Pemphigus foliaceus
  • 36. Pemphigus foliaceus  Epidemiology  Prevalence is less than PV  Dependent of geographic location  All age groups affected Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 37. Pemphigus foliaceus  Etiology  Autoantibodies against Dsg1  Rarely Ab shift  later are formed against Dsg3 and patient develops PV  More often drug-induced than PV  Drugs with sulfhydryl groups  Mechanism might be interference to adhesion molecules, modification of antigenicity and regulation of immune response  May be caused by sunburn or as paraneoplastic sign Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 38. Pemphigus foliaceus  Clinical presentation  Sites of predilection: scalp, face, chest, and back (seborrheic areas) with diffuse scale and erosions  Primary lesion: Small flaccid blister (difficult to find)  Can progress to involve large areas (exfoliative erythroderma)  Facial rash sometimes butterfly pattern  Oral mucosa usually spared  Individual lesions are slowly developing slack blisters that rupture easily, forming erosions and red-brown crusts Sterry, et al., Dermatology , 2006.  Several clinical variants S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 39. Pemphigus foliaceus  PF with diffuse superficial erosion Sterry, et al., Dermatology , 2006.
  • 40. Pemphigus foliaceus S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 41. Pemphigus foliaceus  Exfoliative erythroderma S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 42. Pemphigus foliaceus  Histopathology  Blister forms in stratum corneum or stratum granulosum  Acantholysis rarely seen  Usually just a denuded epithelium and sparse dermal perivascular inflammation Sterry, et al., Dermatology , 2006.
  • 43. Pemphigus foliaceus  Histopathology Sterry, et al., Dermatology , 2006.
  • 44. Pemphigus foliaceus S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 45. Pemphigus foliaceus  Immunopathology  Direct and indirect immunofluorescence:  Superficial deposition of IgG  ELISA  IgG antibodies against Dgs1 Sterry, et al., Dermatology , 2006.
  • 46. P. vulgaris vs P. foliaceus S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 47. Pemphigus foliaceus  Treatment  Same approach as PV  Usually more responsive to therapy  Dapsone may be helpful Sterry, et al., Dermatology , 2006.
  • 48. Bullous pemphigoid
  • 49. Bullous pemphigoid  Epidemiology  Most common autoimmune bullous disease  Incidence range 14-472/1,000,000 yearly  Favors elderly (one estimate 300x more likely at 90 years of age than at 60 years of age)  No known ethnic, racial or sexual predilection  6-40% mortality in 1 year Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 50. Bullous pemphigoid  Etiology  AutoAb directed against two hemidesmosomal proteins:  BP 230 or BP antigen 1 (BPAG1)  BP 180 or BP antigen 2 (BPAG2)  The binding of autoAb leads to complement activation, attraction of eosinophils, release of proteases, and separation between the epidermis and dermis  Less common causes: drugs (benzodiazepine, furosemide, penicillin, sulfasalazine), sunlight, and ionizing radiation. Sterry, et al., Dermatology , 2006.
  • 51. Bullous pemphigoid  Clinical presentation  Before blisters develop, pruritus, dermatitic, and urticarial lesions may be present. The blisters tend to develop in these areas.  Tense blisters, often have a fluid level, and can reach 10cm in diameter  Most common on lower abdomen, thighs and flexor forearms, but can occur anywhere  Oral mucosal involvement in 20%  Several clinical variants Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 52. Bullous pemphigoid  Clinical presentation Sterry, et al., Dermatology , 2006.
  • 53. Bullous pemphigoid  Urticarial lesions S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 54. Bullous pemphigoid  Histopathology  In the prebullous lesions, the presence of unexpected eosinophils is a good clue  Later subepidermal blister formation  Two forms:  Cell-rich form: contains many eosinophils and neutrophils  Cell-poor form: sparse infiltrate  Lamina lucida = roof of the blister  Lamina densa = floor of the blister Sterry, et al., Dermatology , 2006.
  • 55. Bullous pemphigoid S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 56. Bullous pemphigoid S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 57. Bullous pemphigoid  Immunopathology and other lab tests  Direct immunofluorescence:  Band of IgG and C3 along basement membrane zone.  Indirect immunofluorescence:  AutoAb usually attach to just the roof of the blister (bottom of the basal cell), but can appear on the dermal side or in both locations.  7-80% of patient have IgG against normal stratified squamous cell epithelium Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 58. Bullous pemphigoid  Direct immunofluorescence S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 59. Bullous pemphigoid  Indirect immunofluorescence S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 60. Bullous pemphigoid  Immunopathology and other lab tests  ELISA  Identifies Ab against both BPAG1 (230kd) and BPAG2 (180kd) in 60–80% of patients  Those directed specifically against the NC16 epitope of BP 180 correlate best with disease course  Elevated ESR  Eosinophilia  Increased IgE Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 61. Bullous pemphigoid  Treatment  Mainstay is systemic corticosteroids:  Prednisolone 0.75-1 mg/kg daily  As soon as control is reached, tapering to maintenance dose of 8 mg daily.  Try to taper to alternate-day dosage for adrenal-sparing effect  Most widely used steroid-sparing agent:  Azathioprine, cyclophosphamide  Mycophenolate mofetil also appears promising.  MTX 15–20 mg weekly is also effective; it can be combined with high potency topical corticosteroids during the 4-6 weeks of induction Sterry, et al., Dermatology , 2006.
  • 62. Bullous pemphigoid  Treatment  Some patients do well on high-potency topical corticosteroids with less systemic steroid side effects  Large open blisters and erosions may require topical antiseptics  Some patients with localized disease had advantage from topical tacrolimus Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 63. Bullous pemphigoid S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 64. Gestational pemphigoid
  • 65. Gestational pemphigoid  Epidemiology  Occurs in 1:10,000–50,000 pregnancies (least common dermatitis specific to pregnancy)  If same father, high likelihood of recurrence in subsequent pregnancies  No maternal risk  No increase in birth defects  Complications of pregnancy in 15–30%  8% fetal death rate. Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 66. Gestational pemphigoid  Etiology  Mothers often HLA-B8, -DR3, or -DR4  Father often HLA-DR2.  Possible that mothers are sensitized against placental antigens  IgG1 autoAb against  BP 180 (NC16 domain)  BP 230 (less often) Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 67. Gestational pemphigoid  Clinical presentation  Sites of predilection :  Protuberant abdomen and extremities  Mucosal involvement 20%.  Grouped stable blisters with pruritus develop in 2nd/3rd trimester and persist until delivery  Rarely appear postpartum  Resolve within 3months  Occasionally recur with menses or ingestion of OCP  Tends to be worse in next pregnancy.  AutoAb cross the placenta  Newborn can have blisters for a few weeks. Sterry, et al., Dermatology , 2006.
  • 68. Gestational pemphigoid S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 69. Gestational pemphigoid  Histopathology  Subepidermal blister, usually with cell-rich pattern S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 70. Gestational pemphigoid  Immunopathology and other labs  Direct immunofluorescence:  Band of C3 along BMZ; occasionally IgG; all the others uncommon.  Indirect immunofluorescence:  IgG Ab cannot always be demonstrated directly, but their strong complement-fixing properties allow identification (herpes gestationis factor).  IgG attaches to the blister roof  Often hypereosinophilia. Sterry, et al., Dermatology , 2006.
  • 71. Gestational pemphigoid S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 72. Gestational pemphigoid  Treatment  Topical corticosteroids: Usually ineffective  Prednisolone 0.5 mg/kg/d, then try taper to lowest maintenance dose  Severe cases:  High-dose IVIG, immune absorption, or cyclosporine  Persistence after delivery  Luteinizing hormone-releasing hormone might be considered Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 73. Cicatricial pemphigoid
  • 74. Cicatricial pemphigoid  Epidemiology  Incidence about 1/1,000,000 population/year  Female:Male about 1.5-2:1  Mean age of onset about early to middle 60s  No ethnic/racial factor mentioned S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 75. Cicatricial pemphigoid  Etiology  Genetics: HLA DQB1*0301  Disease susceptibility marker: Amino acid position 57 and 71-77 of DQB1 protein  Several different target antigens  BP 180 (BPAG2)  BP 230 (BPAG1)  α6β4 integrin  Laminin5  Topical ophthalmologic medications Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 76. Cicatricial pemphigoid S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 77. Cicatricial pemphigoid  Clinical presentation  Conjunctiva:  Affected in 75% of cases  Starts unilaterally, usually bilateral within 2years  Adhesions, ectropion, corneal damage found  Oral mucosa:  Affected in 75% of cases  Vesicles, blisters, erosions, scarring  Desquamative gingivitis commonly occurs  Much less painful than PV. Sterry, et al., Dermatology , 2006.
  • 78. Cicatricial pemphigoid  Clinical presentation  Esophagus and larynx: Strictures  Genitalia:  In women: narrowing of vaginal orifice  In men: adhesions between glans and foreskin  Rectal mucosa  Skin: (25% of cases)  Usually generalized disease similar to BP  Localized form (Brunsting–Perry disease)  Recurrent blisters develop on persistent plaques Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 79. Cicatricial pemphigoid  Clinical presentation Sterry, et al., Dermatology , 2006.
  • 80. Cicatricial pemphigoid S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 81. Cicatricial pemphigoid S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 82. Cicatricial pemphigoid S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 83. Cicatricial pemphigoid  Histopathology  Subepidermal blister  Lymphocyte and histiocyte infiltration  Variable neutrophil and eosinophil infiltration  In elderly, maybe “cell poor”  Older lesion  Fibrobrast proliferation  Lamellar fibrosis S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 84. Cicatricial pemphigoid  Immunopathology  Direct immunofluorescence:  IgG (60%) and C3 (40%) along BMZ in lesional skin  Occasionally IgM and IgA  In normal skin, about 30% IgG  Indirect immunofluorescence:  IgG reactivity can be seen on either side of the split, or in both locations, depending on target antigen  Patient with both IgG and IgA often has worse prognosis Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 85. Cicatricial pemphigoid S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 86. Cicatricial pemphigoid  Immunopathology  Identify target antigens:  BP 180 is most common; Mucosal and skin disease  α3 subunit of laminin 5 (formerly known as epiligrin); Mucosal and skin disease  α6β4-integrin: only ocular disease. Sterry, et al., Dermatology , 2006.
  • 87. Cicatricial pemphigoid  Treatment S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 88. Cicatricial pemphigoid  Treatment S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 89. Dermatitis herpetiformis
  • 90. Dermatitis herpetiformis  Epidemiology  About 10-39/100,000 population/yr in caucasion  Men are affected twice as often women  Disease of young adults  Starts at any age  Age of about30s to 40s are the most common Sterry, et al., Dermatology , 2006.
  • 91. Dermatitis herpetiformis  Etiology  Abnormal immune response to gluten  Most important sensitizing protein is gliadin  AutoAb against tissue transglutaminase also cross- react with the similar epidermal transglutaminase  Strong HLA association  90% of patients: HLA-DQ2 (A1*0501 and B1*02)  Other 10%: HLA-DQ8 (A1*03, B1*03)  Other genetic factors are involved Sterry, et al., Dermatology , 2006.
  • 92. Dermatitis herpetiformis  Clinical presentation  Sites of predilection:  Knees and elbows (Cottini type)  Buttocks and upper trunk  Facial involvement rare.  Hallmark: intensely pruritic or burning tiny vesicles (usually scratched away)  Undisturbed lesions: rim of peripheral vesicles arranged in herpetiform fashion  Larger blister (Less often) Sterry, et al., Dermatology , 2006.
  • 93. Dermatitis herpetiformis  Clinical presentation  Occasional enteropathy  Malabsorption  Voluminous loose stools  Weight loss  Occasional association with other autoimmune diseases:  Diabetes mellitus  Pernicious anemia  Thyroid disease  Vitiligo. Sterry, et al., Dermatology , 2006.
  • 94. Dermatitis herpetiformis  Clinical presentation  Iodine intolerance and flare with iodine exposures  Iodine challenge or iodine patch test are old diagnostic measures.  Spontaneous remissions may occur, but disease often lifelong  Increased risk for MALT B-cell lymphoma Sterry, et al., Dermatology , 2006.
  • 95. Dermatitis herpetiformis  Clinical presentation Sterry, et al., Dermatology , 2006.
  • 96. Dermatitis herpetiformis  Clinical presentation S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 97. Dermatitis herpetiformis  Pattern of distribution S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 98. Dermatitis herpetiformis  Histopathology  Hallmark: Neutrophilic microabscesses in the papillary dermis  Often admixed with eosinophils  Edema leads to subepidermal blister formation Sterry, et al., Dermatology , 2006.
  • 99. Dermatitis herpetiformis  Histopathology S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 100. Dermatitis herpetiformis  Immunopathology and other labs  Direct immunofluorescence:  Granular deposits of IgA in dermal papillae  Sometimes granular-linear along BMZ present in 95% of patients and persist long after therapy is started  Indirect immunofluorescence:  IgA Ab against smooth muscle endomysium present in 80%. Sterry, et al., Dermatology , 2006.
  • 101. Dermatitis herpetiformis  Immunopathology and other labs  ELISA  IgA-Ab against tissue transglutaminase in at least 80%  Antigliadin Ab (less specific)  Jejunal biopsy:  Flattening of villi (85%) with intraepithelial lymphocytes in 100% Sterry, et al., Dermatology , 2006.
  • 102. Dermatitis herpetiformis  Treatment  Mainstay = gluten-free diet  Dapsone: Usually 25–50 mg is sufficiently effective Sterry, et al., Dermatology , 2006.
  • 103. Linear IgA bullous dermatosis
  • 104. Linear IgA bullous dermatosis  Epidemiology  Presenting age about 40s  Uncommon disease  Female: male ratio 2:1. Sterry, et al., Dermatology , 2006.
  • 105. Linear IgA bullous dermatosis  Etiology  Genetic: HLA-B8?, TNF2 allele  AutoAb (mainly IgA1) against:  Lamina lucida  Type VII collagen in lamina densa  Several drugs  Vancomycin (most common)  Penicillin  Sulfamethoxazole/trimethoprim  Atorvastatin Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 106. Linear IgA bullous dermatosis  Clinical presentation  May be identical to dermatitis herpetiformis (eg. severe pruritus) but without gastrointestinal involvement  Can be resemble BP or even cicatricial pemphigoid with ocular involvement  Up to 70% have mucosal involvement  Papulovesicles, bullae, and/or urticarial plaques predominantly on central or flexural sites Sterry, et al., Dermatology , 2006. DL Longo, et al., Harrison’s Principle of Internal Medicine, 18th edition , 2012.
  • 107. Linear IgA bullous dermatosis S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 108. Linear IgA bullous dermatosis  Histopathology S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 109. Linear IgA bullous dermatosis  Immunopathology  Direct immunofluorescence:  IgA-Ab at dermal-epidermal basement membrane zone  Additional tests:  Eye examination  Jejunal biopsy (to exclude celiac disease) Sterry, et al., Dermatology , 2006.
  • 110. Linear IgA bullous dermatosis  Direct immunofluorescence S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 111. Linear IgA bullous dermatosis  Treatment  Corticosteroids: Best for lamina lucida type  Dapsone: Helpful for lamina densa type  Gluten-free diet? Mostly can not help Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 112. Epidermolysis bullosa acquisita
  • 113. Epidermolysis bullosa acquisita  Epidemiology  Uncommon disorder  Seen in adults in 4th–5th decades  No gender, geographic, ethnic predisposition Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 114. Epidermolysis bullosa acquisita  Etiology  Exact mechanism is unknown  AutoAb (IgG) directed against type VII collagen (a component of the lamina densa)  HLA DR2 might play some role Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 115. Epidermolysis bullosa acquisita  Clinical presentation  Acral mechanobullous form  Fragile skin and blisters on backs of hands healing with milia and scarring  Nail dystrophy  Foot involvement is clue to EBA  Inflammatory form  Similar to BP with stable blisters  Less often resembles cicatricial pemphigoid or dermatitis herpetiformis  Heals with scarring  About 50% of patients have mucosal involvement. Sterry, et al., Dermatology , 2006.
  • 116. Epidermolysis bullosa acquisita  Clinical presentation  Associated diseases:  Inflammatory bowel disease  Lupus erythematosus  Rheumatoid arthritis Sterry, et al., Dermatology , 2006.
  • 117. Epidermolysis bullosa acquisita S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 118. Epidermolysis bullosa acquisita S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 119. Epidermolysis bullosa acquisita  Histopathology  Subepidermal blisters  Clean separation between epidermis and dermis  Variable cellular infiltration  Degree of infalmmatory cell infiltration reflects degree of clinical inflammation S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 120. Epidermolysis bullosa acquisita  Immunopathology  Direct immunofluorescence:  Deposition of IgG (rarely IgA) in BMZ.  Indirect immunofluorescence:  IgG with ability to bind complement found in 50%.  IgG binds to base of blister  ELISA  Antibodies against type VII collagen. Sterry, et al., Dermatology , 2006.
  • 121. Epidermolysis bullosa acquisita  Direct immunofluorescense S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 122. Epidermolysis bullosa acquisita S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 123. Epidermolysis bullosa acquisita S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 124. Paraneoplastic pemphigus
  • 125. Paraneoplastic pemphigus  Epidemiology  Rare but real incidence is unknown  A report found just 12 from 100,000 NHL patient  Suspected of misdiagnosed as erythema multiforme, TENS, SJS and drug rash S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 126. Paraneoplastic pemphigus  Etiology  Most often associated with NHL, leukemia (CLL), Castleman tumor, or thymoma  Not associated with SCC or adenocarcinoma  Anti-Dsg Ab: pathogenetically most important  Presumably cross-reactions between tumor Ag and desmosomal Ag (eg. plakins, desmogleins, and bullous pemphigoid Ag) Additional from PV/PF  HMI also plays a role but not CMI Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 127. Paraneoplastic pemphigus  Tumor associated with paraneoplasic pemphigus S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 128. Paraneoplastic pemphigus  Clinical presentation  The most constant feature is severe, persistent painful stomatitis extending from the lips into the pharynx, larynx, and esophagus  Conjunctival involvement may lead to blindness  Cutaneous changes are polymorphic, ranging from erythematous macules to lichenoid papules to blisters and erosions Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 129. Paraneoplastic pemphigus S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 130. Paraneoplastic pemphigus  Histopathology: Variable  Acantholysis  Lichenoid  Interface change  Non-specific change of inflammation and ulceration Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 131. Paraneoplastic pemphigus S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 132. Paraneoplastic pemphigus  Immunopathology  If indirect immunofluorescence is positive on rat bladder epithelium (Ab also binds to columnar and transitional epithelium), this strongly suggests paraneoplastic pemphigus  The combination of IgG antibodies against plakins and desmogleins confirms the diagnosis  Also granular/linear complement deposition along epidermal basement membrane zone Sterry, et al., Dermatology , 2006. S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 133. Paraneoplastic pemphigus S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 134. Paraneoplastic pemphigus  Management S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 135. Paraneoplastic pemphigus  Treatment  Treating the underlying tumor comes first  The prognosis correlates with the response  There is no consensus on what immunosuppressive regimen to employ, especially in patients required chemotherapy  Recent reports of good success with anti-CD20 antibodies (rituximab) Sterry, et al., Dermatology , 2006.
  • 136. Paraneoplastic pemphigus S Wolff, et al., Fitzpatric’s Dermatology in General Medicine, 7th edition, 2008.
  • 137. Thank you krub

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