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Pemphigus - intra epidermal blistering disorders

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Pemphigus - intra epidermal blistering disorders

  1. 1. Intra-Epidermal blistering disorders Dr.Preethi chekuri MD Dermatology India
  2. 2. Types :  Pemphigus vulgaris  Pemphigus foliaceus  Paraneoplastic pemphigus
  3. 3. Intoduction  Term ‘pemphigus’ refers to a group of autoimmune blistering disorders of skin and mucous membrane that are characterised histologically by intraepidermal blisters due to acantholysis and immunopathologically by in vivo bound and circulating immunoglobulins directed against the cell surface of keratinocyte
  4. 4. Pemphigus vulgaris
  5. 5. Introduction  Supra basal acantholysis  The patients PV may present with more localised disease, one form of which is called pemphigus vegetans of hallopeau and a slightly more extensive form called called pemphigus vegetans of neumann
  6. 6. Epidemiology  Depends on the geographic location as well as the ethnic population in that area  PV is more common in jews and also in people from mediterranean and middle east decent  Ratio of PV:PF ~ Iran – 12 :1 Finland – 0.5 :1  male : female ~ 1 : 1.33 or 2.25  Mean age of onset being 40 yrs
  7. 7. Etiopathogenesis  Pemphigus antigens are desmogleins, transmembrane glycoproteins of desmosomes  Desmogleins are part of the cadherin superfamily of calcium- dependent cell adhesion molecules.  The PF antigen (as well as the fogo selvagem antigen) is desmoglein 1, a 160-kDa protein. The PV antigen is desmoglein 3, a 130-kDa protein  All patients with PV have antidesmoglein 3 antibodies, and some of these patients also have antidesmoglein 1 antibodies  PF patients typically have antibodies against only desmoglein 1
  8. 8. Clinical findings  Cutaneous lesions  Vegetating lesions  Mucous membrane lesions
  9. 9. Cutaneous lesions  Primary lesion – flaccid blister  Blisters are fragile resulting in erosions  May occur anywhere on the skin surface  NIKOLSKY SIGN – erosions can be extended into visibly normal skin by pulling the remnant of the blister wall or rubbing at the periphery of active lesions and erosions can be induced in normal- appearing skin distant from active lesions by pressure or mechanical shear force
  10. 10. Vegetating lesions  In certain patients, erosions have a tendency to develop excessive granulation tissue and crusting, referred to as vegetating lesions  Intertriginous areas, scalp and face
  11. 11. Mucous membrane lesions  Oropharynx  Gastro – intestinal tract ~ oesophagus, stomach, duodenum and anus  Vulvovaginal ,nasal, laryngeal and conjunctival mucosa can also get involved  Rare case reports of corneal erosions are also present
  12. 12.  Oral erosions are painful and makes the patient unable to eat or drink  Painful mucous membrane lesions may be the presenting sign for 32% of the cases  These patients progress to a more generalised from in 5 months to 1 year period  Skin involvement without mucous membrane lesions is less common
  13. 13. Laboratory tests  Skin biopsy  Immunofluorescence – direct indirect  ELISA
  14. 14. Histology  The characteristic histopathologic finding in PV is a suprabasal blister with acantholysis  The basal cells stay attached to the basement membrane, but may lose the contact with their neighbors; as a result, they may appear to be a “row of tombstones”  Usually, the upper epidermis remains intact
  15. 15.  Pemphigus vegetans shows not only suprabasilar acantholysis, but also papillomatosis of the dermal papillae and downward growth of epidermal stands into the dermis, with hyperkeratosis and scale- crust formation  In addition, pemphigus vegetans lesions may show intraepidermal abscesses composed of eosinophils or neutrophils.  Early PV lesions may show eosinophilic spongiosis
  16. 16. Direct immunofluorescence  IgG auto-antibodies against the cell surface of keratinocytes in perilesional skin  It is important that the biopsy for DIF be performed on normal-appearing perilesional skin, as the immune reactants can be difficult to detect in blistered inflamed epidermis (leading to a false negative result)  This is a nonquantitative test (either negative or positive)
  17. 17. Indirect immunoflourescence  Performed by incubating serial dilutions of patients sera with epithelial substrates.  It is reported as a semiquantitative titer (indicating the last dilution at which the serum demonstrates a positive cell surface staining pattern)  Pemphigus patients have circulating antiepithelial cell surface IgG
  18. 18. ELISA  more sensitive and specific than immunofluorescence  ELISAs are easier to perform and less subjective  Use desmogleins 1,3 bound to plates, which are then incubated with patient sera and developed with antihuman IgG reagents  help differentiate between PV and PF due to the different autoantigen profiles
  19. 19. Pemphigus foliaceus
  20. 20. Introduction  Subcorneal acantholysis  Patients with PF may present with a more localised disease called PEMPHIGUS ERYTHEMATOSUS
  21. 21. Epidemiology  Dependent on location  Endemic foci – brazil, colombia and tunisia  FOLO SELVAGEM (wild fire)  Fogo selvagem occurs often in children and young adults, unlike sporadic PF, which is a disease of mostly middle-aged and older patients
  22. 22. Clinical findings  The characteristic clinical lesions of PF are scaly, crusted erosions, often on an erythematous base  In more localized and early disease, these lesions are usually well demarcated and scattered in a seborrheic distribution, including the face, scalp, and upper trunk  In contrast to patients with PV, those with PF very rarely, if ever, have mucous membrane involvement, even with widespread disease.
  23. 23. Histology  Acantholysis just below the stratum corneum and in the granular layer  The epidermis, below the granular layer, remains intact.  Another frequent finding is subcorneal pustules, with neutrophils and acantholytic epidermal cells in the blister cavity
  24. 24. Drug induced pemphigus  Association with penicillamine and captopril is the most significant  PF is more common than PV  Both penicillamine and captopril contain sulfhydryl groups that are postulated to interact with the sulfhydryl groups in desmoglein 1, 3
  25. 25. Treatment  Corticosteroids  Immunosuppressive agents - azathioprine mycophenolate mofetil cyclophosphamide dapsone  Additional therapies - rituximab, plasmapheresis, intravenous immunoglobulin
  26. 26. Corticosteroids  1 to 1.5 mg/kg/ day of prednisolone equivalent used singly or in combination with adjuvant immunosuppressive therapy  Some recommend controlling initial phase with high doses ( upto 240mg/day)  Topical - used to help heal new lesions - mucosal disease benefitted from swish and spit method
  27. 27. DCP pulse therapy  Day 1 : Iv administration of 100mg dexamethasone with 500mg cyclophosphamide in 500ml of 5% dextrose over 1-2 hrs  Day 2 and day 3 : 100mg dexamethasone Pulses repeated every 4 weeks On remaining days, 50 mg of cyclophosphamide given orally 4 phases
  28. 28. Immunosuppressive agents  Azathioprine - 2.5mg/kg/day Due to its toxicity it is reasonable to start with 50- 100mg daily  Mycophenolate mofetil - 30-40 mg/kg/day twice daily  Cyclophosphamide - 1- 2.5mg/kg/day or daily oral therapy of 50 mg
  29. 29. Additional therapy  Rituximab - monoclonal anti CD20 antibody, targets B cells, the precursors of antibody producing cells IV dose of 375mg/m2 once every 4 weeks  Intravenous immunoglobulins - gamma globulin in high doses is given
  30. 30. Paraneoplastic pemphigus
  31. 31. Introduction  It is an autoimmune mucocutaneous blistering disorder characterized by an associated neoplasm and the presence of unique antibodies directed at desmosomal plakins  HLA-DRB1*03
  32. 32. Etiopathogenesis 3 mechanisms postulates :  Molecular mimicry - an immune response against tumor antigens cross reacts with normal epithelium  Tumor may cause cytokine dysregulation leading to synthesis of antibodies to pemphigus autoantigen Dsg 3, with a subsequent secondary autoimmune reaction to intercellular proteins of plakins  Epitope spreading - tumor induces a cell mediated lichenoid interface dermatitis that uncovers previously hidden antigens
  33. 33. Clinical features  Age - 45 to 70 yrs  Recalcitrant stomatitis - painful erosions of oropharynx and vermilion border of lips  Polymorphous and pruritic  Mucocutaneous lesions  Palmoplantar target lesions  Bronchiolitis obliterans  malignancies
  34. 34. Malignancies associated are :  Non - hodgskin lymphoma  Chronic lymphocytic leukemia  Castleman disease  Retro peritoneal sarcoma  thymoma  Waldenstom’s macroglobulinemia
  35. 35. Histology  Supra basal acantholysis, individual cell necrosis, vacuolar interface dermatitis, lichenoid inflammation and lymphocytic exocytosis  The spectrum of changes can include: (1) individual keratinocyte necrosis with lymphocytic infiltration into the epidermis, reminiscent of that seen in EMF or GVHD (2) vacuolar interface change with sparse lymphocytic infiltrate of the basilar epithelium, resembling LE and DM (3) a thick lichenoid band along the DEJ
  36. 36. DIF  the most characteristic changes are those of deposition of IgG and complement components (C3) on both the surface of basilar and suprabasilar keratinocytes and along the epidermal basement membrane zone
  37. 37. IIF and ELISA  Identical to pemphigus vulgaris with staining of the epidermal cell surface  Demonstration of characteristic combination of anti plakin and anti desmoglein auto antibodies by ELISA
  38. 38. Special tests  CT  MRI  Positron emission tomography/ computer tomog- raphy (PET/CT) using fluorodeoxyglucose (FDG) as a biologically active molecule can be more specific
  39. 39. Diagnosis (Anhalt et al criteria) 1.Painful stomatitis and a polymorphous cutaneous eruption with lesions that may be blistering, lichenoid, or resemble EMF . 2.Histologic findings that reflect the variability of the cutaneous lesions, showing acantholysis, lichenoid, or interface change. 3.DIF findings of IgG and C3 deposition in the epidermal intercellular spaces and granular/linear C3 deposition along the epidermal BMZ 4.Serum autoantibodies that bind to the cell surface of skin and mucosae in a pattern typical of pemphigus, but in addition, bind to simple, columnar, and transitional epithelia. 5.The serum autoantibodies identify Dsg 1 and 3 in addition to members of the plakin family of epithelial proteins, such as desmoplakins, envoplakin, and periplakin
  40. 40. Differential diagnosis
  41. 41. Treatment
  42. 42. Thank you

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