CADR, TEN, SJS, vasculitis Flashcards
What are CADR
Unpredictable or idiosyncratic drug eruptions:
-Abnormal immunologic response
-Genetic differences in susceptibility: metabolic or enzymatic deficiencies
What are the mechanisms for CADR
- Classic hypersensitivity reactions (I, II, III, IV)
- Other mechanisms: EM, TEN, superficial suppurative necrolytic dermatitis
Pathogenesis of EM
lymphocyte-mediated apoptosis (direct cytotoxicity)
Keratinocytes: expression of ICAM-I, MHC II, CD1a, CD44 (attraction of lymphocytes, antigen presentation),
b) epidermal and dermal infiltration by T cells CD8 > CD4 (keratinocyte apoptosis),
c) increased numbers of epidermal LC and dermal dendritic cells
What causes of EM have been found
- Infections: D (Pseudomonas otitis; Staphylococcal dermatitis, anal furunculosis; Pneumocystis pneumonia; canine distemper virus, CPV-2, canine herpesvirus); C (herpesvirus); H (herpesvirus); PCR for herpesvirus was negative in 15 D with classic and 14 digs with hyperkeratotic (“old dog”) EM
- Drugs (D: 19-59% of the cases; ; antibiotics, griseofulvin (D, C), itraconazole (D), chlorpyrifos (D), D-limonene (D), ivermectin (D, H), levamizole (D), pyrantel (C), DEC (D), benzoic acid (PO), gold (D, C), otic drops (D, C), T4 (D), propiothiuracil (C), NSAIDs (humans), phenobarbital (D), zonisamide (D), anti-epileptics (humans), progesterone (humans),vaccine
- Food: D (beef, soy);
- Neoplasia: D, C (thymoma), H (lymphoma)
- Connective tissue diseases: humans (rare): LE, Behcet’s disease, IBD
- Topical: H
- Idiopathic: D (23%) especially in “old dogs”; H
Typical target lesions
round, well-defined borders, <3 cm in diameter,
3 zones: central (erythema or purpura or bulla → crust, ulcer), intermediate (lighter erythema and oedema-induration), outer (erythema)
Typical flat target lesion
lacks oedema-induration in the intermediate zone
Atypical raised target lesions
poorly defined, 2 zones of erythema with one of these zones being oedematous and raised
Atypical flat target lesions
poorly defined, 2 zones of erythema ± bulla but no oedematous and raised zone
TH of EM
- Of the cause: e.g. withdrawal of suspected drugs, hypoallergenic diet
- Symptomatic, supportive:
- Immunosuppressive: in idiopathic or persistent cases
a) Glucocorticoids
b) Azathioprine (D, C, humans); mycophenolate mofetil (humans)
c) CsA
d) PTX (D, C)
e) Immunoglobulin IV (C, humans)
f) Dapsone (humans)
Pathogenesis of SJS/TEN
a) mainly Fas-FasL mediated apoptosis: due to TNF-a, INF-γ and soluble FasL produced by KCs, macrophages > DCs, T cells; presentation of the drug through MHC of APCs to T cells; genetic predisposition);
b) direct lymphocyte-mediated cytotoxicity (like EM) by may not be the major mechanism (although a role for soluble FasL has been proposed)-instead granulysin released from cytotoxic T cells and NK cells results in confluent apoptotic cell death of KCs-both apoptosis and lymphocyte satelitosis have been conformed in canine TEN
CAuses of TEN/SJS
- Drugs
- Vaccines
- Food: beef and/or soy (D)
- Infections: e.g. staphylococcal endocarditis (D), Pseudomonas otitis (D), anal sacculitis (D), Mycoplasma bovis,
- Neoplasia: thymoma (C)
- Liver disease
- cannabidiol- containg hemp oil
Clinical signs of SJS/TEN
Systemic (always) fever, anorexia, depression, haemorrhagic diarrhoea
Vesicles, bullae, necrosis, ulcers, epidermal collarets: pain, pseudo-Nickolsky + (positive in the erythematous skin but not in the non-lesional skin)
Skin, footpads, mucocutaneous junctions, oral, corneal ulceration
Ulcerative otitis, nail loss
Th for SJS/TEN
Of the cause: e.g. withdrawal of all suspected drugs
Symptomatic, supportive: analgesia (e.g. morphine + lidocaine + ketamine CRI), ulcer management, fluid-electrolytes, antibiotics
Immunosuppressive: no specific therapy has achieved the standards of EBM
a) Glucocorticoids: controversial, perhaps in drug-induced;
b) Azathioprine (D, C, humans)
c) CsA: has been used as the initial treatment (D, C); may reduce death rate;
d) Inhibitors of TNF-a: PTX (D, C, humans); anti-TNF-a antibodies (humans)
e) Immunoglobulin IV (D, C, humans): blockade of Fas; questionable;
f) Plasmapheresis (humans), N-acetyl-cystein (humans)
Causes of vasulitis
- Non-immune mechanisms (rare)
- Immune-mediated: type III, type I, type II, cell-mediated
- Endothelial cells: increased expression of E-selectin and ICAM-1.
- Neutrophils: endothelium damage → expression of non-self-antigens
- Dendritic cells and T cells: lymphocytic infiltrate
- Auto-antibodies against:
a) endothelial cells,
b) neutrophils
Pathomechanims of vasulitis in non-immunologic
direct damage from:
a) toxins,
b) hemodynamic factors (turbulence, thrombosis),
c) deposition of Ig (cryoglobulinemia),
d) invasion of neoplastic cells,
e) heat (2nd degree thermal burn);
f) trauma
Pathomechanims of vasulitis in immune mediated infections
organisms in the vessel wall of perivascular tissue:
a) bacteria (localized, septicaemia),
b) virus (FIV),
c) protozoa (RMSP, Babesia, Leishmania)
Pathomechanims of vasulitis in immune mediated infections, type III
immune-complexes → complement → neutrophils + basophils → vascular wall necrosis due to
a) drug eruptions, vaccines, ASIT,
b) neoplasia,
c) distant infection,
d) SLE
Pathomechanims of vasulitis in immune mediated infections, type I
mast cells → IL-5 → eosinophils due to a) insect-arachnids, b) mast cell tumours
Pathomechanims of vasulitis- immune -mediated, anti-neutrophil cytoplasmic antibodies (ANCA
anti-neutrophilic Ab on endothelium → direct binding to neutrophil granules → release of toxic mediators
Classification depending on the size of the vessel
- Arteritis
- Phlebitis, thrombophlebitis
- Capillaries, post-capillary venules: the most common
Classification of vasulitis depending on the infiltrate
1.Neutrophilic
2.Eosinophilic
3.Lymphocytic: CD8+ cells
4. Granulomatous
5. Mixed
6. Cell-poor
Neutrophilic vasulitis
type III hypersensitivity
a) non-leukocytoclastic (more common),
b) leukocytoclastic.
Additional findings: i) neutrophilic spongiosis, intraepidermal pustules, folliculitis (bacterial skin infection, drugs), ii) thrombosis (Gram- sepsis, endothelial infections)
Eosinophilic vasulitis
type I hypersensitivity:
a) arthropod reactions,
b) food allergy,
c) eosinophilic granuloma, eosinophilic dermatitis (D);
d) mast cell tumours
Granulomatous vasulitis
secondary (subacute to chronic) + neutrophilic leukocytoclastic:
a) septal panniculitis;
b) Wegener granulomatosis (D);
c) drugs-CsA (D)
