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)
Special forms of vasculitis
1) Proliferative thrombovascular necrosis of the pinnae
2) Proliferative arteritis of nasal philtrum (D)
3) Solar vasculopathy
4) Focal cutaneous vasculitis and alopecia at the site of R vaccination (D): 2-6 months after SC administration
5) Cutaneous and renal glomerular vasculopathy (of Greyhounds)
6) Familial cutaneous vasculopathy of GSD
7) Familial cutaneous vasculopathy of Jack Russell terrier
8) Hereditary pyogranuloma and vasculitis of Scottish terrier
9) Ischemic dermatopathy
10. Pastern dermatitis
11) Puprura haemorrhagica
12) Photoactivated vasculopathy
13) Nodular eosinophilic vasculitis and arteritis
14) Neonatal vasculitis:
Causes of purpura hemorrhagica (edema and petechial haemorrhages)
1) infections (bacterial, viral),
2) vaccines (strangles, influenza),
3) antitoxin (tetanus)
TH for ischemic dermatoptahy
a) PTX + vitamin E,
b) glucocorticoids;
c) oclacitinib
Proliferative thrombovascular necrosis of the pinnae (D)
Possible causes
1) food allergy;
2) vaccines (pinnal apex may also show lesions in vaccine-associated vasculitis in addition to the lesions at the injection site);
3) drugs (fenbendazole)
Clotting factors in vasulitis
- D-dimers: positive if vascular thrombosis (sensitivity 100%, specificity: 64%)
- Fibrinogen: increased irrespectively of thrombosis (sensitivity: 100%)
- FDPs: may be increased
Classification of vasulitis depending on the cause:
- Infectious
- Non-infectious:
a) exogenous antigen;
b) endogenous antigen;
c) unknown antigen
Causes of vasulitis
1.Genetics:
2. Bacterial infections
3. Rickettsial infections: RMSF, Rickettsia conorii
4. Mycobacterial infections: tuberculosis, leprosy
5. Fungal infections
6.Parasitic infection
7.Viral infections
8.Protozoal infections
9.Food hypersensitivity
10. Food poisoning: verotoxin (shiga-like toxin) of E. coli in raw beef implicated in cutaneous and renal glomerular vasculopathy of Greyhounds
11. Drugs
12.Vaccines-biologicals:
13.Neoplasia:
14.Connective tissue diseases: SLE (D, H), DLE, cryoglobulinemia, rheumatoid arthritis (D)
15.Solar-induced vasculitis/vasculopathy (D, H), contactants-photoaggravated (H)
16.Other skin/systemic diseases
17. Idiopathic
Name genetic causes of vasulitis
a) hereditary nasal pyogranuloma and vasculitis of Scottish terrier,
b) cutaneous and renal glomerular vasculopathy of Greyhounds,
c) familial cutaneous vasculopathy of GSD and Jack Russell terrier,
d) dermatomyositis
Bacterial infections associated with vasulitis
deep bacterial pyoderma, staphylococcal hypersensitivity, streptococcal fasciitis, Streptococcus zooepidemicus (H); Corynebacterim (H), Rhodococcus equi (H), pastern dermatophilosis (H), glanders (H), erysipelas ;
b) systemic infections: septicemia (Gram- sepsis), Bartonella spp. (bacillary angiomatosis, ear tip vasculitis); Lyme; Anaplasma phagocytophilum; bacterial endocarditis, omphalitis (H), bronchopneumonia (H), salmonellosis (H), IV catheter thromboembolism, ehrlichiosis (D, H), purpura haemorrhagica-Streptococcus equi (H
FUngal infections associated with vasulitis
disseminated aspergillosis; disseminated histoplasmosis
Viral infections associated with vasulitis
parvovirus (D), herpes virus (D), coronavirus (D)-FIP (C; phlebitis), FeLV, FIV, virulent systemic calicivirus (C), equine herpesvirus-1 (H), viral arteritis (H), influenza (H), infectious anaemia (H); foot and mouth disease disease (B)
Parasitic infections associated with vasulitis
dirofilariosis, harbonemiasis (H), insect/arthropod reactions (D, C, H), Culicoides hypersensitivity (H), severe scabies (D), flea bite hypersensitivity (D)
Protozoal infections associated with vasulitis
toxoplasmosis (C),
sarcocystosis (D),
babesiosis (D),
CanL,
trypanosomiasis,
encephalitozoonosis (D
Drugs associated with vasulitis
antibiotics (D, C, H), itraconazole (D, C), ivermectin (D), fenbedazole (D, C), phenobarbital (D, C), loperamide (D), metoclopramide (D), cimetidine (C), furosemide (D), enalapril (D), hydralazine (D), meloxicam (D), prednisone, dexamethasone (D), phenylbutazone (D, H), propiothiuracil (C), carbimazole (C), ACP (D, H), vincristine (D, C)
Vaccines associated with vasulitis
rabies (D, C),
CRP (C),
ischemic dermatopathy;
strangles-influenza (H),
foot and mouth vaccines (B);
tetanus antitoxin
neoplasia associated with vasulitis
mast cell tumours (D, C, H),
paraneoplastic alopecia (C),
lymphomatoid granulomatosis (L);
lymphoma (H)
NAme connective tissue diseases associated with vasulitis
SLE (D, H), DLE, cryoglobulinemia, rheumatoid arthritis (D)
What is purpura hemorrhagica
- syndrome in horses that manifest with acute neutrophilic vasulitis
-usually 2-4 weeks after upper respiratory infection or 1-2 weeks after vaccination of Streptoccocus equi
-circulating IgA> IgM against M protein deposited on vascular wall
-other causes: C. pseudotuberculosis, Rhodococcus equi, Streptococcus zooepidemicus, herpes, influena, arterivirus
+ in H- we have to give GCs-to avoid side effects of vasulitis!!
Immune complexes most commonly deposit on wich vessesl
post capilary venules
MOA of sulfasalizin
-decreases integrin expression so we have reduced adhesion of neutrophils
-decrease production of myeloperoxidase
What are causes of skin lesions in vasulitis
What are the distribution of skin lesions in vasulitis
How can we make a dg of vasulitis
What is the pathogenesis of vasulitis
What are non-immune mediated causes of vasulitis
What are immune mediated causes of vasulitis
What are the mani causes of vasulitis
What are the infectious patomechanisms of vasulitis
Wich are most common infcetions in dogs that cause vasulitis
Which are mots common infections in cats that cause vasulitis
Which are most common infections in horses that cause vasulitis
What are the most common infections in cows that cause vasulitis
What are the most common infections in pigs that cause vasulitis
What are the main clinical signs with vasulitis
DDX of vasulitis
How can we make a dg of vasulitis
What are the sizes/locations of vessels that can be targeted in vasulitis
What are types of inflammatory cells that can cause vaculitis
FIP- granulomatous vasulitis
-CAFR- eosinophilic
-granulomatous is a sequela to neutrophilic vasulitis (after 24-48h)
Recommened treatment of vasulitis
What are the histo changes with vasculitis
