Cytotoxic and Misc Immune-mediated Diseases Flashcards
1
Q
How often do autoantibodies spontaneously arise?
A
Frequently
Up to ~50% of new T and B cells may bind self-antigens
Usually these are vigorously suppressed
Low-titer, low-affinity IgG or IgM antibodies are important for homeostasis
2
Q
What are the two major categories of autoimmune diseases?
A
1) normal response to an unusual antigen
2) abnormal immune response to a usual antigen
* latter is more common
3
Q
What are the primary ways that abnormal, autoimmune responses are thought to occur?
A
Failure of regulatory control
- ex. defects in CD95 or CD95L on T cells or lymphoid tumors
Infection induced (especially viruses)
- molecular mimicry (same epitopes in infection and autoantigen)
- epitope spreading (reaction to other epitopes on same protein)
- bystander activation (previously hidden tissue antigens exposed)
Microchimerism (ex. maternal cells in boys with dermatomyositis)
4
Q
How does genetic disposition usually associated with autoimmune diseases?
A
- mutations most commonly associated with MHC
–> usually role of genes is complex - dog underwent bottleneck with domestication (~20,000 yr ago) and again when dog breeds were created (~200 yr ago) = loss of MHC polymorphism
5
Q
Which TLR is associated with the development of systemic lupus in humans?
A
TLR7
6
Q
How can the intestinal microbiota contribute to autoimmunity/immune-mediated disease?
A
since the GI microbiota is associated with immunological tolerance, dysbiosis can affect the development of autoimmune disease
7
Q
How can gonadectomy contribute to autoimmunity/immune-mediated disease?
A
Alteration in sex hormones that affect immune function
2016 study found neuter F/M dogs has higher risk for:
- atopic dermatitis
- hypoadrenocorticism
- hypothyroidism
Neuter females were at higher risk for lupus erythematosus than intact
8
Q
What does “lichenoid” mean?
A
dense band of mononuclear cells in the superficial dermis, whether or not there is evidence of epidermal cell death
tends to be lymphocytic but can be lymphoplasmacytic (esp around mucous membranes) or lymphohistiocytic
9
Q
What does “interface” mean?
A
a cytotoxic reaction pattern where keratinocyte cell death is largely restricted to the basal levels of the epidermis (occasional extension into the lower stratum spinosum)
* Lymphocyte exocytosis into the epidermis blurring BMZ
* Apoptosis
* Pigmentary incontinence
* Pronounced vacuolation
* Vesicles (genuine vs. “usable artifact”)
10
Q
What is “panepidermal” cytotoxic dermatitis?
A
a cytotoxic reaction pattern where keratinocyte death occurs throughout epidermal layers
11
Q
Which diseases have a cytotoxic interface dermatitis pattern?
A
- Chronic lupus erythematosus (discoid lupus erythematosus)
- Pemphigus erythematosus
- Epitheliotropic T-cell lymphoma
- Fixed drug reaction
- Mucocutaneous lupus erythematosus
- Ischemic dermatopathy/dermatomyositis
- Exfoliative cutaneous lupus erythematosus
- Vesicular cutaneous lupus erythematosus
- Thymoma-associated exfoliative dermatitis
- Intraepidermal viral diseases
- Lupoid onychitis
- Erythema ab igne
- Uveodermatologic syndrome (as a minor pattern)
12
Q
Which diseases have a panepidermal cytotoxic dermatitis pattern?
A
- Staphylococcal toxic shock syndrome
- Proliferative necrotizing otitis externa of kittens
- Epitheliotropic T-cell lymphoma
- Erythema multiforme
- Stephen-Johnson syndrome
- Toxic epidermal necrolysis
- Thymoma-associated exfoliative dermatitis
- Graft versus host disease
- Intraepidermal viral diseases
- Superficial necrolytic dermatitis (as a minor pattern)
- Vitamin A responsive seborrheic dermatitis (as a minor pattern)
13
Q
Which diseases have a follicular cytotoxic dermatitis?
A
- Chronic lupus erythematosus
- Staphylococcal toxic shock syndrome
- PLIMFD with apoptosis and parakeratosis in dogs
- Epitheliotropic T-cell lymphoma
- Exfoliative cutaneous lupus erythematosus
- Erythema multiforme
- Stephen-Johnson syndrome
- Toxic epidermal necrolysis
- Intraepidermal viral diseases
- Graft versus host disease
14
Q
What is responsible for confluent epidermal lesions of SJS/TEN in people?
A
necroptosis, an RIPK3-dependent and sometimes RIPK1-dependent regulated cell death pathway that typically exhibits a necrotic morphotype and NETosis
15
Q
What is hydropic degeneration/vacuolar change?
A
prominent swollen keratinocytes with pale-staining cytoplasm and vacuoles
16
Q
What are the triggering mechanisms initiating hydropic degeneration?
A
may differ in cell-rich and cell-poor forms of cytotoxic dermatitis
- not fully known in cell-rich but cytotoxic T cells (CTLs) and natural killer cells (NK cells) are present at the dermo-epidermal junction where they mediate apoptotic cell death
- in cell-poor cytotoxic dermatitis hypoxia due to chronic vascular damage likely contributes to the loss of basal keratinocyte viability by inducing endoplasmic reticulum stress and autophagy-associated cell death
17
Q
What are the triggering mechanisms for vacuolar change along the dermo-epidermal junction?
A
disruptions to the basement membrane by edema or deposition of immune complexes trigger apoptosis of basal keratinocytes because b1-integrin sites become vacant (normally protect the keratinocytes)
18
Q
What is “satellitosis”?
A
close approximation of small lymphocytes to apoptotic keratinocytes in the epidermis and/or follicular epithelia
is a morphological representation of CTL-mediated cytotoxicity
19
Q
What are “sunburn” cells?
A
feature of human and animal photodermatoses
isolated apoptotic keratinocytes, typically occurring in the stratum spinosum, unassociated with lymphocytes
20
Q
What is the lymphocyte population usually associated with cytotoxic dermatitis?
A
Th1 immunity comprising INF-y producing CD4+ T cells, CD8+ CTL, and type 1 innate lymphoid cells, including NK and NK-T cells
+/- Th17 cells
21
Q
What lymphocyte population predominates in canine EM?
A
CD8+ T cells
some CD21+ B cells were observed in the superficial dermis
22
Q
What lymphocyte population predominates in graft versus host disease?
A
CD8+ T cells
23
Q
Which cytokine is upregulated in dogs with CLE?
A
CXCL10 (IP-10)
main source with systemic signs: lymphocytes
main source for dogs without systemic signs: keratinocytes
24
Q
When are numerous neutrophils clustering around apoptotic keratinocytes resembling lymphocytic satellitosis typically seen?
A
exotoxin-mediated staphylococcal toxic shock syndrome
- result of rigorous interleukin (IL)-17A production
25
Which cytotoxic dermatitis disease in humans frequently has a large number of eosinophils?
drug-induced EM
* rare in animals
26
What causes pigmentary incontinence?
Keratinocyte death leads to failure of melanin transfer and depigmentation
- free melanin granules are phagocytosed by dermal macrophages
May also result from hyperpigmentation
27
What is squamatization?
change in orientation of the normally cuboidal and vertically orientated basal epidermal cell layer to a flattened and horizontally oriented layer
28
Why does thickening of the basement membrane zone occur in cytotoxic dermatoses?
reflects deposition of immunoglobulins and immune complexes
29
Which cytotoxic dermatoses have thickening of the basement membrane zone as a prominent lesion?
canine DLE
mucocutaneous lupus erythematosus
canine hyperkeratotic EM
30
In which cytotoxic diseases is parakeratotic hyperkeratosis commonly seen?
idiopathic scaling panepidermal cytotoxic diseases
ex. proliferative and necrotizing otitis externa in cats and hyperkeratotic EM in dogs
- marked follicular targeting with infundibular parakeratosis and cytotoxicity often more severe than in the interfollicular epidermis
31
What is dermal fibrosis?
separating band of fibrosis between the dermo-epidermal junction and lichenoid inflammation
32
What are some environmental factors that contribute to abnormal immune responses?
ultraviolet radiation (UVB)
infections
drugs
33
Which virus in dogs can present with primary lesions of cytotoxic dermatitis?
rare manifestation of canine parvovirus infection with lesions affecting skin and mucous membranes
- originally reported as canine parvovirus–associated “EM”
- represents an active viral infection
34
Is human herpesvirus-associated EM associated with an active or prior viral infection?
not the result of an active viral infection
occur after the initial infection and at distant sites from the primary viral-induced lesion
responses against keratinocytes whose antigenicity is altered following the transport of viral components (typically gene fragments) by progenitor dendritic cells to sites distant from the initiating infection
35
In which species has virus-associated “EM” been described?
humans, horses, cats, and pigs
36
How are environmental factors thought to induce lesions of chronic cytotoxic interface dermatitis (lupus erythematosus) in humans?
inducing a skewed type I interferon response in genetically predisposed individuals
drive innate and adaptive autoreactive immune reactions through a variety of mechanisms including induction of chemokines like CXCL10
37
How does CXCL10 (IP-10) contribute to cytotoxic dermatoses?
attract CXCR3 CD8+ cytotoxic lymphocytes to the dermo-epidermal junction
38
How can drug or drug metabolites alter the epidermis and cause immune reactions?
covalently binding as a hapten to cell surface proteins
directly interacting with the MCH/T-cell receptor complex
potentially altering endogenous peptides presented to T cells
39
In cutaneous adverse drug reactions, what are the main mediators of keratinocyte death?
drug-specific CD8+ CTL and activated NK cells
40
Why do fixed drug reactions happen at the same anatomic site ?
because drug-specific CD8+ memory T cells remain in situ
41
Which are the cytotoxic interface diseases most commonly triggered by drugs in people and animals?
drug-induced EM and SJS/TEN
42
In a study on canine adverse drug reactions, what percentage of dogs were highly likely to have a drug induce their EM?
19%
(in another it was 59%)
43
In a study on canine adverse drug reactions, what percentage of dogs were highly likely to have a drug induce their SJS/TEN?
90%
44
What are 5 ways you can divide epidermal cytotoxic dermatitis in groups depending on contributions from epidermis, immune system, and environment?
Response of normally immune system to pathogens/altered keratinocytes
- ex. viruses and EM
Immune-mediated/autoimmune due to environmental factors
- ex. UVB and lupus erythematosus
- ex. drugs and EM/SJS/TEN
Attack of abnormal immune system on keratinocytes
- paraneoplastic
Altered environment affects both epidermis and immune system
- graft versus host disease
Cytotoxic dermatitis of yet to be identified mechanisms
45
What species has thymoma-associated exfoliative dermatitis been reported in?
cats, rabbits, and goats
46
In which disease has intraepithelial neoplastic CD8+ T cells been shown to exhibit cytotoxic activity against keratinocytes?
Lymphoma
- lichenoid mycosis fungoides in people
- canine epitheliotropic T-cell lymphomas
47
In which situation has graft versus host disease been reported in dogs?
bone marrow transplants
engrafted lymphocytes attack host epidermis due to different MCH I
48
Which diseases are characterized histologically by cytotoxic panepidermal dermatitis with marked hyperkeratosis and often parakeratosis?
feline proliferative and necrotizing otitis externa
PLIMFD with apoptosis and parakeratosis in dogs
hyperkeratotic EM
subset of cases of superficial necrolytic dermatitis
lesions in one young lab that got better with Vitamin A
49
What are examples of lupus erythematosus-nonspecific skin lesions
those due to vasculitis, cryoglobulinemias, vesicobullous lesions associated with basement-membrane autoantibodies (i.e. bullous SLE), “lupus panniculitis”
50
Which canine variant of lupus is the equivalent to the human subacute cutaneous LE?
vesicular cutaneous LE
51
Which canine variant of lupus is the equivalent to the human chronic cutaneous LE?
Exfoliative cutaneous LE
Discoid LE
Mucocutaneous LE
52
What breeds are predisposed to vesicular cutaneous lupus erythematosus?
Collies, Shetland sheepdogs and their crosses
53
What breeds are predisposed to exfoliative cutaneous lupus erythematosus?
German shorthaired pointers and Magyar viszlas
54
What breeds are predisposed to mucocutaneous lupus erythematosus?
German shepherd dogs
55
What breeds are predisposed to facial discoid lupus erythematosus?
German shepherd dogs
also Collie, Shetland Sheepdog, and Siberian Husky
56
What breeds are predisposed to generalized lupus erythematosus?
Chinese crested dogs
57
What is the female to male ratio and at what age is vesicular cutaneous lupus erythematosus seen?
female-to-male-ratio: 0.9
2.0 and 11.0 years of age (median 5.5 years)
58
What is the female to male ratio and at what age is exfoliative cutaneous lupus erythematosus seen?
female-to-male-ratio: 1.4
0.7 yrs (0.2–3.5)
59
What is the female to male ratio and at what age is mucocutaneous lupus erythematosus seen?
female-to-male-ratio: 1.8
6.0 yrs (3.0–13.0)
- most had noticeable mucocutaneous lesions in mid-adulthood
60
What is the female to male ratio and at what age is facial discoid lupus erythematosus seen?
female-to-male-ratio: 0.7
7.0 yrs (1.0–12.0)
61
What is the female to male ratio and at what age is generalized lupus erythematosus seen?
female-to-male-ratio: 1.0
9.0 yrs (5.0–12.0)
62
What are the clinical lesions associated with vesicular cutaneous lupus erythematosus?
figurate erythema, flaccid vesicles and erosions in the abdomen, axillae,
medial thighs, concave pinnae and perimucosal areas
typically no systemic signs
63
What are the clinical lesions associated with exfoliative cutaneous lupus erythematosus?
erythema, scaling, follicular casts, alopecia and occasional scarring on the trunk, muzzle, pinnae and abdomen +/- mild pruritus
systemic signs include lymphadenomegaly, arthralgia, reproductive defects, rare mild anemia, fluctuating thrombocytopenia, hyperglobulinemia
64
What are the clinical lesions associated with mucocutaneous lupus erythematosus?
erosions, ulcers with or without peripheral hyperpigmentation at mucocutaneous junctions (do not tend to scar)
typically no systemic signs but may have pain when defecating or urinating
65
What are the clinical lesions associated with facial discoid lupus erythematosus?
depigmentation with loss of normal cobblestone, erosions, ulcers with or without peripheral hyperpigmentation on the nasal planum/dorsal muzzle
- may also be on muzzle, lips, periorbital, ears
- tend to scar
typically no systemic signs
66
What are the clinical lesions associated with generalized discoid lupus erythematosus?
annular (discoid) to polycyclic plaques with dyspigmentation, erythema, erosions, ulcers, scaling, crusting on the trunk, lateral legs and abdomen
- lesions develop central atrophic or hypertrophic scar
- may involve mucocutaneous regions (genitalia)
typically no systemic signs
67
What are the most relevant clinical mimics to vesicular cutaneous lupus erythematosus?
erythema multiforme
68
What are the most relevant clinical mimics to exfoliative cutaneous lupus erythematosus?
sebaceous adenitis
69
What are the most relevant clinical mimics to mucocutaneous lupus erythematosus?
mucocutaneous pyoderma
mucous membrane pemphigoid
erythema multiforme variants
70
What are the most relevant clinical mimics to facial discoid lupus erythematosus?
mucocutaneous pyoderma
epitheliotropic cell lymphoma
uveodermatological syndrome
71
What are the most relevant clinical mimics to generalized discoid lupus erythematosus?
hyperkeratotic erythema multiforme
generalized ischemic dermatopathies
72
What is the histopathology findings associated with discoid lupus erythematosus?
lichenoid cell-rich, lymphocytic interface dermatitis reaction pattern
- Can be subtle in early lesions
Basal cell vacuolar degeneration and apoptosis
- Characteristic , but can be sparse
Patchy or multifocal BMZ thickening
Suprabasilar apoptosis can be present due to “sunburn” cells
Vasculitis / fibrinoid change (solar vasculopathy)
73
What is the histopathology findings associated with vesicular lupus erythematosus?
lymphocyte cell-rich interface dermatitis
prominent basal keratinocyte vacuolation, apoptosis and loss
- causes intrabasal clefts and epidermal vesiculation
- don't confuse with with subepidermal blistering
hair follicle infundibula have similar lymphocytic interface/mural folliculitis
pigmentary incontinence not common due to color/location of lesions
neutrophilic inflammation is common with secondary infections
74
What is the histopathology findings associated with exfoliative cutaneous lupus erythematosus?
Orthokeratotic hyperkeratosis
Cell rich interface dermatitis (multifocal > band like)
Infundibular lymphocytic interface mural folliculitis
Attack and loss of sebaceous glands
lymphocytic apocrine gland infiltrate
*is like lupus + sebaceous adenitis
75
What is the histopathology findings associated with mucocutaneous lupus erythematosus?
cell-rich lymphocytic interface dermatitis with basal keratinocyte damage
- lymphoplasmacytic
pattern was often patchy, or in limited areas
- best at ulcer margin
Interface dermatitis commonly extended to the follicular infundibula
multifocal, patchy to diffuse BMZ thickening
variable pigmentary incontinence
occasional suprabasal keratinocyte apoptosis
- but mild to no lymphocytic satellitosis
76
What type of cytotoxic dermatitis is this?
Interface
77
What type of cytotoxic dermatitis is this?
Panepidermal
78
What is a difference between the histopathologic findings of dermatomyositis and VCLE?
Dermatomyositis presents with lesions of ischemic dermatopathy
- i.e. cell-poor interface dermatitis and ischemic follicular atrophy
VCLE tends to be cell-rich but even cell-poor VCLE lesions have more lymphocyte exocytosis into the basal epidermal layer, with lymphocytic satellitosis of apoptotic basal keratinocytes
79
Biopsy from a 5 year old collie.
VCLE
a: cell-rich, lymphocytic interface dermatitis is present. Marked basal
keratinocyte apoptosis has caused a secondary cleft (vesiculation) through the epidermal basal cell layer, which is typical of the disease. 100X
(b): inset box from image “a”, lymphocytes infiltrate the basal layer and are associated with basal cell vacuolation, apoptosis, loss and disorganization at the cleft margin. 200X
(c): dermal lymphocytic inflammation can be mild, lacking a clear subepidermal band-like (lichenoid) pattern, but lymphocytes are still observed in the basal epidermal layer in association with basal cell loss. 200X (d): chronic lesions can develop epidermal hyperplasia, a prominent dermal infiltrate of lymphocytes and plasma cells and thickening of the basement
membrane zone. 200X
80
What is the immunohistochemistry of cells involved in canine vesicular lupus erythematosus?
25 to 50% of epidermal leukocytes were CD3+/CD8+ T-lymphocytes
fewer CD4+ lymphocytes
some CD1-positive Langerhans cells
Basal keratinocytes had high ICAM-1 and low MCH II
in superficial dermis equal CD4+ and CD8+
81
What is the immunohistochemistry of cells involved in canine exfoliative lupus erythematosus?
CD3+ T lymphocytes in the lower epidermis, superficial dermis, in the infundibulum of hair follicles and around sweat glands
82
What is the immunopathology involved in canine vesicular cutaneous lupus erythematosus?
IgG around blood vessels, at the BMZ, and in keratinocytes
Maybe circulating antinuclear IgG autoantibodies depending on study
- targeting Ro/SSA and/or La/SSB antigens
No deposition of complement
83
What is the immunopathology involved in canine exfoliative cutaneous lupus erythematosus?
IgG > IgM or others at BMZ and follicular basement membrane
antifollicular and anti-sebaceous gland IgG antibodies in the serum
No circulating anti-epidermal basement membrane antibodies
antinuclear antibody serology usually remained below positive
predominant Th1 lymphocytic response with upregulated INF-y
84
What is the immunopathology involved in canine mucocutaneous lupus erythematosus?
positive IgG>>IgA, IgM, C3 lupus band test with direct IF
rare positive ANA titers
85
What is the immunopathology involved in canine discoid lupus erythematosus?
IF or IHC: IgG > IgM at dermo epidermal junction (positive lupus band)
- may have involvement of C3
86
What are the treatments for VCLE?
Sun avoidance
Immunosuppression
- calcineurin inhibitors might be the drug category of choice
- glucocorticoids +/- azathioprine
- mycophenolate mofetil
Relapses are common
- all treated with calcineurin inhibitors did well
- 64% had good response to glucocorticoids +/- azathioprine
87
What are the treatments for DLE?
Sun avoidance
For FDLE
- tetracycline-niacinamide combination (maybe doxycycline)
- topical tacrolimus ointment for FDLE
- not great publications about other (maybe oclacitinib)
For GDLE
- Relapses are common
- oral ciclosporin
- oral hydroxychloroquine + tacrolimus
88
What are the treatments for ECLE?
some benefit of dietary changes, supplementation with fatty acids, anti-seborrheic shampoos, antibiotics and/or oral retinoids
response to immunomodulators is heterogeneous (as in human CCLE)
- hydroxychloroquine slowed it down
- high-dose ciclosporin did not slow it down
- individualized high-dose oral glucocorticoids+/- adjunctives
- case series with oclacitinib
- case report of mycophenolate
over half of dogs are eventually euthanized
89
What are the treatments for MCLE?
respond best to immunosuppressive dosages of oral glucocorticoids
in some dogs, tetracycline antibiotic, with or without niacinamide works
90
From the lip margin of a GSD.
MCLE
91
What happens to humans with the generalized variant of GDLE and a positive ANA titer?
represents a risk factor for development of SLE within five years
* progression of a DLE variant to “clinical” SLE only reported in 1 dog
92
What infectious disease can cause thickening of the basement
membrane zone of the nasal planum?
leishmaniosis
93
Biopsy of a nasal planum and adjacent dorsal muzzle.
FDLE
94
What are the criteria for SLE in dogs?
not clearly defined but can include presence of at least 3 or more criteria:
immune mediated disease targeting at least 2 organ systems and a positive ANA
rule out ehrlichiosis and babesiosis in dogs (should have negative ANA)
95
What are antinuclear antibodies (ANAs)?
autoantibodies against nuclear components, including double-stranded and single-stranded DNA and histones
96
Which oral drugs are commonly used in humans to treat DLE?
hydroxychloroquine and retinoid acitretin
complete resolution in only 50% of patients
97
What are the histopathologic features of feline thymoma-associated
exfoliative dermatitis?
cell-poor to cell-rich CD3+ lymphocytic interface dermatitis
- graft-versus-host-like reaction of autoreactive T cells
Mild/subtle transepidermal and follicular apoptosis
- mural folliculitis
Hyperkeratosis (para- / orthokeratotic)
Reduced / absent sebaceous glands
*EM + SA
98
What are the clinical signs of thymoma-associated exfoliative dermatitis?
Erythema, exfoliation, scale, crust, alopecia often starting on head & neck → generalized
Malassezia dermatitis is not a constant feature
may have other thymoma syndromes: hypercalcemia, myasthenia gravis, keratoconjunctivitis sicca, polymyositis, thrombocytopenia, anemia, granulocytopenia
99
What is nonthymoma-associated exfoliative dermatitis?
Seen in cats that don't have thymomas
18 had no identifiable cause
various causative factors have been identified or suspected, such as non-thymic neoplasms, drug administration, and nutritional factors
treatment is immunosuppression (usually needed life-long)
100
What is hyperaesthetic leukotrichia?
uncommon condition affecting horses primarily in CA
acute development of severe pain over the withers and dorsum
crusts develop in the affected area, which are followed by alopecia
reticular leukotrichia (no leukoderma) is seen when the hair regrows
may be a form of EM
occurred between April and September
- recurred in subsequent years in almost half of the horses
101
What is the difference between hyperaesthetic leukotrichia and reticulated leukotrichia?
Hyperaesthetic leukotrichia:
- painful
- Arabian horses (+ crosses) and Paints over represented
Reticulated leukotrichia: not painful, Quarter Horses predisposed
102
How can EM and hyperaesthetic leukotrichia be differentiated on histopathology?
- Acanthosis, lymphocytic exocytosis, lymphocytic satellitosis and lymphocytic dermal inflammation were more prominent in horses with EM
- pigmentary incontinence and superficial dermal oedema were more prominent on biopsies from horses with HL
103
What are the histopathologic findings of hyperaesthetic leukotrichia and reticulated leukotrichia?
interface dermatitis with apoptotic keratinocytes, prominent superficial dermal oedema and pigmentary incontinence
subepidermal and intraepidermal vesicles can be seen occasionally in early lesions
104
What is the typical clinical picture of a horse with EM?
bilaterally symmetrical papules and plaques that are variably pruritic and occur most commonly on the lateral neck and trunk, but can also occur on the face
105
TEN
106
What is the rule of 9s?
divides the body into regions that are multiples of 9%
- each forelimb represents 9%
- each rear limb 2 nines, or 18%
- head and neck 9%
- dorsal and ventral thorax/abdomen each 18%
107
What is the classic appearance of EM in humans?
Precisely defined targets that are round, sharply demarcated,<3 cm in diameter, with at least three different zone
*not typically seen in animals
108
What are typically considered as potential triggers for EM in animals?
historic tacit acceptance that EM in animals = an adverse drug reaction
recent evidence is very much to the contrary
triggers can include:
- antibiotics (sulfonamides)
- parasiticides (levamisole)
- food
- infections (canine parvovirus-associated, maybe herpes)
*maybe adrenal disease in ferrets
109
What are typically considered as potential triggers for SJS/TEN in animals?
triggers can include:
- antibiotics (sulfonamides, cephalosporins, penicillins)
- NSAIDs
- parasiticides (levamisole and diethylcarbamazine)
--> D-limonene causes an SJS/TEN-like necrotizing dermatitis
- phenobarbital
- vaccination
- neoplasia
110
What is the primary differences between EM minor and EM major in animals?
EM minor has none or 1 mucosa involved
EM major has >1 mucosal involved and are often sick
111
What is the difference in pathomechanism between EM and SJS/TEN in humans?
Lymphocyte-mediated direct cytotoxicity of keratinocytes occurs in EM
Little evidence of cell–cell contact in fully developed lesions of SJS/TEN
- extensive apoptosis is primarily through the Fas–FasL and perforin/granzyme pathways (do also have C8+ T cells and NKs)
112
How can you differentiate SJS and TEN?
extent of skin detachment
- SJS: skin detachment area <10%
- TEN: >30%
- SJS/TEN overlap: 10–30%
113
What are some proposed mechanisms by which drugs cause sensitization in SJS/TEN?
- hapten model
- p-i concept (drug moieties interact with TCR and HLA)
- alterations in the shape of susceptible HLA allotypes after drug binding
114
What are the clinical signs associated with EM in dogs and cats?
Wide range of lesions described, with no consensus
Erythematous macules or papules, often crusted; raised or flat targetoid lesions; polycyclic, arciform, erythematous or purpuric lesions; vesicles, bullae, ulcers; urticaria
* cats tend to be vesicular, bullous and ulcerative lesions on trunk
115
How does the distribution of lesions associated with EM vary between humans and dogs?
In people, EM is predominantly acral and facial
In dogs, lesions typically involve the trunk, particularly the glabrous skin of the groin and axilla, but also the inner pinna, footpads and the mucocutaneous junctions
116
What is the clinical course like in canine and feline EM?
relatively large proportion of chronic or relapsing cases in dogs
especially if a trigger is suspected, dogs and cats may run a mild course, with spontaneous regression
117
What are the clinical signs of SJS/TEN in dogs and cats?
Erosions and ulcers, often affecting mucocutaneous junctions
Large areas of detachment result from minor pressure
- painful vesicles, bullae
Early lesions include erythematous to haemorrhagic macules or patches and coalescing erythematous targetoid lesions
usually involving trunk and footpads
Can also include tracheobronchial, urogenital and esophageal mucosae
Tend to also have fever, lethargy, inappetence
118
How do you differentiate EM major and SJS?
Not a clear consensus, some sources combine EM major and SJS
If <50% of skin affected it is EM, if >50% it is SJS or TEN
119
What are the histopathologic findings of EM/SJS/TEN?
Can't really tell the difference on histopathology
Interface dermatitis (epidermis, follicles)
- Lymphocytic / lymphohistiocytic
- Mild to lichenoid
- Mixed inflammation if ulcerated
Keratinocyte apoptosis, prominent and AT ALL LEVELS
- even forms “pink ghosts” in stratum corneum
Satellitosis
- Lymphocytes close to apoptotic keratinocytes
Lesions go to superficial hair follicles
SJS/TEN are more likely to have full-thickness epidermal coagulative necrosis
- dermis is NOT necrotic (vs. in a thermal burn, infarct)
120
What is the treatment of SJS/TEN in animals?
Drug withdrawal
Advanced supportive therapy
- fluid/electrolyte therapy, pain therapy
- humans go to the burn ward
- IVIG
Adjunctive immunosuppressive therapy is controversial
- cyclosporine does not work fast but it has proven to be effective
121
What is the treatment of EM in animals?
Drug withdrawal in appropriate cases
Supportive therapy
Immunosuppressive therapy in refractory, persistent cases (ex. azathioprine, glucocorticoids, pentoxy, ciclosporin)
- esp with HKEM, cyclosporine and oclacitinib are usually good
122
What is the clinical presentation of hyperkeratotic EM?
age of onset of HKEM was variable
- usually mid- to late adulthood (2/3s of dogs were 8+)
multifocal-to-coalescing, linear and annular macules and plaques with erythema and adherent firm crusting
- usually on trunk, abdomen, mucocutaneous junctions, concave pinna
123
What are the histopathologic findings of hyperkeratotic EM?
Interface dermatitis with panepidermal apoptosis and satellitosis
Epidermal hyperplasia
Marked hyperkeratosis
- Parakeratotic > mixed w/ ortho-
- Laminated to compact
Extensive lymphocytic exocytosis
124
What are the immunopathologic findings of hyperkeratotic EM?
positive LBT was found in seven of 14 (50%) dogs with the anti-IgG and in one dog (5%) with anti- IgA and IgM
125
What is proliferative necrotizing otitis externa?
Uncommon/rare in young cats
Symmetric lesions of ear canal and concave pinna
- may extend onto the face, eyelid, generalized
- once case report of ears not involved
Coalescing plaques with heavy brown/black crusting
126
What are the histopathologic findings associated with proliferative necrotizing otitis externa?
Marked epithelial hyperplasia
- Epidermis + follicular infundibula
Marked parakeratosis hyperkeratosis
Neutrophilic crusts
Panepidermal apoptosis
Lymphocyte satellitosis
Mixed dermal inflammation
127
What causes a lichenoid band?
Persistent immunologic reaction (autoimmune; mucocutaneous junctions)
128
What is psoriasiform-lichenoid dermatitis?
Rare, asymptomatic
There is a form in English Springer Spaniels (likely hereditable)
- Other breeds as well (young, <1.5 yo)
May be a genetic response to superficial staphylococcal infection
Also associated with long standing cyclosporine therapy
129
What is the clinical appearance of psoriasiform-lichenoid dermatitis?
Yellow , waxy, crusted papules --> lichenoid plaques --> papillomatous
Pinnae (medial), external ear canal, ventral abdomen, prepuce, perineum
Typically symmetrical
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What is the histopathologic appearance of psoriasiform-lichenoid dermatitis?
Psoriasiform hyperplasia
- Elongated rete ridges
- roughly even thickness length alternating with long dermal papillae
Dense lichenoid inflammation (increased plasma cells)
- Basal cell damage is uncommon
Frequent pustules (eos/neuts) potentially due to bacterial superantigens
131
What is Sweet’s-like syndrome?
Reported in dogs and a foal
Sterile neutrophilic dermatosis or acute febrile neutrophilic dermatosis
- pyrexia is a key feature, but not always documented
- may be anorexic, lethargic, weak, lame, etc
Acute development of lesions
- Erythematous macules and papules, pustules and plaques
- May have ulcers
- Edema may be present (not as much as Well's)
Usually associated with a drug reaction (esp NSAIDs)
- humans will also have URI, GI disease, or neoplasia
May have a mild neutrophilic leukocytosis
Antigen-driven T-cell-mediated immune reaction is speculated
- unclear if it is truly a separate disease form Well's-like
Treatment is to remove cause, supportive care, +/- immunosuppression
132
Which stain can be helpful in differentiating Sweet's from Well's?
Luna stain
133
What is Well's-like syndrome?
Canine acute eosinophilic dermatitis with oedema
erythroderma, edema, maculopapular rashes, wheals or plaques
- tend to habe more edema than Sweet's
may be febrile (often less than Sweet's)
GI upset is more common than in Sweet's
May have a mild eosinophilic leukocytosis
134
What breeds are predisposed to symmetric lupoid onychodystrophy?
Gordon setters, English setters, German shepherd dogs, Giant Schnauzers and Bearded Collies
- associated with (DLA) class II alleles in Gordon setters
Assocaited with CFA12 and CFA17 (code for DLA) in bearded collies
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What is hypereosinophilic syndrome?
Chronic idiopathic hypereosinophilia + diffuse infiltration of various organs by mature eosinophils
Most common presentation: middle-aged female cats
- Appearance is like CAEDE
- Organs that are infiltrated with eosinophils will dysfunction (spleen, liver, GI tract, lymph nodes)
Histopath: superficial and deep perivascular to interstitial eosinophilic dermatitis
Can try prednisolone, cyclosporine, hydroxyurea – prognosis is poor
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What is idiopathic diffuse lipomatosis?
Extremely rare; adult dogs and cats
Unknown pathogenesis
Progressively enlarging pendulous/heavy skin folds
Skin overlying folds may become thin and hypotrichotic
Histo: Marked, diffuse thickening of the panniculus +/- dysplastic adipocytes
137
What is lichenoid dermatosis?
Rare, idiopathic disorder in dogs and cats
- No breed, sex, or age predilection
- Dobermans make up many of the case reports
Animals are otherwise healthy
Asymptomatic, symmetric, angular, flat-topped papules to markedly hyperkeratotic alopecic plaques on pinnae, ventral thorax, ventral abdomen
Histo: hyperkeratosis, hyperplasia, lichenoid to interface dermatitis with lymphoplasmacytic infiltration
* a lot like psoriasiform lichenoid dermatosis
138
What is split paw pad disease?
Suspected congenital defect in cornification of the foot bad
separation of the superficial layers from the deep layers of epidermis
Presentation: early adult onset, multiple pads on multiple paws
Focal ulceration and hyperkeratosis can develop
- at areas of high friction/trauma
Varying degrees of pain/pruritus
Histo: hypereosinophilic, coagulated appearance extending to superficial dermis (resembling coagulation necrosis of a burn)
Clinical ddx: trauma, thermal injury, EB, PF, drug reaction, vasculitis
Pain medications, protective bandaging, keep paws dry
139
Which breeds of dogs may be prone to EM?
German Shepherd Dogs, Pembroke Welsh Corgis, Old English Sheepdogs, Chow Chows, Cairn Terriers, and Bearded Collies
140
What is an Arthus reaction?
antigen is injected subcutaneously into an animal that already has a high level of antibodies in its bloodstream, inflammation develops at the injection site within 4 to 8 hours
141
How does immunothrombosis occur?
Immune complexes interact with neutrophils --> NETS --> platelet activation and aggregation which causes more NETS --> NETs interact with clotting factors to trigger a thrombus and inflammation
142
What is the most common cause of leukocytoclastic vasculitis in small animals?
type III hypersensitivity reaction
(but half are idiopathic)
