Chapter 9 - autoimmune Flashcards
What is the difference between auto-immune and immune-mediated disease?
Auto-immune = against self Immune-mediated = initial foreign trigger e.g. a drug or virus
Azathioprine antagonises purine metabolism which interferes with the synthesis of what?
DNA and RNA
Azathioprine is metabolised by which organ?
Liver
Low thiopurine methyltransferase (TPMT) levels increases the risk of which adverse effect of Azathioprine?
Myelosuppression
Which species has naturally low thiopurine methyltransferase (TPMT) levels?
Cats
Name five adverse effects of Azathioprine
Anaemia Leukopaenia Thrombocytopaenia Vomiting Hypersensitivity reactions (liver) Pancreatitis Increased ALP Rashes Alopecia Diarrhoea
How long can it take to see a clinical improvement with Azathioprine therapy?
3-6 weeks
The cytotoxic effect of chlorambucil is due to cross-linking of what?
DNA
Name three adverse effects of chlorambucil
Myelosuppresion Anorexia Vomiting Diarrhoea Alopecia Delayed hair growth
How long can it take to see a clinical improvement with chlorambucil?
Several weeks
Which inflammatory cell is most susceptible to cyclophosphamide?
Lymphocytes (B cells > T cells)
Name five adverse effects of cyclophosphamide
Haemorrhagic cystitis Bladder fibrosis Teratogenesis Infertility Alopecia/poor hair growth Nausea Gastrointestinal inflammation Depression of bone marrow and haemopoesis Infections
Mycophenolate mofetil suppresses which inflammatory cells?
B and T lymphocytes
Which veterinary species are affected by pemphigus foliaceus?
Dogs, cats, horses and goats
> 80% of PF cases have lesions at which body site?
Head, face and ears
Which sites are typically affected with pemphigus vulgaris?
Oral cavity and MCJ
What is the Nikolsky sign?
Peeling of the epidermis with a blunt instrument (lack of cohesion)
Epidermal detachment caused by mechanical pressure at the edge of a vesicle or normal skin
Which antigen is targeted in bullous pemphigoid and where is it located?
Collagen XVII, basal cell hemidesmosomes
Name two potential triggers of bullous pemphigoid
Drugs (sulfonamides, penicillins, furosemide)
UV light
Do you see acanthocytes with bullous pemphigoid?
No
Where does the cleft/vesicle form in bullous pemphigoid?
Subepidermal
Which non-mucous membrane sites can be affected in MMP?
Ears, footpads (rarely) and claws
What is the target antigen in epidermolysis bullosa acquisita?
Collagen VII (anchoring fibrils)
Is epidermolysis bullosa acquisita acute or insidious in onset?
Acute
What is the target of IgG autoantibodies in acquired junctional epidermolysis bullosa?
Laminin 332
In what % of SLE cases do you see skin lesions?
40-50%
What is the most common presenting sign of SLE?
Joint disease
In DLE, which body sites are typically affected in cats?
Face and ears (nasal lesions are less prominent than in dogs)
What is the main target antigen in dogs with alopecia areata?
Trichohyalin
Many targets, often basement membrane and pre-cortex
Antibodies are secondary phenomenon and appear late in the course of disease
Which anatomical sites are typically affected with alopecia areata?
Head/face (muzzle, periocular)
Also pinnae and limbs
Linear IgA pustular dermatosis is seen in which breed?
Dachshunds
Which organs are the principal targets in graft versus host disease?
Skin, liver, gastrointestinal
Histopathology of graft versus host disease is similar to which other disease?
Erythema multiforme
What are the typical skin signs in uveodermatologic syndrome?
What lesions were evident in the study by Zarfoss et al. (2018)?
Well demarcated depigmentation of hair and skin usually on the face (nose, lips, eyelids), pads, scrotum, anus and hard palate.
Dermatologic signs included leukoderma [56%]; scaling or erythema [24%]; alopecia [16%]; mucocutaneous erosions often centered around the nasal planum, mouth, eye-lids, or periocular skin [16%] and leukotrichia [14%].
Which histopathological pattern is seen in uveodermatologic syndrome?
Lichenoid interface granulomatous dermatitis with pigmentary incontinence and rare hydropic degeneration of epidermal basal cells
In pemphigus vulgaris, where are lesions most commonly found in dogs?
Lips and/or oral cavity 92%
Gingivae and palate within the oral cavity
What is the reported distribution of ulcers in the four cases of feline pemphigus vulgaris?
Oral cavity, lips and nasal planum
What clinical sign do you see when pemphigus vulgaris affects the nails in dogs?
Onychomadesis
Pemphigus vulgaris has been reported in which species?
Human, dog, cat, horse, goat, monkey, and llama
Pemphigus erythematosus is considered a mild form of pemphigus foliaceus combined with which other disease?
Discoid (facial) lupus erythematosus
PNP has reportedly been associated with which types of neoplasia in dogs and one cat?
Thymoma, a thymic lymphoma and a splenic sarcoma, whereas the single cat with PNP had a lymphocytic thymoma
A combination of which two histopathological disease patterns is seen in cases of PNP?
Pemphigus vulgaris - suprabasal acantholysis
Erythema multiforme - apoptosis of individual keratinocytes at multiple epidermal levels, lymphocytic/vacuolar interface dermatitis, and leukocytic exocytosis
What are the histopathological findings in pemphigus vegetans?
Distinctly hyperplastic epidermal lesions (PF type) and a suprabasal acantholysis typical of PV
In the review by Tham et al. (2020), what % of treated dogs with PV reached complete remission?
65%
PV affecting only the nails/claws cannot be clinically distinguished from canine symmetric lupoid onychodystrophy (SLO) or idiopathic onychitis/onychomadesis, unless what is present?
An erosion/ulcer on the periungual region, which is rarely seen in canine SLO
True or false:
Human patients affected by mucosal-dominant PV only have detectable anti-DSG3 IgG AA, whereas those with mucocutaneous form of PV have both anti-DSG3 and DSG1 IgG AA
True
How does the base of an erosion associated with PV differ from erosions due to other causes?
Deep erosions from other causes can be lined by a single layer of epithelial cells, but these cells are usually flattened and elongated, and thus more typical of a wound healing response.
Which breeds of dog may be at higher risk of developing PF?
Akitas and Chows
Possibly English cocker spaniels, Shar-peis and collies
In Mueller et al. study of 91 dogs with PF, what % had: facial lesions only generalised disease footpad involvement footpad lesions only
facial lesions only - 16%
generalised disease - 66%
footpad involvement - 33%
footpad lesions only - 2%
Roughly what % of dogs with PF are pruritic?
25-50%
Pemphigus foliaceus in animals has been reported in association with which systemic diseases?
Hypothyroidism
Leishmaniasis
Thymoma
Systemic lupus erythematosus
Can intercellular epidermal IgG be found in biopsy specimens obtained from dogs with dermatoses other than PF?
Yes - direct IF is not a specific test
Vasculitis is most often regarded as an immune-mediated, type III hypersensitivity response, resulting in excessive antigen-antibody immune complex deposition in vessel walls. Describe how it occurs?
- Antigen-antibody complexes become trapped in blood vessel walls as a result of incomplete clearance, which activates the complement cascade and inflammatory cell recruitment to the vessel wall.
- The cells then infiltrate vessel walls and release lysosomal con-tents (collagenase and elastase) and reactive oxygen species which damage endothelial cells.
- Over time, this damage results in fibrin deposition, endothelial necrosis, extravasation of erythrocytes and formation of thrombi.
What are the main triggers of vasculitis in dogs?
Drugs, vaccinations, infections and neoplasia
In dogs with PF, do those with vasculopathic lesions present differently in terms of clinical lesions and distribution?
No - some may present with oedema or non-blanching erythema but in most cases, the vascular changes on histopathological evaluation were not sufficiently severe to cause clinical manifestations.
In dogs with PF, do those with vasculopathic lesions present differently in terms of systemic clinical signs?
Dogs with vasculopathic lesions on histopathological evaluation were more likely to present with one or more systemic signs of illness than those without.
In dogs with PF, do vasculopathic lesions affect outcome?
PF and concurrent vasculitis may be more refractory to treatment and take longer to achieve remission than PF without concurrent vascular changes.
What are the major targets of autoantibodies in human and canine PF?
Human - desmoglein-1(Dsg-1)
Canine - desmocollin-1 (Dsc-1)
Mycophenolate mofetil may be more likely to cause GI adverse effects at what dose?
> 30 mg/kg/day
Rank the AISBD in order of prevalence in dogs:
Bullous pemphigoid
Epidermolysis bullosa aquisita
Junctional epidermolysis bullosa aquisita
Linear IgA disease
Mixed AISBD
Mucous membrane pemphigoid
Pemphigoid of gestation
Type 1 bullous systemic lupus erythematosus
- Mucous membrane pemphigoid (48 %)
- Epidermolysis bullosa aquisita (26 %)
- Bullous pemphigoid (10 %)
- Junctional epidermolysis bullosa aquisita (6 %)
- Mixed AISBD (4 %)
- Linear IgA disease (3 %)
- Pemphigoid of gestation and Type 1 bullous systemic lupus erythematosus (1 % each)
In the paper by Tham et al. (2016), what body areas were first affected in dogs with mucous membrane pemphigoid?
Oral/perioral (75 %)
Ocular/periocular (38 %)
Nasal (25 %)
Genital (13 %) and / or concave pinnae (13 %)
In the paper by Tham et al. (2016), what were the clinical signs of mucous membrane pemphigoid?
Skin lesions were symmetrical in 88% and they consisted of erosions and ulcers 100% – an inclusion criterion, crusting 56%, erythema 31%, vesicles/bullae 31%, scarring 19% and hypopigmentation 13%
In the paper by Tham et al. (2016), at presentation 100% of dogs with mucous membrane pemphigoid had lesions on mucosae and MCJ (the nasal planum is a modified mucosa), what % had lesions on haired skin?
38 %
In the paper by Tham et al. (2016), how many dogs with mucous membrane pemphigoid had lesions at more than one mucosal/MCJ site?
94 %
In the paper by Tham et al. (2016), complete remission was achieved in what % of dogs with mucous membrane pemphigoid and in what time frame?
91 % in median of 33 weeks (6-64 weeks)
How can you differentiate DLE and MCLE from MMP?
DLE and MCLE rarely affect the oral cavity and oral lesions are present in the vast majority of dogs with MMP
In the paper by Tham et al. (2016), what treatment was recommended as first line for MMP and which was reportedly the least successful at inducing remission?
- Tetracycline and niacinamide with or without additional immunosuppressive drugs
- Glucocorticoid monotherapy was the most frequent treatment regimen that failed to induce CR
What is anoikis?
Anoikis is a form of apoptosis triggered by a loss of the cell attachment to the appropriate matrix
What are the reportedly targeted antigens in dogs with mucous membrane pemphigoid?
Collagen XVII
BP230
Laminin-332
Which antigen has been shown to be targeted in a cat with mucous membrane pemphigoid?
Laminin-332
What % of epidermal detachment is seen in SJS and TEN?
SJS < 10%
TEN > 30%
Which body areas are typically affected in SJS and TEN in dogs and cats?
Trunk, often axillary and inguinal, mucocutaneous junctions, concave pinnae, pads
Can be generalised
Mucosal involvement is severe – more than one mucosal site affected
How many mucosal sites are affected in EM minor and EM major in cats and dogs?
EM minor – none or 1 site
EM major > 1 site
According to Yager et al. (2014), which ‘drug’ causes of EM in dogs have been confirmed?
Those triggered by beef/soy, commercial dog food and a nutraceutical product have been proved through (unintentional) rechallenge
In SJS/TEN, mucosal lesions typically affect the oral cavity but can be seen at which other mucosal sites?
Tracheobronchial, urogenital and oesophageal mucosae are susceptible.
Corneal involvement occurs in people and animals.
True or false:
In dogs and cats, the follicular infundibular epithelium is usually affected concurrently in EM, SJS and TEN.
True
Toxic epidermal necrolysis is distinguished from a burn by the lack of what histopathological findings?
Dermal necrosis
What are the differential diagnoses for SJS/TEN in dogs?
Burns Bullous autoimmune diseases SLE Superficial suppurative dermatitis of miniature schnauzers Vasculitis Epitheliotropic lymphoma
What novel treatment for hyperkeratotic (old dog) EM was presented by High et al. (2020)?
Oclacitinib 0.6-0.9 mg/kg BID
Which other diseases in cats can present with similar histological signs to EM?
Proliferative and necrotizing otitis externa (PNOE) also has significant outer epidermal apoptosis, which can be confused with lesions of EM.
The microscopic lesions of thymoma-associated paraneoplastic exfoliative dermatosis in cats are EM like, in that they represent an epidermal cytotoxicity reaction pattern. In addition to marked hyperkeratosis, sebaceous glands are targeted and maybe absent in some cases. Similar lesions of exfoliative dermatitis, with no accompanying thymoma, have been characterized as a form of feline EM.
Which other diseases in dogs can present with similar histological signs to EM?
- Ciclosporin-responsive ‘proliferative, lymphocytic, infundibular mural folliculitis and dermatitis with prominent follicular apoptosis and parakeratotic casts’ (PLIMFD), typically in young Labrador retrievers.
- A very similar case, also in a Labrador retriever puppy, was reported in 1983; this showed a rapid clinical response to oral vitamin A (40,000 IU twice daily); treatment was required for life.
- A significantly large subset of canine superficial necrolytic dermatitis cases show prominent single cell death in the outer stratum spinosum.
In Banovic et al. (2015); canine TEN signs were irregular erythematous and purpuric macules that evolved into widespread and severely painful erosions. The number of eroded mucosae varied; however, which mucocutaneous junctions frequently were affected?
Periocular and perilabial
In the study by Banovic et al. (2015) on canine TEN, what was the most common pattern of epidermal necrosis?
Apoptosis at multiple epidermal levels was the most common pattern of epidermal necrosis (12/13 biopsies, 92%). In contrast, full-thickness coagulation necrosis was present less often (7/13 biopsies, 52%).
In uveodermatological syndrome, can dogs develop ophthalmic signs before dermatological signs?
Yes, this occurred in 66% of dogs in the study by Zarfoss et al. (2018)
Which breeds of dog are over-represented in cases of uveodermatological syndrome and which gene mutation is associated?
American Akitas (Siberian Huskies, Samoyeds) Dog leukocyte haplotype (DLA)-DQA1*00201
Has alopecia areata universalis been reported in the dog?
Yes - complete hair loss included eyelashes and vibrissae
Also a report of AAU in a dog with testicular neoplasia; signs worsened following castration and resolved with ciclosporin therapy
Can the nails be affected in dogs with alopecia areata?
Yes - roughening, ridging, and vertical striations (trachyonychia) have been reported
The claw matrix is also an immune-privileged site
Septic vasculitis can be seen with which ectoparasite infestation?
Generalised demodicosis with cellulitis
Familial cutaneous vasculopathy affects which breed of dog?
GSD
Also reported in fox terriers and miniature schnauzers
Proliferative arteritis of the nasal planum classically affects which breed of dog?
Which part of the nose is affected?
St. Bernard (also giant schnauzer, basset hound, Labradors, Newfies and Samoyeds)
Nasal philtrum - often symmetrically
What are the clinical signs of familial cutaneous vasculopathy?
Pyrexia Lethargy Swollen, depigmented footpads Alopecia, crusts and ulceration may also occur - pinnae, tail and nasal planum Usually by seven weeks old
What are the five clinical presentations of ischaemic dermatopathy?
- Familial dermatomyositis
- Juvenile onset dermatomyositis in other breeds
- Post-rabies vaccination panniculitis
- Generalised vaccine-induced ischaemic dermatopathy
- Adult onset with no temporal association with vaccination
Vaccine associated ischaemic dermatopathy lesions occur when?
2-8 months after vaccination
Which vector-borne infectious diseases can be associated with vasculitis?
Babesia Ehrlichia/Anaplasma Bartonella Rickettsia rickettsia Borrelia burgdorferi Leishmania infantum
What is a key histopathological feature of pseudopelade?
Lymphocytic infiltration that targets the mid-isthmus of the hair follicle where the follicular bulge cells (stem cells for hair growth) are present. Destruction of these stem cells results in permanent scarring alopecia.
Is auricular chondritis in dogs and cats painful?
Reports are variable but often considered painful (some are asymptomatic)
Bilateral auricular chondritis may be a manifestation of relapsing polychondritis; which other organs can be affected with this disease?
Nonerosive seronegative inflammatory polyarthritis Nasal chondritis Ocular inflammation Respiratory tract chondritis Cochlear and/or vestibular signs
What are the differentials for the clinical signs of vasculitis?
Sepsis (can cause thrombosis and / or vasculopathy)
Disseminated intravascular coagulation
Cryoglobulinaemia / Cryofibrinogenaemia (cold agglutinin disease)
Frostbite
SLE
Lymphoreticular neoplasia
Subepidermal bullous diseases and burns if ulceration is present
What are the underlying causes of vasculitis in dogs?
Drugs Insect bites Food Infections (viral, bacterial, mycobacterial, fungal, protozoal and rickettsial) Neoplasia, autoimmune disease Genetic/familial Idiopathic
Which antifungal drug is known to trigger vasculitis in dogs and at what dose?
Itraconazole at 10 mg/kg
The case of urticarial vasculitis in a three year old FB reported in Vet Derm by Jan Declerq (2014) was suspected to be triggered by what?
Food
ECVD abstracts - cold urticarial vasculitis and drug (amoxicillin/clavulanic acid)
Which other drugs have reportedly been associated with cutaneous vasculitis in dogs and cats?
Antibiotics Ivermectin Vaccines Itraconazole Metronidazole Phenobarbital Furosemide Enalapril Phenylbutazone Imodium Metoclopramide Fenbendazole Acepromazine NSAIDs (Meloxicam)
Which bacteria has been associated with idiopathic cutaneous renal glomerular vasculopathy in Greyhounds (‘Alabama rot’)?
Verotoxin-producing strains of Escherichia coli O157:H7 – this disease is not thought to be purely infectious and genetic factors may be involved
CRGV in dogs in the UK affects a variety of breeds. What are the clinical signs?
- Skin lesions affecting the limbs (77-81%), body (20%), face/muzzle (7%) and tongue (4%) – usually precede systemic signs
- Vary from small, superficial abrasions (0.5 cm), to large areas of full-thickness ulceration and necrosis (>30 cm), with surrounding bruising and edema. Lesions are commonly circular and erythematous.
- Oligoanuric acute kidney injury – high mortality rate associated with this
- AKI developed on average 3 days after skin lesions (97.6% within 13 days)
In the study by Souza et al. (2019) on dermal arteritis of the nasal planum, which breeds were most commonly affected?
Saint Bernard > bloodhound, great Dane, German shorthaired pointer
In the study by Souza et al. (2019) on dermal arteritis of the nasal planum, what was the mean age of onset?
5.3 years
In the study by Souza et al. (2019) on dermal arteritis of the nasal planum, what treatment did they recommend?
0.1% tacrolimus ointment
Which diseases have reportedly been associated with ear tip ulcerative dermatitis in dogs?
Leishmaniosis, bartonellosis, Rickettsia rickettsia experimental infection, frostbite, cryoglobulinaemia and familiar vasculitides
Which treatment reported by Colombo et al. (2021) was effective in 22/25 dogs with ear tip ulcerative dermatitis?
Oclacitinib 0.4-0.6 mg/kg BID or SID
Proliferative thrombovascular necrosis of the pinna is considered idiopathic; which vessels are targeted?
Small dermal arterioles - fibrinoid degeneration and thickening of small dermal arteriole walls, and fibrin thrombi.
Which breeds of dog are considered to be predisposed to ear tip ulcerative dermatitis?
Dachshunds and Rhodesian Ridgebacks
Which breeds of dog are reportedly predisposed to vaccine associated vasculitis?
Yorkshire terriers, Poodles, Silky terriers, Pekingese and Maltese
Which breeds of dog have familial vasculitides been reported in?
GSD – young puppies with foot pad lesions
Scottish terriers – litter of puppies with nasal lesions of leukocytoclastic vasculitis and pyogranulomatous inflammation
Measurement of which substance in the blood can aid diagnosis of vasculitis?
D-dimers - fibrin degradation product, associated with thrombus formation
Neutrophilic vasculitis can be suggestive of which diseases?
Type III immune-complex hypersensitivity e.g. Staphylococcal dermatitis, SLE, some drug eruptions and septicaemia
Eosinophilic vasculitis can be suggestive of which diseases?
Type I hypersensitivity reactions e.g. arthropod bites, mast cell tumours, EGC in cats, drug and food reactions, canine eosinophilic dermatitis
Lymphocytic vasculitis can be suggestive of which diseases?
Suggests a cell-mediated immune response e.g. rabies vaccine, some drug eruptions
Pruritic, papular lesions on the dorsal head and back of a 19 week old male DSH kitten with concurrent pyrexia showed nodular pyogranulomatous dermatitis with vasculitis and necrosis on histopathology associated with which virus?
Feline coronavirus (FIP)
Do cats with auricular chondritis have lesions in other cartilagenous tissues?
Not usually - one case report of lesions in the sternum, joints, tracheal and laryngeal cartilages
Has auricular chondritis been reported in the dog
Yes - rarely
How do you treat auricular chondritis?
Variable response reported to steroids and ciclosporin Dapsone has been effective in some cases Pinnectomy Spontaneous remission has been reported No treatment if not painful
What are the clinical differences in signs of pseudopelade in dogs and cats?
- In the dog head and neck are sparred
- In the cat the alopecia may begin from the face and then spread to ventrum, legs and paws
- In the cat onychomadesis and onychorrexis can be present
Metatarsal fistulation has been reported in GSDs and which other breeds?
Weimeraner and Greyhound
What are the histopathological findings with metatarsal fistulation in GSDs?
- Nodular to diffuse predominantly pyogranulomatous dermatitis
with fibrosis and fistulous tracts - Hair follicle rupture with endogenous foreign body reaction to keratin and hair shaft is common
What are the three suspected pathomechanisms of sebaceous adenitis?
- Developmental and inherited defect that leads to sebaceous gland destruction
- Abnormality in lipid metabolism or storage
- Keratinisation abnormality that leads to obstruction of the sebaceous ducts, resulting to the inflammation of the sebaceous glands
How does sebaceous adenitis presentin short-coated breeds?
- Annular areas of scaling and alopecia that coalesce
White, fine scales that do not attach to hair - Moth-eaten appearance
Which gene is responsible for perianal fistulas in GSDs?
DLA-DRB1*00101
Perianal fistulas have been reported in GSDs and which other breeds?
Irish Setter, Collie, Border collie, Old English sheepdog, Labrador retriever, English bulldog, Bouvier de Flandres, Spaniels, Beagles
In canine perianal fistulas, what bacterial dysbiosis is reported?
- Increased abundance of Bacteroides vulgatus and Escherichia coli
- Decreased abundance of Megamonas species and Prevotella copri
Which diseases have been linked to cold agglutinin disease in the dog and cat?
Dog: Idiopathic, lead poisoning, infection
Cat: Respiratory infection, idiopathic, lead poisoning
How frequent is hair regrowth in cases of alopecia areata and why does it occur?
39%
Stem cells localized in the HF bulge are usually not targeted
In which dog and cat breeds is there a familial predisposition for amyloidosis?
Shar-Pei, Beagle
Abyssinian, Siamese
Cocker spaniel (may be predisposed to primary cutaneous amyloidosis and extramedullary plasmacytoma resulting in cutaneous amyloidosis