Autoimmune and immune mediated diseases of the skin

Question 1

Outline at what points in the immune system immuno-deficiency can occur?

Answer 1

Question 2

What is a primary immuno-deficiency?

Answer 2

Primary condition

• Genetic defect in the immune system leads to clinical disease
• Rare!

Primary immuno-deficiency disorders – skin disease

• Severe combined immunodeficiency disease
• Lethal acrodermatitis in English bull terriers# (acro= at ends, near feet)
• Defective neutrophil function in Weimaraner’s
• Leukocyte adhesion deficiency of Irish setters (CLAD)
• Canine granulocytopathy syndrome of Irish setters with juvenile bacterial pyoderma
• Canine cyclic haematopoiesis of gray collies
• Hypotrichosis and thymic aplasia in Birman kittens
• Chédiak Higashi syndrome of Persian cats

Question 3

What is a secondary immuno-deficiency condition?

Answer 3

Secondary condition

• Associated with factors such as viral and other infections, endogenous hormones, drugs (steroids), age and malnutrition – leads to impairment of the immune system
• Development of various uncommon conditions

Question 4

What is the pathogenesis of auto-immune conditions?

Answer 4

Question 5

Name a variety of mechanisms that might be involved when an autoimmune disease develops?

Answer 5

• Over expression of self antigen
• Exposure of cryptic/sequestered self antigens
• Epitope spreading
• Molecular mimicry
• Failure of central tolerance
• Auto activation of T cells

Question 6

Why do some animals get these immuno deficiency diseases?

Answer 6

• Genetics
  
  • Collies, shepherds
• Environmental triggers
  
  • UV light / drugs
• Inflammation
• Existing disease
• Trauma
• Infection
• Neoplasia
  
  • e.g. thymoma (particular issue in cats. T cells are called to skin and target hair follicles, take thymoma away and hair grows back)

Question 7

What is the pathogenesis of pemphigus?

Answer 7

Aetiology usually unknown

Associated with abnormal immune regulation or antigenic stimulation:

• Neoplasia *
• Infectious agents *
• Drugs *
• Autoimmune disorders
• Certain haplotypes
• Pregnancy
• Chronic skin disease *

*recognised in animals

Question 8

What are the clinical signs of Canine Pemphigus foliaceus?

Answer 8

Clinical signs

• Any breed of dog (cockers classic breed that get it)
• Onset of signs can be from two to seven years
• Disease is chronic in 75% of cases
• Primary lesions include vesicles and pustules although they are transient because the canine epidermis is comparatively thin and trauma readily leads to crusting and erosions
• Footpads often involved and may be the only area affected
• Skin lesions are usually generalised with scaling, crusting and alopecia
• Large pustules on the trunk, head and pinnae that look like a bacterial infection but do not respond to appropriate antibacterial therapy should be serious candidates for PF
• Pruritus can be a major feature

Question 9

How is Canine Pemphigus foliaceus diagnosed?

Answer 9

Diagnosis

• Tzanck prep of the pustule - cytology reveals numerous acantholytic keratinocytes, neutrophils (eosinophils in some cases), no cocci should be observed
• Bacterial swab and culture & sensitivity testing –
• should be sterile
• Unfortunately Pf lesions can involve substantial secondary bacterial infection and so cocci may also be a feature
• Treat first for microbial infection then collect samples
• Skin biopsy for histopathology (& bacterial & fungal culture)
  
  • using a punch tool - may require 8 mm diameter to encompass the pustule
• Beware: these pustules are very delicate and readily traumatized by the act of collecting a biopsy – you may need several samples!

Acantholytic keratinocytes look like fried eggs (large blue cells with nucleus meaning the layers off skin have broken down and come away from a stratum too early)

Question 10

How does histopathology and immunopathology of pemphigus foliaceus appear?

Answer 10

Histopathology of pemphigus foliaceus:

• Intraepidermal and/or intrafollicular pustules with abundant acantholytic keratinocytes in the granular or upper spinous cell layers

Immunopathology:

• Anti-keratinocyte membrane auto-antibodies demonstrated by direct immunofluorescence in up to 80% of cases
• Usually IgG, occasionally IgM or IgA or C3 associated

Question 11

What is the pathogenesis of feline pemphigus foliaceus?

Answer 11

• Little understood about the pathogenesis
• Assumed that some of the features of canine pemphigus may apply
• Pf is the most common form of auto-immune skin condition in the cat
• Drug eruption has been documented as an underlying cause

Question 12

What are the clinical signs of Feline pemphigus foliaceus (Pf)?

Answer 12

• There are no breed, sex or age predilections
• Skin lesions are usually observed around the head, especially the pinnae, planum nasale and the claw beds
• Can be extension to the face (bridge of the nose, muzzle, around the eyes), tail, ventral abdomen including around the nipples
• Claw beds can have a thick caseous green purulent discharge - multiple digits and feet even the dew claw
• Claws are usually normal in appearance
• Skin lesions consist of pustules and vesicles
• Transient and readily replaced by erosions and overlying crusts
• Pyoniciar = pus around nail bed

Picture shows before and after steroid therapy

Question 13

Feline pemphigus foliaceus diagnosis?

Answer 13

• Feline pemphigus foliaceus diagnosis
• Fairly straightforward with involvement of the claw beds of several feet; or the pinnae
• Other clinical signs may lead to confusion with dermatophytosis
• Hence some cats receive antifungal therapy
• Cats treated with antibiotics for paronychia
• Contains cocci but these organisms are secondary
• Some cases wax and wane
• May suggest a positive response to antimicrobial therapy
• Haematology may show eosinophilia
• ANA (anti nuclear antibody) will usually be negative
• A fungal culture will (usually) be negative
• Cytology from an undisturbed pustule will reveal numerous neutrophils (eosinophils) with acantholytic keratinocytes
• Skin biopsies may be collected with a punch tool, some lesions are best excised
• Cat should be sedated or undergo general anaesthesia
• Pustules are extremely delicate and readily damaged when incised
• Lesions on the top of the head or from the base of the pinnae may be most fruitful

Question 14

How is feline pemphigus foliaceus managed?

Answer 14

• Prednisolone?
• Ciclosporin (tradename atopica) very expensive? Can cause diarrhoea and sickness

Question 15

What is this?

Answer 15

Equine pemphigus foliaceus

Not very common in horses. Can be dramatic in horses. Can see epidermis here massive amount of crusting.

Question 16

What is this?

Answer 16

Pemphigus vulgaris (PV)

• Rare autoimmune blistering skin disease associated with the generation of autoantibodies that target transmembrane desmosomal proteins in the epithelium
• Autoantibodies looking for DSG 3
• First cases of canine PV were reported in 1975 since then a small number of cases have been described
• Most dogs exhibit lesions at the mucosal and
• Mucocutaneous junctions (eyes, anus, lips, nose and prepuce)
• Rare cases are affected with a variant of PV without oral or mucosal involvement
• GSD predisposed

Question 17

What are the differential diagnosis for pemphigus vulgaris?

Answer 17

• Cutaneous manifestations of lupus erythematosus (systemic lupus rare in dogs)
• Epitheliotropic lymphosarcoma
• Uveodermatological syndrome (Japanese akitas)
• Nasal aspergillosis (nose reflects what is going on further up in nasal passages)
• Erythema multiforme (go into mouth as well)
• Mucous membrane pemphigoid

Question 18

What are the treatments for pemphigus?

Answer 18

Treatment of pemphigus:

• Glucocorticoids
  
  • Prednisolone / methylprednisolone
  • <2 mg / kg per day divided until in remission
  • Care with doses > 2 mg / kg
  • Go to alternate day therapy
  • Slowly reduce dose to avoid relapse (every 2-3 weeks)
• Ciclosporin
• Azathioprine (historically)
  
  • not recommended for cats
• Gold salts
• Chlorambucil (old drug occasionally used)
• Apoquel (oclacitinib) No studies probably doesn’t help as it is meant to block IL-31 seen in allergies.

Adjunct therapy

• Chlorhexidine-based shampoo / product for the secondary bacterial component and to remove crust/scale
• Antibiotics for three weeks e.g. cefalexin 20 mg/kg BID
• Gut protectants (e.g. cimetidine omeprazole) to reduce risk of side effects of such therapy
• Methylprednisolone equivalent dose of 0.8 to 1 mg of prednisolone

Question 19

When giving steroids what advice do you provide the owner?

Answer 19

Steroids can make them lethargic and depressed. PU/PD, polyphagic, weight gain, diabetic.

Question 20

Discuss azathioprine Imuran (sometime used for heamolytic anaemia) as a treatment for PF in more detail?

Answer 20

• Dog - dose of 2 mg/kg orally every 24-48 hours
• Cat – no!
  
  • Severe bone marrow suppression
• Adverse effects
  
  • Myelosuppression, pancreatitis and hepatotoxicity
• Complete blood & platelet count initially monitored every two weeks for two months and then every 2 - 3 months
• Slow onset of action - three to six weeks to produce clinical effects

Question 21

Discuss in more detail the use of Chlorambucil in cats to treat PF?

Answer 21

Action: Alkylating agent that inhibits DNA synthesis and function
through cross-linking with cellular DNA. Cell cycle non-specific.
Use: Management of some malignancies, lymphoproliferative, myeloproliferative and immune-mediated diseases. Immunosuppressive effect is not well defined and therefore it should
only be considered where more established therapies such as
prednisolone and azathioprine have failed. May be useful in the
treatment of feline pemphigus foliaceus and severe feline eosinophilic
granuloma complex. Has been used in lymphosarcoma in cockatoos.

• Daily therapy or every other day, in combination with steroids, using 0.1 to 0.2 mg/kg
• Tablet size is 2 mg so most cats receive half a tablet per day
• Therapy given for 4-8 weeks, side effects may include vomiting, diarrhoea, anorexia & bone marrow suppression
• Monitor haematology every two weeks

Question 22

Discuss Aurothioglucose (Gold salt) as a treatment for PF?

Answer 22

• Influences neutrophil migration, lymphocyte function and immunoglobulin production
• Weekly dose of 1.0 mg/kg (by intramuscular injection) to once every two or four weeks. May take 6 - 12 weeks to see the full response
• Adverse effects may include glomerulonephritis, bone marrow suppression, thrombocytopenia, and cutaneous eruptions
• Monitoring every two weeks with haematology, serum biochemistry and urinalysis

Question 23

What is Canine Lupus Erythematosus?

Answer 23

Discoid lupus erythematosus (DLE) is a relatively common autoimmune skin disease of dogs. Autoimmune disease occurs when the immune system targets harmless cells of the body resulting in inflammation and disease. In DLE, skin disease tends to occur around the nose, but can extend to include areas around the eyes, lips and ears. It is distinct from other forms of lupus in dogs that can cause systemic or internal disease along with more widespread skin disease.

Question 24

What causes DLE?

Answer 24

The exact causes of DLE are not known, although genetic, hormonal and environmental factors are likely to be involved as they are in the human disease. In particular, sun exposure is likely to exacerbate or even induce the lesions of DLE.

Question 25

What are the clinical signs of DLE?

Answer 25

DLE usually starts with a loss of pigmentation from the nose, which takes on a slate gray or blueish colour. The normal ‘cobblestone’ appearance of the nasal planum is lost and areas of inflammation, crusting and ulceration develop (Figures 1 and 2). The ulcerated lesions often start at the junction between the haired skin and the nasal planum, and then extend up the bridge of the nose over time. In severe cases, bleeding can be seen from the ulcerated lesions. Despite the marked skin lesions, affected dogs often seem relatively unaffected by the condition.

In very rare cases, lesions have been reported affecting the legs, footpads and around the anus.

Question 26

What treatmeants are there for Discoid lupus erythematosus?

Answer 26

CLE Treatment

• Topical glucocorticoids
• Topical ciclosporin (tacrolimus used in human eczema)
• Topical sunblockers
• Vitamin E400 to 800mg per day?

Drugs can use

• Essential fatty acids: n6 and n3 products
• Niacinamide and Tetracycline
• Oral glucocorticoids
• Azathioprine
• Chlorambucil
• Nasal flap plastic surgery

Question 27

What is this?

Answer 27

Plasma cell pododermatitis

Immune-mediated ?

• Aetiology unknown
• Anaemia
• Hypergammaglobulinemia
• IgG deposition (direct immunostaining) basement membrane zone
• Lymphocytosis affected tissues
• ANA titres positive (some)

Uncommon and usually well recognised condition

Gross swelling of multiple metacarpal/tarsal pads, occasionally foot pads

Ulceration, lameness, pain, occasionally pruritus

Occasionally pad ulceration and lameness

Question 28

How is Feline plasma cell pododermatitis diagnosed and what other differentials are there?

Answer 28

Diagnosis

• Collection of deep biopsies from pads
• Demonstration of numerous plasma cells and lymphocytes in dermis

Differential diagnoses include

• Eosinophilic granuloma complex
• Pemphigus foliaceus
• Viral infection with cowpox
• Multicentric tumours
• Contact dermatitis (rare in cats)
• Metabolic deposits
• Vasculitis

Question 29

What is the therapy for feline plasma cell pododermatitis?

Answer 29

Therapy:

• Resolution without therapy, seasonal recurrence, an allergic response?
• Glucocorticoids
  
  • e.g. Prednisolone 4 mg/kg per day initially (dose?)
• Ciclosporin?
• Gold salts
  
  • take up to 12 weeks to show full effect
• Chlorambucil in conjunction with other drugs especially steroids
• Surgery effective in severe cases especially where bleeding may be a major problem
  
  • Pad tissue regrows after the surgery
• Doxycycline (5 mg/kg twice daily for up to three weeks) - may be initial improvement allowing pulse therapy or low dose continuous therapy
  
  • Mode of action presumed immune-mediated effects

Question 30

What is this?

Answer 30

Idiopathic symmetric lupoid onychodystrophy (ISLO)

• Typical history all of the nails progressively becoming loose or splitting, including the dew claws, with some nails lost altogether.
• Larger breed dogs, including German Shepherds, border collies and greyhound-crosses; also smaller breeds including terriers
• Extremely painful when the nails start to lift off
  
  • Sedate/ anaesthetise
  • Remove all of the lose nails
  • Bandage + antibacterial therapy combined with NSAIDs for pain relief.
• Longer term - cases will have recurrent bouts of nail loss
• Treatment options include high doses of oral essential fatty acids (EFAs).
• Other treatment options may include pentoxifylline (Trental®) or
• Tetracycline and niacinamide
• Severe cases glucocorticoids or ciclosporin
• Nails should be kept short to avoid them being caught and ripped

Question 31

What are the clinical signs of vasculitis?

Answer 31

• Skin affected in dependant areas and extremities especially the paws (including sloughing pads), claws, pinnae, lips, tail, scrotum, oral mucosa.
• Purpura, macules, plaques, haemorrhagic bullae,
• Papules, pustules, necrosis, ulcers, acrocyanosis.
• Oedematous plaques, urticaria, lymphoedema, pain, erythema.
• Septal vasculitis and panniculitis
• Pitting oedema of limbs, ventral trunk, head and scrotum.
• Anorexia, depression, pyrexia, pain, pruritus
• Polyarthropathy, myopathy, neuropathy, hepatopathy,
• Thrombocytopenia, anaemia, lymphadenopathy