1 – Immune Drugs

Question 1

Why use immunosuppressive drugs?

Answer 1

• Treat immune-mediated disease
  o GOAL: reduce clinical signs
  o *can’t cure them
• GOOD EXAMPLE OF RISK MANAGEMENT
  o Balance risk of adverse effects with risk of disease itself

Question 2

What are immune-mediated disease examples?

Answer 2

• IMHA or IMT
• Inflammatory bowel disease
• Immune-mediated polyarthritis
• *immune-mediated derm diseases
• *don’t worry about them now

Question 3

Immunosuppressive effects

Answer 3

• CONTINUUM OF EFFECTS (know the difference b/w high vs low dose)
• Favors one immune response, while minimizing another
• High dose, prolonged duration leads to severe immunosuppression
• Effects don’t occur immediately

Question 4

Immunosuppressive effects do NOT occur immediately

Answer 4

• Typically a few weeks before clinical efficacy is observed
• Steroid-induced immunosuppression occurs faster (5-10 days)

Question 5

What are the basic immunosuppressive drugs: 1st line ?

Answer 5

• Glucocorticoids
• Cyclosporine

Question 6

Glucocorticoids

Answer 6

• Non-specific response (VERY BROAD)
• Anti-inflammatory vs. immunosuppressive effect: DEPENDS ON DOSE USED
  o Higher=more likely it will be immunosuppressive (ex. >2mg/kg/day prednisolone)
• Altered leukocyte migration and function
• Decreased lymphocyte function
• *back bone of immunosuppressive therapy in vet med (work well for many conditions)

Question 7

Altered leukocyte migration and function of glucocorticoids

Answer 7

• Decrease function of monocytes and macrophages
  o Decrease Ig receptors, impaired phagocytosis

Question 8

Decreased lymphocyte function of glucocorticoids

Answer 8

• Cell-mediate immunity decreased most
• *decreased antibody production at HIGH dose

Question 9

What are the vet formulations of glucocorticoids available?

Answer 9

• Prednisone, prednisolone (horses and cats)
• Dexamethasone
• *probably interchangeable in most patients

Question 10

Short vs. long acting injectable formulations of glucocorticoids

Answer 10

• Long: acetate (prednisolone or methylprednisolone)
• Short: succinate (dexamethasone)
• *usually start with short acting formulation
• *often just going ORAL

Question 11

Glucocorticoids therapy

Answer 11

• Start parenteral (in-clinic) and continue orally at home
• *immunosuppressive treatment: start aggressively and taper slowly
  o 2-4mg/kg/day prednisone
  o *takes time to have an effect so try to ‘hit them hard’ and then wind down (some are life threatening)

Question 12

Cyclosporine (Atopica): 1st OR 2nd line systemic immunosuppressive drug

Answer 12

• *most reach for glucocorticoids first, some might use this first
• Inhibits enzyme (calcineurin phosphatase)
  o Prevents induction of genes coding for cytokines and their receptors
  o END RESULT: decrease IL-2 production
• *used for atopic dermatitis
  *still broad but more specific than glucocorticoids

Question 13

What does decreased cytokines (IL-2) with cyclosporine (Atopica) lead to inhibition of?

Answer 13

• T-lymphocyte activation, chemotaxis
• Antigen-presenting cells (Langerhans in skin)
• Mast cell and eosinophil infiltration

Question 14

What are the vet licensed oral forms of Cyclosporine (Atopica) (3)?

Answer 14

• Capsules (dogs): atopic dermatitis
• Solution (cats): various dermatitis conditions
• Used extra-label for other SYSTEMIC immune-mediated diseases

Question 15

What is the bioavailability of cyclosporin (Atopica)?

Answer 15

• Highly variable
• *formulation-dependent
• Plasma concentration does NOT correlate well with efficacy/safety
  o Therapeutic drug monitoring (TDM) NOT helpful
• *PD monitoring is important (IL-2 assay at Mississippi St. Lab) (in states, not Canada)
  o Overall effect of the drug and not an assay!

Question 16

Cyclosporine topical (ophthalmic): Optimmune

Answer 16

• DRY EYE: Keratoconjunctivitis sicca (KCS)
• Choric superficial keratitis (CSK) in dogs
• *sandimmune in humans

Question 17

Compounded cyclosporine CAPSULE potency vs. SOLUTION potency examples

Answer 17

• Capsules: dose was close
• Solution: way outside target zone (lots way too low and way too high)

Question 18

What are the adverse effects of cyclosporine (Atopica)?

Answer 18

• Vomiting
• GI disorder/diarrhea (very few had to stop b/c of it)
• Gingival hyperplasia
• *Immunosuppression: secondary infections are uncommon, but do occur
• *Drug interactions: P-gp/CYP substrates
• *’safer’ than glucocorticoids (but can mitigate effects with monitoring, and likely MORE EFFECTIVE)

Question 19

Atopica oral solution for cats: indication and what is it used for?

Answer 19

• Indication: control of feline allergic dermatitis
• Used for other feline immune-mediate dermatoses
  o Eosinophilic granuloma/indolent ulcer
  o Plasmacytic stomatitis

Question 20

What are the 2nd line SYSTEMIC immunosuppressive?

Answer 20

• Azathioprine (Imuran)
• Chlorambuvil (Leukeran)

Question 21

Azathioprine (Imuran)

Answer 21

• Oral or injectable (all human, NO VET)
• Mechanism: purine anti-metabolite=interferes with DNA synthesis
• Metabolized in liver to a variety of active metabolites and inactive metabolites (variability b/w animals)
• *variety of immunosuppressive uses in dogs (NOT USED IN CATS) (Ex. IMHA)

Question 22

Lymphocytes and purines

Answer 22

• Have to make their own purines
• *more susceptible to azathioprine than other cell types

Question 23

Azathioprine (Imuran) adverse effects

Answer 23

• **Myelosuppression
• Increased liver enzymes (dose-dependent)
• Pancreatitis
• Rebound ‘hyper-immune’ response possible if drug rapidly discontinued=so TAPER SLOWLY

Question 24

Myelosuppression of azathioprine (Imurane)

Answer 24

• Especially in cats (decreased hepatic clearance=increased drug exposure)
• Anemia (common, but NOT severe)

Question 25

Chlorambucil (Leukeran)

Answer 25

• Alkylating agents which cross-links DNA (humans, NO VET)
• Less potent/toxic version of chemotherapy drug cyclophosphamide
• *myelosuppression/vomiting common
  o Fanconi’s syndrome and neurological signs: RARE
• *expensive, so used for cats and small dogs (considered ‘steroid-sparing)

Question 26

Chlorambucil (Leukeran) uses

Answer 26

• Lymphocytic/plasmacytic infiltrative disease (Ex. inflammatory bowel disease)
• Indolent ulcers
• Pemphigus
• Atopy

Question 27

What are some Derm-specific immunosuppressive drugs?

Answer 27

• Apoquel (oclacitinib)
• Cytopoint

Question 28

Apoquel (oclacitinib): how does it work

Answer 28

• Janus kinase (JAK) inhibitors
  o Block intra-cellular communication
  o Inhibits pruritic and pro-inflammatory cytokines (**ex. IL-31) that are dependent on JAK1 or JAK3 enzyme activity
  o Minimal effect on cytokines involved in hematopoiesis (JAK2-dependent)

Question 29

What is the indication of Apoquel?

Answer 29

• Control of PRURITUS associated with allergic dermatitis
• Control of ATOPIC DERMATITIS in dogs at least 12 months of age
• *does NOT fix it

Question 30

Apoquel efficacy

Answer 30

• Rapid effect is typical (faster than cyclosporine)
  o Should see effects within a few days
• *Drug does work and has an impact
• ORAL twice a day (BID) for 14 days

Question 31

What are the adverse events of Apoquel?

Answer 31

• Immunosuppression (secondary infection, demodicosis)
• Low incidence of vomit/diarrhea

Question 32

Cytopoint (canonized monoclonal Ab)

Answer 32

• NOT a drug
• Canine monoclonal Ab against IL-31
• Administered as SC injection: long duration of effect (>30d)
  o Can’t be oral=broken down
  o Can train clients to do them at home (STORAGE, refrigerator)
  o Does decrease over time
• Can be used CONCURRENTLY with other atopic derm therapy: ‘trail and error’ approach

Question 33

What is the indication of Cytopoint?

Answer 33

• Aids in REDUCTION of clinical signs associated with atopic dermatitis in dogs
• *doesn’t solve the underlying allergy problem

Question 34

Apoquel vs. Cytopoint

Answer 34

• No real differences in efficacy or safety