Immunosuppressive Therapy

Question 1

What are the main indications for starting immunosuppressive therapy?

Answer 1

For primary/idiopathic immune mediated disease
- for secondary, may or may not use it depending on underlying disease pathology

Question 2

What is the mainstay of therapy for immune mediated disease? What are the secondary drugs used?

Answer 2

Primary: Glucocorticoids- prednisone, dexamethasone
Secondary: azathioprine, cyclosporine, chlorambucil, leflunomide, mycophenolate mofetil

Question 3

What adjunctive therapies may be used in cases of immune mediated disease?

Answer 3

Human IVIG, Vincristine, Melatonin

Supportive: blood products, antiplatelet therapy

Question 4

What are the factors that impact the selection of immunosuppressive therapy?

Answer 4

1. Expected course and prognosis of disease
2. Concurrent diseases
3. Safety and efficacy
4. Ease of administration- client compliance
5. Cost

Question 5

Describe the use of glucocorticoids for immunosuppression

Answer 5

They are a first line therapy: effective, relatively rapid onset (7-10 days) and cheap

Question 6

What are the major side effects seen with glucocorticoids?

Answer 6

• PUPD, panting, polyphagia (will see this decreased with dose decreases)
• muscle atrophy and weakness
• iatrogenic hyperadrenocorticism
• vacuolar hepatopathy (cholestatic liver pattern- with ALP elevations much higher than ALT)
• infections, sepsis
• GI ulceration (rare)
• hypercoagulability (unsure of mechanism)

Question 7

What are some contraindications for glucocorticoids?

Answer 7

• Diabetes mellitus (better to use combo therapies)
• Infections
• Hyperadrenocorticism
• NSAID therapy (if steroids- NSAID use 2 day washout, if NSAID- steroid wait 5-7 days)

Question 8

How should you dose prednisone and dexamethasone?

Answer 8

Prednisone:
-2 mg/kg/day
-dose cap of 60-80 mg/day in large breeds

Dexamethasone: much more potent (10X)
- 0.2-0.3 mg/kg/day (initially)
- dex SP- 3 mg/mL when doing low dose dex test

Question 9

What is the goal for steroid treatment?

Answer 9

Clinical remission (clinical and pathologic signs) at the lowest effective dose
- taper by 25% every 2-4 weeks (with 2 weeks of stability on BW/signs) over 4-6 months
- discontinue or lowest effective dose (once at lowest dose, move to every other day)
- avoid decreasing other medications at the same time
- if relapse, return to original effective dose

Question 10

When should you consider switching to another therapy when treating immune mediated disease?

Answer 10

• no or poor response
• excessive side effects
• long duration of therapy indicated
• corticosteroids contraindicated

Question 11

Describe the mechanism of action of azathiaprine

Answer 11

Inhibits purine synthesis (DNA) which disrupts lymphocyte proliferation, blocks T cell activation and promotes T cell apoptosis, decreases antibody synthesis

Metabolism limits its use in cats- can lead to very severe myelosuppression

Question 12

What are the main side effects seen with azathiaprine?

Answer 12

-Cytopenias (develop over 2-3 months)
-hepatotoxicity (develops in 1-4 weeks)
-chronic subclinical anemia (PCV >25-30%)
-GI signs- mild and self limiting

Monitoring with CBC and chem is crucial

Question 13

Describe the hepatotoxicity that can be seen with azathioprine

Answer 13

-increases are hard to interpret as patients are also often on concurrent prednisone
-if you start to see more increases in ALT over ALP and increased bilirubin, this is more of a concern that this drug is causing liver toxicity
-most cases are reversible with dose reduction (50%)
-discontinue when you see hyperbilirubinemia
-SAM-e can help prevent and/or reverse hepatotoxicity

Question 14

What are the main indications for azathioprine?

Answer 14

Second line therapy for IMTP, IMHA, IMPA, IBD, SLE
- has glucocorticoid sparing effects (decreases steroid side effects)
- previously was second line agent of choice for IMHA (has been determined that any second line drug is ok)

Question 15

How do you dose azathioprine?

Answer 15

Dose 2 mg/kg q24 hours for 2 weeks
- then decrease to 2 mg/kg q 48 hours
- slow onset
- cheap
- taper after prednisone has been tapered over 2-3 months

Question 16

How is the mechanism of action of cyclosporine different than other immunosuppressives?

Answer 16

It does not interfere with lymphocyte proliferation, but instead impairs the function of the T cells, thus blunting the immune response
- aka no myelosuppression

Question 17

What is one of the main things you need to consider if reaching for cyclosporine in a case?

Answer 17

It has LOTS of drug interactions
- need to check that there are no interactions with any other drug the patient is taking
- antifungals are a big one that interacts with this drug

Question 18

What are the main side effects seen with cyclosporine?

Answer 18

-primarily GI side effects
- can see hepatotoxicity and nephrotoxicity
-gingival hyperplasia, hypertrichosis, excessive shedding, papillomatous, opportunistic infection (especially fungal infections- often very severe)
-can activate platelets (avoid in IMHA)

NO MYELOSUPPRESSION

Question 19

What should you do if you see a skin lesion form on a patient on cyclosporine?

Answer 19

Do cytology or biopsy to determine if fungal infection
- if so, stop med entirely or switch to something else

Question 20

What are some indications for cyclosporine?

Answer 20

IMHA< ITP, IBD, MG, MUE< GN, anal furunculosis, pemphigus foliaceous
-onset of action over days to months
-chronic inflammatory dose 5 mg/kg/day
-acute life-threatening dose: 5-10 mg/kg q 12 h

Question 21

Why is therapeutic drug monitoring often necessary when on cyclosporine?

Answer 21

The same dose may have different effects in different patients

Question 22

What is the recommended formulation of cyclosporine?

Answer 22

Microemulsion form- improves bioavailability
- oil based is not recommended- high variability in bioavailability
- be cautious with generics

ATOPICA is the common name brand used- comes in capsules and oral suspension

Question 23

Describe the use of chlorambucil in vet med

Answer 23

• it is an alkylating antineoplastic agent
• targets B cells (stops proliferation)
• slow onset of action (about 2 weeks)
  -can be very expensive (often need to get compounded)
• Used mostly in cats for IBD, PLE or glomerulonephritis
• used for chronic protein losing enteropathies in dogs

Question 24

What are the main side effects associated with chlorambucil?

Answer 24

GI effects in cats, myelosuppression (dose dependent- monitor CBC), alopecia and poor hair growth (especially in beagles), neuro signs in cats

Question 25

Describe the use of leflunomide in vet med

Answer 25

-it inhibits B and T cell function and proliferation and suppresses antibody production -well tolerated -side effects: GI, myelosuppression, cutaneous drug reactions, hepatotoxicity -must monitor CBC and chem over time (specifically ALT) -main uses are for add on or stand-alone therapy for immune mediated polyarthritis, IMHA, ITP, MUE, histiocytosis, pemphigus, colorectal polyps - dose 2 mg/kg PO q 24h

Question 26

Why is mycophenolate mofetil considered the "more friendly" azathioprine?

Answer 26

Same mechanism of action with less side effects - still can see GI upset at very high doses - there are some drug interactions with fluroquinolones, metronidazole, PPIs, glucocorticoids, cyclosporine and azathioprine

Question 27

When has mycophenolate been used successfully as a standalone therapy?

Answer 27

ITP, IMHA

Question 28

What are some of the main considerations when using mycophenolate?

Answer 28

- dosed at 10 mg/kg PO BID - dosing is easier and cheaper for large breed dogs - there is an oral suspension and IV formulation - can take 2-3 weeks to start working - can be used stand alone or in refractory/relapsing disease