Immunomodulating Drugs: Flashcards
Autoimmune/Immune-mediated Skin diseases:
-Diverse heterogeneous entities and clinical phenotypes
-Pemphigus foliaceus (PF) = most common autoimmune disease of dogs & cats!!!
-Immune-mediated: Any disease process involving an abnormal immune response (more broad term)
-Autoimmune: A specific adaptive immune response mounted against self-antigens
-Antibody-mediated damage:
-Antigen-antibody immune complex, antibody-dependent cell-mediated cytotoxicity, cell adhesion disruption/receptor blockage
-Lymphocyte-mediated damage
-Cytotoxic T cells target cells presenting autoantigen-originated peptides
Therapeutic goals of immuno-targeting drugs:
-Achieve complete remission (CR) as quickly as possible
-Historically, relied on fast-acting and immune broad-targeting glucocorticoids for all diseases
-Taper GCs after CR is achieved to lowest effective dosage/DC
-However, GCs are associated with severe side effects
-Currently, non-steroidal immunomodulators as GC-sparing agents at the start of therapy
T-Cell Targeting Drugs:
-Prednisolone
-Mycophenolate
-Azathioprine
-Leflunomide
-Cyclosporine
-Tacrolimus
-Chlorambucil
-JAK Inhibitors
3 Signals to active T-Cells:
-Signal 1: Mediated by antigen recognition on MHC II Molecules
-Signal 2: Boosts signal 1 in a costimulatory manner
-Signal 3: Differentiate the activated cells into functionally relevant subsets
-If suboptimal activation of T cells then you’ll have apoptosis, unresponsiveness (anergy), and a tolerance to self-antigens
Prednisolone MOA:
-Genomic:
-Direct binding (Transactivation)
-Tethering (Transrepression)
-Non-genomic:
-Cell membranes (decrease in calcium)
-Decrease in ATP and arachidonic acid
-Interaction with signaling proteins
-Results:
-Expression of anti-inflammatory and regulatory proteins
-Suppression of proinflammatory proteins, chemokines, adhesion molecules
Prednisolone Indications & Types:
Indications:
-Broadest immune-targeting drugs across different cell types
-We LOVE that it has an immediate effect
Types:
-Oral prednisone for dogs and Cats (Never give to cats as it has decreased bioavailibility and/or conversion in the liver!!!)
-Oral dexamethasone and triamcinolone for dogs and cats
-Injectable methylprednisolone acetate (Depo-Medrol) should be avoided if possible!!!
-Topical hydrocortisone aceponate, mometasone furoate
-Oral dex sp for feline atopic skin syndrome (FASS): Dexamethasone SP oral admin for 24-28 days then taper
Prednisolone Side Effects:
Systemic:
-PU/PD, polyphagia, muscle wasting, steroid hepatopathy, gastric bleeding/ulcers
-CHF (Cats > dogs), diabetes mellitus
-Potentially increased risk with long-term injectable GCs
Dermatological:
-Dogs: Skin atrophy, bruising, prominent blood vessels, alopecia, calcinosis cutis
-Cats: Alopecia, thin skin and fragility (Skin fragility syndrome)
Steroid-Sparing (Non-steroidal) immunomodulators:
-Mycophenolate, azathioprine, leflunomide, cyclosporine, tacrolimus, chlorambucil, JAK inhibitors
-Have a delayed effect as they are targeting T cells so should always start with steroids at the same time!!
-Consider adding “steroid-saving” agents in addition to GCs from the beginning as an adjunctive therapy
Cyclosporine and tacrolimus:
-Calcineurin inhibitors: Primary effect is on T cells
-Primary MOA is signal 1 inhibition of T-lymphocyte function and IL-2 secretion
-Avoid compounded cyclosporine!!!
-Indications:
-Dogs: Atopic dermatitis
-Cats: Feline allergic skin diseases
-Side Effects in Dogs:
-Acute: Acutely upset GI; To mitigate this do slow increases in dosage as well as giving food and freezing capsules
-Chronic: Gingival hyperplasia; Viral papilloma; Opportunistic fungal infections; psoriasiform-lichenoid dermatitis
-No evidence of increased risk of neoplasia in dogs treated for atopic dermatitis
-Side effects in Cats:
-Acute: Same as for dogs
-Chronic: Increased severity of toxoplasma gondii infection in seronegative cats, but fatal toxoplasmosis only in a cat with 2x higher plasma CSA levels. Screen toxo titers in outdoor cats before administration
-No evidence of increased risk of neoplasia in cats treated for feline hypersensitivity
JAK Inhibitors:
-There are many cytokines and growth factors (EPO) that signal through JAK pathway.
-Once JAKs are phosphorylated they tend to phosphorylate the STAT which goes to the nucleus and promotes a certain region of a gene and does whatever the growth factor function is.
-Many cells have receptors for these different cytokines and growth factors, so many use JAK-STAT signaling
-2 Main drugs to know:
-Oclacitinib (Apoquel)
-Ilunocitinib (Zenrelia)
Oclacitinib (Apoquel):
-Inhibits signaling of JAK1 cytokines (and JAK2)
-T cell proliferation and survival (IL-2 and IL-15)
-Pro-allergic cytokines: IL-4, IL-6, IL-13, IL-31
-Interferons (Antiviral): IFN-a, IFN-b, IFN-k, IFN-y
-Approved for atopic dermatitis in dogs
-Approved for feline allergic skin diseases in cats
-Side effects in dogs:
-Similar to other immunosuppressants, not recommended for patients with neoplasias
-Long-term treatment with oclacitnib did not pose additional risk for malignancy in dogs
-Side effects in cats:
-Transcript quantification and protein levels of JAK2 are much lower in cat cells compared with dog cells
-Sufficient therapeutic index in cats has not been established
Ilunocitinib (Zenrelia):
-Shows higher selectivity for JAK1, JAK2, and TYK2 cytokines
-Broader immunomodulating JAKi compared to oclacitinib
-Side effects in dogs:
-Vaccine-induced disease and inadequate immune response to vaccines
-DC for at least 28 days to 3 months prior to vaccinations and withhold for at least 28 days after vaccinations
-Many dogs achieve more than 50% reduction from baseline in PVAS from day 28 onwards
