Autoimmune and Immunomodulatory Drugs Flashcards
(18 cards)
describe immune-mediated versus autoimmune
-immune mediated: relatively broad term for any disease process involving an abnormal immune response
-autoimmune: a more specific term describing a specific adaptive response mounted against self antigens (autoantigens)
how does autoimmunity develop?
body has mechanisms of tolerance:
-central: autoreactive T cells
-peripheral: autoreactive B cells
-other
-autoreactive cells constantly made but body destroys them usually
genetic predispositions: MHC or non-MHC genes, epigenetics
and
-environmental factors: infectious agents, etc.
result in dysregulation of innate and/or adaptive immunity
how are autoimmune/immune related diseases classified?
- antibody-mediated damage
-antigen-antibody immune complex
-antibody-dependent cell-mediated cytotoxicity
-cell adhesion disruption/receptor blockage
-includes: pemphigus complex and autoimmune subepidermal blistering diseases (AISBDs) - lymphocyte-mediated damage
-cytotoxic T cells target cells presenting autoantigen-originated peptides
-includes: keratinocyte-targeting (SLE, erythema multiforme), melanocyte targeting (vitiligo/uveodermatologic syndrome), sebaceous gland cell targeting (sebaceous adenitis), and hair follicle keratinocyte targeting (alopecia areata, pseudopelade)
describe practical aspects of immunosuppressive therapy/therapeutic goals
therapeutic goals: 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 achieved to lowest effective dosage/discontinue - but GCs have many side effects so currently, non-steroidal immunomodulators as GC-sparing agents as used at the start of therapy
what drugs focus on T cells?
- prednisolone
- mycophenolate
- azathioprine
- leflunomide
- chlorambucil
- janus kinase (JAK) inhibitors
- cyclosprine and tacrolimus
what 3 signals from APCs activate T cells?
(FYI, just for understanding)
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
any impairment of these signals leads to suboptimal activation of T cells and can result in:
-cell death
-unresponsiveness
-tolerance of self-antigens
describe the mechanism of action/use of glucocorticoids (5)
- genomic effects and nongenomic effects
- expression of anti-inflammatory and regulatory proteins
- suppression of proinflammatory proteins, chemokines, adhesions molecules, many others
-VERY BROAD AND NONSPECIFIC
-good to use for all disease bc so broad - use:
-oral most common
-injectable depo-medrol: avoid if can, more side effects
-topical: also common
-can use dex SP oral in cats? - immediate effect, see improvement within a few days!
describe the side effects of glucocorticoids, systemic (5) and dermatologic (3)
systemic
1. PU/PD/PP
2. muscle wasting
3. steroid hepatopathy
4. gastric bleeding/ulcers
5. CHF (cats >dogs)
dermatologic:
1. skin atrophy, bruising, prominent blood vessels, alopecia
2. calcinosis cutis
3. alopecia with think skin and skin fragility
describe steroid-sparing immunomodulators
- consider adding in addition to GCs from the beginning as adjunctive therapy
- take much longer to effect than GCs because targeting T cells to ultimately reduce plasma cells
-but begin at the same time as steroids to allow time to effect plus relief
describe cyclosporine and tacrolimus
- calcineurin inhibitors; signal 1 inhibition of T-lymphocyte function and IL-2 secretion
- MANY different cyclosporine formulations in the US
-some cheaper and some very pricey
-AVOID compounded!! cheapest but very low bioavailablitiy
-many generics available, but wide variation in individual response to generics so may need to play around before find the right one - approved for use:
-in dogs: for atopic dermatitis
-in cats: for feline allergic skin diseases
-many off label usages though for both dog and cat
describe side effects of cyclosporine in dogs
acute:
1. GI upset: vomiting, diarrhea, hypersalivation
-resolve by titrating dose lower until signs resolve ad then increase again
-giving with food and freezing capsules helps with GI signs without changing clinical efficacy
chronic:
-gingival hyperplasia
-viral papilloma
-opportunistic fungal infections
-psoriasiform-lichenoid dermatitis
-NO evidence of increased risk of neoplasia though!
describe side effects of cyclosporine in cats
acute: GI upset like dogs
chronic:
-increased severity of toxoplasma gondii in seronegative cats
fatal toxoplasmosis only in cats with 2x higher plasma CSA levels
-screen toxoplasma titers in outdoor cats before cyclosporine admin
-no evidence of increased risk for neoplasia though!
describe JAK inhibitors
many cytokines and growth factors signal through JAK pathway
Jaks get phosphorylated, go to STATs and phosphorylate, which go to nucleus and make proteins
JAK inhibitors make cells stop responding/getting activated by different cytokines and growth factors
hella many JAKs exist though = complex
-each JAK inhibitors has to be tested for its affinity with each JAKs to see how many effects it may have AND every body metabolizes these differently so each drug will have different effects on different bodies
describe oclacitinib
- predominantly blocks JAK1 cytokines (and JAK2)
- inhibits: T cell proliferation and survival, pro-allergic cytokines, interferons (antiviral), and many others
- approved only to treat atopic dermatitis in DOGS
-cats need much higher doses, and is only off label use - side effects in dogs:
-no label use for dogs <12 months
-infections: papilloma
-cutaneous masses: histiocytomas
-not rec for those with pre-existing neoplasia
-dermatomyositis
-squamous cell carcinoma
-sebaceous adenitis
-osteosarcoma - side effects in cats:
-off label only! NOT approved
describe illunocitinib
- described as a broader immunomodulating JAK-inhibitor than ocalcitinib
-works better but suppresses more of the immune system - high affinity for JAK1, JAK2, and TYK2 cytokines
- MUST discontinue at least 28 days to 3 months prior to vaccination and withhold for at least 28 days after vaccination
-due to risk for vaccine-induced disease and inadequate immune response to vaccines
-ON EXAM PROBABLY
describe antimetabolites
- azathioprine, mycophenolate, leflunomide
- inhibit DNA replication and cell proliferation by impairing de novo synthesis of nucleotides and cytotoxicity
- inhibition can result in hepatotoxicity and myelosuppression
- dogs have higher TMPT levels than humans = greater risk of hepatotoxicity
-need routine CBC and biochem check-ups! every 2 weeks initially and then 1-3 months later
describe mycophenolate mofetil metabolism
- high inter-individual PK variability and efficacy due to gene polymorphisms (in enterocytes and liver)
-some dogs will do well and some will not - side effects:
-GI toxicity: soft stools, diarrhea, vomiting; DISCONTINUE if see (will turn into hemorrhagic gastroenteritis)
-CBC and biochem check=ups not generally required
describe therapeutic immuno-targeting drugs
- tetracyclines and nicotinamide
-most commonly for lupus
-decreases proinflammatory cytokines, decreases neutrophil chemotaxis/activation
-decreases antigen presentation and TLR signaling - hydroxychloroquine: also for lupus
-binds nucleic acid complexes, decreases TLR signaling, inhibition of endolysosomal acidification, phagocytosis, and antigen presentation
