VCS80610_IMsupp2023.pptx

Immunosuppressive Medications VCS 80610 Fall 2023 Andrew Woolcock, DVM, DACVIM Purdue University College of Veterinary Medicine Objectives • Review of Immune Targets • Considerations before immune suppression • Immune-suppressive medications – The old – The new Innate Immunity • Sentinel Cells...

Immunosuppressive Medications VCS 80610 Fall 2023 Andrew Woolcock, DVM, DACVIM Purdue University College of Veterinary Medicine Objectives • Review of Immune Targets • Considerations before immune suppression • Immune-suppressive medications – The old – The new Innate Immunity • Sentinel Cells • Phagocytosis • Vasoactive Molecules • Complement Adaptive Immunity • Lymphocytes • B Cell – Antibody • T Cells – CD8 – Cytotoxic – CD4 – Helper • NK Cells KOPECNY, L. 2013. Veterinary immunology. 9th edn. Edited by IR Tizard . Elsevier, St Louis, 2013. Immune Targets Leflun o Chlora mb Objectives • Review of Immunity and Autoimmunity • Considerations before immune suppression • Immune-suppressive medications – The old – The new Before Immune Suppression • Questions to consider: • Primary or Secondary? • Co-morbid disease? – Interactions with existing medications • Clinical signs vs. Toxicity profile • Licensed veterinary product available? • Appropriate formulation/tablet size available? • Can the owner administer? Afford? • Adjunctive medication necessary? Objectives • Review of Immunity and Autoimmunity • Considerations before immune suppression • Immune-suppressive medications – The old – The new Immune-Suppressive Medications • • • • • • Glucocorticoids Azathioprine Cyclosporine Chlorambucil Leflunomide Mycophenolate Immune-Suppressive Medications • • • • • • Glucocorticoids Azathioprine Chlorambucil Cyclosporine Leflunomide Mycophenolate Glucocorticoids • Broad anti-inflammatory and immunesuppressive properties – Phagocytosis - Lymphocytes – Inflammatory cytokines- Macrophages – Complement – Fc receptors – Neutrophils – Antigen presentation Glucocorticoids • Sentinel Cells • Phagocytosis • Vasoactive Molecules • Complement Decreased activity and differentiation of Dendritic Cells Glucocorticoids • Sentinel Cells • Phagocytosis • Vasoactive Molecules • Complement Decreased myeloid cell function and inhibition of leukocyte emigration Glucocorticoids Inhibition of vasodilation and vascular permeability • Sentinel Cells • Phagocytosis • Vasoactive Molecules E.g. Histamine, Serotonin, Eicosanoids (COX & LOX), etc. Increase blood flow PAIN REDNESS • Complement HEAT Increase vascular permeability SWELLING Glucocorticoids • • • • Sentinel Cells Phagocytosis Vasoactive Molecules Complement Decreased activation of the complement cascade and membrane attack complex Glucocorticoids Decreased gene transcription encoding proinflammatory cytokines and chemokines Glucocorticoids • Dose Ranges – Physiologic, 0.1-0.5 mg/kg/day – Anti-inflammatory, 0.5-1.0 mg/kg/day – Immune-suppressive, 2.0-4.0 mg/kg/day • Considered “gold standard” for most immune-mediated diseases – Multiple mechanisms – Habit/culture Glucocorticoids THE OLD… • Commonly prescribed glucocorticoids: – Prednisone – Prednisolone – Dexamethasone (SP) – Methylprednisolone – Temaril-P Glucocorticoids • Adverse Effects: – PU/PD, Polyphagia – Muscular weakness/atrophy – Panting – Tendon/ligament laxity – Alopecia – Insulin resistance – Hypercoagulability THE OLD… Immune-Suppressive Medications • • • • • • Glucocorticoids Azathioprine Chlorambucil Cyclosporine Leflunomide Mycophenolate Azathioprine • Synthetic derivative of 6-mercaptopurine (6MP) • Interferes with purine synthesis – Faulty nucleotides – Faulty DNA/RNA – Faulty cellular metabolism and mitosis – Faulty lymphocytes Azathioprine • Available formulations – 50 mg tablet (Imuran®) – No parenteral formulation available • Recommended dose: – Dog: 2 mg/kg PO once daily – Cat: Not recommended • Onset of immune suppression: 1-2 weeks Azathioprine THE OLD… • Historically: – IMHA – Inflammatory bowel disease – Refractory immune-mediated diseases • Adverse Effects: – Gastrointestinal upset, pancreatitis – Myelosuppression – Hepatopathy Azathioprine THE NEW… • Hepatotoxicity – Wallisch et al, 2015 – 15% of canine patients developed an increased ALT within 14 days of administration – Resolved with dose reduction or discontinuation Azathioprine THE NEW… • Hepatotoxicity – Resolved with dose reduction or discontinuation – Consider dose reduction after 2 weeks • Every other day Immune-Suppressive Medications • • • • • • Glucocorticoids Azathioprine Chlorambucil Cyclosporine Leflunomide Mycophenolate Chlorambucil • Alkylating agent – Cross-links DNA – Cell cycle non-specific – Primarily targets B-lymphocytes • Historically used as a treatment for lymphoma Chlorambucil • Available formulations: – 2 mg tablets (Leukeran®) • Cost prohibitive • Compounding available and necessary for most patients Chlorambucil • Recommended dose: – Dog 4 mg/m2 q24-48h – Cat – multiple protocols • 3-5 mg/cat every 2 weeks • 2 mg/cat every other day (MWF) • Onset of immune suppression – Slow – Up to two weeks Chlorambucil THE OLD… • Historically: – Adjunctive chemotherapy agent • Lymphoma, mast cell neoplasia – Cytotoxic drug-of-choice for cats Chlorambucil THE OLD… • Adverse effects: – Gastrointestinal – Myelosuppression (7-14 days postadministration) – Neurotoxicity (cats) Chlorambucil THE NEW… • Inflammatory bowel disease vs. small cell GI lymphoma – Cats – Stein et al, JAAHA 2010 – 96% clinical response rate in cats with scGI lymphoma with chlorambucil • Similar response seen in IBD Chlorambucil THE NEW… • Inflammatory bowel disease vs. small cell GI lymphoma – Cats – Al Nadaf et al, JAVMA 2022 – 2 mg PO EOD in cats undergoes rapid absorption and drug clearance without accumulation between doses. Chlorambucil THE NEW… • Inflammatory bowel disease – Dogs – Dandrieux et al, JAVMA 2013 – Dogs with IBD on pred/aza vs pred/chlorambucil – Greater improvement in weight and albumin in pred/chlorambucil group Immune-Suppressive Medications • • • • • • Glucocorticoids Azathioprine Chlorambucil Cyclosporine Leflunomide Mycophenolate Cyclosporine • Calcineurin inhibitor – Intracellular second-messenger system – Blocks gene transcription and cytokines required for T-cell activation • IL-2, TNF-α • Indirect effects on granulocytes Cyclosporine • Licensed veterinary product (Atopica®) – Atopic dermatitis • Available formulations: – Atopica® Capsule (10, 25, 50, 100 mg) – Atopica® Oral Solution for Cats (100 mg/mL) – Cyclavance® Oral Solution for Dogs (100 mg/mL) – Ophthalmic preparation (Optimmune®) Cyclosporine • Recommended Dose - Dogs – Atopic Dermatitis • 3-5 mg/kg PO Q24 – Mild IM Disease (e.g. IMPA, IBD) • 5 mg/kg PO Q12-24 hours – Severe IM Disease (e.g. IMHA, ITP) • 10 mg/kg PO Q12-24 hours Cyclosporine • Recommended Dose - Cats – Atopic Dermatitis • 3 mg/kg PO Q24 – Mild IM Disease (e.g. IBD) • 3-5 mg/kg PO Q24 hours – Severe IM Disease (e.g. IMHA, ITP) • 5-8 mg/kg PO Q24 hours Cyclosporine • Onset of Immune Suppression? • Variable • 2-4 weeks • Bioavailability of cyclosporine is variable and, in general, poor. Cyclosporine • Archer et al, JVIM 2014 • Atopica has the best bioavailability in dogs and cats • Human product, Neoral, and its generic form (keyword, modified cyclosporine) has acceptable bioavailability as well Cyclosporine • When to consider using a human product? – Cost 15 capsules $6.62/capsule Cyclosporine • When to consider using a human product? – Cost 30 capsules $1.02/capsule $0.58/capsule $1.51/capsule Cyclosporine • Cyclosporine pharmacokinetics – Therapeutic drug monitoring Cyclosporine THE OLD… • Historically: – Atopic dermatitis – Perianal fistulas – Immune-mediated hemolytic anemia – Inflammatory bowel disease – Keratoconjunctivitis sicca Cyclosporine THE OLD… • Adverse Effects: – Gastrointestinal upset – Hepatopathy – Secondary infections • High et al, Can Vet J 2020 • Bacterial infections more common in dogs on immune-suppressive doses • 17% of dogs on high dose Cyclosporine • IMHA • Swann et al, JVIM 2016 • Phenotyping IMHA – Increased IL-2 and TNF-α THE NEW… Cyclosporine THE NEW… • Maturation Arrest/Bone Marrow Directed • Morishita et al (2016) • Pred & Cyclosporine in 8 dogs – 5/8 dogs complete remission Cyclosporine THE NEW… • Immune-Mediated Polyarthritis • Rhoades et al (2016) • Cyclosporine monotherapy (5 mg/kg Q12) for dogs with IMPA – 8/10 complete remission at 45 days • + NSAIDs Cyclosporine THE NEW… • Idiopathic Chronic Hepatitis • Ullal et al, JVIM 2019 • ALT remission in 79% of dogs – Median Cyclosporine dose (8 mg/kg/day) – Median time to remission, 2.5 months Cyclosporine THE NEW… • Feline Chronic Pancreatitis • Hoeyrup et al, Animals 2021 • Significant reduction of Spec fPL – Limited study, no clinical sign monitoring Immune-Suppressive Medications • • • • • • Glucocorticoids Azathioprine Chlorambucil Cyclosporine Leflunomide Mycophenolate Leflunomide • Isoxazole immunomodulatory drug • Inhibits pyrimidine synthesis – Faulty DNA… – Inhibits B & T-Lymphocyte proliferation • Common treatment for human rheumatoid arthritis Leflunomide • Available formulations: – 10 mg and 20 mg tablet (Arava®) – Compounding available, and often necessary • Recommended dose: – 2-4 mg/kg PO once daily • Onset of immune suppression – 1-2 weeks Leflunomide THE OLD… • Historically: – Initial used in renal transplant studies – Isolated reports of use in many immunemediated diseases • Steroid-sparing effects Leflunomide • Adverse Effects: – Gastrointestinal upset – Ecchymosis (idiosyncratic) • Thrombotic microangiopathy THE OLD… Leflunomide THE NEW… • Immune-mediated polyarthritis • Colopy et al (2010) – 14 dogs with IMPA – Leflunomide monotherapy – 8/14 complete remission – 5/15 partial remission Leflunomide • Rheumatoid arthritis – Hanna, VCOT 2005 – Safe, effective in cats THE NEW… Leflunomide THE NEW… • Refractory Immune-Mediated Diseases • Sato et al (2016) • 92 cases, leflunomide (1995-2014) – IMPA, IMT, IMHA, cutaneous histiocytosis • Adverse events in 6.5% Immune-Suppressive Medications • • • • • • Glucocorticoids Azathioprine Chlorambucil Cyclosporine Leflunomide Mycophenolate Mycophenolate • Reversible inhibitor of purine synthesis – Inhibits T & B lymphocyte proliferation – May also induce apoptosis in activated T-cells • Commonly used in human transplant patients • Developed as an alternative to azathioprine Mycophenolate • Available formulations: – 250 mg and 500 mg capsules (CellCept®) – Parenteral formulation available • 25 mg/mL Mycophenolate • Recommended dose: – 8-10 mg/kg twice daily • Onset of immune suppression – 1-2 weeks Mycophenolate THE OLD… • Historically: – Canine renal and bone marrow transplantation – Pemphigus complex – Myasthenia gravis Mycophenolate THE OLD… • Adverse Effects: – Gastrointestinal upset – Allergic reaction • Fukushima et al, JVIM 2021 – 34/131 dogs on MMF had AE (25%) • 31/34 were gastrointestinal • Severe enough to discontinue MMF in 15 cases Mycophenolate THE NEW… • Immune-Mediated Thrombocytopenia • Yau et al, JVIM 2014 • 5 dogs with IMT, steroids contraindicated • MMF monotherapy – Remission achieved in all 5 dogs Mycophenolate THE NEW… • Inflammatory CNS disease – Meningoencephalomyelitis of unknown etiology – Vet Med & Sci (2016) – MST similar to other cited protocols Mycophenolate THE NEW… • Refractory immune-mediated disease • Inflammatory bowel disease • Maturation Arrest – Morishita et al (2016) Summary • No standardized approach • Consider the need for adjunctive immunesuppression – Severity of disease – Steroid sparing effects • Treatment NOT including steroids? Thank you!