Intro to Autoimmune Diseases

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giddyupp
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Intro to Autoimmune Diseases
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2011-03-24 21:01:21
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Intro Autoimmune Diseases PHPR524 Test5
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Intro to Autoimmune Diseases
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  1. What are the characteristics of the innate immune response?
    • Early, rapid recognition
    • No antigen specificity
    • <100% immune response
    • Limited specificity
    • Limited antigen recognition
  2. What are the components of the innate immune response?
    • Granulocytes (Eosinophils, Basophils, Neutrophils)
    • Monocytes/Macrophages
    • Dendritic cells
    • Natural killer cells
    • C-reactive protein
    • Lysozymes
    • Complement
    • Interferons
  3. What are the characteristics of the adaptive immune response?
    • Slower response (days)
    • Memory a key component
    • 100% immune response
    • Very specific response
    • Recognizes wide array of antigens
  4. What are the components of the adaptive immune response?
    • Antibodies
    • Cytokines
    • B cells
    • T cells
  5. What is the process for producing the adaptive immune response?
    • Antigen presenting cells (APC) (dendritic cells, monocytes/macrophages) present the antigen to T-helper cells
    • Resting T-helper cells with the appropriate receptor (TCR) and CD4 recognize the antigen and MHC II on the APC (Signal 1)
    • CD80 and CD86 on the APC interact with CD28 on the T-cell (Signal 2)
    • The signal is then passed into the cell through TCR/CD3 complex and the activated T-cell starts expressing IL-2 receptors
    • IL-2 binds to the IL-2 receptor which includes CD25, while IL-15 binds to the IL-15 receptor
    • mTOR and CDK/cyclins are activated
    • Mitosis begins and cell divides and differentiates into TH1, TH2, TH17, etc.
  6. What are the effects of T-cell activation and differentiation on the immune response and autoimmune diseases?
    • TH1 cells secrete IL-2, Interferon gamma, and CD8+ cytotoxic cells, and target intracellular bacteria; viruses; and fungi
    • TH2 cells secrete IL-4, IL-5, and stimulate conversion of B cells to plasma cells which produce lots of antibody, and target parasites
    • TH17 cells probably cause autoimmune diseases, and target extracellular bacteria and fungi
    • APC are also activated, maximizing macrophage activity, increasing conversion of B cells to plasma cells, and releasing inflammatory cytokines
  7. What is the MOA of corticosteroids in immunosuppression?
    • Inhibition of phospholipase A2 conversion of phospholipids to arachidonic acid causing:
    • anti-inflammation
    • anti-proliferation
    • immunosuppression
    • glucocorticoid activity (glucose retention)
    • mineralocorticoid activity (sodium retention)
  8. What are the SE of corticosteroids?
    • GI ulceration
    • Appetite changes
    • Indigestion
    • Glucose intolerance
    • Insomnia, nervousness, psychosis (high dose)
    • Cushion's syndrome (taper off)
    • Osteoporosis
    • Cataracts, glaucoma
    • Fluid and electrolyte disturbance
    • Skin atrophy
    • Telangiectasia
    • Hypopigmentation
    • Steroid acne
    • Rosacea-like eruptions
  9. What are the most widely used corticosteroids?
    • Prednisone
    • Methylprednisolone
  10. What corticosteroid is used in kids and the renally impaired?
    Prednisolone
  11. What are the special considerations for corticosteroids?
    • Response may be seen in 2 wks, but maximal effectiveness may take 6-8 wks
    • Use least potent agent that is effective (esp. in kids and elderly, or for large or thin-skinned areas)
    • Use topical agents 2-4 times daily
    • Only use high-potency agents on thick, chronic lesions over small areas and no longer than 2 wks
    • Tachyphylaxis can occur with prolonged use (requiring higher doses/strength to get same effect)
  12. What is the MOA of methotrexate in immunosuppression?
    Inibition of dihydrofolate reductase, disrupting T-cell purine and thymidylic acid metabolism = disruption of cytokine production
  13. What are the SE of methotrexate?
    • Liver toxicity
    • Stomatitis
    • NV
    • Abdominal pain
    • Myelosuppression
    • Renal toxicity
    • Pneumonitis
    • Pulmonary fibrosis
  14. What are the special considerations of methotrexate?
    • Always dose with folic acid (reduces stomatitis)
    • Leucovorin is used to reverse MTX effects
    • Doses over 15mg/wk should be given parenterally
    • Pregnancy category X
  15. What are the DI of methotrexate?
    • Penicillin
    • TMP/SMX
    • Live vaccines
    • NSAIDs
    • Warfarin
    • Immunosuppressants (Cyclosporine, Leflunomide)
    • Oral retinoids (additive hepatotoxicity)
  16. What is the MOA of leflunomide in immunosuppression?
    Disrupts T cell pyrimidine metabolism and cytokine production
  17. What are the SE of leflunomide?
    • Liver toxicity
    • Drug-induced hepatitis
    • GI distress
    • Myelosuppression
    • Alopecia
  18. What are the special considerations for leflunomide?
    • Loading dose necessary d/t long half-life
    • Pregnancy category X
  19. What are the DI of leflunomide?
    • MTX (additive hepatotoxicity)
    • Warfarin
    • Live vaccines
  20. What is the MOA of the thiopurines (Azathioprine and 6-Mercaptopurine) in immunosuppression?
    • Interfere with purine metabolism
    • Induce T-cell apoptosis
  21. What are the SE of the thiopurines (Azthioprine and 6-Mercaptopurine)?
    • Myelosuppression
    • Hepatotoxicity
    • NV
    • Pancreatitis
    • Hyperuricemia
  22. What are the special considerations for the thiopurines (Azathioprine and 6-Mercaptopurine)?
    • Pregnancy category D
    • Take with food
    • Adjust dose in renal failure (hyperuricemia)
  23. What are the DI of the thiopurines (Azathioprine and 6-Mercaptopurine)?
    • 5-ASA and related compounds (myelosuppression)
    • Allopurinol
  24. What is the MOA of mycophenolate in immunosuppression?
    Non-competitive inhibition of inosine monophosphate dehydrogenase, interfering with purine synthesis
  25. What is are the SE of mycophenolate?
    • Myelosuppression
    • N, D (dose-related)
  26. What are the DI of mycophenolate?
    • Aluminum/Magnesium Antacids (absorption)
    • Cholestyramine (absorption)
  27. What are the special considerations for mycophenolate?
    • Pregnancy category D
    • Adjust dose in renal failure
  28. What is the MOA of cyclophosphamide in immunosuppression?
    • Cross-linking and breaks in DNA, decreasing DNA synthesis
    • Cell apoptosis
  29. What are the SE of cyclophosphamide?
    • Myelosuppression
    • Alopecia
    • Infections
    • Cancer
    • Hemorrhagic cystitis
    • Pneumonitis
    • Pulmonary fibrosis
    • Reproductive toxicities
  30. What are the special considerations for cyclophosphamide?
    • Lower doses used in immunosuppression than in oncology
    • Use MESNA to prevent bladder toxicity
    • Pregnancy category X
    • Mainly used for Lupus nephritis
  31. What is the MOA for calcineurin inhibitors?
    Inhibition of calcineurin causes inhibition of T-cell activation and decreases expression of IL-2 and other cytokines that disrupt T-cell proliferation
  32. What are the SE of systemic calcineurin inhibitors?
    • Nephrotoxicity
    • Increase blood glucose (Tacrolimus more)
    • Drug-induced hyperlipidemia (Cyclosporine more)
    • Electrolyte disturbances (hyperkalemia)
    • Drug-induced hypertension (Cyclosporine more)
    • Hirsutism (Cyclosporine)
    • Alopecia (Tacrolimus)
    • Tremors, disorientation, HA (Tacrolimus more)
    • Gingival hyperplasia (Cyclosporine)
  33. What are the special considerations for calcineurin inhibitors?
    • All three oral formulations are different
    • Standard (Sandimmune) and Modified formulations (Neoral, Gengraf) are not interchangeable
    • Sandimmune absorption is highly variable d/t reliance on bile salt emulsification
    • Narrow therapeutic window = need monitoring
    • Monitor trough for all formulations
    • Monitor C2 for modified formulations
    • Topical use for Psoriasis and Ecsema well tolerated
    • Ophthalmic use for Sjogren syndrome reduces dry eye associated with this inflammation
  34. What are the SE of topical calcineurin inhibitors?
    • Stinging and burning of application site
    • Black Box Warning: lymphoma and skin cancer risk in kids and adults
  35. What are the calcineurin inhibitors used in immunosuppression?
    • Cyclosporin
    • Tacrolimus
    • Pimecrolimus
  36. What are the mTOR inhibitors used for immunosuppression?
    • Sirolimus
    • Everolimus
  37. What is the MOA of mTOR inhibitors in immunosuppression?
    bind mTOR complex 1 and inhibit intracellular mTOR activities (continuation of cell growth and division)
  38. What are the SE of mTOR inhibitors?
    • Hyperlipidemia
    • Peripheral edema
    • Delayed wound healing
    • Mouth ulceration
    • Bone marrow suppression (anemia, leukopenia, thrombocytopenia)
    • Interstitial lung disease
    • Pneumonitis
    • Pneumonia
    • UTI
    • Post-transplant malignancy
    • Comstipation (Everolimus)
    • Teratogenic
  39. What are the special considerations for mTOR inhibitors (Everolimus, Sirolimus)?
    • Narrow therapeutic window = monitoring
    • Monitor trough
  40. What are the DI of mTOR inhibitors (Everolimus, Sirolimus)?
    • 3A4 and p-glycoprotein interacions = many
    • Calcineurin inhibitor SE enhanced
  41. What is the MOA of Fingolimod in immunosuppression?
    • Sphingosine 1-phosphate (S1P) receptor modulator
    • Maybe - reduces migration of lymphocytes from nodes to peripheral circulation
  42. What are the SE of Fingolimod?
    • HA
    • Influenza
    • D
    • Back pain
    • Liver enzyme elevation
    • Cough
  43. What are the DI of Fingolimod?
    • CI antiarrhythmics (Quinidine, Procainamide)
    • CIII antiarrhythmics (Amiodarone, Sotalol)
    • BBL
    • Ketoconazole
    • Live vaccines
  44. What is the MOA of biologic therapy in immunosuppression?
    Typically, through non-covalent binding, disrupt cell signaling and/or cause depletion of B-cells and T-cells
  45. What are the SE of biologic therapies?
    • Infusion/injection reactions (hypotension, injection site rxns, fever, chills, cytokine release)
    • Hypersensitivity
    • Flu-like syndromes
    • Coughing
    • Infections
    • Skin reash (esp. with SQ dosing)
  46. What are the special considerations for biologic therapies?
    • Production of neutralizing antibodies by the host can reduce and eliminate effectiveness
    • Very few drug interactions
    • DO NOT combine biologic agents together
  47. What are the types of biologic therapies used for immunosuppression?
    • Polyclonal antibodies
    • Monoclonal antibodies
    • Intravenous Immune Globulin (IVIG)
  48. What is the MOA of polyclonal antibodies (Atgam, Thymoglobulin)?
    T-cell depletion by killing active T-cells Blocks CD25, CD3 to prevent T-cell activation)
  49. What are the SE of polyclonal antibodies?
    • Fever, chills, cytokine release (use diphenhydramine)
    • Thrombocytopenia
    • Leukopenia
    • HA (first few doses)
  50. What are the special considerations for polyclonal antibodies?
    • Atgam (lymphocyte)(horse):
    • Skin testing strongly recommended before administration
    • Preferred route = central line over 4h
    • Thymoglobulin (antithymocyte)(rabbit):
    • Pre-medicate with APAP and diphenhydramine
    • Infuse with an in-line filter through a central line
  51. What is the MOA of IVIG in immunosuppression?
    Disrupts immune system and tones it down
  52. What are the SE of IVIG?
    • Chills, nausea, HA, flushing during and after infusion (pre-medicate, slow down infusion, or temporarily stop infusion)
    • Acute renal failure
    • Transient neutropenia
    • Risk of infection
    • Hep B, Hep C, HIV
    • Creutzfeldt-Jakob disease
  53. What are the special considerations for IVIG?
    Each preparation is different composition, salt content, and/or pH (Selected - specific IgGs, Unselected - lacks specificity)
  54. What is the MOA of monoclonal antibodies in immunosuppression?
    • Induction of apoptosis
    • Antibody-dependent cell cytotoxicity (ADCC)
    • Antibody-mediated cell death by other cells of the immune system
    • Complement-mediated cell death (CDC)
  55. What are the SE of infliximab?
    • Reactivation of Hep B and TB
    • Serious infection risk
    • Heart failure exacerbation
    • Lymphoma risk
    • Demyelinating disease
  56. What are the SE of adalimumab?
    • Reactivation of Hep B and TB
    • Serious infection risk
    • Heart failure exacerbation
    • Lymphoma risk
    • Demyelinating disease
  57. What are the SE of Certolizumab pegol?
    • Reactivation of Hep B and TB
    • Serious infection risk
    • Heart failure exacerbation
    • Lymphoma risk
    • Demyelinating disease
  58. What are the special considerations for Certolizumab pegol?
    • It is a Fab fragment (no Fc region on the mab)
    • No ADCC or CDC expected
  59. What are the SE of golimumab?
    • Reactivation of Hep B and TB
    • Serious infection risk
    • Heart failure exacerbation
    • Lymphoma risk
    • Demyelinating disease
  60. What are the SE of Tocilizumab?
    • Serious infection risk (neutropenia)
    • Liver toxicity
    • GI perforation
    • Lipid abnormalities
  61. What are the SE of Ustekinumab?
    • Mycobacterial and salmonella infection risk
    • Malignancy risk
    • Risk of Reversible Posterior Leukencephalopathy Syndrome (RPLS; 1 case)
  62. What are the SE of natalizumab?
    • Risk of demyelinating disease (Progressive Multifocal Leukencephalopathy PML; 5 cases)
    • This is fatal, there is no treatment
  63. What are the SE of Rituximab?
    • Demyelinating disease
    • Renal toxicity
    • Infection (monitor CBC)
  64. What are the SE of Daclizumab and Basiliximab?
    generally well tolerated
  65. What is the target of Infliximab, Adalimumab, Certolizumab pegol, and Golimumab?
    TNF alpha
  66. What drugs target TNF alpha?
    • Infliximab
    • Adalimumab
    • Certolizumab pegol
    • Golimumab
  67. What is the target of Tocilizumab?
    IL-6
  68. What is the target of Ustekinumab?
    • IL-12
    • IL-23 (primary)
  69. What is the target of Natalizumab?
    alpha-4-integrin (adhesion molecule)
  70. What is the target of Rituximab?
    CD20 (B cells)
  71. What is the target of Daclizumab and Basiliximab?
    CD25
  72. What drugs target CD25?
    • Daclizumab
    • Basiliximab
  73. What are the meanings of the first infix of monoclonal antibodies?
    • -li-/-l-: immunomodulatory
    • -ki(n)-/-k-: targets interleukins
    • -tu-/-t-: targets tumors
    • -ci-/-c-: targets cardiovascular system
    • -so-/-s-: bone
  74. What are the meanings of the second infix of monoclonal antibodies?
    • -u-: fully human
    • -zu-: humanized
    • -xi-: chimeric
    • -o-: fully mouse
    • -i-: primate
  75. What are the antibody-based fusion proteins used in immunosuppression?
    • Etanercept (TNF alpha)
    • Abatacept (CD80/CD86)
    • Alefacept (LFA-3)
    • Rilonacept (IL-1)
    • Anakinra (IL-1)
  76. What is the target for Etanercept?
    TNF-alpha
  77. What is the target for Abatacept?
    CD80/CD86
  78. What is the target for Alefacept?
    LFA-3
  79. What is the target for Rilonacept?
    IL-1
  80. What is the target for Anakinra?
    IL-1
  81. What are the SE of Etanercept?
    • Reactivation of HepB and TB
    • Heart failure exacerbation
    • Lymphoma risk
    • Demyelinating disease
    • Serious infection risk
  82. Why do TNF-alpha agents cause exacerbation of heart failure?
    TNF-alpha keeps the heart in check
  83. What are the SE of Abatacept?
    • Relatively safe and well tolerated
    • Contains CTLA-4 (endogenous co-stimulation signal blocker)
  84. What are the special considerations for Alefacept?
    • Monitor CD4 counts
    • Mild effects and slow onset
  85. What are the SE of Rilonacept?
    • Injection site reactions
    • URTIs
  86. Which agents prevent T-cell activation?
    • Abatacept (CD80/CD86)
    • Cyclosporine (Calcineurin)
    • Tacrolimus (Calcineurin)
    • Pimecrolimus (Calcineurin)
  87. Which agents decrease the inflammatory effects of cytokines?
    • Corticosteroids
    • Infliximab (TNF)
    • Adalimumab (TNF)
    • Certolizumab pegol (TNF)
    • Golimumab (TNF)
    • Etanercept (TNF)
    • Tocilizumab (IL-6)
    • Ustekinumab (IL-12, IL-23)
    • Rilonacept (IL-1)
    • Anakinra (IL-1)
  88. Which agents interrupt the cell cycle and disrupt cell division/differentiation?
    • Sirolimus (mTOR)
    • Everolimus (mTOR)
  89. Which agents prevent the release of IL-2 and activation of IL-2 receptors, halting the cell cycle and differentiation/division?
    • Daclizumab (CD25)
    • Basiliximab (CD25)
  90. Which agents inhibit B-cells?
    Rituximab (CD20)
  91. What happens if T-cells are not activated?
    • APCs are not activated and:
    • cytokines are not released
    • macrophages are not at full capacity
    • B-cells do not become plasma cells
    • Antibodies are not released

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