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334 Cards in this Set
- Front
- Back
Definition of autoimmunity?
|
Unwanted immune responses against self-tissue antigens that cause chronic inflammatory injury.
This is a chronic condition because self-antigens are always present so the immune response never shut off. This results in tissue damage. |
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What is the prevalence of autoimmunity?
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1-2% of the US population
|
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What are the two major classifications of autoimmunity?
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Organ specific such as IDDM and MS
Non-organ specific such as SLE and RA |
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What are common featues of Autoimmune diseases?
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Symptoms vary significantly
- Sxn wax and wane in severity over time - Disease activity vary from life-threatening to asymptomatic Females are more susceptible to autoimmune diseases - Sex hormones must play a role. However, the mechanism is unclear - IDDM is one exception to this rule Disease overlap: - patients often have sxns of multiple systemic diseases |
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Is there a genetic component to contracting autoimmune diseases?
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Yes, scientists are trying to identify gene mutations that increase susceptibility to autoimmunity
Examples: - CTLA4 is near the loci associated with Type 1 DM - IL10 is found near the loci associated with Lupus (IL10 is a major anti-inflammatory cytokine |
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What HLA allele is associated with an increased risk for Rheumatoid arthritis?
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HLA allele DR4 is associated with a 4 times higher risk for rheumatoid arthritis
|
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What HLA allele is associated with an increased risk for Systemic Lupus Erythematosus?
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HLA allele DR2/DR3 (heterozygote) is associated with a 5 times higher risk for SLE.
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What HLA allele is associated with an increased risk for Type 1 Diabetes?
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HLA allele DR3/DR4 (heterozygote) is associated with a 25 times higher risk for Type 1 diabetes
|
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What HLA allele is associated with an increased risk for Multiple Sclerosis?
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HLA allele DR2 is associated with a 5 times higher risk for MS
|
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What non-MHC are genes can increase susceptibility for Systemic Lupus Erythematosus?
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C1q
Serum amyloid P Fas and Fas ligand FcγRII polymorphism FcγRIII polymorphism |
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What is the physiologic role of C1q?
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Clearance of cellular debris
If patients are deficient in C1q antigens are not cleared efficiently and are around a lot longer to react with antibodies. Patients with SLE are deficient in C1q |
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What is the physiologic role of serum amyloid P?
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Serum amyloid P masks chromatin from the immune system. Patients with lower levels of serum amyloid P have their chromatin exposed to the immune system which is problematic.
Patients with SLE are deficient in serum amyloid P. |
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What is the physiologic role of Fas and Fas Ligand?
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Fas and Fas Ligand work to delete autoreactive lymphocytes. This is a mechanism supporting tolerance induction. Deficiency of Fas and Fas Ligand results in more autoreactive lymphocytes surviving for longer periods of time to cause autoimmune reactions.
Patients with SLE are deficient in Fas and Fas Ligand. |
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What is the physiologic role of FcγRII?
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FcγRII polymorphism encodes for defective receptors involved in clearance of immune complexes in the kidney. The result is organ-specific manifestations of autoimmunity: renal disease.
FcγRII polymorphism is found in patients with SLE. |
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What is the physiologic role of FcγRIII?
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FcγRIII polymorphism encodes for defective receptors involved in clearance of immune complexes in the kidney. The result is organ-specific manifestations of autoimmunity: renal disease.
FcγRIII polymorphism is found in patients with SLE. |
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What are some environmental influences on systemic autoimmunity?
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1. Drugs:
- Procainamide: 1 in 6 patients with Lupus - Hydralazine is also associated with Lupus 2. Toxins: - Mercuric chloride: involved in multiple organ autoimmune diseases 3. Infection: - Infections of particular tissues may induce local inflammation - Molecular mimicry: infectious microbes may contain antigen that cross-react with self antigens (d/t similarity in structure) - Hyper response during infection: This brings down the threshold on auto-reactive T-cells in pts with autoimmune disease - Infection can trigger an autoimmune disease in a patient w/o prior disease - Infection can trigger an exascerbation in a patient with autoimmune disease already |
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Define Rheumatoid Arthritis
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Chronic, systemic, inflammatory disease that primarily effects the synovial membranes of multiple joints in the body.
|
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Is RA more prevelent in men or women, young or old, etc?
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Female > Male (2-3:1)
5% in women over 55 yo 1-2% of the world population |
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Normal vs. RA vs. OA joint antatomy?
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Bone Quailty:
- Normal = normal bone density and anatomy - RA = Bone loss - OA = Bone spurs Synovial Membranes: - Normal = normal thickness and cellular quality - RA = Thickened synovial membranes - OA = Synovial changes Cartilage: - Normal = normal - RA = possibly worn cartilage - OA = possibly worn cartilage |
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What are the four major systemic effects of RA?
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1. Fatigue
2. Rheumatoid nodules 3. Vasculitis 4. Cardiopulmonary Disease - pleurisy - pericarditis |
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What S/S are required for a Diagnosis of RA?
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Four or more of the following are required:
• Morning stiffness • Swelling of three or more joint areas •Swelling of the wrist • Symmetrical joint swelling • Presence of serum rheumatoid factor • Hand radiographic changes – erosions • Rheumatoid nodules |
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Describe the pathogenesis of RA.
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1. T-cell activation by unknown pathogen(s) in the synovium
2. Initiation of inflammatory response - infiltration of T-cells - antibiotics - neutrophils - macrophages 3. Cytokine production --> Synovial inflammation 4. Tissue damage: - Joint swelling/pain - Articular osteoporosis - Articular distortions - Bone erosions |
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What are the two main theories of possible mechanisms of RA?
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T-cell centric theory
Macrophage model |
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What are the main tenants of the T-cell centric theory?
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T-cells intitiate and progogate the disease state.
- There is a known association between RA and MHC II antigens - There are a large number of CD4+ T-cells in the RA synovium |
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What are the main tenants of the Macrophage model?
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T-cells initiate the disease but macrophages propogate the chronic inflammation.
- Relative absence of activated T-cell phenotypes in chronic RA - Preponderance of activated macrophages and fibroblasts in chronic RA |
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What are the three classes of potential peptide antigens, their causes, and examples?
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1. EXOGENOUS
- Due to infection - Bacterial cell wall peptidoglycans 2. ENDOGENOUS: - Due to overactive T-cells - Collagen type II and rheumatoid factor (Fc is recognized by Fab) 3. EXOGENOUS/MIMICRY: - triggered by an infection that causes cross reactivity to self peptides - Epstein-Barr protein (viral) and Heat shock protein (E-coli) - Resembles DR4 |
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What are the main cellular sources of synovial cytokines in RA?
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Macrophages and Fibroblasts
|
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What are the cytokines produced by macrophages?
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IL-1 (+++)
IL-6 (+) TNF alpha (++) M-CSF (+) INF alpha (+-) GM-CSF (+) |
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What are the cytokines produced by fibroblasts?
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IL-6 (+++)
GM-CSF (+) |
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What are the therapeutic options for RA?
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- NSAID: initial management
- Corticosteroids: maintenance therapy - Anti-rheumatic drugs: potentially induce a disease remission - Biological agents that antagonize inflammatory cytokines: • Targeting TNF-alpha : soluble TNF-alpha receptors, monoclonal antibodies to TNF-alpha • Targeting IL-1: IL-1 receptor antagonist |
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What is Systemic Lupus Erythematosus?
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A chronic, inflammatory autoimmune disorder that may affect multiple organ systems.
|
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What is the prevalence of Systemic Lupus Erythematosus?
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* 1 in 700 among women between the ages of 20 to 60 years
* Female : male = 9 : 1 |
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What are the clinical manifestations of SLE?
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• Skin: “butterfly”rash
• Musculoskeletal: joint pain arthritis • Kidney: protein deposition nephritis • Blood: hemolytic anemia thrombocytopenia • Cardiopulmonary Inflammation: myocarditis and pleurisy • CNS: seizures, stroke and cognitive dysfunction |
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What criteria are used to diagnose SLE?
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* All other illnesses must be ruled out
* 4 or more of the following S/S must be present to diagnose: 1. Characteristic rash across the cheek 2. Photosensitivity 3. Oral sores 4. Arthritis 5. Inflammation of membranes in the lungs, the heart, or the abdomen 6. Kidney disorder 7. Neurological problems 8. Blood disorders 9. Immunologic abnormalities 10. Positive antinuclear antibody (ANA) |
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What are the common clinical features of drug-induced SLE?
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Arthritis
Fever Anti-DNA antibodies |
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What are rare clinical features of drug-induced SLE?
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Renal effects(Glomerulonephritis)
Vasculitis CNS |
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What is the possible mechanism of SLE?
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* Various autoantibodies have been found in patients with SLE.
- These antibodies are termed anti-nuclear antibodies (ANA). - They react against ssDNA, dsDNA, histone, chromatin, and other nucleoproteins. * Immune complexes of ANA and their specific antigens play an important role in the pathogenesis of SLE. - The production of high-affinity ANA is dependent on Th2 cells. - Nuclear antigens released from apoptotic cells cause activation of Th2 cells, which in turn, provide help for B cells to produce ANA. * One possible mechanism involves the exposure of the patient to UV light in quantities sufficient to cause apoptosis * The dead cell releases it's nuclear contents * Normally, C1q cleans up the cellular debris but some patients are deficient in C1q * The cellular debris is left circulating and are exposed to the immune system * Th2 cells activate B cells which create antibodies to ssDNA, dsDNA, histone, chromatins, ect. * The ANAs form immune complexes which cause inflammation and tissue damage. |
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What are common medications used to treat SLE?
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1. NSAIDs: reduce pain and swelling
2. Antimalarial drugs (Hydroxychloroquine): polyarthritis and rash 3. Corticosteroids: reduce inflammation |
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What are treatments for aggressive lupus?
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1. High-dose corticosteriods
2. Immunosuppressive drugs (cyclophosphamide, azathioprine, mycophenolate) |
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Belimumab (Benlysta)
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Treatment for SLE
Belimumab (Benlysta): this is an mAb that blocks the activity of B lymphocyte stimulator (BLyS). BLys has the ability to activate B-cells to produce autoantibodies. |
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Stem cell transplant
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Treatment for SLE
Stem cell transplant: strong immunosuppressive drugs are administered to wipe out existing immune system, then adult stem cells are put back to rebuild the immune system |
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Dehydroepiandrosterone (DHEA)
|
Treatment for SLE
Dehydroepiandrosterone (DHEA): a synthetic form of this hormone may improve quality of life in lupus patients |
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Rituximab (Rituxan)
|
Treatment for SLE
Rituximab (Rituxan): this is an mAb that depletes B cells by targeting the pan-B-cell surface marker CD20. |
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Define Insulin-Dependent Diabetes Mellitus (IDDM)
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IDDM
An autoimmune destruction of the insulin-producing cells of the islets in the pancreas |
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What is the prevalence of Insulin-Dependent Diabetes Mellitus (IDDM)?
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* 0.2% of the U.S. population
* Peak age of onset: 11 to 12 years |
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Describe the pathophysiology of IDDM.
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• Lack of insulin-secreting beta cells
• A chronic inflammatory infiltrate composed of CD8+ and CD4+ T cells, B cells, macrophages and NK cells • Abnormality in glucose metabolism - Ketoacidosis, thirst, and increased urine production • Vascular lesions - Atherosclerotic vascular lesion, - Renal failure secondary to glomerular and arterial injury - Blindness caused by arterial aneurysms in the retina |
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What is a possible mechanism of IDDM?
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* Delayed-type hypersensitivity reactions mediated by CD4+ Th1 cells contribute to the pathogenesis of beta cell destruction in IDDM.
* The effector mechanism includes cytotoxic T cell-mediated lysis of islet beta cells. * IL-1 and TNF-alpha released by activated macrophages also cause damage of islet cells. * Autoantibodies can be detected in the blood of IDDM patients. * These antibodies recognize specific islet cell surface antigens, however, their pathogenic role is not clear. |
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Define Multiple Sclerosis (MS).
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An autoimmune disorder, in which the immune system attacks the CNS (myelin)
|
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What are the S/S of Multiple Sclerosis (MS)?
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* bladder and bowel dysfunction
* cognitive dysfunction * vision problems * fatigue * walking difficulty * pain * numbness * dizziness * swallowing disorders * tremors |
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What are the four classifications of MS based on disease activity?
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1. Relapsing remitting: unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity.
2. Secondary progressive: 65 % of patients with an initial relapsing-remitting MS begin to have progressive neurologic decline without any definite periods of remission. The median time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19 years. 3. Primary progressive: 10–15% of individuals who never have remission after their initial MS symptoms. 4. Progressive relapsing: those individuals who, from onset, have a steady neurologic decline but also suffer clear superimposed attacks. This is the least common of all subtypes. |
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Describe the Immuno-pathogenesis of MS?
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* Autoimmune T cells are responsible for initiating the disease
* Inflammatory cells infiltration (CD4, CD8 and activated macrophages) in the brain, spinal cord and cerebrospinal fluid * Autoimmunity to myelin proteins may be inadvertently triggered by microbes which have structural homologies with Myelin Antigens - In contrast to healthy donors, several T-cell lines isolated from MS patients showed cross-reactivity between myelin and Corona virus antigens. |
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Experimental Autoimmune Encephalomyelitis
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1. Induced by immunizing animals with myelin basic protein (MBP)
2. The disease can be transferred to unimmunized animals by CD4+ T cells from MBP-immunized animals |
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What drugs are used to treat acute exacerbations of MS?
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Corticosterois
- Reduce edema and inflammation - Resolve conduction block |
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What are drugs are used to treat complications of MS?
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* Spasticity: Baclofen
* Tremor: Isoniazid * Pain: Carbamazepine and phenytoin * Bladder dysfunction: Anticholinergic agents * Fatigue: Amantadine * Mood disorder: Antidepressant therapies |
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What drugs have disease modification effects on MS?
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Beta-interferons (IFN-beta)
* Avonex and Rebif (IFN beta-1alpha) * Betaseron (IFN beta-1beta) Monoclonal Antibodies * Natalizumab (Tysabri) Immunosuppressants * Mitoxantrone (Novantrone) * Glatiramer Acetate (Copaxone) |
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What are the mechanisms of action of Beta-interferons (IFN-beta)?
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- inhibits leucocyte proliferation
- inhibits antigen presentation - inhibits T-cell migration across the blood-brain barrier - modulates cytokine production to produce an anti-inflammatory environment. |
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What effect do Beta-interferons (IFN-beta) have on MS?
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Reduces relapse rates by one-third
|
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What is the MOA of Natalizumab (Tysabri)?
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Natalizumab (Tysabri) is a mAb targeting alpha4-integrin, which is expressed on lymphocytes and binds to VLA-4 and mediates CNS migration of lymphocytes
|
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How does Natalizumab (Tysabri) effect MS?
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Reduces relapse and delay the accumulation of physical disability
|
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What are side effects associated with Natalizumab (Tysabri)?
|
* Increases the risk of progressive multifocal leukoencephalopathy (PML, a rare fatal brain infection)
* Recommended for patients who have had inadequate responses to other therapies. |
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What is the MOA of Mitoxantrone (Novantrone)?
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It is an immunosuppressant, which has been used to treat leukemia and advanced prostate cancer
|
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How does Mitoxantrone (Novantrone) effect MS?
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Treatment for secondary progressive MS, progressive relapsing MS, and advanced relapsing-remitting MS
|
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What are side effects and considerations associated with Mitoxantrone (Novantrone)?
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* Injected once every 3 months for up to 3 years.
* A higher total dose increases the risk of serious heart damage |
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What is the MOA of Glatiramer Acetate (Copaxone)?
|
- It is a peptide tetramer: Glutamic acid, Lysine, Alanine and Tyrosin (hence, GLATiramer)
- It limits the formation of new MS-related lesions in the CNS and reduces brain atrophy |
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How does Glatiramer Acetate (Copaxone) effect MS?
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Reduces average relapse rate in people with relapsing-remitting MS
|
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What are side effects and considerations associated with Glatiramer Acetate (Copaxone)?
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* Daily s.c. injection of 20 mg.
* Itching and inflammation at injection site |
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Discuss the new drug that is undergoing clinical trials for MS.
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Cladribine (Clarity)
* Mechanism of action • Preferentially induces lymphocyte apoptosis • Reduces proinflammatory cytokines and chemokines * The Clinical Trail • 1326 patients were given 3.5 mg/kg, 5.25 mg/kg, or placebo for a total of 8 to 20 days in a year. • Treatment significantly reduced relapse and deterioration of the disease. • The first tablet treatment eliminating the need for regular injections • Relatively few side effects, but long term risks have yet to be defined |
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____________ promotes the maturation of newly recruited monocytes to macrophages.
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GM-CSF
|
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_______ is an immune-complex-mediated hypersensitivity reaction.
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SLE
|
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_______ is a T cell-mediated autoimmune disease targeting the myelin sheath surrounding the nerve fibres
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MS
|
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Describe the biological effects of the following cytokines: IL-1, TNF-, GM-CSF, IL-6, and IL-8
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GM-CSF - promotes the maturation of newly recruited monocytes to macrophages
|
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In __________ T cells are important in initiating the immune response and that macrophages and fibroblasts are largely responsible for a self-perpetuating state of chronic inflammation.
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RA
|
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What percentage of Americans have RA?
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RA affects only 1-2% of the population
|
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How many patients with RA are disabled?
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60%
|
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What kind of disease is RA?
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RA is a chronic autoimmune inflammatory disease
|
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Are all patient's with RA symptomatic?
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No, the disease starts before clinical manifestations of symptoms appear
|
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Describe the onset of RA.
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The onset of RA is insidious over weeks to months; waxing and waning in nature
|
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What are the systemic S/S of RA?
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- fatigue
- weakness - low-grade fever - decreased appetite - sweating |
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What are the syndromal S/S of RA?
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- joint pain/stiffness
- myalgia - joint swelling (synovitis) - deformity - lymphadenopathy |
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Describe the joint involvement in RA.
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Joint involvement tends to be symmetrical
- Most common: hands (MCO, IP); wrists - Less common: elbows; knee;foot;ankle;cervical spine,TMJ Radiographs show erosions and malalignment |
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Diagnostic criteria for RA
|
>=4 of the 7 criteria and 1 or more of them ongoing for >=6 weeks to diagnose RA:
- Morning stiffness (>=1hr) - Arthritis of 3 or more joints - Arthritis of the hand joints - Symmetric arthritis - rheumatoid nodules - serum rheumatoid factor positive - radiographic changes typical of RA |
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How can RA affect the lymph nodes?
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reactive lymphadenopathies
|
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How can RA affect the kidneys?
|
amyloidosis
|
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How can RA affect the muscles?
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muscle wasting
|
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How can RA affect the nervous system?
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peripheral neuropathy and monopneuritis multiplex
|
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How can RA affect the eyes?
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scleritis and keratoconjunctivitis
|
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How can RA affect the Pleura?
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pleural effusions
|
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How can RA affect the lungs?
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fibrosis
nodules effusions |
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How can RA affect the pericardium?
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effusions
|
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How can RA affect the spleen?
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splenomegaly
|
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How can RA affect the gut?
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amyloidosis
|
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How can RA affect the bone marrow?
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anemia and thombocytosis
|
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How can RA affect the skin?
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thinning and ulceration
|
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What is the ULTIMATE goal for treating RA?
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The ultimate goal is complete remission.
|
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Define remission in RA?
|
remission is defined as the absence of all of the following:
1. symptoms of active inflammatory joint pain 2. morning stiffness 3. fatigue 4. synovitis on joint examination 5. progressive radiographic damage 6. elevated ESR or C-reactive protein Complete remission is not possible for most patients so the goal is to slow the progression of the disease |
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What are the goals in managing RA when complete remission is not possible?
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Management goals:
- control disease activity - alleviate pain - maintain function essential for ADLs - maximize QOL - slow the rate of joint destruction |
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Disease Modifying Anti-Rheumatic Drugs (DMARDs)
|
* Core tratment for patients with RA
* Capable of reducing/preventing joint damage * Preserve joint integrity and function Limitations: - May not prevent damage despite apparent disease control - Efficacy may not last long term - Many agents have toxicities that require diligent monitoring It is now a standard of treatment, DMARD therapy must be initiated by 3 months of RA |
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What three parameters are needed to determine DMARD treatment?
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1. Duration of disease
2. Assessment of disease activity 3. Determination of prognostic factors |
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What is the "Gold Standard" for functional status assessment in clinical trials for RA therapies?
|
ACR 20
This means the medication is 20% efficatious |
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What is used to determine functional status of RA patients in clinical practice?
|
Functional status assessment is handled on a patient by patient basis in clinical practice
Standardized tools are used to assess overall function. |
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What are poor prognostic factors?
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The following are poor prognostic factors:
- Functional limitation (disabled) - extra-articular disease (systemic involvement) - rheumatoid factor positive - Positive anti-cyclic citrulinated peptide antibodies - Bony erosions on radiography Most patients will develope poor prognostic factors even if they do not initially present with them Having even one poor prognostic factor = poor prognosis |
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How many thesholds of disease activity are there in RA?
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Three: Low, moderate, and high
|
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List the non-biologic DMARDs
|
Hydroxychloroquine (Plaquenil)
Minocycline Methotrexate (Rheumatrex, Trexall) Sulfasalazine Leflunomide (Arava)k |
|
Hydroxychloroquine (HCQ)
|
Time to benefit: 2-6 mo
Usual dose: 200 mg bid Role: * Mild RA - duration <= 24 mo * Low disease activity * No poor prognostic factors |
|
Minocycline (MIN)
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Time to benefit: Up to 6 mo
Usual dose: 100 mg bid Role: * Mild RA - duration <= 24 mo * Low disease activity * No poor prognostic factors |
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Sulfasalazine (SSZ)
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Time to benefit: 1-3 mo
Usual dose: 1000 mg bid-tid Role: * Any disease duration * Any disease activity * No poor prognostic factors |
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Mathotrexate (MTX)
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Time to benefit: 1-2 mo
Usual dose: 7.5 to 20 mg q week (up to 25 mg/week) Role: * Any disease duration * All disease activity levels * Irrespective of poor prognostic factors * Tried and true Gold standard (cat X) |
|
Leflunomide (LEF)
|
Time to benefit: 1-3 mo
Usual dose: 100 mg qd x 3 d, then 10-20 mg qd Role: * Any disease duration * All disease activity levels * Irrespective of poor prognostic factors * Newer, more expensive (cat X) |
|
What is the preferred first line DMARD?
|
Methotrexate (MTX)
|
|
What are the benefits of Methotrexate (MTX)?
|
* decrease S/S and structural damage
* Improves physical functioning * CV disease mortality is lower in RA patients on Methotrexate therapy |
|
Is RA a risk factor for CV events?
|
RA alone is not a huge risk factor but in the presence of other risk factors it can be significant
|
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What lab tests/monitoring are needed for Methotrexate?
|
Baseline:
LFT Scr CBC |
|
_________ occurs in the majority of patients and is minimized by: ______________, ___________, and ________________.
|
Gi intolerance in the majority of patients and is minimized by:
* Splitting the weekly oral dose into thirds and take q12h for 3 doses * Supplemental folic acid 1 mg daily (also minimizes anemia) * Subcutaneous dosing instead of oral dosing |
|
T or F
RA patients with GI intolerance and taking methotrexate are the only patients requiring folic acid supplementation. |
False
All RA patients should be taking folic acid acid. |
|
What patient education is key to decrease hepatoxicity risk for patients on methotrexate?
|
* Minimize overall ethanol intake AND
* Abstain the day before, the day of, and the day after their weekly dose So, moderation is key and don't drink with meds |
|
What are the recommended baseline labs for Non-biologic DMARDs?
|
* For all Agents:
* CBC * hepatic transaminases (LFTs) * SCr * Hydroxychoroquine: all of the above plus opthamlmologic exam needed w/in 1 yr * Methotraxate and Leflunamide: Hep B and C testing is also needed if hepatitis risk factors are present (IV drug abuse, multiple sex partners in last 6 mo, health care personel) |
|
What are the receommended ongoing monitoring perameters for Non-biologic DMARDs?
|
Ongoing monitoring of:
* CBC * hepatic transaminases (LFT) * SCr At the following schedule: Sulfasalazine, methotrexate and Leflunamide * <3 mo q2-4w * 3-6 mo q8-12w * >6 mo q12w Hydroxychloroquine - eye exam w/in 1 year for baseline Baseline CBC, LFT, Scr then no other repeated testing needed |
|
What is the purpose of each of the receommended ongoing monitoring perameters for Non-biologic DMARDs?
|
CBC = anemia
LFT = Liver fxn Scr = Renal fxn |
|
Know how to use the algorythm on page 8 but do not memorize
|
SEE PAGE 8 in notes
Pic would be too small sorry |
|
Discuss biologic DMARDs
|
• Significant innovations in therapy; ↓ signs/symptoms and ↓ bone erosion
• For moderate/severely active RA in those who have failed ≥1 DMARD(s) • Generally in combination with another DMARDs, but never another biologic • Typical annual cost is $10,000 to $30,000 (methotrexate is ~$1500) • Approximate time to benefit is 1 to 3 weeks • Serious reactions: |
|
What are the recommended baseline labs for Non-biologic DMARDs?
|
* For all Agents:
* CBC * hepatic transaminases (LFTs) * SCr * Hydroxychoroquine: all of the above plus opthamlmologic exam needed w/in 1 yr * Methotraxate and Leflunamide: Hep B and C testing is also needed if hepatitis risk factors are present (IV drug abuse, multiple sex partners in last 6 mo, health care personel) |
|
What are the receommended ongoing monitoring perameters for Non-biologic DMARDs?
|
Ongoing monitoring of:
* CBC * hepatic transaminases (LFT) * SCr At the following schedule: Sulfasalazine, methotrexate and Leflunamide * <3 mo q2-4w * 3-6 mo q8-12w * >6 mo q12w Hydroxychloroquine - eye exam w/in 1 year for baseline Baseline CBC, LFT, Scr then no other repeated testing needed |
|
What is the purpose of each of the receommended ongoing monitoring perameters for Non-biologic DMARDs?
|
CBC = anemia
LFT = Liver fxn Scr = Renal fxn |
|
Know how to use the algorythm on page 8 but do not memorize
|
SEE PAGE 8 in notes
Pic would be too small sorry |
|
Discuss biologic DMARDs
|
• Significant innovations in therapy; ↓ signs/symptoms and ↓ bone erosion
• For moderate/severely active RA in those who have failed ≥1 DMARD(s) • Generally in combination with another DMARDs, but never another biologic • Typical annual cost is $10,000 to $30,000 (methotrexate is ~$1500) • Approximate time to benefit is 1 to 3 weeks • Serious reactions: |
|
What is the MOA of Infliximab (Remicade)?
|
Monoclonal (murine) antibody to TNF-α
|
|
What is the role of Infliximab (Remicade)?
|
For patients with an inadequate response to MTX as add-on therapy
|
|
What is the adult RA dosing of Infliximab (Remicade)?
|
3 mg/kg IV at 0, 2, 6 wks then q 8 wks; requires 2-hr administration at infusion center
|
|
What are the adverse effects of Infliximab (Remicade)?
|
Potential sepsis, infusion reactions, antibody development, worsening or new onset heart failure
|
|
What is the MOA of Adalimumab (Humira)?
|
Monoclonal (human) antibody to TNF-α
|
|
What is the role of Adalimumab (Humira)?
|
Moderate/severely active RA
|
|
What is the adult RA dosing of Adalimumab (Humira)?
|
40 mg SQ QOW (QW if not on MTX)
|
|
What are the adverse effects of Adalimumab (Humira)?
|
Potential sepsis, injection site reaction, antibody development, worsening or new onset heart failure
|
|
What is the MOA of Certolizumabpegol (Cimiza)?
|
Pegylated monoclonal antibody (does not have Fc region) to TNF-α
|
|
What is the role of Certolizumabpegol (Cimiza)?
|
Moderate/severely active RA
|
|
What is the adult RA dosing of Certolizumabpegol (Cimiza)?
|
400 mg SQ at 0, 2 and 4 wks, then 200 mg q 2 wks or 400 mg q 4 wks
|
|
What are the adverse effects of Certolizumabpegol (Cimiza)?
|
Potential sepsis, injection site reaction, worsening or new onset heart failure
|
|
What is the MOA of Golimumab (Simponi)?
|
Monoclonal (human) antibody to TNF-α (both soluble and transmembrane active)
|
|
What is the role of Golimumab (Simponi)?
|
Moderate/severely active RA in combination with MTX
|
|
What is the adult RA dosing of Golimumab (Simponi)?
|
50 mg SQ q month
|
|
What are the adverse effects of Golimumab (Simponi)?
|
Potential sepsis, infusion reactions, antibody development, worsening or new onset heart failure
|
|
What is the MOA of Etanercept (Enbrel)?
|
Soluble recombinant human TNF-α receptor protein that binds/neutralizes TNF-α
|
|
What is the role of Etanercept (Enbrel)?
|
Moderate/severely active RA
|
|
What is the adult RA dosing of Etanercept (Enbrel)?
|
50 mg SQ QW
|
|
What are the adverse effects of Etanercept (Enbrel)?
|
Potential sepsis, injection site reaction, rash, worsening or new onset heart failure
|
|
What is the MOA of Anakinra (Kineret)?
|
Recombinant human interleukin-1 receptor antagonist
|
|
What is the role of Anakinra (Kineret)?
|
Moderate/severely active RA [Note, less effective than TNF-α blockers]
|
|
What is the adult RA dosing of Anakinra (Kineret)?
|
100 mg SQ daily
|
|
What are the adverse effects of Anakinra (Kineret)?
|
Potential sepsis, injection site reaction, rash
|
|
What is the MOA of Abatacept (Orencia)?
|
Inhibits T-cell activation and decreases cytokine production
|
|
What is the role of Abatacept (Orencia)?
|
Moderate/severely active RA after an inadequate response to ≥1 DMARD(s), such as MTX or TNF antagonists.
|
|
What is the adult RA dosing of Abatacept (Orencia)?
|
500-1000 mg IV, second dose in 2-4 wks then q 4 wks; requires 30-min administration at infusion center
|
|
What are the adverse effects of Abatacept (Orencia)?
|
Potential sepsis, infusion reactions
|
|
What is the MOA of Rituximab (Rituximab)?
|
Monocolonal antibody that depletes CD20 Bcells
|
|
What is the role of Rituximab (Rituximab)?
|
Moderate/severely active RA in combination with MTX after an inadequate response to ≥ 1 TNF antagonists
|
|
What is the adult RA dosing of Rituximab (Rituximab)?
|
1000 mg IV 2 doses separated by 2 wks, methylprednisolone 100 mg IV 30 min prior to reduce infusion reactions
|
|
What are the adverse effects of Rituximab (Rituximab)?
|
Severe infusion reactions, mucocutaneous reactions, hepatitis B reactivation, cardiac arrhythmias, progressive multifocal leukoencephalopathy
|
|
What is the MOA of Certolizumabpegol (Cimiza)?
|
Pegylated monoclonal antibody (does not have Fc region) to TNF-α
|
|
What is the role of Certolizumabpegol (Cimiza)?
|
Moderate/severely active RA
|
|
What is the adult RA dosing of Certolizumabpegol (Cimiza)?
|
400 mg SQ at 0, 2 and 4 wks, then 200 mg q 2 wks or 400 mg q 4 wks
|
|
What are the adverse effects of Certolizumabpegol (Cimiza)?
|
Potential sepsis, injection site reaction
|
|
What is the MOA of Tocilizumab (Actemra)?
|
Interleukin-6 receptor inhibitor
|
|
What is the role of Tocilizumab (Actemra)?
|
Moderate/severely active RA after an inadequate response to ≥ 1 TNF antagonists.
|
|
What is the adult RA dosing of Tocilizumab (Actemra)?
|
4 mg/kg IV q 4 wk; may increase to 8 mg/kg if needed.
|
|
What are the adverse effects of Tocilizumab (Actemra)?
|
Neutropenia, thrombocytopenia, dyslipidemia, hepatotoxicity
|
|
Know the algorythm for the use of biologic agents on pg 12
|
See pg 12 in the notes
|
|
What are adjunctive therapies for RA?
|
NSAIDS
Corticosteroids |
|
What is the role of NSAIDs in RA?
|
• Part of the initial management of RA, but not the sole treatment of RA
• Analgesic/anti-inflammatory effects; will not prevent joint destruction |
|
What is the usual adult RA dose and frequency for Ibuprofen?
|
2400-3200 mg/day
divided TID to QID |
|
What is the usual adult RA dose and frequency for Naproxen?
|
1000-1500 mg/day
divided BID |
|
What is the usual adult RA dose and frequency for Diclofenac?
|
150-225 mg/day
divided BID-TID |
|
What is the usual adult RA dose and frequency for Salsalate?
|
2000-3000 mg/day
divided BID |
|
What is the usual adult RA dose and frequency for Etodolac?
|
1200 mg/day
divided BID-TID |
|
What is the usual adult RA dose and frequency for Nabumetone?
|
1500-2000 mg/day
divided BID |
|
What is the usual adult RA dose and frequency for Celecoxib?
|
200-400 mg/day
divided BID |
|
What is the role of Corticosteroids in RA?
|
• “Burst” Therapy: For acute exacerbations
o Oral therapy (e.g., prednisone 10-20 mg daily) for 2 to 4 weeks o Local injections for single/few joint involvement: |
|
Autograft:
|
a graft into a new position in the body of the same individual
|
|
Allograft:
|
a graft transplanted between genetically nonidentical individuals
|
|
Xenograft:
|
a graft transplanted between members of two different species.
|
|
CAD:
|
cadaveric donor
|
|
LRD
|
living related donor
|
|
LNRD
|
living non-related donor
|
|
Haplotype:
|
the genetic constitution with respect to one member of a pair of allelic genes
|
|
Cytokines
|
antigen-nonspecific proteins that are synthesized in response to antigenic stimuli.
|
|
CD3
|
protein complex between T cell receptor and allograft antigen
|
|
CD4
|
T helper cell
|
|
CD8
|
T killer cell (cytotoxic)
|
|
Delayed Graft Function
|
Need for dialysis in the postoperative period or the failure of the serum creatinine to fall below 4 mg/dL or 30% of pretransplant value
|
|
PRA
|
Panel Reactive Antibody; the percentage PRA value is a measure of the patient’s sensitivity to donor antigens. The higher the PRA, the more sensitized a patient is to the general donor pool.
|
|
Which was transplanted first, the heart, the kidney, or the liver?
|
The kidney
|
|
Why is the death rate low among patients waiting for a kidney (compared to other organs)?
|
Because the patient can be on dialysis
|
|
Why has the # of kidney transplants increased so much over the last few years?
|
Rise is due to increasing prevalence HTN and DM => increased kidney disease => increased transplants
|
|
Are survival rates among transplant patients increasing or decreasing?
|
increasing
|
|
Describe the prevalence of single and multi-organ transplants?
|
• The number of single and multi-organ transplants increased by over 60% between 1990 and 2007 (from 14,978 to 25,451).
- Kidney (16,000+) > liver > heart > lung (1,405 in 2005) - Living donor transplants more than doubled in same time period • 97,986 people are awaiting organ transplant (increased over 14,000 in less than 5 yrs) - kidney: 73, 850; liver: 16,993; heart: 2,800 - Approximately 1,700 live in Colorado |
|
What are the four main reasons for renal transplant?
|
1. Diabetes
2. Hypertension 3. Glomerulonephritis 4. Polycystic kidney disease |
|
How does the graft survival rate compare between cadaveric kidneys and kidneys from a living donor at 1,3, and 5 years?
|
Renal: 1-yr, 3-yr, 5-yr
* At 1 year 90 % of cadaveric kidneys are still functioning and 95% of living donor kidneys are still functioning * At 3 years 78% of cadaveric kidneys are still functioning and 88% of living donor kidneys are still functioning * At 5 years 67% of cadaveric kidneys are still functioning and 80% of living donor kidneys are still functioning |
|
How does the graft survival rate compare between cadaveric liver and liver from a living donor at 1,3, and 5 years?
|
* At 1 year 82% of cadaveric liver are still functioning and 84% of living donor liver are still functioning
* At 3 years 73% of cadaveric liver are still functioning and 76% of living donor liver are still functioning * At 5 years 67% of cadaveric liver are still functioning and 68% of living donor liver are still functioning |
|
How does the graft survival rate compare between cadaveric lung at 1,3, and 5 years?
|
* At 1 year 83% of cadaveric lung are still functioning
* At 3 years 64% of cadaveric lung are still functioning * At 5 years 48% of cadaveric lung are still functioning |
|
What is the median wait time for cadeveric kidney transplant?
|
Median wait time for cadeveric transplant is 39 months (shorter with type AB blood)
|
|
Which ethnic group has worse long-term graft survival rate than that for other ethnicities?
|
African Americans
|
|
Which ethnic group has the best long-term graft survival?
|
Asian
|
|
T or F
Recipients who require dialysis within the first week posttransplant have a lower graft and patient survival rates at all time points than those who do not require dialysis. |
True
|
|
Which cell line is not a key player in transplant rejection?
|
Myeloid cells
|
|
Which cell line is a key component in transplant rejection?
|
Lymphoid cells
|
|
List cells of the Lymphoid line.
|
B cells (humoral-mediated), T cells (cell-mediated), and macrophages which includes a memory response
involved antigen specific immunity |
|
Cell-mediated immunity
|
• Primarily responsible for developing immunity to intracellular pathogens and mediate process of transplant rejection, graft-versus-host disease, and tumor surveillance
• Primary role in acute rejection process • Produce soluble cytokines |
|
Classes of T cells:
|
a. Helper cells (CD4): conductors of graft rejection
* IL-2: stimulates other ymphoid cells *INF:stimulates * IL4: stimulates growth and differentiation of B cells b. Cytotoxic cells (CD8): attack and destroy graft bearing specific antigens c. Suppressor cells: inhibit proliferation and differentiation - Responsible for development of tolerance |
|
Humoral immunity
|
• Responsible for elimination of toxins and extracellular pathogens
• Immunity mediated by the production of immunoglobulins (antibodies) • Role in transplant chronic and hyperacute rejection |
|
Major Histocompatable Complex (MHC) Antigens
|
• Also known as Human Leukocyte Antigens (HLA)
• Two major classes: Class I: A, B, C Class II: DR, DP, DQ *each loci (i.e. A, DR) have -- 50 alleles* • Antigens responsible for transplanted graft being recognized as similar to one’s own tissue or as foreign - function to present antigens recognized by T lymphocytes through specific receptors - incompatibility of the MHC antigens between a donor and a recipient can lead to acute graft rejection - recognition of foreign class II molecules activates helper CD4 lymphocytes, which begins process of acute graft rejection. |
|
What are the 5 types of graft rejection?
|
1. Hyperacute rejection
2. Accelerated rejection 3. Acute rejection 4. Humeral (antibody mediated) rejection 5. Chronic allograft nephropathy |
|
Define hyperacute rejection
|
– Rapid interaction between antibodies in presensitized host and antigens expressed on donor organ.
- Occurs within first hours of transplant - Humoral (antibody) mediated rejection - Example: ABO blood incompatibility - Treatment: No successful treatment prevent with crossmatching |
|
Define accelerated rejection
|
– An immunologic memory response to prior sensitization
- Occurs within first few days of transplant - Example: prior transplant or prior transfusion - Treatment: No successful treatment prevent with crossmatching |
|
Define acute rejection
|
– Primarily T-lymphocyte (cell) mediated process occurring after about 1-3 weeks
- Greatest risk within first weeks to months after transplant - Risk with current therapy 10 - 25 % (CHANGED!!) - Number of acute rejection episodes correlates with risk for chronic rejection - Classification: Banff criteria ( I – IV) - Symptoms: Graft tenderness, fever, increasing sCr, decrease urine output, and weight gain - Treatment: steroids, anti-lymphocyte antibodies |
|
Define humoral (antibody mediated) rejection
|
- Associated with allograft dysfunction, circulating anti-HLA antibodies, C4d deposits (complement activation), and histologic changes on biopsy
- Anti-HLA antibodies can be specific to the donor (DSA) a. Poor long term outcomes if DSA + - Acute and/or chronic process - Treatment: plasmapheresis, IVIG, rituximab, anti-lymphocyte antibodies |
|
Define chronic allograft nephropathy
|
– Slow fibrosis of graft over a period of several months to years by both immune and nonimmune processes leading to graft failure
- Immune component involves both humoral and cellular immunity - Risks include: episodes of acute rejection, delayed hypersensitivity, chronic ischemia, medications, hypertension, hypercholesterolemia - Symptoms: slow rising sCr over time (“Creatinine creep”) - Treatment: No effective treatment. a. Minimization of cyclosporine or tacrolimus |
|
What are the stages of Acute Cell-mediated Rejection?
|
1. Antigen recognition (Allorecognition)
2. ? 3. Activation 4. Differentiation and Amplification 5. Graft destruction (Effector phase) |
|
Discuss Antigen recognition as a stage of acute cell-mediated rejection
|
First stage: Antigen recognition (Allorecognition)
a. direct recognition – T cell receptors directly recognize allograft MHC molecules without antigen presenting cells. Primary pathway for CD8 cells b. indirect recognition – CD4 helper T cell receptors recognize allograft MHC receptors after processing and presentation by self-antigen presenting cells |
|
Discuss Activation as a stage of acute cell-mediated rejection
|
3. Activation
1. signal 1 – Tcell receptor binding to specific antigen receptor. T cell receptor consists of two chains and CD3 complex 2. signal 2 – nonspecific auxiliary receptors on antigen presenting cells and T-Cell Together, these dual signals trigger the CD4 T cell to activate cytokine interleukin-2 (IL-2) and IL-2 receptor, and other cytokines (THE START OF T CELL ACTIVATION) |
|
Discuss Differentiation and Amplification as a stage of acute cell-mediated rejection
|
Cytokine production, migration of activated lymphocytes to graft site, and expression of adhesion molecules
|
|
Discuss the effector stage of Acute Cell-Mediated Rejection
|
The last stage: Graft destruction (Effector phase)
• Both an immunologically specific (MHC mediated) and nonspecific. • Activated CD8 T cells and natural killer cells enter allograft and are in direct contact with donor organ cells. - Rich in intracellular cytolytic granules (perforins, granzymes) which cause membrane damage and induce apoptosis |
|
What immunosupressant therapy is derived from the fungus Tolypocladium inflatum?
|
Cyclosporine A (Sandimmune, Neoral, Gengraf, CyA, CsA)
|
|
What class of drug is Cyclosporine A (Sandimmune, Neoral, Gengraf , CyA, CsA)?
|
Calcineurin inhibitor
|
|
What is the MOA of Cyclosporine A (Sandimmune, Neoral, Gengraf , CyA, CsA)?
|
- Binds to cyclophilins and inhibits T-cell gene transcription
- Inhibits T helper cell activity by decreasing production of IL-2, a potent activator of T-cells - Inhibits clonal expansion of allosensitized T-cells by decreasing numbers of IL-2 receptors |
|
Discuss the absorption profile of Cyclosporine A (Sandimmune, Neoral, Gengraf, CyA, CsA).
|
Absorption:
• Highly variable; dependent on bile salts Peak concentrations seen between 1- 4 hours after dose • Oral bioavailability can range from < 5% to 89%. Avg: 30% • Bioavailability increases with time - at 3 months it can be 50-500% higher than immediate posttransplant • Absorption may be impaired by liver disease (due to effects on bile), post-op ileus, gastroparesis, diarrhea, GVHD |
|
Discuss the distribution profile of Cyclosporine A (Sandimmune, Neoral, Gengraf, CyA, CsA)?
|
Distribution:
• Also highly variable; Vd (range: 0.1 - 15.1 L/kg). Avg: 4-5 L/kg • Liver is the primary body store • Also stored in fat, blood, kidney, heart, lung, pancreas, and brain • 40% is bound to erythrocytes, 20% bound to leukocytes, and 40% bound to lipoproteins in the plasma |
|
Discuss the Metabolism profile of Cyclosporine A (Sandimmune, Neoral, Gengraf, CyA, CsA)?
|
• Metabolized by the liver
• Mediated by a CYP 450 IIIA isoenzyme • Half-life is approximately 6-12 hours • At least 11 metabolites have been isolated |
|
Discuss the elimination profile of Cyclosporine A (Sandimmune, Neoral, Gengraf, CyA, CsA)?
|
Elimination:
• Mean clearance is 5 ml/min/kg • Most of the dose is excreted in the bile • 1% is excreted renally • Hemodialysis does not remove much CsA |
|
Discuss the role of Cyclosporine A (Sandimmune, Neoral, Gengraf, CyA, CsA) in transplant?
|
Used in combination with one or more other immunosuppressants for prevention of acute rejection in solid organ transplant.
|
|
List the adverse effects of Cyclosporine A (Sandimmune, Neoral, Gengraf, CyA, CsA)?
|
• nephrotoxicity
• neurotoxicity • gingival hyperplasia • hirsutism • hyperuricemia • hyperlipidemia • hyperglycemia • hemolytic uremic syndrome • lymphoma development (PTLD) • hepatotoxicity • product taste and smell • hyperkalemia, hypomagnesemia |
|
What drugs increase CyA/Tac levels?
|
Voriconazole
Fluconazole Itraconazole Erythromycin Clarithromycin Metronidazole Diltiazem/Verapamil Amiodarone Warfarin Metoclopramide Grapefruit juice Clotrimazole (Tac) |
|
What drugs decrease CyA/Tac levels?
|
Phenytoin
Phenobarbital Carbamazepine Valproic acid Nafcillin Rifampin Loperamide Saint Johns Wort Antacids (Tac) Cholestyramine Orlistat |
|
What drugs enhance nephrotoxicity?
|
Aminoglycosides
Amphotericin B SMX/TMP Acyclovir Gancyclovir Cidofovir Foscarnet NSAIDs – YES COX IIs |
|
What substances are Immunostimulants?
|
echinacea
astragalus licorice alfalfa sprouts |
|
Dosing for Cyclosporine A (Sandimmune, Neoral, Gengraf, CyA, CsA)
|
* Initial load: 2 – 4 mg/kg/day IV or 5 – 15 mg/kg/day P.O. divided into two daily doses
* Maintenance: 2 – 8 mg/kg/day po divided into two daily doses, adjust dose based on trough levels and adverse drug reactions |
|
What is the rule for converting from IV to PO CyA?
|
Conversion from IV to PO generally a 1:3 rule
|
|
What monitoring is standard for CyA?
|
• Blood levels monitored on a “regular basis”
- Goal concentrations after renal transplant * 0 – 3 months Trough 200-350ng/ml C-2hour 1300-2000ng/ml * 3 – 12 months Trough 150 – 300 ng/ml C-2hour 700 – 1200 ng/ml * past 1 year Trough >100 - 200 ng/ml -Goal range varies with type of transplant, time post transplant, concomitant immunosuppressants, and “practice experience.” • Monitoring and modification of dose follows first order kinetics Example: * Patient currently taking 200mg bid with trough level = 200 ng/dl * Goal level between 250 – 275 * Desired dose = desired level/current level x current dose * X=260/200x400 x = 520mg/day or 250mg in am, 275mg in pm • Monitoring parameters: chem 7, blood pressure, drug trough levels, liver function enzymes, uric acid levels |
|
What immunosuppressant therapy is produced by fermenting Steptomyces tsukubaenis?
|
Tacrolimus (Prograf, FK506, FK)
|
|
Types of Immunosuppression
|
Calcineurin Inhibitors
* cyclosporine * tacrolimus Antiproliferative Agents * mycophenolate mofetil * azathioprine Non-specific Immunosuppressants * prednisone Inhibition of Late T cell Function * sirolimus Monoclonal Antibodies * OKT3 * daclizumab * basiliximab Polyclonal Antibodies * antithymocyte globulin |
|
What is the MOA of Tacrolimus?
|
- Binds to FK binding protein (FKBP-12) which inturn binds to calcineurin and inhibits T-cell gene transcription
- Inhibits T helper cell activity by decreasing production of IL-2, a potent activator of T-cells - Inhibits clonal expansion of allosensitized T-cells by decreasing numbers of IL-2 receptors |
|
What drug class is Tacrolimus?
|
calcineurin inhibitor
|
|
Describe the absorption profile of Tacrolimus.
|
* Highly variable
* Poorly and erratically absorbed after oral administration |
|
Describe the distribution profile of Tacrolimus.
|
• Highly lipophilic with extensive tissue distribution
• 88% bound to plasma proteins |
|
Describe the metabolism of Tacrolimus
|
Completely metabolized by the liver by CYP 450 la & llla; 9 metabolites identified
|
|
Describe the elimination profile of Tacrolimus.
|
• Elimination half-life is 5.5 to 16.6 hours (mean 8.7 hours)
• <1% is excreted unchanged in the bile, urine, and feces |
|
What is the role of Tacrolimus in transplant?
|
- Used in combination with one or more other immunosuppressants for prevention of acute rejection in solid organ transplant.
|
|
What are the adverse effects of Tacrolimus?
|
• nephrotoxicity
• neurotoxicity • mild hyperkalemia • alopecia • hyperlipidemia • aluminum binds to Tac • hyperglycemia /diabetes • hemolytic uremic syndrome • lymphoma development (PTLD) • hepatotoxicity |
|
How is Tacrolimus dosed?
|
* IV: 0.025 – 0.075 mg/kg/day given as a continuous infusion
* PO: 0.15 – 0.3 mg/kg/day divided into two doses |
|
What is the rule for converting IV to PO Tactolimus?
|
Conversion from IV to PO generally 1:4
|
|
How do pediatric doses compare to adult doses of Tacrolimus?
|
Pediatric patients require higher doses than adults to achieve similar blood concentrations
|
|
What monitoring is needed with Tacrolimus therapy?
|
• Trough blood levels monitored on a “regular basis”
- Goal trough concentrations in renal transplant * 0 – 3 months 6 – 12 ng/mL * 3 – 12 months 5 – 10 ng/mL * > 1 year 4 – 8 ng/mL -Varies with type of transplant, time post transplant, concomitant immunosuppressants, and “practice experience.” • Monitoring and modification of dose follows first order kinetics (similar to CYA) • Monitoring parameters: chem 7, blood pressure, drug trough levels, liver function enzymes, uric acid levels |
|
What immunosuppressant therapy was were introduced in 1960s, gained wide acceptance, and, despite many side effects, still continue to be used extensively as chronic therapy.
|
Corticosteroids
|
|
What is the MOA of Corticosteroids?
|
Inhibit the synthesis of IL-1 encoding mRNA, which subsequently inhibits the immune cascade of cytokines (i.e. IL-2, IL-4, etc.)
|
|
What is the role of corticosteroids in transplant?
|
- Used in combination with one or more other immunosuppressants for prevention of acute rejection in solid organ transplant.
- Treatment of acute allograft rejection |
|
What are the adverse effects of corticosteroids?
|
• increase appetite/wt. gain
• acne • hypertension • sodium and water retention • impaired wound healing • myopathy • hyperglycemia • leukopenia • hirsutism • dyslipidemia • GI upsetulceration • adrenal axis suppression • psychosis • cataracts • osteoporosis |
|
What are the dosing parameters for corticosteroids?
|
Pre-op: 250 – 1000 mg Methylprednisolone given preoperatively
Taper: * Day 0 – 3: 250 – 500 mg IV Methylprednisolone * Day 4 – 5: 60 mg po daily * At hospital discharge: 20 mg po daily * At day 30: 15 mg po daily * At day 90: 10 mg po daily * At month 6: 7.5 mg - 5 mg po daily* * At month 12: 5 mg po daily * Administer oral dose and QD taken in the morning Treatment of Acute Rejection: Methylprednisolone 250 – 1000 mg x 3- 5 days |
|
What monitoring is needed with corticosteroid therapy?
|
Therapeutic drug monitoring not necessary
|
|
Which immunosuppressant drug is Structurally related to 6-mercaptopurine (6-MP) and is a prodrug which erythrocytes and liver metabolize to active metabolites?
|
Azathioprine (Imuran,AZA)
|
|
What is the MOA of Azathioprine (Imuran,AZA)?
|
The primary active metabolites are 6-thioguanine nucleotides (TGN) which cause chromosome breaks & nucleic acid malfunction in proliferating T-cells.
AZA also inhibits DNA and RNA synthesis by preventing the formation of adenylic and guanylic acids from inosinic acid and functions as an effective antiproliferative agent against both B- and T-lymphocytes |
|
What is the rols of Azathioprine (Imuran,AZA) in transplant?
|
WAS used in combination with one or more other immunosuppressants for prevention of acute rejection in solid organ transplant.
|
|
What are the adverse effects of Azathioprine (Imuran,AZA)?
|
• bone marrow suppression
• hepatic dysfunction • stomatitis • pancreatitis • increase risk of infection |
|
What drug interactions are of concern with Azathioprine (Imuran,AZA)?
|
• Allopurinol: xanthine oxidaze inhibitor, which blocks the metabolism of the active metabolites of AZA. Decrease AZA dose to 25 – 33% of normal dose
• Medications which may enhanced leukopenia • Warfarin –may see decrease in INR |
|
What is the dosing for Azathioprine (Imuran,AZA)?
|
1 – 3 mg/kg/day given as single po dose
|
|
What monitoring is needed with Azathioprine (Imuran,AZA)?
|
Monitor closely for hematologic toxicities
|
|
What immunosuppressant prodrug(s) is proven to decrease the risk of acute rejection with fewer side effects when used in combination with CYA and steroids vs. AZA/CYA/steroids?
|
Mycophenolate mofetil (Cellcept, MMF) / Mycophenolic Acid (MPA, Myfortic)
|
|
What is the MOA of MMF/MPA?
|
- MMF is metabolized to mycophenolate acid (MPA), its active form
- MPA is an inhibitor of inosine monophosphate dehydrogenase and inhibits de novo pathway of purine synthesis. - MPA also suppresses antibody formation by B-lymphocytes. |
|
What is the role of MMF and MPA in transplant?
|
Used in combination with one or more other immunosuppressants for prevention of acute rejection in solid organ transplant.
|
|
What are the adverse effects of MMF and MPA?
|
* GI intolerance
* anemia * PTLD * leukopenia * increased risk of infection |
|
What drugs interact with MMF/MPA?
|
* Antacids
* Probenecid * Cholestyramine |
|
How is MMF dosed?
|
1 gram po BID
May need to increase interval to TID in patients complaining of GI upset |
|
How is MPA dosed?
|
720 mg po BID
May need to increase interval to TID in patients complaining of GI upset |
|
What monitoring is required for MMF and MPA?
|
• Potential role for therapeutic drug monitoring
o In combination with CYA, goal MPA trough level: 1.0 – 3.5 mg/L • Monitor WBC for leukopenia, which may be more pronounced in patients with impaired renal function (CrCl <25 mL/min) |
|
Which immunosuppressant drug is a macrocyclic antibiotic produced by Streptomyces hygroscopicus?
|
Sirolimus (Rapamune, rapamycin)
|
|
What is the MOA of Sirolimus (Rapamune, rapamycin)?
|
- Binds to FK binding protein which in turn binds to mTOR (a key regulatory enzyme)
- Suppresses cytokine-driven CD-4 T cell activation and proliferation - Anti-proliferative mechanism by inhibiting both DNA and protein synthesis |
|
What is the role of Sirolimus (Rapamune, rapamycin) in transplant?
|
* Used in combination with one or more other immunosuppressants for prevention of acute rejection in solid organ transplant.
* In low risk patients, can withdraw cyclosporine therapy after 3 months and continue with higher dose sirolimus in combination with prednisone |
|
What are the adverse effects of Sirolimus?
|
• hepatic artery thrombosis in liver transplant (Black box warning)
• dyslipidemia (triglycerides mainly) • thrombocytopenia • impaired wound healing • interstitial pneumonitis • diarrhea • hyperglycemia (with Tac or CYA) • aphthous ulcers • hyperkalemia |
|
What drugs interact with Sirolimus?
|
• Cyclosporine – separate by 4 hours
• Ketoconazole • Enzyme inducers: rifampin, phenytoin, phenobarbital, carbamazepine • Grapefruit juice • Verapamil, diltiazem • Saint John’s Wort metabolized by P450 3A4 isoenzyme |
|
How is Sirolimus dosed?
|
2 mg po daily
|
|
What monitoring is needed with Sirolimus?
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* Target trough levels: 5 – 15 ng/ml for most patients
* Dual therapy after CYA withdrawal: 12 – 24 ng/ml * Due to long t ½ (60 hr), wait 2 weeks after dosing change if monitoring is being performed. |
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What immunnosuppressant is a murine monoclonal antibody produced by fusing mouse splenocytes with human myeloma cells creating a hydridoma with immortality?
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OKT3 (muromonab CD3)
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What is the MOA of OKT3 (muromonab CD3)?
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- Binds to T-cell antigen receptor CD3 complex and internalizes it effectively removing it from circulation.
- Initially see cytokine release |
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What is the role of OKT3 (muromonab CD3) in transplantation?
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• Induction therapy for prevention of early acute rejection
• Treatment of acute allograft rejection |
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What are the adverse effects of OKT3 (muromonab CD3)?
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- Flu-like syndrome (cytokine release syndrome, shake –n- bake)
* Fevers, chills, headache, N/V, diarrhea, and myalgias - dyspnea - pulmonary edema - tinnitis - aseptic meningitis - ear stuffiness - tremor - tachycardia - infection - increase risk of malignancy |
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How is OKT3 (muromonab CD3) dosed?
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5 mg / day x 7 – 14 days
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What monitoring is needed with OKT3 (muromonab CD3) therapy?
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Monitor organ function (BUN/creatinine), CD3 count (goal of < 5% or 20 – 30/mcL), anti-murine antibody titers (resistance to OKT3 can develop)
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What are other considerations with OKT3 (muromonab CD3) therapy?
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Due to cytokine release syndrome, patients should be premeditated with high dose steroids, diphenhydramine, and APAP for 1st two – three doses.
Must provide prophylaxis against CMV during coarse of therapy Often decrease doses of concomitant immunosuppressive medications during therapy |
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What immunosuppressant therapies are Monoclonal antibodie produced by recombinant DNA technology.
Composed of both human and murine antibody sequences. |
Daclizumab (Zenapax)
Basiliximab (Simulect) |
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What is the t1/2 of Basiliximab (Simulect)?
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8-9 days
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What is the t1/2 of Daclizumab (Zenapax)?
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20 days
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What is the MOA of Daclizumab (Zenapax) and Basiliximab (Simulect)?
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- IL-2 antagonist that binds with high-affinity to the Tac subunit of the IL-2 receptor complex (CD 25) and inhibits IL-2 binding.
- Inhibits IL-2 induced T cell activation - Suppresses IL-2 receptor for 30 – 45 days |
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What is the role of IL-2 Antagonists in transplantation?
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Induction therapy for prevention of early acute rejection
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What are the side effects of IL-2 Antagonists?
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- Incidence of adverse effects appear similar to placebo
- vomiting - hyperglycemia - HA |
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How is Basiliximab dosed?
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20 mg IV x 2 dose (days 0 & 4)
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How is Daclizumab dosed?
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* 1mg/kg IV x 5 doses (days 0, 14, 28, 42, 56)
* 2 mg/kg IV x 2 doses (day 0 & 14) |
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What monitoring is necessary with IL-2 Antagonist therapy?
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No extra monitoring necessary.
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What is the efficacy of IL-2 antagonist therapy?
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Efficacy in combination with dual therapy (CYA + Pred) vs. placebo shown to decrease acute rejection rates ~ 30%.
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What immunosuppressant therapy is a humanized anti-CD52 monoclonal antibodyand a polyclonpolyclonal specific complement fixing and lymphocyte depleting agent?
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Alemtuzumab (Campath)
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What is Alemtuzumab (Campath) approved by the FDA to treat?
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FDA approved for management of chronic lymphocytic leukemia (CLL)
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What is the MOA of Alemtuzumab (Campath)?
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Binds to CD52 receptor on B and T cells, monocytes, macrophages, and NK cells resulting in cell lysis and prolonged cell line depletion
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What is the role of Alemtuzumab (Campath) in transplant?
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• Utilized by limited number of center as induction agent
• Primary with steroid or calcineurin inhibitor minimization |
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What are the adverse effects of Alemtuzumab (Campath)?
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- Pancytopenia
- Infusion reaction (SEVERE) - Increase infection risk - Concern for increase risk of humoral rejection |
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How is Alemtuzumab (Campath) dosed?
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20 - 30 mg x 2-4 doses
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What immunosuppressant therapies are produced by immunization of horses or rabbits with human lymphoid cells. The resulting serum is then purified and gamma/immune globulin solution obtained.
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1. ATG, Atgam – horse-derived gamma globulin
2. Thymoglobulin – rabbit-derived immune globulin |
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What is the MOA of polyclonal antibodies, Antilymphocyte and Antithymocyte Globulin?
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- Blocks numerous T-cell membrane proteins (CD2, CD3, CD45, and more)
- Depletes circulating T-cells by: i. opsonization and removal by the reticuloendothelial system ii. direct, complement-assisted lysing of lymphocytes - Diminishes the availability of activated cells and also decreases proliferation of T cells |
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What is the role of Polyclonal Antibodies in transplantation?
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• Induction therapy for prevention of early acute rejection
• Treatment of acute allograft rejection |
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What are the adverse effects of polyclonal antibodies?
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- fever, chills
- respiratory distress - arthralgias, myalgias - hypotension - chest pain –back - erythema - pruritis - infection - leukopenia ( much higher incidence with Thymo) - thrombocytopenia - allergic reaction - increase risk for malignancy |
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Compare ATG vs. Thymoglobulin
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Greater degree and longer duration of lymphocyte depletion with Thymoglobulin
Thymoglobulin associated with higher success rate in treating acute rejection and preventing acute rejection in high risk populations Less leukopenia with ATG (4-5% vs. 40%) Less batch to batch variation with Thymoglobulin |
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How is Thymoglobin dosed?
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1 – 1.5 mg/kg/day x 4 – 10 days
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How is ATG dosed?
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* 10 – 20 mg/kg/day x 7 - 14 days
*Optional to continue after 14 days with alternate-day therapy up to total of 21 doses in 28 days. |
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What monitoring and testing is needed with polyclonal antibodies?
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Monitor organ function (BUN/creatinine)
T-cell count: Depression of the circulating T-cells count should be maintained < 5% of the total fraction of circulating lymphocytes (or below 50 – 100) Atgam is derived from horse serum, skin testing is strongly recommended (0.1 ml stock in 100ml of NS, then give 0.1ml intradermally) |
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Thymoglobulin dosage reduction is necessary for neutropenia and thrombocytopenia
What are the appropriate dosing parameters? |
WBC >3000 and Platelets >75,000 use the full dose
WBC 2000-3000 and Platelets 50,000-75,000 use half the normal dose WBC <2000 and platelets <50,000 HOLD the dose |
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CURRENT IMMUNOSUPPRESSIVE STRATEGIES:
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1. Calcineurin inhibitor (CI) + antiproliferative agent / sirolimus + prednisone
2. Induction therapy + CI + antiproliferative agent / sirolimus + prednisone 3. +/- Induction therapy + CI x 3 months + sirolimus + prednisone 4. Induction therapy + CI + mycophenolate mofetil + prednisone withdrawal 5. +/- Induction therapy + mycophenolate mofetil + sirolimus + prednisone Varies with type of transplant, type of donor, patient characteristics, and risk for acute rejection |
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What do studies tell us about the efficacy of the "older Regiments?"
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Increase risk of both acute rejection and graft failure
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What do the studies tell us about the newer regimen (MMF/CYA/P)?
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- Large US trial evaluating MMF/CYA +/- prednisone withdrawal after 3 months
- Large trial, with low rates of induction therapy - Results: (Stopped early because of increase AR rates) - Dramatic increase in AR in African American with steroid withdrawal |
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What do the studies tell us about the newer regimens with induction therapy?
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- Recently published trial with Induction therapy/FK/MMF +/- prednisone shows equal efficacy in primary outcomes (death, graft loss, moderate/severe rejection) at 5 year data
- Results: - Acceptable acute rejection rates, but slightly higher in steroid withdraw arm (17.8% vs. 10.8%) - Steroid arm: More bone fractures + avascular necrosis, more serious adverse effects due to DM or infection, more ATG for acute rejection, higher fasting triglyceride level |
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Calcineurin Inhibitor (CI) Withdrawal
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- Efforts to primarily avoid the harmful nephrotoxic effects of CIs
- Trials with MMF/P or AZA/P have been unsuccessful - Two recent large trials with SIR/P have shown promising results - Sirolimus approved for therapy in CYA withdrawal in low risk patients after 3 months of therapy with CYA/SIR/P - Results with SIR/P: - Small increase in AR (~5%) - Improved GFR, Scr, and blood pressure - Trend towards improved graft survival |
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What are tolerance regimens?
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Immune tolerance: lack of an immune response to the foreign antigens expressed by an organ allograft in the absence of ongoing immunosuppressive therapy
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What agents are part of tolerance regimens?
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• Utilize a variety of agents for “conditioning regimens”:
Irradiation therapy Cyclophosphamide Antibody therapy (thymoglobulin, IVIG, rituximab) Cyclosporine or tacrolimus |
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How is tolerance in transplant measured?
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Many questions exist regarding how to measure tolerance.
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POST TRANSPLANT COMPLICATIONS
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Infections in the first month post-transplant:
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Infection that was present prior to transplant or came with the allograft
- Hepatitis, TB, herpes simplex virus (HSV) Nosocomial bacterial or candidal infections of the surgical wounds, lungs, IV lines, and urinary tract |
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Infections 1-6 months post-transplant
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Viral infections
- Hepatitis, cytomegalovirus (CMV), HSV, Polyoma virus (JC and BK) Opportunistic pathogens - Pneumocystis carinii pneumonia (PCP), Listeria sp., Aspergillus, Candadia sp., Toxoplasma sp. |
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Infections more than 6 months post-transplant
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Chronic viral infections
- CMV retinitis/gastritis, hepatitis, HSV, Polyoma virus, post-transplant lymphoproliferative disease (PTLD) due to epstein barr virus Life-threatening opportunistic infections - Cryptococcus neoformans, Listeria sp., Nocardia asteroides, Community acquired infections - UTI, influenza, pneumonia |
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POST TRANSPLANT MEDICAL COMPLICATIONS
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Hypertension
Dyslipidemia Osteoporosis Nephrotoxicity Glucose intolerance/Post-transplant diabetes (PTDM) Gout Skin/lip cancer Weight gain Acne Gum hyperplasia |
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Post transplant complication: HTN
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Etiology multi-factorial: native kidney, transplanted kidney, polycythemia, medications, acute rejection, transplant renal artery stenosis
Treatment goal: <130/85 Factor in development of CAN Management: calcium channel blockers – dilate afferent arteriole to counteract CYA/TAC constriction – drug interaction with nondihydropyridines beta blockers - drug of choice in patients with CAD ACE inhibitors / ARBs - preferably after first 6 months |
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Post transplant complication: Dyslipidemia
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25 – 40 % of patient on sirolimus will have inc TG
Both calcineurin inhibitors (CYA>TAC) and steroid can cause dyslipidemia Goals: LDL < 130, TG < 200. Lower if CAD or DM (<100) Factor in development of CAN Management: HMG CoA reductase inhibitors - HMG CoA inhibitors may have immunomodulatory actions - Monitor CK for rhabdomyolysis in patient on HMG Co A inh Fenofibrate (Tricor) |
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Post transplant complication:
Osteoporosis |
Corticosteroid induced osteoporosis well described
- Due to decreased Ca2+ absorption, decreased osteoblast activity, & increased bone resorption Occurs at any age, in both genders, and across races Up to 50% of patients on chronic steroid therapy develop osteoporosis Management: Bisphosphonates- alendronate or risidronate Calcium supplementation +/- vit D Weight bearing exercise |
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Post transplant complication:
Nephrotoxicity |
Etiology: calcineurin inhibitor, hypertension, recurrent disease
Calcineurin inhibitor • dose-limiting effect • Mechanism: vsoconstrictive effect on the afferent arterioles resulting in increased renal vascular resistance, decreased renal blood flow, and decreased glomerular filtration rate (GFR). • Subacute nephrotoxicity: increase in serum creatinine with increase in CsA levels that responds to dose reduction • Acute nephrotoxicity: oliguria, anuria or increased serum creatinine Management: Avoid use of other potentially nephrotoxic agents low level calcineurin inhibitor (potential avoidance) hypertension control – CCB or ACE inhibitor use (?) |
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Post transplant complication:
Glucose intolerance/Post-transplant diabetes (PTDM) |
Incidence as high as 30%
Etiology: Underlying diabetes, CYA/TAC, prednisone Impact of PTDM: * Graft survival lower * Decreases in renal function * Increase prevalence of infectious complications * Reduced health-related quality of life * Consistently reduced patient survival Management: PREVENTION PTDM – consider switching to CYA or stopping calcineurin inhibitor oral sulfonylureas insulin thiazolidinediones (pioglitazone or rosiglitazone) byetta or DPP-IV inhibitors |
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Post transplant complication:
Gout |
Hyperuricemia secondary to CYA/TAC
Management: Acute gout treatment: NO NSAIDS. Colchicine Prevention: allopurinol, probenacid, or colchicine |
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Post transplant complication:
Skin/lip Cancer |
– Incidence: 40 – 60% at 20 years
– Sunscreen! – Cervical CA #2, PTLD #3 |
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Post transplant complication:
Weight Gain |
– Average weight gain ~ 10% of body weight
- Exercise and diet |
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Post transplant complication:
Electrolyte abnormalities |
- K and PO4 wasting after transplant
- Treat with electrolyte replacement products |
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Post transplant complication:
Acne |
– Topical clindamycin 10% lotion bid
– Benzol peroxide 5 – 10% lotion bid |
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Post transplant complication:
Gum hyperplasia |
- Regular brushing of teeth and gums
- Surgical resection - Switch from cyclosporine to tacrolimus |