Drug Literacy Program Treating autoimmunity rheumatoid arthritis RA

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Lupus_and_RA.ppt

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Drug Literacy Program Treating autoimmunity: rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) Irina Baltcheva February 11 th, 2013

Epidemiology and clinical manifestations M&S Drug Literacy Program

Systemic Lupus Erythematosus (SLE): Background § SLE name “lupus” (Latin for “wolf”) was first used during the Middle Ages to describe erosive skin lesions evocative of a “wolf’s bite”. § SLE is the prototypic multisystem autoimmune disorder with a broad spectrum of clinical presentations encompassing almost all organs and tissues. § The extreme heterogeneity of the disease has led some investigators to propose that SLE represents a syndrome rather than a single disease. 1 4 World Alzheimer Report 2010 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only A malar rash is present in approximately 46– 65% of lupus sufferers and varies between different populations.

Rheumatoid arthritis (RA): Background § Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks flexible (synovial) joints. § It can be a disabling and painful condition, which can lead to substantial loss of functioning and mobility if not adequately treated. 5 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only

SLE vs RA: Epidemiology § RA is incurable, but treatable. § SLE is incurable, but treatable. § Life expectancy: • lifespan reduced by anywhere from three to 12 years § Prevalence • 1% in general • 5 -6% in some native American groups • Less than 1% in people from Caribbean § The incidence is about 3 cases per 10, 000 population per annum. § Are affected: • Women 3 -5 times as often as men. • 3 times more common in smokers than nonsmokers] - In the 1950 s, most people diagnosed with SLE lived fewer than five years. - Today, over 90% survive for more than ten years, and many live relatively asymptomatically. 80 -90% can expect to live a normal lifespan. § Prevalence - US: 51 per 100’ 000 (200 per 100’ 000 among african americans) - Europe: 40 per 100’ 000 § > 250’ 000 patients in the US § Incidence has tripled in the last 40 years, due to improved diagnosis of mild disease. § Are affected: • A study in 2010 found that those who drank - Females in 90% of cases; modest amounts of alcohol regularly were four times less likely to get rheumatoid - African american and Latin american mestizos 6 | Drug arthritis. Literacy Program | who never drank. SLE & RA | Business Use Only than those I. Baltcheva | 11. 02. 2013 | more than Caucasians

SLE – Pathology M&S Drug Literacy Program

Antigen presentation Antigen-presenting cells (APC) bind antigen on major histocompatibility complexes (MHC). This complex interacts with the T-cell receptor (TCR) and this might lead to inhibition or stimulation of T cells. 13 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only

T cell – B cell interaction B cells act as antigen-presenting cells and stimulate T cells to produce cytokines, which, in turn, act on B cells and promote antibody formation 14 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only

RA – Pathophysiology M&S Drug Literacy Program

SLE – Treatments M&S Drug Literacy Program

Treating SLE is challenging because disease is multisystemic, remitting and relapsing § Current standard of care: • Nonsteroidal anti-inflammatory drugs (aspirine, approved in 1948) (agents that treat the inflammation but not the underlying cause) • Antimalarials (hydroxychloroquine, approved in 1955) • Corticosteroids (approved in 1955) • Immunosuppressive drugs - Methotrexate Azathioprine Mycophenolate mfetil (MMF) Cyclosporine Belimumab (the only biologic approved in 2011) § Above treatments are ineffective for some patients -> unmet medical need § Many more biologics were tested, but failed: rituximab, abatacep, epratuzumab, abetimus, IDEC-131, etc. 24 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only

Hydroxychloroquine Overview § Anti-malarial drug § Mechanism of action: blocks the activation of toll-like receptors (TLR) on dendritic cells, thereby mitigating the inflammatory process. § Remember: Toll-like receptors recognize DNA-containing immune complexes, which leads to the production of interferon and causes the dendritic cells to mature and present antigen to T cells. 25 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only

Corticosteroids Overview § In technical terms, "corticosteroid" refers to both glucocorticoids and mineralocorticoids (as both are mimics of hormones produced by the adrenal cortex), but is often used as a synonym for "glucocorticoid". § Glucocorticoids (GC) are a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. § GCs suppress cell-mediated immunity by • inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and IFN-γ. • This decreases the function and numbers of T lymphocytes. § GCs suppress humoral immunity • B cells produce less IL-2 • B cells express less IL-2 receptors • B cells proliferate less • B cells produce fewer antibodies • B cells can not present antigen to T cells. § List of steroids: Hydrocortisone (cortisol), Cortisone, Prednisolone, Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone, Beclometasone, Fludrocortisone acetate, Deoxycorticosterone acetate (DOCA), Aldosterone. 26 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only

Methotrexate Overview § Is an antimetabolite and antifolate drug. § Interferes with the metabolism of folic acid. § Mechanism of action in RA: • Inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine, or the inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells. 27 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only Methotrexate (green) complexed into the active site of dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis (blue).

Cyclosporine Overview § Is an immunosuppressant drug widely used in organ transplantation to prevent rejection. § Reduces the activity of T cells. § Mechanism of action: • Binds to the cytosolic protein cyclophilin of lymphocytes. This complex of ciclosporin and cyclophilin inhibits calcineurin, which, under normal circumstances, is responsible for activating the transcription of interleukin 2. IL-2 production & proliferation Activated T cell 28 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only

RA – Treatments M&S Drug Literacy Program

Current treatment options for RA: DMARDs Medication Pharmacology Usual dose and route Adverse effects Auranofin Gold salt with unknown mechanism 3 -6 mg daily; oral; 3 mg given twice daily Diarrhea, hypersensitivity reactions. Azathioprine Antiproliferative agent to T cells and B cells 50 -200 mg daily; oral Hepatoxicity, myelotoxicity, gastrointestinal toxicity. Cyclosporin T-cell activation inhibitor (IL-2) 2. 5 -5 mg/kg per day; oral Nephrotoxicity, hypertension. Hydroxychloroquine Interferes with antigen processing and immune function 200 -400 mg daily; oral Retinopathy. Leflunomide Antimetabolite 10 -20 mg daily; oral Hepatotoxicity, myelotoxicity, hypertension. Methotrexate Antimetabolite 7. 5 -25 mg weekly; oral or subcutaneous Hepatotoxicity, myelotoxicity, fibrosing alveolitis. Sodium aurothiomalate Gold salt with unknown mechanism 50 mg weekly; intramuscular Hypersensitivity reactions, nephritis, fibrosing alveolitis. Sulfasalazine Anti-inflammatory and antimicrobial 1000 -1500 mg twice daily; oral Hepatotoxicity, myelotoxicity, hypersensitivity reactions. 37 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only

Current treatment options for RA: TNF inhibitors Approved anti-TNFα biologic agents Medication Pharmacology Usual dose and route Adverse effects Adalimumab Human monoclonal antibody; TNF blockade 40 mg every 2 weeks; subcutaneous Injection site reactions, infections Certolizumab pegol Pegylated Fab' fragment from humanized monoclonal antibody; TNF blockade 200 mg every 2 weeks or 400 mg monthly (two 200 -mg injections); subcutaneous Injection site reactions, infections. Etanercept Recombinant TNF receptor (p 75) dimerized on immunoglobulin frame; TNF blockade 50 mg weekly or 25 mg twice weekly; subcutaneous Injection site reactions, infections. Golimumab Human monoclonal antibody; TNF blockade 50 mg or 100 mg every 4 weeks; subcutaneous Injection site reactions, infections Infliximab Chimeric monoclonal antibody; TNF blockade 3 mg/kg, weeks 0, 2, and 6, then 3 -10 mg/ kg every 4 -8 weeks; intravenous Infusion reactions, infections. 38 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only

Tumor necrosis factor-alpha (TNFα) § Tumor necrosis factor-alpha (TNFα) is a cytokine produced by lymphocytes and macrophages § Has various functions: • It can cause cytolysis of certain tumor cell lines; • it is a potent pyrogen, causing fever by direct action or by stimulation of interleukin-1 secretion; • TNFα mediates the immune response by increasing the transport of white blood cells to sites of inflammation, and through additional molecular mechanisms which initiate and amplify inflammation. 39 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only

Current treatment options for RA: Other biologics Approved therapies Agent Class Pharmacology Abatacept Costimulation blocker (CD 80/CD 86: CD 28 signal) Anakinra Target Usual dose and route Adverse effects CTLA 4 -Ig fusion protein. CD 80 and Blocks T-cell CD 86 costimulation and consequent Th 17 cell response and IL-6. 8 -10 mg/kg (500 -1000 mg) intravenously at weeks 0, 2, and 4, then monthly; or 500 -1000 mg intravenous loading dose, followed by 125 mg subcutaneous within a day, and then once weekly. May also be given subcutaneously without a loading dose. Infusion reactions, infections. Cytokine inhibitor Recombinant IL-1 receptor antagonist IL-1 100 mg daily; subcutaneous Injection site reactions, infections, neutropenia. Rituximab Cell-depleting agent Chimeric monoclonal antibody to CD 20 for Bcell depletion CD 20 1000 mg in 2 infusions, 2 weeks apart, repeating every 4 to 8 months; intravenous Infusion reactions, infections Tocilizumab Cytokine inhibitor Humanized monoclonal antibody; IL-6 receptor blockade IL-6 receptor 8 mg/kg every 4 weeks; intravenous Infusion reactions, infections, elevated cholesterol 40 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only

Rituximab (RTX): mechanism of action § Rituximab is a monoclonal antibody (m. Ab) that binds to CD 20, a surface receptor expressed on B cells. § The resulting effect of RTX binding is death of B cells. The death can occur through 4 different mechanisms. § Approved for the treatment of Non-Hodgkin’s lymphoma, rheumatoid arthritis (RA) and chronic lymphocytic leukemia (CLL) 41 | IB | Estimating B-cell turnover parameters | Business Use Only

Auto-immune diseases: summary and conclusions M&S Drug Literacy Program

Common therapies (approved or tested) to both SLE and RA § § § Corticosteroids – anti-inflammatory Hydroxychloroquine – blocks activation of TLR on dendritic cells Abatacept (approved for RA, not for SLE) – Costimulation blocker Rituximab (approved for RA, not for SLE) – B cell depletor Belimumab (approved for SLE, not for RA) – anti-BLy. S (= anti-BAFF) Belimumab Corticosteroids IL-2 Hydroxychloroquine Rituximab Cyclosporin Abatacept 44 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only Epratuzumab

Treating auto-immune diseases Single-minded message § It’s complicated. . . § Pathophysiology not fully understood. § Several immune pathways, redundancy? § Heterogeneous: patient sub-populations. 45 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only

Appendix M&S Drug Literacy Program

References and sources § Systemic lupus erythematosus: an update on current pharmacotherapy and future directions, Zahi Touma, Murray B Urowitz & Dafna D Gladma, 2013 § Comparative Effectiveness of Current Treatments for Rheumatoid Arthritis, Allan Gibofsky, The American Journal of Managed Care, Vol. 18, no. 13, 2012. § The Pathogenesis of Rheumatoid Arthritis, Iain B. Mc. Innes, Georg Schett, N Engl J Med, December 8, 2011 § Systemic Lupus Erythematosus, Anisur Rahman, and David A. Isenberg, N Engl J Med, February 28, 2008 § Systemic Lupus Erythematosus: Pathogenesis and Clinical Features, George Bertsias, Ricard Cervera, Dimitrios T Boumpas, 2012 § Biologics in the treatment of systemic lupus erythematosus, Aisha Lateefa, b and Michelle Petri, Current Opinion in Rheumatology, 2010, 22: 504– 509 § Wikipedia 47 | Drug Literacy Program | I. Baltcheva | 11. 02. 2013 | SLE & RA | Business Use Only