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AUTOIMMUNE DISEASES Misty Mauldin Medicinal Chemistry Spring 2009 Immune System Autoimmune Disease Pathogenesis Diagnosis Treatments Ankylosing Spondylitits Signs & Symptoms Diagnosis Treatments Anti-inflammatory Drugs NSAIDs Steroidal Opioid Immunosuppressant Drugs DMARDs Ciclosporin Methotrexate Sulfasalazine TNF-α Blockers Enbrel Humira Remicade Future Resources Body’s means of protection against microorganisms and other “foreign” substances Composed of two major parts B lymphocytes- Humoral Immune System produces antibodies and proteins attack “foreign” substances and cause them to be removed from the body T lymphocytes – Cellular Immune System attacks “foreign” substances directly Normally, the immune system can distinguish between “self” and “not self” and only attack those tissues that it recognizes as “not self” Caused by the body producing an inappropriate immune response against its own tissues When immune system ceases to recognize one or more of the body’s normal constituents as “self” and will create autoantibodies (antibodies that attack its own cells, tissues, and/or organs) This leads to inflammation and damage which leads to autoimmune disorders. Currently, there is no cure whatsoever for autoimmune diseases, just treatments 1. Systematic Autoimmune Disease Damages many organs 2. Localized Autoimmune Disease Damages only a single organ or tissue directly Systematic Autoimmune Disease Localized Autoimmune Disease Rheumatoid Arthritis (RA) and Juvenile RA (JRA) – joints, lung, skin Type 1 Diabetes Mellitus – pancreas islets Lupus – skin, joints, kidneys, heart, brain, red blood cells Hashimoto’s thyroiditis Graves’ disease – thyroid Scleroderma – skin, intestine, lung Crohn’s disease – GI tract Sjogren’s syndrome – salivary glands, tear glands, joints Addison’s disease – adrenal Ankylosin Spondyltis – joints, Another one.. The exact cause for autoimmune diseases is unknown, but there appears to be inherited predisposition to developing an autoimmune disease Associated with multiple genes plus other risk factors 3 sets of genes 1. Immunoglobulins 2. T-cell receptors 3. MHC – major histocompatibility complexes Immunoglobulins and T cell receptors are involved in recognition of antigens and are inherently variable and susceptible to recombination These variations enable immune response to respond to a wide variety of invaders, but also these variations might give rise to lymphocytes capable of self-reactivity MHC Class II – strongly correlated with specific autoimmune diseases HLA-DR2: systemic Lupus Erythematosus HLA-DR3: Sjogren’s syndrome HLA-DR4: Rheumatoid Arthritis MHC Class I – fewer correlations with specific autoimmune diseases Most notable is: HLA-B27: ankylosin spondyltis 3 hypothesis that have gained widespread attention: 1. Clonal Deletion Theory Self-reactive lymphoid cells are destroyed during the development of the immune system in an individual 2. Clonal Anergy Theory Self-reactive T- or B- cells become inactivated in the normal individual and cannot amplify the immune response 3. Idiotype Network Theory A network of antibodies capable of neutralizing self-reactive antibodies exists naturally within the body Sex: most known autoimmune diseases show a female preponderance except the disease ankylosing spondylitis which has a male preponderance, and Crohn's disease which is roughly equal Environmental: Inverse relationship seen between infections diseases and autoimmune diseases Areas where multiple infectious diseases are endemic, autoimmune diseases are rare, and vise versa T-Cell Bypass Molecular Mimicry A cross reaction between the Idiotype (molecule recognized by antigen) on an antiviral antibody and a host cell receptor for the virus in question Cytokine Dysregulation An exogenous antigen shares structural similarities with host antigen and when an antibody is produced, it can bind to host antigen Idiotype Cross Reaction The requirement of T cells to activate B cells in order to produce large amounts of antibodies is bypassed Certain cytokines have a role in the prevention of the exaggeration of pro-inflammatory immune response Dendritic Cell Apoptosis Defective dendritic cells can lead to inappropriate systemic lymphocyte activation and a decline in self tolerance Autoantibody blood tests Levels of autoantibodies are measured to determine the progress of the disease Blood tests to measure inflammation and organ function Clinical presentation Non-laboratory examinations (X-rays) Immunosuppressive Anti-inflammatory Palliative (reducing symptoms) Dietary Manipulation Non-immunological therapies A chronic, inflammatory arthritis Affects joints in the spine and the sacroilium in the pelvis, causing eventual fusion of the spine The typical patient is young, aged 18-30, with chronic pain and stiffness in the lower part of the spine, often with pain referred to one or other buttock or back of thigh from the sacroiliac joint early on Pain is often severe on rest, and improves with physical activity Men are affected more than women by a ratio about of 3:1 In 40% of cases, ankylosing spondylitis is associated with an inflammation of the white of the eye (iritis) Another common symptom is generalized fatigue Psoriasis (skin disorder) AS is a systemic rheumatic disease and is one of the seronegative spondyloarthropathies. About 90% of the patients express the HLA-B27 genotype Tumor necrosis factor-alpha (TNF α) and IL-1 are also implicated in ankylosin spondylitits Autoantibodies specific for AS have not been identified. There is no direct test to diagnose AS. A clinical examination and X-ray studies of the spine, which show characteristic spinal changes and sacroiliitis, are the major diagnostic tools. Other options for diagnosis are tomography and MRIs of the sacroiliac joints, but the reliability of these tests is still unclear The Schober's test is a useful clinical measure of flexion of the lumbar spine performed during examination During acute inflammatory periods, AS patients will usually show an increase in the blood concentration of C-reactive protein (CRP) and an increase in the erythrocyte sedimentation rate (ESR) Variations of the HLA-B gene increase the risk of developing ankylosing spondylitis, although it is not a diagnostic test. Those with the HLA-B27 variant are at a higher risk than the general population of developing the disorder. HLA-B27, demonstrated in a blood test, can occasionally help with diagnosis but in itself is not diagnostic of AS in a person with back pain. Anti-inflammatory Steroid/NSAID drugs Immunosuppressive DMARDs TNFα blockers (antagonists) Surgery Physical Therapy NSAIDs Aspirin ibuprofen phenylbutazone Indomethacin Naproxen COX-2 inhibitors Steroidal Opioid analgesics Morphine Oxycodone Hydrocodone DMARDs Cyclosporin Methotrexate Sulfasalazine corticosteroids TNFα blockers (antagonists) Etanercept (Enbrel) Infliximab (Remicade) Adalimumab (Humira) DMARDs Immunosuppressant drug Mostly used for the prevention of organ transplant rejection Discovered in Switzerland on January 31, 1972 Approved for use in US in 1983 Also used for treatment of psoriasis, dermatitis, RA, and related diseases SIDE EFFECTS - Adverse effects with lots of different drugs, including grapefruit juice Convulsions, pancreatitis, fever, vomiting, diarrhea, breathing problems, nephrotoxicity, and Hepatotoxicity Mode of action: It is thought to bind to the cytosolic protein cyclophilin of immunocompetent lymphocytes, especially Tlymphocytes This complex of cyclosporin and cyclophilin inhibits calcineurin, which is responsible for activating the transcription of interleukin 2. It also inhibits lymphokine production and interleukin release, and therefore leads to a reduced function of effector T-cells Marketed under various names: Restasis (topical version) Neoral (orally administered) Cicloral & Gengraf (generics) Uses: - Cancer chemotherapy Medical termination of pregnancy Treatment of autoimmune diseases (a parallel use with TNA-a blockers has been shown to markedly improve symptoms An antimetabolite and antifolate drug used in treatment of cancer and autoimmune diseases Acts by inhibiting the metabolism of folic acid Originated in the 1940’s Mode of Action competitively and reversibly inhibits dihydrofolate reductase (DHFR), and enzyme that participates in the Tetrahydrofolate synthesis. DHFR catalyses the conversion of dihydrofolate to the active Tetrahydrofolate. Folic acid is needed for the de nova synthesis of the nucleoside thymidine, required for DNA synthesis Folate is needed for purine base synthesis, so all purine synthesis will be inhibited Therefore, MTX inhibits the synthesis of DNA, RNA, thymidylates, and proteins MTX acts specifically during DNA and RNA synthesis It has a greater toxic effect on rapidly dividing cells (such as malignant cells), which replicated their DNA more frequently, and thus inhibits the growth and proliferation of these noncancerous cells as well as causing side effects SIDE EFFECTS: anemia, increased risk of bruising Hepatitis Serious adverse effects with penicillin fever, chills, dizziness Lowered risk to infection • • Brand name: Azulfidine (in US) Sulfa drug; used primarily as an antiinflammatory agent for inflammatory bowel disease as well as RA NOT an immunosuppressant! Main mode of action is believed to be inside the intestine It can do this by a number of mechanisms, one of which is by reducing the synthesis of inflammatory mediators. SIDE EFFECTS: Can result in serious Hepatotoxicity Mouth ulcers, sore mouth Loose bowels Headache/ dizziness Rash that can be itchy Type of hepatitis (liver inflammation) Orange discoloration of urine as well as perspiration and content lenses can be stained Severe depression in young males Decrease sperm count in men Temporary infertility in women, but usually safe during pregnancy First synthesized in the early 1990’s at UTSW in Dallas! Treats autoimmune diseases by interfering with the TNF receptor, a part of the immune system A recombinant-DNA drug made by combining two proteins (fusion protein). It links human soluble TNF receptor to the Fc component of human immunoglobulin GI (IgGI) and acts as TNF inhibitor Binds to TNF-a and decreases its role in disorders involving excess inflammation in humans, including autoimmune diseases, such as ankylosing spondylitis, juvenile RA, psoriasis, psoriatic arthritis, and RA. Etanercept mimics the inhibitory effects of naturally occurring soluble TNF receptor, the difference being that since it is a fusion protein rather than simple TNF receptor, it has a greatly extended half-life in the bloodstream, and therefore a more profound and longlasting biologic effect than a naturally occurring soluble TNF receptor. Safety: Immunosuppressant Administration: In May 2, 2008, the FDA Injected subcutaneously, placed a black box typically by patient at warning on Enbrel due to home a number of serious Come in pre-filled infections associated with 50mg/ml syringes in 2004 the drug and a single-use 50mg auto-injector pen in 2006 Cost: $10,000-$40,000 per year (depending on number of treatments TNF inhibitor, binds to TNFα, preventing it from activation TNF receptors immunosuppressant Constructed from a fully human monoclonal antibody Approved by FDA in 2008 for treatment of: Rheumatoid arthritis Psoriatic arthritis Ankylosin spondylitits Crohn’s disease Administration: Injected subcutaneously by patient at home Preloaded 0.8 ml syringes, or Preloaded pen devices (Humira pen) Safety: Serious or fatal blood disorders Serious infections (including TB) Given black box warning by FDA Remicade video Used to treat: -Skin diseases (psoriasis) -Ankylosing spondylitits -Crohn’s disease -RA, PsA Developed at New York University School of Medicine Manufactured by Johnson & Johnson Prevents the binding of TNFα to its receptor cell Artificial antibody, originally developed in mice, as a mouse antibody, and later humized into a human antibody Because it’s a combination of a mouse and human antibody, its called a chimeric monoclonal antibody Administration: IV fusion, typically 6-8 week intervals at clinic or hospital Can NOT be done orally because digestive system would destroy the drug Cost:$19,000-$22,000 per year - approx. $1650 per 100mg Safety: Fatal blood disorders Infections Rare reports of lymphoma and cancer (less likely when used with Methotrexate) Possible Association between TNF Blockers and Cancer | Pharmainfo.net Enbrel is being studied for treatment of Alzheimer’s disease Wikipedia.org Pub Med Remicade.com Pharmainfo.net Simonportfolio.com