autoimmune diseases misty mauldin medicinal chemistry spring 2009
TRANSCRIPT
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 directlySystematic Autoimmune
DiseaseLocalized 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,
jointsAddison’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 The requirement of T cells to activate B cells in order to
produce large amounts of antibodies is bypassed Molecular Mimicry
An exogenous antigen shares structural similarities with host antigen and when an antibody is produced, it can bind to host antigen
Idiotype Cross Reaction 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 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
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)
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
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 diseasesSIDE 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 T-lymphocytes
- 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)
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
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
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 non-cancerous 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 anti-
inflammatory 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 long-lasting biologic effect than a naturally occurring soluble TNF receptor.
Administration: Injected
subcutaneously, typically by patient at home
Come in pre-filled 50mg/ml syringes in 2004 and a single-use 50mg auto-injector pen in 2006
Safety: Immunosuppressant In May 2, 2008, the
FDA placed a black box warning on Enbrel due to a number of serious infections associated with the drugCost:
$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
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
Used to treat:-Skin diseases (psoriasis)-Ankylosing spondylitits-Crohn’s disease-RA, PsA
Administration: IV fusion, typically 6-8 week intervals at
clinic or hospital Can NOT be done orally because
digestive system would destroy the drug
Safety: Fatal blood disorders Infections Rare reports of lymphoma and cancer (less likely
when used with Methotrexate)
Cost:$19,000-$22,000 per year
- approx. $1650 per 100mg
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