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