Pharmacology

Research for Drugs of treatment osteoarthritis and

rheumatoid arthritis

: .

Osteoarthritis
Osteoarthritis (OA) also known as degenerative arthritis or degenerative joint
disease or osteoarthrosis, is a group of mechanical abnormalities involving degradation
of joints, including articular cartilage and subchondral bone. Symptoms may include joint
pain, tenderness, stiffness, locking, and sometimes an effusion. A variety of causes
hereditary, developmental, metabolic, and mechanical deficitsmay initiate processes leading
to loss of cartilage. When bone surfaces become less well protected by cartilage, bone may be
exposed and damaged. As a result of decreased movement secondary to pain, regional
.muscles may atrophy, and ligaments may become more lax
Treatment generally involves a combination of exercise, lifestyle modification, and analgesics.
If pain becomes debilitating, joint replacement surgery may be used to improve the quality of
life. OA is the most common form of arthritis, and the leading cause of chronic disability in the
United States. It affects about 1.9 million people in Australia, 8 million people in the United
.Kingdom and nearly 27 million people in the United States

Causes
Damage from mechanical stress with insufficient self repair by joints is believed to be the
primary cause of osteoarthritis. Sources of this stress may include: misalignments of bones
caused by congenital or pathogenic causes; mechanical injury; excess body weight; loss of
strength in the muscles supporting a joint; and impairment of peripheral nerves, leading to
sudden or uncoordinated movements. However exercise, including running in the absence of
injury, has not been found to increase the risk. Nor has cracking one's knuckles been found to
.play a role

Primary
A number of studies have shown that there is a greater prevalence of the disease
among siblings and especially identical twins, indicating a hereditary basis.[12] Although a
single factor is not generally sufficient to cause the disease, about half of the variation in
.susceptibility has been assigned to genetic factors
As early human ancestors evolved into bipeds, changes occurred in the pelvis, hip joint and
spine which increased the risk of osteoarthritis. Additionally genetic variations that increase
the risk were likely not selected against because usually problems only occur after
.reproductive success
The development of OA is correlated with a history of previous joint injury and with obesity,
especially with respect to knees. Since the correlation with obesity has been observed not
only for knees but also for non-weight bearing joints and the loss of body fat is more closely
related to symptom relief than the loss of body weight, it has been suggested that there may
.be a metabolic link to body fat as opposed to just mechanical loading
Changes in sex hormone levels may play a role in the development of OA as it is more
prevalent among post-menopausal women than among men of the same age. A study of mice

found natural female hormones to be protective while injections of the male

.hormonedihydrotestosterone reduced protection

Secondary
This type of OA is caused by other factors but the resulting pathology is the same as for
:primary OA

Alkaptonuria

Congenital disorders of joints

Diabetes

Ehlers-Danlos Syndrome

Hemochromatosis and Wilson's disease

Inflammatory diseases (such as Perthes' disease), (Lyme disease), and all chronic
forms of arthritis (e.g. costochondritis, gout, and rheumatoid arthritis). In gout, uric
acidcrystals cause the cartilage to degenerate at a faster pace.

Injury to joints or ligaments (such as the ACL), as a result of an accident or orthopedic

operations.

Ligamentous deterioration or instability may be a factor.

Marfan syndrome

Obesity

Septic arthritis (infection of a joint)

Signs and symptoms

The main symptom is pain, causing loss of ability and often stiffness. "Pain" is generally
described as a sharp ache or a burning sensation in the associated muscles and tendons. OA
can cause a crackling noise (called "crepitus") when the affected joint is moved or touched
and people may experience muscle spasms and contractions in the tendons. Occasionally, the
joints may also be filled with fluid. Some people report increased pain associated with cold
temperature, high humidity, and/or a drop in barometric pressure, but studies have had mixed
.results
OA commonly affects the hands, feet, spine, and the large weight bearing joints, such as
the hips and knees, although in theory, any joint in the body can be affected. As OA
progresses, the affected joints appear larger, are stiff and painful, and usually feel better with
gentle use but worse with excessive or prolonged use, thus distinguishing it from rheumatoid
.arthritis

In smaller joints, such as at the fingers, hard bony enlargements, called Heberden's nodes (on
the distal interphalangeal joints) and/orBouchard's nodes (on the proximal interphalangeal
joints), may form, and though they are not necessarily painful, they do limit the movement of
the fingers significantly. OA at the toes leads to the formation of bunions, rendering them red
.or swollen. Some people notice these physical changes before they experience any pain
.OA is the most common cause of a joint effusion of the knee

Diagnosis
Diagnosis is made with reasonable certainty based on history and clinical examination. Xrays may confirm the diagnosis. The typical changes seen on X-ray include: jointspace
narrowing, subchondral sclerosis (increased bone formation around the joint),
subchondral cyst formation, and osteophytes. Plain films may not correlate with the findings
on physical examination or with the degree of pain. Usually other imaging techniques are not
.necessary to clinically diagnose OA
In 1990, the American College of Rheumatology, using data from a multi-center study,
developed a set of criteria for the diagnosis of hand OA based on hard tissue enlargement and
swelling of certain joints. These criteria were found to be 92% sensitive and 98% specific for
hand OA versus other entities such as rheumatoid arthritis andspondyloarthropathies.[33]
Related pathologies whose names may be confused with OA include pseudo-arthrosis. This is
derived from the Greek words pseudo, meaning "false", and arthrosis, meaning "joint."
Radiographic diagnosis results in diagnosis of a fracture within a joint, which is not to be
confused with OA which is a degenerative pathology affecting a high incidence of distal
phalangeal joints of female patients. A polished ivory-like appearance may also develop on the
.bones of the affected joints, reflecting a change called eburnation

Medication
Treatment recommendations by risk factors

GI risk

low

Stroke and
heart risk
low

Option

NSAID, or paracetamol

Moderate Low

Paracetamol, or low dose NSAID withantacid

Low

Paracetamol, or low dose aspirin with an antacid

moderate

Moderate Moderate

Low dose paracetamol, aspirin, and antacid.

Monitoring for abdominal pain or black stool.

The analgesic acetaminophen is the first line treatment for OA. For mild to moderate
symptoms effectiveness is similar to non-steroidal anti-inflammatory drugs (NSAIDs), though
for more severe symptoms NSAIDs may be more effective. [36] NSAIDs such as naproxen while
more effective in severe cases are associated with greater side effects such as gastrointestinal
bleeding. Another class of NSAIDs, COX-2 selective inhibitors (such as celecoxib) are equally
effective to NSAIDs with lower rates of adverse gastrointestinal effects but higher rates of
cardiovascular disease such as myocardial infarction.[51] They are also much more expensive.
Oral steroids are not recommended in the treatment of OA because of their modest benefit and
high rate of adverse effects. There are several NSAIDs available for topical use
including diclofenac. Topical and oral diclofenac work equally well with topical having a
greater risk of mild skin reactions but no greater risk of gastrointestinal adverse
effects. Opioid pain medications such as morphine and fentanyl reduce pain a small amount,
but this benefit is outweighed by frequent adverse events and thus they should not routinely
be used. Topicalcapsaicin is controversial with some reviews finding benefit and others not.
Injection of glucocorticoids (such as hydrocortisone) leads to short term pain relief that may
last between a few weeks and a few months. Joint injections of hyaluronic acid have not been
found to lead to significant improvement, Hyaluronic acid injects have been associated with
significant harm. Nevertheless another study about hyaluronic acid injections says efficacy on
pain and function, and no adverse effect when compared to saline injections. Injections
of platelet rich plasma improves function but not pain and is associated with increased risk.

Rheumatoid arthritis
What is rheumatoid arthritis (RA)?
Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the
joints. Autoimmune diseases are illnesses that occur when the body's tissues are mistakenly
attacked by their own immune system. The immune system contains a complex organization
of cells and antibodies designed normally to "seek and destroy" invaders of the body,
particularly infections. Patients with autoimmune diseases have antibodies and immune cells
in their blood that target their own body tissues, where they can be associated with
inflammation. While inflammation of the tissue around the joints and inflammatory arthritis are
characteristic features of rheumatoid arthritis, the disease can also cause inflammation and
injury in other organs in the body. Because it can affect multiple other organs of the body,
rheumatoid arthritis is referred to as a systemic illness and is sometimes called rheumatoid
disease. Rheumatoid arthritis that begins in people under 16 years of age is referred to as
juvenile idiopathic arthritis (formerly juvenile rheumatoid arthritis).
While rheumatoid arthritis is a chronic illness, meaning it can last for years, patients may
experience long periods without symptoms. However, rheumatoid arthritis is typically a
progressive illness that has the potential to cause significant joint destruction and functional
.disability
A joint is where two bones meet to allow movement of body parts. Arthritis means joint
inflammation. The joint inflammation of rheumatoid arthritis causes swelling, pain, stiffness,
and redness in the joints. The inflammation of rheumatoid disease can also occur in tissues
.around the joints, such as the tendons, ligaments, and muscles
In some people with rheumatoid arthritis, chronic inflammation leads to the destruction of the
cartilage, bone, and ligaments, causing deformity of the joints. Damage to the joints can occur

early in the disease and be progressive. Moreover, studies have shown that the progressive
damage to the joints does not necessarily correlate with the degree of pain, stiffness, or
.swelling present in the joints
Rheumatoid arthritis is a common rheumatic disease, affecting approximately 1.3 million
people in the United States, according to current census data. The disease is three times more
common in women as in men. It afflicts people of all races equally. The disease can begin at
any age and even affects children (juvenile idiopathic arthritis), but it most often starts after 40
years of age and before 60 years of age. Though uncommon, in some families, multiple
.members can be affected, suggesting a genetic basis for the disorder

Causes
The cause of rheumatoid arthritis is unknown. Even though infectious agents such as viruses,
bacteria, and fungi have long been suspected, none has been proven as the cause. The cause
of rheumatoid arthritis is a very active area of worldwide research. It is believed that the
tendency to develop rheumatoid arthritis may be genetically inherited (hereditary). Certain
genes have been identified that increase the risk for rheumatoid arthritis. It is also suspected
that certain infections or factors in the environment might trigger the activation of the immune
system in susceptible individuals. This misdirected immune system then attacks the body's
own tissues. This leads to inflammation in the joints and sometimes in various organs of the
.body, such as the lungs or eyes
It is not known what triggers the onset of rheumatoid arthritis. Regardless of the exact trigger,
the result is an immune system that is geared up to promote inflammation in the joints and
occasionally other tissues of the body. Immune cells, called lymphocytes, are activated and
chemical messengers (cytokines, such as tumor necrosis factor/TNF, interleukin-1/IL-1, and
.interleukin-6/IL-6) are expressed in the inflamed areas
Environmental factors also seem to play some role in causing rheumatoid arthritis. For
example, scientists have reported that smoking tobacco, exposure to silica mineral, and
.chronic periodontal disease all increase the risk of developing rheumatoid arthritis

Signs and symptoms

RA symptoms come and go, depending on the degree of tissue inflammation. When body
tissues are inflamed, the disease is active. When tissue inflammation subsides, the disease is
inactive (in remission). Remissions can occur spontaneously or with treatment and can last
weeks, months, or years. During remissions, symptoms of the disease disappear, and people
generally feel well. When the disease becomes active again (relapse), symptoms return. The
return of disease activity and symptoms is called a flare. The course of rheumatoid arthritis
.varies among affected individuals, and periods of flares and remissions are typical
When the disease is active, RA symptoms can include fatigue, loss of energy, lack of appetite,
low-grade fever, muscle and joint aches, and stiffness. Muscle and joint stiffness are usually
most notable in the morning and after periods of inactivity. This is referred to as morning
stiffness and post-sedentary stiffness. Arthritis is common during disease flares. Also during
flares, joints frequently become warm, red, swollen, painful, and tender. This occurs because
the lining tissue of the joint (synovium) becomes inflamed, resulting in the production of
.excessive joint fluid (synovial fluid). The synovium also thickens with inflammation (synovitis)

Rheumatoid arthritis usually inflames multiple joints and affects both sides of the body. In its
most common form, therefore, it is referred to as a symmetric polyarthritis. Early symptoms
may be subtle. The small joints of both the hands and wrists are often involved. Early
symptoms of rheumatoid arthritis can be pain and prolonged stiffness of joints, particularly in
the morning. Symptoms in the hands with rheumatoid arthritis include difficulty with simple
tasks of daily living, such as turning door knobs and opening jars. The small joints of the feet
are also commonly involved, which can lead to painful walking, especially in the morning after
arising from bed. Occasionally, only one joint is inflamed. When only one joint is involved, the
arthritis can mimic the joint inflammation caused by other forms of arthritis, such as gout or
joint infection. Chronic inflammation can cause damage to body tissues, including cartilage
and bone. This leads to a loss of cartilage and erosion and weakness of the bones as well as
the muscles, resulting in joint deformity, destruction, and loss of function. Rarely, rheumatoid
arthritis can even affect the joint that is responsible for the tightening of our vocal cords to
change the tone of our voice, the cricoarytenoid joint. When this joint is inflamed, it can
cause hoarseness of the voice. Symptoms in children with rheumatoid arthritis
include limping, irritability, crying, and poor appetite

Diagnose
There is no singular test for diagnosing rheumatoid arthritis. The diagnosis is based on the
clinical presentation. Ultimately, rheumatoid arthritis is diagnosed based on a combination of
the presentation of the joints involved, characteristic joint swelling and stiffness in the
morning, the presence of blood rheumatoid factor andcitrulline antibody, as well as findings of
rheumatoid nodules and radiographic changes (X-ray testing). It is important to understand
that there are many forms of joint disease that can mimic rheumatoid arthritis.
The first step in the diagnosis of rheumatoid arthritis is a meeting between the doctor and the
patient. The doctor reviews the history of symptoms, examines the joints for inflammation,
tenderness, swelling, and deformity, the skin for rheumatoid nodules (firm bumps under the
skin, most commonly over the elbows or fingers), and other parts of the body for
inflammation. Certain blood and X-ray tests are often obtained. The diagnosis will be based on
the pattern of symptoms, the distribution of the inflamed joints, and the blood and X-ray
findings. Several visits may be necessary before the doctor can be certain of the diagnosis. A
doctor with special training in arthritis and related diseases is called a rheumatologist.
It is the inflammation in the joint that helps to distinguish rheumatoid arthritis from common
types of arthritis that are not inflammatory, such as osteoarthritis or degenerative arthritis. The
distribution of joint inflammation is also important to the doctor in making a diagnosis. In
rheumatoid arthritis, the small joints of the hands and fingers, wrists, feet, and knees are
typically inflamed in a symmetrical distribution (affecting both sides of the body). When only
one or two joints are inflamed, the diagnosis of rheumatoid arthritis becomes more difficult.
The doctor may then perform other tests to exclude arthritis due to infection or gout. The
detection of rheumatoid nodules (described above), most often around the elbows and fingers,
can suggest the diagnosis.
Abnormal antibodies can be found in the blood of people with rheumatoid arthritis with simple
blood testing. An antibody called "rheumatoid factor" (RF) can be found in 80% of patients
with rheumatoid arthritis. Patients who are felt to have rheumatoid arthritis and do not have
positive rheumatoid factor testing are referred to as having "seronegative rheumatoid
arthritis." Citrulline antibody (also referred to as anticitrulline antibody, anticyclic citrullinated
peptide antibody, and anti-CCP antibody) is present in 50%-75% people with rheumatoid
arthritis. It is useful in the diagnosis of rheumatoid arthritis when evaluating cases of
unexplained joint inflammation. A test for citrulline antibodies is especially helpful in looking
for the cause of previously undiagnosed inflammatory arthritis when the traditional blood test

for rheumatoid arthritis, rheumatoid factor, is not present. Citrulline antibodies have been felt
to represent the earlier stages of rheumatoid arthritis in this setting. Citrulline antibodies also
have been associated with more aggressive forms of rheumatoid arthritis. Another antibody
called the "antinuclear antibody" (ANA) is also frequently found in people with rheumatoid
arthritis.
A blood test called the sedimentation rate (sed rate) is a crude measure of the inflammation of
the joints. The sed rate actually measures how fast red blood cells fall to the bottom of a test
tube. The sed rate is usually faster (high) during disease flares and slower (low) during
remissions. Another blood test that is used to measure the degree of inflammation present in
the body is the C-reactive protein. Blood testing may also reveal anemia, since anemia is
common in rheumatoid arthritis, particularly because of the chronic inflammation.
The rheumatoid factor, ANA, sed rate, and C-reactive protein tests can also be abnormal in
other systemic autoimmune and inflammatory conditions. Therefore, abnormalities in these
blood tests alone are not sufficient for a firm diagnosis of rheumatoid arthritis.
Joint X-rays may be normal or only demonstrate swelling of soft tissues early in the disease.
As the disease progresses, X-rays can reveal bony erosions typical of rheumatoid arthritis in
the joints. Joint X-rays can also be helpful in monitoring the progression of disease and joint
damage over time. Bone scanning, a procedure using a small amount of a radioactive
substance, can also be used to demonstrate the inflamed joints. MRIscanning can also be
used to demonstrate joint damage.
The American College of Rheumatology has developed a system for classifying rheumatoid
arthritis that is primarily based upon the X-ray appearance of the joints. This system helps
medical professionals classify the severity of your rheumatoid arthritis with respect to
cartilage, ligaments, and bone.
Stage I

No damage seen on X-rays, although there may be signs of bone thinning

Stage II

On X-ray, evidence of bone thinning around a joint with or without slight bone damage

Slight cartilage damage possible

Joint mobility may be limited; no joint deformities observed

Atrophy of adjacent muscle

Abnormalities of soft tissue around joint possible

Stage III

On X-ray, evidence of cartilage and bone damage and bone thinning around the joint

Joint deformity without permanent stiffening or fixation of the joint

Extensive muscle atrophy

Abnormalities of soft tissue around joint possible

Stage IV

On X-ray, evidence of cartilage and bone damage and osteoporosis around joint

Joint deformity with permanent fixation of the joint (referred to as ankylosis)

Extensive muscle atrophy

Abnormalities of soft tissue around joint possible

Rheumatologists also classify the functional status of people with rheumatoid arthritis as
follows:

Class I: completely able to perform usual activities of daily living

Class II: able to perform usual self-care and work activities but limited in activities
outside of work (such as playing sports, household chores)

Class III: able to perform usual self-care activities but limited in work and other
activities

Class IV: limited in ability to perform usual self-care, work, and other activities

The doctor may elect to perform an office procedure called arthrocentesis. In this procedure, a
sterile needle and syringe are used to drain joint fluid out of the joint for study in the
laboratory. Analysis of the joint fluid in the laboratory can help to exclude other causes of
arthritis, such as infection and gout. Arthrocentesis can also be helpful in relieving joint
swelling and pain. Occasionally, cortisone medications are injected into the joint during the
arthrocentesis in order to rapidly relieve joint inflammation and further reduce symptoms.

Drugs
here is no cure for rheumatoid arthritis. Medications can reduce inflammation in your joints in order to
relieve pain and prevent or slow joint damage.
Occupational and physical therapy can teach you how to protect your joints. If your joints are severely
damaged by rheumatoid arthritis, surgery may be necessary.

Medications
Many drugs used to treat rheumatoid arthritis have potentially serious side effects. Doctors typically
prescribe medications with the fewest side effects first. You may need stronger drugs or a combination
of drugs if your disease progresses.

NSAIDs. Nonsteroidal anti-inflammatory drugs (NSAIDs) can relieve pain and reduce
inflammation. Over-the-counter NSAIDs include ibuprofen (Advil, Motrin IB) and naproxen sodium
(Aleve). Stronger NSAIDs are available by prescription. Side effects may include ringing in your
ears, stomach irritation, heart problems, and liver and kidney damage.

Steroids. Corticosteroid medications, such as prednisone, reduce inflammation and pain and
slow joint damage. Side effects may include thinning of bones, weight gain and diabetes. Doctors
often prescribe a corticosteroid to relieve acute symptoms, with the goal of gradually tapering off
the medication.

Disease-modifying antirheumatic drugs (DMARDs). These drugs can slow the progression
of rheumatoid arthritis and save the joints and other tissues from permanent damage. Common
DMARDs include methotrexate (Trexall), leflunomide (Arava), hydroxychloroquine (Plaquenil) and
sulfasalazine (Azulfidine).
Side effects vary but may include liver damage, bone marrow suppression and severe lung
infections.

Biologic agents. Also known as biologic response modifiers, this newer class of DMARDs
includes abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia),
etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan) and
tocilizumab (Actemra). Tofacitinib (Xeljanz), a new, synthetic DMARD, is also available in the U.S.
These drugs can target parts of the immune system that trigger inflammation that causes joint and
tissue damage. These types of drugs also increase the risk of infections.
Biologic DMARDs are usually most effective when paired with a nonbiologic DMARD, such as
methotrexate.

Therapy
Your doctor may send you to a therapist who can teach you exercises to help keep your joints flexible.
The therapist may also suggest new ways to do daily tasks, which will be easier on your joints. For
example, if your fingers are sore, you may want to pick up an object using your forearms.
Assistive devices can make it easier to avoid stressing your painful joints. For instance, a kitchen knife
equipped with a saw handle helps protect your finger and wrist joints. Certain tools, such as
buttonhooks, can make it easier to get dressed. Catalogs and medical supply stores are good places
to look for ideas.

Surgery
If medications fail to prevent or slow joint damage, you and your doctor may consider surgery to repair
damaged joints. Surgery may help restore your ability to use your joint. It can also reduce pain and
correct deformities.
Rheumatoid arthritis surgery may involve one or more of the following procedures:

Total joint replacement. During joint replacement surgery, your surgeon removes the
damaged parts of your joint and inserts a prosthesis made of metal and plastic.

Tendon repair. Inflammation and joint damage may cause tendons around your joint to
loosen or rupture. Your surgeon may be able to repair the tendons around your joint.

Joint fusion. Surgically fusing a joint may be recommended to stabilize or realign a joint and
for pain relief when a joint replacement isn't an option.

Surgery carries a risk of bleeding, infection and pain. Discuss the benefits and risks with your doctor.