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April 2013

Handout on Health: Rheumatoid

Arthritis

This publication is for people who have

rheumatoid arthritis, as well as for their family

members, friends, and others who want to find

out more about this disease. The publication

describes how rheumatoid arthritis develops,

how it is diagnosed, and how it is treated,

including what people can do to help manage

their disease. It also highlights current

research efforts supported by the National

Institute of Arthritis and Musculoskeletal and

Skin Diseases (NIAMS) and other components

of the U.S. Department of Health and Human

Services’ National Institutes of Health (NIH). If

you have further questions after reading this

publication, you may wish to discuss them with

your doctor.

What Is Rheumatoid Arthritis?

Rheumatoid arthritis (RA) is an inflammatory

disease that causes pain, swelling, stiffness,

and loss of function in the joints. It occurs

when the immune system, which normally

defends the body from invading organisms,

turns its attack against the membrane lining

the joints.

Features of Rheumatoid

Arthritis

Tender, warm, swollen

joints

Symmetrical pattern of

affected joints

Joint inflammation often

affecting the wrist and

finger joints closest to the

hand

Joint inflammation

sometimes affecting other

joints, including the neck,

shoulders, elbows, hips,

knees, ankles, and feet

Fatigue, occasional fevers,

a loss of energy

Share

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Pain and stiffness lasting

for more than 30 minutes in

the morning or after a long

rest

Symptoms that last for

many years

Variability of symptoms

among people with the

disease

Who Has Rheumatoid Arthritis?

What Happens in Rheumatoid Arthritis?

How Does Rheumatoid Arthritis Affect

People’s Lives?

What Causes Rheumatoid Arthritis?

How Is Rheumatoid Arthritis

Diagnosed?

How Is Rheumatoid Arthritis Treated?

Who Treats Rheumatoid Arthritis?

What You Can Do: The Importance of

Self-Care

What Research Is Being Conducted on

Rheumatoid Arthritis?

Hope for the Future

Key Words

Illustration

Normal Joint and Joint Affected by

Rheumatoid Arthritis

Information Boxes

Features of Rheumatoid Arthritis

Goals of Treatment and Current

Treatment Approaches

Rheumatoid arthritis has several features that

make it different from other kinds of arthritis.

(See box “Features of Rheumatoid Arthritis.”)

For example, rheumatoid arthritis generally

occurs in a symmetrical pattern, meaning that if

one knee or hand is involved, the other one

also is. The disease often affects the wrist

joints and the finger joints closest to the hand.

It can also affect other parts of the body

besides the joints. (See “What Happens in

Rheumatoid Arthritis?”) In addition, people with

rheumatoid arthritis may have fatigue,

occasional fevers, and a loss of energy.

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The course of rheumatoid arthritis can range

from mild to severe. In most cases it is chronic,

meaning it lasts a long time—often a lifetime.

For many people, periods of relatively mild

disease activity are punctuated by flares, or

times of heightened disease activity. In others,

symptoms are constant.

Who Has Rheumatoid Arthritis?

Scientists estimate that about 1.5 million

people, or about 0.6 percent of the U.S. adult

population, have rheumatoid arthritis.

1

Interestingly, some recent studies have

suggested that although the number of new

cases of rheumatoid arthritis for older people is

increasing, the overall number of new cases

may actually be going down. 1

According to the National Arthritis Data

Workgroup, the actual number of new cases of

rheumatoid arthritis is lower than previous

estimates because of changes in the

classification for the condition, as cited in

Helmick CG, Felson DT, Lawrence RC, Gabriel

S, Hirsch R, Kwoh CK, Liang MH, Kremers

HM, Mayes MD, Merkel PA, Pillemer SR,

Reveille JD, Stone JH, for the National Arthritis

Data Workgroup. Estimates of the Prevalence

of Arthritis and Other Rheumatic Conditions in

the United States. Part I. Arthritis Rheum

2008;58(1):15-25.

Rheumatoid arthritis occurs in all races and

ethnic groups. Although the disease often

begins in middle age and occurs with

increased frequency in older people, older

teenagers and young adults may also be

diagnosed with the disease. (Children and

younger teenagers may be diagnosed with

juvenile idiopathic arthritis, a condition related

to rheumatoid arthritis.) Like some other forms

of arthritis, rheumatoid arthritis occurs much

more frequently in women than in men. About

two to three times as many women as men

have the disease.

What Happens in Rheumatoid

Arthritis?

Rheumatoid arthritis is primarily a disease of

the joints. A joint is the point where two or

more bones come together. With a few

exceptions (in the skull and pelvis, for

example), joints are designed to allow

movement between the bones and to absorb

shock from movements like walking or

repetitive motions. The ends of the bones are

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covered by a tough, elastic tissue called

cartilage. The joint is surrounded by a capsule

that protects and supports it (see illustration).

The joint capsule is lined with a type of tissue

called synovium, which produces synovial

fluid, a clear substance that lubricates and

nourishes the cartilage and bones inside the

joint capsule.

Like many other rheumatic diseases,

rheumatoid arthritis is an autoimmune disease (auto means self), so-called because a

person’s immune system, which normally helps

protect the body from infection and disease,

attacks joint tissues for unknown reasons.

White blood cells, the agents of the immune

system, travel to the synovium and cause

inflammation (synovitis), characterized by

warmth, redness, swelling, and pain—typical

symptoms of rheumatoid arthritis. During the

inflammation process, the normally thin

synovium becomes thick and makes the joint

swollen puffy, and sometimes warm to the

touch.

As rheumatoid arthritis progresses, the

inflamed synovium invades and destroys the

cartilage and bone within the joint. The

surrounding muscles, ligaments, and tendons

that support and stabilize the joint become

weak and unable to work normally. These

effects lead to the pain and joint damage often

seen in rheumatoid arthritis. Researchers

studying rheumatoid arthritis now believe that it

begins to damage bones during the first year

or two that a person has the disease, one

reason why early diagnosis and treatment are

so important.

Some people with rheumatoid arthritis also

have symptoms in places other than their

joints. Many people with rheumatoid arthritis

develop anemia, or a decrease in the

production of red blood cells. Other effects that

occur less often include neck pain and dry

eyes and mouth. Very rarely, people may have

inflammation of the blood vessels (vasculitis),

the lining of the lungs (pleurisy), or the sac

enclosing the heart (pericarditis).

A joint (the place where two bones

meet) is surrounded by a capsule

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that protects and supports it. The

joint capsule is lined with a type of

tissue called synovium, which

produces synovial fluid that

lubricates and nourishes joint

tissues. In rheumatoid arthritis, the

synovium becomes inflamed,

causing warmth, redness, swelling,

and pain. As the disease

progresses, the inflamed synovium

invades and damages the cartilage

and bone of the joint. Surrounding

muscles, ligaments, and tendons

become weakened. Rheumatoid

arthritis also can cause more

generalized bone loss that may

lead to osteoporosis (fragile bones

that are prone to fracture).

How Does Rheumatoid Arthritis

Affect People’s Lives?

Rheumatoid arthritis affects people differently.

Some people have mild or moderate forms of

the disease, with periods of worsening

symptoms, called flares, and periods in which

they feel better, called remissions. Others have

a severe form of the disease that is active most

of the time, lasts for many years or a lifetime,

and leads to serious joint damage and

disability.

Although rheumatoid arthritis is primarily a

disease of the joints, its effects are not just

physical. Many people with rheumatoid arthritis

also experience issues related to:

depression, anxiety

feelings of helplessness

low self-esteem.

Rheumatoid arthritis can affect virtually every

area of a person’s life from work life to family

life. It can also interfere with the joys and

responsibilities of family life and may affect the

decision to have children.

Fortunately, current treatment strategies allow

most people with the disease to lead active

and productive lives. These strategies include

pain-relieving drugs and medications that slow

joint damage, a balance between rest and

exercise, and patient education and support

programs. In recent years, research has led to

a new understanding of rheumatoid arthritis

and has increased the likelihood that, in time,

researchers will find even better ways to treat

the disease.

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What Causes Rheumatoid Arthritis?

Scientists still do not know exactly what

causes the immune system to turn against the

body’s own tissues in rheumatoid arthritis, but

research over the last few years has begun to

piece together the factors involved.

Genetic (inherited) factors: Scientists have

discovered that certain genes known to play a

role in the immune system are associated with

a tendency to develop rheumatoid arthritis.

(See “What Research Is Being Conducted on

Rheumatoid Arthritis?” for recent genetic

developments.) For the genes that have been

linked to rheumatoid arthritis, the frequency of

the risky gene is only modestly higher in those

with rheumatoid arthritis compared with healthy

controls. In other words, individual genes by

themselves confer only a small relative risk of

disease. Some people who have these

particular genes never develop the disease.

These observations suggest that although a

person’s genetic makeup plays an important

role in determining if he or she will develop

rheumatoid arthritis, it is not the only factor.

What is clear, however, is that more than one

gene is involved in determining whether a

person develops rheumatoid arthritis and how

severe the disease will become.

Environmental factors: Many scientists think

that something must occur to trigger the

disease process in people whose genetic

makeup makes them susceptible to rheumatoid

arthritis. A variety of factors have been

suggested, but a specific agent has not been

identified.

Other factors: Some scientists also think that

a variety of hormonal factors may be involved.

Women are more likely to develop rheumatoid

arthritis than men. The disease may improve

during pregnancy and flare after pregnancy.

Breastfeeding may also aggravate the disease.

Contraceptive use may increase a person’s

likelihood of developing rheumatoid arthritis.

This suggests hormones, or possibly

deficiencies or changes in certain hormones,

may promote the development of rheumatoid

arthritis in a genetically susceptible person

who has been exposed to a triggering agent

from the environment.

Even though all the answers are not known,

one thing is certain: rheumatoid arthritis

develops as a result of an interaction of many

factors. Researchers are trying to understand

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these factors and how they work together.

(See “What Research Is Being Conducted on

Rheumatoid Arthritis?”)

How Is Rheumatoid Arthritis

Diagnosed?

Rheumatoid arthritis can be difficult to

diagnose in its early stages for several

reasons. First, there is no single test for the

disease. In addition, symptoms differ from

person to person and can be more severe in

some people than in others. Also, symptoms

can be similar to those of other types of

arthritis and joint conditions, and it may take

some time for other conditions to be ruled out.

Finally, the full range of symptoms develops

over time, and only a few symptoms may be

present in the early stages. As a result, doctors

use a variety of the following tools to diagnose

the disease and to rule out other conditions:

Medical history: The doctor begins by asking

the patient to describe the symptoms, and

when and how the condition started, as well as

how the symptoms have changed over time.

The doctor will also ask about any other

medical problems the patient and close family

members have and about any medications the

patient is taking. Accurate answers to these

questions can help the doctor make a

diagnosis and understand the impact the

disease has on the patient’s life.

Good communication between patient and

doctor is especially important. For example, the

patient’s description of pain, stiffness, and joint

function and how these change over time is

critical to the doctor’s initial assessment of the

disease and how it changes over time.

Physical examination: The doctor will check

the patient’s reflexes and general health,

including muscle strength. The doctor will also

examine bothersome joints and observe the

patient’s ability to walk, bend, and carry out

activities of daily living. The doctor will also

look at the skin for a rash and listen to the

chest for signs of inflammation in the lungs.

Laboratory tests: A number of lab tests may

be useful in confirming a diagnosis of

rheumatoid arthritis. Following are some of the

more common ones:

Rheumatoid factor (RF): Rheumatoid

factor is an antibody that is present

eventually in the blood of most people

with rheumatoid arthritis. (An antibody

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is a special protein made by the

immune system that normally helps

fight foreign substances in the body.)

Not all people with rheumatoid arthritis

test positive for rheumatoid factor, and

some people test positive for

rheumatoid factor, yet never develop

the disease. Rheumatoid factor also

can be positive in some other diseases;

however, a positive RF in a person who

has symptoms consistent with those of

rheumatoid arthritis can be useful in

confirming a diagnosis. Furthermore,

high levels of rheumatoid factor are

associated with more severe

rheumatoid arthritis.

Anti-CCP antibodies: This blood test

detects antibodies to cyclic citrullinated

peptide (anti-CCP). This test is positive

in most people with rheumatoid arthritis

and can even be positive years before

rheumatoid arthritis symptoms develop.

When used with the RF, this test’s

results are very useful in confirming a

rheumatoid arthritis diagnosis.

Others: Other common laboratory

tests include a white blood cell count, a

blood test for anemia, which is common

in rheumatoid arthritis; the erythrocyte

sedimentation rate (often called the sed

rate), which measures inflammation in

the body; and C-reactive protein,

another common test for inflammation

that is useful both in making a

diagnosis and monitoring disease

activity and response to

anti-inflammatory therapy.

X rays: X rays are used to determine the

degree of joint destruction. They are not useful

in the early stages of rheumatoid arthritis

before bone damage is evident; however, they

may be used to rule out other causes of joint

pain. They may also be used later to monitor

the progression of the disease.

How Is Rheumatoid Arthritis

Treated?

Doctors use a variety of approaches to treat

rheumatoid arthritis. These are used in

different combinations and at different times

during the course of the disease and are

chosen according to the patient’s individual

situation. No matter what treatment the doctor

and patient choose, however, the goals are the

same: to relieve pain, reduce inflammation,

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slow down or stop joint damage, and improve

the person’s sense of well-being and ability to

function.

Good communication between the patient and

doctor is necessary for effective treatment.

Talking to the doctor can help ensure that

exercise and pain management programs are

provided as needed, and that drugs are

prescribed appropriately. Talking to the doctor

can also help people who are making

decisions about surgery.

Goals of Treatment

Relieve pain

Reduce inflammation

Slow down or stop joint

damage

Improve a person’s sense

of well-being and ability to

function.

Current Treatment

Approaches

Lifestyle

Medications

Surgery

Routine monitoring and

ongoing care.

Health behavior changes: Certain activities

can help improve a person’s ability to function

independently and maintain a positive outlook.

Rest and exercise: People with

rheumatoid arthritis need a good

balance between rest and exercise,

with more rest when the disease is

active and more exercise when it is not.

Rest helps to reduce active joint

inflammation and pain and to fight

fatigue. The length of time for rest will

vary from person to person, but in

general, shorter rest breaks every now

and then are more helpful than long

times spent in bed.

Exercise is important for maintaining

healthy and strong muscles, preserving

joint mobility, and maintaining flexibility.

Exercise can also help people sleep

well, reduce pain, maintain a positive

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attitude, and manage weight. Exercise

programs should take into account the

person’s physical abilities, limitations,

and changing needs.

Joint care: Some people find using a

splint for a short time around a painful

joint reduces pain and swelling by

supporting the joint and letting it rest.

Splints are used mostly on wrists and

hands, but also on ankles and feet. A

doctor or a physical or occupational

therapist can help a person choose a

splint and make sure it fits properly.

Other ways to reduce stress on joints

include self-help devices (for example,

zipper pullers, long-handled shoe

horns); devices to help with getting on

and off chairs, toilet seats, and beds;

and changes in the ways that a person

carries out daily activities.

Stress reduction: People with

rheumatoid arthritis face emotional

challenges as well as physical ones.

The emotions they feel because of the

disease—fear, anger, and frustration

—combined with any pain and physical

limitations can increase their stress

level. Although there is no evidence

that stress plays a role in causing

rheumatoid arthritis, it can make living

with the disease difficult at times.

Stress also may affect the amount of

pain a person feels. There are a

number of successful techniques for

coping with stress. Regular rest

periods can help, as can relaxation,

distraction, or visualization exercises.

Exercise programs, participation in

support groups, and good

communication with the health care

team are other ways to reduce stress.

Healthful diet: With the exception of

several specific types of oils, there is

no scientific evidence that any specific

food or nutrient helps or harms people

with rheumatoid arthritis. However, an

overall nutritious diet with enough—but

not an excess of—calories, protein,

and calcium is important. Some people

may need to be careful about drinking

alcoholic beverages because of the

medications they take for rheumatoid

arthritis. Those taking methotrexate

may need to avoid alcohol altogether

because one of the most serious

long-term side effects of methotrexate

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is liver damage.

Climate: Some people notice that their

arthritis gets worse when there is a

sudden change in the weather.

However, there is no evidence that a

specific climate can prevent or reduce

the effects of rheumatoid arthritis.

Moving to a new place with a different

climate usually does not make a

long-term difference in a person’s

rheumatoid arthritis.

Medications: Most people who have

rheumatoid arthritis take medications. Some

medications (analgesics) are used only for

pain relief; others, such as corticosteroids and

nonsteroidal anti-inflammatory drugs (NSAIDs),

are used to reduce inflammation.

2

Still others,

often called disease-modifying antirheumatic

drugs (DMARDs), are used to try to slow the

course of the disease. Common DMARDs

include hydroxychloroquine, leflunomide,

methotrexate, and sulfasalazine. Other

DMARDs—called biologic response

modifiers—may be used in people with more

serious disease. These are genetically

engineered medications that help reduce

inflammation and structural damage to the

joints by interrupting the cascade of events

that drive inflammation. Currently, several

biologic response modifiers are approved for

rheumatoid arthritis, including abatacept,

adalimumab, anakinra, certolizumab,

etanercept, golimumab, infliximab, rituximab,

tocilizumab, and tofacitinib. They work in one

of several ways:

Etanercept, golimumab, infliximab,

adalimumab and certolizumab, reduce

inflammation by blocking tumor

necrosis factor (TNF), a cytokine or

immune system protein that triggers

inflammation during normal immune

responses.

Anakinra works by blocking a cytokine

called interleukin-1 (IL-1) that is seen in

excess in people with rheumatoid

arthritis.

Rituximab stops the activation of a type

of white blood cell called B cells. This

reduces the overall activity of the

immune system, which is overactive in

people with rheumatoid arthritis.

Abatacept blocks a particular chemical

that triggers the overproduction of

white blood cells called T cells that

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play a role in rheumatoid arthritis

inflammation.

Tocilizumab works by blocking a

cytokine called interleukin 6 (IL-6) to

reduce inflammation in people with

rheumatoid arthritis,

Another DMARD, tofacitinib, from a new class

of drugs call jak kinase (JAK) inhibitors, fights

inflammation from inside the cell to reduce

inflammation in people with rheumatoid

arthritis. 2Warning: NSAIDs can cause stomach irritation

or, less often, they can affect kidney function.

The longer a person uses NSAIDs, the more

likely he or she is to have side effects, ranging

from mild to serious. Many other drugs cannot

be taken when a patient is being treated with

NSAIDs because NSAIDs alter the way the

body uses or eliminates these other drugs.

Check with your health care provider or

pharmacist before you take NSAIDs. Also,

NSAIDs sometimes are associated with serious

gastrointestinal problems, including ulcers,

bleeding, and perforation of the stomach or

intestine. People age 65 and older, as well as

those with any history of ulcers or

gastrointestinal bleeding, should use NSAIDs

with caution.

For many years, doctors initially prescribed

aspirin or other pain-relieving drugs for

rheumatoid arthritis, and waited to prescribe

more powerful drugs only if the disease

worsened. In recent decades this approach to

treatment has changed as studies have shown

that early treatment with more powerful

drugs—and the use of drug combinations

instead of one medication alone—may be more

effective in reducing or preventing joint

damage. Someone with persistent rheumatoid

arthritis symptoms should see a doctor familiar

with the disease and its treatment to reduce

the risk of damage.

The person’s general condition, the current

and predicted severity of the illness, the length

of time he or she will take the drug, and the

drug’s effectiveness and potential side effects

are important considerations in prescribing

drugs for rheumatoid arthritis.

Many of the drugs that help reduce disease in

rheumatoid arthritis do so by reducing the

inflammation that can cause pain and joint

damage. However, in some instances,

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inflammation is one mechanism the body

normally uses to maintain health, such as to

fight infection and possibly to stop tumors from

growing. The magnitude of the risk from the

treatment is hard to judge because infections

and cancer can occur in people with

rheumatoid arthritis who are not on treatment,

and probably more commonly than in healthy

individuals. Nevertheless, appropriate caution

and vigilance are justified.

Surgery: Several types of surgery are

available to patients with severe joint damage.

The primary purpose of these procedures is to

reduce pain, improve the affected joint’s

function, and improve the patient’s ability to

perform daily activities. Surgery is not for

everyone, however, and the decision should

be made only after careful consideration by the

patient and doctor. Together they should

discuss the patient’s overall health, the

condition of the joint or tendon that will be

operated on, and the reason for, as well as the

risks and benefits of, the surgical procedure.

Cost may be another factor.

Following are some of the more common

surgeries performed for rheumatoid arthritis:

Joint replacement: Joint replacement

involves removing all or part of a

damaged joint and replacing it with

synthetic components. Joint

replacement is available for a number

of different joints, but the most

commonly replaced joints are the hips

and knees. Joint replacement surgery

is done primarily to relieve pain and

improve or preserve function.

Although joint replacement traditionally

involved a large incision and long

recovery, new minimally invasive

surgeries are making it possible to do

some forms of joint replacement with

smaller incisions and a shorter, easier

recovery.

Artificial joints are not always

permanent and may eventually have to

be replaced. This may be an important

consideration for young people.

Arthrodesis (fusion): Arthrodesis is a

surgical procedure that involves

removing the joint and fusing the bones

into one immobile unit, often using

bone grafts from the person’s own

pelvis. Although the procedure limits

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movement, it can be useful for

increasing stability and relieving pain in

affected joints. The most commonly

fused joints are the ankles and wrists

and joints of the fingers and toes.

Tendon reconstruction: Rheumatoid

arthritis can damage and even rupture

tendons, the tissues that attach muscle

to bone. This surgery, which is used

most frequently on the hands,

reconstructs the damaged tendon by

attaching an intact tendon to it. This

procedure can help to restore hand

function, especially if the tendon is

completely ruptured.

Synovectomy: In this surgery, the

doctor actually removes the inflamed

synovial tissue. Synovectomy by itself

is seldom performed now because not

all of the tissue can be removed, and it

eventually grows back. Synovectomy is

done as part of reconstructive surgery,

especially tendon reconstruction.

Routine monitoring and ongoing care:

Regular medical care is important to monitor

the course of the disease, determine the

effectiveness and any negative effects of

medications, and change therapies as needed.

Monitoring typically includes regular visits to

the doctor. It also may include blood, urine,

and other laboratory tests and x rays.

People with rheumatoid arthritis may want to

discuss preventing osteoporosis with their

doctors as part of their long-term, ongoing

care. Osteoporosis is a condition in which

bones become weakened and fragile. Having

rheumatoid arthritis increases the risk of

developing osteoporosis for both men and

women, particularly if a person takes

corticosteroids. Such patients may want to

discuss with their doctors the potential benefits

of calcium and vitamin D supplements or other

treatments for osteoporosis.

Alternative and complementary therapies:

Special diets, vitamin supplements, and other

alternative approaches have been suggested

for treating rheumatoid arthritis.

Research shows that some of these, for

example, fish oil supplements, may help

reduce arthritis inflammation. For most,

however, controlled scientific studies either

have not been conducted on them or have

found no definite benefit to these therapies.

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As with any therapy, patients should discuss

the benefits and drawbacks with their doctors

before beginning an alternative or new type of

therapy. If the doctor feels the approach has

value and will not be harmful, it can be

incorporated into a person’s treatment plan.

However, it is important not to neglect regular

health care.

Who Treats Rheumatoid Arthritis?

Diagnosing and treating rheumatoid arthritis

requires a team effort involving the patient and

several types of health care professionals.

The primary doctor to treat arthritis may be an

internist, a doctor who specializes in the

diagnosis and medical treatment of adults, or a

rheumatologist, a doctor who specializes in

arthritis and other diseases of the bones,

joints, and muscles.

As treatment progresses, other professionals

often help. These may include the following:

Orthopaedists: Surgeons who

specialize in the treatment of, and

surgery for, bone and joint diseases.

Physical therapists: Health

professionals who work with patients to

improve joint function.

Occupational therapists: Health

professionals who teach ways to

protect joints, minimize pain, perform

activities of daily living, and conserve

energy.

Dietitians: Health professionals who

teach ways to use a good diet to

improve health and maintain a healthy

weight.

Nurse educators: Nurses who

specialize in helping patients

understand their overall condition and

implement their treatment plans.

Psychologists: Health professionals

who seek to help patients cope with

difficulties in the home and workplace

that may result from their medical

conditions.

What You Can Do: The Importance

of Self-Care

Although health care professionals can

prescribe or recommend treatments to help

patients manage their rheumatoid arthritis, the

real key to living well with the disease lies with

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the patients themselves. Research shows that

people who take part in their own care report

less pain and make fewer doctor visits. They

also enjoy a better quality of life.

Self-management programs teach about

rheumatoid arthritis and its treatments,

exercise and relaxation approaches,

communication between patients and health

care providers, and problem solving. Research

on these programs has shown that they help

people:

understand the disease

reduce their pain while remaining

active

cope physically, emotionally, and

mentally

feel greater control over the disease

and build a sense of confidence in the

ability to function and lead full, active,

and independent lives.

What Research Is Being Conducted

on Rheumatoid Arthritis?

Over the last several decades, research has

greatly increased our understanding of the

immune system, genetics, and biology. This

research is now showing results in several

areas important to rheumatoid arthritis.

Scientists are thinking about rheumatoid

arthritis in exciting ways that were not possible

even 10 years ago.

The National Institutes of Health (NIH) funds a

wide variety of medical research at its

headquarters in Bethesda, MD, and at

universities and medical centers across the

United States. One of the NIH institutes, the

National Institute of Arthritis and

Musculoskeletal and Skin Diseases (NIAMS),

is a major supporter of research and research

training in rheumatoid arthritis through grants

to individual scientists, Specialized Centers of

Research, Multidisciplinary Clinical Research

Centers, and Multipurpose Arthritis and

Musculoskeletal Diseases Centers.

Following are examples of research in

rheumatoid arthritis supported by the Federal

Government through the NIAMS and other

parts of NIH.

Genetics

Researchers are studying genetic factors that

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predispose some people to developing

rheumatoid arthritis, as well as factors

connected with disease severity. Over the past

decade, NIAMS-supported research in this

area has led to several important genetic

discoveries including the following:

Variation in a gene involved in controlling

T-cell activation doubles rheumatoid

arthritis risk: The variation—called a single

nucleotide polymorphism (SNP)—is located

within a gene that codes for PTPN22, an

enzyme known to be involved in controlling the

activation of white blood cells called T cells

that play an important role in the body’s

immune system. Where the SNP is present in

one or both copies of a person’s genes for this

enzyme, T cells and other immune cells

respond too vigorously, causing increased

inflammation and tissue damage. Scientists

say the implications of this finding go beyond a

better understanding of rheumatoid arthritis

risk; it may also help explain why different

autoimmune diseases tend to run in families.

Other studies have the same SNP with type-1

diabetes and juvenile arthritis.

Genetic variation increases risk of

rheumatoid arthritis and lupus: Separate

research found a SNP in a large segment of

the STAT4 gene increases the risk of both

rheumatoid arthritis and another autoimmune

disease, systemic lupus erythematosus

(lupus). The STAT4 gene encodes a protein

that plays an important role in the regulation

and activation of certain cells of the immune

system. One variant form of the gene was

present at a significantly higher frequency in

rheumatoid arthritis patient samples from the

North American Rheumatoid Arthritis

Consortium (NARAC)—a consortium formed to

collect, analyze, and make available clinical

and genetic data on 1,000 sibling pairs with

rheumatoid arthritis—as compared with

controls. Scientists replicated that result in two

independent collections of rheumatoid arthritis

cases and controls.

Twin study shows genetic differences in

rheumatoid arthritis: Because identical twins

have the exact same genes at conception,

scientists believe that changes in the genes

after the genome is constructed may account

for why one of a twin pair can have rheumatoid

arthritis while the other does not. To better

understand what those changes might be,

scientists have used a sophisticated technique

called microarray to examine the expression of

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more than 20,000 genes at a time in 11 pairs of

disease-discordant identical twins (meaning

one twin had the disease, the other did not).

The examination led to the detection of

differences in expression of 827 genes. The

most significantly overexpressed gene was

laeverin, an enzyme that breaks down certain

types of proteins; second was

11ß-hydroxysteroid dehydrogenase type 2

(11ß-HSD2), important in a steroid pathway

linked to inflammation and bone erosion; and

third was cysteine-rich angiogenic inducer 61

(Cyr61), which is known for its role in

angiogenesis, the formation of new blood

vessels. The scientists say their findings are

exciting because they offer new insights into

the mechanisms by which rheumatoid arthritis

is mediated.

Genetic region associated with rheumatoid

arthritis risk: Using the relatively new

genome-wide association approach, which

makes it possible to analyze between 300,000

and 500,000 single nucleotide polymorphisms,

researchers in the United States and Sweden

identified a region of chromosome 9 containing

two genes relevant to chronic inflammation:

TRAF1 (encoding tumor necrosis factor

receptor-associated factor 1) and C5

(encoding complement component 5).

Scientists say it is not yet known how the

genes in the TRAF1-C5 region influence

rheumatoid arthritis risk, but they hope that by

learning more about the genes and their role in

the disease, they may find clues to influencing

treatment of the disease.

Rare gene variants associated with

rheumatoid arthritis: Another genome-wide

association scan was used to determine that

rare variants of a gene that encodes the

enzyme sialic acid acetylesterase (SIAE) are

associated with several autoimmune diseases,

especially rheumatoid arthritis and type 1

diabetes. This discovery suggests that SIAE

plays an important role in autoimmunity. They

also highlight the promise that rare variant

analysis holds for unraveling complex,

multigene diseases.

New Therapies

Researchers continue to identify molecules

that appear to play a role in rheumatoid

arthritis and thus are potential targets for new

treatments. The path between identifying the

molecule and developing a drug that targets it

is long and difficult. Fortunately, this path has

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been successfully negotiated and new drugs

have emerged that successfully reduce

symptoms and damage in rheumatoid arthritis.

Researchers continue to identify more

candidate drugs, with hopes that these will

have fewer side effects or will cure more

patients.

Tofacitinib, approved for the treatment of

rheumatoid arthritis in 2012, is from a new

class of drugs developed to target Janus

kinases. One member of this family, JAK3, was

discovered in the early 1990s by a National

Institutes of Health laboratory in the National

Institute of Arthritis and Musculoskeletal and

Skin Diseases (NIAMS). Subsequent studies

carried out at the National Heart, Lung, and

Blood Institute (NHLBI), in collaboration with

the NIAMS, showed that genetic defects in

JAK3 can cause severe combined

immunodeficiency. This discovery led to the

idea that drugs blocking Janus kinases would

suppress the immune system and might be

protective against the damaging inflammation

of rheumatoid arthritis and certain other

autoimmune diseases.

Understanding Joint Destruction

Advances in understanding the processes that

lead to joint destruction are bringing NIAMSsupported researchers a step closer to new

therapies to stop the destructive process. In

one such study, researchers found a factor

they suspect plays a crucial role in joint

destruction: an adhesion molecule on cells of

the synovium called cadherin-11. Adhesion

molecules allow individual cells to stick

together to form tissues. At normal levels,

cadherin-11 enables the cells (synoviocytes) to

adhere together to form the lining layer of the

synovium. But when overgrowth of the

synovium occurs, cadherin plays a key role in

the destructive behavior of the synovium;

namely, eroding the cartilage, which causes

permanent destruction to the joint. In studies of

mice prone to a disease similar to human

rheumatoid arthritis, blocking cadherin-11

prevented cartilage destruction. The next step

is to determine whether an agent to block an

excess of the molecule has the same beneficial

effect in people with rheumatoid arthritis.

In other research, scientists found that a lack

of apoptosis (programmed cell death)

contributes to a proliferation of cells in the joint

lining and the failure to eliminate immune cells

that react against self. In animal studies, mice

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lacking two proteins that mediate the process

of apoptosis developed arthritis.

Other NIAMS-funded research has led to a

better understanding of autoantibodies and

how they cause joint damage. Studying the

joints of patients with rheumatoid arthritis,

researchers found that anti-CCP and

rheumatoid factor antibodies from the joints

actually bound to a lot of products associated

with joint cartilage and also to histones,

intracellular proteins from the cell nucleus that

associate with DNA in the formation of

chromosomes. The histone deposits may be

derived from cells that died and spilled their

contents, a result of the disease condition.

Furthermore, they found that cartilage in RA is

actually coated with histones, regardless of

whether RA was active or not. Cartilage from

joints of people with osteoarthritis (OA) were

not covered in histones. The researchers

hypothesize that histones on the cartilage bind

with antihistone antibodies, contributing to

joint-damaging inflammation in rheumatoid

arthritis.

Preventing Related Problems

Having rheumatoid arthritis does not make

people immune to other medical problems.

Thus, reducing the risk of problems that can

be associated with rheumatoid arthritis is a

focus of NIAMS research. One recent study

showed that treatment with

hydroxychloroquine, a medication used to treat

rheumatic diseases and malaria, reduced the

incidence of diabetes in people with

rheumatoid arthritis. People with rheumatoid

arthritis who took the medication for more than

4 years showed a reduction in risk of diabetes

of up to 77 percent.

More information on research is available from

the following websites:

NIH Clinical Research Trials and

You was designed to help people learn

more about clinical trials, why they

matter, and how to participate. Visitors

to the website will find information

about the basics of participating in a

clinical trial, first-hand stories from

actual clinical trial volunteers,

explanations from researchers, and

links to how to search for a trial or

enroll in a research-matching program.

ClinicalTrials.gov offers up-to-date

information for locating federally and

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privately supported clinical trials for a

wide range of diseases and conditions.

NIH RePORTER is an electronic tool

that allows users to search a repository

of both intramural and extramural

NIH-funded research projects from the

past 25 years and access publications

(since 1985) and patents resulting from

NIH funding.

PubMed is a free service of the U.S.

National Library of Medicine that lets

you search millions of journal citations

and abstracts in the fields of medicine,

nursing, dentistry, veterinary medicine,

the health care system, and preclinical

sciences.

Hope for the Future

Scientists are making rapid progress in

understanding the complexities of rheumatoid

arthritis: how and why it develops, why some

people get it and others do not, why some

people get it more severely than others.

Results from research are having an impact

today, enabling people with rheumatoid

arthritis to remain active in life, family, and

work far longer than was possible 20 years

ago. There is also hope for tomorrow, as

researchers begin to apply new technologies

such as stem cell transplantation and novel

imaging techniques. (Stem cells have the

capacity to differentiate into specific cell types,

which gives them the potential to change

damaged tissue in which they are placed.)

These and other advances will lead to an

improved quality of life for people with

rheumatoid arthritis.

For More Information

National Institute of Arthritis and

Musculoskeletal and Skin Diseases

(NIAMS)

Information Clearinghouse

National Institutes of Health

1 AMS Circle

Bethesda, MD 20892-3675

Phone: 301-495-4484

Toll Free: 877-22-NIAMS (877-226-4267)

TTY: 301-565-2966

Fax: 301-718-6366

Email: NIAMSinfo@mail.nih.gov

Website: http://www.niams.nih.gov

Other Resources

21 of 27 10/28/13 09:53 AM
National Institute of Allergy and Infectious

Diseases (NIAID)

Website: http://www.niaid.nih.gov/Pages

/default.aspx

National Center for Complementary and

Alternative Medicine

National Institutes of Health

Website: http://nccam.nih.gov

American Academy of Orthopaedic

Surgeons (AAOS)

Website: http://www.aaos.org

American College of Rheumatology

Website: http://www.rheumatology.org

Arthritis Foundation (AF)

Website: http://www.arthritis.org

Key Words

Analgesics. Medications designed to relieve

pain. Pure analgesics do not have an effect on

inflammation.

Anti-CCP antibodies. Antibodies to cyclic

citrullinated peptide (anti-CCP). A positive test

for the antibodies is useful for confirming a

diagnosis of rheumatoid arthritis. In fact, tests

for the antibodies can be positive years before

the development of symptoms.

Apoptosis. Programmed cell death. This is a

mechanism by which the body rids itself of old

or unhealthy cells. A problem with this

mechanism can allow cells that react against

the body’s own tissues to survive.

Arthrodesis. A surgical procedure that

involves removing the joint and fusing the

bones into one immobile unit, often using bone

grafts from the person’s own pelvis. Although

the procedure limits movement, it can be useful

for increasing stability and relieving pain in

affected joints. The most commonly fused

joints are the ankles and wrists and joints of

the fingers and toes.

Autoimmune disease. A disease in which the

immune system, which is designed to protect

the body from foreign invaders, mistakenly

sees the body’s own tissues as foreign and

makes autoantibodies against them, leading to

tissue destruction.

Biologic response modifiers. Genetically

engineered medications that help reduce

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inflammation and structural damage to the

joints by interrupting the cascade of events

that drive inflammation.

C-reactive protein. A protein produced by the

body during the process of inflammation. A

positive blood test for the protein indicates the

presence of inflammation in the body. The test

may be used in diagnosing rheumatoid arthritis

and monitoring disease activity and the

response of treatment.

Cartilage. A tough, elastic tissue that covers

the ends of the bones where they meet to form

joints. In rheumatoid arthritis, the inflamed

synovium invades and destroys joint cartilage.

Collagen. A family of fibrous proteins that are

components of cartilage. Collagens are the

building blocks of skin, tendon, bone, and

other connective tissues.

Corticosteroids. Powerful anti-inflammatory

hormones made naturally in the body or man

made for use as medicine. Corticosteroids may

be taken orally to relieve the systemic

inflammation of rheumatoid arthritis or injected

directly into an inflamed joint to temporarily

reduce inflammation and relieve pain.

COX-2 inhibitors. A subclass of nonsteroidal

anti-inflammatory drugs (NSAIDs) that are

formulated to relieve pain and inflammation

with less risk of gastrointestinal ulcers. For

information about the risk posed by NSAIDs,

see “NSAIDs” in the “How Is Rheumatoid

Arthritis Treated?” section.

Diabetes. A disease that affects the body’s

ability to produce or use insulin, resulting in an

inability to control the level of sugar in the

blood. If not properly treated, high blood sugar

levels can eventually lead to problems such as

kidney disease, heart disease, and blindness.

Dietitian. A health professional who teaches

ways to use a good diet to improve health and

maintain a healthy weight.

Disease-modifying antirheumatic drugs

(DMARDs). A class of medications used in the

treatment of rheumatoid arthritis. DMARDs do

more than ease the symptoms of rheumatoid

arthritis like some other treatments. They often

slow or stop the course of the disease to help

prevent joint damage.

Erythrocyte sedimentation rate (sed rate).

A blood test used to detect and monitor

inflammation. It is measured by recording the

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rate at which red blood cells fall and form

sediment at the bottom of a test tube.

Flare. A period of heightened disease activity.

In rheumatoid arthritis, a flare may be

characterized by increased fatigue; fever; and

painful, swollen, and tender joints.

Hydroxychloroquine. An anti-inflammatory

drug used in the treatment of rheumatoid

arthritis, malaria, and lupus.

Immune system. A complex network of cells

and tissues that work in concert to protect the

body against invaders such as viruses and

bacteria.

Joint capsule. A tough membrane sac that

holds the bones and other joint parts together.

Ligaments. Tough bands of connective tissue

that attach bones to each other, providing

stability.

Lupus. A chronic inflammatory condition in

which the immune system attacks the skin,

joints, heart, lungs, blood, kidneys and brain.

Also called systemic lupus erythematosus.

Muscles. Bundles of specialized cells that

contract and relax to produce movement when

stimulated by nerves.

Nonsteroidal anti-inflammatory drugs

(NSAIDs). A class of medications available

over the counter or with a prescription that

ease pain and inflammation.

Nurse educator. A nurse who specializes in

helping patients understand their overall

condition and implementing their treatment

plans.

Occupational therapist. A health professional

who teaches ways to protect joints, minimize

pain, perform activities of daily living, and

conserve energy.

Orthopaedist. A surgeon who specializes in

the treatment of, and surgery for, bone and

joint diseases. Also called orthopaedic

surgeon.

Pericarditis. Inflammation of the pericardium,

the thin sac-like membrane that surrounds the

heart. Pericarditis can be caused by

rheumatoid arthritis.

Physical therapist. A health professional who

works with patients to improve joint function.

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Pleurisy. Inflammation of the pleura, the

linings surrounding the lungs. Pleurisy can be

caused by rheumatoid arthritis.

Psychologist. A health professional who

seeks to help patients cope with difficulties in

the home and workplace that may result from

their medical conditions.

Rheumatoid arthritis. A form of arthritis in

which the immune system attacks the tissues

of the joints, leading to pain, inflammation, and

eventually joint damage and malformation. It

causes swelling and redness in joints, and may

make people feel sick, tired, and feverish.

Rheumatoid arthritis may also affect skin

tissue, the lungs, the eyes, or the blood

vessels.

Rheumatoid factor (RF). An antibody that is

present eventually in the blood of most people

with rheumatoid arthritis. Not all people with

rheumatoid arthritis test positive for rheumatoid

factor, and some people test positive for

rheumatoid factor, yet never develop the

disease. Rheumatoid factor also can be

positive in some other diseases.

Synovectomy. Removal of the synovium

(joint lining). As a treatment for rheumatoid

arthritis, synovectomy is much less common

than it once was because not all of the tissue

can be removed, and it eventually grows back.

Synovectomy is done as part of reconstructive

surgery, especially tendon reconstruction.

Synovium. A thin membrane inside the joint

capsule that secretes synovial fluid. In

rheumatoid arthritis, the synovium is attacked

by the immune system.

Synovial fluid. A fluid secreted by the

synovium that lubricates the joint and keeps

the cartilage smooth and healthy.

Tendons. Tough, fibrous cords that connect

muscles to bones.

Vasculitis. Inflammation of the blood vessels.

Vasculitis can occur as a complication of

rheumatoid arthritis.

X ray. A procedure in which low-level radiation

is passed through the body to produce a

picture called a radiograph. X rays of joints

affected by rheumatoid arthritis are used to

determine the degree of joint destruction.

Acknowledgments

25 of 27 10/28/13 09:53 AM
The NIAMS gratefully acknowledges the

assistance of the following individuals in the

preparation and review of previous versions of

this publication: John H. Klippel, M.D., Arthritis

Foundation, Atlanta, GA; Amye L. Leong,

Paris, France; Michael D. Lockshin, M.D.,

Barbara Volcker Center for Women and

Rheumatic Disease, Hospital for Special

Surgery, New York, NY; Kate Lorig, R.N.,

Dr.P.H., Stanford University, Stanford, CA; J.

Lee Nelson, M.D., Fred Hutchinson Cancer

Research Center, Seattle, WA; Paul G.

Rochmis, M.D., Fairfax, VA; Ronald L. Wilder,

M.D., Ph.D., MedImmune, Inc., Gaithersburg,

MD; Stanley R. Pillemer, M.D, NIH; and Reva

Lawrence, M.P.H., Paul H. Plotz, M.D., and

Susana Serrate-Sztein, M.D., NIAMS/NIH.

Special thanks also go to Cheryl Yarboro,

R.N., B.S.P.A., NIAMS/NIH, and to the patients

who reviewed this publication and provided

valuable input.

The mission of the National Institute of Arthritis

and Musculoskeletal and Skin Diseases

(NIAMS), a part of the U.S. Department of

Health and Human Services’ National Institutes

of Health (NIH), is to support research into the

causes, treatment, and prevention of arthritis

and musculoskeletal and skin diseases; the

training of basic and clinical scientists to carry

out this research; and the dissemination of

information on research progress in these

diseases. The NIAMS Information

Clearinghouse is a public service sponsored

by NIAMS that provides health information and

information sources. Additional information can

be found on the NIAMS Website at

www.niams.nih.gov.

For Your Information

This publication contains information about

medications used to treat the health condition

discussed here. When this publication was

developed, we included the most up-to-date

(accurate) information available. Occasionally,

new information on medication is released.

For updates and for any questions about any

medications you are taking, please contact

U.S. Food and Drug Administration

Toll Free: 888–INFO–FDA

(888–463–6332)

Website: http://www.fda.gov

For additional information on specific

medications, visit Drugs@FDA at

26 of 27 10/28/13 09:53 AM
www.accessdata.fda.gov/scripts

/cder/drugsatfda. Drugs@FDA is a

searchable catalog of FDA-approved

drug products.

For updates and questions about statistics,

please contact

Centers for Disease Control and

Prevention's National Center for

Health Statistics

Website: http://www.cdc.gov/nchs

This publication is not copyrighted. Readers

are encouraged to duplicate and distribute as

many copies as needed.

Additional copies of this publication are

available from:

National Institute of Arthritis and

Musculoskeletal and Skin Diseases

(NIAMS)

Information Clearinghouse

National Institutes of Health

1 AMS Circle

Bethesda, MD 20892-3675

Phone: 301-495-4484

Toll Free: 877-22-NIAMS

(877-226-4267)

TTY: 301-565-2966

Fax: 301-718-6366

Email: NIAMSinfo@mail.nih.gov

Website: http://www.niams.nih.gov

NIH Publication No. 12-4179

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