Rheumatoid arthritis

Information and facts about Autoimmune diseases.

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disorder that causes the immune system to attack the joints. It is a disabling and painful inflammatory condition, which can lead to substantial loss of mobility due to pain and joint destruction. The disease is also systemic in that it often also affects many extra-articular tissues throughout the body including the skin, blood vessels, heart, lungs, and muscles.

The name is derived from the Greek rheumatos meaning "flowing", the suffix -oid meaning "in the shape of", arthr meaning "joint" and the suffix -itis, a "condition involving inflammation".

Features
Rheumatoid arthritis is a chronic, inflammatory autoimmune disorder that causes the immune system to attack the joints. The symptoms that distinguish rheumatoid arthritis from other forms of arthritis are inflammation and soft-tissue swelling of many joints at the same time (polyarthritis). The joints are generally affected in a symmetric fashion. The pain generally improves with use of the affected joints, and there is usually stiffness of all joints in the morning that lasts over 1 hour. Thus, the pain of rheumatoid arthritis is usually worse in the morning compared to the classic pain of osteoarthritis where the pain worsens over the day as the joints are used.

If the arthritis has been longstanding, the inflammatory activity has led to erosion and destruction of the joint surface, which impairs their range of movement and leads to deformity. The fingers are typically deviated towards the little finger (ulnar deviation) and can assume unnatural shapes.

Subcutaneous nodules on extensor surfaces, such as the elbows, are often present.

Most patients also suffer of anemia, either as a consequence of the disease itself or as a consequence of gastrointestinal bleeding as a side effect of drugs used in treatment, especially NSAIDs (non-steroidal anti-inflammatory drugs) used for analgesia.

Diagnosis
The American College of Rheumatology has defined (1987) the following criteria for the diagnosis of rheumatoid arthritis [1]:

Morning stiffness of >1 hour.
Arthritis and soft-tissue swelling of >3 of 14 joints/joint groups
Arthritis of hand joints
Symmetric arthritis
Subcutaneous nodules in specific places
Rheumatoid factor at a level above the 95th percentile
Radiological changes suggestive of joint erosion
At least four criteria have to be met to establish the diagnosis, although many patients are treated despite not meeting the criteria.

When RA is being clinically suspected, immunological studies are required, such as rheumatoid factor[2] (RF, a specific antibody). A negative RF does not rule out RA; rather, the arthritis is called seronegative. During the first year of illness, rheumatoid factor is frequently negative. 80% patients eventually convert to seropositive status. RF is also seen in other illnesses, like Sjögren's syndrome, and in approximately 10% of the healthy population, therefore the test is not very specific. Because of this low specificity, a new serological test has been developed in recent years, which tests for the presence of so called anti-citrullinated protein (ACP) antibodies. Like RF, this test can detect approximately 80% of all RA patients, but is rarely positive in non-RA patients, giving it a specificity of around 98%. In addition, ACP antibodies can be often detected in early stages of the disease, or even before disease onset. Currently, most common test for ACP antibodies is the anti-CCP[3] (cyclic citrulinated peptide) test. Also, several other blood tests are usually done to allow for other causes of arthritis, such as lupus erythematosus. The erythrocyte sedimentation rate (ESR), C-reactive protein[4], full blood count, renal function, liver enzymes and immunological tests (e.g. antinuclear antibody/ANA)[5] are all performed at this stage. Ferritin can reveal hemochromatosis, which can mimic RA.

Pathophysiology

Joint abnormalities in rheumatoid arthritisThe cause of RA is unknown, but long suspected to be infectious. Mycoplasma, Erysipelothrix, Epstein-Barr virus, parvovirus and rubella have been suspected but never supported in epidemiological studies. As in other autoimmune diseases, the "mistaken identity" theory suggests that an offending organism causes an immune response that leaves behind antibodies that are specific to that organism. The antibodies are not specific enough, though. They begin an immune attack against, in this case, the synovium, because some molecule in the synovium "looks like" a molecule on the offending organism that created the initial immune reaction.

Autoimmune diseases require that the affected individual have a defect in the ability to distinguish self from foreign molecules. This ability is acquired in the first year of life. There are markers on many cells that confer this self-identifying feature. However, some classes of markers allow for RA to happen. 90% of patients with RA have the cluster of markers known as the HLA-DR4/DR1 cluster, whereas only 40% of controls do. Thus, in theory, RA requires susceptibility to the disease through genetic endowment with specific markers and an infectious event that triggers an autoimmune response.

Once triggered, the immune response causes inflammation of the synovium. Early and intermediate molecular mediators of inflammation include tumor necrosis factor alpha (TNF-α), interleukins IL-1, IL-6, IL-8 and IL-15, transforming growth factor beta, fibroblast growth factor and platelet-derived growth factor. Modern pharmacological treatments of RA target these mediators. Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues.

Treatment
Pharmacological treatment of RA can be divided into disease-modifying antirheumatic drugs (DMARDs), anti-inflammatory agents and analgesics [6]. DMARDs have been found to produce durable remissions and delay or halt disease progression. This is not true of anti-inflammatories and analgesics.

DMARDs
DMARDs can be further subdivided into xenobiotic agents and biological agents. Xenobiotic agents are those DMARDs that do not occur naturally in the body, as opposed to biologicals.

Xenobiotics
Xenobiotics include:

azathioprine
cyclosporin A
D-penicillamine
gold salts
hydroxychloroquine
leflunomide
methotrexate (MTX)
minocycline
sulfasalazine (SSZ)
The most important and most common adverse events relate to liver and bone marrow toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds, D-penicillamine), renal toxicity (cyclosporine A, parenteral gold salts, D-penicillamine), pneumonitis (MTX), allergic skin reactions (gold compounds, SSZ), autoimmunity (D-penicillamine, SSZ, minocycline) and infections (azathioprine, cyclosporine A). Hydroxychloroquine may cause ocular toxicity.

Biological agents
Biological agents include:

tumor necrosis factor (TNFα) blockers - etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira)
interleukin-1 blockers - anakinra

Anti-inflammatory agents and analgesics
Anti-inflammatory agents include:

glucocorticoids
Non-steroidal anti-inflammatory drug (NSAIDs, most also act as analgesics)
Analgesics include:

acetaminophen
opiates
lidocaine topical

Other therapies
Other therapies are weight loss, physiotherapy, joint injections, and special tools to improve hard movements (e.g. special tin-openers).

Severely affected joints may require joint replacement surgery, such as knee replacement.

Epidemiology
The incidence of RA is 30 cases per 10,000 population. The peak incidence is in the twenties and forties. The prevalence rate is 1%, with women affected three to five times as often as men. Some Native American groups have higher prevalence rates (5-6%) and black persons from the Caribbean region have lower prevalence rates. First-degree relatives prevalence rate is 2-3% and disease concordance in monozygotic twins is approximately 15-20%.

Prognosis
The course of the disease varies greatly from patient to patient. Some patients have mild short-term symptoms, but in most the disease is progressive for life.

Disability
Daily living activities are impaired in most patients.
After 5 years of disease, approximately 33% of patients will not be working
After 10 years, approximately half will have substantial functional disability.

Prognostic factors
Poor prognostic factors include persistent synovitis, early erosive disease, extra-articular findings (including subcutaneous rheumatoid nodules), positive serum RF findings, family history of RA, male sex, advanced age, poor functional status, socioeconomic factors, elevated acute phase response (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]), and increased clinical severity.

Mortality
Life expectancy for patients with RA is shortened by 5-10 years, although those who respond to therapy may have lower mortality rates.

Prevention
Regular exercise and carefully controlled diet can help lessen the pain and stiffness associated with arthritic flare-ups.

History
The first known traces of arthritis date back as far as 4500 BC. It was noted in skeletal remains of Indians found in Tennessee. A text dated 123 AD first describes symptoms very similair to rheumatoid arthritis. In 1859 the disease got its current name.

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