What is Rheumatoid Arthritis?

Rheumatoid arthritis is one of more than 100 forms of arthritis. It is a chronic (ongoing) condition in which the synovium (the tissue that lines and lubricates the joints) becomes inflamed. Rheumatoid arthritis is an autoimmune disorder that causes the immune system to attack the joints. Large and small joints, as well as both sides of the body, are usually affected. Over time, the joints become deformed and knotted-looking if the disease is not treated properly.  The disease is also systemic and may affects many 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".

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 usually affected initially asymmetrically (one side of the body) and then in a symmetrical (both sides of the body) fashion as the disease progresses. 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.

What are the Symptoms and Signs of Rheumatoid Arthritis?

The symptoms of rheumatoid arthritis tend to come and go. Periods of severe symptoms (flare-ups) will be followed by periods when the symptoms of rheumatoid arthritis are nearly gone. While rheumatoid arthritis can begin suddenly, it usually appears gradually and affects the smaller joints of the body, such as the fingers and toes. The main symptom is pain, and the major sign of the disease is tenderness in nearly all inflamed joints. Eventually, the synovial lining inside the joint becomes thicker.

If a joint on one side of the body is affected, usually the same joint on the other side of the body will also be affected. For example, if the left wrist is inflamed, the right one usually is,  too. It usually affects the hands, feet, wrists, elbows and ankles, but it can occur in any joint, even the neck.

Other symptoms or signs include:

• A low-grade fever
• Changes in appearance of the joints
• Difficulty sleeping because of the pain
• Feeling tired, fatigued or unwell in the early afternoon
• Inflammation of the tear glands, salivary glands, linings of the heart and lung, lungs and (in rare cases) the blood vessels. These are more rare today with modern treatment and early recognition of the disease.
• Small lumps (rheumatoid nodules) that form under the skin at pressure points, such as the elbows, hands, feet and Achilles tendons. They may also occur in other places, such as the back of the scalp or in the lungs. These nodules can range from being as small as a pea to as large as a walnut. They usually do not hurt.
• Stiffness that lasts 45 minutes or more when getting up in the morning or after a period of not moving

What Causes Rheumatoid Arthritis?

Unlike osteoarthritis, which results from wear and tear on the joints, rheumatoid arthritis is an inflammatory condition. The cause of rheumatoid arthritis is not known. Some researchers suspect that rheumatoid arthritis is triggered by an infection in people who have inherited the tendency to develop rheumatoid arthritis. Other environmental factors are currently being examined as triggers, such as prior exposure to immunizations, medications, etc. Other researchers believe that hormones may play a role in the development or severity of r heumatoid arthritis. We already know that smoking is a risk factor for rheumatoid arthritis susceptibility as well as severity. Women are two to three times more likely than men to develop rheumatoid arthritis. It can develop at any age, but it most often occurs in people between the ages of 25 and 50.

The inflammation and damage to the joints may be a result of the body's immune attacking the joints as if they were foreign bodies. White blood cells, which normally attack bacteria or viruses, move from the bloodstream into the synovium, making it swell and become tender. This inflammation causes proteins to be released that over months and years make the synovium grow thicker. These proteins also damage cartilage, bone, tendons and ligaments. In time, if treatment is not instituted promptly, the joint loses its shape and the bones no longer line up correctly.

How is Rheumatoid Arthritis Diagnosed?

To diagnose rheumatoid arthritis, a doctor will perform a physical examination and discuss the symptoms. If arthritis of any kind is suspected, the patient is referred to a rheumatologist, a specialist who is trained to recognize and treat rheumatoid arthritis, as well as other kinds of arthritis. There are a number of forms of arthritis, and each must be considered and ruled out before a diagnosis can be made. Additionally, conditions like lupus, sarcoidosis, amyloidosis, ankylosing spondylitis and Whipple's disease can mimic rheumatoid arthritis.

Diagnostic criteria
The American College of Rheumatology has defined (1987) the following criteria for the diagnosis of rheumatoid arthritis

• 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.

 The doctor may order the following tests:

• Blood tests. These may show a higher than normal level of antibodies called rheumatoid factors. (Higher levels of these factors are also found in a number of other chronic conditions, and a positive test does not necessarily mean rheumatoid arthritis.) 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% of 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.

Autoimmune diseases require that the affected individual have a defect in the ability to distinguish self from foreign molecules. 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 unaffected 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.

• Samples of synovial fluid.
• X-rays. During the first months of the disease, only the swelling of the soft tissues around the joint can be seen. As the disease condition progresses, there may be a narrowing of the space in which the joints move and damage to the ends of the bones.
• MRI. This test may be used early in the course of the disease to help make a diagnosis and separate the condition (rheumatoid arthritis) from other possible problems that affect the bones and joints.

As the pathology progresses the inflammatory activity leads 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.

Classical deformities in rheumatoid arthritis are the

• Boutonniere deformity (Hyperflexion at the proximal interphalangeal joint with hyperextension at the distal interphalangeal joint)
• Swan neck deformity (Hyperextension at the proximal interphalangeal joint, hyperflexion at the distal interphalangeal joint). 
• "Z-Thumb" deformity with fixed flexion and subluxation at the metacarpophalangeal joint, leading to a "squared" appearance in the hand.

Extra-Articular Manifestations

Distinguish this disease from osteoarthritis (hence it is a multisystemic disease). For example, most patients also suffer of anemia, either as a consequence of the disease itself (anaemia of chronic disease) 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. Splenomegaly may occur with concurrent leukopaenia (Felty's syndrome), and lymphocytic infiltration may affect the salivary and lacrimal glands (Sjögren's syndrome).

• Dermatological: Subcutaneous nodules on extensor surfaces, such as the elbows, are often present.
• Pulmonary: The lungs may become involved as a part of the primary disease process or as a consequence of therapy. Fibrosis may occur spontaneously or as a consequence of therapy (for example methotrexate). Caplan's nodules are found as are pulmonary effusions.
• Autoimmune: Vasculitic disorders, giving nail fold infarcts, neuropathies and nephropathies.
• Renal: Amyloidosis, which can also give muscular pseudohypertrophy.
• Cardiovascular: Pericarditis, valvulitis and fibrosis.
• Ocular: Keratoconjunctivitis sicca (dry eyes), episcleritis and scleromalacia, which can lead to fissure and leaking of eye contents.
• Neurological: There can be signs of mononeuritis multiplex and atlanto-axial subluxation. The latter is due to erosion of the odontoid process and or/transverse ligaments in the cervical spine's connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping over one another and compressing the spinal cord. At first the patient experiences clumsiness but without due care this can progress to quadraplegia.

How is Rheumatoid Arthritis Treated?

During the first year after a diagnosis, three out of four people with rheumatoid arthritis will require a more aggressive approach with drugs that can effectively eliminate pain, reduce functional disability and prevent damage to the joints. Rheumatologists typically use combinations of drugs, even including new agents that have been developed through research into the molecular mechanisms that cause joint inflammation.

Some patients (a minority) will be managed effectively with anti-inflammatory drugs only or local injections of cortisone into the joints. A determination of the risk for disease progression is important for your rheumatologist to make because this assessment will guide therapeutic decisions. In addition to management of the disease with medications, a number of important maneuvers and adjunctive approaches can be employed, including:

• Assistive devices that can help relieve stress on your joints
• Complete bed rest when the condition is most active and painful. Regular rest may be needed in less severe cases
• Diet
• Drug therapy
• Exercise
• Joint injections or aspiration
• Making lifestyle changes that can ease the condition
• Managing pain
• Physical rehabilitation

If medical approaches do not control the symptoms, surgery may be needed. Available surgical procedures include:

• Arthroscopic synovectomy
• Arthroplasty, in which parts of the joint are replaced with artificial parts. This may be done if there is joint damage that limits the movement of the joint
• Total joint replacement. This is typically done with the hip and knee
• Fusion of joints, so that the damaged parts are not moving against each other

Pharmacological treatment of Rheumatoid Arthritis

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

• Disease modifying anti-rheumatic drugs (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
  • azathioprine
  • ciclosporin (cyclosporine 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
  • tumor necrosis factor (TNFa) blockers - etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira)
  • interleukin-1 blockers - anakinra
  • anti-B cell (CD20) antibody - rituximab (Rituxan)
• Anti-inflammatory agents and analgesics
  • glucocorticoids
  • Non-steroidal anti-inflammatory drug (NSAIDs, most also act as analgesics
  • acetaminophen
  • opiates
  • lidocaine topical