|Classification and external resources|
A hand affected by rheumatoid arthritis
|eMedicine||article/331715 article/1266195 article/305417 article/401271 article/335186 article/808419|
Rheumatoid arthritis (RA) is an autoimmune disease that results in a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks flexible (synovial) joints. It can be a disabling and painful condition, which can lead to substantial loss of functioning and mobility if not adequately treated.
The process involves an inflammatory response of the capsule around the joints (synovium) secondary to swelling (turgescence) of synovial cells, excess synovial fluid, and the development of fibrous tissue (pannus) in the synovium. The pathology of the disease process often leads to the destruction of articular cartilage and ankylosis (fusion) of the joints. RA can also produce diffuse inflammation in the lungs, the membrane around the heart (pericardium), the membranes of the lung (pleura), and white of the eye (sclera), and also nodular lesions, most common in subcutaneous tissue. Although the cause of RA is unknown, autoimmunity plays a big part, and RA is a systemic autoimmune disease. It is a clinical diagnosis made on the basis of symptoms, physical exam, radiographs (X-rays) and labs.
Treatments are pharmacological and non-pharmacological. Non-pharmacological treatment includes physical therapy, orthoses, occupational therapy and nutritional therapy but these don't stop the progression of joint destruction. Analgesics (painkillers) and anti-inflammatory drugs, including steroids, suppress symptoms, but don't stop the progression of joint destruction either. Disease-modifying antirheumatic drugs (DMARDs) slow or halt the progress of the disease. The newer biologics are DMARDs. The evidence for complementary and alternative medicine (CAM) treatments for RA related pain is weak, with the lack of high quality evidence leading to the conclusions that their use is currently not supported by the evidence. Patients should inform their health care provider of any CAM treatments and continue taking traditional treatments.
The name is based on the term "rheumatic fever", an illness which includes joint pain and is derived from the Greek word ῥεύμα-rheuma (nom.), ῥεύματος-rheumatos (gen.) ("flow, current"). The suffix -oid ("resembling") gives the translation as joint inflammation that resembles rheumatic fever. The first recognized description of RA was made in 1800 by Dr. Augustin Jacob Landré-Beauvais (1772–1840) of Paris.
- 1 Signs and symptoms
- 2 Causes
- 3 Pathophysiology
- 4 Diagnosis
- 5 Management
- 6 Prevention
- 7 Prognosis
- 8 Epidemiology
- 9 History
- 10 References
- 11 External links
Signs and symptoms
RA primarily affects joints, however it also affects other organs in 15–25% of individuals. It can be difficult to determine whether disease manifestations are directly caused by the rheumatoid process itself, or from side effects of the medications used to treat it – for example, lung fibrosis from methotrexate or osteoporosis from corticosteroids.
Arthritis of joints involves inflammation of the synovial membrane. Joints become swollen, tender and warm, and stiffness limits their movement. With time, multiple joints are affected (it is a polyarthritis). Most commonly involved are the small joints of the hands, feet and cervical spine, but larger joints like the shoulder and knee can also be involved. :1089 Synovitis can lead to tethering of tissue with loss of movement and erosion of the joint surface causing deformity and loss of function.
RA typically manifests with signs of inflammation, with the affected joints being swollen, warm, painful and stiff, particularly early in the morning on waking or following prolonged inactivity. Increased stiffness early in the morning is often a prominent feature of the disease and typically lasts for more than an hour. Gentle movements may relieve symptoms in early stages of the disease. These signs help distinguish rheumatoid from non-inflammatory problems of the joints, often referred to as osteoarthritis or "wear-and-tear" arthritis. In arthritis of non-inflammatory causes, signs of inflammation and early morning stiffness are less prominent with stiffness typically less than 1 hour, and movements induce pain caused by mechanical arthritis. The pain associated with RA is induced at the site of inflammation and classified as nociceptive as opposed to neuropathic. The joints are often affected in a fairly symmetrical fashion, although this is not specific, and the initial presentation may be asymmetrical. :1089
As the pathology progresses the inflammatory activity leads to tendon tethering and erosion and destruction of the joint surface, which impairs range of movement and leads to deformity. The fingers may suffer from almost any deformity depending on which joints are most involved. Specific deformities, which also occur in osteoarthritis, include ulnar deviation, boutonniere deformity, swan neck deformity and "Z-thumb." "Z-thumb" or "Z-deformity" consists of hyperextension of the interphalangeal joint, fixed flexion and subluxation of the metacarpophalangeal joint and gives a "Z" appearance to the thumb. :1089 The hammer toe deformity may be seen. In the worst case, joints are known as arthritis mutilans due to the mutilating nature of the deformities.
The rheumatoid nodule, which is sometimes cutaneous, is the feature most characteristic of RA. It is a type of inflammatory reaction known to pathologists as a "necrotizing granuloma". The initial pathologic process in nodule formation is unknown but may be essentially the same as the synovitis, since similar structural features occur in both. The nodule has a central area of fibrinoid necrosis that may be fissured and which corresponds to the fibrin-rich necrotic material found in and around an affected synovial space. Surrounding the necrosis is a layer of palisading macrophages and fibroblasts, corresponding to the intimal layer in synovium and a cuff of connective tissue containing clusters of lymphocytes and plasma cells, corresponding to the subintimal zone in synovitis. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences, such as the olecranon, the calcaneal tuberosity, the metacarpophalangeal joint, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF (rheumatoid factor) titer and severe erosive arthritis. Rarely, these can occur in internal organs or at diverse sites on the body.
Several forms of vasculitis occur in RA. A benign form occurs as microinfarcts around the nailfolds. More severe forms include livedo reticularis, which is a network (reticulum) of erythematous to purplish discoloration of the skin caused by the presence of an obliterative cutaneous capillaropathy.
Other, rather rare, skin associated symptoms include pyoderma gangrenosum, Sweet's syndrome, drug reactions, erythema nodosum, lobe panniculitis, atrophy of finger skin, palmar erythema, diffuse thinning (rice paper skin), and skin fragility (often worsened by corticosteroid use).
Fibrosis of the lungs is a recognized response to rheumatoid disease. It is also a rare but well recognized consequence of therapy (for example with methotrexate and leflunomide). Caplan's syndrome describes lung nodules in individuals with RA and additional exposure to coal dust. Pleural effusions are also associated with RA. Another complication of RA is Rheumatoid Lung Disease. It is estimated that about one quarter of Americans with RA develop Rheumatoid Lung Disease.
Renal amyloidosis can occur as a consequence of chronic inflammation. RA may affect the kidney glomerulus directly through a vasculopathy or a mesangial infiltrate but this is less well documented (though this is not surprising, considering immune complex-mediated hypersensitivities are known for pathogenic deposition of immune complexes in organs where blood is filtered at high pressure to form other fluids, such as urine and synovial fluid). Treatment with Penicillamine and gold salts are recognized causes of membranous nephropathy.
Heart and blood vessels
People with RA are more prone to atherosclerosis, and risk of myocardial infarction (heart attack) and stroke is markedly increased. Other possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis. Many people with RA do not experience the same chest pain that others feel when they have angina or myocardial infarction. To reduce cardiovascular risk, it is crucial to maintain optimal control of the inflammation caused by RA (which may be involved in causing the cardiovascular risk), and to use exercise and medications appropriately to reduce other cardiovascular risk factors such as blood lipids and blood pressure. Doctors who treat RA patients should be sensitive to cardiovascular risk when prescribing anti-inflammatory medications, and may want to consider prescribing routine use of low doses of aspirin if the gastrointestinal effects are tolerable.
- The eye is directly affected in the form of episcleritis which when severe can very rarely progress to perforating scleromalacia. Rather more common is the indirect effect of keratoconjunctivitis sicca, which is a dryness of eyes and mouth caused by lymphocyte infiltration of lacrimal and salivary glands. When severe, dryness of the cornea can lead to keratitis and loss of vision. Preventive treatment of severe dryness with measures such as nasolacrimal duct blockage is important.
- Cytokine production in joints and/or hepatic (liver) Kupffer cells leads to increased activity of hepatocytes with increased production of acute-phase proteins, such as C-reactive protein, and increased release of enzymes such as alkaline phosphatase into the blood. In Felty's syndrome, Kupffer cell activation is so marked that the resulting increase in hepatocyte activity is associated with nodular hyperplasia of the liver, which may be palpably enlarged. Although Kupffer cells are within the hepatic parenchyma, they are separate from hepatocytes. As a result there is little or no microscopic evidence of hepatitis (immune-mediated destruction of hepatocytes). Hepatic involvement in RA is essentially asymptomatic.
- Anemia is by far the most common abnormality of the blood cells which can be caused by a variety of mechanisms. The chronic inflammation caused by RA leads to raised hepcidin levels, leading to anemia of chronic disease where iron is poorly absorbed and also sequestered into macrophages. RA may also cause a warm autoimmune hemolytic anemia. The red cells are of normal size and colour (normocytic and normochromic). A low white blood cell count (neutropenia) usually only occurs in patients with Felty's syndrome with an enlarged liver and spleen. The mechanism of neutropenia is complex. An increased platelet count (thrombocytosis) occurs when inflammation is uncontrolled.
- Peripheral neuropathy and mononeuritis multiplex may occur. The most common problem is carpal tunnel syndrome caused by compression of the median nerve by swelling around the wrist. Atlanto-axial subluxation can occur, owing 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. Clumsiness is initially experienced, but without due care this can progress to quadriplegia.
- Constitutional symptoms
- Constitutional symptoms including fatigue, low grade fever, malaise, morning stiffness, loss of appetite and loss of weight are common systemic manifestations seen in patients with active RA.
- Local osteoporosis occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines. More general osteoporosis is probably contributed to by immobility, systemic cytokine effects, local cytokine release in bone marrow and corticosteroid therapy.
RA is a form of autoimmunity, the causes of which are still not completely known. It is a systemic (whole body) disorder principally affecting synovial tissues. There is no evidence that physical and emotional effects or stress could be a trigger for the disease. The many negative findings suggest that either the trigger varies, or that it might in fact be a chance event inherent with the immune response
Half of the risk for RA is believed to be genetic. It is strongly associated with the inherited tissue type major histocompatibility complex (MHC) antigen HLA-DR4 (most specifically DR0401 and 0404), and the genes PTPN22 and PADI4—hence family history is an important risk factor. Inheriting the PTPN22 gene has been shown to double a person's susceptibility to RA. PADI4 has been identified as a major risk factor in people of Asian descent, but not in those of European descent. First-degree relatives prevalence rate is 2–3% and disease genetic concordance in monozygotic twins is approximately 15–20%.
Smoking is the most significant non-genetic risk with RA being up to three times more common in smokers than non-smokers, particularly in men, heavy smokers, and those who are rheumatoid factor positive. Modest alcohol consumption may be protective.
Epidemiological studies have confirmed a potential association between RA and two herpesvirus infections:Epstein-Barr virus (EBV) and Human Herpes Virus 6 (HHV-6). Individuals with RA are more likely to exhibit an abnormal immune response to EBV and have high levels of anti-EBV antibodies.
The key pieces of evidence relating to pathogenesis are:
- A genetic link with HLA-DR4 and related allotypes of MHC Class II and the T cell-associated protein PTPN22.
- An undeniable link to the pathogenesis of vascular disease of many types, including the possibility of a strong causal connection to rheumatoid vasculitis, a typical feature of this condition.
- A remarkable deceleration of disease progression in many cases by blockade of the cytokine TNF (alpha).
- A similar dramatic response in many cases to depletion of B lymphocytes, but no comparable response to depletion of T lymphocytes.
- A more or less random pattern of whether and when predisposed individuals are affected.
- The presence of autoantibodies to IgGFc, known as rheumatoid factors (RF), and antibodies to citrullinated peptides (ACPA).
These data suggest that the disease involves abnormal B cell–T cell interaction, with presentation of antigens by B cells to T cells via HLA-DR eliciting T cell help and consequent production of RF and ACPA. Inflammation is then driven either by B cell or T cell products stimulating release of TNF and other cytokines. The process may be facilitated by an effect of smoking on citrullination but the stochastic (random) epidemiology suggests that the rate limiting step in genesis of disease in predisposed individuals may be an inherent stochastic process within the immune response such as immunoglobulin or T cell receptor gene recombination and mutation. (See entry under autoimmunity for general mechanisms.)
If TNF release is stimulated by B cell products in the form of RF or ACPA -containing immune complexes, through activation of immunoglobulin Fc receptors, then RA can be seen as a form of Type III hypersensitivity. If TNF release is stimulated by T cell products such as interleukin-17 it might be considered closer to type IV hypersensitivity although this terminology may be getting somewhat dated and unhelpful. The debate on the relative roles of immune complexes and T cell products in inflammation in RA has continued for 30 years. There is little doubt that both B and T cells are essential to the disease. However, there is good evidence for neither cell being necessary at the site of inflammation. This tends to favour immune complexes (based on antibody synthesised elsewhere) as the initiators, even if not the sole perpetuators of inflammation. Moreover, work by Thurlings and others in Paul-Peter Tak's group and also by Arthur Kavanagh's group suggest that if any immune cells are relevant locally they are the plasma cells, which derive from B cells and produce in bulk the antibodies selected at the B cell stage.
Although TNF appears to be the dominant, other cytokines (chemical mediators) are likely to be involved in inflammation in RA. Blockade of TNF does not benefit all patients or all tissues (lung disease and nodules may get worse). Blockade of IL-1, IL-15 and IL-6 also have beneficial effects and IL-17 may be important. Constitutional symptoms such as fever, malaise, loss of appetite and weight loss are also caused by cytokines released into the blood stream.
As with most autoimmune diseases, it is important to distinguish between the cause(s) that trigger the process, and those that may permit it to persist and progress.
Abnormal immune response
The factors that allow an abnormal immune response, once initiated, to become permanent and chronic, are becoming more clearly understood. The genetic association with HLA-DR4, as well as the newly discovered associations with the gene PTPN22 and with two additional genes, all implicate altered thresholds in regulation of the adaptive immune response. It has also become clear from recent studies that these genetic factors may interact with the most clearly defined environmental risk factor for RA, namely cigarette smoking Other environmental factors also appear to modulate the risk of acquiring RA, and hormonal factors in the individual may explain some features of the disease, such as the higher occurrence in women, the not-infrequent onset after child-birth, and the (slight) modulation of disease risk by hormonal medications. Exactly how altered regulatory thresholds allow the triggering of a specific autoimmune response remains uncertain. However, one possibility is that negative feedback mechanisms that normally maintain tolerance of self are overtaken by aberrant positive feedback mechanisms for certain antigens such as IgG Fc (bound by RF) and citrullinated fibrinogen (bound by ACPA) (see entry on autoimmunity).
Once the abnormal immune response has become established (which may take several years before any symptoms occur), plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes in large quantities. These are not deposited in the way that they are in systemic lupus. Rather, they activate macrophages through Fc receptor and complement binding, which seems to play an important role in the intense inflammatory response present in RA. This contributes to inflammation of the synovium, in terms of edema, vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). Synovial macrophages and dendritic cells further function as antigen presenting cells by expressing MHC class II molecules, leading to an established local immune reaction in the tissue. The disease progresses in concert with formation of granulation tissue at the edges of the synovial lining (pannus) with extensive angiogenesis and production of enzymes that cause tissue damage. 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.
X-rays of the hands and feet are generally performed in people with a polyarthritis. In RA, there may be no changes in the early stages of the disease, or the x-ray may demonstrate juxta-articular osteopenia, soft tissue swelling and loss of joint space. As the disease advances, there may be bony erosions and subluxation. X-rays of other joints may be taken if symptoms of pain or swelling occur in those joints.
Other medical imaging techniques such as magnetic resonance imaging (MRI) and ultrasound are also used in RA.
There have been technical advances in ultrasonography. High-frequency transducers (10 MHz or higher) have improved the spatial resolution of ultrasound images; these images can depict 20% more erosions than conventional radiography. Also, color Doppler and power Doppler ultrasound, which show vascular signals of active synovitis depending on the degree of inflammation, are useful in assessing synovial inflammation. This is important, since in the early stages of RA, the synovium is primarily affected, and synovitis seems to be the best predictive marker of future joint damage.
When RA is clinically suspected, immunological studies are required, such as testing for the presence of rheumatoid factor (RF, a non-specific antibody). A negative RF does not rule out RA; rather, the arthritis is called seronegative. This is the case in about 15% of patients. During the first year of illness, rheumatoid factor is more likely to be negative with some individuals converting to seropositive status over time. RF is also seen in other illnesses, for example Sjögren's syndrome, hepatitis C, systemic lupus erythematosus, chronic infections and in approximately 10% of the healthy population, therefore the test is not very specific.
Because of this low specificity, new serological tests have been developed, which test for the presence of the anti-citrullinated protein antibodies (ACPAs) or anti-CCP. Like RF, these tests are positive in only a proportion (67%) of all RA cases, but are rarely positive if RA is not present, giving it a specificity of around 95%. As with RF, there is evidence for ACPAs being present in many cases even before onset of clinical disease.
The most common tests for ACPAs are the anti-CCP (cyclic citrullinated peptide) test and the Anti-MCV assay (antibodies against mutated citrullinated Vimentin). Recently a serological point-of-care test (POCT) for the early detection of RA has been developed. This assay combines the detection of rheumatoid factor and anti-MCV for diagnosis of RA and shows a sensitivity of 72% and specificity of 99.7%.
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, full blood count, renal function, liver enzymes and other immunological tests (e.g., antinuclear antibody/ANA) are all performed at this stage. Elevated ferritin levels can reveal hemochromatosis, a mimic of RA, or be a sign of Still's disease, a seronegative, usually juvenile, variant of rheumatoid arthritis.
In 2010 the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria were introduced. These new classification criteria overruled the "old" ACR criteria of 1987 and are adapted for early RA diagnosis. The "new" classification criteria, jointly published by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) establish a point value between 0 and 10. Every patient with a point total of 6 or higher is unequivocally classified as an RA patient, provided he has synovitis in at least one joint and given that there is no other diagnosis better explaining the synovitis. Four areas are covered in the diagnosis:
- joint involvement, designating the metacarpophalangeal joints, proximal interphalangeal joints, the interphalangeal joint of the thumb, second through fifth metatarsophalangeal joint and wrist as small joints, and shoulders, elbows, hip joints, knees, and ankles as large joints:
- Involvement of 1 large joint gives 0 points
- Involvement of 2–10 large joints gives 1 point
- Involvement of 1–3 small joints (with or without involvement of large joints) gives 2 points
- Involvement of 4–10 small joints (with or without involvement of large joints) gives 3 points
- Involvement of more than 10 joints (with involvement of at least 1 small joint) gives 5 points
- serological parameters – including the rheumatoid factor as well as ACPA – "ACPA" stands for "anti-citrullinated protein antibody":
- Negative RF and negative ACPA gives 0 points
- Low-positive RF or low-positive ACPA gives 2 points
- High-positive RF or high-positive ACPA gives 3 points
- acute phase reactants: 1 point for elevated erythrocyte sedimentation rate, ESR, or elevated CRP value (c-reactive protein)
- duration of arthritis: 1 point for symptoms lasting six weeks or longer
The new criteria accommodate to the growing understanding of RA and the improvements in diagnosing RA and disease treatment. In the "new" criteria serology and autoimmune diagnostics carries major weight, as ACPA detection is appropriate to diagnose the disease in an early state, before joints destructions occur. Destruction of the joints viewed in radiological images was a significant point of the ACR criteria from 1987. This criterion no longer is regarded to be relevant, as this is just the type of damage that treatment is meant to avoid.
The criteria are not intended for the diagnosis for routine clinical care; they were primarily intended to categorize research (classification criteria). In clinical practice, the following criteria apply:
- two or more swollen joints
- morning stiffness lasting more than one hour for at least six weeks
- the detection of rheumatoid factors or autoantibodies against ACPA such as autoantibodies to mutated citrullinated vimentin can confirm the suspicion of RA. A negative autoantibody result does not exclude a diagnosis of RA.
- Crystal induced arthritis (gout, and pseudogout) – usually involves particular joints (knee, MTP1, heels) and can be distinguished with aspiration of joint fluid if in doubt. Redness, asymmetric distribution of affected joints, pain occurs at night and the starting pain is less than an hour with gout.
- Osteoarthritis – distinguished with X-rays of the affected joints and blood tests, age (mostly older patients), starting pain less than an hour, a-symmetric distribution of affected joints and pain worsens when using joint for longer periods.
- Systemic lupus erythematosus (SLE) – distinguished by specific clinical symptoms and blood tests (antibodies against double-stranded DNA)
- One of the several types of psoriatic arthritis resembles RA – nail changes and skin symptoms distinguish between them
- Lyme disease causes erosive arthritis and may closely resemble RA – it may be distinguished by blood test in endemic areas
- Reactive arthritis (previously Reiter's disease) – asymmetrically involves heel, sacroiliac joints, and large joints of the leg. It is usually associated with urethritis, conjunctivitis, iritis, painless buccal ulcers, and keratoderma blennorrhagica.
- Ankylosing spondylitis – this involves the spine, although a RA-like symmetrical small-joint polyarthritis may occur in the context of this condition.
- Hepatitis C – RA-like symmetrical small-joint polyarthritis may occur in the context of this condition. Hepatitis C may also induce Rheumatoid Factor auto-antibodies
Rarer causes that usually behave differently but may cause joint pains:
- Sarcoidosis, amyloidosis, and Whipple's disease can also resemble RA.
- Hemochromatosis may cause hand joint arthritis.
- Acute rheumatic fever can be differentiated from RA by a migratory pattern of joint involvement and evidence of antecedent streptococcal infection. Bacterial arthritis (such as streptococcus) is usually asymmetric, while RA usually involves both sides of the body symmetrically.
- Gonococcal arthritis (another bacterial arthritis) is also initially migratory and can involve tendons around the wrists and ankles.
The progression of RA can be followed using scores such as Disease Activity Score of 28 joints (DAS28). It is widely used as an indicator of RA disease activity and response to treatment, but is not always a reliable indicator of treatment effect. The joints included in DAS28 are (bilaterally): proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), elbows (2), shoulders (2) and knees (2). When looking at these joints, both the number of joints with tenderness upon touching (TEN28) and swelling (SW28) are counted. In addition, the erythrocyte sedimentation rate (ESR) is measured. Also, the patient makes a subjective assessment (SA) of disease activity during the preceding 7 days on a scale between 0 and 100, where 0 is "no activity" and 100 is "highest activity possible". With these parameters, DAS28 is calculated as:
From this, the disease activity of the patient can be classified as follows:
|DAS28 decrease from initial value|
|> 1.2||> 0.6 but ≤ 1.2||≤ 0.6|
|≤ 3.2||Inactive||Good improvement||Moderate improvement||No improvement|
|> 3.2 but ≤ 5.1||Moderate||Moderate improvement||Moderate improvement||No improvement|
|> 5.1||Very active||Moderate improvement||No improvement||No improvement|
There is no cure for RA, but treatments can improve symptoms and slow the progress of the disease. Disease-modifying treatment has the best results when it is started early and aggressively.
The goals of treatment are to minimize symptoms such as pain and swelling, to prevent bone deformity (for example, bone erosions visible in X-rays), and to maintain day-to-day functioning. This can often be achieved using two main classes of medications: analgesics such as NSAIDs, and disease-modifying antirheumatic drugs (DMARDs). RA should generally be treated with at least one specific anti-rheumatic medication. The use of benzodiazepines (such as diazepam) to treat the pain is not recommended as it does not appear to help and is associated with risks. Analgesics, other than NSAIDs, offer lesser, but some benefit with respect to pain. whilst not causing the same level of gastrointestinal irritation.
Disease modifying agents
Disease-modifying antirheumatic drugs (DMARD) are the primary treatment for RA. They are a diverse collection of drugs, grouped by use and convention. They have been found to improve symptoms, decrease joint damage, and improve overall functional abilities. They should be started very early in the disease as when they result in disease remission in approximately half of people and improved outcomes overall.
The most commonly used agent is methotrexate with other frequently used agents including sulfasalazine and leflunomide. Sodium aurothiomalate (Gold) and cyclosporin are less commonly used due to more common adverse effects. Agents may be used in combinations.
Methotrexate is the most important and useful DMARD and is usually the first treatment. Adverse effects should be monitored regularly with toxicity including gastrointestinal, hematologic, pulmonary, and hepatic. Side effects such as nausea, vomiting or abdominal pain can be reduced by taking folic acid. The most common undesirable affect is that it increases liver enzymes in almost 15% of people. It is thus recommended that those who consistently demonstrate abnormal levels of liver enzymes or have a history of liver disease or alcohol use undergo liver biopsies. Methotrexate is also considered a teratogenic and as such, it is recommended women of childbearing age should use contraceptives to avoid pregnancy and to discontinue its use if pregnancy is planned.
Biological agents should generally only be used if methotrexate and other conventional agents are not effective after a trial of three months. These agents include: tumor necrosis factor alpha (TNFα) blockers such as infliximab; interleukin 1 blockers such as anakinra, monoclonal antibodies against B cells such as rituximab, T cell costimulation blocker such as abatacept among others. They are often used in combination with either methotrexate or leflunomide.
TNF blockers and methotrexate appear to have similar effectiveness when used alone and better results are obtained when used together. TNF blockers appear to have equivalent effectiveness with etanercept appearing to be the safest. Abatacept appears effective for RA with 20% more people improving with treatment than without. There however is a lack of evidence to distinguish between the biologics available for RA. Issues with the biologics include their high cost and association with infections including tuberculosis.
NSAIDs reduce both pain and stiffness in those with RA. Generally they appear to have no effect on people's long term disease course and thus are no longer first line agents. NSAIDs should be used with caution in those with gastrointestinal, cardiovascular, or kidney problems.
COX-2 inhibitors, such as celecoxib, and NSAIDs are equally effective. They have a similar gastrointestinal risk as an NSAIDs plus a proton pump inhibitor. In the elderly there is less gastrointestinal intolerance to celecoxib than to NSAIDs alone. There however is an increased risk of myocardial infarction with COX-2 inhibitors. Anti-ulcer medications are not recommended routinely but only in those high risk of gastrointestinal problems.
Glucocorticoids can be used in the short term for flare-ups, while waiting for slow-onset drugs to take effect. Injection of glucocorticoids into individual joints is also effective. While long-term use reduces joint damage it also results in osteoporosis and susceptibility to infections, and thus is not recommended.
In early phases of the disease, an arthroscopic or open synovectomy may be performed. It consists of the removal of the inflamed synovia and prevents a quick destruction of the affected joints. Severely affected joints may require joint replacement surgery, such as knee replacement. Postoperatively, physiotherapy is always necessary.
There has been an increasing interest in the use of complementary and alternative medicine interventions for the treatment of pain in rheumatoid arthritis. While there have been multiple studies showing beneficial effects in RA on a wide variety of CAM modalities, these studies are often affected by publication bias and are generally not high quality evidence such as randomized controlled trials (RCTs), making definitive conclusions difficult to reach.
The National Center for Complementary and Alternative Medicine has concluded, "In general, there is not enough scientific evidence to prove that any complementary health approaches are beneficial for RA, and there are safety concerns about some of them. Some mind and body practices and dietary supplements may help people with RA manage their symptoms and therefore may be beneficial additions to conventional RA treatments, but there is not enough evidence to draw conclusions." A systematic review of CAM modalities (excluding fish oil) found "The major limitation in reviewing the evidence for CAMs is the paucity of RCTs in the area. The available evidence does not support their current use in the management of RA." One review suggests that of the various alternative medicine treatments evaluated, only acupuncture, bee venom acupuncture, herbal remedies, dietary omega-3 fatty acids, and pulsed electromagnetic field therapy have been studied with RCTs and show promise in treating the pain of RA, though no definitive conclusions could be reached.
The American College of Rheumatology states that no herbal medicines have health claims supported by high quality evidence and thus they do not recommend their use. There is no scientific basis to suggest that herbal supplements advertised as "natural" are safer for use than conventional medications as both are chemicals. Herbal medications, although labelled "natural", may be toxic or fatal if consumed. Some evidence supports omega-3 fatty acids and gamma-linolenic acid in RA. The benefit from omega-3 appears modest but consistent, though the current evidence is not strong enough to determine that supplementation with omega-3 polyunsaturated fatty acids (found in fish oil) is an effective treatment for RA. Gamma-linolenic acid, which may reduce pain, tender joint count and stiffness, is generally safe.
The following show promise as treatments for RA, based on preliminary studies: boswellic acid, curcumin, Devil's claw, Euonymus alatus, and Thunder god vine (Tripterygium wilfordii).
Herbal supplements can often have significant side effects, and can interact with prescription medications being taken at the same time. These risks are often exacerbated by the false general belief by patients that herbal supplements are always safe and the hesitancy by patients in reporting the use of herbal supplements to physicians. NCCAM has noted that, "In particular, the herb thunder god vine (Tripterygium wilfordii) can have serious side effects."
There is no known prevention for the contraction. Reduction of risk factors and aggressive treatment after diagnosis are recommended actions.
The course of the disease varies greatly. Some people have mild short-term symptoms, but in most the disease is progressive for life. Around 20%–30% will have subcutaneous nodules (known as rheumatoid nodules); this is associated with a poor prognosis.
Poor prognostic factors include persistent synovitis, early erosive disease, extra-articular findings (including subcutaneous rheumatoid nodules), positive serum RF findings, positive serum anti-CCP autoantibodies, carriership of HLA-DR4 "Shared Epitope" alleles, family history of RA, poor functional status, socioeconomic factors, elevated acute phase response (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]), and increased clinical severity.
RA is known to reduce the lifespan of patients by anywhere from three to 12 years. A new line of research does, however, show that the use of new biologic drug therapies extend the lifespan of patients with RA and reduce the risk and progression of atherosclerosis. According to the UK's National Rheumatoid Arthritis Society, "Young age at onset, long disease duration, the concurrent presence of other health problems (called co-morbidity), and characteristics of severe RA—such as poor functional ability or overall health status, a lot of joint damage on x-rays, the need for hospitalisation or involvement of organs other than the joints—have been shown to associate with higher mortality". Positive responses to treatment may indicate a better prognosis. A 2005 study by the Mayo Clinic noted that RA sufferers suffer a doubled risk of heart disease, independent of other risk factors such as diabetes, alcohol abuse, and elevated cholesterol, blood pressure and body mass index. The mechanism by which RA causes this increased risk remains unknown; the presence of chronic inflammation has been proposed as a contributing factor.
RA affects between 0.5 and 1% of adults in the developed world with between 5 and 50 per 100,000 people newly developing the condition each year. In 2010 it resulted in about 49,000 deaths globally.
Onset is uncommon under the age of 15 and from then on the incidence rises with age until the age of 80. Women are affected three to five times as often as men.
The age at which the disease most commonly starts is in women between 40 and 50 years of age, and for men somewhat later. RA is a chronic disease, and although rarely, a spontaneous remission may occur, the natural course is almost invariably one of persistent symptoms, waxing and waning in intensity, and a progressive deterioration of joint structures leading to deformations and disability.
|This section needs additional citations for verification. (February 2014)|
The first known traces of arthritis date back at least as far as 4500 BC. A text dated 123 AD first describes symptoms very similar to RA. It was noted in skeletal remains of Native Americans found in Tennessee. In the Old World, the disease is vanishingly rare before the 17th century. and on this basis investigators believe it spread across the Atlantic during the Age of Exploration. In 1859 the disease acquired its current name.
An anomaly has been noticed from investigation of Pre-Columbian bones. The bones from the Tennessee site show no signs of tuberculosis even though it was prevalent at the time throughout the Americas. Jim Mobley, at Pfizer, has discovered a historical pattern of epidemics of tuberculosis followed by a surge in the number of RA cases a few generations later. Mobley attributes the spikes in arthritis to selective pressure caused by tuberculosis. A hypervigilant immune system is protective against tuberculosis at the cost of an increased risk of autoimmune disease.
The art of Peter Paul Rubens may possibly depict the effects of RA. In his later paintings, his rendered hands show, in the opinion of some physicians, increasing deformity consistent with the symptoms of the disease. RA appears to some to have been depicted in 16th-century paintings. However, it is generally recognised in art historical circles that the painting of hands in the 16th and 17th century followed certain stylised conventions, most clearly seen in the Mannerist movement. It was conventional, for instance to show the upheld right hand of Christ in what now appears a deformed posture. These conventions are easily misinterpreted as portrayals of disease.
The first recognized description of RA was in 1800 by the French physician Dr Augustin Jacob Landré-Beauvais (1772–1840) who was based in the famed Salpêtrière Hospital in Paris. The name "rheumatoid arthritis" itself was coined in 1859 by British rheumatologist Dr Alfred Baring Garrod.
Historic treatments for RA have also included: rest, ice, compression and elevation, apple diet, nutmeg, some light exercise every now and then, nettles, bee venom, copper bracelets, rhubarb diet, extractions of teeth, fasting, honey, vitamins, insulin, magnets, and electroconvulsive therapy (ECT). Most of these have either had no effect at all, or their effects have been modest and transient, while not being generalizable. The Prosorba column blood filtering device (removing IgG) was approved by the FDA in 1999 for treatment of RA However it was discontinued at the end of 2006.
- Majithia V, Geraci SA (2007). "Rheumatoid arthritis: diagnosis and management". Am. J. Med. 120 (11): 936–9. doi:10.1016/j.amjmed.2007.04.005. PMID 17976416.
- Efthimiou, P; Kukar, M (2010). "Complementary and alternative medicine use in rheumatoid arthritis: proposed mechanism of action and efficacy of commonly used modalities[disambiguation needed].". Rheumatology international 30 (5): 571–86. doi:10.1007/s00296-009-1206-y. PMID 19876631.
- Macfarlane GJ, El-Metwally A, De Silva V, Ernst E, Dowds GL, Moots RJ (2011). "Evidence for the efficacy of complementary and alternative medicines in the management of rheumatoid arthritis: a systematic review". Rheumatology (Oxford) 50 (9): 1672–83. doi:10.1093/rheumatology/ker119. PMID 21652584.
- "Rheumatoid Arthritis and Complementary Health Approaches". National Center for Complementary and Alternative Medicine. Retrieved 21 April 2013.
- 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; National Arthritis Data, Workgroup (January 2008). "Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I". Arthritis and rheumatism 58 (1): 15–25. doi:10.1002/art.23177. PMID 18163481.
- "Handout on Health: Rheumatoid Arthritis". National Institute of Arthritis and Musculoskeletal and Skin Diseases. April 2009. Retrieved 2013-03-26.
- Landré-Beauvais AJ (1800). La goutte asthénique primitive (doctoral thesis). Paris. reproduced in Landré-Beauvais AJ (2001). "The first description of rheumatoid arthritis. Unabridged text of the doctoral dissertation presented in 1800". Joint Bone spine 68 (2): 130–43. doi:10.1016/S1297-319X(00)00247-5. PMID 11324929.
- Turesson C, O'Fallon WM, Crowson CS, Gabriel SE, Matteson EL (2003). "Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years". Ann. Rheum. Dis. 62 (8): 722–7. doi:10.1136/ard.62.8.722. PMC 1754626. PMID 12860726.
- Davidson's principles and practice of medicine. (21st ed. ed.). Edinburgh: Churchill Livingstone/Elsevier. 2010. ISBN 978-0-7020-3084-0.
- "An approach to Early Arthritis". Pn.lifehugger.com. 12 January 2009. Archived from the original on 2010-05-27.
- Gaffo A, Saag KG, Curtis JR (2006). "Treatment of rheumatoid arthritis". Am J Health Syst Pharm 63: 2451–2465.
- "Rheumatoid Lung Disease – What Is Rheumatoid Lung Disease?". Arthritis.about.com. February 27, 2011. Retrieved March 3, 2011.
- de Groot K (August 2007). "[Renal manifestations in rheumatic diseases]". Internist (Berl) 48 (8): 779–85. doi:10.1007/s00108-007-1887-9. PMID 17571244.
- Robbins, Stanley Leonard; Kumar, Vinay; Abbas, Abdul K.; Cotran, Ramzi S.; Fausto, Nelson (2010). "Robbins and Cotran pathologic basis of disease". In Vinay Kumar, Abul K. Abbas, Nelson Fausto. Robbins Pathology Series (Elsevier). p. 205. ISBN 978-1-4160-3121-5.
- Wolfe F; Mitchell DM; Sibley JT; Fries, James F.; Bloch, Daniel A.; Williams, Catherine A.; Spitz, Patricia W.; Haga, May et al. (April 1994). "The mortality of rheumatoid arthritis". Arthritis Rheum. 37 (4): 481–94. doi:10.1002/art.1780370408. PMID 8147925.
- Aviña-Zubieta JA; Choi HK; Sadatsafavi M; Etminan, Mahyar; Esdaile, John M.; Lacaille, Diane (2008). "Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies". Arthritis Rheum. 59 (12): 1690–1697. doi:10.1002/art.24092. PMID 19035419.
- Gupta A and Fomberstein B (2009). "Evaluating cardiovascular risk in rheumatoid arthritis". Journal of Musculoskeletal Medicine 26 (8): 481–94.
- Citation: H. Rehman : Hemolytic Anemia following Mycoplasma Infection . The Internet Journal of Hematology. 2008 Volume 4 Number 1 
- Baecklund, E.; Iliadou, A.; Askling, J.; Ekbom, A.; Backlin, C.; Granath, F.; Catrina, A. I.; Rosenquist, R.; Feltelius, N.; Sundström, C.; Klareskog, L. (2006). "Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis". Arthritis & Rheumatism 54 (3): 692–701. doi:10.1002/art.21675. PMID 16508929.
- Franklin, J.; Lunt, M.; Bunn, D.; Symmons, D.; Silman, A. (2006). "Incidence of lymphoma in a large primary care derived cohort of cases of inflammatory polyarthritis". Annals of the Rheumatic Diseases 65 (5): 617–622. doi:10.1136/ard.2005.044784. PMC 1798140. PMID 16249224.
- Edwards JC, Cambridge G, Abrahams VM (1999). "Do self-perpetuating B lymphocytes drive human autoimmune disease?". Immunology 97 (2): 188–96. doi:10.1046/j.1365-2567.1999.00772.x. PMC 2326840. PMID 10447731.
- Scott, DL; Wolfe, F; Huizinga, TW (Sep 25, 2010). "Rheumatoid arthritis". Lancet 376 (9746): 1094–108. doi:10.1016/S0140-6736(10)60826-4. PMID 20870100.
- Plenge, Robert M.; Seielstad, Padyukov (05-09-2007). "TRAF1–C5 as a Risk Locus for Rheumatoid Arthritis — A Genomewide Study". The New England Journal of Medicine 357 (12): 1199–209. doi:10.1056/NEJMoa073491. PMC 2636867. PMID 17804836.
- Goeldner I, Skare TL, de Messias Reason IT, Nisihara RM, Silva MB, Utiyama SR (Aug 2010). "Anti-cyclic citrullinated peptide antibodies and rheumatoid factor in rheumatoid arthritis patients and relatives from Brazil". Rheumatology (Oxford) 49 (8): 1590–3. doi:10.1093/rheumatology/keq134. PMID 20457731.
- "The Genetics Behind Rheumatoid Arthritis". Arthritis Foundation. Retrieved 17 December 2012.
- Silman, A.; MacGregor, A.; Thomson, W.; Holligan, S.; Carthy, D.; Farhan, A.; Ollier, W. (1993). "Twin concordance rates for rheumatoid arthritis: Results from a nationwide study". British journal of rheumatology 32 (10): 903–907. doi:10.1093/rheumatology/32.10.903. PMID 8402000.
- Bellamy, N.; Duffy, D.; Martin, N.; Mathews, J. (1992). "Rheumatoid arthritis in twins: A study of aetiopathogenesis based on the Australian Twin Registry". Annals of the rheumatic diseases 51 (5): 588–593. PMC 1005687. PMID 1616321.
- Sugiyama D, Nishimura K, Tamaki K, Tsuji G, Nakazawa T, Morinobu A, Kumagai S (2010). "Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies". Ann Rheum Dis. 69 (1): 70–81. doi:10.1136/ard.2008.096487. PMID 19174392.
- Liao, KP; Alfredsson, L; Karlson, EW (May 2009). "Environmental influences on risk for rheumatoid arthritis". Current Opinion in Rheumatology 21 (3): 279–83. doi:10.1097/BOR.0b013e32832a2e16. PMC 2898190. PMID 19318947.
- Alvarez-Lafuente R; Fernández-Gutiérrez B; de Miguel S; Jover, JA; Rollin, R; Loza, E; Clemente, D; Lamas, JR (September 2005). "Potential relationship between herpes viruses and rheumatoid arthritis: analysis with quantitative real time polymerase chain reaction". Ann. Rheum. Dis. 64 (9): 1357–9. doi:10.1136/ard.2004.033514. PMC 1755640. PMID 16100341.
- Balandraud N, Roudier J, Roudier C (2004). "Epstein-Barr virus and rheumatoid arthritis". Autoimmun Rev 3 (5): 362–7. doi:10.1016/j.autrev.2004.02.002. PMID 15288002.
- Wen, H; Baker, JF (March 2011). "Vitamin D, immunoregulation, and rheumatoid arthritis". Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases 17 (2): 102–7. doi:10.1097/RHU.0b013e31820edd18. PMID 21364350.
- Albano, Shirley A.; Santana-Sahagun, Ernesto; Weisman, Michael H. (2001). "Cigarette smoking and rheumatoid arthritis". Seminars in Arthritis and Rheumatism 31 (3): 146–159. doi:10.1053/sarh.2001.27719. PMID 11740796.
- "HBP310 Immunology". SUNY Stony Brook Pathology Department. Archived from the original on 2006-08-07. Retrieved September 20, 2008.
- Ghaffar, Abdul. "Hypersensitivity reactions". University of South Carolina School of Medicine. Retrieved September 20, 2008.
- Holmes, N. (1999). "Lecture 14: Hypersensitivity". Immunology Division, Department of Pathology, University of Cambridge. Archived from the original on 2006-02-06. Retrieved September 20, 2008.
- Plenge RM; Seielstad M; Padyukov L; Lee, Annette T.; Remmers, Elaine F.; Ding, Bo; Liew, Anthony; Khalili, Houman et al. (2007). "TRAF1-C5 as a Risk Locus for Rheumatoid Arthritis — A Genomewide Study". N. Engl. J. Med. 357 (12): 1199–209. doi:10.1056/NEJMoa073491. PMC 2636867. PMID 17804836.
- Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L (2004). "A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis". Arthritis Rheum. 50 (10): 3085–92. doi:10.1002/art.20553. PMID 15476204.
- Boldt AB, Goeldner I, de Messias-Reason IJ. Relevance of the lectin pathway of complement in rheumatic diseases. Adv Clin Chem. 2012;56:105-53. Review. PMID: 22397030
- Schueller-Weidekamm C. Modern ultrasound methods yield stronger arthritis work-up. Diagnostic Imaging. May 2010:20–22.
- Westwood OM, Nelson PN, Hay FC (2006). "Rheumatoid factors: what's new?". Rheumatology (Oxford) 45 (4): 379–85. doi:10.1093/rheumatology/kei228. PMID 16418203.
- Nishimura K; Sugiyama D; Kogata Y; Tsuji, G; Nakazawa, T; Kawano, S; Saigo, K; Morinobu, A et al. (2007). "Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis". Ann. Intern. Med. 146 (11): 797–808. doi:10.7326/0003-4819-146-11-200706050-00008. PMID 17548411.
- Renger F, Bang H, Fredenhagen G, Natusch A, Backhaus M, Feist E, Egerer K, Burmester GR. "Anti-MCV Antibody Test for the Diagnosis of Rheumatoid Arthritis Using a POCT-Immunoassay". American College of Rheumatology, 2008 Annual Scientific Meeting, poster presentation.
- Luime JJ, Colin EM, Hazes JM, Lubberts E. (2009). "Does anti-MCV has additional value as serological marker in the diagnostic and prognostic work-up of patients with rheumatoid arthritis? A systematic review". Ann Rheum Dis 69 (2): 337–44. doi:10.1136/ard.2008.103283. PMID 19289382.
- Aletaha D; Neogi T; Silman AJ; Funovits, J.; Felson, D. T.; Bingham, C. O.; Birnbaum, N. S.; Burmester, G. R. et al. (2010). "2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative". Ann. Rheum. Dis. 69 (9): 1580–8. doi:10.1136/ard.2010.138461. PMID 20699241. Archived from the original on 2010-08-21. Retrieved February 8, 2011.
- Arnett F, Edworthy S, Bloch D, McShane D, Fries J, Cooper N, Healey L, Kaplan S, Liang M, Luthra H (1988). "The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis". Arthritis Rheum 31 (3): 315–24. doi:10.1002/art.1780310302. PMID 3358796. Archived from the original on 2011-01-24. Retrieved February 8, 2011.
- Berkow R, ed. (1992). The Merck Manual (16th ed.). Merck Publishing Group. pp. 1307–08. ISBN 0-911910-16-6.
- Lovy MR, Starkebaum G, Uberoi S (1996). "Hepatitis C infection presenting with rheumatic manifestations: a mimic of rheumatoid arthritis". J. Rheumatol. 23 (6): 1238–9. PMID 8782126.
- Kelly, Janis (22 February 2005) DAS28 not always a reliable indicator of treatment effect in RA, Medscape Medical News.
- Prevoo, M. L.; Van 't Hof, M. A.; Kuper, H. H.; Van Leeuwen, M. A.; Van De Putte, L. B.; Van Riel, P. L. (1995). "Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis". Arthritis and rheumatism 38 (1): 44–48. doi:10.1002/art.1780380107. PMID 7818570.
- Saag KG, Teng GG, Patkar NM, et al. (2008). "American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis". Arthritis Rheum. 59 (6): 762–84. doi:10.1002/art.23721. PMID 18512708.
- Amy M. Wasserman (2011). "Diagnosis and Management of Rheumatoid Arthritis". American Family Physician 84 (11): 1245–1252. PMID 22150658.
- Chris Deighton, Rachel O’Mahony, Jonathan Tosh, Claire Turner, Michael Rudolf, and Guideline Development Group (2009). "Management of rheumatoid arthritis: summary of NICE guidance". British Medical Journal 338: 710–712. doi:10.1136/bmj.b702.
- Richards, BL; Whittle, SL; Buchbinder, R (Jan 18, 2012). "Muscle relaxants for pain management in rheumatoid arthritis". In Richards, Bethan L. Cochrane database of systematic reviews (Online) 1: CD008922. doi:10.1002/14651858.CD008922.pub2. PMID 22258993.
- Hurkmans, E; van der Giesen, FJ; Vliet Vlieland, TP; Schoones, J; Van den Ende, EC (Oct 7, 2009). "Dynamic exercise programs (aerobic capacity and/or muscle strength training) in patients with rheumatoid arthritis". In Hurkmans, Emalie. Cochrane database of systematic reviews (Online) (4): CD006853. doi:10.1002/14651858.CD006853.pub2. PMID 19821388.
- Hagen, KB; Byfuglien, MG; Falzon, L; Olsen, SU; Smedslund, G (Jan 21, 2009). "Dietary interventions for rheumatoid arthritis". In Hagen, Kåre Birger. Cochrane database of systematic reviews (Online) (1): CD006400. doi:10.1002/14651858.CD006400.pub2. PMID 19160281.
- Gramling A, O'Dell JR (2012). "Initial management of rheumatoid arthritis". Rheum. Dis. Clin. North Am. 38 (2): 311–25. doi:10.1016/j.rdc.2012.05.003. PMID 22819086.
- DiPiro, Joseph T., Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, and L. Michael Posey (2008) Pharmacotherapy: a pathophysiologic approach. 7th ed. New York: McGraw-Hill, ISBN 978-0-07-147899-1.
- Shea, B; Swinden, MV; Tanjong Ghogomu, E; Ortiz, Z; Katchamart, W; Rader, T; Bombardier, C; Wells, GA; Tugwell, P (May 31, 2013). "Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.". The Cochrane database of systematic reviews 5: CD000951. doi:10.1002/14651858.CD000951.pub2. PMID 23728635.
- American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines (2002). "Guidelines for the management of rheumatoid arthritis: 2002 Update". Arthritis & Rheumatism 46 (2): 328–346. doi:10.1002/art.10148.
- Task Force for the Diagnosis and Management of, Syncope; European Society of Cardiology, (ESC); European Heart Rhythm Association, (EHRA); Heart Failure Association, (HFA); Heart Rhythm Society, (HRS); Moya, A; Sutton, R; Ammirati, F; Blanc, JJ; Brignole, M; Dahm, JB; Deharo, JC; Gajek, J; Gjesdal, K; Krahn, A; Massin, M; Pepi, M; Pezawas, T; Ruiz Granell, R; Sarasin, F; Ungar, A; van Dijk, JG; Walma, EP; Wieling, W (November 2009). "Guidelines for the diagnosis and management of syncope (version 2009)". European heart journal 30 (21): 2631–71. doi:10.1093/eurheartj/ehp298. PMC 3295536. PMID 19713422.
- Edwards J, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close D, Stevens R, Shaw T (2004). "Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis". N Engl J Med 350 (25): 2572–81. doi:10.1056/NEJMoa032534. PMID 15201414.
- Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordström DC, Blom M (2012). "Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis". In Hernandez, Adrian V. PLoS ONE 7 (1): e30275. doi:10.1371/journal.pone.0030275. PMC 3260264. PMID 22272322.
- Maxwell, L; Singh, JA (Oct 7, 2009). "Abatacept for rheumatoid arthritis". In Maxwell, Lara. Cochrane database of systematic reviews (Online) (4): CD007277. doi:10.1002/14651858.CD007277.pub2. PMID 19821401.
- Singh, JA; Christensen, R; Wells, GA; Suarez-Almazor, ME; Buchbinder, R; Lopez-Olivo, MA; Tanjong Ghogomu, E; Tugwell, P (Oct 7, 2009). "Biologics for rheumatoid arthritis: an overview of Cochrane reviews". In Singh, Jasvinder A. Cochrane database of systematic reviews (Online) (4): CD007848. doi:10.1002/14651858.CD007848.pub2. PMID 19821440.
- Tarp, S; Bartels, EM; Bliddal, H; Furst, DE; Boers, M; Danneskiold-Samsøe, B; Rasmussen, M; Christensen, R (November 2012). "Effect of nonsteroidal antiinflammatory drugs on the C-reactive protein level in rheumatoid arthritis: a meta-analysis of randomized controlled trials". Arthritis and rheumatism 64 (11): 3511–21. doi:10.1002/art.34644. PMID 22833186.
- Radner, H; Ramiro, S; Buchbinder, R; Landewé, RB; van der Heijde, D; Aletaha, D (Jan 18, 2012). "Pain management for inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and other spondylarthritis) and gastrointestinal or liver comorbidity". In Radner, Helga. Cochrane database of systematic reviews (Online) 1: CD008951. doi:10.1002/14651858.CD008951.pub2. PMID 22258995.
- McCormack, PL (Dec 24, 2011). "Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis". Drugs 71 (18): 2457–89. doi:10.2165/11208240-000000000-00000. PMID 22141388.
- Marks, JL; Colebatch, AN; Buchbinder, R; Edwards, CJ (Oct 5, 2011). "Pain management for rheumatoid arthritis and cardiovascular or renal comorbidity". In Marks, Jonathan L. Cochrane database of systematic reviews (Online) (10): CD008952. doi:10.1002/14651858.CD008952.pub2. PMID 21975789.
- Chen, YF; Jobanputra, P; Barton, P; Bryan, S; Fry-Smith, A; Harris, G; Taylor, RS (April 2008). "Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation". Health technology assessment (Winchester, England) 12 (11): 1–278, iii. PMID 18405470.
- Wang, X; Tian, HJ; Yang, HK; Wanyan, P; Peng, YJ (October 2011). "Meta-analysis: cyclooxygenase-2 inhibitors are no better than nonselective nonsteroidal anti-inflammatory drugs with proton pump inhibitors in regard to gastrointestinal adverse events in osteoarthritis and rheumatoid arthritis". European journal of gastroenterology & hepatology 23 (10): 876–80. doi:10.1097/MEG.0b013e328349de81. PMID 21900785.
- Mallen, SR; Essex, MN; Zhang, R (July 2011). "Gastrointestinal tolerability of NSAIDs in elderly patients: a pooled analysis of 21 randomized clinical trials with celecoxib and nonselective NSAIDs". Current medical research and opinion 27 (7): 1359–66. doi:10.1185/03007995.2011.581274. PMID 21561397.
- "Nonsteroidal anti-inflammatory drugs: add an anti-ulcer drug for patients at high risk only. Always limit the dose and duration of treatment with NSAIDs". Prescrire Int 20 (119): 216–9. 2011. PMID 21954519.
- "Herbal Remedies, Supplements and Acupuncture for Arthritis". American College of Rheumatology. Retrieved 3 May 2013.
- Pirotta, M (September 2010). "Arthritis disease – the use of complementary therapies". Australian family physician 39 (9): 638–40. PMID 20877766.
- Miles, EA; Calder, PC (June 2012). "Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis". The British journal of nutrition. 107 Suppl 2: S171–84. doi:10.1017/S0007114512001560. PMID 22591891.
- Ruggiero, C; Lattanzio, F; Lauretani, F; Gasperini, B; Andres-Lacueva, C; Cherubini, A (2009). "Omega-3 polyunsaturated fatty acids and immune-mediated diseases: inflammatory bowel disease and rheumatoid arthritis". Current pharmaceutical design 15 (36): 4135–48. doi:10.2174/138161209789909746. PMID 20041815.
- Soeken, K L; Miller, S A; Ernst, E. "Herbal medicines for the treatment of rheumatoid arthritis: a systematic review". Centre for Reviews and Dissemination. National Institute for Health Research. Retrieved March 23, 2013.
- Abdel-Tawab, M; Werz, O; Schubert-Zsilavecz, M (June 2011). "Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data". Clinical pharmacokinetics 50 (6): 349–69. doi:10.2165/11586800-000000000-00000. PMID 21553931.
- White, B; Judkins, DZ (March 2011). "Clinical Inquiry. Does turmeric relieve inflammatory conditions?". The Journal of family practice 60 (3): 155–6. PMID 21369559.
- Wegener, T. (1999). "Therapy of degenerative diseases of the musculoskeletal system with South African devil's claw (Harpagophytum procumbens DC)". Wiener medizinische Wochenschrift (1946) 149 (8–10): 254–257. PMID 10483693.
- Denner, S. S. (2007). "A review of the efficacy and safety of devil's claw for pain associated with degenerative musculoskeletal diseases, rheumatoid, and osteoarthritis". Holistic nursing practice 21 (4): 203–207. doi:10.1097/01.HNP.0000280932.65581.72. PMID 17627199.
- Zhang, LF; Zhao, JX (December 2005). "The recent research situation of Euonymus alatus". Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 30 (24): 1895–8. PMID 16494017.
- Bao, J.; Dai, S. M. (2011). "A Chinese herb Tripterygium wilfordii Hook F in the treatment of rheumatoid arthritis: Mechanism, efficacy, and safety". Rheumatology International 31 (9): 1123–1129. doi:10.1007/s00296-011-1841-y. PMID 21365177.
- Lee MS, Shin B-C, Ernst E (2008). "Acupuncture for rheumatoid arthritis: a systematic review". Rheumatology 47 (12): 1747–53. doi:10.1093/rheumatology/ken330. PMID 18710899.
- Macfarlane, GJ; Paudyal, P; Doherty, M; Ernst, E; Lewith, G; MacPherson, H; Sim, J; Jones, GT (2012). "A systematic review of evidence for the effectiveness of practitioner-based complementary and alternative therapies in the management of rheumatic diseases: rheumatoid arthritis". Rheumatology 51 (9): 1707–13. doi:10.1093/rheumatology/kes133. PMID 22661556.
- Atzeni, F.; Turiel, M.; Caporali, R.; Cavagna, L.; Tomasoni, L.; Sitia, S.; Sarzi-Puttini, P. (2010). "The effect of pharmacological therapy on the cardiovascular system of patients with systemic rheumatic diseases". Autoimmunity Reviews 9 (12): 835–839. doi:10.1016/j.autrev.2010.07.018. PMID 20678592.
- Kitas, George (4 April 2006) Why is life span shortened by Rheumatoid Arthritis? National Rheumatoid Arthritis Society
- Rheumatoid Arthritis Patients Have Double the Risk of Heart Failure. mayoclinic.org (3 February 2005).
- "Cardiac disease in rheumatoid arthritis". John Hopkins University. 2002. Archived from the original on 2006-10-09.
- "WHO Disease and injury country estimates". World Health Organization. 2009. Retrieved November 11, 2009.
- Lozano, 1R; Naghavi, M; Foreman, K; Lim, S; Shibuya, K; Aboyans, V; Abraham, J; Adair, T et al. (Dec 15, 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.
- Alamanos Y, Voulgari PV, Drosos AA (2006). "Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review". Semin. Arthritis Rheum. 36 (3): 182–8. doi:10.1016/j.semarthrit.2006.08.006. PMID 17045630.
- Rothschild, Bruce M. "Tennessee Origins of Rheumatoid Arthritis". Mcclungmuseum.utk.edu. Archived from the original on 2012-02-02. Retrieved March 3, 2011.
- "Bones of contention". Arthritis Research UK. April 1999. Archived from the original on 2003-02-19. Retrieved 2013-02-05.
- Rothschild BM, Rothschild C, Helbling M (2003). "Unified theory of the origins of erosive arthritis: conditioning as a protective/directing mechanism?". J. Rheumatol. 30 (10): 2095–102. PMID 14528501.
- Patel, Sunil (1 February 2005). Scientist finds surprising links between arthritis and tuberculosis. Michigan Daily.
- Appelboom T, de Boelpaepe C, Ehrlich GE, Famaey JP (1981). "Rubens and the question of antiquity of rheumatoid arthritis". JAMA 245 (5): 483–6. doi:10.1001/jama.245.5.483. PMID 7005475.
- Kelly, Janis (14 June 2005). "Did RA travel from New World to Old? The Rubens connection". Medscape. Retrieved March 3, 2011.
- Dequeker J. and Rico H. (1992). "Rheumatoid arthritis-like deformities in an early 16th-century painting of the Flemish-Dutch school". JAMA 268 (2): 249–251. doi:10.1001/jama.268.2.249. PMID 1608144.
- Garrod AB (1859). The Nature and Treatment of Gout and Rheumatic Gout. London: Walton and Maberly.
- Hart FD (1976). "History of the treatment of rheumatoid arthritis". Br Med J 1 (6012): 763–5. doi:10.1136/bmj.1.6012.763. PMC 1639217. PMID 177148.
- Fresenius HemoCare, Inc., "New Hope for Rheumatoid Arthritis Patients," press release, September 17, 1999.
- "Prosorba Column – Which Rheumatoid Arthritis Patients Are Good Candidates for the Prosorba Column?". Arthritis.about.com. Retrieved March 3, 2011.
|Wikimedia Commons has media related to Rheumatoid arthritis.|
- Rheumatoid arthritis on the Open Directory Project
- Charles Weber. "History of rheumatoid arthritis".
- "National Institute of Arthritis and Musculoskeletal and Skin Diseases". National Institute of Arthritis and Musculoskeletal and Skin Diseases.