Rheumatoid arthritis: Difference between revisions

Rheumatoid arthritis
Rheumatoid arthritis
	A hand affected by rheumatoid arthritis
Specialty	Rheumatology
Symptoms	Warm, swollen, painful joints
Complications	Low red blood cells, inflammation around the lungs, inflammation around the heart
Usual onset	Middle age
Duration	Lifelong
Causes	Unknown
Diagnostic method	Based on symptoms, medical imaging, blood tests
Differential diagnosis	Systemic lupus erythematosus, psoriatic arthritis, fibromyalgia
Medication	Pain medications, steroids, Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs
Frequency	0.5–1% (adults in developed world)
Deaths	30,000 (2015)

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Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints.^[1] It typically results in warm, swollen, and painful joints.^[1] Pain and stiffness often worsen following rest.^[1] Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body.^[1] The disease may also affect other parts of the body.^[1] This may result in a low red blood cell count, inflammation around the lungs, and inflammation around the heart.^[1] Fever and low energy may also be present.^[1] Often, symptoms come on gradually over weeks to months.^[2]

While the cause of rheumatoid arthritis is not clear, it is believed to involve a combination of genetic and environmental factors.^[1] The underlying mechanism involves the body's immune system attacking the joints.^[1] This results in inflammation and thickening of the joint capsule.^[1] It also affects the underlying bone and cartilage.^[1] The diagnosis is made mostly on the basis of a person's signs and symptoms.^[2] X-rays and laboratory testing may support a diagnosis or exclude other diseases with similar symptoms.^[1] Other diseases that may present similarly include systemic lupus erythematosus, psoriatic arthritis, and fibromyalgia among others.^[2]

The goals of treatment are to reduce pain, decrease inflammation, and improve a person's overall functioning.^[5] This may be helped by balancing rest and exercise, the use of splints and braces, or the use of assistive devices.^[1] Pain medications, steroids, and NSAIDs are frequently used to help with symptoms.^[1] Disease-modifying antirheumatic drugs (DMARDs), such as hydroxychloroquine and methotrexate, may be used to try to slow the progression of disease.^[1] Biological DMARDs may be used when disease does not respond to other treatments.^[6] However, they may have a greater rate of adverse effects.^[7] Surgery to repair, replace, or fuse joints may help in certain situations.^[1] Most alternative medicine treatments are not supported by evidence.^[8]^[9]

RA affects about 24.5 million people as of 2015.^[10] This is between 0.5 and 1% of adults in the developed world with 5 and 50 per 100,000 people newly developing the condition each year.^[3] Onset is most frequent during middle age and women are affected 2.5 times as frequently as men.^[1] In 2013, it resulted in 38,000 deaths up from 28,000 deaths in 1990.^[11] The first recognized description of RA was made in 1800 by Dr. Augustin Jacob Landré-Beauvais (1772–1840) of Paris.^[12] The term rheumatoid arthritis is based on the Greek for watery and inflamed joints.^[13]

Signs and symptoms

RA primarily affects joints, but it also affects other organs in more than 15–25% of cases.^[14] Associated problems include cardiovascular disease, osteoporosis, interstitial lung disease, infection, cancer, feeling tired, depression, mental difficulties, and trouble working.^[15]

Joints

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 (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.^[16]^: 1098 Synovitis can lead to tethering of tissue with loss of movement and erosion of the joint surface causing deformity and loss of function.^[2]

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, such as osteoarthritis. In arthritis of non-inflammatory causes, signs of inflammation and early morning stiffness are less prominent.^{[citation needed]} The pain associated with RA is induced at the site of inflammation and classified as nociceptive as opposed to neuropathic.^[17] The joints are often affected in a fairly symmetrical fashion, although this is not specific, and the initial presentation may be asymmetrical.^[16]^: 1098

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 (also "buttonhole deformity", flexion of proximal interphalangeal joint and extension of distal interphalangeal joint of the hand), swan neck deformity (hyperextension at proximal interphalangeal joint and flexion at distal interphalangeal joint) 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.^[16]^: 1098 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.^[18]

Skin

The rheumatoid nodule, which is sometimes in the skin, is the most common non-joint feature and occurs in 30% of people who have RA.^[19] 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 elbow, the heel, the knuckles, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF (rheumatoid factor) titer, ACPA, and severe erosive arthritis. Rarely, these can occur in internal organs or at diverse sites on the body.^{[citation needed]}

Several forms of vasculitis occur in RA, but are mostly seen with long-standing and untreated disease. The most common presentation is due to involvement of small- and medium-sized vessels. Rheumatoid vasculitis can thus commonly present with skin ulceration and vasculitic nerve infarction known as mononeuritis multiplex.^[20]

Other, rather rare, skin associated symptoms include pyoderma gangrenosum, Sweet's syndrome, drug reactions, erythema nodosum, lobe panniculitis, atrophy of finger skin, palmar erythema, and skin fragility (often worsened by corticosteroid use).^{[citation needed]}

Diffuse alopecia areata (Diffuse AA) occurs more commonly in people with rheumatoid arthritis.^[21] RA is also seen more often in those with relatives who have AA.^[21]

Lungs

Lung fibrosis is a recognized complication of rheumatoid arthritis. 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. Exudative pleural effusions are also associated with RA.^[22]^[23]

Heart and blood vessels

People with RA are more prone to atherosclerosis, and risk of myocardial infarction (heart attack) and stroke is markedly increased.^[24]^[25]^[26] Other possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis.^[27] 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 people with RA 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.^[27]

Blood

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. The red cells are of normal size and color (normocytic and normochromic). A low white blood cell count usually only occurs in people with Felty's syndrome with an enlarged liver and spleen. The mechanism of neutropenia is complex. An increased platelet count occurs when inflammation is uncontrolled.

Other

Kidneys

Renal amyloidosis can occur as a consequence of untreated chronic inflammation.^[28] Treatment with penicillamine and gold salts are recognized causes of membranous nephropathy.^{[citation needed]}

Eyes: The eye can be directly affected in the form of episcleritis or scleritis, 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.^{[citation needed]}

Liver: Liver problems in people with rheumatoid arthritis may be due to the underlying disease process or as a result of the medications used to treat the disease.^[29] A coexisting autoimmune liver disease, such as primary biliary cirrhosis or autoimmune hepatitis may also cause problems.^[29]

Neurological: 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. Rheumatoid disease of the spine can lead to myelopathy. 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 or even death.^[30]

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 people with active RA.

Bones: 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.^{[citation needed]}

Cancer: The incidence of lymphoma is increased, although it is uncommon and associated with the chronic inflammation, not the treatment of RA.^[31]^[32]

Risk factors

RA is a systemic (whole body) autoimmune disease. Some genetic and environmental factors affect the risk for RA.

Genetic

A family history of RA increases the risk around three to five times; as of 2016 it was estimated that genetics may account for between 40 and 65% of cases of seropositive RA, but only around 20% for seronegative RA.^[3] RA is strongly associated with genes of the inherited tissue type major histocompatibility complex (MHC) antigen HLA-DR4 is the major genetic factor implicated – the relative importance varies across ethnic groups.^[33] Genome-wide association studies examining single-nucleotide polymorphisms have found around one hundred genes associated with RA risk, with most of them involving the HLA system (particularly HLA-DRB1) which controls recognition of self versus nonself molecules; other mutations affecting co-stimulatory immune pathways, for example CD28 and CD40), cytokine signaling, lymphocyte receptor activation threshold (e.g., PTPN22), and innate immune activation appear to have less influence than HLA mutations.^[3]

Environmental

There are established epigenetic and environmental risk factors for RA.^[34]^[3] Smoking is an established risk factor for RA in Caucasian populations, increasing the risk three times compared to non-smokers, particularly in men, heavy smokers, and those who are rheumatoid factor positive.^[35] Modest alcohol consumption may be protective.^[36]

Silica exposure has been linked to RA.^[37]

Negative findings

No infectious agent has been consistently linked with RA and there is no evidence of disease clustering to indicate its infectious cause,^[33] but periodontal disease has been consistently associated with RA.^[3]

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.^[38]

Pathophysiology

RA primarily starts as a state of persistent cellular activation leading to autoimmunity and immune complexes in joints and other organs where it manifests.^{[citation needed]} The initial site of disease is the synovial membrane, where swelling and congestion lead to infiltration by immune cells. Three phases of progression of RA are an initiation phase (due to non-specific inflammation), an amplification phase (due to T cell activation), and chronic inflammatory phase, with tissue injury resulting from the cytokines, IL–1, TNF-alpha and IL–6.^[18]

Non-specific inflammation

Factors allowing an abnormal immune response, once initiated, become permanent and chronic. These factors are genetic disorders which change regulation of the adaptive immune response.^[3] Genetic factors interact with environmental risk factors for RA, with cigarette smoking as the most clearly defined risk factor.^[35]^[39]

Other environmental and hormonal factors may explain higher risks for women, including onset after childbirth and hormonal medications. A possibility for increased susceptibility is that negative feedback mechanisms – which normally maintain tolerance – are overtaken by positive feedback mechanisms for certain antigens, such as IgG Fc bound by rheumatoid factor and citrullinated fibrinogen bound by antibodies to citrullinated peptides (ACPA - Anti–citrullinated protein antibody). A debate on the relative roles of B-cell produced immune complexes and T cell products in inflammation in RA has continued for 30 years, but neither cell is necessary at the site of inflammation, only autoantibodies to IgGFc, known as rheumatoid factors and ACPA, with ACPA having a 80% specificity for diagnosing RA.^[40] As with other autoimmune diseases, people with RA have abnormally glycosylated antibodies, which are believed to promote joint inflammation.^[41]^{[page needed]}

Amplification in the synovium

Once the generalized 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 activate macrophages through Fc receptor and complement binding, which is part of the intense inflammation in RA.^[42]2024^{[page needed]} Binding of an autoreactive antibody to the Fc receptors is mediated through the antibody's N-glycans, which are altered to promote inflammation in people with RA.^[41]^{[page needed]}

This contributes to local inflammation in a joint, specifically the synovium with edema, vasodilation and entry of activated T-cells, mainly CD4 in microscopically nodular aggregates and CD8 in microscopically diffuse infiltrates.^{[citation needed]} Synovial macrophages and dendritic cells function as antigen-presenting cells by expressing MHC class II molecules, which establishes the immune reaction in the tissue.^{[citation needed]}

Chronic inflammation

X-ray of the wrist of a woman with rheumatoid arthritis, showing unaffected carpal bones in the left image, and ankylosing fusion of the carpal bones 8 years later in the right image.

The disease progresses by forming granulation tissue at the edges of the synovial lining, pannus with extensive angiogenesis and enzymes causing tissue damage.^[43] The synovium thickens, cartilage and underlying bone disintegrate, and the joint deteriorates, with raised calprotectin levels serving as a biomarker of these events.^[44]

Cytokines and chemokines attract and accumulate immune cells, i.e. activated T- and B cells, monocytes and macrophages from activated fibroblasts, in the joint space. By signalling through RANKL and RANK, they eventually trigger osteoclast production, which degrades bone tissue.^[3]^[45]^{[page needed]}

Tumor necrosis factors (TNF alpha) plays a major role and several theories exist on how TNF release happens in RA. Tumor necrosis factor‐alpha (TNF‐α) is a proinflammatory cytokine that plays a pivotal role in regulating the inflammatory response in rheumatoid arthritis (RA).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.^[46]2024^[47] As of 1999, if TNF release is stimulated by T cell products such as interleukin-17 it might be closer to type IV hypersensitivity although this terminology may be getting somewhat dated and unhelpful.^[48]

Although TNF appears to be the dominant chemical mediator other cytokines are involved in inflammation in RA, because blocking TNF does not benefit all persons and all tissues, particularly lung disease and nodules may get worse. Blocking IL-1, IL-15 and IL-6 have beneficial effects and IL-17 may be important.^[49]

Diagnosis

Imaging

X-ray of the hand in rheumatoid arthritis.

X-rays of the hands and feet are generally performed when many joints affected. In RA, there may be no changes in the early stages of the disease or the x-ray may show osteopenia near the joint, soft tissue swelling, and a smaller than normal joint space. As the disease advances, there may be bony erosions and subluxation. Other medical imaging techniques such as magnetic resonance imaging (MRI) and ultrasound are also used in RA.^[18]^[51]

Technical advances in ultrasonography like high-frequency transducers (10 MHz or higher) have improved the spatial resolution of ultrasound images depicting 20% more erosions than conventional radiography. Color Doppler and power Doppler ultrasound are useful in assessing the degree of synovial inflammation as they can show vascular signals of active synovitis. 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.^[52]

Blood tests

When RA is clinically suspected, a physician may test for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs measured as anti-CCP antibodies).^[53]^{[page needed]} It is positive in 75-85%, but a negative RF or CCP antibody does not rule out RA, rather, the arthritis is called seronegative, which is in about 15-25% of people with RA.^[54] During the first year of illness, rheumatoid factor is more likely to be negative with some individuals becoming seropositive over time. RF is a non-specific antibody and seen in about 10% of healthy people, in many other chronic infections like hepatitis C, and chronic autoimmune diseases such as Sjögren's syndrome and systemic lupus erythematosus. Therefore, the test is not specific for RA.^[18]

Hence, new serological tests check for anti-citrullinated protein antibodies ACPAs . These tests are again positive in 61-75% of all RA cases, but with a specificity of around 95%.^[55] As with RF, ACPAs are many times present before symptoms have started.^[18]

The by far most common clinical test for ACPAs is the anti-cyclic citrullinated peptide (anti CCP) ELISA. In 2008 a serological point-of-care test for the early detection of RA combined the detection of RF and anti-MCV with a sensitivity of 72% and specificity of 99.7%.^[56]^{[better source needed]}^[57]

Other blood tests are usually done to differentiate from other causes of arthritis, like the erythrocyte sedimentation rate (ESR), C-reactive protein, full blood count, kidney 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.^{[citation needed]}

Classification Criteria

In 2010 the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria were introduced.^[58]

The new criterion is not a diagnostic criterion but a classification criterion to identify disease with a high likelihood of developing a chronic form.^[18] However a score of 6 or greater unequivocally classifies a person with a diagnosis of rheumatoid arthritis.

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. Four areas are covered in the diagnosis:^[58]

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.^[59] This criterion no longer is regarded to be relevant, as this is just the type of damage that treatment is meant to avoid.

In clinical practice, the following criteria apply:^{[citation needed]}

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.

Differential diagnoses

Several other medical conditions can resemble RA, and need to be distinguished from it at the time of diagnosis:^[60]^[61]

Crystal induced arthritis (gout, and pseudogout) – usually involves particular joints (knee, MTP1, heels) and can be distinguished with an 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, older age, starting pain less than an hour, asymmetric 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.
Axial spondyloarthritis (including ankylosing spondylitis) – this involves the spine, although an 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 which usually behave differently but may cause joint pains:^[60]

Sarcoidosis, amyloidosis, and Whipple's disease can also resemble RA.
Hemochromatosis may cause hand joint arthritis.
Acute rheumatic fever can be differentiated by a migratory pattern of joint involvement and evidence of antecedent streptococcal infection.
Bacterial arthritis (such as by Streptococcus) is usually asymmetric, while RA usually involves both sides of the body symmetrically.
Gonococcal arthritis (a bacterial arthritis) is also initially migratory and can involve tendons around the wrists and ankles.

Sometimes arthritis is in an undifferentiated stage (i.e. none of the above criteria is positive), even if synovitis is witnessed and assessed with ultrasound imaging.

Monitoring progression

Many tools can be used to monitor remission in rheumatoid arthritis.

DAS28: Disease Activity Score of 28 joints (DAS28) is widely used as an indicator of RA disease activity and response to treatment. Joints included 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. The erythrocyte sedimentation rate (ESR) is measured and the affected person 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:^[62]

$DAS28=0.56\times {\sqrt {TEN28}}+0.28\times {\sqrt {SW28}}+0.70\times \ln(ESR)+0.014\times SA$

From this, the disease activity of the affected person can be classified as follows:^[62]

Current DAS28		DAS28 decrease from initial value
Current DAS28		> 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

It is not always a reliable indicator of treatment effect.^[63] One major limitation is that low-grade synovitis may be missed.^[64]

Other: Other tools to monitor remission in rheumatoid arthritis are: ACR-EULAR Provisional Definition of Remission of Rheumatoid arthritis, Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI).^[65] Some scores do not require input from a healthcare professional and allow self-monitoring by the person, like HAQ-DI.^[66]^{[page needed]}

Prevention

There is no known prevention for the condition other than the reduction of risk factors.^[67]

Management

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.^[68]

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.^[69] This is primarily addressed with disease-modifying antirheumatic drugs (DMARDs); analgesics may be used to help manage pain.^[5] RA should generally be treated with at least one specific anti-rheumatic medication.^[6] 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.^[70]

Lifestyle

Regular exercise is recommended as both safe and useful to maintain muscles strength and overall physical function.^[71] It is uncertain if specific dietary measures have an effect.^[72] Physical activity is beneficial for persons with rheumatoid arthritis complaining of fatigue.^[73] Occupational therapy has a positive role to play in improving functional ability of persons with rheumatoid arthritis.^[74]

Disease modifying agents

Disease-modifying antirheumatic drugs (DMARDs) are the primary treatment for RA.^[6] 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.^[6] DMARDs should be started early in the disease as they result in disease remission in approximately half of people and improved outcomes overall.^[6]

The following drugs are considered as DMARDs: methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, TNF-alpha inhibitors (certolizumab, infliximab and etanercept), abatacept, and anakinra. Rituximab and tocilizumab are monoclonal antibodies and are also DMARDs.^[6]

Hydroxychloroquine, apart from its low toxicity profile, is considered effective in the moderate RA treatment.^[75]

The most commonly used agent is methotrexate with other frequently used agents including sulfasalazine and leflunomide.^[6] Leflunomide is effective when used from 6–12 months, with similar effectivness to methorexate when used for 2 years.^[76] Sodium aurothiomalate (gold) and cyclosporin are less commonly used due to more common adverse effects.^[6] Agents may be used in combinations.^[6] Methotrexate is the most important and useful DMARD and is usually the first treatment.^[6]^[5]^[77] Adverse effects should be monitored regularly with toxicity including gastrointestinal, hematologic, pulmonary, and hepatic.^[77] Side effects such as nausea, vomiting or abdominal pain can be reduced by taking folic acid.^[78]

A 2015 Cochrane review found rituximab with methotrexate to be effective in improving symptoms compared to methotrexate alone.^[79] Rituximab works by depicting levels of B-cells (immune cell that is involved in inflammation). People taking rituximab had improved pain, function, reduced disease activity and reduced joint damage based on x-ray images. After 6 months, 21% more people had improvement in their symptoms using rituximab and methotrexate.^[79]

Biological agents should generally only be used if methotrexate and other conventional agents are not effective after a trial of three months.^[6] They are associated with a higher rate of serious infections as compared to other DMARDs.^[80] Biological DMARD agents used to treat rheumatoid arthritis include: tumor necrosis factor alpha (TNFα) blockers such as infliximab; interleukin 1 blockers such as anakinra, monoclonal antibodies against B cells such as rituximab, and tocilizumab T cell co-stimulation blocker such as abatacept. They are often used in combination with either methotrexate or leflunomide.^[6]^[3] Abatacept should not be used at the same time as other biologics.^[81] In those who are well controlled on TNF blockers decreasing the dose does not appear to affect overall function.^[82] Persons should be screened for latent tuberculosis before starting any TNF blockers therapy to avoid reactivation.^[18]

TNF blockers and methotrexate appear to have similar effectiveness when used alone and better results are obtained when used together. Golimumab showed significant effectivness when used with methotraxate.^[83] TNF blockers appear to have equivalent effectiveness with etanercept appearing to be the safest.^[84] Abatacept appears effective for RA with 20% more people improving with treatment than without but long term safety studies are yet unavailable.^[85] However, there is a lack of evidence to distinguish between the biologics available for RA.^[86] Issues with the biologics include their high cost and association with infections including tuberculosis.^[3]

Anti-inflammatory and analgesic agents

Glucocorticoids can be used in the short term and at the lowest dose possible for flare-ups and while waiting for slow-onset drugs to take effect.^[6]^[3]

Non-NSAID drugs to relieve pain, like paracetamol may be used to help relieve the pain symptoms; they do not change the underlying disease.^[5]

NSAIDs reduce both pain and stiffness in those with RA but do not affect the underlying disease and appear to have no effect on people's long term disease course and thus are no longer first line agents.^[3]^[87] NSAIDs should be used with caution in those with gastrointestinal, cardiovascular, or kidney problems.^[88]^[89]^[90] Use of methotrexate together with NSAIDS is safe, if adequate monitoring is done.^[91] COX-2 inhibitors, such as celecoxib, and NSAIDs are equally effective.^[92]

The neuromodulator agents topical capsaicin may be reasonable to use in an attempt to reduce pain.^[93] Nefopam by mouth and cannabis are not recommended as of 2012 as the risks of use appear to be greater than the benefits.^[93]

Surgery

Especially for affected fingers, hands, and wrists, synovectomy may be needed to prevent pain or tendon rupture when drug treatment has failed. Severely affected joints may require joint replacement surgery, such as knee replacement. Postoperatively, physiotherapy is always necessary.^[16]^{: 1080, 1103}

Alternative medicine

In general, there is not enough evidence to support any complementary health approaches for RA, with safety concerns for some of them. Some mind and body practices and dietary supplements may help people with symptoms and therefore may be beneficial additions to conventional treatments, but there is not enough evidence to draw conclusions.^[9] A systematic review of CAM modalities (excluding fish oil) found that " The available evidence does not support their current use in the management of RA.".^[94] Studies showing beneficial effects in RA on a wide variety of CAM modalities are often affected by publication bias and are generally not high quality evidence such as randomized controlled trials (RCTs).^[8]

A 2005 Cochrane review states that low level laser therapy can be tried to improve pain and morning stiffness due to rheumatoid arthritis as there are few side-effects.^[95]

There is some evidence that Tai Chi improves the range of motion of a joint in persons with rheumatoid arthritis.^[96] The evidence for acupuncture is inconclusive^[97] with it appearing to be equivalent to sham acupuncture.^[98]

Dietary supplements

Fatty acids: Gamma-linolenic acid, an omega-6 fatty acid, may reduce pain, tender joint count and stiffness, and is generally safe.^[99] For omega-3 polyunsaturated fatty acids (found in fish oil), a meta-analysis reported a favorable effect on pain, although confidence in the effect was considered moderate. The same review reported less inflammation but no difference in joint function.^[100] A review examined the effect of marine oil omega-3 fatty acids on pro-inflammatory eicosanoid concentrations; leukotriene₄ (LTB₄) was lowered in people with rheumatoid arthritis but not in those with non-autoimmune chronic diseases. (LTB₄) increases vascular permeabiltity and stimulates other inflammatory substances.^[101] A third meta-analysis looked at fish consumption. The result was a weak, non-statistically significant inverse association between fish consumption and RA.^[102] A fourth review limited inclusion to trials in which people eat ≥2.7 g/day for more than three months. Use of pain relief medication was decreased, but improvements in tender or swollen joints, morning stiffness and physical function were not changed.^[103] Collectively, the current evidence is not strong enough to determine that supplementation with omega-3 fatty acids or regular consumption of fish are effective treatments for rheumatoid arthritis.^[100]^[101]^[102]^[103]

Herbal: 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.^[104] 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.^[104]

Due to the false belief that herbal supplements are always safe, there is sometimes a hesitancy to report their use which may increase the risk of adverse reaction.^[8]

The following are under investigation for treatments for RA, based on preliminary promising results (not recommended for clinical use yet): boswellic acid,^[105] curcumin,^[106] devil's claw,^[107]^[108] Euonymus alatus,^[109] and thunder god vine (Tripterygium wilfordii).^[110] NCCIH has noted that, "In particular, the herb thunder god vine (Tripterygium wilfordii) can have serious side effects."^[9]

There is conflicting evidence on the role of erythropoiesis-stimulating agents for treatment of anemia in persons with rheumatoid arthritis.^[111]

Pregnancy

More than 75% of women with rheumatoid arthritis have symptoms improve during pregnancy but might have symptoms worsen after delivery.^[18] Methotrexate and leflunomide are teratogenic (harmful to foetus) and not used in pregnancy. It is recommended women of childbearing age should use contraceptives to avoid pregnancy and to discontinue its use if pregnancy is planned.^[69]^[77] Low dose of prednisolone, hydroxychloroquine and sulfasalazine are considered safe in pregnant persons with rheumatoid arthritis.

Vaccinations

People with RA have an increased risk of infections and mortality and recommended vaccinations can reduce these risks.^[112] The inactivated influenza vaccine should be received annually.^[113] The pneumococcal vaccine should be administered twice for people under the age 65 and once for those over 65.^[114] Lastly, the live-attenuated zoster vaccine should be administered once after the age 60, but is not recommended in people on a tumor necrosis factor alpha blocker.^[115]

Prognosis

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.^{[citation needed]}

Prognostic factors

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])
Increased clinical severity.

Mortality

RA reduces lifespan on average from three to twelve years.^[69] Young age at onset, long disease duration, the presence of other health problems, 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.^[117] 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,^[118] 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.^[119] It is possible that the use of new biologic drug therapies extend the lifespan of people with RA and reduce the risk and progression of atherosclerosis.^[120] This is based on cohort and registry studies, and still remains hypothetical. It is still uncertain whether biologics improve vascular function in RA or not. There was an increase in total cholesterol and HDLc levels and no improvement of the atherogenic index.^[121]

Epidemiology

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.^[3] In 2010 it resulted in about 49,000 deaths globally.^[122]

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.^[18]

The age at which the disease most commonly starts is in women between 40 and 50 years of age, and for men somewhat later.^[123] RA is a chronic disease, and although rarely, a spontaneous remission may occur, the natural course is almost invariably one of the persistent symptoms, waxing and waning in intensity, and a progressive deterioration of joint structures leading to deformations and disability.

History

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.^{[citation needed]} It was noted in skeletal remains of Native Americans found in Tennessee.^[124] In Europe, the disease is vanishingly rare before the 17th century.^[125] The first recognized description of RA in modern medicine was in 1800 by the French physician Dr Augustin Jacob Landré-Beauvais (1772–1840) who was based in the famed Salpêtrière Hospital in Paris.^[12] The name "rheumatoid arthritis" itself was coined in 1859 by British rheumatologist Dr Alfred Baring Garrod.^[126]

An anomaly has been noticed from the 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.^[127]

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.^[128]^[129] RA appears to some to have been depicted in 16th-century paintings.^[130] However, it is generally recognized in art historical circles that the painting of hands in the 16th and 17th century followed certain stylized 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.

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).^[131]

Etymology

Rheumatoid arthritis 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. Rhuma which means watery discharge might refer to the fact that the joints are swollen or that the disease may be made worse by wet weather.^[13]

Research

Meta-analysis found an association between periodontal disease and RA, but the mechanism of this association remains unclear.^[132] Two bacterial species associated with periodontitis are implicated as mediators of protein citrullination in the gums of people with RA.^[3]

Vitamin D deficiency is more common in people with rheumatoid arthritis than in the general population.^[133]^[134] However, whether vitamin D deficiency is a cause or a consequence of the disease remains unclear.^[135] One meta-analysis found that vitamin D levels are low in people with rheumatoid arthritis and that vitamin D status correlates inversely with prevalence of rheumatoid arthritis, suggesting that vitamin D deficiency is associated with susceptibility to rheumatoid arthritis.^[136]

References

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External links

Template:Dmoz
Charles Weber. "History of rheumatoid arthritis".

[NIH2014-1] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x "Handout on Health: Rheumatoid Arthritis". National Institute of Arthritis and Musculoskeletal and Skin Diseases. August 2014. Archived from the original on June 30, 2015. Retrieved July 2, 2015. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[Majithia2007-2] ^ ^a ^b ^c ^d ^e ^f 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.

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[NICE2015-5] "Rheumatoid arthritis in adults: management: recommendations: Guidance and guidelines". NICE. December 2015. Archived from the original on 2017-04-16. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[ACR2015-6] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Singh, JA; Saag, KG; Bridges SL, Jr; Ak l; et al. (January 2016). "2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis". Arthritis & Rheumatology. 68 (1): 1–26. doi:10.1002/art.39480. PMID 26545940. {{cite journal}}: Explicit use of et al. in: |first4= (help); Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[7] Singh, JA; Wells, GA; Christensen, R; et al. (16 February 2011). "Adverse effects of biologics: a network meta-analysis and Cochrane overview". The Cochrane Database of Systematic Reviews (2): CD008794. doi:10.1002/14651858.CD008794.pub2. PMID 21328309. {{cite journal}}: Explicit use of et al. in: |last4= (help)

[Ef2010-8] Efthimiou P, Kukar M (2010). "Complementary and alternative medicine use in rheumatoid arthritis: proposed mechanism of action and efficacy of commonly used modalities". Rheumatology International. 30 (5): 571–86. doi:10.1007/s00296-009-1206-y. PMID 19876631.

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[GBD2015Pre-10] GBD 2015 Disease and Injury Incidence and Prevalence, Collaborators. (8 October 2016). "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545–1602. doi:10.1016/S0140-6736(16)31678-6. PMC 5055577. PMID 27733282. {{cite journal}}: |first1= has generic name (help)CS1 maint: numeric names: authors list (link)

[GDB2013-11] GBD 2013 Mortality and Causes of Death, Collaborators (17 December 2014). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 385 (9963): 117–71. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604. PMID 25530442. {{cite journal}}: |first1= has generic name (help)CS1 maint: numeric names: authors list (link)

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[98] Macfarlane GJ, Paudyal P, Doherty M, Ernst E, Lewith G, MacPherson H, Sim J, Jones GT; Paudyal; Doherty; Ernst; Lewith; MacPherson; Sim; Jones; Arthritis Research UK Working Group on Complementary Alternative Therapies for the Management of the Rheumatic Diseases (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.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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[114] Black, CL; Yue, X; Ball, SW; Donahue, SM; Izrael, D; de Perio, MA; Laney, AS; Lindley, MC; Graitcer, SB; Lu, PJ; Williams, WW; Bridges, CB; DiSogra, C; Sokolowski, J; Walker, DK; Greby, SM (19 September 2014). "Influenza vaccination coverage among health care personnel – United States, 2013–14 influenza season". MMWR. Morbidity and Mortality Weekly Report. 63 (37): 805–11. PMC 5779456. PMID 25233281.

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[biologics_cv_effects/_cancer-121] Damjanov, N; Nurmohamed, MT; Szekanecz, Z (Mar 18, 2014). "Biologics, cardiovascular effects and cancer". BMC Medicine. 12 (1): 48. doi:10.1186/1741-7015-12-48. PMC 3984692. PMID 24642038.{{cite journal}}: CS1 maint: unflagged free DOI (link)

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@@ Line 18: / Line 18: @@
 | prognosis       =
 | frequency       = 0.5–1% (adults in [[developed world]])<ref name=Lancet2016/>
-| deaths          = 30,000 (2015)<ref name=GBD2015De>{{cite journal|last1=GBD 2015 Mortality and Causes of Death|first1=Collaborators.|title=Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015.|journal=Lancet|date=8 October 2016|volume=388|issue=10053|pages=1459–1544|pmid=27733281|doi=10.1016/S0140-6736(16)31012-1|pmc=5388903}}</ref>
+| deaths          = 30,000 (2015)<ref name=GBD2015De>{{cite journal|last1=GBD 2015 Mortality and Causes of Death|first1=Collaborators.|title=Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015|journal=Lancet|date=8 October 2016|volume=388|issue=10053|pages=1459–1544|pmid=27733281|doi=10.1016/S0140-6736(16)31012-1|pmc=5388903}}</ref>
 }}
 <!-- Definition and symptoms -->
@@ Line 27: / Line 27: @@
 <!-- Treatment -->
-The goals of treatment are to reduce pain, decrease inflammation, and improve a person's overall functioning.<ref name=NICE2015>{{cite web|title=Rheumatoid arthritis in adults: management: recommendations: Guidance and guidelines|url=https://www.nice.org.uk/guidance/CG79/chapter/Recommendations|publisher=NICE|date=December 2015|deadurl=no|archiveurl=https://web.archive.org/web/20170416130024/https://www.nice.org.uk/guidance/CG79/chapter/Recommendations|archivedate=2017-04-16|df=}}</ref> This may be helped by balancing rest and exercise, the use of [[orthoses|splints and braces]], or the use of assistive devices.<ref name=NIH2014/> [[Analgesics|Pain medications]], [[glucocorticoid|steroids]], and [[Nonsteroidal anti-inflammatory drug|NSAIDs]] are frequently used to help with symptoms.<ref name=NIH2014/> [[Disease-modifying antirheumatic drug]]s (DMARDs), such as [[hydroxychloroquine]] and [[methotrexate]], may be used to try to slow the progression of disease.<ref name=NIH2014/> Biological DMARDs may be used when disease does not respond to other treatments.<ref name=ACR2015>{{cite journal|last1=Singh|first1=JA|last2=Saag|first2=KG|last3=Bridges SL|first3=Jr|last4=Ak l|first4=et al|title=2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.|journal=Arthritis & Rheumatology|date=January 2016|volume=68|issue=1|pages=1–26|pmid=26545940|doi=10.1002/art.39480|url=http://onlinelibrary.wiley.com/doi/10.1002/art.39480/full|deadurl=no|archiveurl=https://web.archive.org/web/20170416220727/http://onlinelibrary.wiley.com/doi/10.1002/art.39480/full|archivedate=2017-04-16|df=}}</ref> However, they may have a greater rate of adverse effects.<ref>{{cite journal|last1=Singh|first1=JA|last2=Wells|first2=GA|last3=Christensen|first3=R|last4=et al|title=Adverse effects of biologics: a network meta-analysis and Cochrane overview.|journal=The Cochrane Database of Systematic Reviews|date=16 February 2011| issue=2| pages=CD008794| pmid=21328309|doi=10.1002/14651858.CD008794.pub2}}</ref> Surgery to repair, [[joint replacement|replace]], or [[arthrodesis|fuse]] joints may help in certain situations.<ref name=NIH2014/> Most [[complementary and alternative medicine|alternative medicine treatments]] are not supported by evidence.<ref name=Ef2010>{{cite journal |vauthors=Efthimiou P, Kukar M | title = Complementary and alternative medicine use in rheumatoid arthritis: proposed mechanism of action and efficacy of commonly used modalities| journal = Rheumatology international | volume = 30 | issue = 5 | pages = 571–86 | year = 2010 | pmid = 19876631 | doi = 10.1007/s00296-009-1206-y }}</ref><ref name=NCCIH>{{cite web|title=Rheumatoid Arthritis and Complementary Health Approaches|url=http://nccih.nih.gov/health/RA/getthefacts.htm|publisher=National Center for Complementary and Integrative Health|accessdate=July 1, 2015|deadurl=no|archiveurl=https://web.archive.org/web/20150705082102/https://nccih.nih.gov/health/RA/getthefacts.htm|archivedate=July 5, 2015|df=}}</ref>
+The goals of treatment are to reduce pain, decrease inflammation, and improve a person's overall functioning.<ref name=NICE2015>{{cite web|title=Rheumatoid arthritis in adults: management: recommendations: Guidance and guidelines|url=https://www.nice.org.uk/guidance/CG79/chapter/Recommendations|publisher=NICE|date=December 2015|deadurl=no|archiveurl=https://web.archive.org/web/20170416130024/https://www.nice.org.uk/guidance/CG79/chapter/Recommendations|archivedate=2017-04-16|df=}}</ref> This may be helped by balancing rest and exercise, the use of [[orthoses|splints and braces]], or the use of assistive devices.<ref name=NIH2014/> [[Analgesics|Pain medications]], [[glucocorticoid|steroids]], and [[Nonsteroidal anti-inflammatory drug|NSAIDs]] are frequently used to help with symptoms.<ref name=NIH2014/> [[Disease-modifying antirheumatic drug]]s (DMARDs), such as [[hydroxychloroquine]] and [[methotrexate]], may be used to try to slow the progression of disease.<ref name=NIH2014/> Biological DMARDs may be used when disease does not respond to other treatments.<ref name=ACR2015>{{cite journal|last1=Singh|first1=JA|last2=Saag|first2=KG|last3=Bridges SL|first3=Jr|last4=Ak l|first4=et al|title=2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis|journal=Arthritis & Rheumatology|date=January 2016|volume=68|issue=1|pages=1–26|pmid=26545940|doi=10.1002/art.39480|deadurl=no|df=}}</ref> However, they may have a greater rate of adverse effects.<ref>{{cite journal|last1=Singh|first1=JA|last2=Wells|first2=GA|last3=Christensen|first3=R|last4=et al|title=Adverse effects of biologics: a network meta-analysis and Cochrane overview|journal=The Cochrane Database of Systematic Reviews|date=16 February 2011| issue=2| pages=CD008794| pmid=21328309|doi=10.1002/14651858.CD008794.pub2}}</ref> Surgery to repair, [[joint replacement|replace]], or [[arthrodesis|fuse]] joints may help in certain situations.<ref name=NIH2014/> Most [[complementary and alternative medicine|alternative medicine treatments]] are not supported by evidence.<ref name=Ef2010>{{cite journal |vauthors=Efthimiou P, Kukar M | title = Complementary and alternative medicine use in rheumatoid arthritis: proposed mechanism of action and efficacy of commonly used modalities| journal = Rheumatology International | volume = 30 | issue = 5 | pages = 571–86 | year = 2010 | pmid = 19876631 | doi = 10.1007/s00296-009-1206-y }}</ref><ref name=NCCIH>{{cite web|title=Rheumatoid Arthritis and Complementary Health Approaches|url=http://nccih.nih.gov/health/RA/getthefacts.htm|publisher=National Center for Complementary and Integrative Health|accessdate=July 1, 2015|deadurl=no|archiveurl=https://web.archive.org/web/20150705082102/https://nccih.nih.gov/health/RA/getthefacts.htm|archivedate=July 5, 2015|df=}}</ref>
 <!-- Epidemiology and history -->
-RA affects about 24.5 million people as of 2015.<ref name=GBD2015Pre>{{cite journal|last1=GBD 2015 Disease and Injury Incidence and Prevalence| first1=Collaborators.|title=Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.|journal=Lancet|date=8 October 2016| volume=388| issue=10053| pages=1545–1602| pmid=27733282| doi=10.1016/S0140-6736(16)31678-6|pmc=5055577}}</ref> This is between 0.5 and 1% of adults in the [[developed world]] with 5 and 50 per 100,000 people newly developing the condition each year.<ref name=Lancet2016>{{Cite journal|last=Smolen|first=Josef S.|last2=Aletaha|first2=Daniel|last3=McInnes|first3=Iain B.| date=2016-10-22| title=Rheumatoid arthritis| journal=Lancet| volume=388|issue=10055|pages=2023–2038|doi=10.1016/S0140-6736(16)30173-8|pmid=27156434}}</ref> Onset is most frequent during middle age and women are affected 2.5 times as frequently as men.<ref name=NIH2014/> In 2013, it resulted in 38,000 deaths up from 28,000 deaths in 1990.<ref name=GDB2013>{{cite journal|last1=GBD 2013 Mortality and Causes of Death|first1=Collaborators|title=Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013.|journal=Lancet|date=17 December 2014|pmid=25530442|doi=10.1016/S0140-6736(14)61682-2|volume=385|issue=9963|pages=117–71|pmc=4340604}}</ref> The first recognized description of RA was made in 1800 by Dr. [[Augustin Jacob Landré-Beauvais]] (1772–1840) of Paris.<ref name=Landre1800>{{cite book | author=Landré-Beauvais AJ | title=La goutte asthénique primitive (doctoral thesis) | year=1800 | location=Paris}} reproduced in {{cite journal |author=Landré-Beauvais AJ |title=The first description of rheumatoid arthritis. Unabridged text of the doctoral dissertation presented in 1800 |journal=Joint Bone Spine |volume=68 |issue=2 |pages=130–43 |year=2001 |pmid=11324929 |doi= 10.1016/S1297-319X(00)00247-5}}</ref> The term ''rheumatoid arthritis'' is based on the Greek for watery and inflamed joints.<ref name=Paget2002>{{cite book|last1=Paget|first1=Stephen A.|last2=Lockshin|first2=Michael D.|last3=Loebl|first3=Suzanne|title=The Hospital for Special Surgery Rheumatoid Arthritis Handbook Everything You Need to Know.|date=2002|publisher=John Wiley & Sons|location=New York|isbn=9780471223344|page=32|url=https://books.google.com/books?id=akacOyQrnKkC&pg=PA32|deadurl=no|archiveurl=https://web.archive.org/web/20170222110341/https://books.google.com/books?id=akacOyQrnKkC&pg=PA32|archivedate=2017-02-22|df=}}</ref>
+RA affects about 24.5 million people as of 2015.<ref name=GBD2015Pre>{{cite journal|last1=GBD 2015 Disease and Injury Incidence and Prevalence| first1=Collaborators.|title=Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015|journal=Lancet|date=8 October 2016| volume=388| issue=10053| pages=1545–1602| pmid=27733282| doi=10.1016/S0140-6736(16)31678-6|pmc=5055577}}</ref> This is between 0.5 and 1% of adults in the [[developed world]] with 5 and 50 per 100,000 people newly developing the condition each year.<ref name=Lancet2016>{{Cite journal|last=Smolen|first=Josef S.|last2=Aletaha|first2=Daniel|last3=McInnes|first3=Iain B.| date=2016-10-22| title=Rheumatoid arthritis| journal=Lancet| volume=388|issue=10055|pages=2023–2038|doi=10.1016/S0140-6736(16)30173-8|pmid=27156434}}</ref> Onset is most frequent during middle age and women are affected 2.5 times as frequently as men.<ref name=NIH2014/> In 2013, it resulted in 38,000 deaths up from 28,000 deaths in 1990.<ref name=GDB2013>{{cite journal|last1=GBD 2013 Mortality and Causes of Death|first1=Collaborators|title=Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013|journal=Lancet|date=17 December 2014|pmid=25530442|doi=10.1016/S0140-6736(14)61682-2|volume=385|issue=9963|pages=117–71|pmc=4340604}}</ref> The first recognized description of RA was made in 1800 by Dr. [[Augustin Jacob Landré-Beauvais]] (1772–1840) of Paris.<ref name=Landre1800>{{cite book | author=Landré-Beauvais AJ | title=La goutte asthénique primitive (doctoral thesis) | year=1800 | location=Paris}} reproduced in {{cite journal |author=Landré-Beauvais AJ |title=The first description of rheumatoid arthritis. Unabridged text of the doctoral dissertation presented in 1800 |journal=Joint Bone Spine |volume=68 |issue=2 |pages=130–43 |year=2001 |pmid=11324929 |doi= 10.1016/S1297-319X(00)00247-5}}</ref> The term ''rheumatoid arthritis'' is based on the Greek for watery and inflamed joints.<ref name=Paget2002>{{cite book|last1=Paget|first1=Stephen A.|last2=Lockshin|first2=Michael D.|last3=Loebl|first3=Suzanne|title=The Hospital for Special Surgery Rheumatoid Arthritis Handbook Everything You Need to Know|date=2002|publisher=John Wiley & Sons|location=New York|isbn=9780471223344|page=32|url=https://books.google.com/books?id=akacOyQrnKkC&pg=PA32|deadurl=no|archiveurl=https://web.archive.org/web/20170222110341/https://books.google.com/books?id=akacOyQrnKkC&pg=PA32|archivedate=2017-02-22|df=}}</ref>
 {{TOC limit|3}}
 ==Signs and symptoms==
-RA primarily affects [[joints]], but it also affects other [[Organ (anatomy)|organs]] in more than 15–25% of cases.<ref name="pmid12860726">{{cite journal |vauthors=Turesson C, O'Fallon WM, Crowson CS, Gabriel SE, Matteson EL | title = Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years | journal = Ann. Rheum. Dis. | volume = 62 | issue = 8 | pages = 722–7 | year = 2003 | pmid = 12860726 | pmc = 1754626 | doi = 10.1136/ard.62.8.722 }}</ref> Associated problems include cardiovascular disease, osteoporosis, interstitial lung disease, infection, cancer, feeling tired, depression, mental difficulties, and trouble working.<ref>{{Cite journal |last=Cutolo |first=Maurizio |last2=Kitas |first2=George D. |last3=van Riel |first3=Piet L.C.M. |date= February 2014 |title= Burden of disease in treated rheumatoid arthritis patients: Going beyond the joint |url= https://doi.org/10.1016/j.semarthrit.2013.08.004 |journal= Seminars in Arthritis and Rheumatism |volume=43 |issue=4 |pages= 479–488 |doi= 10.1016/j.semarthrit.2013.08.004 |issn= 0049-0172 |pmid= 24080116}}</ref>
+RA primarily affects [[joints]], but it also affects other [[Organ (anatomy)|organs]] in more than 15–25% of cases.<ref name="pmid12860726">{{cite journal |vauthors=Turesson C, O'Fallon WM, Crowson CS, Gabriel SE, Matteson EL | title = Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years | journal = Ann. Rheum. Dis. | volume = 62 | issue = 8 | pages = 722–7 | year = 2003 | pmid = 12860726 | pmc = 1754626 | doi = 10.1136/ard.62.8.722 }}</ref> Associated problems include cardiovascular disease, osteoporosis, interstitial lung disease, infection, cancer, feeling tired, depression, mental difficulties, and trouble working.<ref>{{Cite journal |last=Cutolo |first=Maurizio |last2=Kitas |first2=George D. |last3=van Riel |first3=Piet L.C.M. |date= February 2014 |title= Burden of disease in treated rheumatoid arthritis patients: Going beyond the joint |journal= Seminars in Arthritis and Rheumatism |volume=43 |issue=4 |pages= 479–488 |doi= 10.1016/j.semarthrit.2013.08.004 |issn= 0049-0172 |pmid= 24080116}}</ref>
 ===Joints===
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 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, such as [[osteoarthritis]]. In arthritis of non-inflammatory causes, signs of inflammation and early morning stiffness are less prominent.{{Citation needed|date=August 2018}}
-The pain associated with RA is induced at the site of inflammation and classified as [[nociceptive]] as opposed to [[neuropathic]].<ref>{{cite journal |vauthors=Gaffo A, Saag KG, Curtis JR | title = Treatment of rheumatoid arthritis | journal = Am J Health Syst Pharm | volume = 63 | issue = 24 | pages = 2451–2465 | year = 2006 | pmid = 17158693 | doi = 10.2146/ajhp050514 }}</ref> The joints are often affected in a fairly symmetrical fashion, although this is not specific, and the initial presentation may be asymmetrical.<ref name=Davidson2014>{{cite book|editor1-last=Walker|editor1-first=Brian R.|editor2-last=Colledge|editor2-first=Nicki R.|editor3-last=Ralston|editor3-first=Stuart H.|editor4-last=Penman|editor4-first=Ian D.|title=Davidson's principles and practice of medicine|date=2014|publisher=Churchill Livingstone/Elsevier|isbn=978-0-7020-5035-0|edition=22nd}}</ref>{{rp|1098}}
+The pain associated with RA is induced at the site of inflammation and classified as [[nociceptive]] as opposed to [[neuropathic]].<ref>{{cite journal |vauthors=Gaffo A, Saag KG, Curtis JR | title = Treatment of rheumatoid arthritis | journal = Am J Health Syst Pharm | volume = 63 | issue = 24 | pages = 2451–2465 | year = 2006 | pmid = 17158693 | pmc = 5164397 | doi = 10.2146/ajhp050514 }}</ref> The joints are often affected in a fairly symmetrical fashion, although this is not specific, and the initial presentation may be asymmetrical.<ref name=Davidson2014>{{cite book|editor1-last=Walker|editor1-first=Brian R.|editor2-last=Colledge|editor2-first=Nicki R.|editor3-last=Ralston|editor3-first=Stuart H.|editor4-last=Penman|editor4-first=Ian D.|title=Davidson's principles and practice of medicine|date=2014|publisher=Churchill Livingstone/Elsevier|isbn=978-0-7020-5035-0|edition=22nd}}</ref>{{rp|1098}}
 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]] (also "buttonhole deformity", [[flexion]] of proximal interphalangeal joint and extension of distal [[Interphalangeal articulations of hand|interphalangeal joint]] of the hand), [[swan neck deformity]] (hyperextension at proximal interphalangeal joint and flexion at distal interphalangeal joint) 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.<ref name=Davidson2014 />{{rp|1098}} 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.<ref name="McGraw Hill">{{cite book|last1=Shah|first1=Ankur|date=2012|title=Harrison's Principles of Internal Medicine|publisher=McGraw Hill|location=United States|isbn=978-0-07174889-6|page=2738|edition=18th}}</ref>
 ===Skin===
-The [[rheumatoid nodule]], which is sometimes in the skin, is the most common non-joint feature and occurs in 30% of people who have RA.<ref name=Tur2013>{{cite journal|last1=Turesson|first1=C|title=Extra-articular rheumatoid arthritis.|journal=Current Opinion in Rheumatology|date=May 2013|volume=25|issue=3|pages=360–6|pmid=23425964|doi=10.1097/bor.0b013e32835f693f}}</ref> 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 [[fissure]]d 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 [[lymphocyte]]s and [[plasma cell]]s, 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|elbow]], the [[calcaneal tuberosity|heel]], the [[metacarpophalangeal joints|knuckles]], or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF ([[rheumatoid factor]]) [[titer]], ACPA, and severe erosive arthritis. Rarely, these can occur in internal organs or at diverse sites on the body.{{Citation needed|date=October 2014}}
+The [[rheumatoid nodule]], which is sometimes in the skin, is the most common non-joint feature and occurs in 30% of people who have RA.<ref name=Tur2013>{{cite journal|last1=Turesson|first1=C|title=Extra-articular rheumatoid arthritis|journal=Current Opinion in Rheumatology|date=May 2013|volume=25|issue=3|pages=360–6|pmid=23425964|doi=10.1097/bor.0b013e32835f693f}}</ref> 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 [[fissure]]d 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 [[lymphocyte]]s and [[plasma cell]]s, 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|elbow]], the [[calcaneal tuberosity|heel]], the [[metacarpophalangeal joints|knuckles]], or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF ([[rheumatoid factor]]) [[titer]], ACPA, and severe erosive arthritis. Rarely, these can occur in internal organs or at diverse sites on the body.{{Citation needed|date=October 2014}}
 Several forms of [[vasculitis]] occur in RA, but are mostly seen with long-standing and untreated disease. The most common presentation is due to involvement of small- and medium-sized vessels. Rheumatoid vasculitis can thus commonly present with skin ulceration and vasculitic nerve infarction known as [[mononeuritis multiplex]].<ref>{{Cite journal|last=Genta|first=Marcia S.|last2=Genta|first2=Robert M.|last3=Gabay|first3=Cem|date=2006-10-01|title=Systemic rheumatoid vasculitis: a review|journal=Seminars in Arthritis and Rheumatism|volume=36|issue=2|pages=88–98|doi=10.1016/j.semarthrit.2006.04.006|pmid=17023257}}</ref>
@@ Line 53: / Line 53: @@
 Other, rather rare, skin associated symptoms include [[pyoderma gangrenosum]], [[Sweet's syndrome]], drug reactions, [[erythema nodosum]], lobe [[panniculitis]], [[atrophy]] of finger skin, [[palmar erythema]], and skin fragility (often worsened by corticosteroid use).{{Citation needed|date=October 2014}}
-[[Diffuse alopecia areata]] (Diffuse AA) occurs more commonly in people with rheumatoid arthritis.<ref name=":1" /> RA is also seen more often in those with relatives who have AA.<ref name=":1">{{Cite journal|last=Khan Mohammad Beigi|first=Pooya|date=2018|title=Alopecia Areata|url=https://link.springer.com/10.1007/978-3-319-72134-7|language=en-gb|doi=10.1007/978-3-319-72134-7}}</ref>
+[[Diffuse alopecia areata]] (Diffuse AA) occurs more commonly in people with rheumatoid arthritis.<ref name=":1" /> RA is also seen more often in those with relatives who have AA.<ref name=":1">{{Cite book|last=Khan Mohammad Beigi|first=Pooya|date=2018|title=Alopecia Areata|language=en-gb|doi=10.1007/978-3-319-72134-7|isbn=978-3-319-72133-0}}</ref>
 ===Lungs===
@@ Line 71: / Line 71: @@
 ;Eyes: The eye can be directly affected in the form of [[episcleritis]] or [[scleritis]], 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 gland|lacrimal]] and [[salivary gland]]s. 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.{{citation needed|date=January 2017}}
-;Liver: Liver problems in people with rheumatoid arthritis may be due to the underlying disease process or as a result of the medications used to treat the disease.<ref name=Selmi2011/> A coexisting autoimmune liver disease, such as [[primary biliary cirrhosis]] or [[autoimmune hepatitis]] may also cause problems.<ref name=Selmi2011>{{cite journal | last=Selmi | first=Carlo | last2=Santis | first2=Maria De | last3=Gershwin | first3=M Eric | title=Liver involvement in subjects with rheumatic disease | journal=[[Arthritis Research & Therapy]] | publisher=BioMed Central | volume=13 | issue=3 | year=2011 | page=226 | doi=10.1186/ar3319 | pmid=21722332 | pmc=3218873}}</ref>
+;Liver: Liver problems in people with rheumatoid arthritis may be due to the underlying disease process or as a result of the medications used to treat the disease.<ref name=Selmi2011/> A coexisting autoimmune liver disease, such as [[primary biliary cirrhosis]] or [[autoimmune hepatitis]] may also cause problems.<ref name=Selmi2011>{{cite journal | last=Selmi | first=Carlo | last2=Santis | first2=Maria De | last3=Gershwin | first3=M Eric | title=Liver involvement in subjects with rheumatic disease | journal=[[Arthritis Research & Therapy]] | volume=13 | issue=3 | year=2011 | page=226 | doi=10.1186/ar3319 | pmid=21722332 | pmc=3218873}}</ref>
 ;Neurological: [[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. [[Rheumatoid disease of the spine]] can lead to [[myelopathy]]. [[Atlanto-axial joint|Atlanto-axial]] [[subluxation]] can occur, owing to erosion of the [[odontoid process]] and/or [[transverse ligament]]s 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]] or even death.<ref>{{Cite journal|last=Wasserman|first=Bradley R.|last2=Moskovich|first2=Ronald|last3=Razi|first3=Afshin E.|date=2011|title=Rheumatoid arthritis of the cervical spine--clinical considerations|url=http://hjdbulletin.org/files/archive/pdfs/222.pdf|journal=Bulletin of the New York University Hospital for Joint Diseases|volume=69|issue=2|pages=136–148|issn=1936-9727|pmid=22035393}}</ref>
@@ Line 91: / Line 91: @@
 There are established epigenetic and environmental risk factors for RA.<ref name=Firestein2017>{{Cite journal|last=Firestein|first=Gary S.|last2=McInnes|first2=Iain B.|date=2017-02-21|title=Immunopathogenesis of Rheumatoid Arthritis| journal=Immunity| volume=46|issue=2| pages=183–196| doi=10.1016/j.immuni.2017.02.006| pmid=28228278|pmc=5385708}}{{subscription}}</ref><ref name=Lancet2016/> [[Tobacco smoking|Smoking]] is an established risk factor for RA in Caucasian populations, increasing the risk three times compared to non-smokers, particularly in men, heavy smokers, and those who are rheumatoid factor positive.<ref name=Sugiyama2010/> Modest alcohol consumption may be protective.<ref>{{cite journal |vauthors=Liao KP, Alfredsson L, Karlson EW | title = Environmental influences on risk for rheumatoid arthritis | journal = Current Opinion in Rheumatology | volume = 21 | issue = 3 | pages = 279–83 | date = May 2009 | pmid = 19318947 | pmc = 2898190 | doi = 10.1097/BOR.0b013e32832a2e16 }}{{subscription}}</ref>
-[[Silica]] exposure has been linked to RA.<ref>{{cite journal|last1=Pollard|first1=Kenneth Michael|title=Silica, Silicosis, and Autoimmunity|journal=Frontiers in Immunology|date=11 March 2016|volume=7|doi=10.3389/fimmu.2016.00097|pmc=4786551|pmid=27014276}}</ref>
+[[Silica]] exposure has been linked to RA.<ref>{{cite journal|last1=Pollard|first1=Kenneth Michael|title=Silica, Silicosis, and Autoimmunity|journal=Frontiers in Immunology|date=11 March 2016|volume=7|pages=97|doi=10.3389/fimmu.2016.00097|pmc=4786551|pmid=27014276}}</ref>
 ===Negative findings===
@@ Line 107: / Line 107: @@
 ===Amplification in the synovium===
-Once the generalized abnormal immune response has become established &ndash; which may take several years before any symptoms occur &ndash; plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes in large quantities. These activate macrophages through Fc receptor and complement binding, which is part of the intense inflammation in RA.<ref>{{cite journal|author=Boldt AB, Goeldner I, de Messias-Reason IJ|pmid=22397030|title=Relevance of the lectin pathway of complement in rheumatic diseases|doi=10.1016/B978-0-12-394317-0.00012-1|volume=56|journal=Adv Clin Chem|pages=105–53|year=2012|series=Advances in Clinical Chemistry|isbn=9780123943170}}{{subscription}}</ref>{{year|date=July 2017}}{{page needed|date=July 2017}} Binding of an autoreactive antibody to the Fc receptors is mediated through the antibody's N-glycans, which are altered to promote inflammation in people with RA.<ref name = "immune_glycan"/>{{page needed|date=July 2017}}
+Once the generalized abnormal immune response has become established &ndash; which may take several years before any symptoms occur &ndash; plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes in large quantities. These activate macrophages through Fc receptor and complement binding, which is part of the intense inflammation in RA.<ref>{{Cite book|author=Boldt AB, Goeldner I, de Messias-Reason IJ|pmid=22397030|title=Relevance of the lectin pathway of complement in rheumatic diseases|doi=10.1016/B978-0-12-394317-0.00012-1|volume=56|journal=Adv Clin Chem|pages=105–53|year=2012|series=Advances in Clinical Chemistry|isbn=9780123943170}}{{subscription}}</ref>{{year|date=July 2017}}{{page needed|date=July 2017}} Binding of an autoreactive antibody to the Fc receptors is mediated through the antibody's N-glycans, which are altered to promote inflammation in people with RA.<ref name = "immune_glycan"/>{{page needed|date=July 2017}}
 This contributes to local inflammation in a joint, specifically the synovium with [[edema]], [[vasodilation]] and entry of activated T-cells, mainly CD4 in microscopically nodular aggregates and CD8 in microscopically diffuse infiltrates.{{citation needed|date=July 2017}} Synovial macrophages and [[dendritic cell]]s function as [[antigen-presenting cell]]s by expressing MHC class II molecules, which establishes the immune reaction in the tissue.{{citation needed|date=July 2017}}
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-The disease progresses by forming granulation tissue at the edges of the synovial lining, [[pannus]] with extensive [[angiogenesis]] and enzymes causing tissue damage.<ref>{{cite journal|pmc=4879881|year=2015|author1=Elshabrawy|first1=H. A|title=The Pathogenic Role of Angiogenesis in Rheumatoid Arthritis|journal=Angiogenesis|volume=18|issue=4|pages=433–448|last2=Chen|first2=Z|last3=Volin|first3=M. V|last4=Ravella|first4=S|last5=Virupannavar|first5=S|last6=Shahrara|first6=S|doi=10.1007/s10456-015-9477-2}}</ref> The synovium thickens, cartilage and underlying bone disintegrate, and the joint deteriorates, with raised [[calprotectin]] levels serving as a [[biomarker]] of these events.<ref>{{cite journal|pmid=25729036|year=2015|author1=Abildtrup|first1=M|title=Calprotectin as a biomarker for rheumatoid arthritis: A systematic review|journal=The Journal of Rheumatology|volume=42|issue=5|pages=760–70|last2=Kingsley|first2=G. H|last3=Scott|first3=D. L|doi=10.3899/jrheum.140628}}</ref>
+The disease progresses by forming granulation tissue at the edges of the synovial lining, [[pannus]] with extensive [[angiogenesis]] and enzymes causing tissue damage.<ref>{{cite journal|pmc=4879881|year=2015|author1=Elshabrawy|first1=H. A|title=The Pathogenic Role of Angiogenesis in Rheumatoid Arthritis|journal=Angiogenesis|volume=18|issue=4|pages=433–448|last2=Chen|first2=Z|last3=Volin|first3=M. V|last4=Ravella|first4=S|last5=Virupannavar|first5=S|last6=Shahrara|first6=S|doi=10.1007/s10456-015-9477-2|pmid=26198292}}</ref> The synovium thickens, cartilage and underlying bone disintegrate, and the joint deteriorates, with raised [[calprotectin]] levels serving as a [[biomarker]] of these events.<ref>{{cite journal|pmid=25729036|year=2015|author1=Abildtrup|first1=M|title=Calprotectin as a biomarker for rheumatoid arthritis: A systematic review|journal=The Journal of Rheumatology|volume=42|issue=5|pages=760–70|last2=Kingsley|first2=G. H|last3=Scott|first3=D. L|doi=10.3899/jrheum.140628}}</ref>
-Cytokines and chemokines attract and accumulate immune cells, i.e. activated T- and B cells, monocytes and macrophages from activated [[fibroblasts]], in the joint space. By signalling through [[RANKL]] and [[RANK]], they eventually trigger [[osteoclast]] production, which degrades bone tissue.<ref name=Lancet2016/><ref name=Chiu2017rev>{{cite journal|last1=Chiu|first1=YG|last2=Ritchlin|first2=CT|title=Denosumab: targeting the RANKL pathway to treat rheumatoid arthritis.|journal=Expert opinion on biological therapy |date=January 2017| volume=17|issue=1 |pages=119–128 |pmid=27871200| doi=10.1080/14712598.2017.1263614}}{{subscription}}</ref>{{page needed|date=July 2017}}
+Cytokines and chemokines attract and accumulate immune cells, i.e. activated T- and B cells, monocytes and macrophages from activated [[fibroblasts]], in the joint space. By signalling through [[RANKL]] and [[RANK]], they eventually trigger [[osteoclast]] production, which degrades bone tissue.<ref name=Lancet2016/><ref name=Chiu2017rev>{{cite journal|last1=Chiu|first1=YG|last2=Ritchlin|first2=CT|title=Denosumab: targeting the RANKL pathway to treat rheumatoid arthritis|journal=Expert Opinion on Biological Therapy |date=January 2017| volume=17|issue=1 |pages=119–128 |pmid=27871200|pmc=5794005| doi=10.1080/14712598.2017.1263614}}{{subscription}}</ref>{{page needed|date=July 2017}}
-[[Tumor necrosis factors]] (TNF alpha) plays a major role and several theories exist on how TNF release happens in RA. Tumor necrosis factor‐alpha (TNF‐α) is a proinflammatory cytokine that plays a pivotal role in regulating the inflammatory response in rheumatoid arthritis (RA).If TNF release is stimulated by B cell products in the form of RF or ACPA -containing immune complexes, through activation of immunoglobulin [[Fc receptor]]s, then RA can be seen as a form of [[Type III hypersensitivity]].<ref>{{cite web |url=http://www.path.sunysb.edu/coursemat/hbp310immun.htm |archiveurl=https://web.archive.org/web/20060807074858/http://www.path.sunysb.edu/coursemat/hbp310immun.htm |archivedate=August 7, 2006 |title=HBP310 Immunology|work=SUNY Stony Brook Pathology Department |accessdate=September 20, 2008}}</ref>{{year|date=July 2017}}<ref>{{cite web|url=http://www.microbiologybook.org/book/immunol-sta.htm|title=Hypersensitivity States|author=Ghaffar, Abdul|work=University of South Carolina School of Medicine|accessdate=May 29, 2016|deadurl=no|archiveurl=https://web.archive.org/web/20160518095824/http://www.microbiologybook.org/book/immunol-sta.htm|archivedate=May 18, 2016|df=}}</ref> As of 1999, if TNF release is stimulated by T cell products such as [[interleukin-17]] it might be closer to [[type IV hypersensitivity]] although this terminology may be getting somewhat dated and unhelpful.<ref>{{cite web |url=http://www-immuno.path.cam.ac.uk/~immuno/part1/lec13/lec13_97.html|archiveurl=https://web.archive.org/web/20060206220202/http://www-immuno.path.cam.ac.uk/~immuno/part1/lec13/lec13_97.html| archivedate=February 6, 2006|title=Lecture 14: Hypersensitivity|accessdate=September 20, 2008|author=Holmes, N. |year= 1999|work=Immunology Division, Department of Pathology, University of Cambridge}}</ref>
+[[Tumor necrosis factors]] (TNF alpha) plays a major role and several theories exist on how TNF release happens in RA. Tumor necrosis factor‐alpha (TNF‐α) is a proinflammatory cytokine that plays a pivotal role in regulating the inflammatory response in rheumatoid arthritis (RA).If TNF release is stimulated by B cell products in the form of RF or ACPA -containing immune complexes, through activation of immunoglobulin [[Fc receptor]]s, then RA can be seen as a form of [[Type III hypersensitivity]].<ref>{{cite web |url=http://www.path.sunysb.edu/coursemat/hbp310immun.htm |archiveurl=https://web.archive.org/web/20060807074858/http://www.path.sunysb.edu/coursemat/hbp310immun.htm |archivedate=August 7, 2006 |title=HBP310 Immunology|website=SUNY Stony Brook Pathology Department |accessdate=September 20, 2008}}</ref>{{year|date=July 2017}}<ref>{{cite web|url=http://www.microbiologybook.org/book/immunol-sta.htm|title=Hypersensitivity States|author=Ghaffar, Abdul|website=University of South Carolina School of Medicine|accessdate=May 29, 2016|deadurl=no|archiveurl=https://web.archive.org/web/20160518095824/http://www.microbiologybook.org/book/immunol-sta.htm|archivedate=May 18, 2016|df=}}</ref> As of 1999, if TNF release is stimulated by T cell products such as [[interleukin-17]] it might be closer to [[type IV hypersensitivity]] although this terminology may be getting somewhat dated and unhelpful.<ref>{{cite web |url=http://www-immuno.path.cam.ac.uk/~immuno/part1/lec13/lec13_97.html|archiveurl=https://web.archive.org/web/20060206220202/http://www-immuno.path.cam.ac.uk/~immuno/part1/lec13/lec13_97.html| archivedate=February 6, 2006|title=Lecture 14: Hypersensitivity|accessdate=September 20, 2008|author=Holmes, N. |year= 1999|website=Immunology Division, Department of Pathology, University of Cambridge}}</ref>
-Although TNF appears to be the dominant chemical mediator other cytokines are involved in inflammation in RA, because blocking TNF does not benefit all persons and all tissues, particularly  lung disease and nodules may get worse. Blocking IL-1, [[Interleukin 15|IL-15]] and [[Interleukin 6|IL-6]] have beneficial effects and [[Interleukin 17|IL-17]] may be important.<ref>{{Cite journal|last=Gaffen|first=Sarah L.|date=2017-01-22|title=Role of IL-17 in the Pathogenesis of Rheumatoid Arthritis|journal=Current rheumatology reports|volume=11|issue=5|pages=365–370|issn=1523-3774|pmc=2811488|pmid=19772832}}{{subscription}}</ref>
+Although TNF appears to be the dominant chemical mediator other cytokines are involved in inflammation in RA, because blocking TNF does not benefit all persons and all tissues, particularly  lung disease and nodules may get worse. Blocking IL-1, [[Interleukin 15|IL-15]] and [[Interleukin 6|IL-6]] have beneficial effects and [[Interleukin 17|IL-17]] may be important.<ref>{{Cite journal|last=Gaffen|first=Sarah L.|date=2017-01-22|title=Role of IL-17 in the Pathogenesis of Rheumatoid Arthritis|journal=Current Rheumatology Reports|volume=11|issue=5|pages=365–370|issn=1523-3774|pmc=2811488|pmid=19772832}}{{subscription}}</ref>
 ==Diagnosis==
@@ Line 135: / Line 135: @@
 [[Image:RheumatoideArthritisAP.jpg|thumb|X-ray of the hand in rheumatoid arthritis.]]
 [[Image:Inflamatory arthritis2010.JPG|thumb|Appearance of synovial fluid from a joint with inflammatory arthritis.]]
-[[File:X-ray of right fourth PIP joint with bone erosions by rheumatoid arthritis.jpg|thumb|Closeup of [[bone erosion]]s in rheumatoid arthritis.<ref>{{cite journal|last1=Ideguchi|first1=Haruko|last2=Ohno|first2=Shigeru|last3=Hattori|first3=Hideaki|last4=Senuma|first4=Akiko|last5=Ishigatsubo|first5=Yoshiaki|journal=Arthritis Research & Therapy|volume=8|issue=3|year=2006|pages=R76|issn=1478-6354|doi=10.1186/ar1943|title=Bone erosions in rheumatoid arthritis can be repaired through reduction in disease activity with conventional disease-modifying antirheumatic drugs}}</ref>]]
+[[File:X-ray of right fourth PIP joint with bone erosions by rheumatoid arthritis.jpg|thumb|Closeup of [[bone erosion]]s in rheumatoid arthritis.<ref>{{cite journal|last1=Ideguchi|first1=Haruko|last2=Ohno|first2=Shigeru|last3=Hattori|first3=Hideaki|last4=Senuma|first4=Akiko|last5=Ishigatsubo|first5=Yoshiaki|journal=Arthritis Research & Therapy|volume=8|issue=3|year=2006|pages=R76|issn=1478-6354|doi=10.1186/ar1943|pmid=16646983|pmc=1526642|title=Bone erosions in rheumatoid arthritis can be repaired through reduction in disease activity with conventional disease-modifying antirheumatic drugs}}</ref>]]
-[[X-ray]]s of the hands and feet are generally performed when many joints affected. In RA, there may be no changes in the early stages of the disease or the x-ray may show [[osteopenia]] near the joint, soft tissue swelling, and a smaller than normal joint space. As the disease advances, there may be bony erosions and subluxation. Other medical imaging techniques such as [[magnetic resonance imaging]] (MRI) and ultrasound are also used in RA.<ref name="McGraw Hill"/><ref>{{cite journal|last1=Takase-Minegishi|first1=K|last2=Horita|first2=N|last3=Kobayashi|first3=K|last4=Yoshimi|first4=R|last5=Kirino|first5=Y|last6=Ohno|first6=S|last7=Kaneko|first7=T|last8=Nakajima|first8=H|last9=Wakefield|first9=RJ|last10=Emery|first10=P|title=Diagnostic test accuracy of ultrasound for synovitis in rheumatoid arthritis: systematic review and meta-analysis.|journal=Rheumatology (Oxford, England)|date=1 January 2018|volume=57|issue=1|pages=49–58|doi=10.1093/rheumatology/kex036|pmid=28340066}}</ref>
+[[X-ray]]s of the hands and feet are generally performed when many joints affected. In RA, there may be no changes in the early stages of the disease or the x-ray may show [[osteopenia]] near the joint, soft tissue swelling, and a smaller than normal joint space. As the disease advances, there may be bony erosions and subluxation. Other medical imaging techniques such as [[magnetic resonance imaging]] (MRI) and ultrasound are also used in RA.<ref name="McGraw Hill"/><ref>{{cite journal|last1=Takase-Minegishi|first1=K|last2=Horita|first2=N|last3=Kobayashi|first3=K|last4=Yoshimi|first4=R|last5=Kirino|first5=Y|last6=Ohno|first6=S|last7=Kaneko|first7=T|last8=Nakajima|first8=H|last9=Wakefield|first9=RJ|last10=Emery|first10=P|title=Diagnostic test accuracy of ultrasound for synovitis in rheumatoid arthritis: systematic review and meta-analysis|journal=Rheumatology (Oxford, England)|date=1 January 2018|volume=57|issue=1|pages=49–58|doi=10.1093/rheumatology/kex036|pmid=28340066}}</ref>
 Technical advances in ultrasonography like high-frequency transducers (10&nbsp;MHz or higher) have improved the spatial resolution of ultrasound images depicting 20% more erosions than conventional radiography. Color Doppler and power Doppler ultrasound are useful in assessing the degree of synovial inflammation as they can show vascular signals of active synovitis. 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.<ref>Schueller-Weidekamm C. [http://www.diagnosticimaging.com/ultrasound/content/article/113619/1561958 Modern ultrasound methods yield stronger arthritis work-up] {{webarchive|url=https://web.archive.org/web/20100515141455/http://www.diagnosticimaging.com/ultrasound/content/article/113619/1561958 |date=2010-05-15 }}. Diagnostic Imaging. May 2010:20–22.</ref>
@@ Line 146: / Line 146: @@
 Hence, new serological tests check for anti-citrullinated protein antibodies ACPAs . These tests are again positive in 61-75% of all RA cases, but with a specificity of around 95%.<ref>{{Cite journal|last=van Venrooij|first=Walther J.|last2=van Beers|first2=Joyce J. B. C.|last3=Pruijn|first3=Ger J. M.|date=2011-06-07|title=Anti-CCP antibodies: the past, the present and the future|journal=Nature Reviews. Rheumatology| volume=7| issue=7|pages=391–398| doi=10.1038/nrrheum.2011.76| issn=1759-4804|pmid=21647203}}{{subscription}}</ref> As with RF, ACPAs are many times present before symptoms have started.<ref name="McGraw Hill"/>
-The by far most common clinical test for ACPAs is the anti-[[cyclic citrullinated peptide]] (anti CCP) ELISA. In 2008 a serological [[Point-of-care testing|point-of-care test]] for the early detection of RA  combined the detection of RF and anti-MCV with a sensitivity of 72% and specificity of 99.7%.<ref>{{cite journal |vauthors=Renger F, Bang H, Fredenhagen G, et al |title=Anti-MCV Antibody Test for the Diagnosis of Rheumatoid Arthritis Using a POCT-Immunoassay |journal=American College of Rheumatology, 2008 Annual Scientific Meeting, poster presentation |url=http://acr.confex.com/acr/2008/webprogram/Paper2009.html |deadurl=yes |archiveurl=https://web.archive.org/web/20100527234743/http://acr.confex.com/acr/2008/webprogram/Paper2009.html |archivedate=2010-05-27 |df= }}</ref>{{better source |date=July 2017}}<ref>{{cite journal |vauthors=Luime JJ, Colin EM, Hazes JM, Lubberts E |title=Does anti-MCV has additional value as serological marker in the diagnostic and prognostic work-up of patients with rheumatoid arthritis? A systematic review |journal=Ann Rheum Dis |pmid= 19289382 |doi= 10.1136/ard.2008.103283 |year=2009 |volume=69 |issue=2 |pages=337–44}}{{subscription}}</ref>
+The by far most common clinical test for ACPAs is the anti-[[cyclic citrullinated peptide]] (anti CCP) ELISA. In 2008 a serological [[Point-of-care testing|point-of-care test]] for the early detection of RA  combined the detection of RF and anti-MCV with a sensitivity of 72% and specificity of 99.7%.<ref>{{cite journal |vauthors=Renger F, Bang H, Fredenhagen G, et al |title=Anti-MCV Antibody Test for the Diagnosis of Rheumatoid Arthritis Using a POCT-Immunoassay |journal=American College of Rheumatology, 2008 Annual Scientific Meeting, Poster Presentation |url=http://acr.confex.com/acr/2008/webprogram/Paper2009.html |deadurl=yes |archiveurl=https://web.archive.org/web/20100527234743/http://acr.confex.com/acr/2008/webprogram/Paper2009.html |archivedate=2010-05-27 |df= }}</ref>{{better source |date=July 2017}}<ref>{{cite journal |vauthors=Luime JJ, Colin EM, Hazes JM, Lubberts E |title=Does anti-MCV has additional value as serological marker in the diagnostic and prognostic work-up of patients with rheumatoid arthritis? A systematic review |journal=Ann Rheum Dis |pmid= 19289382 |doi= 10.1136/ard.2008.103283 |year=2009 |volume=69 |issue=2 |pages=337–44|url=http://ard.bmj.com/cgi/content/short/ard.2008.103283v1 }}{{subscription}}</ref>
 Other blood tests are usually done to differentiate from other causes of arthritis, like the [[erythrocyte sedimentation rate]] (ESR), [[C-reactive protein]], [[full blood count]], [[kidney function]], [[liver enzyme]]s 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 [[Adult-onset Still's disease|Still's disease]], a seronegative, usually juvenile, variant of rheumatoid arthritis.{{Citation needed|date=July 2008}}
@@ Line 177: / Line 177: @@
 ===Differential diagnoses===
-Several other medical conditions can resemble RA, and need to be distinguished from it at the time of diagnosis:<ref name=Merckmanual>{{cite book | editor= Berkow R | title=The Merck Manual | edition=16th | publisher=Merck Publishing Group |year=1992 | pages=1307–08 | isbn=0-911910-16-6}}{{subscription}}</ref><ref>{{cite journal |vauthors=Lovy MR, Starkebaum G, Uberoi S | title = Hepatitis C infection presenting with rheumatic manifestations: a mimic of rheumatoid arthritis | journal = J. Rheumatol. | volume = 23 | issue = 6 | pages = 1238–9 | year = 1996 | pmid = 8782126}}{{subscription}}</ref>
+Several other medical conditions can resemble RA, and need to be distinguished from it at the time of diagnosis:<ref name=Merckmanual>{{cite book | editor= Berkow R | title=The Merck Manual | edition=16th | publisher=Merck Publishing Group |year=1992 | pages=1307–08 | isbn=978-0-911910-16-2}}{{subscription}}</ref><ref>{{cite journal |vauthors=Lovy MR, Starkebaum G, Uberoi S | title = Hepatitis C infection presenting with rheumatic manifestations: a mimic of rheumatoid arthritis | journal = J. Rheumatol. | volume = 23 | issue = 6 | pages = 1238–9 | year = 1996 | pmid = 8782126}}{{subscription}}</ref>
 * Crystal induced arthritis ([[gout]], and [[pseudogout]]) – usually involves particular joints (knee, MTP1, heels) and can be distinguished with an 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-ray]]s of the affected joints and blood tests, older age, starting pain less than an hour, asymmetric distribution of affected joints and pain worsens when using joint for longer periods.
@@ Line 218: / Line 218: @@
 It is not always a reliable indicator of treatment effect.<ref>Kelly, Janis (22 February 2005) [http://www.medscape.com/viewarticle/538134 DAS28 not always a reliable indicator of treatment effect in RA] {{webarchive|url=https://web.archive.org/web/20110225054141/http://www.medscape.com/viewarticle/538134 |date=2011-02-25 }}, Medscape Medical News.</ref> One major limitation is that low-grade synovitis may be missed.<ref>{{cite journal |last1=Uribea |first1=Liliana |last2=Ceróna  |first2=Carmen |last3=Amarilesb |first3=Pedro |last4=Fernando Llanoa |first4=Juan |last5=Restrepob |first5=Margarita |last6=Montoyaa |first6=Nora |last7=Alonso Gonzáleza |first7=Luis |last8=Felipe Díaza |first8=Oscar Jair |last9=Alejandra Saldarriagaa |first9=Margarita |last10=Gómez-Puerta |first10=José A. |display-authors=5 |date=July–September 2016 |title=Correlación entre la actividad clínica por DAS-28 y ecografía en pacientes con artritis reumatoide |trans-title=Correlation between clinical activity measured by DAS-28 and ultrasound in patients with rheumatoid arthritis |url= |journal=Revista Colombiana de Reumatología |volume=23 |issue=3 |pages=159–169 |language=es |doi=10.1016/j.rcreu.2016.05.002 |access-date= }}</ref>
-;Other: Other tools to monitor remission in rheumatoid arthritis are: ACR-EULAR Provisional Definition of Remission of Rheumatoid arthritis, [[Simplified Disease Activity Index]] (SDAI) and [[Clinical Disease Activity Index]] (CDAI).<ref>{{cite journal|last1=Yazici|first1=Yusuf|title=Tools for monitoring remission in rheumatoid arthritis: any will do, let’s just pick one and start measuring|journal=[[Arthritis Research & Therapy]]|date=2013|volume=15|page=104|doi=10.1186/ar4139}}{{subscription}}</ref> Some scores do not require input from a healthcare professional and allow self-monitoring by the person, like HAQ-DI.<ref>{{Cite journal|last=Bruce|first=Bonnie|last2=Fries|first2=James F.|date=2003-01-01|title=The Stanford Health Assessment Questionnaire: Dimensions and Practical Applications|url=https://dx.doi.org/10.1186/1477-7525-1-20|journal=Health and Quality of Life Outcomes| volume=1| pages=20| doi=10.1186/1477-7525-1-20| issn=1477-7525|pmc=165587|pmid=12831398}}{{subscription}}</ref>{{page needed|date=July 2017}}
+;Other: Other tools to monitor remission in rheumatoid arthritis are: ACR-EULAR Provisional Definition of Remission of Rheumatoid arthritis, [[Simplified Disease Activity Index]] (SDAI) and [[Clinical Disease Activity Index]] (CDAI).<ref>{{cite journal|last1=Yazici|first1=Yusuf|title=Tools for monitoring remission in rheumatoid arthritis: any will do, let's just pick one and start measuring|journal=[[Arthritis Research & Therapy]]|date=2013|volume=15|issue=1|page=104|doi=10.1186/ar4139|pmid=23374997|pmc=3672754}}{{subscription}}</ref> Some scores do not require input from a healthcare professional and allow self-monitoring by the person, like HAQ-DI.<ref>{{Cite journal|last=Bruce|first=Bonnie|last2=Fries|first2=James F.|date=2003-01-01|title=The Stanford Health Assessment Questionnaire: Dimensions and Practical Applications|journal=Health and Quality of Life Outcomes| volume=1| pages=20| doi=10.1186/1477-7525-1-20| issn=1477-7525|pmc=165587|pmid=12831398}}{{subscription}}</ref>{{page needed|date=July 2017}}
 ==Prevention==
@@ Line 229: / Line 229: @@
 ===Lifestyle===
-Regular exercise is recommended as both safe and useful to maintain muscles strength and overall physical function.<ref>{{cite journal | author = Hurkmans E, van der Giesen FJ, Vliet Vlieland TP, Schoones J, Van den Ende EC | title = Dynamic exercise programs (aerobic capacity and/or muscle strength training) in patients with rheumatoid arthritis | journal = Cochrane Database of Systematic Reviews | issue = 4 | pages = CD006853 | date = Oct 7, 2009 | pmid = 19821388 | doi = 10.1002/14651858.CD006853.pub2 | editor1-last = Hurkmans | editor1-first = Emalie }}</ref> It is uncertain if specific dietary measures have an effect.<ref>{{cite journal | author = Hagen KB, Byfuglien MG, Falzon L, Olsen SU, Smedslund G | title = Dietary interventions for rheumatoid arthritis | journal = Cochrane Database of Systematic Reviews | issue = 1 | pages = CD006400 | date = Jan 21, 2009 | pmid = 19160281 | doi = 10.1002/14651858.CD006400.pub2 | editor1-last = Hagen | editor1-first = Kåre Birger }}</ref> Physical activity is beneficial for persons with rheumatoid arthritis complaining of fatigue.<ref>{{cite journal|last1=Cramp|first1=Fiona|title=Non-pharmacological interventions for fatigue in rheumatoid arthritis.|journal=Cochrane Database of Systematic Reviews|date=2013|issue=8|page=Art. No.: CD008322|doi=10.1002/14651858.CD008322.pub2}}</ref> Occupational therapy has a positive role to play in improving functional ability of persons with rheumatoid arthritis.<ref>{{cite journal|last1=Steultjens|first1=Esther EMJ|title=Occupational therapy for rheumatoid arthritis|journal=Cochrane Database of Systematic Reviews|date=2004|issue=1|doi=10.1002/14651858.CD003114.pub2}}</ref>
+Regular exercise is recommended as both safe and useful to maintain muscles strength and overall physical function.<ref>{{cite journal | author = Hurkmans E, van der Giesen FJ, Vliet Vlieland TP, Schoones J, Van den Ende EC | title = Dynamic exercise programs (aerobic capacity and/or muscle strength training) in patients with rheumatoid arthritis | journal = Cochrane Database of Systematic Reviews | issue = 4 | pages = CD006853 | date = Oct 7, 2009 | pmid = 19821388 | doi = 10.1002/14651858.CD006853.pub2 | editor1-last = Hurkmans | editor1-first = Emalie }}</ref> It is uncertain if specific dietary measures have an effect.<ref>{{cite journal | author = Hagen KB, Byfuglien MG, Falzon L, Olsen SU, Smedslund G | title = Dietary interventions for rheumatoid arthritis | journal = Cochrane Database of Systematic Reviews | issue = 1 | pages = CD006400 | date = Jan 21, 2009 | pmid = 19160281 | doi = 10.1002/14651858.CD006400.pub2 | editor1-last = Hagen | editor1-first = Kåre Birger }}</ref> Physical activity is beneficial for persons with rheumatoid arthritis complaining of fatigue.<ref>{{cite journal|last1=Cramp|first1=Fiona|title=Non-pharmacological interventions for fatigue in rheumatoid arthritis|journal=Cochrane Database of Systematic Reviews|date=2013|issue=8|pages=CD008322|doi=10.1002/14651858.CD008322.pub2|pmid=23975674}}</ref> Occupational therapy has a positive role to play in improving functional ability of persons with rheumatoid arthritis.<ref>{{cite journal|last1=Steultjens|first1=Esther EMJ|title=Occupational therapy for rheumatoid arthritis|journal=Cochrane Database of Systematic Reviews|date=2004|issue=1|pages=CD003114|doi=10.1002/14651858.CD003114.pub2|pmid=14974005|hdl=2066/58846}}</ref>
 ===Disease modifying agents===
@@ Line 236: / Line 236: @@
 The following drugs are considered as DMARDs: [[methotrexate]], [[hydroxychloroquine]], [[sulfasalazine]], [[leflunomide]], TNF-alpha inhibitors ([[Certolizumab pegol|certolizumab]], [[infliximab]] and [[etanercept]]), [[abatacept]], and [[anakinra]]. [[Rituximab]] and [[tocilizumab]] are monoclonal antibodies and are also DMARDs.<ref name=ACR2015/>
-[[Hydroxychloroquine]], apart from its low toxicity profile, is considered effective in the moderate RA treatment.<ref>{{cite journal |last1=Suarez-Almazor |first1=ME |last2=Belseck |first2=E |last3=Shea |first3=B |last4=Homik |first4=J |last5=Wells |first5=G |last6=Tugwell |first6=P |title=Antimalarials for treating rheumatoid arthritis. |journal=The Cochrane Database of Systematic Reviews |date=2000 |issue=4 |pages=CD000959 |doi=10.1002/14651858.CD000959 |pmid=11034691}}</ref>
+[[Hydroxychloroquine]], apart from its low toxicity profile, is considered effective in the moderate RA treatment.<ref>{{cite journal |last1=Suarez-Almazor |first1=ME |last2=Belseck |first2=E |last3=Shea |first3=B |last4=Homik |first4=J |last5=Wells |first5=G |last6=Tugwell |first6=P |title=Antimalarials for treating rheumatoid arthritis |journal=The Cochrane Database of Systematic Reviews |date=2000 |issue=4 |pages=CD000959 |doi=10.1002/14651858.CD000959 |pmid=11034691}}</ref>
-The most commonly used agent is methotrexate with other frequently used agents including sulfasalazine and leflunomide.<ref name=ACR2015/> Leflunomide is effective when used from 6–12 months, with similar effectivness to methorexate when used for 2 years.<ref>{{cite journal |last1=Osiri |first1=M |last2=Shea |first2=B |last3=Robinson |first3=V |last4=Suarez-Almazor |first4=M |last5=Strand |first5=V |last6=Tugwell |first6=P |last7=Wells |first7=G |title=Leflunomide for treating rheumatoid arthritis. |journal=The Cochrane Database of Systematic Reviews |date=2003 |issue=1 |pages=CD002047 |doi=10.1002/14651858.CD002047 |pmid=12535423}}</ref> [[Sodium aurothiomalate]] (gold) and [[cyclosporin]] are less commonly used due to more common adverse effects.<ref name=ACR2015/> Agents may be used in combinations.<ref name=ACR2015/>  Methotrexate is the most important and useful DMARD and is usually the first treatment.<ref name=ACR2015/><ref name=NICE2015/><ref name="chapter94">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}}.</ref>  Adverse effects should be monitored regularly with toxicity including gastrointestinal, hematologic, pulmonary, and hepatic.<ref name="chapter94" /> Side effects such as nausea, vomiting or abdominal pain can be reduced by taking folic acid.<ref>{{cite journal | title = Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 5 | issue = 5 | pages = CD000951 | date = May 31, 2013 | pmid = 23728635 | doi = 10.1002/14651858.CD000951.pub2 | last2 = Swinden | first2 = M.V. | last3 = Tanjong Ghogomu | first3 = E. | last4 = Ortiz | first4 = Z. | last5 = Katchamart | first5 = W. | last6 = Rader | first6 = T. | last7 = Bombardier | first7 = C. | last8 = Wells | first8 = George A | last9 = Tugwell | first9 = Peter |last1 = Shea|first1 = B.}}</ref>
+The most commonly used agent is methotrexate with other frequently used agents including sulfasalazine and leflunomide.<ref name=ACR2015/> Leflunomide is effective when used from 6–12 months, with similar effectivness to methorexate when used for 2 years.<ref>{{cite journal |last1=Osiri |first1=M |last2=Shea |first2=B |last3=Robinson |first3=V |last4=Suarez-Almazor |first4=M |last5=Strand |first5=V |last6=Tugwell |first6=P |last7=Wells |first7=G |title=Leflunomide for treating rheumatoid arthritis |journal=The Cochrane Database of Systematic Reviews |date=2003 |issue=1 |pages=CD002047 |doi=10.1002/14651858.CD002047 |pmid=12535423}}</ref> [[Sodium aurothiomalate]] (gold) and [[cyclosporin]] are less commonly used due to more common adverse effects.<ref name=ACR2015/> Agents may be used in combinations.<ref name=ACR2015/>  Methotrexate is the most important and useful DMARD and is usually the first treatment.<ref name=ACR2015/><ref name=NICE2015/><ref name="chapter94">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}}.</ref>  Adverse effects should be monitored regularly with toxicity including gastrointestinal, hematologic, pulmonary, and hepatic.<ref name="chapter94" /> Side effects such as nausea, vomiting or abdominal pain can be reduced by taking folic acid.<ref>{{cite journal | title = Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 5 | issue = 5 | pages = CD000951 | date = May 31, 2013 | pmid = 23728635 | doi = 10.1002/14651858.CD000951.pub2 | last2 = Swinden | first2 = M.V. | last3 = Tanjong Ghogomu | first3 = E. | last4 = Ortiz | first4 = Z. | last5 = Katchamart | first5 = W. | last6 = Rader | first6 = T. | last7 = Bombardier | first7 = C. | last8 = Wells | first8 = George A | last9 = Tugwell | first9 = Peter |last1 = Shea|first1 = B.}}</ref>
 A 2015 [[Cochrane (organisation)|Cochrane]] review found rituximab with methotrexate to be effective in improving symptoms compared to methotrexate alone.<ref name=":0" /> Rituximab works by depicting levels of B-cells (immune cell that is involved in inflammation). People taking rituximab had improved pain, function, reduced disease activity and reduced joint damage based on x-ray images. After 6 months, 21% more people had improvement in their symptoms using rituximab and methotrexate.<ref name=":0">{{Cite journal|last=Lopez-Olivo|first=Maria Angeles|last2=Amezaga Urruela|first2=Matxalen|last3=McGahan|first3=Lynda|last4=Pollono|first4=Eduardo N.|last5=Suarez-Almazor|first5=Maria E.|date=2015-01-20|title=Rituximab for rheumatoid arthritis|journal=The Cochrane Database of Systematic Reviews|volume=1|pages=CD007356|doi=10.1002/14651858.CD007356.pub2|issn=1469-493X|pmid=25603545}}</ref>
@@ Line 244: / Line 244: @@
 Biological agents should generally only be used if methotrexate and other conventional agents are not effective after a trial of three months.<ref name=ACR2015/>  They are associated with a higher rate of serious infections as compared to other DMARDs.<ref>{{cite journal|last1=Singh|first1=Jasvinder A|last2=Cameron|first2=Chris|last3=Noorbaloochi|first3=Shahrzad|last4=Cullis|first4=Tyler|last5=Tucker|first5=Matthew|last6=Christensen|first6=Robin|last7=Ghogomu|first7=Elizabeth Tanjong|last8=Coyle|first8=Doug|last9=Clifford|first9=Tammy|last10=Tugwell|first10=Peter|last11=Wells|first11=George A|title=Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis|journal=The Lancet|date=May 2015|doi=10.1016/S0140-6736(14)61704-9|volume=386|issue=9990|pages=258–265|pmc=4580232|pmid=25975452}}</ref>  Biological DMARD agents used to treat rheumatoid arthritis include: [[tumor necrosis factor alpha]] (TNFα) blockers such as [[infliximab]]; [[interleukin 1]] blockers such as [[anakinra]], [[monoclonal antibody|monoclonal antibodies]] against [[B cell]]s such as [[rituximab]], and tocilizumab [[T cell]] co-stimulation blocker such as abatacept. They are often used in combination with either methotrexate or leflunomide.<ref name=ACR2015/><ref name=Lancet2016/> Abatacept should not be used at the same time as other biologics.<ref>{{Cite journal|last=Maxwell|first=Lara|last2=Singh|first2=Jasvinder A.|date=2009-10-07|title=Abatacept for rheumatoid arthritis|url=|journal=The Cochrane Database of Systematic Reviews|volume=|issue=4|pages=CD007277|doi=10.1002/14651858.CD007277.pub2|issn=1469-493X|pmid=19821401|via=}}</ref> In those who are well controlled on TNF blockers decreasing the dose does not appear to affect overall function.<ref>{{cite journal|last1=van Herwaarden|first1=N|last2=den Broeder|first2=AA|last3=Jacobs|first3=W|last4=van der Maas|first4=A|last5=Bijlsma|first5=JW|last6=van Vollenhoven|first6=RF|last7=van den Bemt|first7=BH|title=Down-titration and discontinuation strategies of tumor necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity|journal=The Cochrane Database of Systematic Reviews|date=Sep 29, 2014|volume=9|issue=9|pages=CD010455|pmid=25264908|doi=10.1002/14651858.CD010455.pub2}}</ref> Persons should be screened for [[latent tuberculosis]] before starting any [[TNF inhibitor|TNF blockers]] therapy to avoid reactivation.<ref name="McGraw Hill"/>
-TNF blockers and methotrexate appear to have similar effectiveness when used alone and better results are obtained when used together. [[Golimumab]] showed significant effectivness when used with methotraxate.<ref>{{cite journal |last1=Singh |first1=JA |last2=Noorbaloochi |first2=S |last3=Singh |first3=G |title=Golimumab for rheumatoid arthritis. |journal=The Cochrane Database of Systematic Reviews |date=20 January 2010 |issue=1 |pages=CD008341 |doi=10.1002/14651858.CD008341 |pmid=20091667}}</ref> TNF blockers appear to have equivalent effectiveness with [[etanercept]] appearing to be the safest.<ref>{{cite journal |author=Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordström DC, Blom M |title=Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis |journal=PLoS ONE |volume=7 |issue=1 |pages=e30275 |year=2012 |pmid=22272322 |pmc=3260264 |doi=10.1371/journal.pone.0030275 |editor1-last=Hernandez |editor1-first=Adrian V|last2=Virkki |last3=Malmivaara |last4=Konttinen |last5=Nordström |last6=Blom }}</ref> Abatacept appears effective for RA with 20% more people improving with treatment than without but long term safety studies are yet unavailable.<ref>{{cite journal | author = Maxwell L, Singh JA | title = Abatacept for rheumatoid arthritis | journal = Cochrane Database of Systematic Reviews | issue = 4 | pages = CD007277 | date = Oct 7, 2009 | pmid = 19821401 | doi = 10.1002/14651858.CD007277.pub2 | editor1-last = Maxwell | editor1-first = Lara | last2 = Singh }}</ref> However, there is a lack of evidence to distinguish between the biologics available for RA.<ref>{{cite journal | author = Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, Tanjong Ghogomu E, Tugwell P | title = Biologics for rheumatoid arthritis: an overview of Cochrane reviews | journal = Cochrane Database of Systematic Reviews | issue = 4 | pages = CD007848 | date = Oct 7, 2009 | pmid = 19821440 | doi = 10.1002/14651858.CD007848.pub2 | editor1-last = Singh | editor1-first = Jasvinder A | last2 = Christensen | last3 = Wells | last4 = Suarez-Almazor | last5 = Buchbinder | last6 = Lopez-Olivo | last7 = Tanjong Ghogomu | last8 = Tugwell }}</ref> Issues with the biologics include their high cost and association with infections including [[tuberculosis]].<ref name=Lancet2016/>
+TNF blockers and methotrexate appear to have similar effectiveness when used alone and better results are obtained when used together. [[Golimumab]] showed significant effectivness when used with methotraxate.<ref>{{cite journal |last1=Singh |first1=JA |last2=Noorbaloochi |first2=S |last3=Singh |first3=G |title=Golimumab for rheumatoid arthritis |journal=The Cochrane Database of Systematic Reviews |date=20 January 2010 |issue=1 |pages=CD008341 |doi=10.1002/14651858.CD008341 |pmid=20091667}}</ref> TNF blockers appear to have equivalent effectiveness with [[etanercept]] appearing to be the safest.<ref>{{cite journal |author=Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordström DC, Blom M |title=Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis |journal=PLoS ONE |volume=7 |issue=1 |pages=e30275 |year=2012 |pmid=22272322 |pmc=3260264 |doi=10.1371/journal.pone.0030275 |editor1-last=Hernandez |editor1-first=Adrian V|last2=Virkki |last3=Malmivaara |last4=Konttinen |last5=Nordström |last6=Blom }}</ref> Abatacept appears effective for RA with 20% more people improving with treatment than without but long term safety studies are yet unavailable.<ref>{{cite journal | author = Maxwell L, Singh JA | title = Abatacept for rheumatoid arthritis | journal = Cochrane Database of Systematic Reviews | issue = 4 | pages = CD007277 | date = Oct 7, 2009 | pmid = 19821401 | doi = 10.1002/14651858.CD007277.pub2 | editor1-last = Maxwell | editor1-first = Lara | last2 = Singh }}</ref> However, there is a lack of evidence to distinguish between the biologics available for RA.<ref>{{cite journal | author = Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, Tanjong Ghogomu E, Tugwell P | title = Biologics for rheumatoid arthritis: an overview of Cochrane reviews | journal = Cochrane Database of Systematic Reviews | issue = 4 | pages = CD007848 | date = Oct 7, 2009 | pmid = 19821440 | doi = 10.1002/14651858.CD007848.pub2 | editor1-last = Singh | editor1-first = Jasvinder A | last2 = Christensen | last3 = Wells | last4 = Suarez-Almazor | last5 = Buchbinder | last6 = Lopez-Olivo | last7 = Tanjong Ghogomu | last8 = Tugwell | url = http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802010000500013 | format = Submitted manuscript }}</ref> Issues with the biologics include their high cost and association with infections including [[tuberculosis]].<ref name=Lancet2016/>
 ===Anti-inflammatory and analgesic agents===
@@ Line 251: / Line 251: @@
 Non-[[Nonsteroidal anti-inflammatory drug|NSAID]] drugs to relieve pain, like [[paracetamol]] may be used to help relieve the pain symptoms; they do not change the underlying disease.<ref name=NICE2015/>
-[[Nonsteroidal anti-inflammatory drug|NSAIDs]] reduce both pain and stiffness in those with RA but do not affect the underlying disease and appear to have no effect on people's long term disease course and thus are no longer first line agents.<ref name=Lancet2016/><ref>{{cite journal | author = Tarp S, Bartels EM, Bliddal H, Furst DE, Boers M, Danneskiold-Samsøe B, Rasmussen M, Christensen R | title = Effect of nonsteroidal antiinflammatory drugs on the C-reactive protein level in rheumatoid arthritis: a meta-analysis of randomized controlled trials | journal = Arthritis and Rheumatism | volume = 64 | issue = 11 | pages = 3511–21 | date = November 2012 | pmid = 22833186 | doi = 10.1002/art.34644 | last2 = Bartels | last3 = Bliddal | last4 = Furst | last5 = Boers | last6 = Danneskiold-Samsøe | last7 = Rasmussen | last8 = Christensen }}</ref> NSAIDs should be used with caution in those with [[gastrointestinal problem|gastrointestinal]], [[cardiovascular]], or kidney problems.<ref>{{cite journal | author = Radner H, Ramiro S, Buchbinder R, Landewé RB, van der Heijde D, Aletaha D | title = Pain management for inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and other spondylarthritis) and gastrointestinal or liver comorbidity | journal = Cochrane Database of Systematic Reviews | volume = 1 | pages = CD008951 | date = Jan 18, 2012 | pmid = 22258995 | doi = 10.1002/14651858.CD008951.pub2 | editor1-last = Radner | editor1-first = Helga | last2 = Ramiro | last3 = Buchbinder | last4 = Landewé | last5 = Van Der Heijde | last6 = Aletaha }}</ref><ref name="pmid22141388">{{cite journal | author = McCormack PL | title = Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis | journal = Drugs | volume = 71 | issue = 18 | pages = 2457–89 | year = 2011 | pmid = 22141388 | doi = 10.2165/11208240-000000000-00000 }}</ref><ref>{{cite journal | author = Marks JL, Colebatch AN, Buchbinder R, Edwards CJ | title = Pain management for rheumatoid arthritis and cardiovascular or renal comorbidity | journal = Cochrane Database of Systematic Reviews | issue = 10 | pages = CD008952 | date = Oct 5, 2011 | pmid = 21975789 | doi = 10.1002/14651858.CD008952.pub2 | editor1-last = Marks | editor1-first = Jonathan L | last2 = Colebatch | last3 = Buchbinder | last4 = Edwards }}</ref> Use of methotrexate together with NSAIDS is safe, if adequate monitoring is done.<ref>{{cite journal|last1=Colebatch|first1=AN|last2=Marks|first2=Jonathan L|last3=Edwards|first3=Christopher J|title=Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis)|journal=Cochrane Database of Systematic Reviews|date=2011|doi=10.1002/14651858.CD008872.pub2|pmid=22071858|issue=11|page=CD008872}}</ref> [[COX-2 inhibitor]]s, such as [[celecoxib]], and NSAIDs are equally effective.<ref name=Job2008>{{cite journal | author = Chen YF, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, Taylor RS | title = 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 | journal = Health technology assessment (Winchester, England) | volume = 12 | issue = 11 | pages = 1–278, iii | date = April 2008 | pmid = 18405470 | last2 = Jobanputra | last3 = Barton | last4 = Bryan | last5 = Fry-Smith | last6 = Harris | last7 = Taylor | doi=10.3310/hta12110}}</ref>
+[[Nonsteroidal anti-inflammatory drug|NSAIDs]] reduce both pain and stiffness in those with RA but do not affect the underlying disease and appear to have no effect on people's long term disease course and thus are no longer first line agents.<ref name=Lancet2016/><ref>{{cite journal | author = Tarp S, Bartels EM, Bliddal H, Furst DE, Boers M, Danneskiold-Samsøe B, Rasmussen M, Christensen R | title = Effect of nonsteroidal antiinflammatory drugs on the C-reactive protein level in rheumatoid arthritis: a meta-analysis of randomized controlled trials | journal = Arthritis and Rheumatism | volume = 64 | issue = 11 | pages = 3511–21 | date = November 2012 | pmid = 22833186 | doi = 10.1002/art.34644 | last2 = Bartels | last3 = Bliddal | last4 = Furst | last5 = Boers | last6 = Danneskiold-Samsøe | last7 = Rasmussen | last8 = Christensen }}</ref> NSAIDs should be used with caution in those with [[gastrointestinal problem|gastrointestinal]], [[cardiovascular]], or kidney problems.<ref>{{cite journal | author = Radner H, Ramiro S, Buchbinder R, Landewé RB, van der Heijde D, Aletaha D | title = Pain management for inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and other spondylarthritis) and gastrointestinal or liver comorbidity | journal = Cochrane Database of Systematic Reviews | volume = 1 | pages = CD008951 | date = Jan 18, 2012 | pmid = 22258995 | doi = 10.1002/14651858.CD008951.pub2 | editor1-last = Radner | editor1-first = Helga | last2 = Ramiro | last3 = Buchbinder | last4 = Landewé | last5 = Van Der Heijde | last6 = Aletaha }}</ref><ref name="pmid22141388">{{cite journal | author = McCormack PL | title = Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis | journal = Drugs | volume = 71 | issue = 18 | pages = 2457–89 | year = 2011 | pmid = 22141388 | doi = 10.2165/11208240-000000000-00000 }}</ref><ref>{{cite journal | author = Marks JL, Colebatch AN, Buchbinder R, Edwards CJ | title = Pain management for rheumatoid arthritis and cardiovascular or renal comorbidity | journal = Cochrane Database of Systematic Reviews | issue = 10 | pages = CD008952 | date = Oct 5, 2011 | pmid = 21975789 | doi = 10.1002/14651858.CD008952.pub2 | editor1-last = Marks | editor1-first = Jonathan L | last2 = Colebatch | last3 = Buchbinder | last4 = Edwards }}</ref> Use of methotrexate together with NSAIDS is safe, if adequate monitoring is done.<ref>{{cite journal|last1=Colebatch|first1=AN|last2=Marks|first2=Jonathan L|last3=Edwards|first3=Christopher J|title=Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis)|journal=Cochrane Database of Systematic Reviews|date=2011|doi=10.1002/14651858.CD008872.pub2|pmid=22071858|issue=11|page=CD008872}}</ref> [[COX-2 inhibitor]]s, such as [[celecoxib]], and NSAIDs are equally effective.<ref name=Job2008>{{cite journal | author = Chen YF, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, Taylor RS | title = 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 | journal = Health Technology Assessment (Winchester, England) | volume = 12 | issue = 11 | pages = 1–278, iii | date = April 2008 | pmid = 18405470 | last2 = Jobanputra | last3 = Barton | last4 = Bryan | last5 = Fry-Smith | last6 = Harris | last7 = Taylor | doi=10.3310/hta12110}}</ref>
-The neuromodulator agents topical [[capsaicin]] may be reasonable to use in an attempt to reduce pain.<ref name=Ric2012/> [[Nefopam]] by mouth and [[cannabis]] are not recommended as of 2012 as the risks of use appear to be greater than the benefits.<ref name=Ric2012>{{cite journal |last1=Richards |first1=BL |last2=Whittle |first2=SL |last3=Buchbinder |first3=R |title=Neuromodulators for pain management in rheumatoid arthritis. |journal=The Cochrane Database of Systematic Reviews |date=18 January 2012 |volume=1 |pages=CD008921 |doi=10.1002/14651858.CD008921.pub2 |pmid=22258992}}</ref>
+The neuromodulator agents topical [[capsaicin]] may be reasonable to use in an attempt to reduce pain.<ref name=Ric2012/> [[Nefopam]] by mouth and [[cannabis]] are not recommended as of 2012 as the risks of use appear to be greater than the benefits.<ref name=Ric2012>{{cite journal |last1=Richards |first1=BL |last2=Whittle |first2=SL |last3=Buchbinder |first3=R |title=Neuromodulators for pain management in rheumatoid arthritis |journal=The Cochrane Database of Systematic Reviews |date=18 January 2012 |volume=1 |pages=CD008921 |doi=10.1002/14651858.CD008921.pub2 |pmid=22258992}}</ref>
 ===Surgery===
@@ Line 263: / Line 263: @@
 A 2005 Cochrane review states that [[low level laser therapy]] can be tried to improve pain and morning stiffness due to rheumatoid arthritis as there are few side-effects.<ref>{{cite journal |vauthors=Brosseau L, Robinson V, Wells G, Debie R, Gam A, Harman K, Morin M, Shea B, Tugwell P | title = Low level laser therapy (Classes I, II and III) for treating rheumatoid arthritis | journal = Cochrane Database Syst Rev | volume =4 | pages =CD002049 | date = 2005 | pmid = 16235295 | doi = 10.1002/14651858.CD002049.pub2| issue=4}}</ref>
-There is some evidence that [[Tai Chi]] improves the range of motion of a joint in persons with rheumatoid arthritis.<ref>{{cite journal|last1=Han|first1=Alcie|last2=Judd|first2=Maria|last3=Welch|first3=Vivian|last4=Wu|first4=Taixiang|last5=Tugwell|first5=Peter|last6=Wells|first6=George A|title=Tai chi for treating rheumatoid arthritis|journal=Cochrane Database of Systematic Reviews|date=2004|issue=3|doi=10.1002/14651858.CD004849}}</ref> The evidence for acupuncture is inconclusive<ref>{{cite journal|author=Lee MS, Shin B-C, Ernst E|journal=Rheumatology|title=Acupuncture for rheumatoid arthritis: a systematic review|year=2008|volume=47|pages=1747–53|doi=10.1093/rheumatology/ken330|pmid=18710899|issue=12|last2=Shin|last3=Ernst}}</ref> with it appearing to be equivalent to sham acupuncture.<ref>{{cite journal | author = Macfarlane GJ, Paudyal P, Doherty M, Ernst E, Lewith G, MacPherson H, Sim J, Jones GT | title = A systematic review of evidence for the effectiveness of practitioner-based complementary and alternative therapies in the management of rheumatic diseases: rheumatoid arthritis | journal = Rheumatology | volume = 51 | issue = 9 | pages = 1707–13 | year = 2012 | pmid = 22661556 | doi = 10.1093/rheumatology/kes133 | last2 = Paudyal | last3 = Doherty | last4 = Ernst | last5 = Lewith | last6 = MacPherson | last7 = Sim | last8 = Jones | author9 = Arthritis Research UK Working Group on Complementary Alternative Therapies for the Management of the Rheumatic Diseases }}</ref>
+There is some evidence that [[Tai Chi]] improves the range of motion of a joint in persons with rheumatoid arthritis.<ref>{{cite journal|last1=Han|first1=Alcie|last2=Judd|first2=Maria|last3=Welch|first3=Vivian|last4=Wu|first4=Taixiang|last5=Tugwell|first5=Peter|last6=Wells|first6=George A|title=Tai chi for treating rheumatoid arthritis|journal=Cochrane Database of Systematic Reviews|date=2004|issue=3|pages=CD004849|doi=10.1002/14651858.CD004849|pmid=15266544}}</ref> The evidence for acupuncture is inconclusive<ref>{{cite journal|author=Lee MS, Shin B-C, Ernst E|journal=Rheumatology|title=Acupuncture for rheumatoid arthritis: a systematic review|year=2008|volume=47|pages=1747–53|doi=10.1093/rheumatology/ken330|pmid=18710899|issue=12|last2=Shin|last3=Ernst}}</ref> with it appearing to be equivalent to sham acupuncture.<ref>{{cite journal | author = Macfarlane GJ, Paudyal P, Doherty M, Ernst E, Lewith G, MacPherson H, Sim J, Jones GT | title = A systematic review of evidence for the effectiveness of practitioner-based complementary and alternative therapies in the management of rheumatic diseases: rheumatoid arthritis | journal = Rheumatology | volume = 51 | issue = 9 | pages = 1707–13 | year = 2012 | pmid = 22661556 | doi = 10.1093/rheumatology/kes133 | last2 = Paudyal | last3 = Doherty | last4 = Ernst | last5 = Lewith | last6 = MacPherson | last7 = Sim | last8 = Jones | author9 = Arthritis Research UK Working Group on Complementary Alternative Therapies for the Management of the Rheumatic Diseases }}</ref>
 ====Dietary supplements====
-;Fatty acids: [[Gamma-linolenic acid]], an omega-6 fatty acid, may reduce pain, tender joint count and stiffness, and is generally safe.<ref>{{cite web|url=http://www.crd.york.ac.uk/CRDWeb/ShowRecord.asp?AccessionNumber=12003000980|title=Herbal medicines for the treatment of rheumatoid arthritis: a systematic review|last=Soeken|first=K L|last2=Miller|first2=S A|last3=Ernst|first3=E |year=2003 |publisher=[[National Institute for Health Research]]|work=[[Centre for Reviews and Dissemination]]|accessdate=March 23, 2013|deadurl=no|archiveurl=https://web.archive.org/web/20140116101729/http://www.crd.york.ac.uk/CRDWeb/ShowRecord.asp?AccessionNumber=12003000980|archivedate=January 16, 2014|df=}}</ref> For [[omega-3 polyunsaturated fatty acids]] (found in fish oil), a meta-analysis reported a favorable effect on pain, although confidence in the effect was considered moderate. The same review reported less inflammation but no difference in joint function.<ref name="Senft">{{cite journal |vauthors=Senftleber NK, Nielsen SM, Andersen JR, Bliddal H, Tarp S, Lauritzen L, Furst DE, Suarez-Almazor ME, Lyddiatt A, Christensen R |title=Marine Oil Supplements for Arthritis Pain: A Systematic Review and Meta-Analysis of Randomized Trials |journal=Nutrients |volume=9 |issue=1 |page= 42|year=2017 |pmid=28067815 |pmc=5295086 |doi=10.3390/nu9010042 |url=}}</ref> A review examined the effect of marine oil omega-3 fatty acids on pro-inflammatory eicosanoid concentrations; [[Leukotriene B4|leukotriene<sub>4</sub>]] (LTB<sub>4</sub>) was lowered in people with rheumatoid arthritis but not in those with non-autoimmune chronic diseases. (LTB<sub>4</sub>) increases vascular permeabiltity and stimulates other inflammatory substances.<ref name="Jiang">{{cite journal |vauthors=Jiang J, Li K, Wang F, Yang B, Fu Y, Zheng J, Li D |title=Effect of Marine-Derived n-3 Polyunsaturated Fatty Acids on Major Eicosanoids: A Systematic Review and Meta-Analysis from 18 Randomized Controlled Trials |journal=PLoS ONE |volume=11 |issue=1 |pages=e0147351 |year=2016 |pmid=26808318 |pmc=4726565 |doi=10.1371/journal.pone.0147351 |url=}}</ref> A third meta-analysis looked at fish consumption. The result was a weak, non-statistically significant inverse association between fish consumption and RA.<ref name="DiG">{{cite journal |vauthors=Di Giuseppe D, Crippa A, Orsini N, Wolk A |title=Fish consumption and risk of rheumatoid arthritis: a dose-response meta-analysis |journal=Arthritis Res. Ther. |volume=16 |issue=5 |pages=446 |year=2014 |pmid=25267142 |pmc=4201724 |doi=10.1186/s13075-014-0446-8 |url=}}</ref> A fourth review limited inclusion to trials in which people eat ≥2.7 g/day for more than three months. Use of pain relief medication was decreased, but improvements in tender or swollen joints, morning stiffness and physical function were not changed.<ref name="Lee">{{cite journal |vauthors=Lee YH, Bae SC, Song GG |title=Omega-3 polyunsaturated fatty acids and the treatment of rheumatoid arthritis: a meta-analysis |journal=Arch. Med. Res. |volume=43 |issue=5 |pages=356–62 |year=2012 |pmid=22835600 |doi=10.1016/j.arcmed.2012.06.011 |url=}}</ref> Collectively, the current evidence is not strong enough to determine that supplementation with omega-3 fatty acids or regular consumption of fish are effective treatments for rheumatoid arthritis.<ref name="Senft"/><ref name="Jiang"/><ref name="DiG"/><ref name="Lee"/>
+;Fatty acids: [[Gamma-linolenic acid]], an omega-6 fatty acid, may reduce pain, tender joint count and stiffness, and is generally safe.<ref>{{cite web|url=http://www.crd.york.ac.uk/CRDWeb/ShowRecord.asp?AccessionNumber=12003000980|title=Herbal medicines for the treatment of rheumatoid arthritis: a systematic review|last=Soeken|first=K L|last2=Miller|first2=S A|last3=Ernst|first3=E |year=2003 |publisher=[[National Institute for Health Research]]|website=[[Centre for Reviews and Dissemination]]|accessdate=March 23, 2013|deadurl=no|archiveurl=https://web.archive.org/web/20140116101729/http://www.crd.york.ac.uk/CRDWeb/ShowRecord.asp?AccessionNumber=12003000980|archivedate=January 16, 2014|df=}}</ref> For [[omega-3 polyunsaturated fatty acids]] (found in fish oil), a meta-analysis reported a favorable effect on pain, although confidence in the effect was considered moderate. The same review reported less inflammation but no difference in joint function.<ref name="Senft">{{cite journal |vauthors=Senftleber NK, Nielsen SM, Andersen JR, Bliddal H, Tarp S, Lauritzen L, Furst DE, Suarez-Almazor ME, Lyddiatt A, Christensen R |title=Marine Oil Supplements for Arthritis Pain: A Systematic Review and Meta-Analysis of Randomized Trials |journal=Nutrients |volume=9 |issue=1 |page= 42|year=2017 |pmid=28067815 |pmc=5295086 |doi=10.3390/nu9010042 |url=}}</ref> A review examined the effect of marine oil omega-3 fatty acids on pro-inflammatory eicosanoid concentrations; [[Leukotriene B4|leukotriene<sub>4</sub>]] (LTB<sub>4</sub>) was lowered in people with rheumatoid arthritis but not in those with non-autoimmune chronic diseases. (LTB<sub>4</sub>) increases vascular permeabiltity and stimulates other inflammatory substances.<ref name="Jiang">{{cite journal |vauthors=Jiang J, Li K, Wang F, Yang B, Fu Y, Zheng J, Li D |title=Effect of Marine-Derived n-3 Polyunsaturated Fatty Acids on Major Eicosanoids: A Systematic Review and Meta-Analysis from 18 Randomized Controlled Trials |journal=PLoS ONE |volume=11 |issue=1 |pages=e0147351 |year=2016 |pmid=26808318 |pmc=4726565 |doi=10.1371/journal.pone.0147351 |url=}}</ref> A third meta-analysis looked at fish consumption. The result was a weak, non-statistically significant inverse association between fish consumption and RA.<ref name="DiG">{{cite journal |vauthors=Di Giuseppe D, Crippa A, Orsini N, Wolk A |title=Fish consumption and risk of rheumatoid arthritis: a dose-response meta-analysis |journal=Arthritis Res. Ther. |volume=16 |issue=5 |pages=446 |year=2014 |pmid=25267142 |pmc=4201724 |doi=10.1186/s13075-014-0446-8 |url=}}</ref> A fourth review limited inclusion to trials in which people eat ≥2.7 g/day for more than three months. Use of pain relief medication was decreased, but improvements in tender or swollen joints, morning stiffness and physical function were not changed.<ref name="Lee">{{cite journal |vauthors=Lee YH, Bae SC, Song GG |title=Omega-3 polyunsaturated fatty acids and the treatment of rheumatoid arthritis: a meta-analysis |journal=Arch. Med. Res. |volume=43 |issue=5 |pages=356–62 |year=2012 |pmid=22835600 |doi=10.1016/j.arcmed.2012.06.011 |url=}}</ref> Collectively, the current evidence is not strong enough to determine that supplementation with omega-3 fatty acids or regular consumption of fish are effective treatments for rheumatoid arthritis.<ref name="Senft"/><ref name="Jiang"/><ref name="DiG"/><ref name="Lee"/>
 ;Herbal: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.<ref name=ACRCAM/> 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.<ref name=ACRCAM>{{cite web|title=Herbal Remedies, Supplements and Acupuncture for Arthritis|url=http://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Herbal_Remedies,_Supplements_and_Acupuncture_for_Arthritis/|publisher=American College of Rheumatology|accessdate=May 3, 2013|deadurl=no|archiveurl=https://web.archive.org/web/20130505001915/http://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Herbal_Remedies,_Supplements_and_Acupuncture_for_Arthritis/|archivedate=May 5, 2013|df=}}</ref>
 Due to the false belief that herbal supplements are always safe, there is sometimes a hesitancy to report their use which may increase the risk of adverse reaction.<ref name=Ef2010/>
-The following are under investigation for treatments for RA, based on preliminary promising results (not recommended for clinical use yet): [[boswellic acid]],<ref>{{cite journal | author = Abdel-Tawab M, Werz O, Schubert-Zsilavecz M | title = Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data | journal = Clinical pharmacokinetics | volume = 50 | issue = 6 | pages = 349–69 | date = June 2011 | pmid = 21553931 | doi = 10.2165/11586800-000000000-00000 | last2 = Werz | last3 = Schubert-Zsilavecz }}</ref> [[curcumin]],<ref>{{cite journal | author = White B, Judkins DZ | title = Clinical Inquiry. Does turmeric relieve inflammatory conditions? | journal = The Journal of family practice | volume = 60 | issue = 3 | pages = 155–6 | date = March 2011 | pmid = 21369559 | last2 = Judkins }}</ref> [[Harpagophytum|devil's claw]],<ref>{{cite journal | last1 = Wegener | first1 = T. | title = Therapy of degenerative diseases of the musculoskeletal system with South African devil's claw (Harpagophytum procumbens DC) | journal = Wiener medizinische Wochenschrift (1946) | volume = 149 | issue = 8–10 | pages = 254–257 | year = 1999 | pmid = 10483693 }}</ref><ref name="pmid17627199">{{cite journal | author = Denner SS | title = A review of the efficacy and safety of devil's claw for pain associated with degenerative musculoskeletal diseases, rheumatoid, and osteoarthritis | journal = Holist Nurs Pract | volume = 21 | issue = 4 | pages = 203–7 | year = 2007 | pmid = 17627199 | doi = 10.1097/01.HNP.0000280932.65581.72 }}</ref> [[Euonymus alatus]],<ref>{{cite journal | author = Zhang LF, Zhao JX | title = The recent research situation of Euonymus alatus | journal = Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica | volume = 30 | issue = 24 | pages = 1895–8 | date = December 2005 | pmid = 16494017 | last2 = Zhao }}</ref> and [[Tripterygium wilfordii|thunder god vine (''Tripterygium wilfordii'')]].<ref name="pmid21365177">{{cite journal | author = Bao J, Dai SM | title = A Chinese herb Tripterygium wilfordii Hook F in the treatment of rheumatoid arthritis: mechanism, efficacy, and safety | journal = Rheumatol. Int. | volume = 31 | issue = 9 | pages = 1123–9 | year = 2011 | pmid = 21365177 | doi = 10.1007/s00296-011-1841-y | last2 = Dai }}</ref> [[National Center for Complementary and Integrative Health|NCCIH]] has noted that, "In particular, the herb thunder god vine (Tripterygium wilfordii) can have serious side effects."<ref name=NCCIH/>
+The following are under investigation for treatments for RA, based on preliminary promising results (not recommended for clinical use yet): [[boswellic acid]],<ref>{{cite journal | author = Abdel-Tawab M, Werz O, Schubert-Zsilavecz M | title = Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data | journal = Clinical Pharmacokinetics | volume = 50 | issue = 6 | pages = 349–69 | date = June 2011 | pmid = 21553931 | doi = 10.2165/11586800-000000000-00000 | last2 = Werz | last3 = Schubert-Zsilavecz }}</ref> [[curcumin]],<ref>{{cite journal | author = White B, Judkins DZ | title = Clinical Inquiry. Does turmeric relieve inflammatory conditions? | journal = The Journal of Family Practice | volume = 60 | issue = 3 | pages = 155–6 | date = March 2011 | pmid = 21369559 | last2 = Judkins }}</ref> [[Harpagophytum|devil's claw]],<ref>{{cite journal | last1 = Wegener | first1 = T. | title = Therapy of degenerative diseases of the musculoskeletal system with South African devil's claw (Harpagophytum procumbens DC) | journal = Wiener Medizinische Wochenschrift (1946) | volume = 149 | issue = 8–10 | pages = 254–257 | year = 1999 | pmid = 10483693 }}</ref><ref name="pmid17627199">{{cite journal | author = Denner SS | title = A review of the efficacy and safety of devil's claw for pain associated with degenerative musculoskeletal diseases, rheumatoid, and osteoarthritis | journal = Holist Nurs Pract | volume = 21 | issue = 4 | pages = 203–7 | year = 2007 | pmid = 17627199 | doi = 10.1097/01.HNP.0000280932.65581.72 }}</ref> [[Euonymus alatus]],<ref>{{cite journal | author = Zhang LF, Zhao JX | title = The recent research situation of Euonymus alatus | journal = Zhongguo Zhong Yao Za Zhi = Zhongguo Zhongyao Zazhi = China Journal of Chinese Materia Medica | volume = 30 | issue = 24 | pages = 1895–8 | date = December 2005 | pmid = 16494017 | last2 = Zhao }}</ref> and [[Tripterygium wilfordii|thunder god vine (''Tripterygium wilfordii'')]].<ref name="pmid21365177">{{cite journal | author = Bao J, Dai SM | title = A Chinese herb Tripterygium wilfordii Hook F in the treatment of rheumatoid arthritis: mechanism, efficacy, and safety | journal = Rheumatol. Int. | volume = 31 | issue = 9 | pages = 1123–9 | year = 2011 | pmid = 21365177 | doi = 10.1007/s00296-011-1841-y | last2 = Dai }}</ref> [[National Center for Complementary and Integrative Health|NCCIH]] has noted that, "In particular, the herb thunder god vine (Tripterygium wilfordii) can have serious side effects."<ref name=NCCIH/>
 There is conflicting evidence on the role of [[erythropoiesis]]-stimulating agents for treatment of anemia in persons with rheumatoid arthritis.<ref>{{cite journal|title=Erythropoiesis-stimulating agents for anemia in rheumatoid arthritis|journal=Cochrane Database of Systematic Reviews |doi=10.1002/14651858.CD000332.pub3|year=2013|last1=Martí-Carvajal|first1=Arturo J|last2=Agreda-Pérez|first2=Luis H|last3=Solà|first3=Ivan|last4=Simancas-Racines|first4=Daniel|pmid=23450527|issue=2|page=CD000332}}</ref>
@@ Line 280: / Line 280: @@
 ===Vaccinations===
-People with RA have an increased risk of infections and mortality and recommended vaccinations can reduce these risks.<ref>{{cite journal|last1=Perry|first1=Lisa M.|last2=Winthrop|first2=Kevin L.|last3=Curtis|first3=Jeffrey R.|title=Vaccinations for Rheumatoid Arthritis|journal=Current Rheumatology Reports|date=13 June 2014|volume=16|issue=8|doi=10.1007/s11926-014-0431-x|url=https://link.springer.com/article/10.1007%2Fs11926-014-0431-x#|pmc=4080407|pmid=24925587}}</ref> The inactivated [[influenza vaccine]] should be received annually.<ref>{{cite journal|last1=Grohskopf|first1=LA|last2=Olsen|first2=SJ|last3=Sokolow|first3=LZ|last4=Bresee|first4=JS|last5=Cox|first5=NJ|last6=Broder|first6=KR|last7=Karron|first7=RA|last8=Walter|first8=EB|last9=Centers for Disease Control and|first9=Prevention|title=Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP) – United States, 2014–15 influenza season|journal=MMWR. Morbidity and Mortality Weekly Report|date=15 August 2014|volume=63|issue=32|pages=691–7|pmid=25121712}}</ref> The [[pneumococcal vaccine]] should be administered twice for people under the age 65 and once for those over 65.<ref>{{cite journal|last1=Black|first1=CL|last2=Yue|first2=X|last3=Ball|first3=SW|last4=Donahue|first4=SM|last5=Izrael|first5=D|last6=de Perio|first6=MA|last7=Laney|first7=AS|last8=Lindley|first8=MC|last9=Graitcer|first9=SB|last10=Lu|first10=PJ|last11=Williams|first11=WW|last12=Bridges|first12=CB|last13=DiSogra|first13=C|last14=Sokolowski|first14=J|last15=Walker|first15=DK|last16=Greby|first16=SM|title=Influenza vaccination coverage among health care personnel – United States, 2013–14 influenza season.|journal=MMWR. Morbidity and Mortality Weekly Report|date=19 September 2014|volume=63|issue=37|pages=805–11|pmid=25233281}}</ref> Lastly, the live-attenuated [[zoster vaccine]] should be administered once after the age 60, but is not recommended in people on a [[tumor necrosis factor alpha]] blocker.<ref>{{cite journal|last1=Hales|first1=CM|last2=Harpaz|first2=R|last3=Ortega-Sanchez|first3=I|last4=Bialek|first4=SR|last5=Centers for Disease Control and Prevention|first5=(CDC)|title=Update on recommendations for use of herpes zoster vaccine.|journal=MMWR. Morbidity and Mortality Weekly Report|date=22 August 2014|volume=63|issue=33|pages=729–31|pmid=25144544}}</ref>
+People with RA have an increased risk of infections and mortality and recommended vaccinations can reduce these risks.<ref>{{cite journal|last1=Perry|first1=Lisa M.|last2=Winthrop|first2=Kevin L.|last3=Curtis|first3=Jeffrey R.|title=Vaccinations for Rheumatoid Arthritis|journal=Current Rheumatology Reports|date=13 June 2014|volume=16|issue=8|pages=431|doi=10.1007/s11926-014-0431-x|pmc=4080407|pmid=24925587}}</ref> The inactivated [[influenza vaccine]] should be received annually.<ref>{{cite journal|last1=Grohskopf|first1=LA|last2=Olsen|first2=SJ|last3=Sokolow|first3=LZ|last4=Bresee|first4=JS|last5=Cox|first5=NJ|last6=Broder|first6=KR|last7=Karron|first7=RA|last8=Walter|first8=EB|last9=Centers for Disease Control and|first9=Prevention|title=Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP) – United States, 2014–15 influenza season|journal=MMWR. Morbidity and Mortality Weekly Report|date=15 August 2014|volume=63|issue=32|pages=691–7|pmid=25121712|pmc=4584910}}</ref> The [[pneumococcal vaccine]] should be administered twice for people under the age 65 and once for those over 65.<ref>{{cite journal|last1=Black|first1=CL|last2=Yue|first2=X|last3=Ball|first3=SW|last4=Donahue|first4=SM|last5=Izrael|first5=D|last6=de Perio|first6=MA|last7=Laney|first7=AS|last8=Lindley|first8=MC|last9=Graitcer|first9=SB|last10=Lu|first10=PJ|last11=Williams|first11=WW|last12=Bridges|first12=CB|last13=DiSogra|first13=C|last14=Sokolowski|first14=J|last15=Walker|first15=DK|last16=Greby|first16=SM|title=Influenza vaccination coverage among health care personnel – United States, 2013–14 influenza season|journal=MMWR. Morbidity and Mortality Weekly Report|date=19 September 2014|volume=63|issue=37|pages=805–11|pmid=25233281|pmc=5779456}}</ref> Lastly, the live-attenuated [[zoster vaccine]] should be administered once after the age 60, but is not recommended in people on a [[tumor necrosis factor alpha]] blocker.<ref>{{cite journal|last1=Hales|first1=CM|last2=Harpaz|first2=R|last3=Ortega-Sanchez|first3=I|last4=Bialek|first4=SR|last5=Centers for Disease Control and Prevention|first5=(CDC)|title=Update on recommendations for use of herpes zoster vaccine|journal=MMWR. Morbidity and Mortality Weekly Report|date=22 August 2014|volume=63|issue=33|pages=729–31|pmid=25144544|pmc=5779434}}</ref>
 ==Prognosis==
-[[Image:Rheumatoid arthritis world map - DALY - WHO2004.svg|thumb|upright=1.3|[[Disability-adjusted life year]] for RA per 100,000&nbsp;inhabitants in 2004.<ref>{{cite web |url=http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html |title=WHO Disease and injury country estimates |year=2009 |work=World Health Organization |accessdate=November 11, 2009 |deadurl=no |archiveurl=https://web.archive.org/web/20091111101009/http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html |archivedate=November 11, 2009 |df= }}</ref>
+[[Image:Rheumatoid arthritis world map - DALY - WHO2004.svg|thumb|upright=1.3|[[Disability-adjusted life year]] for RA per 100,000&nbsp;inhabitants in 2004.<ref>{{cite web |url=http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html |title=WHO Disease and injury country estimates |year=2009 |website=World Health Organization |accessdate=November 11, 2009 |deadurl=no |archiveurl=https://web.archive.org/web/20091111101009/http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html |archivedate=November 11, 2009 |df= }}</ref>
 {{colbegin}}
 {{legend|#b3b3b3|no data}}
@@ Line 316: / Line 316: @@
 ===Mortality===
-RA reduces lifespan on average from three to twelve years.<ref name="Wasserman"/> Young age at onset, long disease duration, the presence of other health problems, 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.<ref>Kitas, George (4 April 2006) [https://web.archive.org/web/20060924153339/http://www.rheumatoid.org.uk/article.php?article_id=112 Why is life span shortened by Rheumatoid Arthritis?] National Rheumatoid Arthritis Society</ref> 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,<ref>[https://web.archive.org/web/20050306030726/http://mayoclinic.org/news2005-rst/2654.html Rheumatoid Arthritis Patients Have Double the Risk of Heart Failure]. mayoclinic.org (3 February 2005).</ref> 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.<ref>{{cite web|url=http://www.hopkins-arthritis.org/news-archive/2002/cardiac.html |archiveurl=https://web.archive.org/web/20061009112820/http://www.hopkins-arthritis.org/news-archive/2002/cardiac.html |archivedate=October 9, 2006 |title=Cardiac disease in rheumatoid arthritis |publisher=Johns Hopkins University|year=2002}}</ref> It is possible that the use of new biologic drug therapies extend the lifespan of people with RA and reduce the risk and progression of atherosclerosis.<ref name="pmid20678592">{{cite journal | author = Atzeni F, Turiel M, Caporali R, Cavagna L, Tomasoni L, Sitia S, Sarzi-Puttini P | title = The effect of pharmacological therapy on the cardiovascular system of patients with systemic rheumatic diseases | journal = Autoimmun Rev | volume = 9 | issue = 12 | pages = 835–9 | year = 2010 | pmid = 20678592 | doi = 10.1016/j.autrev.2010.07.018 | last2 = Turiel | last3 = Caporali | last4 = Cavagna | last5 = Tomasoni | last6 = Sitia | last7 = Sarzi-Puttini }}</ref> This is based on cohort and registry studies, and still remains hypothetical. It is still uncertain whether biologics improve vascular function in RA or not. There was an increase in total cholesterol and HDLc levels and no improvement of the atherogenic index.<ref name="biologics cv effects/ cancer">{{cite journal|last1=Damjanov|first1=N|last2=Nurmohamed|first2=MT|last3=Szekanecz|first3=Z|title=Biologics, cardiovascular effects and cancer.|journal=BMC Medicine|date=Mar 18, 2014|volume=12|pages=48|pmid=24642038|doi=10.1186/1741-7015-12-48|pmc=3984692|issue=1}}</ref>
+RA reduces lifespan on average from three to twelve years.<ref name="Wasserman"/> Young age at onset, long disease duration, the presence of other health problems, 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.<ref>Kitas, George (4 April 2006) [https://web.archive.org/web/20060924153339/http://www.rheumatoid.org.uk/article.php?article_id=112 Why is life span shortened by Rheumatoid Arthritis?] National Rheumatoid Arthritis Society</ref> 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,<ref>[https://web.archive.org/web/20050306030726/http://mayoclinic.org/news2005-rst/2654.html Rheumatoid Arthritis Patients Have Double the Risk of Heart Failure]. mayoclinic.org (3 February 2005).</ref> 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.<ref>{{cite web|url=http://www.hopkins-arthritis.org/news-archive/2002/cardiac.html |archiveurl=https://web.archive.org/web/20061009112820/http://www.hopkins-arthritis.org/news-archive/2002/cardiac.html |archivedate=October 9, 2006 |title=Cardiac disease in rheumatoid arthritis |publisher=Johns Hopkins University|year=2002}}</ref> It is possible that the use of new biologic drug therapies extend the lifespan of people with RA and reduce the risk and progression of atherosclerosis.<ref name="pmid20678592">{{cite journal | author = Atzeni F, Turiel M, Caporali R, Cavagna L, Tomasoni L, Sitia S, Sarzi-Puttini P | title = The effect of pharmacological therapy on the cardiovascular system of patients with systemic rheumatic diseases | journal = Autoimmun Rev | volume = 9 | issue = 12 | pages = 835–9 | year = 2010 | pmid = 20678592 | doi = 10.1016/j.autrev.2010.07.018 | last2 = Turiel | last3 = Caporali | last4 = Cavagna | last5 = Tomasoni | last6 = Sitia | last7 = Sarzi-Puttini }}</ref> This is based on cohort and registry studies, and still remains hypothetical. It is still uncertain whether biologics improve vascular function in RA or not. There was an increase in total cholesterol and HDLc levels and no improvement of the atherogenic index.<ref name="biologics cv effects/ cancer">{{cite journal|last1=Damjanov|first1=N|last2=Nurmohamed|first2=MT|last3=Szekanecz|first3=Z|title=Biologics, cardiovascular effects and cancer|journal=BMC Medicine|date=Mar 18, 2014|volume=12|pages=48|pmid=24642038|doi=10.1186/1741-7015-12-48|pmc=3984692|issue=1}}</ref>
 ==Epidemiology==
@@ Line 328: / Line 328: @@
 ==History==
-The first known traces of arthritis date back at least as far as 4500&nbsp;BC. A text dated 123&nbsp;AD first describes symptoms very similar to RA.{{citation needed|date=July 2015}} It was noted in skeletal remains of Native Americans found in Tennessee.<ref>{{cite web|url=http://mcclungmuseum.utk.edu/research/renotes/rn-05txt.htm|archiveurl=https://web.archive.org/web/20120202085715/http://mcclungmuseum.utk.edu/research/renotes/rn-05txt.htm|archivedate=February 2, 2012|author=Rothschild, Bruce M. |title=Tennessee Origins of Rheumatoid Arthritis |publisher=Mcclungmuseum.utk.edu |accessdate=March 3, 2011}}</ref> In Europe, the disease is vanishingly rare before the 17th century.<ref>{{cite web|url=http://www.arc.org.uk/newsviews/arctdy/104/bones.htm |archiveurl=https://web.archive.org/web/20030219095659/http://www.arc.org.uk/newsviews/arctdy/104/bones.htm |archivedate=February 19, 2003 |title=Bones of contention|work= Arthritis Research UK |date=April 1999|accessdate=February 5, 2013}}</ref> The first recognized description of RA in modern medicine was in 1800 by the French physician [[Augustin Jacob Landré-Beauvais|Dr Augustin Jacob Landré-Beauvais]] (1772–1840) who was based in the famed [[Pitié-Salpêtrière Hospital|Salpêtrière Hospital]] in Paris.<ref name=Landre1800/> The name "rheumatoid arthritis" itself was coined in 1859 by British rheumatologist Dr [[Alfred Baring Garrod]].<ref>{{cite book |author=Garrod AB | title=The Nature and Treatment of Gout and Rheumatic Gout | year=1859 | publisher=Walton and Maberly | location=London}}</ref>
+The first known traces of arthritis date back at least as far as 4500&nbsp;BC. A text dated 123&nbsp;AD first describes symptoms very similar to RA.{{citation needed|date=July 2015}} It was noted in skeletal remains of Native Americans found in Tennessee.<ref>{{cite web|url=http://mcclungmuseum.utk.edu/research/renotes/rn-05txt.htm|archiveurl=https://web.archive.org/web/20120202085715/http://mcclungmuseum.utk.edu/research/renotes/rn-05txt.htm|archivedate=February 2, 2012|author=Rothschild, Bruce M. |title=Tennessee Origins of Rheumatoid Arthritis |publisher=Mcclungmuseum.utk.edu |accessdate=March 3, 2011}}</ref> In Europe, the disease is vanishingly rare before the 17th century.<ref>{{cite web|url=http://www.arc.org.uk/newsviews/arctdy/104/bones.htm |archiveurl=https://web.archive.org/web/20030219095659/http://www.arc.org.uk/newsviews/arctdy/104/bones.htm |archivedate=February 19, 2003 |title=Bones of contention|website= Arthritis Research UK |date=April 1999|accessdate=February 5, 2013}}</ref> The first recognized description of RA in modern medicine was in 1800 by the French physician [[Augustin Jacob Landré-Beauvais|Dr Augustin Jacob Landré-Beauvais]] (1772–1840) who was based in the famed [[Pitié-Salpêtrière Hospital|Salpêtrière Hospital]] in Paris.<ref name=Landre1800/> The name "rheumatoid arthritis" itself was coined in 1859 by British rheumatologist Dr [[Alfred Baring Garrod]].<ref>{{cite book |author=Garrod AB | title=The Nature and Treatment of Gout and Rheumatic Gout | year=1859 | publisher=Walton and Maberly | location=London}}</ref>
 An anomaly has been noticed from the 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.<ref name="pmid14528501">{{cite journal |author=Rothschild BM, Rothschild C, Helbling M |title=Unified theory of the origins of erosive arthritis: conditioning as a protective/directing mechanism? |journal=[[J. Rheumatol.]] |volume=30 |issue=10 |pages=2095–102 |year=2003 |pmid=14528501|last2=Rothschild |last3=Helbling }}</ref>

Classification	D ICD-10: M05-M06, M45 ICD-9-CM: 714 OMIM: 180300 MeSH: D001172 DiseasesDB: 11506
External resources	MedlinePlus: 000431 eMedicine: article/331715 article/1266195 article/305417 article/401271 article/335186 article/808419 Patient UK: Rheumatoid arthritis