Rheumatoid arthritis

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Rheumatoid arthritis
Classification and external resources
Rheumatoid Arthritis.JPG
A hand affected by rheumatoid arthritis
ICD-10 M05-M06
ICD-9 714
OMIM 180300
DiseasesDB 11506
MedlinePlus 000431
eMedicine article/331715 article/1266195 article/305417 article/401271 article/335186 article/808419
MeSH D001172

Rheumatoid arthritis (RA) is an autoimmune disease that results in a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks flexible (synovial) joints. It can be a disabling and painful condition, which can lead to substantial loss of functioning and mobility if not adequately treated.

The process involves an inflammatory response of the capsule around the joints (synovium) secondary to swelling (turgescence) of synovial cells, excess synovial fluid, and the development of fibrous tissue (pannus) in the synovium. The pathology of the disease process often leads to the destruction of articular cartilage and ankylosis (fusion) of the joints. RA can also produce diffuse inflammation in the lungs, the membrane around the heart (pericardium), the membranes of the lung (pleura), and white of the eye (sclera), and also nodular lesions, most common in subcutaneous tissue. Although the cause of RA is unknown, autoimmunity plays a big part, and RA is a systemic autoimmune disease. It is a clinical diagnosis made on the basis of symptoms, physical exam, radiographs (X-rays) and labs.[1]

Treatments are pharmacological and non-pharmacological. Non-pharmacological treatment includes physical therapy, orthoses, occupational therapy and nutritional therapy but these do not stop the progression of joint destruction. Analgesics (painkillers) and anti-inflammatory drugs, including steroids, suppress symptoms, but do not stop the progression of joint destruction either. Disease-modifying antirheumatic drugs (DMARDs) slow or halt the progress of the disease. The newer biologics are DMARDs.[1] The evidence for complementary and alternative medicine (CAM) treatments for RA related pain is weak,[2] with the lack of high quality evidence leading to the conclusions that their use is currently not supported by the evidence.[3] Patients should inform their health care provider of any CAM treatments and continue taking traditional treatments.[4]

About 0.6% of the United States adult population has RA, women two to three times as often as men.[5] Onset is most frequent during middle age, but people of any age can be affected.[6]

The name is based on the term "rheumatic fever", an illness which includes joint pain and is derived from the Greek word ῥεύμα-rheuma (nom.), ῥεύματος-rheumatos (gen.) ("flow, current"). The suffix -oid ("resembling") gives the translation as joint inflammation that resembles rheumatic fever. The first recognized description of RA was made in 1800 by Dr. Augustin Jacob Landré-Beauvais (1772–1840) of Paris.[7]

Signs and symptoms[edit]

RA primarily affects joints, however it also affects other organs in 15–25% of individuals.[8] It can be difficult to determine whether disease manifestations are directly caused by the rheumatoid process itself, or from side effects of the medications used to treat it – for example, lung fibrosis from methotrexate or osteoporosis from corticosteroids.

Joints[edit]

A diagram showing how rheumatoid arthritis affects a joint

Arthritis of joints involves inflammation of the synovial membrane. Joints become swollen, tender and warm, and stiffness limits their movement. With time, multiple joints are affected (it is a polyarthritis). Most commonly involved are the small joints of the hands, feet and cervical spine, but larger joints like the shoulder and knee can also be involved.[9]:1089 Synovitis can lead to tethering of tissue with loss of movement and erosion of the joint surface causing deformity and loss of function.[1]

RA typically manifests with signs of inflammation, with the affected joints being swollen, warm, painful and stiff, particularly early in the morning on waking or following prolonged inactivity. Increased stiffness early in the morning is often a prominent feature of the disease and typically lasts for more than an hour. Gentle movements may relieve symptoms in early stages of the disease. These signs help distinguish rheumatoid from non-inflammatory problems of the joints, often referred to as osteoarthritis or "wear-and-tear" arthritis. In arthritis of non-inflammatory causes, signs of inflammation and early morning stiffness are less prominent with stiffness typically less than one hour, and movements induce pain caused by mechanical arthritis.[10] The pain associated with RA is induced at the site of inflammation and classified as nociceptive as opposed to neuropathic.[11] The joints are often affected in a fairly symmetrical fashion, although this is not specific, and the initial presentation may be asymmetrical.[9]:1089

As the pathology progresses the inflammatory activity leads to tendon tethering and erosion and destruction of the joint surface, which impairs range of movement and leads to deformity. The fingers may suffer from almost any deformity depending on which joints are most involved. Specific deformities, which also occur in osteoarthritis, include ulnar deviation, boutonniere deformity, swan neck deformity and "Z-thumb." "Z-thumb" or "Z-deformity" consists of hyperextension of the interphalangeal joint, fixed flexion and subluxation of the metacarpophalangeal joint and gives a "Z" appearance to the thumb.[9]:1089 The hammer toe deformity may be seen. In the worst case, joints are known as arthritis mutilans due to the mutilating nature of the deformities.[citation needed]

Skin[edit]

The rheumatoid nodule, which is sometimes cutaneous, is the feature most characteristic of RA. It is a type of inflammatory reaction known to pathologists as a "necrotizing granuloma". The initial pathologic process in nodule formation is unknown but may be essentially the same as the synovitis, since similar structural features occur in both. The nodule has a central area of fibrinoid necrosis that may be fissured and which corresponds to the fibrin-rich necrotic material found in and around an affected synovial space. Surrounding the necrosis is a layer of palisading macrophages and fibroblasts, corresponding to the intimal layer in synovium and a cuff of connective tissue containing clusters of lymphocytes and plasma cells, corresponding to the subintimal zone in synovitis. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences, such as the olecranon, the calcaneal tuberosity, the metacarpophalangeal joint, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF (rheumatoid factor) titer and severe erosive arthritis. Rarely, these can occur in internal organs or at diverse sites on the body.

Several forms of vasculitis occur in RA. A benign form occurs as microinfarcts around the nailfolds. More severe forms include livedo reticularis, which is a network (reticulum) of erythematous to purplish discoloration of the skin caused by the presence of an obliterative cutaneous capillaropathy.

Other, rather rare, skin associated symptoms include pyoderma gangrenosum, Sweet's syndrome, drug reactions, erythema nodosum, lobe panniculitis, atrophy of finger skin, palmar erythema, diffuse thinning (rice paper skin), and skin fragility (often worsened by corticosteroid use).

Lungs[edit]

Fibrosis of the lungs is a recognized response to rheumatoid disease. It is also a rare but well recognized consequence of therapy (for example with methotrexate and leflunomide). Caplan's syndrome describes lung nodules in individuals with RA and additional exposure to coal dust. Pleural effusions are also associated with RA. Another complication of RA is Rheumatoid Lung Disease. It is estimated that about one quarter of Americans with RA develop Rheumatoid Lung Disease.[12]

Kidneys[edit]

Renal amyloidosis can occur as a consequence of chronic inflammation.[13] RA may affect the kidney glomerulus directly through a vasculopathy or a mesangial infiltrate but this is less well documented (though this is not surprising, considering immune complex-mediated hypersensitivities are known for pathogenic deposition of immune complexes in organs where blood is filtered at high pressure to form other fluids, such as urine and synovial fluid[14]). Treatment with Penicillamine and gold salts are recognized causes of membranous nephropathy.

Heart and blood vessels[edit]

People with RA are more prone to atherosclerosis, and risk of myocardial infarction (heart attack) and stroke is markedly increased.[15][16] Other possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis.[17] Many people with RA do not experience the same chest pain that others feel when they have angina or myocardial infarction. To reduce cardiovascular risk, it is crucial to maintain optimal control of the inflammation caused by RA (which may be involved in causing the cardiovascular risk), and to use exercise and medications appropriately to reduce other cardiovascular risk factors such as blood lipids and blood pressure. Doctors who treat RA patients should be sensitive to cardiovascular risk when prescribing anti-inflammatory medications, and may want to consider prescribing routine use of low doses of aspirin if the gastrointestinal effects are tolerable.[17]

Other[edit]

Ocular
The eye is directly affected in the form of episcleritis which when severe can very rarely progress to perforating scleromalacia. Rather more common is the indirect effect of keratoconjunctivitis sicca, which is a dryness of eyes and mouth caused by lymphocyte infiltration of lacrimal and salivary glands. When severe, dryness of the cornea can lead to keratitis and loss of vision. Preventive treatment of severe dryness with measures such as nasolacrimal duct blockage is important.
Hepatic
Cytokine production in joints and/or hepatic (liver) Kupffer cells leads to increased activity of hepatocytes with increased production of acute-phase proteins, such as C-reactive protein, and increased release of enzymes such as alkaline phosphatase into the blood. In Felty's syndrome, Kupffer cell activation is so marked that the resulting increase in hepatocyte activity is associated with nodular hyperplasia of the liver, which may be palpably enlarged. Although Kupffer cells are within the hepatic parenchyma, they are separate from hepatocytes. As a result there is little or no microscopic evidence of hepatitis (immune-mediated destruction of hepatocytes). Hepatic involvement in RA is essentially asymptomatic.
Hematological
Anemia is by far the most common abnormality of the blood cells which can be caused by a variety of mechanisms. The chronic inflammation caused by RA leads to raised hepcidin levels, leading to anemia of chronic disease where iron is poorly absorbed and also sequestered into macrophages. RA may also cause a warm autoimmune hemolytic anemia.[18] The red cells are of normal size and colour (normocytic and normochromic). A low white blood cell count (neutropenia) usually only occurs in patients with Felty's syndrome with an enlarged liver and spleen. The mechanism of neutropenia is complex. An increased platelet count (thrombocytosis) occurs when inflammation is uncontrolled.
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. Atlanto-axial subluxation can occur, owing to erosion of the odontoid process and/or transverse ligaments in the cervical spine's connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping over one another and compressing the spinal cord. Clumsiness is initially experienced, but without due care this can progress to quadriplegia.
Constitutional symptoms
Constitutional symptoms including fatigue, low grade fever, malaise, morning stiffness, loss of appetite and loss of weight are common systemic manifestations seen in patients with active RA.
Osteoporosis
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.
Lymphoma
The incidence of lymphoma is increased in RA, although it is still uncommon.[19][20]

Causes[edit]

RA is a form of autoimmunity, the causes of which are still not completely known. It is a systemic (whole body) disorder principally affecting synovial tissues. There is no evidence that physical and emotional effects or stress could be a trigger for the disease. The many negative findings suggest that either the trigger varies, or that it might in fact be a chance event inherent with the immune response.[21]

Half of the risk for RA is believed to be genetic.[22] It is strongly associated with the inherited tissue type major histocompatibility complex (MHC) antigen HLA-DR4 (most specifically DR0401 and 0404), and the genes PTPN22 and PADI4—hence family history is an important risk factor.[23][24] Inheriting the PTPN22 gene has been shown to double a person's susceptibility to RA. PADI4 has been identified as a major risk factor in people of Asian descent, but not in those of European descent.[25] First-degree relatives prevalence rate is 2–3% and disease genetic concordance in monozygotic twins is approximately 15–20%.[26][27]

Smoking is the most significant non-genetic risk[22] with RA being up to three times more common in smokers than non-smokers, particularly in men, heavy smokers, and those who are rheumatoid factor positive.[28] Modest alcohol consumption may be protective.[29]

Epidemiological studies have confirmed a potential association between RA and two herpesvirus infections:Epstein-Barr virus (EBV) and Human Herpes Virus 6 (HHV-6).[30] Individuals with RA are more likely to exhibit an abnormal immune response to EBV and have high levels of anti-EBV antibodies.[31]

Vitamin D deficiency is common in those with RA and may be causally associated.[32] Some trials have found a decreased risk for RA with vitamin D supplementation while others have not.[32]

Vitamin D deficiency is more common in patients with rheumatoid arthritis than in the general population.[33] However, whether vitamin D deficiency is a cause or a consequence of the disease remains unclear.[34] 1α,25-dihydroxyvitamin D3 (1,25D), an active metabolite of vitamin D, effects bone metabolism indirectly through control of calcium and phosphate homeostasis. Interaction between 1,25D and the vitamin D receptor (VDR) effects the production of RANKL and delays osteoclastogenesis.[35]

Pathophysiology[edit]

The key pieces of evidence relating to pathogenesis are the following:

  1. A genetic link with HLA-DR4 and related allotypes of MHC Class II and the T cell-associated protein PTPN22.
  2. An undeniable link to the pathogenesis of vascular disease of many types, including the possibility of a strong causal connection to rheumatoid vasculitis, a typical feature of this condition.[36]
  3. A remarkable deceleration of disease progression in many cases by blockade of the cytokine TNF (alpha).
  4. A similar dramatic response in many cases to depletion of B lymphocytes, but no comparable response to depletion of T lymphocytes.
  5. A more or less random pattern of whether and when predisposed individuals are affected.
  6. The presence of autoantibodies to IgGFc, known as rheumatoid factors (RF), and antibodies to citrullinated peptides (ACPA).
  7. Initial site of disease is synovial membrane
  8. Women (30 to 50 years) are more commonly affected

These data suggest that the disease involves abnormal B cell–T cell interaction, with presentation of antigens by B cells to T cells via HLA-DR eliciting T cell help and consequent production of RF and ACPA. Inflammation is then driven either by B cell or T cell products stimulating release of TNF and other cytokines. The process may be facilitated by an effect of smoking on citrullination but the stochastic (random) epidemiology suggests that the rate limiting step in genesis of disease in predisposed individuals may be an inherent stochastic process within the immune response such as immunoglobulin or T cell receptor gene recombination and mutation. (See entry under autoimmunity for general mechanisms.)

If TNF release is stimulated by B cell products in the form of RF or ACPA -containing immune complexes, through activation of immunoglobulin Fc receptors, then RA can be seen as a form of Type III hypersensitivity.[37][38] If TNF release is stimulated by T cell products such as interleukin-17 it might be considered closer to type IV hypersensitivity although this terminology may be getting somewhat dated and unhelpful.[39] The debate on the relative roles of immune complexes and T cell products in inflammation in RA has continued for 30 years. There is little doubt that both B and T cells are essential to the disease. However, there is good evidence for neither cell being necessary at the site of inflammation. This tends to favour immune complexes (based on antibody synthesised elsewhere) as the initiators, even if not the sole perpetuators of inflammation. Moreover, work by Thurlings and others in Paul-Peter Tak's group and also by Arthur Kavanagh's group suggest that if any immune cells are relevant locally they are the plasma cells, which derive from B cells and produce in bulk the antibodies selected at the B cell stage.[citation needed]

Although TNF appears to be the dominant, other cytokines (chemical mediators) are likely to be involved in inflammation in RA. Blockade of TNF does not benefit all patients or all tissues (lung disease and nodules may get worse). Blockade of IL-1, IL-15 and IL-6 also have beneficial effects and IL-17 may be important. Constitutional symptoms such as fever, malaise, loss of appetite and weight loss are also caused by cytokines released into the blood stream.

As with most autoimmune diseases, it is important to distinguish between the cause(s) that trigger the process, and those that may permit it to persist and progress.

Phases[edit]

  • Initiation phase – It is due to non – specific inflammation
  • Amplification phase – Due to T cell activation
  • Chronic inflammatory phase – Due to cytokines IL–1, TNF-alpha and IL–6

Abnormal immune response[edit]

The factors that allow an abnormal immune response, once initiated, to become permanent and chronic, are becoming more clearly understood. The genetic association with HLA-DR4, as well as the newly discovered associations with the gene PTPN22 and with two additional genes,[40] all implicate altered thresholds in regulation of the adaptive immune response. It has also become clear from recent studies that these genetic factors may interact with the most clearly defined environmental risk factor for RA, namely cigarette smoking[28][41] Other environmental factors also appear to modulate the risk of acquiring RA, and hormonal factors in the individual may explain some features of the disease, such as the higher occurrence in women, the not-infrequent onset after child-birth, and the (slight) modulation of disease risk by hormonal medications. Exactly how altered regulatory thresholds allow the triggering of a specific autoimmune response remains uncertain. However, one possibility is that negative feedback mechanisms that normally maintain tolerance of self are overtaken by aberrant positive feedback mechanisms for certain antigens such as IgG Fc (bound by RF) and citrullinated fibrinogen (bound by ACPA) (see entry on autoimmunity).

Once the abnormal immune response has become established (which may take several years before any symptoms occur), plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes in large quantities. These are not deposited in the way that they are in systemic lupus. Rather, they activate macrophages through Fc receptor and complement binding, which seems to play an important role in the intense inflammatory response present in RA.[42] This contributes to inflammation of the synovium, in terms of edema, vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). Synovial macrophages and dendritic cells further function as antigen presenting cells by expressing MHC class II molecules, leading to an established local immune reaction in the tissue. The disease progresses in concert with formation of granulation tissue at the edges of the synovial lining (pannus) with extensive angiogenesis and production of enzymes that cause tissue damage. Modern pharmacological treatments of RA target these mediators. Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues.

Diagnosis[edit]

Imaging[edit]

X-ray of the hand in rheumatoid arthritis.
Appearance of synovial fluid from a joint with inflammatory arthritis.
Signs of destruction and inflammation on ultrasonography and magnetic resonance imaging in the second metacarpophalangeal joint in established RA. Thin arrows indicate an erosive change; thick arrows indicate synovitis. Ultrasonography (left side of image) in the (a) longitudinal and (b) the transverse planes shows both signs of destruction and inflammation. Axial T1-weighted magnetic resonance images were obtained (c) before and (d) after contrast administration, also demonstrating synovitis. Additionally, a coronal T1-weighted magnetic resonance image (e) before contrast administration visualizes the same bone erosion as shown in panels c and d.

X-rays of the hands and feet are generally performed in people with a polyarthritis. In RA, there may be no changes in the early stages of the disease, or the x-ray may demonstrate juxta-articular osteopenia, soft tissue swelling and loss of joint space. As the disease advances, there may be bony erosions and subluxation. X-rays of other joints may be taken if symptoms of pain or swelling occur in those joints.

Other medical imaging techniques such as magnetic resonance imaging (MRI) and ultrasound are also used in RA.[citation needed]

There have been technical advances in ultrasonography. High-frequency transducers (10 MHz or higher) have improved the spatial resolution of ultrasound images; these images can depict 20% more erosions than conventional radiography. Also, color Doppler and power Doppler ultrasound, which show vascular signals of active synovitis depending on the degree of inflammation, are useful in assessing synovial inflammation. This is important, since in the early stages of RA, the synovium is primarily affected, and synovitis seems to be the best predictive marker of future joint damage.[43]

Blood tests[edit]

When RA is clinically suspected, immunological studies are required, such as testing for the presence of rheumatoid factor (RF, a non-specific antibody).[44] A negative RF does not rule out RA; rather, the arthritis is called seronegative. This is the case in about 15% of patients.[45][46] During the first year of illness, rheumatoid factor is more likely to be negative with some individuals converting to seropositive status over time. RF is also seen in other illnesses, for example Sjögren's syndrome, hepatitis C, systemic lupus erythematosus, chronic infections and in approximately 10% of the healthy population, therefore the test is not very specific.[citation needed]

Because of this low specificity, new serological tests have been developed, which test for the presence of the anti-citrullinated protein antibodies (ACPAs) or anti-CCP. Like RF, these tests are positive in only a proportion (67%) of all RA cases, but are rarely positive if RA is not present, giving it a specificity of around 95%.[45] As with RF, there is evidence for ACPAs being present in many cases even before onset of clinical disease.[citation needed]

The most common tests for ACPAs are the anti-CCP (cyclic citrullinated peptide) test and the Anti-MCV assay (antibodies against mutated citrullinated Vimentin). Recently a serological point-of-care test (POCT) for the early detection of RA has been developed. This assay combines the detection of rheumatoid factor and anti-MCV for diagnosis of RA and shows a sensitivity of 72% and specificity of 99.7%.[47][48]

Also, several other blood tests are usually done to allow for other causes of arthritis, such as lupus erythematosus. The erythrocyte sedimentation rate (ESR), C-reactive protein, full blood count, renal function, liver enzymes and other immunological tests (e.g., antinuclear antibody/ANA) are all performed at this stage. Elevated ferritin levels can reveal hemochromatosis, a mimic of RA, or be a sign of Still's disease, a seronegative, usually juvenile, variant of rheumatoid arthritis.[citation needed]

Criteria[edit]

In 2010 the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria were introduced.[49][50]

These new classification criteria overruled the "old" ACR criteria of 1987 and are adapted for early RA diagnosis. The "new" classification criteria, jointly published by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) establish a point value between 0 and 10. Every patient with a point total of 6 or higher is unequivocally classified as an RA patient, provided he has synovitis in at least one joint and given that there is no other diagnosis better explaining the synovitis. Four areas are covered in the diagnosis:[49]

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

The criteria are not intended for the diagnosis for routine clinical care; they were primarily intended to categorize research (classification criteria). In clinical practice, the following criteria apply:[citation needed]

Differential diagnoses[edit]

Several other medical conditions can resemble RA, and usually need to be distinguished from it at the time of diagnosis:[52][53]

  • Crystal induced arthritis (gout, and pseudogout) – usually involves particular joints (knee, MTP1, heels) and can be distinguished with aspiration of joint fluid if in doubt. Redness, asymmetric distribution of affected joints, pain occurs at night and the starting pain is less than an hour with gout.
  • Osteoarthritis – distinguished with X-rays of the affected joints and blood tests, age (mostly older patients), starting pain less than an hour, a-symmetric distribution of affected joints and pain worsens when using joint for longer periods.
  • Systemic lupus erythematosus (SLE) – distinguished by specific clinical symptoms and blood tests (antibodies against double-stranded DNA)
  • One of the several types of psoriatic arthritis resembles RA – nail changes and skin symptoms distinguish between them
  • Lyme disease causes erosive arthritis and may closely resemble RA – it may be distinguished by blood test in endemic areas
  • Reactive arthritis (previously Reiter's disease) – asymmetrically involves heel, sacroiliac joints, and large joints of the leg. It is usually associated with urethritis, conjunctivitis, iritis, painless buccal ulcers, and keratoderma blennorrhagica.
  • Ankylosing spondylitis – this involves the spine, although a RA-like symmetrical small-joint polyarthritis may occur in the context of this condition.
  • Hepatitis C – RA-like symmetrical small-joint polyarthritis may occur in the context of this condition. Hepatitis C may also induce Rheumatoid Factor auto-antibodies

Rarer causes that usually behave differently but may cause joint pains:[52]

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

Monitoring progression[edit]

The progression of RA can be followed using scores such as Disease Activity Score of 28 joints (DAS28). It is widely used as an indicator of RA disease activity and response to treatment, but is not always a reliable indicator of treatment effect.[54] The joints included in DAS28 are (bilaterally): proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), elbows (2), shoulders (2) and knees (2). When looking at these joints, both the number of joints with tenderness upon touching (TEN28) and swelling (SW28) are counted. In addition, the erythrocyte sedimentation rate (ESR) is measured. Also, the patient makes a subjective assessment (SA) of disease activity during the preceding 7 days on a scale between 0 and 100, where 0 is "no activity" and 100 is "highest activity possible". With these parameters, DAS28 is calculated as:[55] 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 patient can be classified as follows:[55]

Current
DAS28
DAS28 decrease from initial value
> 1.2 > 0.6 but 1.2 ≤ 0.6
3.2 Inactive Good improvement Moderate improvement No improvement
> 3.2 but ≤ 5.1 Moderate Moderate improvement Moderate improvement No improvement
> 5.1 Very active Moderate improvement No improvement No improvement

Management[edit]

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.[56]

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.[57] This can often be achieved using two main classes of medications: analgesics such as NSAIDs, and disease-modifying antirheumatic drugs (DMARDs).[58] RA should generally be treated with at least one specific anti-rheumatic medication.[56] 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.[59] Analgesics, other than NSAIDs, offer lesser, but some benefit with respect to pain.[22] whilst not causing the same level of gastrointestinal irritation.

Lifestyle[edit]

Regular exercise is recommended as both safe and useful to maintain muscles strength and overall physical function.[60] It is uncertain if specific dietary measures have an effect.[61]

Disease modifying agents[edit]

Disease-modifying antirheumatic drugs (DMARD) are the primary treatment for RA.[22] 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.[22] They should be started very early in the disease as when they result in disease remission in approximately half of people and improved outcomes overall.[62]

The most commonly used agent is methotrexate with other frequently used agents including sulfasalazine and leflunomide. Sodium aurothiomalate (Gold) and cyclosporin are less commonly used due to more common adverse effects. Agents may be used in combinations.[22]

Methotrexate is the most important and useful DMARD and is usually the first treatment.[57][58][63] Adverse effects should be monitored regularly with toxicity including gastrointestinal, hematologic, pulmonary, and hepatic.[63] Side effects such as nausea, vomiting or abdominal pain can be reduced by taking folic acid.[64] The most common undesirable affect is that it increases liver enzymes in almost 15% of people.[63] It is thus recommended that those who consistently demonstrate abnormal levels of liver enzymes or have a history of liver disease or alcohol use undergo liver biopsies.[65] Methotrexate is also considered a teratogenic and as such, it is recommended women of childbearing age should use contraceptives to avoid pregnancy and to discontinue its use if pregnancy is planned.[57][63]

Biological agents should generally only be used if methotrexate and other conventional agents are not effective after a trial of three months.[66] These agents include: tumor necrosis factor alpha (TNFα) blockers[22] such as infliximab; interleukin 1 blockers such as anakinra, monoclonal antibodies against B cells such as rituximab,[67] T cell costimulation blocker such as abatacept among others. They are often used in combination with either methotrexate or leflunomide.[22]

TNF blockers and methotrexate appear to have similar effectiveness when used alone and better results are obtained when used together. TNF blockers appear to have equivalent effectiveness with etanercept appearing to be the safest.[68] Abatacept appears effective for RA with 20% more people improving with treatment than without.[69] There however is a lack of evidence to distinguish between the biologics available for RA.[70] Issues with the biologics include their high cost and association with infections including tuberculosis.[22]

Anti-inflammatory agents[edit]

NSAIDs reduce both pain and stiffness in those with RA.[22] Generally they appear to have no effect on people's long term disease course and thus are no longer first line agents.[22][71] NSAIDs should be used with caution in those with gastrointestinal, cardiovascular, or kidney problems.[72][73][74]

COX-2 inhibitors, such as celecoxib, and NSAIDs are equally effective.[75] They have a similar gastrointestinal risk as an NSAIDs plus a proton pump inhibitor.[76] In the elderly there is less gastrointestinal intolerance to celecoxib than to NSAIDs alone.[77] There however is an increased risk of myocardial infarction with COX-2 inhibitors.[75] Anti-ulcer medications are not recommended routinely but only in those high risk of gastrointestinal problems.[78]

Glucocorticoids can be used in the short term for flare-ups, while waiting for slow-onset drugs to take effect.[22] Injection of glucocorticoids into individual joints is also effective.[22] While long-term use reduces joint damage it also results in osteoporosis and susceptibility to infections, and thus is not recommended.[22]

Surgery[edit]

In early phases of the disease, an arthroscopic or open synovectomy may be performed. It consists of the removal of the inflamed synovia and prevents a quick destruction of the affected joints. Severely affected joints may require joint replacement surgery, such as knee replacement.[22] Postoperatively, physiotherapy is always necessary.

Alternative medicine[edit]

There has been an increasing interest in the use of complementary and alternative medicine interventions for the treatment of pain in rheumatoid arthritis. While there have been multiple studies showing beneficial effects in RA on a wide variety of CAM modalities, these studies are often affected by publication bias and are generally not high quality evidence such as randomized controlled trials (RCTs), making definitive conclusions difficult to reach.[2]

The National Center for Complementary and Alternative Medicine has concluded, "In general, there is not enough scientific evidence to prove that any complementary health approaches are beneficial for RA, and there are safety concerns about some of them. Some mind and body practices and dietary supplements may help people with RA manage their symptoms and therefore may be beneficial additions to conventional RA treatments, but there is not enough evidence to draw conclusions."[4] A systematic review of CAM modalities (excluding fish oil) found "The major limitation in reviewing the evidence for CAMs is the paucity of RCTs in the area. The available evidence does not support their current use in the management of RA."[3] One review suggests that of the various alternative medicine treatments evaluated, only acupuncture, bee venom acupuncture, herbal remedies, dietary omega-3 fatty acids, and pulsed electromagnetic field therapy have been studied with RCTs and show promise in treating the pain of RA, though no definitive conclusions could be reached.[2]

Dietary supplements[edit]

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.[79] 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.[79] Some evidence supports omega-3 fatty acids and gamma-linolenic acid in RA.[80] The benefit from omega-3 appears modest but consistent,[81] though the current evidence is not strong enough to determine that supplementation with omega-3 polyunsaturated fatty acids (found in fish oil) is an effective treatment for RA.[82] Gamma-linolenic acid, which may reduce pain, tender joint count and stiffness, is generally safe.[83]

The following show promise as treatments for RA, based on preliminary studies: boswellic acid,[84] curcumin,[85] Devil's claw,[86][87] Euonymus alatus,[88] and Thunder god vine (Tripterygium wilfordii).[89]

Herbal supplements can often have significant side effects, and can interact with prescription medications being taken at the same time. These risks are often exacerbated by the false general belief by patients that herbal supplements are always safe and the hesitancy by patients in reporting the use of herbal supplements to physicians.[2] NCCAM has noted that, "In particular, the herb thunder god vine (Tripterygium wilfordii) can have serious side effects."[4]

Manual therapies[edit]

The evidence for acupuncture is inconclusive[90] with it appearing to be equivalent to sham acupuncture.[91]

Prevention[edit]

There is no known prevention for the contraction. Reduction of risk factors and aggressive treatment after diagnosis are recommended actions.[92]

Prognosis[edit]

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.

Prognostic factors[edit]

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[edit]

RA is known to reduce the lifespan of patients by anywhere from three to 12 years.[93] 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,[94] 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.[95] 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.[96] 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 increase in total cholesterol and HDLc levels and no improvement of the atherogenic index.[97]

Epidemiology[edit]

Disability-adjusted life year for RA per 100,000 inhabitants in 2004.[98]
  no data
  <40
  40–50
  50–60
  60–70
  70–80
  80–90
  90–100
  100–110
  110–120
  120–130
  130–140
  >140

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.[22] In 2010 it resulted in about 49,000 deaths globally.[99]

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.[citation needed]

Some Native American groups have higher prevalence rates (5–6%) and people from the Caribbean region have lower prevalence rates.

The age at which the disease most commonly starts is in women between 40 and 50 years of age, and for men somewhat later.[100] RA is a chronic disease, and although rarely, a spontaneous remission may occur, the natural course is almost invariably one of persistent symptoms, waxing and waning in intensity, and a progressive deterioration of joint structures leading to deformations and disability.

History[edit]

The first known traces of arthritis date back at least as far as 4500 BC. A text dated 123 AD first describes symptoms very similar to RA. It was noted in skeletal remains of Native Americans found in Tennessee.[101] In the Old World, the disease is vanishingly rare before the 17th century.[102] In 1859 the disease acquired its current name.

An anomaly has been noticed from investigation of Pre-Columbian bones. The bones from the Tennessee site show no signs of tuberculosis even though it was prevalent at the time throughout the Americas.[103] Jim Mobley, at Pfizer, has discovered a historical pattern of epidemics of tuberculosis followed by a surge in the number of RA cases a few generations later.[104] Mobley attributes the spikes in arthritis to selective pressure caused by tuberculosis. A hypervigilant immune system is protective against tuberculosis at the cost of an increased risk of autoimmune disease.

The art of Peter Paul Rubens may possibly depict the effects of RA. In his later paintings, his rendered hands show, in the opinion of some physicians, increasing deformity consistent with the symptoms of the disease.[105][106] RA appears to some to have been depicted in 16th-century paintings.[107] However, it is generally recognised in art historical circles that the painting of hands in the 16th and 17th century followed certain stylised conventions, most clearly seen in the Mannerist movement. It was conventional, for instance to show the upheld right hand of Christ in what now appears a deformed posture. These conventions are easily misinterpreted as portrayals of disease.

The first recognized description of RA was in 1800 by the French physician Dr Augustin Jacob Landré-Beauvais (1772–1840) who was based in the famed Salpêtrière Hospital in Paris.[7] The name "rheumatoid arthritis" itself was coined in 1859 by British rheumatologist Dr Alfred Baring Garrod.[108]

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).[109] Most of these have either had no effect at all, or their effects have been modest and transient, while not being generalizable.[citation needed] The Prosorba column blood filtering device (removing IgG) was approved by the FDA in 1999 for treatment of RA[110] However it was discontinued at the end of 2006.[111]

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