Rheumatoid arthritis

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Rheumatoid arthritis
Rheumatoid arthritis
Classification and external resources

A hand affected by rheumatoid arthritis ICD-10 ICD-9 OMIM DiseasesDB M 05. 714
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-M 06.

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180300 11506

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MedlinePlus 000431 [6] eMedicine MeSH article/331715 D001172
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article/1266195

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article/305417

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article/401271

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article/335186

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article/808419

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Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium (synovitis) secondary to hyperplasia of synovial cells, excess synovial fluid, and the development of pannus in the synovium. The pathology of the disease process often leads to the destruction of articular cartilage and ankylosis of the joints. Rheumatoid arthritis can also produce diffuse inflammation in the lungs, pericardium, pleura, and sclera, and also nodular lesions, most common in subcutaneous tissue. Although the cause of rheumatoid arthritis is unknown, autoimmunity plays a pivotal role in both its chronicity and progression, and RA is considered a systemic autoimmune disease. About 1% of the world's population is afflicted by rheumatoid arthritis, women three times more often than men. Onset is most frequent between the ages of 40 and 50, but people of any age can be affected. It can be a disabling and painful condition, which can lead to substantial loss of functioning and mobility if not adequately treated. It is a clinical diagnosis made on the basis of symptoms, physical exam, radiographs (X-rays) and labs; although the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) publish diagnostic guidelines. Diagnosis and long-term management are typically performed by a rheumatologist, an expert in auto-immune diseases.[14] Various treatments are available. Non-pharmacological treatment includes physical therapy, orthoses, occupational therapy and nutritional therapy but do not stop progression of joint destruction. Analgesia (painkillers) and anti-inflammatory drugs, including steroids, are used to suppress the symptoms, while disease-modifying antirheumatic drugs (DMARDs) are required to inhibit or halt the underlying immune process and prevent long-term

but larger joints like the shoulder and knee can also be involved. tender and warm. such as ulnar deviation. with the affected joints being swollen. the joints are often affected in a fairly symmetrical fashion.[14] The name is based on the term "rheumatic fever".[14] Rheumatoid arthritis typically manifests with signs of inflammation. feet and cervical spine. warm. 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. although this is not specific. Synovitis can lead to tethering of tissue with loss of movement and erosion of the joint surface causing deformity and loss of function.[16] It can be difficult to determine whether disease manifestations are directly caused by the rheumatoid process itself. most commonly small joints of the hands. current"). and the initial presentation may be asymmetrical.Rheumatoid arthritis damage. since they occur in osteoarthritis as well.[17] In RA. lung fibrosis from methotrexate or osteoporosis from corticosteroids.) ("flow. swan neck deformity and "Z-thumb. These signs help distinguish rheumatoid from non-inflammatory problems of the joints. A diagram showing how rheumatoid arthritis affects a joint As the pathology progresses the inflammatory activity leads to tendon tethering and erosion and destruction of the joint surface. an illness which includes joint pain and is derived from the Greek word ῥεύμα-rheuma (nom. painful and stiff. The suffix -oid ("resembling") gives the translation as joint inflammation that resembles rheumatic fever. ῥεύματος-rheumatos (gen." but these are of no more significance to diagnosis or disability than other variants. . or from side effects of the medications commonly used to treat it – for example. Joints The arthritis of joints known as synovitis is inflammation of the synovial membrane that lines joints and tendon sheaths. The first recognized description of rheumatoid arthritis was made in 1800 by Dr Augustin Jacob Landré-Beauvais (1772–1840) of Paris. boutonniere deformity. In arthritis of non-inflammatory causes. fixed flexion and subluxation of the metacarpophalangeal joint and gives a "Z" appearance to the thumb. Joints become swollen. which impairs range of movement and leads to deformity. With time RA nearly always affects multiple joints (it is a polyarthritis). Extra-articular ("outside the joints") manifestations other than anemia (which is very common) are clinically evident in about 15–25% of individuals with rheumatoid arthritis. Medical students are taught to learn names for specific deformities.[15] 2 Signs and symptoms While rheumatoid arthritis primarily affects joints. the newer group of biologics has increased treatment options. The fingers may suffer from almost any deformity depending on which joints are most involved. and movements induce pain caused by mechanical arthritis. signs of inflammation and early morning stiffness are less prominent with stiffness typically less than 1 hour. often referred to as osteoarthritis or "wear-and-tear" arthritis. In recent times. problems involving other organs of the body are known to occur. "Z-thumb" or "Z-deformity" consists of hyperextension of the interphalangeal joint. particularly early in the morning on waking or following prolonged inactivity. and stiffness limits their movement.).

a necrotizing. Treatment with Penicillamine and gold salts are recognized causes of membranous nephropathy. To reduce cardiovascular risk.[22] Many people with rheumatoid arthritis do not experience the same chest pain that others feel when they have angina or myocardial infarction. corresponding to the intimal layer in synovium and a cuff of connective tissue containing clusters of lymphocytes and plasma cells. A benign form occurs as microinfarcts around the nailfolds. Pleural effusions are also associated with rheumatoid arthritis. corresponding to the subintimal zone in synovitis. and risk of myocardial infarction (heart attack) and stroke is markedly increased. noninfectious neutrophilic dermatosis. It is also a rare but well recognized consequence of therapy (for example with methotrexate and leflunomide). and skin fragility (often worsened by corticosteroid use). valvulitis and fibrosis. Rarely. endocarditis. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences. More severe forms include livedo reticularis. it is crucial to maintain optimal control of the inflammation caused by rheumatoid arthritis (which may be involved in causing the cardiovascular risk). the calcaneal tuberosity. and to use exercise and medications appropriately to reduce other cardiovascular risk factors such as blood lipids and blood pressure. Doctors who treat rheumatoid arthritis patients should be sensitive to cardiovascular risk when prescribing anti-inflammatory medications. these can occur in internal organs or at diverse sites on the body. ulcerative. such as the olecranon. or other areas that sustain repeated mechanical stress. Several forms of vasculitis occur in rheumatoid arthritis. Sweet's syndrome.[19] Rheumatoid arthritis may affect the kidney glomerulus directly through a vasculopathy or a mesangial infiltrate but this is less well documented. and may . Another complication of RA is Rheumatoid Lung Disease. skin associated symptoms include: • • • • • • • • pyoderma gangrenosum. Other. It is estimated that about one quarter of Americans with RA develop Rheumatoid Lung Disease. Lungs Fibrosis of the lungs is a recognized response to rheumatoid disease. is the cutaneous feature most characteristic of rheumatoid arthritis. the metacarpophalangeal joint. 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. left ventricular failure. Surrounding the necrosis is a layer of palisading macrophages and fibroblasts. rather rare. since similar structural features occur in both. which is often subcutaneous. Caplan's syndrome describes lung nodules in individuals with rheumatoid arthritis and additional exposure to coal dust. Heart and blood vessels People with rheumatoid arthritis are more prone to atherosclerosis. The initial pathologic process in nodule formation is unknown but may be essentially the same as the synovitis.[20] [21] Other possible complications that may arise include: pericarditis.Rheumatoid arthritis 3 Skin The rheumatoid nodule. Nodules are associated with a positive RF (rheumatoid factor) titer and severe erosive arthritis. a neutrophilic dermatosis usually associated with myeloproliferative disorders drug reactions erythema nodosum lobular panniculitis atrophy of digital skin palmar erythema diffuse thinning (rice paper skin).[18] Kidneys Renal amyloidosis can occur as a consequence of chronic inflammation. which is a network (reticulum) of erythematous to purplish discoloration of the skin caused by the presence of an obliterative cutaneous capillaropathy.

It is postulated to be partially caused by inflammatory cytokines. In Felty's syndrome. malaise. An increased platelet count (thrombocytosis) occurs when inflammation is uncontrolled. Hepatic Cytokine production in joints and/or hepatic Kupffer cells leads to increased activity of hepatocytes with increased production of acute-phase proteins. local cytokine release in bone marrow and corticosteroid therapy. low grade fever. Atlanto-axial subluxation can occur. Lymphoma The incidence of lymphoma is increased in RA. Neurological Peripheral neuropathy and mononeuritis multiplex may occur. morning stiffness. but without due care this can progress to quadriplegia. Osteoporosis Local osteoporosis occurs in RA around inflamed joints. Rheumatoid arthritis may cause a warm autoimmune hemolytic anemia.[22] 4 Other Ocular The eye is directly affected in the form of episcleritis which when severe can very rarely progress to perforating scleromalacia. such as C-reactive protein. Kuppfer cell activation is so marked that the resulting increase in hepatocyte activity is associated with nodular hyperplasia of the liver. .Rheumatoid arthritis want to consider prescribing routine use of low doses of aspirin if the gastrointestinal effects are tolerable. loss of appetite and loss of weight are common systemic manifestations seen in patients with active rheumatoid arthritis. as does the anemia. dryness of the cornea can lead to keratitis and loss of vision. there is little or no evidence of hepatitis. Hematological Anemia is by far the most common abnormality of the blood cells. 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. Preventive treatment of severe dryness with measures such as nasolacrimal duct occlusion is important. which may be palpably enlarged. Clumsiness is initially experienced. Because Kuppfer cells are not within the liver parenchyma. systemic cytokine effects. which is a dryness of eyes and mouth caused by lymphocyte infiltration of lacrimal and salivary glands. When severe. More general osteoporosis is probably contributed to by immobility. although it is still uncommon. The most common problem is carpal tunnel syndrome caused by compression of the median nerve by swelling around the wrist. and increased release of enzymes such as alkaline phosphatase into the blood. Hepatic involvement in RA is essentially asymptomatic. Rather more common is the indirect effect of keratoconjunctivitis sicca. owing to erosion of the odontoid process and or/transverse ligaments in the cervical spine's connection to the skull. Constitutional symptoms Constitutional symptoms including fatigue. Such an erosion (>3mm) can give rise to vertebrae slipping over one another and compressing the spinal cord.[23] The red cells are of normal size and colour (normocytic and normochromic).

High-frequency transducers (10 MHz or higher) have improved the spatial resolution of ultrasound images. such as testing for the presence of rheumatoid factor (RF. rheumatoid factor is more likely to be negative with some individuals converting to seropositive status over time. As the disease advances. the arthritis is called seronegative. and synovitis seems to be the best predictive marker of future joint damage.[24] X-ray of the hand in rheumatoid arthritis. for example Sjögren's syndrome. Blood tests When RA is clinically suspected. new serological tests have been developed. This is the case in about 15% of patients. In rheumatoid arthritis. Like RF.[26] As with RF. or the x-ray may demonstrate juxta-articular osteopenia. The most common tests for ACPAs are the anti-CCP (cyclic citrullinated peptide) test and the Anti-MCV assay (antibodies against . soft tissue swelling and loss of joint space. therefore the test is not very specific. giving it a specificity of around 95%. there is evidence for ACPAs being present in many cases even before onset of clinical disease. Also.[26] During the first year of illness. Appearance of synovial fluid from a joint with inflammatory arthritis. since in the early stages of rheumatoid arthritis. Because of this low specificity. This is important. color Doppler and power Doppler ultrasound. these images can depict 20% more erosions than conventional radiography. are useful in assessing synovial inflammation. immunological studies are required.Rheumatoid arthritis 5 Diagnosis Imaging X-rays of the hands and feet are generally performed in people with a polyarthritis. which test for the presence of the anti-citrullinated protein antibodies (ACPAs) or anti-CCP. there may be no changes in the early stages of the disease. chronic infections and in approximately 10% of the healthy population. which show vascular signals of active synovitis depending on the degree of inflammation. There have been technical advances in ultrasonography. a non-specific antibody). there may be bony erosions and subluxation. Other medical imaging techniques such as magnetic resonance imaging (MRI) and ultrasound are also used in rheumatoid arthritis. rather.[25] A negative RF does not rule out RA. these tests are positive in only a proportion (67%) of all RA cases. RF is also seen in other illnesses. X-rays of other joints may be taken if symptoms of pain or swelling occur in those joints. but are rarely positive if RA is not present. Hepatitis C. the synovium is primarily affected.

a seronegative. The erythrocyte sedimentation rate (ESR). Criteria In 2010 the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria were introduced. The "new" classification criteria. In the "new" criteria serology and autoimmune diagnostics carries major weight. C-reactive protein. renal function. • acute phase reactants: 1 point for elevated erythrocyte sedimentation rate. 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. Additionally. usually juvenile. several other blood tests are usually done to allow for other causes of arthritis. also demonstrating synovitis. a mimic RA. In clinical practice. This assay combines the detection of rheumatoid factor and anti-MCV for diagnosis of rheumatoid arthritis and shows a sensitivity of 72% and specificity of 99. variant of rheumatoid. Four areas are covered in the diagnosis: • joint involvement – depending on the type and number of joints: up to 5 points • serological parameters – including the rheumatoid factors as well as ACPA – "ACPA" stands for "anti-citrullinated protein antibody": up to 3 points depending on titre level Signs of destruction and inflammation on ultrasonography and magnetic resonance imaging in the second metacarpophalangeal joint in established rheumatoid arthritis. Every patient with a point total of 6 or higher is unequivocally classified as an RA patient. liver enzymes and other immunological tests (e.[30] This criterion no longer is regarded to be relevant. a coronal T1-weighted magnetic resonance image (e) before contrast administration visualizes the same bone erosion as shown in panels c and d. . Thin arrows indicate an erosive change. as this is just the type of damage that treatment is meant to avoid. ESR. as ACPA detection is appropriate to diagnose the disease in an early state.7%. Axial T1-weighted magnetic resonance images were obtained (c) before and (d) after contrast administration. antinuclear antibody/ANA) are all performed at this stage.Rheumatoid arthritis 6 mutated citrullinated Vimentin). 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 rheumatoid arthritis and the improvements in diagnosing RA and disease treatment. Destruction of the joints viewed in radiological images was a significant point of the ACR criteria from 1987. provided he has synovitis in at least one joint and given that there is no other diagnosis better explaining the synovitis.g. such as lupus erythematosus. A negative autoantibody result does not exclude a diagnosis of RA. Elevated ferritin levels can reveal hemochromatosis. Recently a serological point-of-care test (POCT) for the early detection of RA has been developed. they were primarily intended to categorize research (classification criteria). before joints destructions occur. full blood count.[29] These new classification criteria overruled the "old" ACR criteria of 1987 and are adapted for early RA diagnosis. or be a sign of Still's disease . the following criteria apply: • two or more swollen joints • morning stiffness lasting more than one hour for at least six weeks • the detection of rheumatoid factors or autoantibodies against ACPA such as autoantibodies to mutated citrullinated vimentin can confirm the suspicion of rheumatoid arthritis. jointly published by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) establish a point value between 0 and 10.. The criteria are not intended for the diagnosis for routine clinical care.[27] [28] Also.

• Gonococcal arthritis (another bacterial arthritis) is also initially migratory and can involve tendons around the wrists and ankles. • Hemochromatosis may cause hand joint arthritis. 6. although a RA-like symmetrical small-joint polyarthritis may occur in the context of this condition. sacroiliac joints. and large joints of the leg. These data suggest that the disease involves abnormal B cell–T cell interaction. conjunctivitis. 4. Hepatitis C may also induce Rheumatoid Factor auto-antibodies Rarer causes that usually behave differently but may cause joint pains:[31] • Sarcoidosis. painless buccal ulcers. iritis. amyloidosis. and usually need to be distinguished from it at the time of diagnosis:[31] [32] • Crystal induced arthritis (gout. A remarkable deceleration of disease progression in many cases by blockade of the cytokine TNF (alpha).Rheumatoid arthritis 7 Differential diagnoses Several other medical conditions can resemble RA. while RA usually involves both sides of the body symmetrically. It is usually associated with urethritis. A link with cigarette smoking that appears to be causal. and Whipple's disease can also resemble RA. • Hepatitis C – RA-like symmetrical small-joint polyarthritis may occur in the context of this condition. with presentation of antigens by B cells to T cells via HLA-DR eliciting T cell help and consequent production of RF and ACPA. 3. and antibodies to citrullinated peptides (ACPA). The presence of autoantibodies to IgGFc. A similar dramatic response in many cases to depletion of B lymphocytes. Bacterial arthritis (such as streptococcus) is usually asymmetric. but no comparable response to depletion of T lymphocytes. and pseudogout) – usually involves particular joints and can be distinguished with aspiration of joint fluid if in doubt • Osteoarthritis – distinguished with X-rays of the affected joints and blood tests • 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. 5. • Acute rheumatic fever can be differentiated from RA by a migratory pattern of joint involvement and evidence of antecedent streptococcal infection. Pathophysiology and causes Rheumatoid arthritis is a form of autoimmunity. A genetic link with HLA-DR4 and related allotypes of MHC Class II and the T cell-associated protein PTPN22. The key pieces of evidence relating to pathogenesis are: 1. known as rheumatoid factors (RF). A more or less random pattern of whether and when predisposed individuals are affected. and keratoderma blennorrhagica. It is a systemic (whole body) disorder principally affecting synovial tissues. the causes of which are still incompletely known. 2. • Ankylosing spondylitis – this involves the spine and is usually diagnosed in males. The process may be facilitated by an effect of smoking on citrullination but the stochastic (random) epidemiology suggests that the rate . Inflammation is then driven either by B cell or T cell products stimulating release of TNF and other cytokines.

but these associations have never been supported in epidemiological studies.[40] Continued abnormal immune response The factors that allow an abnormal immune response. Blockade of IL-1. As with most autoimmune diseases. loss of appetite and weight loss are also caused by cytokines released in to the blood stream.[37] [38] The allele HLA-DRB1*0404 is associated with low frequencies of T cells specific for the EBV glycoprotein 110 and predisposes one to develop RA. Because the normal host molecule "looks like" a molecule on the offending organism that triggered the initial immune reaction—this phenomenon is called molecular mimicry. it is important to distinguish between the cause(s) that trigger the process. once initiated.[33] [34] 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. are becoming more clearly understood. there is good evidence for neither cell being necessary at the site of inflammation. The genetic association with HLA-DR4. and those that may permit it to persist and progress.[36] Individuals with RA are more likely to exhibit an abnormal immune response to the Epstein-Barr virus. and set off an immune attack against part of the host. 8 Possible infectious triggers It has long been suspected that certain infections could be triggers for this disease. or that it might in fact be a chance event inherent with the immune response. Moreover.Rheumatoid arthritis 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.) If TNF release is stimulated by B cell products in the form of RF or ACPA -containing immune complexes. The "mistaken identity" theory suggests that an infection triggers an immune response. malaise. as suggested by Edwards et al. IL-15 and IL-6 also have beneficial effects and IL-17 may be important. Blockade of TNF does not benefit all patients or all tissues (lung disease and nodules may get worse). However. The antibodies are not sufficiently specific. Although TNF appears to be the dominant. It has also become clear from recent studies that these genetic factors may interact . The many negative findings suggest that either the trigger varies. as well as the newly discovered associations with the gene PTPN22 and with two additional genes[41] . Constitutional symptoms such as fever. though. This tends to favour immune complexes (based on antibody synthesised elsewhere) as the initiators. leaving behind antibodies that should be specific to that organism. other cytokines (chemical mediators) are likely to be involved in inflammation in RA. Nor has convincing evidence been presented for other types of triggers such as food allergies. There is little doubt that both B and T cells are essential to the disease. Some infectious organisms suspected of triggering rheumatoid arthritis include Mycoplasma.[35] The debate on the relative roles of immune complexes and T cell products in inflammation in RA has continued for 30 years. even if not the sole perpetuators of inflammation. to become permanent and chronic. 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.[39] Psychological factors There is no evidence that physical and emotional effects or stress could be a trigger for the disease. all implicate altered thresholds in regulation of the adaptive immune response. (See entry under autoimmunity for general mechanisms. which derive from B cells and produce in bulk the antibodies selected at the B cell stage. Erysipelothrix. Epidemiological studies have confirmed a potential association between RA and two herpesvirus infections: Epstein-Barr virus (EBV) and Human Herpes Virus 6 (HHV-6). parvovirus B19 and rubella. then RA can be seen as a form of Type III hypersensitivity. through activation of immunoglobulin Fc receptors.

These are not deposited in the way that they are in systemic lupus. published in 2008. the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues. Rather. Recommendations of the American College of Rheumatology (ACR). how active the disease is. anti-cyclic citrullinated peptide.[44] Cortisone therapy has offered relief in the past. 9 Treatment There is no known cure for rheumatoid arthritis. prednisone or prednisolone. These two goals may not always coincide: while pain relievers may achieve the first goal. more aggressive treatment of RA. and prognostic factors (such as X-ray evidence of bone erosion. Pharmacological treatment of RA can be divided into disease-modifying antirheumatic drugs (DMARDs).[45] However. also named DMARD (see below).g. Synovial macrophages and dendritic cells further function as antigen presenting cells by expressing MHC class II molecules. Modern pharmacological treatments of RA target these mediators. they do not have any impact on the long-term consequences. and reflected heightened expectations of treatment effectiveness. namely cigarette smoking[42] [43] Other environmental factors also appear to modulate the risk of acquiring RA. 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. Once the inflammatory reaction is established. but many different types of treatment can alleviate symptoms and/or modify the disease process. anti-inflammatory agents and analgesics. However. the ACR recommends that RA should generally be treated with at least one specific anti-rheumatic medication. and using low dosages of daily cortisone (e. This can contribute to inflammation of the synovium. in terms of edema. and preventing the future destruction of the joints with the resulting handicap if the disease is left unchecked. they appear to activate macrophages through Fc receptor and perhaps complement binding. including remission or substantial alleviation of symptoms for a rising percentage of patients. age and gender. Exactly how altered regulatory thresholds allow the triggering of a specific autoimmune response remains uncertain. and hormonal factors in the individual may explain some features of the disease. such as the higher occurrence in women. leading to an established local immune reaction in the tissue. plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes in large quantities. physical functioning. to which other medications may be added depending on how long a person has had RA. 5–7.. vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). but its long-term effects have been deemed undesirable. the not-infrequent onset after child-birth. . Once the abnormal immune response has become established (which may take several years before any symptoms occur). followed a trend in supporting earlier. and the (slight) modulation of disease risk by hormonal medications.[44] The goal of treatment is twofold: alleviating the current symptoms. C-reactive protein.Rheumatoid arthritis with the most clearly defined environmental risk factor for rheumatoid arthritis. for example). the synovium thickens.[46] [47] Treatment also includes rest and physical activity. and erythrocyte sedimentation rate. 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).5 mg daily) can also have an important benefit if added to a proper specific anti-rheumatic treatment. cortisone injections can be valuable adjuncts to a long-term treatment plan. For these reasons. elevation of blood factors such as Rheumatoid factor. and smoking.

when they are most responsive to therapy and have the most to gain. disease modifying anti-rheumatic drugs must be administered before the deformities appear or the erosive disease occurs. From the earliest stages of the disease. Ultrasound and MRI are more sensitive methods of imaging the joints and have demonstrated that joint damage occurs much earlier and in more sufferers than was previously thought.Rheumatoid arthritis 10 Disease modifying anti-rheumatic drugs (DMARDs) The term Disease modifying anti-rheumatic drug (DMARD) originally meant a drug that affects biological measures such as ESR and haemoglobin and autoantibody levels. and methotrexate – hydroxychloroquine – sulfasalazine. People with normal X-rays will often have erosions detectable by ultrasound that X ray could not demonstrate. but is now usually used to mean a drug that reduces the rate of damage to bone and cartilage. and assess progression clinically and using X-rays. methotrexate – sulfasalazine. In order to be effective. DMARDs have been found both to produce durable symptomatic remissions and to delay or halt progression.[50] Traditional small molecular mass drugs Chemically synthesised DMARDs: • • • • • • • • • azathioprine ciclosporin (cyclosporine A) D-penicillamine gold salts hydroxychloroquine leflunomide methotrexate (MTX) minocycline sulfasalazine (SSZ) Cytotoxic drugs: • Cyclophosphamide .[48] Disease modifying anti-rheumatic drugs have been used in the treatment of rheumatic arthritis for a long time now.[49] Common combinations of DMARDs include methotrexate – hydroxychloroquine. Usually. Rheumatologists do not wait for the fulfillment of the criteria for classification of RA as published by the American College of Rheumatology (ACR) and start treatment with this type of drugs if the pain and synovitis persist and the function is compromised. Delaying therapy for as little as a few months after the onset of symptoms can result in worse outcomes in the long term. There may be other reasons why starting DMARDs early is beneficial as well as prevention of structural joint damage. sulfasalazine – hydroxychloroquine. This is important as such damage is usually irreversible. There is therefore considerable interest in establishing the most effective therapy with early arthritis. If there was evidence that joint damage was starting to occur then a more potent DMARD would be prescribed. The aim now is to treat before damage occurs. the joints are infiltrated by cells of the immune system that signal to one another in ways that may involve a variety of positive feedback loops (it has long been observed that a single corticosteroid injection may abort synovitis in a particular joint for long periods). Over 90% of rheumatologists now use combination therapy of multiple disease modifying drugs for rheumatoid arthritis as it has become apparent that using combination of these drugs does not increase their relative toxicity profiles. There is an increasing recognition among rheumatologists that permanent damage to the joints occurs at a very early stage in the disease. Anti-inflammatories and analgesics improve pain and stiffness but do not prevent joint damage or slow the disease progression. In the past it was common to start with just an anti-inflammatory drug. Interrupting this process as early as possible with an effective DMARD (such as methotrexate) appears to improve the outcome from the RA for years afterwards.

sulphasalazine may cause side effects that can range in severity from mild to serious. Yet. A much more worrisome side effect from treatment with anti-malarials is the damage that these drugs seem to be causing to the cornea and retina. Mild side effects that may arise from treatment with sulphasalazine include nausea and skin rash. Also. people who were prescribed methotrexate stayed on their medication the longest (the others stopped because of either side-effects or failure of the drug to control the arthritis). and is usually insufficient to control symptoms on its own. Although methotrexate does have the potential to suppress bone marrow or cause hepatitis. In clinical trials. This reputation is not entirely justified.5 mg/kg. Sodium aurothiomalate (Myocrisin) on the other hand is another type of gold compound that is injected and which appears to be as efficient 11 . Leukopenia has also been reported in therapies with sulphasalazine. gold compounds.[51] Gold compounds are also options in treating this type of disease. Sulphasalazine : Although it appears to be a highly efficient drug in the treatment of rheumatoid arthritis. bone marrow suppression may occur. Generally. these effects can be monitored using regular blood tests. The latter is estimated to have occurred in approximately 2% of the patients but death and further complications were avoided by removing the drug from the patient's therapy. Methotrexate is often preferred by rheumatologists because if it does not control arthritis on its own then it works well in combination with many other drugs. azathioprine. anti-malarials may also produce side effects.Rheumatoid arthritis The most important and most common adverse events relate to liver and bone marrow toxicity (MTX. and the drug withdrawn at an early stage if the tests are abnormal before any serious harm is done (typically the blood tests return to normal after stopping the drug). cyclosporine A). aplastic anemia and agranulocytosis can develop as a result of anti-malarial therapy and may potentially cause the death of the patient. It has been pointed out. As most drugs. although this is rare. and because hydroxychloroquine does not affect the bone marrow or liver it is often considered to be the DMARD with the least toxicity. parenteral gold salts. Unfortunately hydroxychloroquine is not very potent. Specialists agree that injectable gold is much more effective in the treatment of rheumatoid arthritis than auranofin. More serious. and at times can result in people being denied the most effective treatment for their arthritis. there have been approximately 700 of patients in whom this medicine caused blood dyscrasis. the risks of developing ocular complications are minimal. Anti-malarials such as chloroquine and hydroxychloroquine have been used to treat rheumatoid arthritis. Auranofin is therefore not considered efficient in the treatment of rheumatoid arthritis because of its poor results and because it is intolerable for most patients. nausea that appears as a result of treatment with this DMARD occurs in the first days of treatment and then it tends to diminish to disappearance. Methotrexate is considered by many rheumatologists to be the most important and useful DMARD. allergic skin reactions (gold compounds. Rare side effects include Stevens–Johnson syndrome and reduced fertility due to reversible oligospermia. SSZ. methotrexate is often considered as a very 'toxic' drug. through clinical studies. renal toxicity (cyclosporine A. though rare. auranofin seems to be causing more side effects than any other type of DMARD. D-penicillamine). Mild side effects from hydroxychloroquine include nausea and skin rash. autoimmunity (D-penicillamine. SSZ). Skin rash has been reported in nearly 5% of the patients and it may present pruritus. pneumonitis (MTX). Other DMARDs may not be as effective or as safe in combination with biological agents. Although hydroxyxhloroquine appears to be more efficient in treating rheumatoid arthritis than placebo. D-penicillamine). where one of a range of different DMARDs were used. Hydroxychloroquine may cause ocular toxicity. SSZ. are aplastic anemia and neutropenia which may result in the death of the patient. Nevertheless. Also. that chloroquine has a higher toxicity compared to hydroxychloroquine. especially in what concerns preventing the joint damage that is caused by the disease. it is also inferior to sulphasalazine. especially the biological agents. To avoid nausea. but in very rare cases. Severe side effects that can appear from therapy with sulphasalazine. Recent studies have however shown that if the dosage of hydroxychloroquine given to the patients does not exceed 6. this type of drug has been shown to be more efficient than placebo and even though its level of toxicity is quite low. largely because of lower drop-out rates for reasons of toxicity. minocycline) and infections (azathioprine. according to WHO. leflunomide. though rare. specialists recommend starting with low doses and then gradually increasing them until the usual dosage is achieved.

podiatry. special tin-openers).[53] Biological agents Biological agents (biologics) include: • tumor necrosis factor alpha (TNFα) blockers[54] [55] [56] – etanercept (Enbrel). they are usually not included in the treatment plan for rheumatoid arthritis. infliximab (Remicade). or their effects have been modest and transient. physiotherapy. vitamins.[59] Other therapies Other therapies are weight loss. Oxaprozin. orthoses. it was found to increase mobility and make patients twice as likely to achieve a 50% improvement in symptoms. Actemra) 12 Anti-inflammatory agents and analgesics Anti-inflammatory agents include: • glucocorticoids • Non-steroidal anti-inflammatory drug (NSAIDs. and piroxicam.[60] Ayurveda. extractions of teeth. magnets. bee venom. compression and elevation. indomethicin.g. copper bracelets. and electroconvulsive therapy (ECT). Regular exercise is important for maintaining joint mobility and making the joint muscles stronger. A Cochrane systematic review has determined that Abatacept was an effective treatment for rheumatoid arthritis. sulindac. nabumetone. some light exercise every now and then. mostly in southern India. occupational therapy.[58] Most of these have either had no effect at all.[52] However Cochrane has called for more studies to be conducted. acupuncture. naproxen. etodolac. rhubarb diet. diclofenac. is another source of treatment. there are some questions as to the usefulness of the procedure over a long period of time. diflusinal. adalimumab (Humira). fasting. nettles. Given that there is not enough proof that gold compounds are indeed efficient in preventing the progression of erosions and the high toxicity of these drugs. Cortisone therapy became a controversial medical solution because even though it can provide great relief. choline magnesium salicylate. d-penicillamine and methotrexate. nutmeg. apple diet. most also act as analgesics) Analgesics include: • • • • paracetamol (acetaminophen in US and Canada) opiates diproqualone lidocaine topical Historic treatments for RA have also included: rest. meloxicam. . certolizumab pegol (Cimzia). and while it is popular in India there are no studies to show that it benefits patients with RA. tolementin. A Cochrane Review of studies determined that exercise programs designed to improve strength and stamina were safe and led to moderate benefits for RA sufferers. Against placebo. insulin. golimumab (Simponi) • Interleukin 1 (IL-1) blockers – anakinra (Kineret) • monoclonal antibodies against B cells – rituximab (Rituxan)[57] • T cell costimulation blocker – abatacept (Orencia) • Interleukin 6 (IL-6) blockers – tocilizumab (an anti-IL-6 receptor antibody) (RoActemra. immunoadsorption therapy. Ketoprofen. joint injections. and special tools to improve hand movements (e. ice. honey.Rheumatoid arthritis as sulphasalazine. NSAIDs used in the treatment of RA include ibuprofen. given the lack of evidence to distinguish between the biologics available for rheumatoid arthritis. while not being generalizable.

but in most the disease is progressive for life. was among the five most common reasons for the medicinal use of cannabis. C-reactive protein [CRP]). like methotrexate. this is associated with a poor prognosis. family history of RA. 13 Prognosis The course of the disease varies greatly. According to the UK's National Rheumatoid Arthritis Society. the concurrent presence of other health problems (called co-morbidity).Rheumatoid arthritis A survey in the United Kingdom between 1998 and 2002 found that arthritis. Mortality Estimates of the life-shortening effect of RA vary. The mechanism by which RA causes this increased risk remains unknown. long disease duration. "Young age at onset. could damage the liver when taken with large amounts of alcohol. elevated acute phase response (erythrocyte sedimentation rate [ESR]. • After 10 years. Some people have mild short-term symptoms. Prognostic factors Poor prognostic factors include persistent synovitis. positive serum RF findings. Around 20%-30% will have subcutaneous nodules (known as rheumatoid nodules).[68] independent of other risk factors such as diabetes.[66] Severely affected joints may require joint replacement surgery.[67] Positive responses to treatment may indicate a better prognosis. blood pressure and body mass index. and "more rigorous research seems to be warranted" according to one study. extra-articular findings (including subcutaneous rheumatoid nodules). and elevated cholesterol. most sources cite a lifespan reduction of 5 to 10 years. approximately half will have substantial functional disability.[61] The Prosorba column blood filtering device (removing IgG) was approved by the FDA in 1999 for treatment of RA[62] However it was discontinued at the end of 2006. poor functional status. socioeconomic factors. and characteristics of severe RA—such as poor functional ability or overall health status. Disability • Daily living activities are impaired in most individuals. alcohol abuse.[63] The effectiveness of treating RA with acupuncture is inconclusive.[69] . the need for hospitalisation or involvement of organs other than the joints—have been shown to associate with higher mortality". in its various forms. and increased clinical severity.[65] [66] However a spokeswoman for the Arthritis Research UK (who co-funded the study) warned that some RA treatments. the presence of chronic inflammation has been proposed as a contributing factor. approximately 33% of sufferers will not be working. • After 5 years of disease. such as knee replacement. A 2005 study by the Mayo Clinic noted that RA sufferers suffer a doubled risk of heart disease. a lot of joint damage on x-rays.[64] One study of 873 patients with RA found that those who drank some alcohol (none drank more than 10 units of alcohol a week) had reduced severity of symptoms compared to those who drank no alcohol. early erosive disease. carriership of HLA-DR4 "Shared Epitope" alleles. positive serum anti-CCP autoantibodies.

2009. in the opinion of some physicians. World Health Organization. It is strongly associated with the inherited tissue type Major histocompatibility complex (MHC) antigen HLA-DR4 (most specifically DR0401 and 0404)—hence family history is an important risk factor. for instance to show the upheld right hand of Christ in what now appears a deformed posture. The prevalence rate is 1%.  no data  less than often as men. the natural course is almost invariably one of persistent symptoms.[65] [71] Some Native American groups have higher prevalence rates (5-6%) and people from the Caribbean region have lower prevalence rates. History The first known traces of arthritis date back at least as far as 4500 BC. women affected three to five times as "WHO Disease and injury country estimates".000 inhabitants in 2004. It is 4 times more 40  40-50  50-60  60-70  70-80  80-90  90-100  100-110  110-120  120-130  130-140  more common in smokers than than 140 non-smokers.[75] Jim Mobley. In his later paintings. The art of Peter Paul Rubens may possibly depict the effects of rheumatoid arthritis. waxing and waning in intensity.[73] In the Old World the disease is vanishingly rare before the 1600s. a spontaneous remission may occur.[77] [78] Rheumatoid arthritis appears to some to have been depicted in 16th century paintings. Onset is uncommon under the age of 15 and from then on the incidence rises with age until the age of 80. A text dated 123 AD first describes symptoms very similar to rheumatoid arthritis. and for men somewhat later. Retrieved Nov. An anomaly has been noticed from investigation of Precolumbian bones. The bones from the Tennessee site show no signs of tuberculosis even though it was prevalent at the time throughout the Americas. Rheumatoid arthritis affects women three times more often than men. They are much too widespread for this to be plausible. and a progressive deterioration of joint structures leading to deformations and disability. and it can first develop at any age. A hypervigilant immune system is protective against tuberculosis at the cost of an increased risk of autoimmune disease. The first recognized description of rheumatoid arthritis was in 1800 by the French physician Dr Augustin Jacob Landré-Beauvais (1772–1840) who was based in the famed Salpêtrière Hospital in Paris.000 population per annum.[15] The name "rheumatoid arthritis" itself was coined in 1859 by British rheumatologist Dr Alfred Baring Garrod.[74] and on this basis investigators believe it spread across the Atlantic during the Age of Exploration. . it is generally recognised in art historical circles that the painting of hands in the sixteenth and seventeenth century followed certain stylised conventions. In 1859 the disease acquired its current name. 11.[72] RA is a chronic disease. 2009. It was noted in skeletal remains of Native Americans found in Tennessee.[76] Mobley attributes the spikes in arthritis to selective pressure caused by tuberculosis. These conventions are easily misinterpreted as portrayals of disease.Rheumatoid arthritis 14 Epidemiology The incidence of RA is in the region of 3 cases per 10. increasing deformity consistent with the symptoms of the disease. A study in 2010 found that those who drank modest amounts of alcohol regularly were four times less likely to get rheumatoid arthritis than those who never drank. It was conventional. The risk of first developing the disease (the disease incidence) appears to be greatest for women between 40 and 50 years of age. with Disability-adjusted life year for rheumatoid arthritis per 100.[80] . has discovered a historical pattern of epidemics of tuberculosis followed by a surge in the number of rheumatoid arthritis cases a few generations later. his rendered hands show. and although rarely. most clearly seen in the Mannerist movement. First-degree relatives prevalence rate is 2-3% and disease genetic concordance in monozygotic twins is approximately 15-20%.[79] However. at Pfizer.

[20] Wolfe F. nlm. Nobel prize winning scientist. Erik has been a spokesman for the arthritis drug Enbrel.1002/art. Ann. int/ classifications/ apps/ icd/ icd10online/ ?gm05. aviator and member of the X-Prize administration. as a result of his success with the treatment. doi:10. gov/ medlineplus/ ency/ article/ 000431. . "The mortality of rheumatoid arthritis". 59 (12): 1690–1697. nih. nih. Mitchell DM. htm [7] http:/ / emedicine. medscape. Arthritis Rheum. who. • Sandy Koufax.1016/j. [22] Gupta A and Fomberstein B (August 2009). pubmedcentral. reproduced in Landré-Beauvais AJ (March 2001). htm+ m06 [3] http:/ / www. lifehugger. Joint Bone Spine 68 (2): 130–43. Med. • James Coburn claimed to have healed the condition using pills containing a sulfur-containing compound on his return to acting. American actor. [15] Landré-Beauvais AJ (1800). medscape. com/ article/ 331715-overview [8] http:/ / emedicine. com/ doc/ 459/ An_approach_to_Early_Arthritis) [18] http:/ / arthritis. PMID 8147925. PMC 1754626. bass singer of the Temptations. nlm. 62 (8): 722–7. gov/ cgi/ mesh/ 2010/ MB_cgi?field=uid& term=D001172 [14] Majithia V.8. Dis. com/ article/ 1266195-overview [9] http:/ / emedicine. "The first description of rheumatoid arthritis. [17] Jijith Krishnan. PMID 12860726. Matteson EL (2003).Rheumatoid arthritis 15 Notable cases • Dorothy Hodgkin. htm+ m05 [2] http:/ / apps.[82] • Kathleen Turner and Aida Turturro have worked to raise public awareness of the condition[83] • Billy Bowden. whose later 'softer' style might have reflected in some way his severe disability. com/ article/ 401271-overview [11] http:/ / emedicine. com/ getICD9Code. fcgi?tool=pmcentrez& artid=1754626). J. References [1] http:/ / apps. PMID 17571244. . [21] Aviña-Zubieta JA. Crowson CS. int/ classifications/ apps/ icd/ icd10online/ ?gm05. "Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years" (http:/ / www. "Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies".1780370408.005. com/ retrieve/ pii/ S1297319X00002475). nlm. Internist (Berl) 48 (8): 779–85.1007/s00108-007-1887-9. gov/ articlerender. com/ article/ 305417-overview [10] http:/ / emedicine. gov/ omim/ 180300 [5] http:/ / www.04. doi:10. Paris. doi:10.Document on Rhuematoid arthritis (http:/ / pn. Gabriel SE. • Auguste Renoir. about. Choi HK. • Jamie Farr. "Rheumatoid arthritis: diagnosis and management". PMID 11324929. Geraci SA (2007). nih.24092. famous for his role as Max Klinger on the 1970s television series M*A*S*H. who. doi:10. [16] Turesson C. Sadatsafavi M et al (Dec 2008). medscape.62. 37 (4): 481–94. PMID 19035419. htm [6] http:/ / www. Rheum. Unabridged text of the doctoral dissertation presented in 1800" (http:/ / linkinghub. nih. • Christiaan Barnard. ashx?icd9=714 [4] http:/ / www. "[Renal manifestations in rheumatic diseases]". .[81] • Bob Mortimer British comedian and actor. diseasesdatabase. He also wrote a book on living with arthritis. doi:10. htm [19] de Groot K (August 2007). medscape.722. In spite of this she continued her career and developed X-ray crystallography. international cricket umpire who had to retire from active play because of rheumatoid arhtirits. musculoskeletalnetwork. • Melvin Franklin. Sibley JT. He treated RA with cortisone shots so he could perform. com/ display/ article/ 1145622/ 1433094). doi:10. com/ od/ rheumatoidarthritis/ a/ rheumatoidlung. com/ ddb11506. Am. O'Fallon WM. impressionist painter. elsevier. developed severe deforming rheumatoid arthritis at age 28. She also discovered the structure of insulin and enabled the discovery of the genetic code. com/ article/ 808419-overview [13] http:/ / www. icd9data. "Evaluating cardiovascular risk in rheumatoid arthritis" (http:/ / www. PMID 17976416. et al (April 1994). the first surgeon to perform a human-to-human heart transplant had to retire owing to the condition. Journal of Musculoskeletal Medicine 26 (8): 481–94. ncbi.2007. com/ article/ 335186-overview [12] http:/ / emedicine.1002/art.amjmed. • Erik Lindbergh. which underpins much of the information known about rheumatoid arthritis. 120 (11): 936–9. La goutte asthénique primitive (doctoral thesis). medscape. medscape. Arthritis Rheum. An American Hall-of-Fame baseball pitcher who played from 1955 to 1966 for the Los Angeles Dodgers.1136/ard.1016/S1297-319X(00)00247-5.

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Hsurya. Kevin Forsyth. Endofskull. ZooFari. Phgao. Illuminatedwax. The Man in Question. Nonpareility. Axl. M dorothy. My Core Competency is Competency.php?title=File:Inflamatory_arthritis2010. Wiz9999. Paysseh. Shirik.DALY . Nunquam Dormio. Rjwilmsi. PierreAbbat. JTN. Diberri. Giftlite. Hathawayc. OwenX. Gwernol. Hannabee. Integrativewellness. Sepeople. Victor cure arth. Ageekgal. Krich. ClockworkSoul. Pocopocopocopoco. Nbauman. Jfmarchini. Ixixixi. Jw1969. Casadelqueso. Tarek. Search4Lancer. Corvus cornix. CiaranG. Vintagedirtbiker. Florescent. Mehrenberg. KBlott. Fæ. Briancollins. Åkebråke. Charlotte Strandberg. Jfdwolff.wikipedia.Article Sources and Contributors 19 Article Sources and Contributors Rheumatoid arthritis  Source: http://en. 647 anonymous edits Image Sources. Pigman. The undertow. Dr. SandyGeorgia. SylviaStanley.gif  Source: http://en.wikipedia. Lady Cairns. Tower. Jmh649. Rich Farmbrough. Coopermd. Knowledge Seeker. org/ licenses/ by-sa/ 3. Mccready. Mikael Häggström. 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Ultra megatron. Smartse. Llort.org/w/index. Richieang. Jagath Vasanthathilaka. Rklawton. SHCarter. David Justin. Bhzmr. Fuzbaby. Fvasconcellos. Seans Potato Business. Rmky87. B. Dadude3320. Squirepants101. Hipocrite.JPG  License: Creative Commons Attribution-Sharealike 3. Jonathon Bolster. Excirial. Superperro. Mkurnali. N5iln. FQ1513. Stwalkerster. RC93. Jgervais118. Tommy2010. FisherQueen. Alex. W.org/w/index. Reinoutr.0  Contributors: User:Jmh649 File:Rheumatoid arthritis joint. Bisqwit. Mike Dill. Arthritis info. Mike Rosoft. Mrweewee. Coolhandscot.php?title=File:Rheumatoid_arthritis_joint. AubreyEllenShomo. GraemeL.gif  License: Creative Commons Attribution 2. Steveblevins. Martin Hinks. Krashlandon. RonaldFrits. BBerryhill. Selfhelp. Scray. Hippo99. Eva Narvestad. Sbmehta. Chhajjusandeep.0 Unported http:/ / creativecommons. Borgx. Engliss. PeteThePill.5  Contributors: User:Lokal_Profil License Creative Commons Attribution-Share Alike 3. HiDrNick. Pinethicket. Langrl2. Mothball666. Mmoneypenny.JPG  License: Creative Commons Attribution-Sharealike 3. Darthgriz98. DuncanHill.saeid. Puldis.0  Contributors: User:Jmh649 Image:Rheumatoid arthritis ultrasound MRI MCP joint ar1904-2. Aheaphy. Gabbe. Sickboyra. Fratrep. Elfbabe.php?title=File:Rheumatoid_arthritis_world_map_-_DALY_-_WHO2004. OverlordQ. Bennybp. Leevanjackson. 2over0.wikipedia.wikipedia. Z0OMD. Amalthea. Ched Davis. Dgmaybury. Mav. Chipmunkk. Massagenj. Jebus989. Barbara Shack. Lrunge. WLU. Instinct. TamePhysician. Ldnlighthouse. Mwanner. 0/ . CERminator. Keakealani. Wikipedia brown. Unitseven. Novickas. Linalouis56.php?oldid=406494241  Contributors: 21655. ScAvenger. Gordon711. Contentmaven. Eugeneltc. Piano non troppo. Neiljpatel. Tedernst. Thingg. Amja. Alex43223. ArthritisCritic. Pspekoc61. Davidahearn. SimonT12.tan. Rebelyell1916. Smoe. Bensnowden. Jpkoester1.svg  License: Creative Commons Attribution-Sharealike 2. DW729. Reyk. Cayte. Rajah. Tobias Hoevekamp. Luk. Semperf. Ketiltrout. Nishanthb. Nicolaennio.org/w/index. Nmg20. Dwight666. Henrik S Thomsen and Mikkel Østergaard. Jenday. Eliz81. So God created Manchester. Deli nk. Karl E Jensen. Robneild. Osm agha. Jevansen.wikipedia. Coffeeholic!. Nhyty. Maynard17x1. Iridescent. Rowan Savage. Clovis Sangrail. Sliggy. CABoge. Arcadian.jpg  Source: http://en. The*rising*tide. Jeremy68. Draeco. NCurse. Brokenchairs. Pajast.wikipedia. Nihiltres. Scottj2250. Benbest. Gurps npc. Claus Diff. Michel Court-Payen. Utcursch. Isoptera. Tomstateler. Athanos. Eneuron. Image:Rheumatoid arthritis world map . Axxaer. Electrosaurus. Oxymoron83. Salgueiro.