Rheumatoid arthritis
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225855747
2008-07-15T18:42:32Z
12.154.49.226
/* Joints */ 'localised' to 'localized'
{{Infobox_Disease |
Name = Rheumatoid arthritis |
Image = Rheumatoid arthritis joint.gif |
Caption = A diagram showing how rheumatoid arthritis affects a joint |
DiseasesDB = 11506 |
ICD10 = {{ICD10|M|05||m|05}}-{{ICD10|M|06||m|05}} |
ICD9 = {{ICD9|714}} |
ICDO = |
OMIM = 180300 |
MedlinePlus = 000431 |
eMedicineSubj = med |
eMedicineTopic = 2024 |
eMedicine_mult = {{eMedicine2|emerg|48}} {{eMedicine2|pmr|124}} |
MeshID = D001172 |
}}
'''Rheumatoid arthritis''' ('''RA''') is a chronic, [[systemic disease|systemic]] [[autoimmunity|autoimmune disorder]] that causes the [[immune system]] to attack the [[joints]], where it causes inflammation ([[arthritis]]) and destruction, and some organs, such as the [[lung]]s and [[skin]]. It can be a disabling and [[pain]]ful condition, which can lead to substantial loss of functioning and mobility. It is diagnosed with [[blood test]]s (especially a test called [[rheumatoid factor]]) and [[medical imaging|X-rays]]. Diagnosis and long-term management are typically performed by a [[rheumatology|rheumatologist]], an expert in the diseases of joints and connective tissues.<ref name=Majithia2007/>
Various treatments are available. Non-pharmacological treatment includes [[physical therapy]] and [[occupational therapy]]. [[Analgesia]] (painkillers) and [[anti-inflammatory]] drugs, as well as [[glucocorticoid|steroids]], are used to suppress the symptoms, while [[disease-modifying antirheumatic drug]]s (DMARDs) are often required to reverse the disease process and prevent long-term damage; classic DMARDs are [[methotrexate]] and [[sulfasalazine]]. In recent times, the newer group of [[biologics]], which includes highly-effective agents such as [[infliximab]] (Remicade), [[etanercept]] (Enbrel), [[adalimumab]] (Humira), [[abatacept]] (Orencia) and [[rituximab]] (Rituxan/Mabthera), has increased treatment options.<ref name=Majithia2007/>
The name is based on the term "[[rheumatic fever]]", an illness which includes joint pain and is derived from the Greek word ''rheumatos'' ("flowing"). The suffix -''oid'' ("resembling") gives the translation as ''joint inflammation that resembles rheumatic fever''. The first recognized description of rheumatoid arthritis was made in 1800 by Dr [[Augustin Jacob Landré-Beauvais]] (1772-1840) of Paris.<ref name=Landre1800/>
==Signs and symptoms==
While rheumatoid arthritis primarily affects joints, problems involving all other organs of the body are known to occur. Extra-articular ("outside the joints") manifestations occur in about 15% of individuals with rheumatoid arthritis.<ref name="pmid12860726">{{cite journal |author=Turesson C, O'Fallon WM, Crowson CS, Gabriel SE, Matteson EL |title=Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years |journal=Ann. Rheum. Dis. |volume=62 |issue=8 |pages=722–7 |year=2003 |pmid=12860726| doi = 10.1136/ard.62.8.722}}</ref> It can be difficult to determine whether disease manifestations are directly caused by the rheumatoid process itself, or from side effects of the medications commonly used to treat it - for example, lung fibrosis from methotrexate, or osteoporosis from corticosteroids.
===Joints===
The arthritis of rheumatoid arthritis is due to [[synovitis]], which is inflammation of the [[synovial membrane]] that covers the joint. Joints become red, swollen, tender and warm, and stiffness prevents their use. By definition, RA affects multiple joints (it is a [[polyarthritis]]). Most commonly, small joints of the hands, feet and cervical spine are affected, but larger joints like the shoulder and knee can also be involved, differing per individual. Eventually, synovitis leads to erosion of the joint surface, causing deformity and loss of function.<ref name=Majithia2007>{{cite journal |author=Majithia V, Geraci SA |title=Rheumatoid arthritis: diagnosis and management |journal=Am. J. Med. |volume=120 |issue=11 |pages=936–9 |year=2007 |pmid=17976416 |doi=10.1016/j.amjmed.2007.04.005}}</ref>
Inflammation in the joints manifests itself as a soft, "doughy" swelling, causing pain and tenderness to palpation and movement, a sensation of localized warmth, and restricted movement. Increased stiffness upon waking is often a prominent feature and may last for more than an hour. These signs help distinguish rheumatoid from non-inflammatory diseases of the joints such as [[osteoarthritis]] (sometimes referred to as the "wear-and-tear" of the joints). In RA, the joints are usually affected in a fairly symmetrical fashion although the initial presentation may be asymmetrical.
[[Image:Arthrite rhumatoide.jpg|thumb|right|Hands affected by RA]]
As the pathology progresses the inflammatory activity leads to erosion and destruction of the joint surface, which impairs their range of movement and leads to deformity. The fingers are typically deviated towards the little finger (''[[ulnar deviation]]'') and can assume unnatural shapes. Common deformities in rheumatoid arthritis are the [[Boutonniere deformity]] (Hyperflexion at the [[proximal interphalangeal joint]] with hyperextension at the [[distal interphalangeal joint]]), [[swan neck deformity]] (Hyperextension at the proximal interphalangeal joint, hyperflexion at the distal interphalangeal joint). The thumb may develop a "Z-thumb" deformity with fixed flexion and [[subluxation]] at the [[metacarpophalangeal joint]], and hyperextension at the IP joint.
===Skin===
The ''[[rheumatoid nodule]]'' is the cutaneous (strictly speaking subcutaneous) feature most characteristic of rheumatoid arthritis. The initial pathologic process in nodule formation is unknown but is thought to be related to small-vessel inflammation. The mature lesion(a part of an organ or tissue which has been damaged) is defined by an area of central [[necrosis]] surrounded by palisading [[macrophages]] and [[fibroblasts]] and a cuff of cellular [[connective tissue]] and [[chronic inflammatory cells]]. 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 [[Calcaneus#Calcaneal_tuberosity|calcaneal tuberosity]], the metacarpophalangeal joints, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF titer and severe erosive arthritis. Rarely, they can occur in internal organs.
Several forms of ''[[vasculitis]]'' are also cutaneous manifestations associated with rheumatoid arthritis. 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 due to the presence of an obliterative cutaneous capillaropathy.
Other, rather rare, skin associated symtoms include:
*[[pyoderma gangrenosum]], a necrotizing, ulcerative, noninfectious neutrophilic dermatosis.
*[[Sweet's syndrome]], 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), and skin fragility (often worsened by corticosteroid use).
===Lungs===
[[Fibrosis]] of the [[lungs]] is a recognised response to rheumatoid disease. It is also a rare but well recognised consequence of therapy (for example with methotrexate and [[leflunomide]]). [[Caplan's syndrome]] describes lung nodules in individuals with rheumatoid arthritis and additional exposure to [[coal]] dust. [[Pleural effusion]]s are also associated with rheumatoid arthritis.
===Kidneys===
Renal [[amyloidosis]] can occur as a consequence of chronic inflammation. <ref>{{cite journal | author = de Groot K | title = [Renal manifestations in rheumatic diseases] | journal = Internist (Berl) | year = 2007 | month=Aug | volume=48 | issue=8 | pages=779-85 | pmid =17571244 | doi = 10.1007/s00108-007-1887-9}}</ref> Rheumatoid vasculitis is a rare cause of glomerular disease in the kidney. Treatment with [[Penicillamine]] and gold salts are recognized causes of [[membranous nephropathy]].
===Heart and blood vessels===
People with rheumatoid arthritis are more prone to [[atherosclerosis]], and risk of [[myocardial infarction]] (heart attack) and [[stroke]] is markedly increased.<ref>{{cite journal |author=Wolfe F, Mitchell DM, Sibley JT, ''et al'' |title=The mortality of rheumatoid arthritis |journal=Arthritis Rheum. |volume=37 |issue=4 |pages=481–94 |year=1994 |month=April |pmid=8147925}}</ref>
Other possible complications that may arise include: [[pericarditis]], [[endocarditis]], left ventricular failure, valvulitis and [[fibrosis]].{{fact | date=July 2008}}
===Other===
;Ocular: [[keratoconjunctivitis sicca]] (dry eyes), [[scleritis]], [[episcleritis]] and [[scleromalacia]].
;Gastrointestinal and hematological: [[Felty syndrome]], [[anemia]], [[thrombocytosis]].
;Neurological: [[peripheral neuropathy]] and [[mononeuritis multiplex]] may occur. The most common problem is carpal tunnel syndrome due to 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 rheumatoid arthritis.
;Vasculitis: [[Vasculitis]] in rheumatoid arthritis is common. It typically presents as vasculitic nailfold infarcts.
;Osteoporosis: [[Osteoporosis]] classically occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines.
;Lymphoma: The incidence of [[lymphoma]] is increased in RA as it is in most autoimmune conditions.{{fact|date=July 2008}}
==Diagnosis==
===X-rays===
X-rays of the hands and feet are generally performed in people with a polyarthritis. In rheumatoid arthritis, these may not show any changes in the early stages of the disease, but in more advanced cases demonstrates erosions and bone resorption. X-rays of other joints may be taken if symptoms of pain or swelling occur in those joints.{{fact|date=May 2008}}
===Blood tests===
When RA is clinically suspected, [[immunology|immunological]] studies are required, such as testing for the presence of rheumatoid factor (RF, a specific [[antibody]]).<ref>{{cite journal |author=Westwood OM, Nelson PN, Hay FC |title=Rheumatoid factors: what's new? |journal=Rheumatology (Oxford) |volume=45 |issue=4 |pages=379–85 |year=2006 |month=April |pmid=16418203 |doi=10.1093/rheumatology/kei228 |url=http://rheumatology.oxfordjournals.org/cgi/content/full/45/4/379}}</ref> A negative RF does not rule out RA; rather, the arthritis is called ''[[seronegative]]''. This is the case in 69% of patients.<ref name=Nishimura>{{cite journal |author=Nishimura K, Sugiyama D, Kogata Y, ''et al'' |title=Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis |journal=Ann. Intern. Med. |volume=146 |issue=11 |pages=797–808 |year=2007 |month=June |pmid=17548411 |doi= |url=http://www.annals.org/cgi/reprint/146/11/797 | format=PDF}}</ref> During the first year of illness, rheumatoid factor is frequently negative. 80% of these individuals eventually convert to seropositive status. RF is also seen in other illnesses, for example [[Sjögren's syndrome]], and in approximately 10% of the healthy population, therefore the test is not very specific.
Because of this low [[Specificity (tests)|specificity]], a new serological test has been developed, which tests for the presence of so called [[anti-citrullinated protein antibodies]] (ACPAs). Like RF, this test is positive in only a proportion (67%) of all RA cases, but is rarely positive if RA is not present, giving it a specificity of around 95%.<ref name=Nishimura/> In addition, ACPAs can sometimes be detected in early stages of the disease, even before onset of clinical disease.{{fact | date=July 2008}} Currently, the most common test for ACPAs is the anti-CCP ([[cyclic citrullinated peptide]]) test.
Also, several other blood tests are usually done to allow for other causes of arthritis, such as [[lupus erythematosus]]. The [[erythrocyte sedimentation rate]] (ESR), [[C-reactive protein]], [[full blood count]], [[renal function]], [[liver enzyme]]s and other immunological tests (e.g. [[antinuclear antibody]]/ANA) are all performed at this stage. Elevated [[ferritin]] levels can reveal [[hemochromatosis]], a mimic RA, or be a sign of [[Still's disease]] a seronegative, usually juvenile, variant of rheumatoid.{{fact | date=July 2008}}
===Diagnostic criteria===
The [[American College of Rheumatology]] has defined ([[1987]]) the following criteria for the classification of rheumatoid arthritis:<ref>{{cite journal | author = Arnett F, Edworthy S, Bloch D, McShane D, Fries J, Cooper N, Healey L, Kaplan S, Liang M, Luthra H | title = The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. | journal = Arthritis Rheum | volume = 31 | issue = 3 | pages = 315–24 | year = 1988 | pmid = 3358796 | url=http://www.rheumatology.org/publications/classification/ra/ra.asp?aud=mem | doi = 10.1002/art.1780310302 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
* Morning stiffness of >1 hour most mornings for at least 6 weeks.
* Arthritis and soft-tissue swelling of >3 of 14 joints/[[joint group]]s, present for at least 6 weeks
* Arthritis of hand joints, present for at least 6 weeks
* Symmetric arthritis, present for at least 6 weeks
* Subcutaneous nodules in specific places
* [[Rheumatoid factor]] at a level above the 95th percentile
* Radiological changes suggestive of joint erosion
At least four criteria have to be met for classification as RA. These criteria are not intended for the diagnosis for routine clinical care; they were primarily intended to categorize research. For example: one of the criteria is the presence of bone erosion on X-Ray. Prevention of bone erosion is one of the main aims of treatment because it is generally irreversible. To wait until all of the ACR criteria for rheumatoid arthritis are met may sometimes result in a worse outcome. Most sufferers and rheumatologists would agree that it would be better to treat the condition as early as possible and prevent bone erosion from occurring, even if this means treating people who don't fulfill the ACR criteria. The ACR criteria are, however, very useful for categorising established rheumatoid arthritis, for example for epidemiological purposes.{{fact|date=July 2008}}
===Differential diagnosis===
Several other medical conditions can resemble RA, and usually need to be distinguished from it at the time of diagnosis:<ref name=Merckmanual>{{cite book | editor= Berkow R | title=The Merck Manual | edition=16th | publisher=Merck Publishing Group |year=1992 | pages=1307-08 | isbn=0-91191-016-6}}</ref>
* Crystal induced arthritis ([[gout]], and [[pseudogout]]) - usually involves particular joints and can be distinguished with aspiration of joint fluid if in doubt
* [[Osteoarthritis]] - distinguished with [[X-ray]]s 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, [[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 and is usually diagnosed in males, although a RA-like symmetrical small-joint polyarthritis may occur in the context of this condition.
Rarer causes that usually behave differently but may cause joint pains:<ref name=Merckmanual/>
* [[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.
==Pathophysiology==
[[Image:Rheumatoid arthritis joint.gif|thumb|right|Joint abnormalities in rheumatoid arthritis]]
Rheumatoid arthritis is an autoimmune disease, the cause for which is still unknown. It is a systemic (whole body) disorder principally affecting synovial joints.
Chemical mediators (Cytokines) give rise to inflammation of joint synovium. Constitutional symptoms such as fever, malaise, loss of appetite and weight loss are also due to cytokines released in to the blood stream. Blood vessel inflammation (vasculitis) affecting many other organ systems can give rise to systemic complications. <ref>{{cite journal |author= Choy EHS, Panayi GS |title= Cytokine pathways and joint inflammation in rheumatoid arthritis. |journal= N Engl J Med |volume= 344|pages=907–916|year=2001|pmid= 11259725| doi = 10.1056/NEJM200103223441207}}</ref>
As with most autoimmune disease, it is important to distinguish between the cause(s) that trigger the inflammatory process, and those that permit it to persist and progress.
It has long been suspected that certain infections could be triggers for this disease. The "mistaken identity" theory suggests that an infection triggers an immune response, leaving behind antibodies that should be specific to that organism. The antibodies are not sufficiently specific, though, and set off an immune attack against part of the host. 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]]. Some infectious organisms suspected of triggering rheumatoid arthritis include ''[[Mycoplasma]]'', ''[[Erysipelothrix]]'', [[parvovirus|parvovirus B19]] and [[rubella]], ''but these associations have never been supported in epidemiological studies''. Nor has convincing evidence been presented for other types of triggers such as food allergies.
There is also no clear evidence that physical and emotional effects, stress and improper diet 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, as suggested by Edwards et al <ref>Edwards JC, Cambridge G, Abrahams VM. Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology. 1999;97:188-96.</ref>.
Epidemiological studies have confirmed a potential association between RA and two [[herpesvirus]] infections: [[Epstein-Barr virus]] (EBV) and [[Human Herpesvirus Six|Human Herpes Virus 6]] (HHV-6). <ref>{{cite journal |author=Alvarez-Lafuente R, Fernández-Gutiérrez B, de Miguel S, ''et al'' |title=Potential relationship between herpes viruses and rheumatoid arthritis: analysis with quantitative real time polymerase chain reaction |journal=Ann. Rheum. Dis. |volume=64 |issue=9 |pages=1357–9 |year=2005 |month=September |pmid=16100341 |doi=10.1136/ard.2004.033514 |url=http://ard.bmj.com/cgi/content/abstract/64/9/1357}}</ref> Individuals with RA are more likely to exhibit an abnormal immune response to the Epstein-Barr virus. <ref name = Ferrell>{{cite journal |author=Ferrell PB, Aitcheson CT, Pearson GR, Tan EM |title=Seroepidemiological study of relationships between Epstein-Barr virus and rheumatoid arthritis |journal=J. Clin. Invest. |volume=67 |issue=3 |pages=681–7 |year=1981 |month=March |pmid=6259207 |pmc=370617 |doi=10.1172/JCI110083}}</ref><ref>{{cite journal |author=Catalano MA, Carson DA, Slovin SF, Richman DD, Vaughan JH |title=Antibodies to Epstein-Barr virus-determined antigens in normal subjects and in patients with seropositive rheumatoid arthritis |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=76 |issue=11 |pages=5825–8 |year=1979 |month=November |pmid=230491 |pmc=411744 |doi= |url=}}</ref> 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.<ref>{{cite journal |author=Balandraud N, Roudier J, Roudier C |title=Epstein-Barr virus and rheumatoid arthritis |journal=Autoimmun Rev |volume=3 |issue=5 |pages=362–7 |year=2004 |month=July |pmid=15288002 |doi=10.1016/j.autrev.2004.02.002 |url=}}</ref>
The factors that allow the inflammation, once initiated, to become permanent and chronic, are much more clearly understood. The genetic association with HLA-DR4 is believed to play a major role in this, as well as the newly discovered associations with the gene PTPN22 and with two additional genes <ref>{{cite journal |author=Plenge RM, Seielstad M, Padyukov L, ''et al'' |title=TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study |journal=N. Engl. J. Med. |volume=357 |issue=12 |pages=1199–209 |year=2007 |month=September |pmid=17804836 |doi=10.1056/NEJMoa073491}}</ref>, all involved in regulating immune responses. It has also become clear from recent studies that these genetic factors may interact with the most clearly defined environmental risk factor for rheumatoid arthritis, namely cigarette smoking <ref>{{cite journal |author=Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L |title=A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis |journal=Arthritis Rheum. |volume=50 |issue=10 |pages=3085–92 |year=2004 |month=October |pmid=15476204 |doi=10.1002/art.20553}}</ref> 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.
Autoimmune diseases require that the affected individual have a defect in the ability to distinguish foreign molecules from the body's own. There are markers on many cells that confer this self-identifying feature. However, some classes of markers allow for RA to happen. 90% of individuals with RA have the cluster of markers known as the HLA-DR4/DR1 cluster, whereas only 40% of unaffected [[Scientific control|controls]] do. Thus, in theory, RA requires susceptibility to the disease through genetic endowment with specific markers ''and'' an infectious event that triggers an autoimmune response.
Once triggered, B lymphocytes produce immunoglobins and rheumatoid factors of the IgG and IgM classes that are deposited in the tissue. This subsequently leads to the activation of the serum complement cascade and the recruitment of the phagocytic arm of the immune response, which further exacerbates the inflammation of the synovium, leading to edema, vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). Early and intermediate molecular mediators of inflammation include [[tumor necrosis factor alpha]] (TNF-α), [[interleukin]]s [[IL-1]], [[Interleukin 6|IL-6]], [[IL-8]] and [[IL-15]], [[transforming growth factor]] beta, [[fibroblast growth factor]] and [[platelet-derived growth factor]]. 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.
==Treatment==
There is no known cure for rheumatoid arthritis. However, many different types of treatment can be used to alleviate symptoms and/or to modify the disease process.
The goal of treatment in this chronic disease must be two-fold: to alleviate the current symptoms, and to prevent the future destruction of the joints and resulting handicap if the disease is left unchecked. These two goals may not always coincide: while pain relievers may achieve the first goal, they do not have any impact on the long-term consequences. For these reasons, most authorities believe that most RA should be treated by at least one specific anti-rheumatic medication, also named DMARD (see below), to which other medications and non-medical interventions can be added as needed.
[[Cortisone]] therapy has offered relief in the past, but its long-term effects have been deemed undesirable.<ref>{{cite journal | author=Boland EW, Headley NE | title=Results of long-continued cortisone administration in rheumatoid arthritis | journal=Calif Med | year=1951 | month=June | volume=74 | issue=6 | pages=416-423 | pmc=1520676}}</ref>. However, cortisone injections can be valuable adjuncts to a long-term treatment plan, and using low dosages of daily cortisone (e.g., prednisone or prednisolone, 5-7.5 mg daily) can also have an important benefit if added to a proper specific anti-rheumatic treatment.{{fact|date=July 2008}}
[[Pharmacology|Pharmacological]] treatment of RA can be divided into disease-modifying antirheumatic drugs (DMARDs), anti-inflammatory agents and [[analgesic]]s.<ref>{{cite journal | author = O'Dell J | title = Therapeutic strategies for rheumatoid arthritis. | journal = N Engl J Med | volume = 350 | issue = 25 | pages = 2591–602 | year = 2004 | pmid = 15201416 | doi = 10.1056/NEJMra040226}}</ref><ref>{{cite journal | author = Hasler P | title = Biological therapies directed against cells in autoimmune disease. | journal = Springer Semin Immunopathol | volume = 27 | issue = 4 | pages = 443–56 | year = 2006 | month=Jun | pmid = 16738955 | doi = 10.1007/s00281-006-0013-8 }}</ref> DMARDs have been found to produce durable remissions and delay or halt disease progression. In particular they prevent bone and joint damage from occurring secondary to the uncontrolled inflammation. This is important as such damage is usually irreversible. Anti-inflammatories and analgesics improve pain and stiffness but do not prevent joint damage or slow the disease progression.
There is an increasing recognition amongst rheumatologists that permanent damage to the joints occurs at a very early stage in the disease. In the past the strategy used was to start with just an anti-inflammatory drug, and assess progression clinically and using X-rays. If there was evidence that joint damage was starting to occur then a more potent DMARD would be prescribed. Tools such as 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. People with normal X-rays will often have erosions detectable by ultrasound that X ray could not demonstrate.
There may be other reasons why starting DMARDs early is beneficial as well as prevention of structural joint damage. In the early stage of the disease, the joints are increasingly infiltrated by cells of the immune system that signal to one another and are thought to set up self-perpetuating chronic inflammation. 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. Delaying therapy for as little as a few months after the onset of symptoms can result in worse outcomes in the long term. There is therefore considerable interest in establishing the most effective therapy with early arthritis, when they are most responsive to therapy and have the most to gain.<ref>{{cite journal | author = Vital E, Emery P | title = Advances in the treatment of early rheumatoid arthritis. | journal = Am Fam Physician | volume = 72 | issue = 6 | pages = 1002, 1004 | year = 2005 | month=Sep 15 | pmid = 16190499 | url=http://www.aafp.org/afp/20050915/editorials.html}}</ref>
Treatment also includes rest and physical activity. Regular exercise is important for maintaining joint mobility and making the joint muscles stronger. Swimming is especially good, as it allows for exercise with a minimum of stress on the joints. Heat and cold applications are modalities that can ease symptoms before and after exercise. Pain in the joints is sometimes alleviated by oral [[acetaminophen]] (paracetamol). Other areas of the body, such as the eyes and lining of the heart, are treated individually. However, there is no diet that has been shown to alleviate rheumatoid arthritis, although fish oil may have anti-inflammatory effects.
===Disease modifying anti-rheumatic drugs (DMARDs)===
The term "disease modifying anti-rheumatic drug" was originally introduced to indicate a drug that reduced evidence of processes thought to underly the disease, such as a raised erythrocyte sedimentation rate, reduced haemoglobin level, raised rheumatoid factor level and more recently, raised C-reactive protein level. More recently, the term has been used to indicate a drug that reduces the rate of damage to bone and cartilage. DMARDs can be further subdivided into traditional small molecular mass drugs synthesised chemically and newer 'biological' agents produced through genetic engineering.
Traditional small molecular mass drugs:
*[[azathioprine]]
*[[ciclosporin]] (cyclosporine A)
*[[D-penicillamine]]
*[[gold salts]]
*[[hydroxychloroquine]]
*leflunomide
*methotrexate (MTX)
*[[minocycline]]
*sulfasalazine (SSZ)
Cytotoxic drugs:
*[[Cyclophosphamide]]
The most important and most common adverse events relate to [[liver]] and [[bone marrow]] toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds, D-penicillamine), renal toxicity (cyclosporine A, parenteral gold salts, D-penicillamine), pneumonitis (MTX), allergic skin reactions (gold compounds, SSZ), autoimmunity (D-penicillamine, SSZ, minocycline) and infections (azathioprine, cyclosporine A). Hydroxychloroquine may cause ocular toxicity, 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. Unfortunately hydroxychloroquine is not very potent, and is usually insufficient to control symptoms on its own.
Many rheumatologists consider methotrexate to be the most important and useful DMARD, largely because of lower drop-out rates for reasons of toxicity. Nevertheless, methotrexate is often considered as a very 'toxic' drug. This reputation is not entirely justified, and at times can result in people being denied the most effective treatment for their arthritis. Although methotrexate does have the potential to suppress bone marrow or cause hepatitis, these effects can be monitored using regular blood tests, 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). In clinical trials, where one of a range of different DMARDs were used, 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). 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, especially the biological agents. Other DMARDs may not be as effective or as safe in combination with biological agents.
====Biological agents====
Biological agents (biologics) include:
*[[tumor necrosis factor alpha]] (TNFα) blockers - [[etanercept]] (Enbrel), [[infliximab]] (Remicade), [[adalimumab]] (Humira)
*[[Interleukin 1]] (IL-1) blockers - [[anakinra]] (Kineret)
* [[monoclonal antibody|monoclonal antibodies]] against [[B cell]]s - [[rituximab]] (Rituxan)<ref>{{cite journal | author = Edwards J, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close D, Stevens R, Shaw T | title = Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. | journal = N Engl J Med | volume = 350 | issue = 25 | pages = 2572–81 | year = 2004 | pmid = 15201414 | doi = 10.1056/NEJMoa032534 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
* [[T cell]] activation blocker - [[abatacept]] (Orencia)
===Anti-inflammatory agents and analgesics===
Anti-inflammatory agents include:
*[[glucocorticoids]]
*[[Non-steroidal anti-inflammatory drug]] (NSAIDs, most also act as analgesics)
Analgesics include:
*acetaminophen (Paracetamol outside US)
*[[opiates]]
*[[diproqualone]]
*[[lidocaine]] topical
The [[Prosorba column]] blood filtering device was approved by the FDA for treatment of RA in 1999 <ref>Fresenius HemoCare, Inc., "New Hope for Rheumatoid Arthritis Patients," press release, September 17, 1999.</ref> However, the results have been very modest.{{fact|date=July 2008}}
Historic treatments for RA have also included: [[RICE (medicine)|rest, ice , compression and elevation]], [[acupuncture]], [[apple]] diet, [[nutmeg]], some light exercise every now and then, [[nettle]]s, [[bee]] venom, [[copper]] bracelets, [[rhubarb diet]], rest, extractions of teeth, [[fasting]], [[honey]], [[vitamin]]s, [[insulin]], [[magnet]]s, and [[electroconvulsive therapy]] (ECT).<ref>{{cite journal |author=Hart FD |title=History of the treatment of rheumatoid arthritis |journal=Br Med J |volume=1 |issue=6012 |pages=763–5 |year=1976 |month=March |pmid=177148 |pmc=1639217}}</ref>. Most of these have either had no effect at all, or their effects have been modest and transient, while not being generalizable.
===Other therapies===
Other therapies are [[weight loss]], occupational therapy, [[podiatry]], [[physiotherapy]], [[joint injection]]s, and special tools to improve hard movements (e.g. special tin-openers).
[[Radon therapy]], popular in Germany and Eastern Europe, can induce beneficial long-term effects for rheumatoid arthritis.<ref>{{cite journal |author=Franke A, Reiner L, Pratzel HG, Franke T, Resch KL |title=Long-term efficacy of radon spa therapy in rheumatoid arthritis--a randomized, sham-controlled study and follow-up |journal=Rheumatology (Oxford) |volume=39 |issue=8 |pages=894–902 |year=2000 |month=August |pmid=10952746 |doi= |url=http://rheumatology.oxfordjournals.org/cgi/content/full/39/8/894}}</ref>
Severely affected joints may require [[joint replacement]] surgery, such as knee replacement.
==Prognosis==
The course of the disease varies greatly. Some people have mild short-term symptoms, but in most the disease is progressive for life. Around 20%-30% will have subcutaneous nodules (known as rheumatoid nodules); this is associated with a poor prognosis.
===Disability===
*Daily living activities are impaired in most individuals.
*After 5 years of disease, approximately 33% of sufferers will not be working
*After 10 years, approximately half will have substantial functional disability.
===Prognostic factors===
Poor prognostic factors include persistent synovitis, early erosive disease, extra-articular findings (including subcutaneous rheumatoid nodules), positive serum RF findings, positive serum anti-CCP autoantibodies, carriership of HLA-DR4 "Shared Epitope" alleles, family history of RA, poor functional status, socioeconomic factors, elevated acute phase response (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]), and increased clinical severity.
===Mortality===
Estimates of the life-shortening effect of RA vary; most sources cite a lifespan reduction of 5 to 10 years. According to the [[UK]]'s National Rheumatoid Arthritis Society, "Young age at onset, long disease duration, the concurrent presence of other health problems (called co-morbidity), and characteristics of severe RA – such as poor functional ability or overall health status, a lot of joint damage on x-rays, the need for hospitalisation or involvement of organs other than the joints – have been shown to associate with higher mortality".<ref>[http://www.rheumatoid.org.uk/article.php?article_id=112 Excess mortality in rheumatoid arthritis]</ref> Positive responses to treatment may indicate a better prognosis. A 2005 study by the [[Mayo Clinic]] noted that RA sufferers suffer a doubled risk of heart disease,<ref>[http://www.mayoclinic.org/news2005-rst/2654.html The second largest contributor of mortality is cerebrovascular disease. Increased risk of heart disease in rheumatoid arthritis patients]</ref> independent of other risk factors such as [[diabetes]], alcohol abuse, and elevated [[cholesterol]], blood pressure and [[body mass index]]. The mechanism by which RA causes this increased risk remains unknown; the presence of chronic inflammation has been proposed as a contributing factor.<ref>[http://www.hopkins-arthritis.org/news-archive/2002/cardiac.html Cardiac disease in rheumatoid arthritis]</ref>
==Epidemiology==
The [[incidence (epidemiology)|incidence]] of RA is in the region of 3 cases per 10,000 population per annum. Onset is uncommon under the age of 15 and from then on the incidence rises with age until the age of 80. The [[prevalence]] rate is 1%, with women affected three to five times as often as men. It is 4 times more common in smokers than non-smokers. Some [[Indigenous peoples of the Americas|Native American]] groups have higher prevalence rates (5-6%) and people from the [[Caribbean]] region have lower prevalence rates. First-degree relatives prevalence rate is 2-3% and disease [[genetic concordance]] in [[Twin#Identical twins|monozygotic twins]] is approximately 15-20%.{{fact|date=July 2008}}
It is strongly associated with the inherited tissue type [[Major histocompatibility complex]] (MHC) antigen [[Human leukocyte antigen|HLA]]-DR4 (most specifically DR0401 and 0404) — hence family history is an important risk factor.{{fact|date=July 2008}}
Rheumatoid arthritis affects women three times more often than men, and it can first develop at any age. The risk of first developing the disease (the disease [[incidence]]) appears to be greatest for women between 40 and 50 years of age, and for men somewhat later.<ref name="pmid17045630">{{cite journal |author=Alamanos Y, Voulgari PV, Drosos AA |title=Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review |journal=Semin. Arthritis Rheum. |volume=36 |issue=3 |pages=182–8 |year=2006 |pmid=17045630 |doi=10.1016/j.semarthrit.2006.08.006}}</ref> 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==
The first known traces of arthritis date back at least as far as [[4500 BC]]. A text dated [[123 AD]] first describes [[symptom]]s very similar to rheumatoid arthritis. It was noted in skeletal remains of Native Americans found in [[Tennessee]].<ref>http://mcclungmuseum.utk.edu/research/renotes/rn-05txt.htm Tennessee Origins of Rheumatoid Arthritis</ref> In the Old World the disease is vanishingly rare before the 1600s.<ref>http://www.arc.org.uk/newsviews/arctdy/104/bones.htm
Bones of Contention</ref> and on this basis investigators believe it spread across the Atlantic during the [[Age of Exploration]]. In [[1859]] the disease acquired its current name.
An anomaly has been noticed from investigation of Precolumbian bones. The bones from the Tennessee site show no signs of tuberculosis even though it was prevalent at the time throughout the Americas.<ref name="pmid14528501">{{cite journal |author=Rothschild BM, Rothschild C, Helbling M |title=Unified theory of the origins of erosive arthritis: conditioning as a protective/directing mechanism? |journal=J. Rheumatol. |volume=30 |issue=10 |pages=2095–102 |year=2003 |pmid=14528501 |doi=}}</ref> Jim Mobley, at Pfizer, has discovered a historical pattern of epidemics of tuberculosis followed by a surge in the number of rheumatoid arthritis cases a few generations later.<ref>[http://media.www.michigandaily.com/media/storage/paper851/news/2005/02/01/News/Scientist.Finds.Surprising.Links.Between.Arthritis.And.Tuberculosis-1428389.shtml?sourcedomain=www.michigandaily.com&MIIHost=media.collegepublisher.com Scientist finds surprising links between arthritis and tuberculosis]</ref> 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 depict the effects of rheumatoid arthritis, for it is presumed that he used his own hands as a model. In his later paintings, his rendered hands show increasing deformity consistent with the symptoms of the disease.<ref name="pmid7005475">{{cite journal |author=Appelboom T, de Boelpaepe C, Ehrlich GE, Famaey JP |title=Rubens and the question of antiquity of rheumatoid arthritis |journal=JAMA |volume=245 |issue=5 |pages=483–6 |year=1981 |pmid=7005475| doi = 10.1001/jama.245.5.483 <!--Retrieved from CrossRef by DOI bot-->}}</ref><ref>http://japan.medscape.com/viewarticle/538251 Did RA travel from New World to Old? The Rubens connection</ref>
Rheumatoid arthritis appears to have been depicted in 16th century paintings.<ref>{{cite journal |author= Dequeker J., Rico H.|title=Rheumatoid arthritis-like deformities in an early 16th-century painting of the Flemish-Dutch school |journal= JAMA|volume= 268|pages=249–251|year=1992|pmid=1608144 | doi = 10.1001/jama.268.2.249 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
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 [[Pitié-Salpêtrière Hospital|Salpêtrière Hospital]] in Paris.<ref name=Landre1800>{{cite book | author=Landré-Beauvais AJ | title=La goutte asthénique primitive (doctoral thesis) | year=1800 | location=Paris}} reproduced in {{cite journal |author=Landré-Beauvais AJ |title=The first description of rheumatoid arthritis. Unabridged text of the doctoral dissertation presented in 1800 |journal=Joint Bone Spine |volume=68 |issue=2 |pages=130–43 |year=2001 |month=March |pmid=11324929 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S1297319X00002475}}</ref> The name "rheumatoid arthritis" itself was coined in 1859 by British rheumatologist Dr [[Alfred Baring Garrod]].<ref>{{cite book |author=Garrod AB | title=The Nature and Treatment of Gout and Rheumatic Gout | year=1859 | publisher=Walton and Maberly | location=London}}</ref>
===Notable cases===
*[[Christiaan Barnard]], the first surgeon to perform a human-to-human heart transplant had to retire owing to the condition. He also wrote a book on living with arthritis.
*[[James Coburn]] claimed to have healed the condition using pills containing a sulfur-containing compound on his return to acting.
*[[Erik Lindbergh]], aviator and member of the [[X-Prize]] administration. Erik has been a spokesman for the arthritis drug [[Enbrel]], as a result of his success with the treatment.<ref>{{cite news|url=http://seattlepi.nwsource.com/business/113804_theinsider24.shtml|title=The Insider: Amgen recruits high-flier to help Enbrel sales take off|publisher=[[Seattle Post-Intelligencer]]|date=[[2007-11-07]]|accessdate=2003-03-24}}</ref>
*[[Kathleen Turner]] and [[Aida Turturro]] have worked to raise public awareness of the condition<ref>{{cite web |url=http://findarticles.com/p/articles/mi_pwwi/is_200308/ai_mark654573218 |title="Sopranos" Star Aida Turturro Brings Rheumatoid Arthritis Awareness Campaign to Philadelphia | Market Wire | Find Articles at BNET.com |accessdate=2007-12-18 |format= |work=}}</ref>
*[[Billy Bowden]], international cricket umpire who had to retire from active playing due to RA
==See also==
* [[Juvenile idiopathic arthritis]]
* [[Synovitis]]
* [[Biologics]]
* [[Arthritis Care]]
==References==
{{reflist|2}}
==External links==
* {{Dmoz|Health/Conditions_and_Diseases/Musculoskeletal_Disorders/Arthritis/Rheumatoid|Rheumatoid arthritis}}
* {{cite web | title=Rheumatoid Arthritis | url=http://www.arthritis.org/conditions/DiseaseCenter/RA/default.asp | publisher=Arthritis Foundation}}
* {{cite web | title=Rheumatoid Arthritis | url=http://www.arc.org.uk/arthinfo/patpubs/6033/6033.asp | publisher=Arthritis Research Campaign}}
* {{cite web | author=Charles Weber | title=History of rheumatoid arthritis | url= http://charles_w.tripod.com/arthritis2.html}}
{{Diseases of the musculoskeletal system and connective tissue}}
[[Category:Aging-associated diseases]]
[[Category:Arthritis]]
[[Category:Autoimmune diseases]]
[[Category:Diseases involving the fasciae]]
[[ar:التهاب المفاصل الرثياني]]
[[cs:Revmatoidní artritida]]
[[de:Rheumatoide Arthritis]]
[[es:Artritis reumatoide]]
[[fr:Polyarthrite rhumatoïde]]
[[it:Artrite reumatoide]]
[[he:דלקת מפרקים שיגרונית]]
[[nl:Reumatoïde artritis]]
[[ja:関節リウマチ]]
[[pl:Reumatoidalne zapalenie stawów]]
[[pt:Artrite reumatóide]]
[[ru:Ревматоидный артрит]]
[[fi:Nivelreuma]]
[[sv:Reumatoid artrit]]
[[tr:Romatoid artrit]]
[[zh:類風濕性關節炎]]