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| {{Infobox disease
| | The writer is known by the name of Numbers Lint. Her spouse and her reside in Puerto Rico but she will have to transfer one working day or an additional. Supervising is my occupation. To collect badges is what her family members and her enjoy.<br><br>my blog ... [http://4rt.us/dietmealsdelivered20142 weight loss food delivery] |
| | Name = Rheumatoid arthritis
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| | Image = Rheumatoid_Arthritis.JPG
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| | Caption = A hand affected by rheumatoid arthritis
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| | DiseasesDB = 11506
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| | ICD10 = {{ICD10|M|05||m|05}}-{{ICD10|M|06||m|05}}
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| | ICD9 = {{ICD9|714}}
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| | OMIM = 180300
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| | MedlinePlus = 000431
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| | eMedicineSubj = article
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| | eMedicineTopic = 331715
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| | eMedicine_mult = {{eMedicine2|article|1266195}} {{eMedicine2|article|305417}} {{eMedicine2|article|401271}} {{eMedicine2|article|335186}} {{eMedicine2|article|808419}}
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| | MeshID = D001172
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| }}
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| '''Rheumatoid arthritis ''' ('''RA''') is an [[autoimmune disease]] that results in a chronic, [[systemic disease|systemic]] [[inflammation|inflammatory disorder]] that may affect many tissues and organs, but principally attacks flexible ([[synovial joints|synovial]]) joints. It can be a disabling and [[pain]]ful condition, which can lead to substantial loss of functioning and mobility if not adequately treated.
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| The process involves an inflammatory response of the capsule around the joints ([[synovium]]) secondary to swelling ([[turgescence]]) of synovial cells, excess synovial fluid, and the development of fibrous tissue ([[pannus]]) in the synovium. The [[pathology]] of the disease process often leads to the destruction of articular cartilage and [[ankylosis]] (fusion) of the joints. RA can also produce diffuse inflammation in the [[lung]]s, the membrane around the heart ([[pericardium]]), the membranes of the lung ([[pleura]]), and white of the eye ([[sclera]]), and also nodular lesions, most common in [[subcutaneous tissue]]. Although the cause of RA is unknown, [[autoimmunity]] plays a big part, and RA is a [[systemic autoimmune disease]]. It is a [[clinical diagnosis]] made on the basis of symptoms, physical exam, radiographs ([[medical imaging|X-rays]]) and labs.<ref name=Majithia2007/>
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| Treatments are pharmacological and non-pharmacological. Non-pharmacological treatment includes [[physical therapy]], [[orthoses]], [[occupational therapy]] and nutritional therapy but these don't stop the progression of joint destruction. [[Analgesics]] (painkillers) and [[anti-inflammatory]] drugs, including [[glucocorticoid|steroids]], suppress symptoms, but don't stop the progression of joint destruction either. [[Disease-modifying antirheumatic drug]]s (DMARDs) slow or halt the progress of the disease. The newer [[biologic medical product|biologics]] are DMARDs.<ref name=Majithia2007/> The evidence for [[complementary and alternative medicine]] (CAM) treatments for RA related pain is weak,<ref name=Efthimiou>{{cite journal|last=Efthimiou|first=P|coauthors=Kukar, M|title=Complementary and alternative medicine use in rheumatoid arthritis: proposed mechanism of action and efficacy of commonly used [[modality|modalities]].|journal=Rheumatology international|year=2010 |volume=30|issue=5|pages=571–86|pmid=19876631|doi=10.1007/s00296-009-1206-y}}</ref> with the lack of high quality evidence leading to the conclusions that their use is currently not supported by the evidence.<ref name = Macfarlane/> Patients should inform their health care provider of any CAM treatments and continue taking traditional treatments.<ref name=NCCAM/>
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| About 0.6% of the United States adult population has RA, women two to three times as often as men.<ref>{{cite journal|last=Helmick|first=CG|coauthors=Felson, DT; Lawrence, RC; Gabriel, S; Hirsch, R; Kwoh, CK; Liang, MH; Kremers, HM; Mayes, MD; Merkel, PA; Pillemer, SR; Reveille, JD; Stone, JH; National Arthritis Data, Workgroup|title=Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I|journal=Arthritis and rheumatism|date=January 2008|volume=58|issue=1|pages=15–25|pmid=18163481|doi=10.1002/art.23177}}</ref> Onset is most frequent during middle age, but people of any age can be affected.<ref>
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| {{cite web
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| |url=http://www.niams.nih.gov/Health_Info/Rheumatic_Disease/default.asp
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| |title=Handout on Health: Rheumatoid Arthritis
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| |publisher=[[National Institute of Arthritis and Musculoskeletal and Skin Diseases]]
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| |date=April 2009
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| |accessdate=2013-03-26
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| }}</ref>
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| The name is based on the term "[[rheumatic fever]]", an illness which includes joint pain and is derived from the Greek word ''ῥεύμα-rheuma (nom.), ῥεύματος-rheumatos (gen.)'' ("flow, current"). The suffix -''oid'' ("resembling") gives the translation as ''joint inflammation that resembles rheumatic fever''. The first recognized description of RA was made in 1800 by Dr. [[Augustin Jacob Landré-Beauvais]] (1772–1840) of Paris.<ref name=Landre1800/>
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| {{TOC limit|3}}
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| ==Signs and symptoms==
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| RA primarily affects [[joints]], however it also affects other [[Organ (anatomy)|organs]] in 15–25% of individuals.<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 |pmc=1754626}}</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 used to treat it – for example, [[lung fibrosis]] from [[methotrexate]] or [[osteoporosis]] from corticosteroids.
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| ===Joints===
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| [[File:Rheumatoid arthritis joint.gif|thumb|A diagram showing how rheumatoid arthritis affects a joint]]
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| [[Arthritis]] of joints involves inflammation of the [[synovial membrane]]. Joints become swollen, tender and warm, and stiffness limits their movement. With time, multiple joints are affected (it is a [[polyarthritis]]). Most commonly involved are the small joints of the [[hand]]s, [[foot|feet]] and [[cervical spine]], but larger joints like the shoulder and knee can also be involved.<ref name=DAVIDSONS2010 /> {{rp|1089}} Synovitis can lead to [[Tether (cell biology)|tethering]] of tissue with loss of movement and 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>
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| RA typically manifests with signs of inflammation, with the affected joints being swollen, warm, painful and stiff, particularly early in the morning on waking or following prolonged inactivity. Increased stiffness early in the morning is often a prominent feature of the disease and typically lasts for more than an hour. Gentle movements may relieve symptoms in early stages of the disease. These signs help distinguish rheumatoid from non-inflammatory problems of the joints, often referred to as [[osteoarthritis]] or "wear-and-tear" arthritis. In arthritis of non-inflammatory causes, signs of inflammation and early morning stiffness are less prominent with stiffness typically less than 1 hour, and movements induce pain caused by mechanical arthritis.<ref>{{cite web|url=http://pn.lifehugger.com/doc/459/An_approach_to_Early_Arthritis |archiveurl=http://web.archive.org/web/20100527035630/http://pn.lifehugger.com/doc/459/An_approach_to_Early_Arthritis |archivedate=2010-05-27 |title=An approach to Early Arthritis|publisher=Pn.lifehugger.com|date=12 January 2009}}</ref>
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| The pain associated with RA is induced at the site of inflammation and classified as nociceptive as opposed to neuropathic.<ref>{{cite journal |author=Gaffo A, Saag KG, Curtis JR |title=Treatment of rheumatoid arthritis |journal=Am J Health Syst Pharm |volume=63 |pages=2451–2465 |year=2006}}</ref> The joints are often affected in a fairly symmetrical fashion, although this is not specific, and the initial presentation may be asymmetrical.<ref name=DAVIDSONS2010>{{cite book|first=the editors Nicki R. Colledge, Brian R. Walker, Stuart H. Ralston ; illustated by Robert Britton|title=Davidson's principles and practice of medicine.|year=2010|publisher=Churchill Livingstone/Elsevier|location=Edinburgh|isbn=978-0-7020-3084-0|edition=21st ed.}}</ref> {{rp|1089}}
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| As the pathology progresses the inflammatory activity leads to tendon tethering and erosion and destruction of the joint surface, which impairs range of movement and leads to deformity. The fingers may suffer from almost any deformity depending on which joints are most involved. Specific deformities, which also occur in osteoarthritis, include [[ulnar deviation]], [[boutonniere deformity]], [[swan neck deformity]] and "Z-thumb." "Z-thumb" or "Z-deformity" consists of [[hyperextension]] of the [[interphalangeal joint]], fixed [[flexion]] and [[subluxation]] of the [[metacarpophalangeal joint]] and gives a "Z" appearance to the thumb.<ref name=DAVIDSONS2010 /> {{rp|1089}} The [[hammer toe]] deformity may be seen. In the worst case, joints are known as [[arthritis mutilans]] due to the mutilating nature of the deformities. {{citation needed|date=October 2013}}
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| ===Skin===
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| The ''[[rheumatoid nodule]]'', which is sometimes [[cutaneous]], is the feature most characteristic of RA. It is a type of inflammatory reaction known to pathologists as a "[[necrotizing]] [[granuloma]]". The [[initial]] pathologic process in nodule formation is unknown but may be essentially the same as the synovitis, since similar structural features occur in both. The nodule has a central area of [[fibrinoid necrosis]] that may be [[fissure]]d and which corresponds to the [[fibrin]]-rich necrotic material found in and around an affected synovial space. Surrounding the necrosis is a layer of [[palisading]] [[macrophages]] and [[fibroblasts]], corresponding to the [[intimal layer]] in synovium and a cuff of [[connective tissue]] containing clusters of [[lymphocyte]]s and [[plasma cell]]s, corresponding to the [[subintimal zone]] in synovitis. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences, such as the [[olecranon]], the [[calcaneal tuberosity]], the [[metacarpophalangeal joints|metacarpophalangeal joint]], or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF ([[rheumatoid factor]]) [[titer]] and severe erosive arthritis. Rarely, these can occur in internal organs or at diverse sites on the body.
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| Several forms of ''[[vasculitis]]'' occur in RA. A [[benign]] form occurs as [[microinfarct]]s around the [[Paronychium|nailfold]]s. More severe forms include [[livedo reticularis]], which is a network (reticulum) of [[erythematous]] to purplish discoloration of the skin caused by the presence of an obliterative cutaneous [[capillaropathy]].
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| Other, rather rare, skin associated symptoms include [[pyoderma gangrenosum]], [[Sweet's syndrome]], drug reactions, [[erythema nodosum]], lobe [[panniculitis]], [[atrophy]] of finger skin, [[palmar erythema]], diffuse thinning (rice paper skin), and skin fragility (often worsened by corticosteroid use).
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| ===Lungs===
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| [[Fibrosis]] of the [[lungs]] is a recognized response to rheumatoid disease. It is also a rare but well recognized consequence of therapy (for example with [[methotrexate]] and [[leflunomide]]). [[Caplan's syndrome]] describes lung nodules in individuals with RA and additional exposure to [[coal]] dust. [[Pleural effusion]]s are also associated with RA. Another complication of RA is [[Rheumatoid Lung Disease]]. It is estimated that about one quarter of Americans with RA develop Rheumatoid Lung Disease.<ref>{{cite web|url=http://arthritis.about.com/od/rheumatoidarthritis/a/rheumatoidlung.htm |title=Rheumatoid Lung Disease – What Is Rheumatoid Lung Disease? |publisher=Arthritis.about.com |date=February 27, 2011 |accessdate=March 3, 2011}}</ref>
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| ===Kidneys===
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| 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) |date=August 2007 | volume=48 | issue=8 | pages=779–85 | pmid =17571244 | doi = 10.1007/s00108-007-1887-9}}</ref> RA may affect the kidney [[glomerulus]] directly through a [[vasculopathy]] or a [[Mesangium|mesangial]] [[Infiltration (medical)|infiltrate]] but this is less well documented (though this is not surprising, considering immune complex-mediated hypersensitivities are known for [[pathogenic]] deposition of immune complexes in organs where blood is filtered at high pressure to form other fluids, such as urine and synovial fluid<ref name="Robbins&Cotran2010">{{cite book | last1 = Robbins | first1 = Stanley Leonard | last2 = Kumar | first2 = Vinay | last3 = Abbas | first3 = Abdul K. | last4 = Cotran | first4 = Ramzi S. | last5 = Fausto | first5 = Nelson | title = Robbins and Cotran pathologic basis of disease | editors = Vinay Kumar, Abul K. Abbas, Nelson Fausto | work = Robbins Pathology Series | publisher = Elsevier | year = 2010 | page = 205 |isbn = 978-1-4160-3121-5}}</ref>). Treatment with [[Penicillamine]] and [[gold salts]] are recognized causes of [[membranous nephropathy]].
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| ===Heart and blood vessels===
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| People with RA are more prone to [[atherosclerosis]], and risk of [[myocardial infarction]] (heart attack) and [[stroke]] is markedly increased.<ref>{{cite journal |author=Wolfe F |title=The mortality of rheumatoid arthritis |journal=Arthritis Rheum. |volume=37 |issue=4 |pages=481–94 |date=April 1994 |pmid=8147925 |doi=10.1002/art.1780370408 |author2=Mitchell DM |author3=Sibley JT |last4=Fries |first4=James F. |last5=Bloch |first5=Daniel A. |last6=Williams |first6=Catherine A. |last7=Spitz |first7=Patricia W. |last8=Haga |first8=May |last9=Kleinheksel |first9=Sue M.}}</ref><ref>{{cite journal |author=Aviña-Zubieta JA |title=Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies |journal=Arthritis Rheum. |volume=59 |pages=1690–1697 |year=2008 |pmid=19035419 |doi=10.1002/art.24092 |issue=12 |author2=Choi HK |author3=Sadatsafavi M |last4=Etminan |first4=Mahyar |last5=Esdaile |first5=John M. |last6=Lacaille |first6=Diane }}</ref>
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| Other possible complications that may arise include: [[pericarditis]], [[endocarditis]], left ventricular failure, valvulitis and [[fibrosis]].<ref name="Gupta">{{cite journal |author=Gupta A and Fomberstein B |title=Evaluating cardiovascular risk in rheumatoid arthritis |journal=Journal of Musculoskeletal Medicine |volume=26 |issue=8 |pages=481–94 |year=2009 |url=http://www.musculoskeletalnetwork.com/rheumatoid-arthritis/content/article/1145622/1433094}}</ref> Many people with RA do not experience the same chest pain that others feel when they have angina or myocardial infarction. To reduce cardiovascular risk, it is crucial to maintain optimal control of the inflammation caused by RA (which may be involved in causing the cardiovascular risk), and to use exercise and medications appropriately to reduce other cardiovascular risk factors such as blood lipids and blood pressure. Doctors who treat RA patients should be sensitive to cardiovascular risk when prescribing anti-inflammatory medications, and may want to consider prescribing routine use of low doses of aspirin if the gastrointestinal effects are tolerable.<ref name="Gupta"/>
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| ===Other===
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| ;Ocular: The eye is directly affected in the form of [[episcleritis]] which when severe can very rarely progress to perforating [[scleromalacia]]. Rather more common is the indirect effect of [[keratoconjunctivitis sicca]], which is a dryness of eyes and mouth caused by [[lymphocyte]] infiltration of [[lacrimal gland|lacrimal]] and [[salivary gland]]s. When severe, dryness of the cornea can lead to [[keratitis]] and loss of vision. Preventive treatment of severe dryness with measures such as [[nasolacrimal duct]] blockage is important.
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| ;[[Hepatic]]: [[Cytokine]] production in joints and/or hepatic (liver) [[Kupffer cells]] leads to increased activity of [[hepatocyte]]s with increased production of [[acute-phase protein]]s, such as [[C-reactive protein]], and increased release of [[enzyme]]s such as [[alkaline]] [[phosphatase]] into the blood. In [[Felty's syndrome]], Kupffer cell activation is so marked that the resulting increase in hepatocyte activity is associated with nodular [[hyperplasia]] of the liver, which may be palpably enlarged. Although Kupffer cells are within the hepatic [[parenchyma]], they are separate from hepatocytes. As a result there is little or no microscopic evidence of [[hepatitis]] (immune-mediated destruction of hepatocytes). Hepatic involvement in RA is essentially asymptomatic.
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| ;[[Hematology|Hematological]]: [[Anemia]] is by far the most common abnormality of the blood cells which can be caused by a variety of mechanisms. The chronic inflammation caused by RA leads to raised [[hepcidin]] levels, leading to [[anemia of chronic disease]] where iron is poorly absorbed and also sequestered into [[macrophages]]. RA may also cause a [[warm autoimmune hemolytic anemia]].<ref>Citation: H. Rehman : Hemolytic Anemia following Mycoplasma Infection . The Internet Journal of Hematology. 2008 Volume 4 Number 1 [http://www.ispub.com/journal/the_internet_journal_of_hematology/volume_4_number_1_22/article/hemolytic_anemia_following_mycoplasma_infection.html]</ref> The red cells are of normal size and colour (normocytic and normochromic). A low white blood cell count ([[neutropenia]]) usually only occurs in patients with [[Felty's syndrome]] with an enlarged liver and spleen. The mechanism of neutropenia is complex. An increased [[platelet]] count ([[thrombocytosis]]) occurs when inflammation is uncontrolled.
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| ;Neurological: [[Peripheral neuropathy]] and [[mononeuritis multiplex]] may occur. The most common problem is [[carpal tunnel syndrome]] caused by compression of the median nerve by swelling around the wrist. [[Atlanto-axial joint|Atlanto-axial]] [[subluxation]] can occur, owing to erosion of the [[odontoid process]] and/or [[transverse ligament]]s in the [[cervical spine]]'s connection to the skull. Such an erosion (>3mm) can give rise to [[vertebrae]] slipping over one another and compressing the spinal cord. Clumsiness is initially experienced, but without due care this can progress to [[quadriplegia]].
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| ;Constitutional symptoms: [[Constitutional symptoms]] including [[fatigue (medical)|fatigue]], low grade [[fever]], [[malaise]], [[morning stiffness]], [[loss of appetite]] and [[loss of weight]] are common systemic manifestations seen in patients with active RA.
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| ;Osteoporosis: Local [[osteoporosis]] occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines. More general osteoporosis is probably contributed to by immobility, systemic cytokine effects, local cytokine release in bone marrow and corticosteroid therapy.
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| ;Lymphoma: The incidence of [[lymphoma]] is increased in RA, although it is still uncommon.<ref>{{Cite pmid|16508929}}</ref><ref>{{Cite pmid|16249224}}</ref>
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| == Causes ==
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| RA is a form of autoimmunity, the causes of which are still not completely known. It is a systemic (whole body) disorder principally affecting synovial tissues. There is no evidence that physical and emotional effects or stress could be a trigger for the disease. The many negative findings suggest that either the trigger varies, or that it might in fact be a chance event inherent with the immune response<ref>{{cite journal|author=Edwards JC, Cambridge G, Abrahams VM |title=Do self-perpetuating B lymphocytes drive human autoimmune disease? |journal=Immunology|volume=97|issue=2 |pages=188–96 |year=1999|pmid=10447731 |pmc=2326840 |doi=10.1046/j.1365-2567.1999.00772.x}}</ref>
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| Half of the risk for RA is believed to be genetic.<ref name=Lancet2010>{{cite journal|last=Scott|first=DL|coauthors=Wolfe, F; Huizinga, TW|title=Rheumatoid arthritis|journal=Lancet|date=Sep 25, 2010|volume=376|issue=9746|pages=1094–108|pmid=20870100|doi=10.1016/S0140-6736(10)60826-4}}</ref> It is strongly associated with the inherited tissue type [[major histocompatibility complex]] (MHC) antigen [[Human leukocyte antigen|HLA]]-DR4 (most specifically DR0401 and 0404), and the genes PTPN22 and PADI4—hence family history is an important risk factor.<ref>{{cite journal|last=Plenge|first=Robert M.|coauthors=Seielstad, Padyukov|title=TRAF1–C5 as a Risk Locus for Rheumatoid Arthritis — A Genomewide Study|journal=The New England Journal of Medicine|date=05-09-2007|year=2007|volume=357|pages=1199–209|doi=10.1056/NEJMoa073491|pmid=17804836|issue=12|pmc=2636867}}</ref><ref>{{cite journal | author = Goeldner I, Skare TL, de Messias Reason IT, Nisihara RM, Silva MB, Utiyama SR |date=Aug 2010 | title = Anti-cyclic citrullinated peptide antibodies and rheumatoid factor in rheumatoid arthritis patients and relatives from Brazil | url = | journal = Rheumatology (Oxford) | volume = 49 | issue = 8| pages = 1590–3 | doi = 10.1093/rheumatology/keq134 | pmid = 20457731 }}</ref> Inheriting the PTPN22 gene has been shown to double a person's susceptibility to RA. PADI4 has been identified as a major risk factor in people of Asian descent, but not in those of European descent.<ref>{{cite web|title=The Genetics Behind Rheumatoid Arthritis|url=http://www.arthritis.org/genetics-ra.php|publisher=Arthritis Foundation|accessdate=17 December 2012}}</ref>
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| First-degree relatives prevalence rate is 2–3% and disease [[genetic concordance]] in [[monozygotic twins]] is approximately 15–20%.<ref>{{Cite pmid|8402000}}</ref><ref>{{Cite pmid|1616321}}</ref>
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| Smoking is the most significant non-genetic risk<ref name=Lancet2010/> with RA being up to three times more common in smokers than non-smokers, particularly in men, heavy smokers, and those who are rheumatoid factor positive.<ref name=Sugiyama2010/> Modest alcohol consumption may be protective.<ref>{{cite journal|last=Liao|first=KP|coauthors=Alfredsson, L; Karlson, EW|title=Environmental influences on risk for rheumatoid arthritis|journal=Current Opinion in Rheumatology|date=May 2009|volume=21|issue=3|pages=279–83|pmid=19318947|doi=10.1097/BOR.0b013e32832a2e16|pmc=2898190}}</ref>
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| 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 |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 |date=September 2005 |pmid=16100341 |doi=10.1136/ard.2004.033514|url=http://ard.bmj.com/cgi/content/abstract/64/9/1357|pmc=1755640|author2=Fernández-Gutiérrez B |author3=de Miguel S|last4=Jover|first4=JA |last5=Rollin |first5=R |last6=Loza |first6=E |last7=Clemente |first7=D |last8=Lamas|first8=JR}}</ref>
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| Individuals with RA are more likely to exhibit an abnormal immune response to EBV and have high levels of anti-EBV antibodies.<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|pmid=15288002|doi=10.1016/j.autrev.2004.02.002}}</ref>
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| [[Vitamin D deficiency]] is common in those with RA and may be causally associated.<ref name=Wen2011>{{cite journal|last=Wen|first=H|coauthors=Baker, JF|title=Vitamin D, immunoregulation, and rheumatoid arthritis|journal=Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases|date=March 2011|volume=17|issue=2|pages=102–7|pmid=21364350|doi=10.1097/RHU.0b013e31820edd18}}</ref> Some trials have found a decreased risk for RA with vitamin D supplementation while others have not.<ref name=Wen2011/>
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| ==Pathophysiology==
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| The key pieces of evidence relating to pathogenesis are:
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| #A genetic link with [[HLA-DR4]] and related allotypes of [[MHC Class II]] and the T cell-associated protein [[PTPN22]].
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| #An undeniable link to the pathogenesis of vascular disease of many types, including the possibility of a strong causal connection to rheumatoid vasculitis, a typical feature of this condition.<ref name="AlbanoSantana-Sahagun2001">{{cite journal|last1=Albano|first1=Shirley A.|last2=Santana-Sahagun|first2=Ernesto|last3=Weisman|first3=Michael H.|title=Cigarette smoking and rheumatoid arthritis|journal=Seminars in Arthritis and Rheumatism|volume=31|issue=3|year=2001|pages=146–159|doi=10.1053/sarh.2001.27719|pmid=11740796}}</ref>
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| #A remarkable deceleration of disease progression in many cases by blockade of the cytokine [[Tumor necrosis factors|TNF]] (alpha).
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| #A similar dramatic response in many cases to depletion of [[B lymphocyte]]s, but no comparable response to depletion of [[T lymphocyte]]s.
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| #A more or less random pattern of whether and when predisposed individuals are affected.
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| #The presence of autoantibodies to IgGFc, known as [[rheumatoid factor]]s (RF), and [[Anti-citrullinated protein antibody|antibodies to citrullinated peptide]]s (ACPA).
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| These data suggest that the disease involves abnormal B cell–T cell interaction, with presentation of antigens by B cells to T cells via HLA-DR eliciting T cell help and consequent production of RF and ACPA. Inflammation is then driven either by B cell or T cell products stimulating release of TNF and other cytokines. The process may be facilitated by an effect of smoking on [[citrullination]] but the stochastic (random) epidemiology suggests that the rate limiting step in genesis of disease in predisposed individuals may be an inherent stochastic process within the immune response such as immunoglobulin or T cell receptor gene recombination and mutation. (See entry under [[autoimmunity]] for general mechanisms.)
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| If TNF release is stimulated by B cell products in the form of RF or ACPA -containing immune complexes, through activation of immunoglobulin [[Fc receptor]]s, then RA can be seen as a form of [[Type III hypersensitivity]].<ref>{{cite web |url=http://www.path.sunysb.edu/coursemat/hbp310immun.htm |archiveurl=http://web.archive.org/web/20060807074858/http://www.path.sunysb.edu/coursemat/hbp310immun.htm |archivedate=2006-08-07 |title=HBP310 Immunology|work=SUNY Stony Brook Pathology Department |accessdate=September 20, 2008}}</ref><ref>{{cite web |url=http://pathmicro.med.sc.edu/ghaffar/hyper00.htm |author=Ghaffar, Abdul |work=University of South Carolina School of Medicine|title=Hypersensitivity reactions |accessdate=September 20, 2008}}</ref>
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| 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.<ref>{{cite web |url=http://www-immuno.path.cam.ac.uk/~immuno/part1/lec13/lec13_97.html|archiveurl=http://web.archive.org/web/20060206220202/http://www-immuno.path.cam.ac.uk/~immuno/part1/lec13/lec13_97.html|archivedate=2006-02-06|title=Lecture 14: Hypersensitivity|accessdate=September 20, 2008|author=Holmes, N. |year= 1999|work=Immunology Division, Department of Pathology, University of Cambridge}}</ref>
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| The debate on the relative roles of immune complexes and T cell products in inflammation in RA has continued for 30 years. There is little doubt that both B and T cells are essential to the disease. However, there is good evidence for neither cell being necessary at the site of inflammation. This tends to favour immune complexes (based on antibody synthesised elsewhere) as the initiators, even if not the sole perpetuators of inflammation. Moreover, work by Thurlings and others in Paul-Peter Tak's group and also by Arthur Kavanagh's group suggest that if any immune cells are relevant locally they are the plasma cells, which derive from B cells and produce in bulk the antibodies selected at the B cell stage.{{Citation needed|date=November 2009}}
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| Although TNF appears to be the dominant, other [[cytokines]] (chemical mediators) are likely to be involved in inflammation in RA. Blockade of TNF does not benefit all patients or all tissues (lung disease and nodules may get worse). Blockade of IL-1, [[Interleukin 15|IL-15]] and [[Interleukin 6|IL-6]] also have beneficial effects and [[Interleukin 17|IL-17]] may be important. Constitutional symptoms such as fever, malaise, loss of appetite and weight loss are also caused by cytokines released into the blood stream.
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| As with most autoimmune diseases, it is important to distinguish between the cause(s) that trigger the process, and those that may permit it to persist and progress.
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| === Abnormal immune response ===
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| The factors that allow an abnormal immune response, once initiated, to become permanent and chronic, are becoming more clearly understood. The genetic association with HLA-DR4, as well as the newly discovered associations with the gene [[PTPN22]] and with two additional genes,<ref>{{cite journal |author=Plenge RM |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 |pmid=17804836 |doi=10.1056/NEJMoa073491 |pmc=2636867 |author2=Seielstad M |author3=Padyukov L|last4=Lee |first4=Annette T. |last5=Remmers |first5=Elaine F. |last6=Ding |first6=Bo |last7=Liew |first7=Anthony |last8=Khalili |first8=Houman |last9=Chandrasekaran |first9=Alamelu}}</ref> all implicate altered thresholds in regulation of the adaptive immune response. It has also become clear from recent studies that these genetic factors may interact with the most clearly defined environmental risk factor for RA, namely cigarette smoking<ref name=Sugiyama2010>{{cite journal |author=Sugiyama D, Nishimura K, Tamaki K, Tsuji G, Nakazawa T, Morinobu A, Kumagai S |title=Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies |journal=Ann Rheum Dis. |volume=69 |issue=1 |pages=70–81 |year=2010 |url=http://ard.bmj.com/content/69/01/70.abstract |doi=10.1136/ard.2008.096487 |pmid=19174392}}</ref><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 |pmid=15476204 |doi=10.1002/art.20553}}</ref>
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| Other environmental factors also appear to modulate the risk of acquiring RA, and hormonal factors in the individual may explain some features of the disease, such as the higher occurrence in women, the not-infrequent onset after child-birth, and the (slight) modulation of disease risk by hormonal medications. Exactly how altered regulatory thresholds allow the triggering of a specific autoimmune response remains uncertain. However, one possibility is that negative feedback mechanisms that normally maintain tolerance of self are overtaken by aberrant positive feedback mechanisms for certain antigens such as IgG Fc (bound by RF) and citrullinated fibrinogen (bound by ACPA) (see entry on [[autoimmunity]]).
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| Once the abnormal immune response has become established (which may take several years before any symptoms occur), plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes in large quantities. These are not deposited in the way that they are in systemic lupus. Rather, they activate macrophages through Fc receptor and complement binding, which seems to play an important role in the intense inflammatory response present in RA.<ref>Boldt AB, Goeldner I, de Messias-Reason IJ. Relevance of the lectin pathway of complement in rheumatic diseases. Adv Clin Chem. 2012;56:105-53. Review. [[PMID]]: [[22397030]]</ref> This contributes to inflammation of the synovium, in terms of edema, vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). Synovial macrophages and dendritic cells further function as antigen presenting cells by expressing MHC class II molecules, leading to an established local immune reaction in the tissue. The disease progresses in concert with formation of granulation tissue at the edges of the synovial lining ([[pannus]]) with extensive angiogenesis and production of enzymes that cause tissue damage. Modern pharmacological treatments of RA target these mediators. Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues.
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| ==Diagnosis==
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| ===Imaging===
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| [[Image:RheumatoideArthritisAP.jpg|thumb|X-ray of the hand in rheumatoid arthritis.]]
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| [[Image:Inflamatory arthritis2010.JPG|thumb|Appearance of synovial fluid from a joint with inflammatory arthritis.]]
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| [[Image:Rheumatoid arthritis ultrasound MRI MCP joint ar1904-2.gif|thumb|Signs of destruction and inflammation on [[medical ultrasound|ultrasonography]] and [[magnetic resonance imaging]] in the second [[metacarpophalangeal joint]] in established RA. Thin arrows indicate an erosive change; thick arrows indicate [[synovitis]]. Ultrasonography (left side of image) in the (a) longitudinal and (b) the transverse planes shows both signs of destruction and inflammation. Axial T1-weighted magnetic resonance images were obtained (c) before and (d) after contrast administration, also demonstrating synovitis. Additionally, a coronal T1-weighted magnetic resonance image (e) before contrast administration visualizes the same bone erosion as shown in panels c and d.]]
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| [[X-ray]]s of the hands and feet are generally performed in people with a polyarthritis. In RA, there may be no changes in the early stages of the disease, or the x-ray may demonstrate juxta-articular osteopenia, soft tissue swelling and loss of joint space. As the disease advances, there may be bony erosions and subluxation. X-rays of other joints may be taken if symptoms of pain or swelling occur in those joints.
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| Other medical imaging techniques such as magnetic resonance imaging (MRI) and ultrasound are also used in RA.{{citation needed|date=December 2010}}
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| There have been technical advances in ultrasonography. High-frequency transducers (10 MHz or higher) have improved the spatial resolution of ultrasound images; these images can depict 20% more erosions than conventional radiography. Also, color Doppler and power Doppler ultrasound, which show vascular signals of active synovitis depending on the degree of inflammation, are useful in assessing synovial inflammation. This is important, since in the early stages of RA, the synovium is primarily affected, and synovitis seems to be the best predictive marker of future joint damage.<ref>Schueller-Weidekamm C. [http://www.diagnosticimaging.com/ultrasound/content/article/113619/1561958 Modern ultrasound methods yield stronger arthritis work-up]. Diagnostic Imaging. May 2010:20–22.</ref>
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| ===Blood tests===
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| When RA is clinically suspected, [[immunology|immunological]] studies are required, such as testing for the presence of [[rheumatoid factor]] (RF, a non-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|pmid=16418203 |doi=10.1093/rheumatology/kei228 }}</ref> A negative RF does not rule out RA; rather, the arthritis is called ''[[seronegative]]''. This is the case in about 15% of patients.<ref name=Nishimura>{{cite journal |author=Nishimura K |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 |pmid=17548411 |author2=Sugiyama D |author3=Kogata Y|last4=Tsuji |first4=G |last5=Nakazawa |first5=T |last6=Kawano |first6=S |last7=Saigo |first7=K |last8=Morinobu |first8=A |last9=Koshiba |first9=M |doi=10.7326/0003-4819-146-11-200706050-00008}}</ref> During the first year of illness, rheumatoid factor is more likely to be negative with some individuals converting to seropositive status over time. RF is also seen in other illnesses, for example [[Sjögren's syndrome]], Hepatitis C, chronic infections and in approximately 10% of the healthy population, therefore the test is not very specific.
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| Because of this low [[Specificity (tests)|specificity]], new serological tests have been developed, which test for the presence of the anti-citrullinated protein antibodies ([[anti-citrullinated protein antibodies|ACPAs]]) or anti-CCP. Like RF, these tests are positive in only a proportion (67%) of all RA cases, but are rarely positive if RA is not present, giving it a specificity of around 95%.<ref name=Nishimura/> As with RF, there is evidence for ACPAs being present in many cases even before onset of clinical disease.{{Citation needed|date=July 2008}}
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| The most common tests for ACPAs are the anti-CCP ([[cyclic citrullinated peptide]]) test and the [[mutated citrullinated Vimentin|Anti-MCV]] assay (antibodies against mutated citrullinated Vimentin). Recently a serological [[POCT|point-of-care test]] (POCT) for the early detection of RA has been developed. This assay combines the detection of rheumatoid factor and anti-MCV for diagnosis of RA and shows a sensitivity of 72% and specificity of 99.7%.<ref>{{cite journal |author= Renger F, Bang H, Fredenhagen G, Natusch A, Backhaus M, Feist E, Egerer K, Burmester GR |title=Anti-MCV Antibody Test for the Diagnosis of Rheumatoid Arthritis Using a POCT-Immunoassay |journal=American College of Rheumatology, 2008 Annual Scientific Meeting, poster presentation |url= http://acr.confex.com/acr/2008/webprogram/Paper2009.html}}</ref><ref>{{cite journal |author=Luime JJ, Colin EM, Hazes JM, Lubberts E. |title=Does anti-MCV has additional value as serological marker in the diagnostic and prognostic work-up of patients with rheumatoid arthritis? A systematic review |journal=Ann Rheum Dis. 2009 March 15. [Epub ahead of print]|pmid= 19289382 |doi= 10.1136/ard.2008.103283|url=http://ard.bmj.com/cgi/rapidpdf/ard.2008.103283v1 |year=2009 |volume=69 |issue=2 |pages=337–44}}</ref>
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| 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 of RA, or be a sign of [[Adult-onset Still's disease|Still's disease]], a seronegative, usually juvenile, variant of rheumatoid arthritis.{{Citation needed|date=July 2008}}
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| ===Criteria===
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| In 2010 the ''2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria'' were introduced.<ref name=acr-eular>{{cite journal |author=Aletaha D |title=2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative |journal=Ann. Rheum. Dis. |volume=69 |issue=9 |pages=1580–8 |year=2010|pmid=20699241 |doi=10.1136/ard.2010.138461 |url=http://www.rheumatology.org/practice/clinical/classification/ra/2010_revised_criteria_classification_ra.pdf |archiveurl=http://web.archive.org/web/20100821113205/http://www.rheumatology.org/practice/clinical/classification/ra/2010_revised_criteria_classification_ra.pdf |archivedate=2010-08-21 | accessdate = February 8, 2011 |author2=Neogi T |author3=Silman AJ |last4=Funovits |first4=J. |last5=Felson |first5=D. T. |last6=Bingham |first6=C. O. |last7=Birnbaum |first7=N. S. |last8=Burmester |first8=G. R. |last9=Bykerk |first9=V. P.}}</ref> These new classification criteria overruled the "old" ACR criteria of 1987 and are adapted for early RA diagnosis. The "new" classification criteria, jointly published by the [[American College of Rheumatology]] (ACR) and the [[European League Against Rheumatism]] (EULAR) establish a point value between 0 and 10. Every patient with a point total of 6 or higher is unequivocally classified as an RA patient, provided he has synovitis in at least one joint and given that there is no other diagnosis better explaining the synovitis. Four areas are covered in the diagnosis:<ref name=acr-eular/>
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| * joint involvement, designating the [[metacarpophalangeal joint]]s, [[proximal interphalangeal joint]]s, the [[interphalangeal articulations of hand|interphalangeal joint]] of the thumb, second through fifth [[metatarsophalangeal joint]] and [[wrist]] as ''small joints'', and [[shoulder]]s, [[elbow]]s, [[hip joint]]s, [[knee]]s, and [[ankle]]s as ''large joints'':
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| **Involvement of 1 large joint gives 0 points
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| **Involvement of 2–10 large joints gives 1 point
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| **Involvement of 1–3 small joints (with or without involvement of large joints) gives 2 points
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| **Involvement of 4–10 small joints (with or without involvement of large joints) gives 3 points
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| **Involvement of more than 10 joints (with involvement of at least 1 small joint) gives 5 points
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| * serological parameters – including the [[rheumatoid factor]] as well as [[anti-citrullinated protein antibody|ACPA]] – "ACPA" stands for "anti-citrullinated protein antibody":
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| **Negative RF ''and'' negative ACPA gives 0 points
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| **Low-positive RF ''or'' low-positive ACPA gives 2 points
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| **High-positive RF ''or'' high-positive ACPA gives 3 points
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| * acute phase reactants: 1 point for elevated erythrocyte sedimentation rate, [[Erythrocyte sedimentation rate|ESR]], or elevated [[C-reactive protein|CRP]] value (c-reactive protein)
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| * duration of [[arthritis]]: 1 point for symptoms lasting six weeks or longer
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| The new criteria accommodate to the growing understanding of RA and the improvements in diagnosing RA and disease treatment. In the "new" criteria serology and [[autoimmune disease|autoimmune diagnostics]] carries major weight, as ACPA detection is appropriate to diagnose the disease in an early state, before joints destructions occur. Destruction of the joints viewed in radiological images was a significant point of the ACR criteria from 1987.<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/practice/clinical/classification/ra/1987_revised_criteria_classification_ra.pdf | archiveurl=http://web.archive.org/web/20110124173431/http://www.rheumatology.org/practice/clinical/classification/ra/1987_revised_criteria_classification_ra.pdf | archivedate=2011-01-24 | doi = 10.1002/art.1780310302 | accessdate = February 8, 2011}}</ref> This criterion no longer is regarded to be relevant, as this is just the type of damage that treatment is meant to avoid.
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| The criteria are not intended for the diagnosis for routine clinical care; they were primarily intended to categorize research (''classification'' criteria). In clinical practice, the following criteria apply:{{citation needed|date=September 2010}}
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| * two or more swollen joints
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| * morning stiffness lasting more than one hour for at least six weeks
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| * the detection of [[rheumatoid factor]]s or [[autoantibody|autoantibodies]] against [[anti-citrullinated protein antibody|ACPA]] such as autoantibodies to [[anti-MCV|mutated citrullinated vimentin]] can confirm the suspicion of RA. A negative autoantibody result does not exclude a diagnosis of RA.
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| ===Differential diagnoses===
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| 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=0-911910-16-6}}</ref><ref>{{cite journal | author = Lovy MR, Starkebaum G, Uberoi S | title = Hepatitis C infection presenting with rheumatic manifestations: a mimic of rheumatoid arthritis | journal = [[J. Rheumatol.]] | volume = 23 | issue = 6 | pages = 1238–9 | year = 1996 | pmid = 8782126}}</ref>
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| * Crystal induced arthritis ([[gout]], and [[pseudogout]]) – usually involves particular joints (knee, MTP1, heels) and can be distinguished with aspiration of joint fluid if in doubt. Redness, asymmetric distribution of affected joints, pain occurs at night and the starting pain is less than an hour with gout.
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| * [[Osteoarthritis]] – distinguished with [[X-ray]]s of the affected joints and blood tests, age (mostly older patients), starting pain less than an hour, a-symmetric distribution of affected joints and pain worsens when using joint for longer periods.
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| * [[Systemic lupus erythematosus]] (SLE) – distinguished by specific clinical symptoms and blood tests (antibodies against double-stranded DNA)
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| * One of the several types of [[psoriatic arthritis]] resembles RA – nail changes and skin symptoms distinguish between them
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| * [[Lyme disease]] causes erosive arthritis and may closely resemble RA – it may be distinguished by blood test in endemic areas
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| * [[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]].
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| * [[Ankylosing spondylitis]] – this involves the spine, although a RA-like symmetrical small-joint polyarthritis may occur in the context of this condition.
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| * [[Hepatitis C]] – RA-like symmetrical small-joint polyarthritis may occur in the context of this condition. Hepatitis C may also induce Rheumatoid Factor auto-antibodies
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| Rarer causes that usually behave differently but may cause joint pains:<ref name=Merckmanual/>
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| * [[Sarcoidosis]], amyloidosis, and [[Whipple's disease]] can also resemble RA.
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| * [[Hemochromatosis]] may cause hand joint arthritis.
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| * 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.
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| * [[Gonococcal]] arthritis (another bacterial arthritis) is also initially migratory and can involve [[tendons]] around the wrists and ankles.
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| ===Monitoring progression===
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| The progression of RA can be followed using scores such as ''Disease Activity Score of 28 joints'' ({{visible anchor|DAS28}}). It is widely used as an indicator of RA disease activity and response to treatment, but is not always a reliable indicator of treatment effect.<ref>Kelly, Janis (22 February 2005) [http://www.medscape.com/viewarticle/538134 DAS28 not always a reliable indicator of treatment effect in RA], Medscape Medical News.</ref> The joints included in DAS28 are ([[bilateral symmetry|bilaterally]]): [[proximal interphalangeal joint]]s (10 joints), [[metacarpophalangeal joint]]s (10), [[wrist]]s (2), [[elbow]]s (2), [[shoulder]]s (2) and [[knee]]s (2). When looking at these joints, both the number of joints with tenderness upon touching ('''TEN28''') and swelling ('''SW28''') are counted. In addition, the [[erythrocyte sedimentation rate]] ('''ESR''') is measured. Also, the patient makes a subjective assessment ('''SA''') of disease activity during the preceding 7 days on a scale between 0 and 100, where 0 is "no activity" and 100 is "highest activity possible". With these parameters, DAS28 is calculated as:<ref name=Prevoo1995/>
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| <math>DAS28=0.56 \times \sqrt{TEN28} + 0.28 \times \sqrt{SW28} + 0.70 \times \ln(ESR) + 0.014 \times SA</math>
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| From this, the disease activity of the patient can be classified as follows:<ref name=Prevoo1995>{{cite pmid|7818570}}</ref>
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| {|class="wikitable"
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| |-
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| !colspan=2 rowspan=2| Current <br>DAS28 !!colspan=3| DAS28 decrease from initial value
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| |-
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| | [[more than|>]] 1.2 || > 0.6 but [[less than or equal to|≤]] 1.2 || ≤ 0.6
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| |-
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| | [[less than or equal to|≤]] 3.2 || Inactive || Good improvement || Moderate improvement || No improvement
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| |-
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| | [[more than|>]] 3.2 but ≤ 5.1 || Moderate || Moderate improvement || Moderate improvement || No improvement
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| |-
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| | > 5.1 || Very active || Moderate improvement || No improvement || No improvement
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| |}
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| ==Management==
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| There is no cure for RA, but treatments can improve symptoms and slow the progress of the disease. Disease-modifying treatment has the best results when it is started early and aggressively.<ref name=ACR2008>{{cite journal |author=Saag KG, Teng GG, Patkar NM, ''et al.'' |title=American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis |journal=Arthritis Rheum. |volume=59 |issue=6 |pages=762–84 |year=2008 |pmid=18512708 |doi=10.1002/art.23721 }}</ref>
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| The goals of treatment are to minimize symptoms such as pain and swelling, to prevent bone deformity (for example, bone erosions visible in X-rays), and to maintain day-to-day functioning.<ref name=Wasserman>{{cite journal | author=Amy M. Wasserman| title=Diagnosis and Management of Rheumatoid Arthritis | journal=American Family Physician | year=2011| volume=84 | issue=11 | pages=1245–1252 | pmid=22150658}}</ref> This can often be achieved using two main classes of medications: analgesics such as NSAIDs, and [[disease-modifying antirheumatic drugs]] (DMARDs).<ref name=NICEguidelines>{{cite journal | author=Chris Deighton, Rachel O’Mahony, Jonathan Tosh, Claire Turner, Michael Rudolf, and Guideline Development Group| title=Management of rheumatoid arthritis: summary of NICE guidance | journal=British Medical Journal | year=2009 | volume=338 | pages=710–712 | doi=10.1136/bmj.b702}}</ref> RA should generally be treated with at least one specific anti-rheumatic medication.<ref name=ACR2008/> The use of [[benzodiazepines]] (such as [[diazepam]]) to treat the pain is not recommended as it does not appear to help and is associated with risks.<ref>{{cite journal|last=Richards|first=BL|coauthors=Whittle, SL; Buchbinder, R|title=Muscle relaxants for pain management in rheumatoid arthritis|journal=Cochrane database of systematic reviews (Online)|date=Jan 18, 2012|volume=1|pages=CD008922|pmid=22258993|doi=10.1002/14651858.CD008922.pub2|editor1-last=Richards|editor1-first=Bethan L}}</ref> [[Analgesics]], other than NSAIDs, offer lesser, but some benefit with respect to pain.<ref name=Lancet2010/> whilst not causing the same level of gastrointestinal irritation.
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| ===Lifestyle===
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| Regular exercise is recommended as both safe and useful to maintain muscles strength and overall physical function.<ref>{{cite journal|last=Hurkmans|first=E|coauthors=van der Giesen, FJ; Vliet Vlieland, TP; Schoones, J; Van den Ende, EC|title=Dynamic exercise programs (aerobic capacity and/or muscle strength training) in patients with rheumatoid arthritis|journal=Cochrane database of systematic reviews (Online)|date=Oct 7, 2009|issue=4|pages=CD006853|pmid=19821388|doi=10.1002/14651858.CD006853.pub2|editor1-last=Hurkmans|editor1-first=Emalie}}</ref> It is uncertain if specific dietary measures have an effect.<ref>{{cite journal|last=Hagen|first=KB|coauthors=Byfuglien, MG; Falzon, L; Olsen, SU; Smedslund, G|title=Dietary interventions for rheumatoid arthritis|journal=Cochrane database of systematic reviews (Online)|date=Jan 21, 2009|issue=1|pages=CD006400|pmid=19160281|doi=10.1002/14651858.CD006400.pub2|editor1-last=Hagen|editor1-first=Kåre Birger}}</ref>
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| ===Disease modifying agents===
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| [[Disease-modifying antirheumatic drugs]] (DMARD) are the primary treatment for RA.<ref name=Lancet2010/> They are a diverse collection of drugs, grouped by use and convention. They have been found to improve symptoms, decrease joint damage, and improve overall functional abilities.<ref name=Lancet2010/> They should be started very early in the disease as when they result in disease remission in approximately half of people and improved outcomes overall.<ref>{{cite journal |author=Gramling A, O'Dell JR |title=Initial management of rheumatoid arthritis |journal=Rheum. Dis. Clin. North Am. |volume=38 |issue=2 |pages=311–25 |year=2012|pmid=22819086 |doi=10.1016/j.rdc.2012.05.003}}</ref>
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| The most commonly used agent is [[methotrexate]] with other frequently used agents including [[sulfasalazine]] and [[leflunomide]].<!-- <ref name=Lancet2010/> --> [[Sodium aurothiomalate]] (Gold) and [[cyclosporin]] are less commonly used due to more common adverse effects.<!-- <ref name=Lancet2010/> --> Agents may be used in combinations.<ref name=Lancet2010/>
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| Methotrexate is the most important and useful DMARD and is usually the first treatment.<ref name="Wasserman" /><ref name="NICEguidelines" /><ref name="chapter94">DiPiro, Joseph T., Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, and L. Michael Posey (2008) Pharmacotherapy: a pathophysiologic approach. 7th ed. New York: McGraw-Hill, ISBN 978-0-07-147899-1.</ref> Adverse effects should be monitored regularly with toxicity including gastrointestinal, hematologic, pulmonary, and hepatic.<ref name="chapter94" /> Side effects such as nausea, vomiting or abdominal pain can be reduced by taking folic acid.<ref>{{cite journal|last=Shea|first=B|coauthors=Swinden, MV; Tanjong Ghogomu, E; Ortiz, Z; Katchamart, W; Rader, T; Bombardier, C; Wells, GA; Tugwell, P|title=Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.|journal=The Cochrane database of systematic reviews|date=May 31, 2013|volume=5|pages=CD000951|doi=10.1002/14651858.CD000951.pub2|pmid=23728635}}</ref> The most common undesirable affect is that it increases liver enzymes in almost 15% of people.<ref name="chapter94" /> It is thus recommended that those who consistently demonstrate abnormal levels of liver enzymes or have a history of liver disease or alcohol use undergo liver biopsies.<ref name=ACR2002>{{cite journal | author=American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines| title=Guidelines for the management of rheumatoid arthritis: 2002 Update | journal=Arthritis & Rheumatism | year=2002 | volume=46 | issue=2 | pages=328–346| doi=10.1002/art.10148}}</ref> Methotrexate is also considered a [[teratogenic]] and as such, it is recommended women of childbearing age should use contraceptives to avoid pregnancy and to discontinue its use if pregnancy is planned.<ref name="Wasserman" /><ref name="chapter94" />
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| [[Biological agents]] should generally only be used if methotrexate and other conventional agents are not effective after a trial of three months.<ref>{{cite journal|last=Task Force for the Diagnosis and Management of|first=Syncope|coauthors=European Society of Cardiology, (ESC); European Heart Rhythm Association, (EHRA); Heart Failure Association, (HFA); Heart Rhythm Society, (HRS); Moya, A; Sutton, R; Ammirati, F; Blanc, JJ; Brignole, M; Dahm, JB; Deharo, JC; Gajek, J; Gjesdal, K; Krahn, A; Massin, M; Pepi, M; Pezawas, T; Ruiz Granell, R; Sarasin, F; Ungar, A; van Dijk, JG; Walma, EP; Wieling, W|title=Guidelines for the diagnosis and management of syncope (version 2009)|journal=European heart journal|date=November 2009|volume=30|issue=21|pages=2631–71|pmid=19713422|doi=10.1093/eurheartj/ehp298|pmc=3295536}}</ref> These agents include: [[tumor necrosis factor alpha]] (TNFα) blockers<ref name=Lancet2010/> such as [[infliximab]]; [[interleukin 1]] blockers such as [[anakinra]], [[monoclonal antibody|monoclonal antibodies]] against [[B cell]]s such as [[rituximab]],<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}}</ref> [[T cell]] costimulation blocker such as [[abatacept]] among others. They are often used in combination with either methotrexate or leflunomide.<ref name=Lancet2010/>
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| [[TNF inhibitor|TNF blockers]] and [[methotrexate]] appear to have similar effectiveness when used alone and better results are obtained when used together. TNF blockers appear to have equivalent effectiveness with [[etanercept]] appearing to be the safest.<ref>{{cite journal |author=Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordström DC, Blom M |title=Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis |journal=PLoS ONE |volume=7 |issue=1 |pages=e30275 |year=2012 |pmid=22272322 |pmc=3260264 |doi=10.1371/journal.pone.0030275 |editor1-last=Hernandez |editor1-first=Adrian V}}</ref> [[Abatacept]] appears effective for RA with 20% more people improving with treatment than without.<ref>{{cite journal|last=Maxwell|first=L|coauthors=Singh, JA|title=Abatacept for rheumatoid arthritis|journal=Cochrane database of systematic reviews (Online)|date=Oct 7, 2009|issue=4|pages=CD007277|pmid=19821401|doi=10.1002/14651858.CD007277.pub2|editor1-last=Maxwell|editor1-first=Lara}}</ref> There however is a lack of evidence to distinguish between the biologics available for RA.<ref>{{cite journal|last=Singh|first=JA|coauthors=Christensen, R; Wells, GA; Suarez-Almazor, ME; Buchbinder, R; Lopez-Olivo, MA; Tanjong Ghogomu, E; Tugwell, P|title=Biologics for rheumatoid arthritis: an overview of Cochrane reviews|journal=Cochrane database of systematic reviews (Online)|date=Oct 7, 2009|issue=4|pages=CD007848|pmid=19821440|doi=10.1002/14651858.CD007848.pub2|editor1-last=Singh|editor1-first=Jasvinder A}}</ref> Issues with the biologics include their high cost and association with infections including [[tuberculosis]].<ref name=Lancet2010/>
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| ===Anti-inflammatory agents===
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| [[NSAIDs]] reduce both pain and stiffness in those with RA.<ref name=Lancet2010/> Generally they appear to have no effect on people's long term disease course and thus are no longer first line agents.<ref name=Lancet2010/><ref>{{cite journal|last=Tarp|first=S|coauthors=Bartels, EM; Bliddal, H; Furst, DE; Boers, M; Danneskiold-Samsøe, B; Rasmussen, M; Christensen, R|title=Effect of nonsteroidal antiinflammatory drugs on the C-reactive protein level in rheumatoid arthritis: a meta-analysis of randomized controlled trials|journal=Arthritis and rheumatism|date=November 2012|volume=64|issue=11|pages=3511–21|pmid=22833186|doi=10.1002/art.34644}}</ref> NSAIDs should be used with caution in those with [[gastrointestinal]], [[cardiovascular]], or kidney problems.<ref>{{cite journal|last=Radner|first=H|coauthors=Ramiro, S; Buchbinder, R; Landewé, RB; van der Heijde, D; Aletaha, D|title=Pain management for inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and other spondylarthritis) and gastrointestinal or liver comorbidity|journal=Cochrane database of systematic reviews (Online)|date=Jan 18, 2012|volume=1|pages=CD008951|pmid=22258995|doi=10.1002/14651858.CD008951.pub2|editor1-last=Radner|editor1-first=Helga}}</ref><ref>{{cite journal|last=McCormack|first=PL|title=Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis|journal=Drugs|date=Dec 24, 2011|volume=71|issue=18|pages=2457–89|pmid=22141388|doi=10.2165/11208240-000000000-00000}}</ref><ref>{{cite journal|last=Marks|first=JL|coauthors=Colebatch, AN; Buchbinder, R; Edwards, CJ|title=Pain management for rheumatoid arthritis and cardiovascular or renal comorbidity|journal=Cochrane database of systematic reviews (Online)|date=Oct 5, 2011|issue=10|pages=CD008952|pmid=21975789|doi=10.1002/14651858.CD008952.pub2|editor1-last=Marks|editor1-first=Jonathan L}}</ref>
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| [[COX-2 inhibitor]]s, such as [[celecoxib]], and NSAIDs are equally effective.<ref name=Job2008>{{cite journal|last=Chen|first=YF|coauthors=Jobanputra, P; Barton, P; Bryan, S; Fry-Smith, A; Harris, G; Taylor, RS|title=Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation|journal=Health technology assessment (Winchester, England)|date=April 2008|volume=12|issue=11|pages=1–278, iii|pmid=18405470}}</ref> They have a similar gastrointestinal risk as an NSAIDs plus a [[proton pump inhibitor]].<ref>{{cite journal|last=Wang|first=X|coauthors=Tian, HJ; Yang, HK; Wanyan, P; Peng, YJ|title=Meta-analysis: cyclooxygenase-2 inhibitors are no better than nonselective nonsteroidal anti-inflammatory drugs with proton pump inhibitors in regard to gastrointestinal adverse events in osteoarthritis and rheumatoid arthritis|journal=European journal of gastroenterology & hepatology|date=October 2011|volume=23|issue=10|pages=876–80|pmid=21900785|doi=10.1097/MEG.0b013e328349de81}}</ref> In the elderly there is less gastrointestinal intolerance to celecoxib than to NSAIDs alone.<ref>{{cite journal|last=Mallen|first=SR|coauthors=Essex, MN; Zhang, R|title=Gastrointestinal tolerability of NSAIDs in elderly patients: a pooled analysis of 21 randomized clinical trials with celecoxib and nonselective NSAIDs|journal=Current medical research and opinion|date=July 2011|volume=27|issue=7|pages=1359–66|pmid=21561397|doi=10.1185/03007995.2011.581274}}</ref> There however is an increased risk of [[myocardial infarction]] with COX-2 inhibitors.<ref name=Job2008/> Anti-ulcer medications are not recommended routinely but only in those high risk of gastrointestinal problems.<ref>{{cite journal|title=Nonsteroidal anti-inflammatory drugs: add an anti-ulcer drug for patients at high risk only. Always limit the dose and duration of treatment with NSAIDs|journal=Prescrire Int|year=2011|pmid=21954519|volume=20|issue=119|pages=216–9}}</ref>
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| [[Glucocorticoids]] can be used in the short term for flare-ups, while waiting for slow-onset drugs to take effect.<ref name=Lancet2010/> Injection of glucocorticoids into individual joints is also effective.<ref name=Lancet2010/> While long-term use reduces joint damage it also results in osteoporosis and susceptibility to infections, and thus is not recommended.<ref name=Lancet2010/>
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| ===Surgery===
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| In early phases of the disease, an arthroscopic or open [[synovectomy]] may be performed. It consists of the removal of the inflamed [[synovia]] and prevents a quick destruction of the affected joints. Severely affected joints may require [[joint replacement]] surgery, such as knee replacement.<ref name=Lancet2010/> Postoperatively, [[physiotherapy]] is always necessary.
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| ===Alternative medicine===
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| There has been an increasing interest in the use of complementary and alternative medicine interventions for the treatment of pain in rheumatoid arthritis. While there have been multiple studies showing beneficial effects in RA on a wide variety of CAM modalities, these studies are often affected by [[publication bias]] and are generally not high quality evidence such as [[randomized controlled trial]]s (RCTs), making definitive conclusions difficult to reach.<ref name=Efthimiou/>
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| The [[National Center for Complementary and Alternative Medicine]] has concluded, "In general, there is not enough scientific evidence to prove that any complementary health approaches are beneficial for RA, and there are safety concerns about some of them. Some mind and body practices and dietary supplements may help people with RA manage their symptoms and therefore may be beneficial additions to conventional RA treatments, but there is not enough evidence to draw conclusions."<ref name=NCCAM>{{cite web|title=Rheumatoid Arthritis and Complementary Health Approaches|url=http://nccam.nih.gov/health/RA/getthefacts.htm|publisher=National Center for Complementary and Alternative Medicine|accessdate=21 April 2013}}</ref> A [[systematic review]] of CAM modalities (excluding fish oil) found "The major limitation in reviewing the evidence for CAMs is the paucity of RCTs in the area. The available evidence does not support their current use in the management of RA."<ref name=Macfarlane>{{cite journal |author=Macfarlane GJ, El-Metwally A, De Silva V, Ernst E, Dowds GL, Moots RJ |title=Evidence for the efficacy of complementary and alternative medicines in the management of rheumatoid arthritis: a systematic review |journal=Rheumatology (Oxford) |volume=50 |issue=9 |pages=1672–83 |year=2011|pmid=21652584 |doi=10.1093/rheumatology/ker119 }}</ref> One review suggests that of the various alternative medicine treatments evaluated, only [[acupuncture]], [[Apitherapy#Clinical practice|bee venom acupuncture]], herbal remedies, dietary [[omega-3 fatty acids]], and [[pulsed electromagnetic field therapy]] have been studied with RCTs and show promise in treating the pain of RA, though no definitive conclusions could be reached.<ref name=Efthimiou/>
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| ====Dietary supplements====
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| The [[American College of Rheumatology]] states that no herbal medicines have health claims supported by high quality evidence and thus they do not recommend their use.<ref name=ACRCAM/> There is no scientific basis to suggest that herbal supplements advertised as "natural" are safer for use than conventional medications as both are chemicals. Herbal medications, although labelled "natural", may be toxic or fatal if consumed.<ref name=ACRCAM>{{cite web|title=Herbal Remedies, Supplements and Acupuncture for Arthritis|url=http://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Herbal_Remedies,_Supplements_and_Acupuncture_for_Arthritis/|publisher=American College of Rheumatology|accessdate=3 May 2013}}</ref> Some evidence supports omega-3 fatty acids and gamma-linolenic acid in RA.<ref>{{cite journal|last=Pirotta|first=M|title=Arthritis disease – the use of complementary therapies|journal=Australian family physician|date=September 2010|volume=39|issue=9|pages=638–40|pmid=20877766}}</ref> The benefit from omega-3 appears modest but consistent,<ref>{{cite journal|last=Miles|first=EA|coauthors=Calder, PC|title=Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis|journal=The British journal of nutrition|date=June 2012|volume=107 Suppl 2|pages=S171–84|pmid=22591891|doi=10.1017/S0007114512001560}}</ref> though the current evidence is not strong enough to determine that supplementation with [[Omega-3 fatty acid|omega-3 polyunsaturated fatty acids]] (found in fish oil) is an effective treatment for RA.<ref>{{cite journal|last=Ruggiero|first=C|coauthors=Lattanzio, F; Lauretani, F; Gasperini, B; Andres-Lacueva, C; Cherubini, A|title=Omega-3 polyunsaturated fatty acids and immune-mediated diseases: inflammatory bowel disease and rheumatoid arthritis|journal=Current pharmaceutical design|year=2009|volume=15|issue=36|pages=4135–48|pmid=20041815|doi=10.2174/138161209789909746|url=http://www.researchgate.net/publication/40818808_Omega-3_polyunsaturated_fatty_acids_and_immune-mediated_diseases_inflammatory_bowel_disease_and_rheumatoid_arthritis/file/d912f50eefc97a4450.pdf}}</ref> Gamma-linolenic acid, which may reduce pain, tender joint count and stiffness, is generally safe.<ref>
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| {{cite web|url=http://www.crd.york.ac.uk/CRDWeb/ShowRecord.asp?AccessionNumber=12003000980|title=Herbal medicines for the treatment of rheumatoid arthritis: a systematic review|last=Soeken|first=K L|last2=Miller|first2=S A|last3=Ernst|first3=E|publisher=[[National Institute for Health Research]]|work=[[Centre for Reviews and Dissemination]]|accessdate=March 23, 2013}}</ref>
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| The following show promise as treatments for RA, based on preliminary studies: [[boswellic acid]],<ref>{{cite journal|last=Abdel-Tawab|first=M|coauthors=Werz, O; Schubert-Zsilavecz, M|title=Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data|journal=Clinical pharmacokinetics|date=June 2011|volume=50|issue=6|pages=349–69|pmid=21553931|doi=10.2165/11586800-000000000-00000}}</ref> [[curcumin]],<ref>{{cite journal|last=White|first=B|coauthors=Judkins, DZ|title=Clinical Inquiry. Does turmeric relieve inflammatory conditions?|journal=The Journal of family practice|date=March 2011|volume=60|issue=3|pages=155–6|pmid=21369559}}</ref> [[Harpagophytum|Devil's claw]],<ref>{{cite pmid|10483693}}</ref><ref>{{cite pmid|17627199}}</ref> [[Euonymus alatus]],<ref>{{cite journal|last=Zhang|first=LF|coauthors=Zhao, JX|title=The recent research situation of Euonymus alatus|journal=Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica|date=December 2005|volume=30|issue=24|pages=1895–8|pmid=16494017}}</ref> and [[Tripterygium wilfordii|Thunder god vine (''Tripterygium wilfordii'')]].<ref>{{cite pmid|21365177}}</ref>
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| Herbal supplements can often have significant side effects, and can interact with prescription medications being taken at the same time. These risks are often exacerbated by the false general belief by patients that herbal supplements are always safe and the hesitancy by patients in reporting the use of herbal supplements to physicians.<ref name=Efthimiou/> NCCAM has noted that, "In particular, the herb thunder god vine (Tripterygium wilfordii) can have serious side effects."<ref name=NCCAM/>
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| ====Manual therapies====
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| The evidence for acupuncture is inconclusive<ref>{{cite journal|author=Lee MS, Shin B-C, Ernst E|journal=Rheumatology|title=Acupuncture for rheumatoid arthritis: a systematic review|year=2008|volume=47|pages=1747–53|doi=10.1093/rheumatology/ken330|pmid=18710899|issue=12}}</ref> with it appearing to be equivalent to sham acupuncture.<ref>{{cite journal|last=Macfarlane|first=GJ|coauthors=Paudyal, P; Doherty, M; Ernst, E; Lewith, G; MacPherson, H; Sim, J; Jones, GT|title=A systematic review of evidence for the effectiveness of practitioner-based complementary and alternative therapies in the management of rheumatic diseases: rheumatoid arthritis|journal=Rheumatology|year=2012 |volume=51|issue=9|pages=1707–13|pmid=22661556|doi=10.1093/rheumatology/kes133}}</ref>
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| ==Prevention==
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| There is no known prevention for the contraction. Reduction of risk factors and aggressive treatment after diagnosis are recommended actions.<ref>http://www.nice.org.uk/nicemedia/live/12131/43326/43326.pdf</ref>
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| ==Prognosis==
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| 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 nodule]]s); this is associated with a poor prognosis.
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| ===Prognostic factors===
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| 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.
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| ===Mortality===
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| RA is known to reduce the lifespan of patients by anywhere from three to 12 years.<ref name="Wasserman" /> A new line of research does, however, show that the use of new biologic drug therapies extend the lifespan of patients with RA and reduce the risk and progression of atherosclerosis.<ref>{{cite pmid|20678592}}</ref> 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>Kitas, George (4 April 2006) [http://web.archive.org/web/20060924153339/http://www.rheumatoid.org.uk/article.php?article_id=112 Why is life span shortened by Rheumatoid Arthritis?] National Rheumatoid Arthritis Society</ref> Positive responses to treatment may indicate a better prognosis. A 2005 study by the [[Mayo Clinic]] noted that RA sufferers suffer a doubled risk of heart disease,<ref>[http://web.archive.org/web/20050306030726/http://mayoclinic.org/news2005-rst/2654.html Rheumatoid Arthritis Patients Have Double the Risk of Heart Failure]. mayoclinic.org (3 February 2005).</ref> independent of other risk factors such as [[diabetes]], alcohol abuse, and elevated [[cholesterol]], blood pressure and [[body mass index]]. The mechanism by which RA causes this increased risk remains unknown; the presence of chronic inflammation has been proposed as a contributing factor.<ref>{{cite web|url=http://www.hopkins-arthritis.org/news-archive/2002/cardiac.html |archiveurl=http://web.archive.org/web/20061009112820/http://www.hopkins-arthritis.org/news-archive/2002/cardiac.html |archivedate=2006-10-09 |title=Cardiac disease in rheumatoid arthritis |publisher=John Hopkins University|year=2002}}</ref>
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| ==Epidemiology==
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| [[Image:Rheumatoid arthritis world map - DALY - WHO2004.svg|thumb|[[Disability-adjusted life year]] for RA per 100,000 inhabitants in 2004.<ref>{{cite web |url=http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html |title=WHO Disease and injury country estimates |year=2009 |work=World Health Organization |accessdate=November 11, 2009}}</ref>
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| {{Multicol}}
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| {{legend|#b3b3b3|no data}}
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| {{legend|#ffff65|<40}}
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| {{legend|#fff200|40–50}}
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| {{legend|#ffdc00|50–60}}
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| {{legend|#ffc600|60–70}}
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| {{legend|#ffb000|70–80}}
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| {{legend|#ff9a00|80–90}}
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| {{Multicol-break}}
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| {{legend|#ff8400|90–100}}
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| {{legend|#ff6e00|100–110}}
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| {{legend|#ff5800|110–120}}
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| {{legend|#ff4200|120–130}}
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| {{legend|#ff2c00|130–140}}
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| {{legend|#cb0000|>140}}
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| {{Multicol-end}}]]
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| RA affects between 0.5 and 1% of adults in the developed world with between 5 and 50 per 100,000 people newly developing the condition each year.<ref name=Lancet2010/> In 2010 it resulted in about 49,000 deaths globally.<ref name=Loz2012>{{cite journal|last1=Lozano|first=1R|last2=Naghavi|first2=M|last3=Foreman|first3=K|last4=Lim|first4=S|last5=Shibuya|first5=K|last6=Aboyans|first6=V|last7=Abraham|first7=J|last8=Adair|first8=T|last9=Aggarwal|first9=R|title=Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010|journal=Lancet|date=Dec 15, 2012|volume=380|issue=9859|pages=2095–128|pmid=23245604|doi=10.1016/S0140-6736(12)61728-0}}</ref>
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| Onset is uncommon under the age of 15 and from then on the incidence rises with age until the age of 80. Women are affected three to five times as often as men.
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| 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.
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| The age at which the disease most commonly starts is in women between 40 and 50 years of age, and for men somewhat later.<ref>{{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.
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| ==History==
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| 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 RA. It was noted in skeletal remains of Native Americans found in [[Tennessee]].<ref>{{cite web|url=http://mcclungmuseum.utk.edu/research/renotes/rn-05txt.htm|archiveurl=http://web.archive.org/web/20120202085715/http://mcclungmuseum.utk.edu/research/renotes/rn-05txt.htm|archivedate=2012-02-02|author=Rothschild, Bruce M. |title=Tennessee Origins of Rheumatoid Arthritis |publisher=Mcclungmuseum.utk.edu |accessdate=March 3, 2011}}</ref> In the Old World, the disease is vanishingly rare before the 17th century.<ref>{{cite web|url=http://www.arc.org.uk/newsviews/arctdy/104/bones.htm |archiveurl=http://web.archive.org/web/20030219095659/http://www.arc.org.uk/newsviews/arctdy/104/bones.htm |archivedate=2003-02-19 |title=Bones of contention|work= Arthritis Research UK |date=April 1999|accessdate=2013-02-05}}</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.
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| An anomaly has been noticed from investigation of Pre-Columbian bones. The bones from the Tennessee site show no signs of tuberculosis even though it was prevalent at the time throughout the Americas.<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}}</ref> Jim Mobley, at Pfizer, has discovered a historical pattern of epidemics of tuberculosis followed by a surge in the number of RA cases a few generations later.<ref>Patel, Sunil (1 February 2005). [http://www.michigandaily.com/content/scientist-finds-surprising-links-between-arthritis-and-tuberculosis Scientist finds surprising links between arthritis and tuberculosis]. ''Michigan Daily''.</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.
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| The art of [[Peter Paul Rubens]] may possibly depict the effects of RA. In his later paintings, his rendered hands show, in the opinion of some physicians, increasing deformity consistent with the symptoms of the disease.<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}}</ref><ref>{{cite web|url=http://www.medscape.com/viewarticle/538251 |title=Did RA travel from New World to Old? The Rubens connection |publisher=Medscape|author=Kelly, Janis |date=14 June 2005 |accessdate=March 3, 2011}}</ref> RA appears to some to have been depicted in 16th-century paintings.<ref>{{cite journal |author= Dequeker J. and 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 |issue= 2}}</ref> However, it is generally recognised in art historical circles that the painting of hands in the 16th and 17th century followed certain stylised conventions, most clearly seen in the Mannerist movement. It was conventional, for instance to show the upheld right hand of Christ in what now appears a deformed posture. These conventions are easily misinterpreted as portrayals of disease. They are much too widespread for this to be plausible.
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| The first recognized description of RA was in 1800 by the French physician [[Augustin Jacob Landré-Beauvais|Dr Augustin Jacob Landré-Beauvais]] (1772–1840) who was based in the famed [[Pitié-Salpêtrière Hospital|Salpêtrière Hospital]] in Paris.<ref name=Landre1800>{{cite book | author=Landré-Beauvais AJ | title=La goutte asthénique primitive (doctoral thesis) | year=1800 | location=Paris}} reproduced in {{cite journal |author=Landré-Beauvais AJ |title=The first description of rheumatoid arthritis. Unabridged text of the doctoral dissertation presented in 1800 |journal=Joint Bone spine |volume=68 |issue=2 |pages=130–43 |year=2001 |pmid=11324929 |doi= 10.1016/S1297-319X(00)00247-5}}</ref> The 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>
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| Historic treatments for RA have also included: [[RICE (medicine)|rest, ice, compression and elevation]], [[apple]] diet, [[nutmeg]], some light exercise every now and then, [[Urtica|nettles]], [[bee]] venom, [[copper]] bracelets, [[rhubarb diet]], 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|pmid=177148|pmc=1639217 |doi=10.1136/bmj.1.6012.763}}</ref> Most of these have either had no effect at all, or their effects have been modest and transient, while not being generalizable.{{Citation needed|date=September 2010}} The [[Prosorba column]] blood filtering device (removing [[IgG]]) was approved by the FDA in 1999 for treatment of RA<ref>Fresenius HemoCare, Inc., "New Hope for Rheumatoid Arthritis Patients," press release, September 17, 1999.</ref> However it was discontinued at the end of 2006.<ref>{{cite web|url=http://arthritis.about.com/od/arthqa/f/prosorba.htm|title=Prosorba Column – Which Rheumatoid Arthritis Patients Are Good Candidates for the Prosorba Column? |publisher=Arthritis.about.com |accessdate=March 3, 2011}}</ref>
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| ==References==
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| {{Reflist|2}}
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| ==External links==
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| {{commons category|Rheumatoid arthritis}}
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| * {{Dmoz|Health/Conditions_and_Diseases/Musculoskeletal_Disorders/Arthritis/Rheumatoid|Rheumatoid arthritis}}
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| * {{cite web | author=Charles Weber | title=History of rheumatoid arthritis | url= http://charles_w.tripod.com/arthritis2.html}}
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| * {{cite web | title=National Institute of Arthritis and Musculoskeletal and Skin Diseases | url=http://www.niams.nih.gov/ | publisher=National Institute of Arthritis and Musculoskeletal and Skin Diseases}}
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| {{Diseases of the musculoskeletal system and connective tissue}}
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| {{Autoimmune diseases}}
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| {{DEFAULTSORT:Rheumatoid Arthritis}}
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| [[Category:Connective tissue diseases]]
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| [[Category:Arthritis]]
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| [[Category:Autoimmune diseases]]
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| [[Category:Diseases involving the fasciae]]
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