View source for Medicine:Rheumatoid arthritis

{{short description|Type of autoimmune arthritis}}
{{Hatnote|For juvenile rheumatoid arthritis, see [[Medicine:Juvenile idiopathic arthritis|juvenile idiopathic arthritis]].}}
{{Infobox medical condition (new)
| name          = Rheumatoid arthritis
| image         = Rheumatoid_Arthritis.JPG
| caption       = A hand severely affected by rheumatoid arthritis. This degree of swelling and deformation does not typically occur with current treatment.
| field         = [[Medicine:Rheumatology|Rheumatology]], [[Biology:Immunology|Immunology]]
| symptoms      = Warm, swollen, painful joints<ref name=NIH2014/>
| complications = [[Medicine:Anemia|Low red blood cells]], [[Medicine:Pleurisy|inflammation around the lungs]], [[Medicine:Pericarditis|inflammation around the heart]]<ref name=NIH2014/>
| onset         = Middle age<ref name=NIH2014/>
| duration      = Lifelong<ref name=NIH2014/>
| causes        = Unknown<ref name=NIH2014/>
| risks         =
| diagnosis     = Based on symptoms, [[Medicine:Medical imaging|medical imaging]], blood tests<ref name=NIH2014/><ref name=Majithia2007/>
| differential  = [[Medicine:Systemic lupus erythematosus|Systemic lupus erythematosus]], [[Medicine:Psoriatic arthritis|psoriatic arthritis]], [[Medicine:Fibromyalgia|fibromyalgia]]<ref name=Majithia2007/>
| prevention    =
| treatment     =
| medication    = Pain medications, [[Chemistry:Glucocorticoid|steroids]], [[Chemistry:Nonsteroidal anti-inflammatory drug|Nonsteroidal anti-inflammatory drug]]s, disease-modifying antirheumatic drugs<ref name=NIH2014/>
| prognosis     =
| frequency     = 0.5–1% (adults in developed world)<ref name=Lancet2016/>
| deaths        = 30,000 (2015)<ref name=GBD2015De>{{cite journal | vauthors = Wang H, Naghavi M, Allen C, Barber RM, Bhutta ZA, Carter A, etal | collaboration = GBD 2015 Mortality and Causes of Death Collaborators | title = Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015 | journal = Lancet | volume = 388 | issue = 10053 | pages = 1459–1544 | date = October 2016 | pmid = 27733281 | pmc = 5388903 | doi = 10.1016/S0140-6736(16)31012-1 }}</ref>
}}
'''Rheumatoid arthritis''' ('''RA''') is a long-term autoimmune disorder that primarily affects joints.<ref name=NIH2014/> It typically results in warm, swollen, and painful joints.<ref name=NIH2014/> Pain and stiffness often worsen following rest.<ref name=NIH2014/> Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body.<ref name=NIH2014/> The disease may also affect other parts of the body, including skin, eyes, lungs, heart, nerves, and blood.<ref name=NIH2014/> This may result in a [[Medicine:Anemia|low red blood cell count]], [[Medicine:Pleurisy|inflammation around the lungs]], and [[Medicine:Pericarditis|inflammation around the heart]].<ref name=NIH2014/> Fever and low energy may also be present.<ref name=NIH2014>{{cite web|title=Handout on Health: Rheumatoid Arthritis|url=http://www.niams.nih.gov/health_info/Rheumatic_Disease/default.asp|website=National Institute of Arthritis and Musculoskeletal and Skin Diseases|access-date=July 2, 2015|date=August 2014|url-status=live|archive-url=https://web.archive.org/web/20150630212818/http://niams.nih.gov/Health_Info/Rheumatic_Disease/default.asp|archive-date=June 30, 2015}}</ref> Often, symptoms come on gradually over weeks to months.<ref name=Majithia2007/>

While the cause of rheumatoid arthritis is not clear, it is believed to involve a combination of genetic and environmental factors.<ref name=NIH2014/> The underlying mechanism involves the body's [[Biology:Immune system|immune system]] attacking the joints.<ref name=NIH2014/> This results in inflammation and thickening of the joint capsule.<ref name=NIH2014/> It also affects the underlying [[Biology:Bone|bone]] and [[Biology:Cartilage|cartilage]].<ref name=NIH2014/> The diagnosis is made mostly on the basis of a person's signs and symptoms.<ref name=Majithia2007/> [[Medicine:Medical imaging|X-rays]] and laboratory testing may support a diagnosis or exclude other diseases with similar symptoms.<ref name=NIH2014/> Other diseases that may present similarly include [[Medicine:Systemic lupus erythematosus|systemic lupus erythematosus]], [[Medicine:Psoriatic arthritis|psoriatic arthritis]], and [[Medicine:Fibromyalgia|fibromyalgia]] among others.<ref name=Majithia2007>{{cite journal | vauthors = Majithia V, Geraci SA | title = Rheumatoid arthritis: diagnosis and management | journal = The American Journal of Medicine | volume = 120 | issue = 11 | pages = 936–939 | date = November 2007 | pmid = 17976416 | doi = 10.1016/j.amjmed.2007.04.005 }}</ref>

The goals of treatment are to reduce pain, decrease inflammation, and improve a person's overall functioning.<ref name=NICE2015>{{cite web|title=Rheumatoid arthritis in adults: management: recommendations: Guidance and guidelines|url=https://www.nice.org.uk/guidance/CG79/chapter/Recommendations|publisher=NICE|date=December 2015|url-status=live|archive-url=https://web.archive.org/web/20170416130024/https://www.nice.org.uk/guidance/CG79/chapter/Recommendations|archive-date=2017-04-16}}</ref> This may be helped by balancing rest and exercise, the use of splints and braces, or the use of assistive devices.<ref name="NIH2014" /><ref name=":12">{{cite journal | vauthors = Rausch Osthoff AK, Juhl CB, Knittle K, Dagfinrud H, Hurkmans E, Braun J, Schoones J, Vliet Vlieland TP, Niedermann K | title = Effects of exercise and physical activity promotion: meta-analysis informing the 2018 EULAR recommendations for physical activity in people with rheumatoid arthritis, spondyloarthritis and hip/knee osteoarthritis | journal = RMD Open | volume = 4 | issue = 2 | pages = e000713 | date = 2018-12-04 | pmid = 30622734 | pmc = 6307596 | doi = 10.1136/rmdopen-2018-000713 }}</ref><ref name=":13">{{cite journal | vauthors = Park Y, Chang M | title = Effects of rehabilitation for pain relief in patients with rheumatoid arthritis: a systematic review | journal = Journal of Physical Therapy Science | volume = 28 | issue = 1 | pages = 304–308 | date = January 2016 | pmid = 26957779 | pmc = 4756025 | doi = 10.1589/jpts.28.304 }}</ref> Pain medications, [[Chemistry:Glucocorticoid|steroids]], and [[Chemistry:Nonsteroidal anti-inflammatory drug|NSAIDs]] are frequently used to help with symptoms.<ref name=NIH2014/> Disease-modifying antirheumatic drugs (DMARDs), such as [[Chemistry:Hydroxychloroquine|hydroxychloroquine]] and [[Chemistry:Methotrexate|methotrexate]], may be used to try to slow the progression of disease.<ref name=NIH2014/> Biological DMARDs may be used when the disease does not respond to other treatments.<ref name=ACR2015>{{cite journal | vauthors = Singh JA, Saag KG, Bridges SL, Akl EA, Bannuru RR, Sullivan MC, Vaysbrot E, McNaughton C, Osani M, Shmerling RH, Curtis JR, Furst DE, Parks D, Kavanaugh A, O'Dell J, King C, Leong A, Matteson EL, Schousboe JT, Drevlow B, Ginsberg S, Grober J, St Clair EW, Tindall E, Miller AS, McAlindon T | title = 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis | journal = Arthritis & Rheumatology | volume = 68 | issue = 1 | pages = 1–26 | date = January 2016 | pmid = 26545940 | doi = 10.1002/art.39480 | s2cid = 42638848 | doi-access = free }}</ref> However, they may have a greater rate of adverse effects.<ref>{{cite journal | vauthors = Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L, Macdonald JK, Filippini G, Skoetz N, Francis D, Lopes LC, Guyatt GH, Schmitt J, La Mantia L, Weberschock T, Roos JF, Siebert H, Hershan S, Lunn MP, Tugwell P, Buchbinder R | title = Adverse effects of biologics: a network meta-analysis and Cochrane overview | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD008794 | date = February 2011 | volume = 2011 | pmid = 21328309 | doi = 10.1002/14651858.CD008794.pub2 | pmc = 7173749 }}</ref> Surgery to repair, [[Medicine:Joint replacement|replace]], or [[Medicine:Arthrodesis|fuse]] joints may help in certain situations.<ref name=NIH2014/>

RA affects about 24.5 million people as of 2015.<ref name=GBD2015Pre>{{cite journal | vauthors = Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, etal | collaboration = GBD 2015 Disease and Injury Incidence and Prevalence Collaborators | title = Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015 | journal = Lancet | volume = 388 | issue = 10053 | pages = 1545–1602 | date = October 2016 | pmid = 27733282 | pmc = 5055577 | doi = 10.1016/S0140-6736(16)31678-6 }}</ref> This is 0.5–1% of adults in the developed world with between 5 and 50 per 100,000 people newly developing the condition each year.<ref name=Lancet2016>{{cite journal | vauthors = Smolen JS, Aletaha D, McInnes IB | s2cid = 37973054 | title = Rheumatoid arthritis | journal = Lancet | volume = 388 | issue = 10055 | pages = 2023–2038 | date = October 2016 | pmid = 27156434 | doi = 10.1016/S0140-6736(16)30173-8 | url = http://eprints.gla.ac.uk/131249/1/131249.pdf }}</ref> Onset is most frequent during middle age and women are affected 2.5 times as frequently as men.<ref name=NIH2014/> It resulted in 38,000 deaths in 2013, up from 28,000 deaths in 1990.<ref name=GDB2013>{{cite journal | title = Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013 | journal = Lancet | volume = 385 | issue = 9963 | pages = 117–171 | date = January 2015 | pmid = 25530442 | pmc = 4340604 | doi = 10.1016/S0140-6736(14)61682-2 | vauthors = ((GBD 2013 Mortality Causes of Death Collaborators)) }}</ref> The first recognized description of RA was made in 1800 by Dr. Augustin Jacob Landré-Beauvais (1772–1840) of Paris.<ref name=Landre1800>{{cite book | vauthors = Landré-Beauvais AJ | title=La goutte asthénique primitive (doctoral thesis) | year=1800 | location=Paris}} reproduced in {{cite journal | vauthors = 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 = 130–143 | date = March 2001 | pmid = 11324929 | doi = 10.1016/S1297-319X(00)00247-5 }}</ref> The term ''rheumatoid arthritis'' is based on the Greek for watery and inflamed joints.<ref name=Paget2002>{{cite book | vauthors = Paget SA, Lockshin MD, Loebl S |title=The Hospital for Special Surgery Rheumatoid Arthritis Handbook Everything You Need to Know |date=2002 |publisher=John Wiley & Sons |location=New York |isbn=978-0-471-22334-4 |pages = 32 |url= https://books.google.com/books?id=akacOyQrnKkC&pg=PA32 |url-status=live |archive-url= https://web.archive.org/web/20170222110341/https://books.google.com/books?id=akacOyQrnKkC&pg=PA32 |archive-date=2017-02-22}}</ref>

==Signs and symptoms==
RA primarily affects joints, but it also affects other [[Biology:Organ (anatomy)|organs]] in more than 15–25% of cases.<ref name="pmid12860726">{{cite journal | vauthors = Turesson C, O'Fallon WM, Crowson CS, Gabriel SE, Matteson EL | title = Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years | journal = Annals of the Rheumatic Diseases | volume = 62 | issue = 8 | pages = 722–727 | date = August 2003 | pmid = 12860726 | pmc = 1754626 | doi = 10.1136/ard.62.8.722 }}</ref> Associated problems include cardiovascular disease, osteoporosis, interstitial lung disease, infection, cancer, feeling tired, depression, mental difficulties, and trouble working.<ref>{{cite journal | vauthors = Cutolo M, Kitas GD, van Riel PL | title = Burden of disease in treated rheumatoid arthritis patients: going beyond the joint | journal = Seminars in Arthritis and Rheumatism | volume = 43 | issue = 4 | pages = 479–488 | date = February 2014 | pmid = 24080116 | doi = 10.1016/j.semarthrit.2013.08.004 }}</ref>

===Joints===
[[File:Rheumatoid arthritis joint.gif|thumb|upright=1.2|A diagram showing how rheumatoid arthritis affects a joint]]

[[Medicine:Arthritis|Arthritis]] of joints involves [[Medicine:Inflammation|inflammation]] of the synovial membrane. Joints become swollen, tender and warm, and stiffness limits their movement. With time, multiple joints are affected ([[Medicine:Polyarthritis|polyarthritis]]). Most commonly involved are the small joints of the hands, [[Biology:Foot|feet]] and cervical spine, but larger joints like the shoulder and knee can also be involved.<ref name=Davidson2014/>{{rp|1098}} [[Medicine:Synovitis|Synovitis]] can lead to [[Biology:Tether (cell biology)|tethering]] of tissue with loss of movement and erosion of the joint surface causing [[Biology:Deformity|deformity]] and loss of function.<ref name=Majithia2007/> The [[Biology:Fibroblast-like synoviocyte|fibroblast-like synoviocyte]]s (FLS), highly specialized mesenchymal cells found in the synovial membrane, have an active and prominent role in these pathogenic processes of the rheumatic joints.<ref name="nygaard">{{cite journal | vauthors = Nygaard G, Firestein GS | s2cid = 218573182 | title = Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes | journal = Nature Reviews. Rheumatology | volume = 16 | issue = 6 | pages = 316–333 | date = June 2020 | pmid = 32393826 | doi = 10.1038/s41584-020-0413-5 | pmc = 7987137 }}</ref>

RA typically manifests with signs of inflammation, with the affected joints being swollen, warm, painful and stiff, particularly early in the morning on waking or following prolonged inactivity. Increased stiffness early in the morning is often a prominent feature of the disease and typically lasts for more than an hour. Gentle movements may relieve symptoms in early stages of the disease. These signs help distinguish rheumatoid from non-inflammatory problems of the joints, such as [[Medicine:Osteoarthritis|osteoarthritis]]. In arthritis of non-inflammatory causes, signs of inflammation and early morning stiffness are less prominent.<ref>{{cite journal | vauthors = Suresh E | title = Diagnosis of early rheumatoid arthritis: what the non-specialist needs to know | journal = Journal of the Royal Society of Medicine | volume = 97 | issue = 9 | pages = 421–424 | date = September 2004 | pmid = 15340020 | pmc = 1079582 | doi = 10.1177/014107680409700903 }}</ref>
The pain associated with RA is induced at the site of inflammation and classified as nociceptive as opposed to neuropathic.<ref>{{cite journal | vauthors = Gaffo A, Saag KG, Curtis JR | title = Treatment of rheumatoid arthritis | journal = American Journal of Health-System Pharmacy | volume = 63 | issue = 24 | pages = 2451–2465 | date = December 2006 | pmid = 17158693 | pmc = 5164397 | doi = 10.2146/ajhp050514 }}</ref> The joints are often affected in a fairly symmetrical fashion, although this is not specific, and the initial presentation may be asymmetrical.<ref name=Davidson2014>{{cite book| veditors = Walker BR, Colledge NR, Ralston SH, Penman ID |title=Davidson's principles and practice of medicine|date=2014|publisher=Churchill Livingstone/Elsevier|isbn=978-0-7020-5035-0 |edition=22nd}}</ref>{{rp|1098}}

As the pathology progresses the inflammatory activity leads to tendon tethering and erosion and destruction of the joint surface, which impairs range of movement and leads to [[Biology:Deformity|deformity]]. The fingers may develop almost any [[Biology:Deformity|deformity]] depending on which joints are most involved. Specific [[Biology:Deformity|deformities]], which also occur in [[Medicine:Osteoarthritis|osteoarthritis]], include ulnar deviation, [[Medicine:Boutonniere deformity|boutonniere deformity]] (also "buttonhole deformity", flexion of proximal interphalangeal joint and extension of distal interphalangeal joint of the hand), [[Medicine:Swan neck deformity|swan neck deformity]] (hyperextension at proximal interphalangeal joint and flexion at distal interphalangeal joint) and "Z-thumb." "Z-thumb" or "Z-deformity" consists of hyperextension of the interphalangeal joint, fixed flexion and [[Medicine:Subluxation|subluxation]] of the metacarpophalangeal joint and gives a "Z" appearance to the thumb.<ref name=Davidson2014 />{{rp|1098}} The hammer toe [[Biology:Deformity|deformity]] may be seen. In the worst case, joints are known as [[Medicine:Arthritis mutilans|arthritis mutilans]] due to the mutilating nature of the deformities.<ref name="McGraw Hill">{{cite book | vauthors = Shah A |date=2012 |title=Harrison's Principles of Internal Medicine |publisher=McGraw Hill |location=United States |isbn=978-0-07-174889-6 |pages = 2738 |edition=18th}}</ref>

===Skin===
The [[Medicine:Rheumatoid nodule|rheumatoid nodule]], which is sometimes in the skin, is the most common non-joint feature and occurs in 30% of people who have RA.<ref name=Tur2013>{{cite journal | vauthors = Turesson C | title = Extra-articular rheumatoid arthritis | journal = Current Opinion in Rheumatology | volume = 25 | issue = 3 | pages = 360–366 | date = May 2013 | pmid = 23425964 | doi = 10.1097/bor.0b013e32835f693f | s2cid = 21462453 }}</ref> It is a type of inflammatory reaction known to pathologists as a "necrotizing [[Medicine:Granuloma|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 [[Biology:Fibrinoid necrosis|fibrinoid necrosis]] that may be [[Biology:Fissure (anatomy)|fissured]] and which corresponds to the [[Biology:Fibrin|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 [[Biology:Lymphocyte|lymphocyte]]s and [[Biology:Plasma cell|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 elbow, the heel, the knuckles, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF ([[Medicine:Rheumatoid factor|rheumatoid factor]]) [[Biology:Titer|titer]], ACPA, and severe erosive arthritis. Rarely, these can occur in internal organs or at diverse sites on the body.<ref>{{cite journal | vauthors = Ziff M | title = The rheumatoid nodule | journal = Arthritis and Rheumatism | volume = 33 | issue = 6 | pages = 761–767 | date = June 1990 | pmid = 2194460 | doi = 10.1002/art.1780330601 | doi-access = free }}</ref>

Several forms of [[Medicine:Vasculitis|vasculitis]] occur in RA, but are mostly seen with long-standing and untreated disease. The most common presentation is due to involvement of small- and medium-sized vessels. Rheumatoid vasculitis can thus commonly present with skin ulceration and vasculitic nerve infarction known as mononeuritis multiplex.<ref>{{cite journal | vauthors = Genta MS, Genta RM, Gabay C | title = Systemic rheumatoid vasculitis: a review | journal = Seminars in Arthritis and Rheumatism | volume = 36 | issue = 2 | pages = 88–98 | date = October 2006 | pmid = 17023257 | doi = 10.1016/j.semarthrit.2006.04.006 }}</ref>

Other, rather rare, skin associated symptoms include [[Medicine:Pyoderma gangrenosum|pyoderma gangrenosum]], Sweet's syndrome, drug reactions, [[Medicine:Erythema nodosum|erythema nodosum]], lobe [[Medicine:Panniculitis|panniculitis]], [[Medicine:Atrophy|atrophy]] of finger skin, palmar erythema, and skin fragility (often worsened by corticosteroid use).{{Citation needed|date=October 2014}}

Diffuse alopecia areata (Diffuse AA) occurs more commonly in people with rheumatoid arthritis.<ref name=":1" /> RA is also seen more often in those with relatives who have AA.<ref name=":1">{{cite book | vauthors = Khan P, Beigi M |s2cid=46954629 |date=2018|title=Alopecia Areata|doi=10.1007/978-3-319-72134-7|isbn=978-3-319-72133-0 }}</ref>

===Lungs===
{{Main|Medicine:Rheumatoid lung disease}}
Lung fibrosis is a recognized complication of rheumatoid arthritis. It is also a rare but well-recognized consequence of therapy (for example with [[Chemistry:Methotrexate|methotrexate]] and [[Chemistry:Leflunomide|leflunomide]]). Caplan's syndrome describes lung nodules in individuals with RA and additional exposure to [[Earth:Coal|coal]] dust. [[Biology:Exudate|Exudative]] pleural effusions are also associated with RA.<ref>{{cite journal | vauthors = Kim EJ, Collard HR, King TE | title = Rheumatoid arthritis-associated interstitial lung disease: the relevance of histopathologic and radiographic pattern | journal = Chest | volume = 136 | issue = 5 | pages = 1397–1405 | date = November 2009 | pmid = 19892679 | pmc = 2818853 | doi = 10.1378/chest.09-0444 }}</ref><ref>{{cite journal | vauthors = Balbir-Gurman A, Yigla M, Nahir AM, Braun-Moscovici Y | title = Rheumatoid pleural effusion | journal = Seminars in Arthritis and Rheumatism | volume = 35 | issue = 6 | pages = 368–378 | date = June 2006 | pmid = 16765714 | doi = 10.1016/j.semarthrit.2006.03.002 }}</ref>

===Heart and blood vessels===
People with RA are more prone to [[Medicine:Atherosclerosis|atherosclerosis]], and risk of [[Medicine:Myocardial infarction|myocardial infarction]] (heart attack) and [[Medicine:Stroke|stroke]] is markedly increased.<ref>{{cite journal | vauthors = Wolfe F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA, Spitz PW, Haga M, Kleinheksel SM, Cathey MA | title = The mortality of rheumatoid arthritis | journal = Arthritis and Rheumatism | volume = 37 | issue = 4 | pages = 481–494 | date = April 1994 | pmid = 8147925 | doi = 10.1002/art.1780370408 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D | title = Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies | journal = Arthritis and Rheumatism | volume = 59 | issue = 12 | pages = 1690–1697 | date = December 2008 | pmid = 19035419 | doi = 10.1002/art.24092 }}</ref><ref>{{cite journal | vauthors = Alenghat FJ | title = The Prevalence of Atherosclerosis in Those with Inflammatory Connective Tissue Disease by Race, Age, and Traditional Risk Factors | journal = Scientific Reports | volume = 6 | pages = 20303 | date = February 2016 | pmid = 26842423 | pmc = 4740809 | doi = 10.1038/srep20303 | bibcode = 2016NatSR...620303A }}</ref>
Other possible complications that may arise include: [[Medicine:Pericarditis|pericarditis]], [[Medicine:Endocarditis|endocarditis]], left ventricular failure, valvulitis and [[Medicine:Fibrosis|fibrosis]].<ref name="Gupta">{{cite journal |vauthors=Gupta A, Fomberstein B |title=Evaluating cardiovascular risk in rheumatoid arthritis |journal=Journal of Musculoskeletal Medicine |volume=26 |issue=8 |pages=481–494 |year=2009 |url=http://www.musculoskeletalnetwork.com/rheumatoid-arthritis/content/article/1145622/1433094 |url-status=live |archive-url=https://web.archive.org/web/20120723164920/http://www.musculoskeletalnetwork.com/rheumatoid-arthritis/content/article/1145622/1433094 |archive-date=2012-07-23 }}</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 [[Medicine:Inflammation|inflammation]] caused by RA (which may be involved in causing the cardiovascular risk), and to use exercise and medications appropriately to reduce other cardiovascular risk factors such as blood lipids and blood pressure. Doctors who treat people with RA should be sensitive to cardiovascular risk when prescribing anti-inflammatory medications, and may want to consider prescribing routine use of low doses of aspirin if the gastrointestinal effects are tolerable.<ref name="Gupta"/>

===Blood===
[[Medicine:Anemia|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 [[Biology:Hepcidin|hepcidin]] levels, leading to [[Medicine:Anemia of chronic disease|anemia of chronic disease]] where iron is poorly absorbed and also sequestered into macrophages. The red cells are of normal size and color (normocytic and Normochromic).<ref>{{cite journal | vauthors = Wilson A, Yu HT, Goodnough LT, Nissenson AR | title = Prevalence and outcomes of anemia in rheumatoid arthritis: a systematic review of the literature | journal = The American Journal of Medicine | volume = 116 | issue = Suppl 7A | pages = 50S–57S | date = April 2004 | pmid = 15050886 | doi = 10.1016/j.amjmed.2003.12.012 }}</ref>

A [[Medicine:Neutropenia|low white blood cell count]] usually only occurs in people with [[Medicine:Felty's syndrome|Felty's syndrome]] with an enlarged liver and spleen. The mechanism of neutropenia is complex. An increased platelet count occurs when inflammation is uncontrolled.<ref>{{cite journal | vauthors = Tramś E, Malesa K, Pomianowski S, Kamiński R | title = Role of Platelets in Osteoarthritis-Updated Systematic Review and Meta-Analysis on the Role of Platelet-Rich Plasma in Osteoarthritis | journal = Cells | volume = 11 | issue = 7 | pages = 1080 | date = March 2022 | pmid = 35406644 | pmc = 8997794 | doi = 10.3390/cells11071080 | doi-access = free }}</ref>

===Other===
The role of the circadian clock in rheumatoid arthritis suggests a correlation between an early morning rise in circulating levels of pro-inflammatory cytokines, such as interleukin-6 and painful morning joint stiffness.<ref name="pmid23427807">{{cite journal | vauthors = Gibbs JE, Ray DW | title = The role of the circadian clock in rheumatoid arthritis | journal = Arthritis Res Ther | volume = 15 | issue = 1 | pages = 205 | date = February 2013 | pmid = 23427807 | pmc = 3672712 | doi = 10.1186/ar4146 | doi-access = free }}</ref>

==== Kidneys ====
Renal [[Medicine:Amyloidosis|amyloidosis]] can occur as a consequence of untreated chronic inflammation.<ref>{{cite journal | vauthors = de Groot K | title = [Renal manifestations in rheumatic diseases] | journal = Der Internist | volume = 48 | issue = 8 | pages = 779–785 | date = August 2007 | pmid = 17571244 | doi = 10.1007/s00108-007-1887-9 | s2cid = 28781598 }}</ref> Treatment with [[Chemistry:Penicillamine|penicillamine]] or [[Chemistry:Gold salts|gold salts]] such as [[Chemistry:Sodium aurothiomalate|sodium aurothiomalate]] are recognized causes of membranous nephropathy.<ref>{{cite journal | vauthors = Moroni G, Ponticelli C | title = Secondary Membranous Nephropathy. A Narrative Review | journal = Frontiers in Medicine | year = 2020 | volume = 7 | pages = 611317 | pmid = 33344486 | doi = 10.3389/fmed.2020.611317 | pmc = 7744820 | doi-access = free }}</ref>

==== Eyes ====
The eye can be directly affected in the form of [[Medicine:Episcleritis|episcleritis]]<ref name=Schonberg>{{cite book | vauthors = Schonberg S, Stokkermans TJ | chapter = Episcleritis | date = January 2020 | pmid = 30521217 | url = http://www.ncbi.nlm.nih.gov/books/nbk534796/ | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing }}</ref> or [[Medicine:Scleritis|scleritis]], which when severe can very rarely progress to perforating scleromalacia. Rather more common is the indirect effect of keratoconjunctivitis sicca, which is a dryness of eyes and mouth caused by [[Biology:Lymphocyte|lymphocyte]] infiltration of [[Medicine:Lacrimal gland|lacrimal]] and salivary glands. When severe, dryness of the cornea can lead to [[Medicine:Keratitis|keratitis]] and loss of vision as well as being painful. Preventive treatment of severe dryness with measures such as [[Medicine:Nasolacrimal duct|nasolacrimal duct]] blockage is important.<ref>{{cite journal | vauthors = Dammacco R, Guerriero S, Alessio G, Dammacco F | title = Natural and iatrogenic ocular manifestations of rheumatoid arthritis: a systematic review | journal = International Ophthalmology | volume = 42 | issue = 2 | pages = 689–711 | date = February 2022 | pmid = 34802085 | pmc = 8882568 | doi = 10.1007/s10792-021-02058-8 }}</ref>

==== Liver ====
Liver problems in people with rheumatoid arthritis may be due to the underlying disease process or as a result of the medications used to treat the disease.<ref name="Selmi2011" /> A coexisting autoimmune liver disease, such as primary biliary cirrhosis or [[Medicine:Autoimmune hepatitis|autoimmune hepatitis]] may also cause problems.<ref name="Selmi2011">{{cite journal | vauthors = Selmi C, De Santis M, Gershwin ME | title = Liver involvement in subjects with rheumatic disease | journal = Arthritis Research & Therapy | volume = 13 | issue = 3 | pages = 226 | date = June 2011 | pmid = 21722332 | pmc = 3218873 | doi = 10.1186/ar3319 | doi-access = free }}</ref>

==== Neurological ====
[[Medicine:Peripheral neuropathy|Peripheral neuropathy]] and mononeuritis multiplex may occur. The most common problem is [[Medicine:Carpal tunnel syndrome|carpal tunnel syndrome]] caused by compression of the median nerve by swelling around the wrist. [[Medicine:Rheumatoid disease of the spine|Rheumatoid disease of the spine]] can lead to myelopathy. Atlanto-axial [[Medicine:Subluxation|subluxation]] can occur, owing to erosion of the odontoid process and/or transverse ligaments in the cervical spine's connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping over one another and compressing the spinal cord. Clumsiness is initially experienced, but without due care, this can progress to [[Medicine:Quadriplegia|quadriplegia]] or even death.<ref>{{cite journal | vauthors = Wasserman BR, Moskovich R, Razi AE | title = Rheumatoid arthritis of the cervical spine--clinical considerations | journal = Bulletin of the NYU Hospital for Joint Diseases | volume = 69 | issue = 2 | pages = 136–148 | year = 2011 | pmid = 22035393 | url = http://hjdbulletin.org/files/archive/pdfs/222.pdf }}</ref>

==== Constitutional symptoms ====
Constitutional symptoms including fatigue, low grade [[Medicine:Fever|fever]], malaise, morning stiffness, loss of appetite and loss of weight are common systemic manifestations seen in people with active RA.

==== Bones ====
Local [[Medicine:Osteoporosis|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.<ref name="pmid16271143">{{cite journal | vauthors = Ginaldi L, Di Benedetto MC, De Martinis M | title = Osteoporosis, inflammation and ageing | journal = Immunity & Ageing | volume = 2 | issue = | pages = 14 | date = November 2005 | pmid = 16271143 | pmc = 1308846 | doi = 10.1186/1742-4933-2-14 | doi-access = free }}</ref><ref name="pmid25905202">{{cite book | vauthors = Ilias I, Milionis C, Zoumakis E | chapter = An Overview of Glucocorticoid-Induced Osteoporosis. | date = March 2022 | title = Endotext [Internet]. | location = South Dartmouth (MA) | publisher = MDText.com, Inc. | url = https://www.ncbi.nlm.nih.gov/sites/books/NBK278968/ | pmid = 25905202 | veditors = Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, Ilias I, Milionis C, Zoumakis E | display-editors = 6 }}</ref>

==== Cancer ====
The incidence of [[Medicine:Lymphoma|lymphoma]] is increased, although it is uncommon and associated with the chronic inflammation, not the treatment of RA.<ref>{{cite journal | vauthors = Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F, Catrina AI, Rosenquist R, Feltelius N, Sundström C, Klareskog L | title = Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis | journal = Arthritis and Rheumatism | volume = 54 | issue = 3 | pages = 692–701 | date = March 2006 | pmid = 16508929 | doi = 10.1002/art.21675 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Franklin J, Lunt M, Bunn D, Symmons D, Silman A | title = Incidence of lymphoma in a large primary care derived cohort of cases of inflammatory polyarthritis | journal = Annals of the Rheumatic Diseases | volume = 65 | issue = 5 | pages = 617–622 | date = May 2006 | pmid = 16249224 | pmc = 1798140 | doi = 10.1136/ard.2005.044784 }}</ref> The risk of non-melanoma skin cancer is increased in people with RA compared to the general population, an association possibly due to the use of [[Biology:Immunosuppression|immunosuppression]] agents for treating RA.<ref>{{cite journal | vauthors = Assassi S | title = Rheumatoid arthritis, TNF inhibitors, and non-melanoma skin cancer | journal = BMJ | volume = 352 | pages = i472 | date = January 2016 | pmid = 26822198 | doi = 10.1136/bmj.i472 | s2cid = 45857932 }}</ref>

==== Teeth ====
[[Medicine:Periodontal disease|Periodontitis]] and tooth loss are common in people with rheumatoid arthritis.<ref name="pmid19337286">{{cite journal | vauthors = de Pablo P, Chapple IL, Buckley CD, Dietrich T | s2cid = 7173008 | title = Periodontitis in systemic rheumatic diseases | journal = Nature Reviews. Rheumatology | volume = 5 | issue = 4 | pages = 218–224 | date = April 2009 | pmid = 19337286 | doi = 10.1038/nrrheum.2009.28 }}</ref>

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

===Genetic===
Worldwide, RA affects approximately 1% of the adult population and occurs one in 1,000 children. Studies show RA primarily affects individuals between the ages of 40–60 years and is seen more commonly in females.<ref name=":14">{{cite journal | vauthors = Rennie KL, Hughes J, Lang R, Jebb SA | title = Nutritional management of rheumatoid arthritis: a review of the evidence | journal = Journal of Human Nutrition and Dietetics | volume = 16 | issue = 2 | pages = 97–109 | date = April 2003 | pmid = 12662368 | doi = 10.1046/j.1365-277x.2003.00423.x }}</ref><ref name=":16" /> A family history of RA increases the risk around three to five times; as of 2016, it was estimated that genetics may account for 40–65% of cases of seropositive RA, but only around 20% for seronegative RA.<ref name=Lancet2016/> RA is strongly associated with genes of the inherited tissue type [[Biology:Major histocompatibility complex|major histocompatibility complex]] (MHC) antigen. [[Biology:HLA-DR4|HLA-DR4]] is the major genetic factor implicated – the relative importance varies across ethnic groups.<ref name="Elsevier"/>

Genome-wide association studies examining [[Biology:Single-nucleotide polymorphism|single-nucleotide polymorphism]]s have found around one hundred alleles associated with RA risk.<ref>{{cite journal | vauthors = Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Yoshida S, Graham RR, Manoharan A, Ortmann W, Bhangale T, Denny JC, Carroll RJ, Eyler AE, Greenberg JD, Kremer JM, Pappas DA, Jiang L, Yin J, Ye L, Su DF, Yang J, Xie G, Keystone E, Westra HJ, Esko T, Metspalu A, Zhou X, Gupta N, Mirel D, Stahl EA, Diogo D, Cui J, Liao K, Guo MH, Myouzen K, Kawaguchi T, Coenen MJ, van Riel PL, van de Laar MA, Guchelaar HJ, Huizinga TW, Dieudé P, Mariette X, Bridges SL, Zhernakova A, Toes RE, Tak PP, Miceli-Richard C, Bang SY, Lee HS, Martin J, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Rantapää-Dahlqvist S, Arlestig L, Choi HK, Kamatani Y, Galan P, Lathrop M, Eyre S, Bowes J, Barton A, de Vries N, Moreland LW, Criswell LA, Karlson EW, Taniguchi A, Yamada R, Kubo M, Liu JS, Bae SC, Worthington J, Padyukov L, Klareskog L, Gregersen PK, Raychaudhuri S, Stranger BE, De Jager PL, Franke L, Visscher PM, Brown MA, Yamanaka H, Mimori T, Takahashi A, Xu H, Behrens TW, Siminovitch KA, Momohara S, Matsuda F, Yamamoto K, Plenge RM | title = Genetics of rheumatoid arthritis contributes to biology and drug discovery | journal = Nature | volume = 506 | issue = 7488 | pages = 376–381 | date = February 2014 | pmid = 24390342 | pmc = 3944098 | doi = 10.1038/nature12873 | bibcode = 2014Natur.506..376. }}</ref> Risk alleles within the [[Biology:Human leukocyte antigen|HLA]] (particularly HLA-DRB1) genes harbor more risk than other loci.<ref>{{cite journal | vauthors = Raychaudhuri S, Sandor C, Stahl EA, Freudenberg J, Lee HS, Jia X, Alfredsson L, Padyukov L, Klareskog L, Worthington J, Siminovitch KA, Bae SC, Plenge RM, Gregersen PK, de Bakker PI | title = Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis | journal = Nature Genetics | volume = 44 | issue = 3 | pages = 291–296 | date = January 2012 | pmid = 22286218 | pmc = 3288335 | doi = 10.1038/ng.1076 }}</ref> The HLA encodes proteins that control recognition of self- versus non-self molecules. Other risk loci include genes affecting co-stimulatory immune pathways{{em dash}}for example [[Biology:CD28|CD28]] and CD40, cytokine signaling, lymphocyte receptor activation threshold (e.g., [[Biology:PTPN22|PTPN22]]), and innate immune activation{{em dash}}appear to have less influence than HLA mutations.<ref name=Lancet2016/><ref name="pmid131669381">{{cite journal | vauthors = Ghorban K, Ezzeddini R, Eslami M, Yousefi B, Sadighi Moghaddam B, Tahoori MT, Dadmanesh M, Salek Farrokhi A | title = PTPN22 1858 C/T polymorphism is associated with alteration of cytokine profiles as a potential pathogenic mechanism in rheumatoid arthritis | journal = Immunology Letters | volume = 216 | pages = 106–113 | date = December 2019 | pmid = 31669381 | doi = 10.1016/j.imlet.2019.10.010 | s2cid = 204966226 }}</ref>

===Environmental===
There are established epigenetic and environmental risk factors for RA.<ref name=Firestein2017>{{cite journal | vauthors = Firestein GS, McInnes IB | title = Immunopathogenesis of Rheumatoid Arthritis | journal = Immunity | volume = 46 | issue = 2 | pages = 183–196 | date = February 2017 | pmid = 28228278 | pmc = 5385708 | doi = 10.1016/j.immuni.2017.02.006 }}{{subscription required}}</ref><ref name=Lancet2016/> [[Chemistry:Tobacco smoking|Smoking]] is an established risk factor for RA in Caucasian populations, increasing the risk three times compared to non-smokers, particularly in men, heavy smokers, and those who are rheumatoid factor positive.<ref name=Sugiyama2010/> Modest alcohol consumption may be protective.<ref>{{cite journal | vauthors = Liao KP, Alfredsson L, Karlson EW | title = Environmental influences on risk for rheumatoid arthritis | journal = Current Opinion in Rheumatology | volume = 21 | issue = 3 | pages = 279–283 | date = May 2009 | pmid = 19318947 | pmc = 2898190 | doi = 10.1097/BOR.0b013e32832a2e16 }}{{subscription required}}</ref>

[[Chemistry:Silica|Silica]] exposure has been linked to RA.<ref>{{cite journal | vauthors = Pollard KM | title = Silica, Silicosis, and Autoimmunity | journal = Frontiers in Immunology | volume = 7 | pages = 97 | date = 11 March 2016 | pmid = 27014276 | pmc = 4786551 | doi = 10.3389/fimmu.2016.00097 | doi-access = free }}</ref>

===Negative findings===
No infectious agent has been consistently linked with RA and there is no evidence of disease clustering to indicate its infectious cause,<ref name="Elsevier">{{cite book| vauthors = Doherty M, Lanyon P, Ralston SH |title=Musculosketal Disorders-Davidson's Principle of Internal Medicine| publisher=Elsevier|pages=1100–1106|edition=20th}}</ref> but [[Medicine:Periodontal disease|periodontal disease]] has been consistently associated with RA.<ref name=Lancet2016/>

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 | vauthors = Edwards JC, Cambridge G, Abrahams VM | title = Do self-perpetuating B lymphocytes drive human autoimmune disease? | journal = Immunology | volume = 97 | issue = 2 | pages = 188–196 | date = June 1999 | pmid = 10447731 | pmc = 2326840 | doi = 10.1046/j.1365-2567.1999.00772.x }}{{subscription required}}</ref>

==Pathophysiology==
RA primarily starts as a state of persistent cellular activation leading to [[Medicine:Autoimmunity|autoimmunity]] and [[Biology:Immune complex|immune complex]]es in joints and other organs where it manifests.<ref>{{cite journal | vauthors = Coates LC, FitzGerald O, Helliwell PS, Paul C | title = Psoriasis, psoriatic arthritis, and rheumatoid arthritis: Is all inflammation the same? | journal = Seminars in Arthritis and Rheumatism | volume = 46 | issue = 3 | pages = 291–304 | date = December 2016 | pmid = 27388027 | doi = 10.1016/j.semarthrit.2016.05.012 | s2cid = 22539356 | doi-access = free }}</ref>

The clinical manifestations of disease are primarily inflammation of the synovial membrane and joint damage, and the fibroblast-like synoviocytes play a key role in these pathogenic processes.<ref name="nygaard" /> Three phases of progression of RA are an initiation phase (due to non-specific inflammation), an amplification phase (due to [[Biology:T cell|T cell]] activation), and chronic inflammatory phase, with tissue injury resulting from the cytokines, IL–1, TNF-alpha, and IL–6.<ref name="McGraw Hill" />

===Non-specific inflammation===
Factors allowing an abnormal immune response, once initiated, become permanent and chronic. These factors are [[Medicine:Genetic disorder|genetic disorder]]s which change regulation of the [[Biology:Adaptive immune system|adaptive immune response]].<ref name=Lancet2016/> Genetic factors interact with environmental risk factors for RA, with cigarette smoking as the most clearly defined risk factor.<ref name=Sugiyama2010>{{cite journal | vauthors = Sugiyama D, Nishimura K, Tamaki K, Tsuji G, Nakazawa T, Morinobu A, Kumagai S | s2cid = 11303269 | title = Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies | journal = Annals of the Rheumatic Diseases | volume = 69 | issue = 1 | pages = 70–81 | date = January 2010 | pmid = 19174392 | doi = 10.1136/ard.2008.096487 | url = http://www.lib.kobe-u.ac.jp/repository/90001457.pdf | access-date = 2018-04-20 | archive-date = 2021-03-01 | archive-url = https://web.archive.org/web/20210301195736/http://www.lib.kobe-u.ac.jp/repository/90001457.pdf | url-status = dead }}{{subscription required}}</ref><ref>{{cite journal | vauthors = 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 and Rheumatism | volume = 50 | issue = 10 | pages = 3085–3092 | date = October 2004 | pmid = 15476204 | doi = 10.1002/art.20553 | url = http://rsp.ima-press.net/rsp/article/view/1939 }}{{subscription required}}</ref>

Other environmental and hormonal factors may explain higher risks for women, including onset after childbirth and hormonal medications. A possibility for increased susceptibility is that negative feedback mechanisms – which normally maintain tolerance – are overtaken by positive feedback mechanisms for certain antigens, such as IgG Fc bound by [[Medicine:Rheumatoid factor|rheumatoid factor]] and citrullinated fibrinogen bound by antibodies to citrullinated peptides (ACPA – Anti–citrullinated protein antibody). A debate on the relative roles of B-cell produced immune complexes and T cell products in inflammation in RA has continued for 30 years, but neither cell is necessary at the site of inflammation, only autoantibodies to IgGFc, known as rheumatoid factors and ACPA, with ACPA having an 80% specificity for diagnosing RA.<ref>{{cite journal | vauthors = Hua C, Daien CI, Combe B, Landewe R | title = Diagnosis, prognosis and classification of early arthritis: results of a systematic review informing the 2016 update of the EULAR recommendations for the management of early arthritis | journal = RMD Open | volume = 3 | issue = 1 | pages = e000406 | year = 2017 | pmid = 28155923 | pmc = 5237764 | doi = 10.1136/rmdopen-2016-000406 }}</ref> As with other autoimmune diseases, people with RA have abnormally glycosylated antibodies, which are believed to promote joint inflammation.<ref name="immune_glycan">{{cite journal | vauthors = Maverakis E, Kim K, Shimoda M, Gershwin ME, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB | title = Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review | journal = Journal of Autoimmunity | volume = 57 | issue = 6 | pages = 1–13 | date = February 2015 | pmid = 25578468 | pmc = 4340844 | doi = 10.1016/j.jaut.2014.12.002 }}{{subscription required}}</ref>{{page needed|date=July 2017}}

===Amplification in the synovium===
Once the generalized abnormal immune response has become established – which may take several years before any symptoms occur – plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes in large quantities. These activate macrophages through Fc receptor and complement binding, which is part of the intense inflammation in RA.<ref>{{cite book|vauthors=Boldt AB, Goeldner I, de Messias-Reason IJ |pmid=22397030|title=Relevance of the lectin pathway of complement in rheumatic diseases|doi=10.1016/B978-0-12-394317-0.00012-1|volume=56 |pages=105–153|year=2012| journal = Advances in Clinical Chemistry|publisher=Elsevier |isbn=978-0-12-394317-0 }}{{subscription required}}</ref> Binding of an autoreactive antibody to the Fc receptors is mediated through the antibody's N-glycans, which are altered to promote inflammation in people with RA.<ref name = "immune_glycan"/>{{page needed|date=July 2017}}

This contributes to local inflammation in a joint, specifically the synovium with [[Medicine:Edema|edema]], [[Medicine:Vasodilation|vasodilation]] and entry of activated T-cells, mainly CD4 in microscopically nodular aggregates and CD8 in microscopically diffuse infiltrates.<ref name=":02">{{cite journal | vauthors = Jonsson AH, Zhang F, Dunlap G, Gomez-Rivas E, Watts GF, Faust HJ, Rupani KV, Mears JR, Meednu N, Wang R, Keras G, Coblyn JS, Massarotti EM, Todd DJ, Anolik JH, McDavid A, Wei K, Rao DA, Raychaudhuri S, Brenner MB | title = Granzyme K<sup>+</sup> CD8 T cells form a core population in inflamed human tissue | journal = Science Translational Medicine | volume = 14 | issue = 649 | pages = eabo0686 | date = June 2022 | pmid = 35704599 | pmc = 9972878 | doi = 10.1126/scitranslmed.abo0686 }}</ref>

Synovial macrophages and [[Biology:Dendritic cell|dendritic cell]]s function as antigen-presenting cells by expressing MHC class II molecules, which establishes the immune reaction in the tissue.<ref name=":02" />

===Chronic inflammation===
{{multiple image
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| image2            = Rheumatoid arthritis with carpal ankylosis 2017.jpg
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The disease progresses by forming granulation tissue at the edges of the synovial lining, [[Medicine:Pannus|pannus]] with extensive [[Biology:Angiogenesis|angiogenesis]] and enzymes causing tissue damage.<ref>{{cite journal | vauthors = Elshabrawy HA, Chen Z, Volin MV, Ravella S, Virupannavar S, Shahrara S | title = The pathogenic role of angiogenesis in rheumatoid arthritis | journal = Angiogenesis | volume = 18 | issue = 4 | pages = 433–448 | date = October 2015 | pmid = 26198292 | pmc = 4879881 | doi = 10.1007/s10456-015-9477-2 }}</ref> The fibroblast-like synoviocytes have a prominent role in these pathogenic processes.<ref name=nygaard/> The synovium thickens, cartilage and underlying bone disintegrate, and the joint deteriorates, with raised [[Biology:Calprotectin|calprotectin]] levels serving as a [[Biology:Biomarker|biomarker]] of these events.<ref>{{cite journal | vauthors = Abildtrup M, Kingsley GH, Scott DL | title = Calprotectin as a biomarker for rheumatoid arthritis: a systematic review | journal = The Journal of Rheumatology | volume = 42 | issue = 5 | pages = 760–770 | date = May 2015 | pmid = 25729036 | doi = 10.3899/jrheum.140628 | s2cid = 43537545 | doi-access = free }}</ref> Importantly inflammatory events are not limited to synovium but it appear to be systemic, evidence suggest that alterations in T helper profile favoring inflammation such as inflammatory IL-17A producing T helper cells and pathogenic Th17 cells are come from both memory and effector compartment in RA patients peripheral blood.<ref>{{cite journal | vauthors = Peroumal D, Abimannan T, Tagirasa R, Parida JR, Singh SK, Padhan P, Devadas S | title = Inherent low Erk and p38 activity reduce Fas Ligand expression and degranulation in T helper 17 cells leading to activation induced cell death resistance | journal = Oncotarget | volume = 7 | issue = 34 | pages = 54339–54359 | date = August 2016 | pmid = 27486885 | pmc = 5342346 | doi = 10.18632/oncotarget.10913 }}</ref>

Cytokines and chemokines attract and accumulate immune cells, i.e. activated T- and B cells, monocytes and macrophages from activated fibroblast-like synoviocytes, in the joint space. By signalling through [[Biology:RANKL|RANKL]] and [[Biology:RANK|RANK]], they eventually trigger [[Biology:Osteoclast|osteoclast]] production, which degrades bone tissue.<ref name=Lancet2016/><ref name=Chiu2017rev>{{cite journal | vauthors = Chiu YG, Ritchlin CT | title = Denosumab: targeting the RANKL pathway to treat rheumatoid arthritis | journal = Expert Opinion on Biological Therapy | volume = 17 | issue = 1 | pages = 119–128 | date = January 2017 | pmid = 27871200 | pmc = 5794005 | doi = 10.1080/14712598.2017.1263614 }}{{subscription required}}</ref>{{page needed|date=July 2017}} The fibroblast-like synoviocytes that are present in the synovium during rheumatoid arthritis display altered phenotype compared to the cells present in normal tissues. The aggressive phenotype of fibroblast-like synoviocytes in rheumatoid arthritis and the effect these cells have on the microenvironment of the joint can be summarized into hallmarks that distinguish them from healthy fibroblast-like synoviocytes. These hallmark features of fibroblast-like synoviocytes in rheumatoid arthritis are divided into seven cell-intrinsic hallmarks and four cell-extrinsic hallmarks.<ref name=nygaard/> The cell-intrinsic hallmarks are: reduced apoptosis, impaired contact inhibition, increased migratory invasive potential, changed epigenetic landscape, temporal and spatial heterogeneity, genomic instability and mutations, and reprogrammed cellular metabolism. The cell-extrinsic hallmarks of FLS in RA are: promotes osteoclastogenesis and bone erosion, contributes to cartilage degradation, induces synovial angiogenesis, and recruits and stimulates immune cells.<ref name=nygaard/>

==Diagnosis==

===Imaging===
[[Image:RheumatoideArthritisAP.jpg|thumb|X-ray of the hand in rheumatoid arthritis]]
[[Image:Inflamatory arthritis2010.JPG|thumb|Appearance of synovial fluid from a joint with inflammatory arthritis]]
[[File:X-ray of right fourth PIP joint with bone erosions by rheumatoid arthritis.jpg|thumb|Closeup of [[Medicine:Bone erosion|bone erosion]]s in rheumatoid arthritis<ref>{{cite journal | vauthors = Ideguchi H, Ohno S, Hattori H, Senuma A, Ishigatsubo Y | title = Bone erosions in rheumatoid arthritis can be repaired through reduction in disease activity with conventional disease-modifying antirheumatic drugs | journal = Arthritis Research & Therapy | volume = 8 | issue = 3 | pages = R76 | year = 2006 | pmid = 16646983 | pmc = 1526642 | doi = 10.1186/ar1943 | doi-access = free }}</ref>]]
[[Physics:X-ray|X-ray]]s of the hands and feet are generally performed when many joints affected. In RA, there may be no changes in the early stages of the disease or the x-ray may show [[Unsolved:Osteopenia|osteopenia]] near the joint, soft tissue swelling, and a smaller than normal joint space. As the disease advances, there may be bony erosions and subluxation. Other medical imaging techniques such as [[Physics:Magnetic resonance imaging|magnetic resonance imaging]] (MRI) and ultrasound are also used in RA.<ref name="McGraw Hill"/><ref>{{cite journal | vauthors = Takase-Minegishi K, Horita N, Kobayashi K, Yoshimi R, Kirino Y, Ohno S, Kaneko T, Nakajima H, Wakefield RJ, Emery P | title = Diagnostic test accuracy of ultrasound for synovitis in rheumatoid arthritis: systematic review and meta-analysis | journal = Rheumatology | volume = 57 | issue = 1 | pages = 49–58 | date = January 2018 | pmid = 28340066 | doi = 10.1093/rheumatology/kex036 | doi-access = free }}</ref>

Technical advances in ultrasonography like high-frequency transducers (10&nbsp;MHz or higher) have improved the spatial resolution of ultrasound images depicting 20% more erosions than conventional radiography. Color Doppler and power Doppler ultrasound are useful in assessing the degree of synovial inflammation as they can show vascular signals of active synovitis. This is important, since in the early stages of RA, the synovium is primarily affected, and synovitis seems to be the best predictive marker of future joint damage.<ref>{{cite journal |vauthors=Schueller-Weidekamm C |date=Apr 29, 2010 |title=Modern ultrasound methods yield stronger arthritis work-up |journal=Diagnostic Imaging |volume=32 |url=http://www.diagnosticimaging.com/ultrasound/modern-ultrasound-methods-yield-stronger-arthritis-work |access-date=October 21, 2018 |archive-date=April 9, 2019 |archive-url=https://web.archive.org/web/20190409091359/https://www.diagnosticimaging.com/ultrasound/modern-ultrasound-methods-yield-stronger-arthritis-work |url-status=dead }}</ref>

===Blood tests===
When RA is clinically suspected, a physician may test for [[Medicine:Rheumatoid factor|rheumatoid factor]] (RF) and anti-citrullinated protein antibodies (ACPAs measured as anti-CCP antibodies).<ref>{{cite journal | vauthors = Westwood OM, Nelson PN, Hay FC | title = Rheumatoid factors: what's new? | journal = Rheumatology | volume = 45 | issue = 4 | pages = 379–385 | date = April 2006 | pmid = 16418203 | doi = 10.1093/rheumatology/kei228 | doi-access = free }}{{subscription required}}</ref>{{page needed|date=July 2017}}
The test is positive approximately two-thirds of the time, but a negative RF or CCP antibody does not rule out RA; rather, the arthritis is called ''seronegative'', which occurs in approximately a third of people with RA.<ref>{{cite journal | vauthors = Salman E, Çetiner S, Boral B, Kibar F, Erken E, Ersözlü ED, Badak SÖ, Bilici Salman R, Sertdemir Y, Çetin Duran A, Yaman A | title = Importance of 14-3-3eta, anti-CarP, and anti-Sa in the diagnosis of seronegative rheumatoid arthritis | journal = Turkish Journal of Medical Sciences | volume = 49 | issue = 5 | pages = 1498–1502 | date = October 2019 | pmid = 31651120 | pmc = 7018368 | doi = 10.3906/sag-1812-137 }}</ref> During the first year of illness, rheumatoid factor is more likely to be negative with some individuals becoming seropositive over time. RF is a non-specific antibody and seen in about 10% of healthy people, in many other chronic infections like [[Medicine:Hepatitis C|hepatitis C]], and chronic autoimmune diseases such as Sjögren's syndrome and [[Medicine:Systemic lupus erythematosus|systemic lupus erythematosus]]. Therefore, the test is not specific for RA.<ref name="McGraw Hill"/>

Hence, new serological tests check for anti-citrullinated protein antibodies ACPAs. These tests are again positive in 61–75% of all RA cases, but with a specificity of around 95%.<ref>{{cite journal | vauthors = van Venrooij WJ, van Beers JJ, Pruijn GJ | s2cid = 11858403 | title = Anti-CCP antibodies: the past, the present and the future | journal = Nature Reviews. Rheumatology | volume = 7 | issue = 7 | pages = 391–398 | date = June 2011 | pmid = 21647203 | doi = 10.1038/nrrheum.2011.76 }}{{subscription required}}</ref> As with RF, ACPAs are many times present before symptoms have started.<ref name="McGraw Hill"/>

The by far most common clinical test for ACPAs is the anti-cyclic citrullinated peptide (anti CCP) ELISA. In 2008 a serological [[Medicine:Point-of-care testing|point-of-care test]] for the early detection of RA combined the detection of RF and anti-MCV with a sensitivity of 72% and specificity of 99.7%.<ref>{{cite journal |vauthors=Renger F, Bang H, Fredenhagen G, et al |title=Anti-MCV Antibody Test for the Diagnosis of Rheumatoid Arthritis Using a POCT-Immunoassay |journal=American College of Rheumatology, 2008 Annual Scientific Meeting, Poster Presentation |url=http://acr.confex.com/acr/2008/webprogram/Paper2009.html |url-status=dead |archive-url=https://web.archive.org/web/20100527234743/http://acr.confex.com/acr/2008/webprogram/Paper2009.html |archive-date=2010-05-27 }}</ref>{{better source needed |date=July 2017}}<ref>{{cite journal | vauthors = Luime JJ, Colin EM, Hazes JM, Lubberts E | s2cid = 22283893 | title = Does anti-mutated citrullinated vimentin have additional value as a serological marker in the diagnostic and prognostic investigation of patients with rheumatoid arthritis? A systematic review | journal = Annals of the Rheumatic Diseases | volume = 69 | issue = 2 | pages = 337–344 | date = February 2010 | pmid = 19289382 | doi = 10.1136/ard.2008.103283 | url = http://ard.bmj.com/cgi/content/short/ard.2008.103283v1 }}{{subscription required}}</ref>

To improve the diagnostic capture rate in the early detection of patients with RA and to risk stratify these individuals, the rheumatology field continues to seek complementary markers to both RF and anti-CCP. 14-3-3η ([[Biology:YWHAH|YWHAH]]) is one such marker that complements RF and anti-CCP, along with other serological measures like [[Chemistry:C-reactive protein|C-reactive protein]]. In a systematic review, 14-3-3η has been described as a welcome addition to the rheumatology field. The authors indicate that the serum based 14-3-η marker is additive to the armamentarium of existing tools available to clinicians, and that there is adequate clinical evidence to support its clinical benefits.<ref>{{cite journal| vauthors = Abdelhafiz D, Kilborn S, Bukhari M | title = The role of 14-3-3 η as a biomarker in rheumatoid arthritis | journal = Rheumatology and Immunology Research. | date = June 2021 | volume = 2 | issue = 2 | pages = 87–90 | doi = 10.2478/rir-2021-0012 | pmid = 36465971 | pmc = 9524784 | s2cid = 238231522 }}</ref>

Other blood tests are usually done to differentiate from other causes of arthritis, like the [[Erythrocyte sedimentation rate|erythrocyte sedimentation rate]] (ESR), C-reactive protein, full blood count, kidney function, liver enzymes and other immunological tests (e.g., [[Biology:Antinuclear antibody|antinuclear antibody]]/ANA) are all performed at this stage. Elevated [[Biology:Ferritin|ferritin]] levels can reveal hemochromatosis, a mimic of RA, or be a sign of [[Medicine:Adult-onset Still's disease|Still's disease]], a seronegative, usually juvenile, variant of rheumatoid Arthritis.<ref>{{cite journal | vauthors = Barton JC, Barton JC | title = Autoimmune Conditions in 235 Hemochromatosis Probands with HFE C282Y Homozygosity and Their First-Degree Relatives | journal = Journal of Immunology Research | volume = 2015 | pages = 453046 | date = 2015 | pmid = 26504855 | pmc = 4609477 | doi = 10.1155/2015/453046 | doi-access = free }}</ref>

===Classification criteria===
In 2010, the ''2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria'' were introduced.<ref name=acr-eular>{{cite journal | vauthors = Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G | s2cid = 1191830 | title = 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative | journal = Annals of the Rheumatic Diseases | volume = 69 | issue = 9 | pages = 1580–1588 | date = September 2010 | pmid = 20699241 | doi = 10.1136/ard.2010.138461 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/78045/1/27584_ftp.pdf | hdl = 2027.42/78045 | hdl-access = free }}</ref>

The new criteria are not diagnostic criteria, but are classification criteria to identify disease with a high likelihood of developing a chronic form.<ref name="McGraw Hill"/> However a score of 6 or greater unequivocally classifies a person with a diagnosis of rheumatoid arthritis.{{citation needed|date=July 2022}}

These new classification criteria overruled the "old" ACR criteria of 1987 and are adapted for early RA diagnosis. The "new" classification criteria, jointly published by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) establish a point value between 0 and 10. Four areas are covered in the diagnosis:<ref name=acr-eular/>
* joint involvement, designating the metacarpophalangeal joints, proximal interphalangeal joints, the interphalangeal joint of the thumb, second through fifth metatarsophalangeal joint and wrist as ''small joints'', and shoulders, [[Medicine:Elbow|elbow]]s, hip joints, knees, and ankles as ''large joints'':
** Involvement of 1 large joint gives 0 points
** Involvement of 2–10 large joints gives 1 point
** Involvement of 1–3 small joints (with or without involvement of large joints) gives 2 points
** Involvement of 4–10 small joints (with or without involvement of large joints) gives 3 points
** Involvement of more than 10 joints (with involvement of at least 1 small joint) gives 5 points
* serological parameters – including the [[Medicine:Rheumatoid factor|rheumatoid factor]] as well as ACPA – "ACPA" stands for "anti-citrullinated protein antibody":
** Negative RF ''and'' negative ACPA gives 0 points
** Low-positive RF ''or'' low-positive ACPA gives 2 points
** High-positive RF ''or'' high-positive ACPA gives 3 points
* acute phase reactants: 1 point for elevated erythrocyte sedimentation rate, [[Erythrocyte sedimentation rate|ESR]], or elevated [[Chemistry:C-reactive protein|CRP]] value (c-reactive protein)
* duration of [[Medicine:Arthritis|arthritis]]: 1 point for symptoms lasting six weeks or longer

The new criteria accommodate to the growing understanding of RA and the improvements in diagnosing RA and disease treatment. In the "new" criteria, serology and [[Medicine: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 | vauthors = Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS | title = The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis | journal = Arthritis and Rheumatism | volume = 31 | issue = 3 | pages = 315–34 | date = March 1988 | pmid = 3358796 | doi = 10.1002/art.1780310302 | doi-access = free }}</ref> This criterion no longer is regarded to be relevant, as this is just the type of damage that treatment is meant to avoid.

===Differential diagnoses===
Several other medical conditions can resemble RA, and need to be distinguished from it at the time of diagnosis:<ref name=Merckmanual>{{cite book | editor=Berkow R | title=The Merck Manual | edition=16th | publisher=Merck Publishing Group | year=1992 | pages=1307–1308 | isbn=978-0-911910-16-2 | url=https://archive.org/details/merckmanualofdia16berk }}{{subscription required}}</ref>
* Crystal induced arthritis ([[Medicine:Gout|gout]], and pseudogout) – usually involves particular joints (knee, MTP1, heels) and can be distinguished with an aspiration of joint fluid if in doubt. Redness, asymmetric distribution of affected joints, pain occurs at night and the starting pain is less than an hour with gout.
* [[Medicine:Osteoarthritis|Osteoarthritis]] – distinguished with [[Physics:X-ray|X-ray]]s of the affected joints and blood tests, older age, starting pain less than an hour, asymmetric distribution of affected joints and pain worsens when using joint for longer periods.
* [[Medicine:Systemic lupus erythematosus|Systemic lupus erythematosus]] (SLE) – distinguished by specific clinical symptoms and blood tests (antibodies against double-stranded DNA)
* One of the several types of [[Medicine:Psoriatic arthritis|psoriatic arthritis]] resembles RA – nail changes and skin symptoms distinguish between them
* [[Unsolved:Lyme disease|Lyme disease]] causes erosive arthritis and may closely resemble RA – it may be distinguished by blood test in endemic areas
* [[Medicine:Reactive arthritis|Reactive arthritis]] – asymmetrically involves heel, sacroiliac joints and large joints of the leg. It is usually associated with [[Medicine:Urethritis|urethritis]], [[Medicine:Conjunctivitis|conjunctivitis]], iritis, painless buccal ulcers, and keratoderma blennorrhagica.
* [[Medicine:Axial spondyloarthritis|Axial spondyloarthritis]] (including [[Medicine:Ankylosing spondylitis|ankylosing spondylitis]]) – this involves the spine, although an RA-like symmetrical small-joint polyarthritis may occur in the context of this condition.
* [[Medicine:Hepatitis C|Hepatitis C]] – RA-like symmetrical small-joint polyarthritis may occur in the context of this condition. Hepatitis C may also induce rheumatoid factor auto-antibodies.

Rarer causes which usually behave differently but may cause joint pains:<ref name=Merckmanual/>
* [[Medicine:Sarcoidosis|Sarcoidosis]], [[Medicine:Amyloidosis|amyloidosis]], and [[Medicine:Whipple's disease|Whipple's disease]] can also resemble RA.
* Hemochromatosis may cause hand joint arthritis.
* Acute rheumatic fever can be differentiated by a migratory pattern of joint involvement and evidence of antecedent streptococcal infection.
* Bacterial arthritis (such as by ''[[Biology:Streptococcus|Streptococcus]]'') is usually asymmetric, while RA usually involves both sides of the body symmetrically.
* Gonococcal arthritis (a bacterial arthritis) is also initially migratory and can involve [[Biology:Tendon|tendon]]s around the wrists and ankles.

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

=== Difficult-to-treat ===
Rheumatoid arthritis (D2T RA) is a specific classification RA by the European League against Rheumatism (EULAR).<ref>{{cite journal | vauthors = Roodenrijs NM, Welsing PM, van der Goes MC, Jacobs JW, van der Heijde D, van Laar JM, Nagy G | title = Response to: 'Correspondence on 'EULAR definition of difficult-to-treat rheumatoid arthritis'' by Novella-Navarro ''et al'' | journal = Annals of the Rheumatic Diseases | pages = annrheumdis–2020–219535 | date = December 2020 | volume = 82 | issue = 3 | pmid = 33277239 | doi = 10.1136/annrheumdis-2020-219535 | s2cid = 227275679 }}</ref>

Signs of illness:

# Persistence of signs and symptoms
# [[Biology:Drug resistance|Drug resistance]]
# Does not respond on two or more biological treatments
# Does not respond on anti-rheumatic drugs with different mechanism of action

Factors contributing to difficult-to-treat disease:

# Genetic risk factors
# Environmental factors (diet, smoking, physical activity)
# Overweight and obese

===Genetic factors===

Genetic factors such as HLA-DR1B1,<ref>{{cite journal | vauthors = Raychaudhuri S | title = Recent advances in the genetics of rheumatoid arthritis | journal = Current Opinion in Rheumatology | volume = 22 | issue = 2 | pages = 109–118 | date = March 2010 | pmid = 20075733 | pmc = 3121048 | doi = 10.1097/bor.0b013e328336474d }}</ref> TRAF1, PSORS1C1 and [[Biology:MicroRNA|microRNA]] 146a<ref>{{cite journal | vauthors = Conigliaro P, Triggianese P, De Martino E, Fonti GL, Chimenti MS, Sunzini F, Viola A, Canofari C, Perricone R | title = Challenges in the treatment of Rheumatoid Arthritis | journal = Autoimmunity Reviews | volume = 18 | issue = 7 | pages = 706–713 | date = July 2019 | pmid = 31059844 | doi = 10.1016/j.autrev.2019.05.007 | hdl-access = free | s2cid = 146811143 | hdl = 2108/225718 }}</ref> are associated with difficult to treat rheumatoid arthritis, other gene polymorphisms seem to be correlated with response to biologic modifying anti-rheumatic drugs (bDMARDs). Next one is FOXO3A gene region been reported as associated with worst disorder. The minor allele at FOXO3A summon a differential response of monocytes in RA patients. FOXO3A can provide an increase of pro-inflammatory cytokines, including TNFα. Possible gene polymorphism: STAT4, PTPN2, PSORS1C1 and TRAF3IP2 genes had been correlated with response to TNF inhibitors.<ref>{{cite journal |last1=Conigliaro |first1=Paola |last2=Ciccacci |first2=Cinzia |last3=Politi |first3=Cristina |last4=Triggianese |first4=Paola |last5=Rufini |first5=Sara |last6=Kroegler |first6=Barbara |last7=Perricone |first7=Carlo |last8=Latini |first8=Andrea |last9=Novelli |first9=Giuseppe |last10=Borgiani |first10=Paola |last11=Perricone |first11=Roberto |date=2017-01-20 |editor-last=Ahuja |editor-first=Sunil K |title=Polymorphisms in STAT4, PTPN2, PSORS1C1 and TRAF3IP2 Genes Are Associated with the Response to TNF Inhibitors in Patients with Rheumatoid Arthritis |journal=PLOS ONE |language=en |volume=12 |issue=1 |pages=e0169956 |doi=10.1371/journal.pone.0169956 |issn=1932-6203 |pmc=5249113 |pmid=28107378 |bibcode=2017PLoSO..1269956C |doi-access=free }}</ref>

===HLA-DR1 and HLA-DRB1 gene===

The ''HLA''-''DRB1'' gene is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex is the human version of the major histocompatibility complex (MHC). Currently, have been identified at least 2479 different versions of the ''HLA''-''DRB1'' gene.<ref>{{cite journal | vauthors = Klimenta B, Nefic H, Prodanovic N, Jadric R, Hukic F | title = Association of biomarkers of inflammation and HLA-DRB1 gene locus with risk of developing rheumatoid arthritis in females | journal = Rheumatology International | volume = 39 | issue = 12 | pages = 2147–2157 | date = December 2019 | pmid = 31451934 | doi = 10.1007/s00296-019-04429-y | s2cid = 201644677 }}</ref> The presence of HLA-DRB1 alleles seems to predict radiographic damage, which may be partially mediated by ACPA development, and also elevated sera inflammatory levels and high swollen joint count. HLA-DR1 is encoded by the most risk allele HLA-DRB1 which share a conserved 5-aminoacid sequence that is correlated with the development of anti-citrullinated protein antibodies.<ref>{{cite journal | vauthors = Gregersen PK, Silver J, Winchester RJ | title = The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis | journal = Arthritis and Rheumatism | volume = 30 | issue = 11 | pages = 1205–1213 | date = November 1987 | pmid = 2446635 | doi = 10.1002/art.1780301102 | doi-access = free }}</ref> HLA-DRB1 gene have more strong correlation with disease development. Susceptibility to and outcome for rheumatoid arthritis (RA) may associate with particular HLA-DR alleles, but these alleles vary among ethnic groups and geographic areas.<ref>{{cite journal | vauthors = Kapitány A, Zilahi E, Szántó S, Szücs G, Szabó Z, Végvári A, Rass P, Sipka S, Szegedi G, Szekanecz Z | title = Association of rheumatoid arthritis with HLA-DR1 and HLA-DR4 in Hungary | journal = Annals of the New York Academy of Sciences | volume = 1051 | issue = 1 | pages = 263–270 | date = June 2005 | pmid = 16126967 | doi = 10.1196/annals.1361.067 | s2cid = 6515443 | bibcode = 2005NYASA1051..263K }}</ref>

===MicroRNAs===

MicroRNAs are a factor in the development of that type of disease. MicroRNAs usually operate as a negative regulator of the expression of target proteins and their increased concentration after biologic treatment (bDMARDs) or after anti-rheumatic drugs. Level of miRNA before and after anti-TNFa/DMRADs combination therapy are potential novel biomarkers for predicting and monitoring outcome. For instance, some of them were found significantly upregulated by anti-TNFa/DMRADs combination therapy. For example, miRNA-16-5p, miRNA-23-3p, miRNA125b-5p, miRNA-126-3p, miRNA-146a-5p, miRNA-223-3p. Curious fact is that only responder patients showed an increase in those miRNAs after therapy, and paralleled the reduction of TNFα, interleukin (IL)-6, IL-17, rheumatoid factor (RF), and C-reactive protein (CRP).<ref>{{cite journal | vauthors = Castro-Villegas C, Pérez-Sánchez C, Escudero A, Filipescu I, Verdu M, Ruiz-Limón P, Aguirre MA, Jiménez-Gomez Y, Font P, Rodriguez-Ariza A, Peinado JR, Collantes-Estévez E, González-Conejero R, Martinez C, Barbarroja N, López-Pedrera C | title = Circulating miRNAs as potential biomarkers of therapy effectiveness in rheumatoid arthritis patients treated with anti-TNFα | journal = Arthritis Research & Therapy | volume = 17 | issue = 1 | pages = 49 | date = March 2015 | pmid = 25860297 | pmc = 4377058 | doi = 10.1186/s13075-015-0555-z | doi-broken-date = 2024-01-27 | doi-access = free }}</ref>

===Monitoring progression===

Many tools can be used to monitor remission in rheumatoid arthritis.
* DAS28: ''Disease Activity Score of 28 joints'' ({{visible anchor|DAS28}}) is widely used as an indicator of RA disease activity and response to treatment. Joints included are (bilaterally): proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), [[Medicine:Elbow|elbow]]s (2), shoulders (2) and knees (2). When looking at these joints, both the number of joints with tenderness upon touching (TEN28) and swelling (SW28) are counted. The [[Erythrocyte sedimentation rate|erythrocyte sedimentation rate]] (ESR) is measured and the affected person makes a subjective assessment (SA) of disease activity during the preceding 7 days on a scale between 0 and 100, where 0 is "no activity" and 100 is "highest activity possible". With these parameters, DAS28 is calculated as:<ref name=Prevoo1995/>
<math>DAS28=0.56 \times \sqrt{TEN28} + 0.28 \times \sqrt{SW28} + 0.70 \times \ln(ESR) + 0.014 \times SA</math>

From this, the disease activity of the affected person can be classified as follows:<ref name=Prevoo1995>{{cite journal | vauthors = Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL | title = Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis | journal = Arthritis and Rheumatism | volume = 38 | issue = 1 | pages = 44–48 | date = January 1995 | pmid = 7818570 | doi = 10.1002/art.1780380107 | url = http://www.pharmacoeconomics.ru/jour/article/view/135 | hdl = 2066/20651 | s2cid = 11192145 | hdl-access = free }}{{subscription required}}</ref>
{|class="wikitable"
|-
!colspan=2 rowspan=2| Current <br>DAS28 !!colspan=3| DAS28 decrease from initial value
|-
| > 1.2 || > 0.6 but ≤ 1.2 || ≤ 0.6
|-
| ≤ 3.2 || Inactive || Good improvement || Moderate improvement || No improvement
|-
| > 3.2 but ≤ 5.1 || Moderate || Moderate improvement || Moderate improvement || No improvement
|-
| > 5.1 || Very active || Moderate improvement || No improvement || No improvement
|}

It is not always a reliable indicator of treatment effect.<ref>Kelly, Janis (22 February 2005) [http://www.medscape.com/viewarticle/538134 DAS28 not always a reliable indicator of treatment effect in RA] {{webarchive|url=https://web.archive.org/web/20110225054141/http://www.medscape.com/viewarticle/538134 |date=2011-02-25 }}, Medscape Medical News.</ref> One major limitation is that low-grade synovitis may be missed.<ref>{{cite journal | vauthors= Uribe L, Cerón C, Amariles P, Llano JF, Restrepo M, Montoya N, González LA, Díaz OJ, Saldarriaga MA, Gómez-Puerta JA |date=July–September 2016 |title=Correlación entre la actividad clínica por DAS-28 y ecografía en pacientes con artritis reumatoide |trans-title=Correlation between clinical activity measured by DAS-28 and ultrasound in patients with rheumatoid arthritis |journal=Revista Colombiana de Reumatología |volume=23 |issue=3 |pages=159–169 |language=es |doi=10.1016/j.rcreu.2016.05.002 }}</ref>
* Other: Other tools to monitor remission in rheumatoid arthritis are: ACR-EULAR Provisional Definition of Remission of Rheumatoid arthritis, Simplified Disease Activity Index and Clinical Disease Activity Index.<ref>{{cite journal | vauthors = Yazici Y, Simsek I | title = Tools for monitoring remission in rheumatoid arthritis: any will do, let's just pick one and start measuring | journal = Arthritis Research & Therapy | volume = 15 | issue = 1 | pages = 104 | date = January 2013 | pmid = 23374997 | pmc = 3672754 | doi = 10.1186/ar4139 | doi-access = free }}{{subscription required}}</ref> Some scores do not require input from a healthcare professional and allow self-monitoring by the person, like HAQ-DI.<ref>{{cite journal | vauthors = Bruce B, Fries JF | title = The Stanford Health Assessment Questionnaire: dimensions and practical applications | journal = Health and Quality of Life Outcomes | volume = 1 | pages = 20 | date = June 2003 | pmid = 12831398 | pmc = 165587 | doi = 10.1186/1477-7525-1-20 | doi-access = free }}{{subscription required}}</ref>{{page needed|date=July 2017}}

==Management==
There is no cure for RA, but treatments can improve symptoms and slow the progress of the disease. Disease-modifying treatment has the best results when it is started early and aggressively.<ref name=ACR2008>{{cite journal | vauthors = Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, Mudano A, Pisu M, Elkins-Melton M, Outman R, Allison JJ, Suarez Almazor M, Bridges SL, Chatham WW, Hochberg M, MacLean C, Mikuls T, Moreland LW, O'Dell J, Turkiewicz AM, Furst DE | title = American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis | journal = Arthritis and Rheumatism | volume = 59 | issue = 6 | pages = 762–784 | date = June 2008 | pmid = 18512708 | doi = 10.1002/art.23721 | doi-access = free }}</ref><ref name=":16">{{cite book |last1=Donahue |first1=Katrina E. |url=http://www.ncbi.nlm.nih.gov/books/NBK524950/ |title=Drug Therapy for Early Rheumatoid Arthritis: A Systematic Review Update |last2=Gartlehner |first2=Gerald |last3=Schulman |first3=Elizabeth R. |last4=Jonas |first4=Beth |last5=Coker-Schwimmer |first5=Emmanuel |last6=Patel |first6=Sheila V. |last7=Weber |first7=Rachel Palmieri |last8=Lohr |first8=Kathleen N. |last9=Bann |first9=Carla |date=2018 |publisher=Agency for Healthcare Research and Quality (US) |series=AHRQ Comparative Effectiveness Reviews |location=Rockville (MD) |pmid=30199187}}</ref> The results of a recent systematic review found that combination therapy with tumor necrosis factor (TNF) and non-TNF biologics plus methotrexate (MTX) resulted in improved disease control, Disease Activity Score (DAS)-defined remission, and functional capacity compared with a single treatment of either methotrexate or a biologic alone.<ref>{{cite journal | vauthors = Donahue KE, Schulman ER, Gartlehner G, Jonas BL, Coker-Schwimmer E, Patel SV, Weber RP, Bann CM, Viswanathan M | title = Comparative Effectiveness of Combining MTX with Biologic Drug Therapy Versus Either MTX or Biologics Alone for Early Rheumatoid Arthritis in Adults: a Systematic Review and Network Meta-analysis | journal = Journal of General Internal Medicine | volume = 34 | issue = 10 | pages = 2232–2245 | date = October 2019 | pmid = 31388915 | pmc = 6816735 | doi = 10.1007/s11606-019-05230-0 }}</ref>

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 | vauthors = Wasserman AM | title = Diagnosis and management of rheumatoid arthritis | journal = American Family Physician | volume = 84 | issue = 11 | pages = 1245–1252 | date = December 2011 | pmid = 22150658 }}</ref> This is primarily addressed with disease-modifying antirheumatic drugs (DMARDs); dosed physical activity; analgesics and [[Medicine:Physical therapy|physical therapy]] may be used to help manage pain.<ref name=":13" /><ref name=NICE2015/><ref name=":12" /> RA should generally be treated with at least one specific anti-rheumatic medication<ref name=ACR2015/> while combination therapies and [[Biology:Corticosteroid|corticosteroid]]s are common in treatment.<ref>{{cite journal|last1=Donahue |first1=Katrina E. |last2=Gartlehner |first2=Gerald |last3=Schulman |first3=Elizabeth R. |last4=Jonas |first4=Beth |last5=Coker-Schwimmer |first5=Emmanuel |last6=Patel |first6=Sheila V. |last7=Weber |first7=Rachel Palmieri |last8=Lohr |first8=Kathleen N. |last9=Bann |first9=Carla |last10=Viswanathan |first10=Meera |date=2018-07-16 |title=Drug Therapy for Early Rheumatoid Arthritis: A Systematic Review Update |url=https://effectivehealthcare.ahrq.gov/topics/rheumatoid-arthritis-medicine-update/final-report-update-2018 |doi=10.23970/ahrqepccer211|s2cid=81414779|journal=Effective Health Care Program|doi-access=free }}</ref> The use of benzodiazepines (such as [[Chemistry:Diazepam|diazepam]]) to treat the pain is not recommended as it does not appear to help and is associated with risks.<ref>{{cite journal | vauthors = Richards BL, Whittle SL, Buchbinder R | title = Muscle relaxants for pain management in rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD008922 | date = January 2012 | pmid = 22258993 | doi = 10.1002/14651858.CD008922.pub2 | s2cid = 73769165 | veditors = Richards BL }}</ref>

===Lifestyle===
Regular exercise is recommended as both safe and useful to maintain muscle strength and overall physical function.<ref>{{cite journal | vauthors = Hurkmans E, van der Giesen FJ, Vliet Vlieland TP, Schoones J, Van den Ende EC | title = Dynamic exercise programs (aerobic capacity and/or muscle strength training) in patients with rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD006853 | date = October 2009 | volume = 2009 | pmid = 19821388 | pmc = 6769170 | doi = 10.1002/14651858.CD006853.pub2 | veditors = Hurkmans E }}</ref> Physical activity is beneficial for people with rheumatoid arthritis who experience fatigue,<ref>{{cite journal | vauthors = Cramp F, Hewlett S, Almeida C, Kirwan JR, Choy EH, Chalder T, Pollock J, Christensen R | title = Non-pharmacological interventions for fatigue in rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD008322 | date = August 2013 | pmid = 23975674 | doi = 10.1002/14651858.CD008322.pub2 }}</ref> although there was little to no evidence to suggest that exercise may have an impact on physical function in the long term, a study found that carefully dosed exercise has shown significant improvements in patients with RA.<ref name=":12" /><ref>{{cite journal | vauthors = Williams MA, Srikesavan C, Heine PJ, Bruce J, Brosseau L, Hoxey-Thomas N, Lamb SE | title = Exercise for rheumatoid arthritis of the hand | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | pages = CD003832 | date = July 2018 | issue = 7 | pmid = 30063798 | pmc = 6513509 | doi = 10.1002/14651858.cd003832.pub3 }}</ref> Physical activity increases the production of synovial fluid, which lubricates the joints and reduces friction.<ref>{{cite web |last1=Jabeen |first1=Attiya |title=The Benefits of Exercise in Rheumatoid Arthritis: A Comprehensive Guide |url=https://rheumatologydelaware.com/benefits-exercise-in-rheumatoid-arthritis/ |website=rheumatologydelaware |date=16 August 2023 |publisher=Attiya Jabeen |access-date=August 16, 2023}}</ref> Moderate effects have been found for aerobic exercises and resistance training on cardiovascular fitness and muscle strength in RA. Furthermore, physical activity had no detrimental side effects like increased disease activity in any exercise dimension.<ref>{{cite journal | vauthors = Rausch Osthoff AK, Juhl CB, Knittle K, Dagfinrud H, Hurkmans E, Braun J, Schoones J, Vliet Vlieland TP, Niedermann K | title = Effects of exercise and physical activity promotion: meta-analysis informing the 2018 EULAR recommendations for physical activity in people with rheumatoid arthritis, spondyloarthritis and hip/knee osteoarthritis | journal = RMD Open | volume = 4 | issue = 2 | pages = e000713 | date = December 2018 | pmid = 30622734 | pmc = 6307596 | doi = 10.1136/rmdopen-2018-000713 }}</ref> It is uncertain if eating or avoiding specific foods or other specific dietary measures help improve symptoms.<ref>{{cite journal | vauthors = Hagen KB, Byfuglien MG, Falzon L, Olsen SU, Smedslund G | title = Dietary interventions for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD006400 | date = January 2009 | pmid = 19160281 | doi = 10.1002/14651858.CD006400.pub2 | veditors = Hagen KB }}</ref> [[Medicine:Occupational therapy|Occupational therapy]] has a positive role to play in improving functional ability in people with rheumatoid arthritis.<ref>{{cite journal | vauthors = Steultjens EM, Dekker J, Bouter LM, van Schaardenburg D, van Kuyk MA, van den Ende CH | title = Occupational therapy for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD003114 | date = 2004 | volume = 2004 | pmid = 14974005 | doi = 10.1002/14651858.CD003114.pub2 | pmc = 7017227 | hdl = 2066/58846 | url = https://repository.ubn.ru.nl/bitstream/2066/58846/1/58846.pdf }}</ref> Weak evidence supports the use of wax baths (thermotherapy) to treat arthritis in the hands.<ref>{{cite journal | vauthors = Robinson V, Brosseau L, Casimiro L, Judd M, Shea B, Wells G, Tugwell P | title = Thermotherapy for treating rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD002826 | date = 2002-04-22 | pmid = 12076454 | doi = 10.1002/14651858.cd002826 | pmc = 6991938 }}</ref>

Educational approaches that inform people about tools and strategies available to help them cope with rheumatoid arthritis may improve a person's psychological status and level of depression in the shorter-term.<ref name=":4">{{cite journal | vauthors = Riemsma RP, Kirwan JR, Taal E, Rasker JJ | title = Patient education for adults with rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 2009 | issue = 2 | pages = CD003688 | date = 2003-04-22 | pmid = 12804484 | doi = 10.1002/14651858.cd003688 | url = https://research.utwente.nl/en/publications/patient-education-for-adults-with-rheumatoid-arthritis-review(6d6c077a-30a1-4b7c-8021-f72f1a8b6a5c).html }}</ref> The use of extra-depth shoes and molded insoles may reduce pain during weight-bearing activities such as walking.<ref name=":5">{{cite journal | vauthors = Egan M, Brosseau L, Farmer M, Ouimet MA, Rees S, Wells G, Tugwell P | title = Splints/orthoses in the treatment of rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD004018 | date = 2001-10-23 | volume = 2001 | pmid = 12535502 | doi = 10.1002/14651858.cd004018 | pmc = 8762649 }}</ref> Insoles may also prevent the progression of [[Medicine:Bunion|bunion]]s.<ref name=":5" />

===Disease-modifying agents===
Disease-modifying antirheumatic drugs (DMARDs) are the primary treatment for RA.<ref name=ACR2015/> 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=ACR2015/> DMARDs should be started early in the disease as they result in disease remission in approximately half of people and improved outcomes overall.<ref name=ACR2015/>

The following drugs are considered DMARDs: [[Chemistry:Methotrexate|methotrexate]], [[Chemistry:Sulfasalazine|sulfasalazine]], [[Chemistry:Leflunomide|leflunomide]], [[Chemistry:Hydroxychloroquine|hydroxychloroquine]], [[Biology:TNF inhibitor|TNF inhibitor]]s ([[Chemistry:Certolizumab pegol|certolizumab]], [[Chemistry:Adalimumab|adalimumab]], [[Chemistry:Infliximab|infliximab]] and [[Biology:Etanercept|etanercept]]), [[Chemistry:Abatacept|abatacept]], [[Chemistry:Anakinra|anakinra]], and [[Chemistry:Auranofin|auranofin]]. Additionally, [[Chemistry:Rituximab|rituximab]] and [[Chemistry:Tocilizumab|tocilizumab]] are monoclonal antibodies and are also DMARDs.<ref name=ACR2015/> Use of tocilizumab is associated with a risk of increased cholesterol levels.<ref>{{cite book | vauthors = Isaacs D | editor-first1 = Jasvinder A. | editor-last1 = Singh | title = Cochrane Database of Systematic Reviews | chapter = Tocilizumab for rheumatoid arthritis | series = Advances in Experimental Medicine and Biology | volume = 764 | pages = 151–158 | date = 2010-07-07 | publisher = John Wiley & Sons | pmid = 23654064 | doi = 10.1002/14651858.cd008331.pub2 }}</ref>

The most commonly used agent is methotrexate with other frequently used agents including sulfasalazine and leflunomide.<ref name=ACR2015/> Leflunomide is effective when used from 6–12 months, with similar effectiveness to methotrexate when used for 2 years.<ref>{{cite journal | vauthors = Osiri M, Shea B, Robinson V, Suarez-Almazor M, Strand V, Tugwell P, Wells G | title = Leflunomide for treating rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD002047 | date = 2003 | volume = 2002 | pmid = 12535423 | doi = 10.1002/14651858.CD002047 | pmc = 8437750 }}</ref> Sulfasalazine also appears to be most effective in the short-term treatment of rheumatoid arthritis.<ref>{{cite journal | vauthors = Suarez-Almazor ME, Belseck E, Shea B, Wells G, Tugwell P | title = Sulfasalazine for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD000958 | date = 1998-04-27 | volume = 1998 | pmid = 10796400 | doi = 10.1002/14651858.cd000958 | pmc = 7047550 }}</ref>

[[Chemistry:Hydroxychloroquine|Hydroxychloroquine]], in addition to its low toxicity profile, is considered effective for treatment of moderate RA treatment.<ref>{{cite journal | vauthors = Suarez-Almazor ME, Belseck E, Shea B, Homik J, Wells G, Tugwell P | title = Antimalarials for treating rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD000959 | date = 2000 | volume = 2010 | pmid = 11034691 | doi = 10.1002/14651858.CD000959 | pmc = 8407035 }}</ref>

Agents may be used in combination, however, people may experience greater side effects.<ref name=ACR2015/><ref>{{cite journal | vauthors = Katchamart W, Trudeau J, Phumethum V, Bombardier C | title = Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD008495 | date = April 2010 | volume = 2015 | pmid = 20393970 | doi = 10.1002/14651858.cd008495 | pmc = 8946299 }}</ref> Methotrexate is the most important and useful DMARD and is usually the first treatment.<ref name=ACR2015/><ref name=NICE2015/><ref name="chapter94">{{cite book | vauthors = DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM | date = 2008 | title = Pharmacotherapy: a Pathophysiologic Approach | edition = 7th | location = New York | publisher = McGraw-Hill | isbn = 978-0-07-147899-1 }}</ref> A combined approach with methotrexate and biologics improves ACR50, HAQ scores and RA remission rates.<ref>{{cite journal | vauthors = Singh JA, Hossain A, Mudano AS, Tanjong Ghogomu E, Suarez-Almazor ME, Buchbinder R, Maxwell LJ, Tugwell P, Wells GA | title = Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 5 | pages = CD012657 | date = May 2017 | issue = 5 | pmid = 28481462 | pmc = 6481641 | doi = 10.1002/14651858.cd012657 }}</ref><ref name=":16" /> This benefit from the combination of methotrexate with biologics occurs both when this combination is the initial treatment and when drugs are prescribed in a sequential or step-up manner.<ref name=":16" /> Triple therapy consisting of methotrexate, sulfasalazine and hydroxychloroquine may also effectively control disease activity.<ref>{{cite journal | vauthors = Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe DJ, Bombardier C | title = Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis: A network meta-analysis | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD010227 | date = August 2016 | volume = 2016 | pmid = 27571502 | doi = 10.1002/14651858.cd010227.pub2 | pmc = 7087436 }}</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 | vauthors = Shea B, 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 | volume = 5 | issue = 5 | pages = CD000951 | date = May 2013 | pmid = 23728635 | doi = 10.1002/14651858.CD000951.pub2 | pmc = 7046011 }}</ref>

Rituximab combined with methotrexate appears to be more effective in improving symptoms compared to methotrexate alone.<ref name=":0" /> Rituximab works by decreasing levels of B-cells (immune cell that is involved in inflammation). People taking rituximab had improved pain, function, reduced disease activity and reduced joint damage based on x-ray images. After 6 months, 21% more people had improvement in their symptoms using rituximab and methotrexate.<ref name=":0">{{cite journal | vauthors = Lopez-Olivo MA, Amezaga Urruela M, McGahan L, Pollono EN, Suarez-Almazor ME | title = Rituximab for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD007356 | date = January 2015 | pmid = 25603545 | doi = 10.1002/14651858.CD007356.pub2 }}</ref>

Biological agents should generally be used only if methotrexate and other conventional agents are not effective after a trial of three months.<ref name=ACR2015/> They are associated with a higher rate of serious infections as compared to other DMARDs.<ref>{{cite journal | vauthors = Singh JA, Cameron C, Noorbaloochi S, Cullis T, Tucker M, Christensen R, Ghogomu ET, Coyle D, Clifford T, Tugwell P, Wells GA | title = Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis | journal = Lancet | volume = 386 | issue = 9990 | pages = 258–265 | date = July 2015 | pmid = 25975452 | pmc = 4580232 | doi = 10.1016/S0140-6736(14)61704-9 }}</ref> Biological DMARD agents used to treat rheumatoid arthritis include: [[Biology:Tumor necrosis factor alpha|tumor necrosis factor alpha]] inhibitors (TNF inhibitors) such as [[Chemistry:Infliximab|infliximab]]; interleukin 1 blockers such as [[Chemistry:Anakinra|anakinra]], [[Biology:Monoclonal antibody|monoclonal antibodies]] against [[Biology:B cell|B cell]]s such as [[Chemistry:Rituximab|rituximab]], interleukin 6 blockers such as tocilizumab, and [[Biology:T cell|T cell]] co-stimulation blockers such as abatacept. They are often used in combination with either methotrexate or leflunomide.<ref name=ACR2015/><ref name=Lancet2016/> Biologic monotherapy or [[Chemistry:Tofacitinib|tofacitinib]] with methotrexate may improve ACR50, RA remission rates and function.<ref>{{cite journal | vauthors = Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Tugwell P, Wells GA | title = Biologic or tofacitinib monotherapy for rheumatoid arthritis in people with traditional disease-modifying anti-rheumatic drug (DMARD) failure: a Cochrane Systematic Review and network meta-analysis (NMA) | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | pages = CD012437 | date = November 2016 | issue = 11 | pmid = 27855242 | pmc = 6469573 | doi = 10.1002/14651858.cd012437 }}</ref><ref>{{cite journal | vauthors = Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Maxwell LJ, Buchbinder R, Lopez-Olivo MA, Suarez-Almazor ME, Tugwell P, Wells GA | title = Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: a systematic review and network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD012591 | date = March 2017 | issue = 3 | pmid = 28282491 | pmc = 6472522 | doi = 10.1002/14651858.cd012591 }}</ref> Abatacept should not be used at the same time as other biologics.<ref>{{cite journal | vauthors = Maxwell L, Singh JA | title = Abatacept for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD007277 | date = October 2009 | volume = 2009 | pmid = 19821401 | pmc = 6464777 | doi = 10.1002/14651858.CD007277.pub2 }}</ref> In those who are well controlled (low disease activity) on TNF inhibitors, decreasing the dose does not appear to affect overall function.<ref name=":11">{{cite journal | vauthors = Verhoef LM, van den Bemt BJ, van der Maas A, Vriezekolk JE, Hulscher ME, van den Hoogen FH, Jacobs WC, van Herwaarden N, den Broeder AA | title = Down-titration and discontinuation strategies of tumour necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity | journal = The Cochrane Database of Systematic Reviews | volume = 5 | pages = CD010455 | date = May 2019 | issue = 6 | pmid = 31125448 | pmc = 6534285 | doi = 10.1002/14651858.CD010455.pub3 }}</ref> Discontinuation of TNF inhibitors (as opposed to gradually lowering the dose) by people with low disease activity may lead to increased disease activity and may affect remission, damage that is visible on an x-ray, and a person's function.<ref name=":11" /> People should be screened for [[Medicine:Latent tuberculosis|latent tuberculosis]] before starting any [[Biology:TNF inhibitor|TNF inhibitor]] therapy to avoid reactivation of tuberculosis.<ref name="McGraw Hill"/>

TNF inhibitors and methotrexate appear to have similar effectiveness when used alone and better results are obtained when used together.<ref>{{Cite report |url=https://doi.org/10.23970/AHRQEPCCER211 |title=Drug Therapy for Early Rheumatoid Arthritis: A Systematic Review Update |last=Donahue |first=Katrina E. |last2=Gartlehner |first2=Gerald |date=2018-07-16 |publisher=Agency for Healthcare Research and Quality (AHRQ) |doi=10.23970/ahrqepccer211 |language=en |last3=Schulman |first3=Elizabeth R. |last4=Jonas |first4=Beth |last5=Coker-Schwimmer |first5=Emmanuel |last6=Patel |first6=Sheila V. |last7=Weber |first7=Rachel Palmieri |last8=Lohr |first8=Kathleen N. |last9=Bann |first9=Carla}}</ref> [[Chemistry:Golimumab|Golimumab]] is effective when used with methotraxate.<ref>{{cite journal | vauthors = Singh JA, Noorbaloochi S, Singh G | title = Golimumab for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD008341 | date = January 2010 | volume = 2010 | pmid = 20091667 | doi = 10.1002/14651858.CD008341 | pmc = 10732339 }}</ref> TNF inhibitors may have equivalent effectiveness with [[Biology:Etanercept|etanercept]] appearing to be the safest.<ref>{{cite journal | vauthors = 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 | veditors = Hernandez AV | bibcode = 2012PLoSO...730275A | doi-access = free }}</ref> Injecting etanercept, in addition to methotrexate twice a week may improve ACR50 and decrease radiographic progression for up to 3 years.<ref>{{cite journal | vauthors = Lethaby A, Lopez-Olivo MA, Maxwell L, Burls A, Tugwell P, Wells GA | title = Etanercept for the treatment of rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD004525 | date = May 2013 | volume = 2014 | pmid = 23728649 | doi = 10.1002/14651858.cd004525.pub2 | pmc = 10771320 }}</ref> Abatacept appears effective for RA with 20% more people improving with treatment than without but long term safety studies are yet unavailable.<ref>{{cite journal | vauthors = Maxwell L, Singh JA | title = Abatacept for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD007277 | date = October 2009 | volume = 2009 | pmid = 19821401 | doi = 10.1002/14651858.CD007277.pub2 | veditors = Maxwell L | pmc = 6464777 }}</ref> [[Chemistry:Adalimumab|Adalimumab]] slows the time for the radiographic progression when used for 52 weeks.<ref>{{cite journal | vauthors = Navarro-Sarabia F, Ariza-Ariza R, Hernandez-Cruz B, Villanueva I | title = Adalimumab for treating rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD005113 | date = July 2005 | pmid = 16034967 | doi = 10.1002/14651858.CD005113.pub2 }}</ref> However, there is a lack of evidence to distinguish between the biologics available for RA.<ref>{{cite journal | vauthors = Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, Tanjong Ghogomu E, Tugwell P | title = Biologics for rheumatoid arthritis: an overview of Cochrane reviews | journal = The Cochrane Database of Systematic Reviews | volume = 128 | issue = 4 | pages = CD007848 | date = October 2009 | pmid = 19821440 | doi = 10.1002/14651858.CD007848.pub2 | type = Submitted manuscript | veditors = Singh JA | pmc = 10636593 }}</ref> Issues with the biologics include their high cost and association with infections including [[Medicine:Tuberculosis|tuberculosis]].<ref name=Lancet2016/> Use of biological agents may reduce fatigue.<ref name=":2" /> The mechanism of how biologics reduce fatigue is unclear.<ref name=":2">{{cite journal | vauthors = Almeida C, Choy EH, Hewlett S, Kirwan JR, Cramp F, Chalder T, Pollock J, Christensen R | title = Biologic interventions for fatigue in rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 6 | pages = CD008334 | date = June 2016 | volume = 2016 | pmid = 27271314 | doi = 10.1002/14651858.cd008334.pub2 | pmc = 7175833 }}</ref>

====Gold and cyclosporin====
{{Anchor|Gold|Sodium aurothiomalate|Auranofin|Cyclosporin}}
[[Chemistry:Sodium aurothiomalate|Sodium aurothiomalate]], [[Chemistry:Auranofin|auranofin]], and cyclosporin are less commonly used due to more common adverse effects.<ref name=ACR2015/> However, cyclosporin was found to be effective in the progressive RA when used up to one year.<ref>{{cite journal | vauthors = Wells G, Haguenauer D, Shea B, Suarez-Almazor ME, Welch VA, Tugwell P | title = Cyclosporine for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD001083 | date = 2000 | volume = 1998 | pmid = 10796412 | doi = 10.1002/14651858.CD001083 | pmc = 8406939 }}</ref>

===Anti-inflammatory and analgesic agents===
[[Chemistry:Glucocorticoid|Glucocorticoid]]s can be used in the short term and at the lowest dose possible for flare-ups and while waiting for slow-onset drugs to take effect.<ref name=ACR2015/><ref name=Lancet2016/><ref>{{cite journal | vauthors = Criswell LA, Saag KG, Sems KM, Welch V, Shea B, Wells G, Suarez-Almazor ME | title = Moderate-term, low-dose corticosteroids for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD001158 | date = 1998-07-27 | volume = 2010 | pmid = 10796420 | doi = 10.1002/14651858.cd001158 | pmc = 8406983 }}</ref> Combination of glucocorticoids and conventional therapy has shown a decrease in rate of erosion of bones.<ref>{{cite journal | vauthors = Kirwan JR, Bijlsma JW, Boers M, Shea BJ | title = Effects of glucocorticoids on radiological progression in rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD006356 | date = January 2007 | volume = 2010 | pmid = 17253590 | pmc = 6465045 | doi = 10.1002/14651858.cd006356 }}</ref> Steroids may be injected into affected joints during the initial period of RA, prior to the use of DMARDs or oral steroids.<ref name=":3">{{cite journal | vauthors = Wallen M, Gillies D | title = Intra-articular steroids and splints/rest for children with juvenile idiopathic arthritis and adults with rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD002824 | date = January 2006 | volume = 2008 | pmid = 16437446 | doi = 10.1002/14651858.cd002824.pub2 | pmc = 8453330 }}</ref>

Non-[[Chemistry:Nonsteroidal anti-inflammatory drug|NSAID]] drugs to relieve pain, like [[Chemistry:Paracetamol|paracetamol]] may be used to help relieve the pain symptoms; they do not change the underlying disease.<ref name=NICE2015/> The use of paracetamol may be associated with the risk of developing ulcers.<ref name=":9">{{cite journal | vauthors = Ramiro S, Radner H, van der Heijde D, van Tubergen A, Buchbinder R, Aletaha D, Landewé RB | title = Combination therapy for pain management in inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis) | journal = The Cochrane Database of Systematic Reviews | issue = 10 | pages = CD008886 | date = October 2011 | pmid = 21975788 | doi = 10.1002/14651858.cd008886.pub2 }}</ref>

[[Chemistry:Nonsteroidal anti-inflammatory drug|NSAIDs]] reduce both pain and stiffness in those with RA but do not affect the underlying disease and appear to have no effect on people's long term disease course and thus are no longer first line agents.<ref name=Lancet2016/><ref>{{cite journal | vauthors = Tarp S, Bartels EM, Bliddal H, Furst DE, Boers M, Danneskiold-Samsøe B, Rasmussen M, Christensen R | title = Effect of nonsteroidal antiinflammatory drugs on the C-reactive protein level in rheumatoid arthritis: a meta-analysis of randomized controlled trials | journal = Arthritis and Rheumatism | volume = 64 | issue = 11 | pages = 3511–3521 | date = November 2012 | pmid = 22833186 | doi = 10.1002/art.34644 | doi-access = free }}</ref> NSAIDs should be used with caution in those with gastrointestinal, cardiovascular, or kidney problems.<ref>{{cite journal | vauthors = Radner H, Ramiro S, Buchbinder R, Landewé RB, van der Heijde D, Aletaha D | title = Pain management for inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and other spondylarthritis) and gastrointestinal or liver comorbidity | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD008951 | date = January 2012 | issue = 2 | pmid = 22258995 | doi = 10.1002/14651858.CD008951.pub2 | pmc = 8950811 | veditors = Radner H }}</ref><ref name="pmid22141388">{{cite journal | vauthors = McCormack PL | title = Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis | journal = Drugs | volume = 71 | issue = 18 | pages = 2457–2489 | date = December 2011 | pmid = 22141388 | doi = 10.2165/11208240-000000000-00000 | s2cid = 71357689 }}</ref><ref>{{cite journal | vauthors = Marks JL, Colebatch AN, Buchbinder R, Edwards CJ | title = Pain management for rheumatoid arthritis and cardiovascular or renal comorbidity | journal = The Cochrane Database of Systematic Reviews | issue = 10 | pages = CD008952 | date = October 2011 | pmid = 21975789 | doi = 10.1002/14651858.CD008952.pub2 | veditors = Marks JL }}</ref><ref name=":9" /> Rofecoxib was withdrawn from the global market as its long-term use was associated to an increased risk of heart attacks and strokes.<ref>{{cite journal | vauthors = Garner SE, Fidan DD, Frankish RR, Judd MG, Towheed TE, Wells G, Tugwell P | title = Rofecoxib for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD003685 | date = January 2005 | volume = 2010 | pmid = 15674912 | doi = 10.1002/14651858.cd003685.pub2 | pmc = 8725608 }}</ref> Use of methotrexate together with NSAIDs is safe, if adequate monitoring is done.<ref>{{cite journal | vauthors = Colebatch AN, Marks JL, Edwards CJ | title = Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis) | journal = The Cochrane Database of Systematic Reviews | issue = 11 | pages = CD008872 | date = November 2011 | pmid = 22071858 | doi = 10.1002/14651858.CD008872.pub2 }}</ref> [[Biology:COX-2 inhibitor|COX-2 inhibitor]]s, such as [[Biology:Celecoxib|celecoxib]], and NSAIDs are equally effective.<ref name=Job2008>{{cite journal | vauthors = Chen YF, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, Taylor RS | title = Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation | journal = Health Technology Assessment | volume = 12 | issue = 11 | pages = 1–278, iii | date = April 2008 | pmid = 18405470 | doi = 10.3310/hta12110 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Fidahic M, Jelicic Kadic A, Radic M, Puljak L | title = Celecoxib for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 6 | pages = CD012095 | date = June 2017 | issue = 6 | pmid = 28597983 | pmc = 6481589 | doi = 10.1002/14651858.CD012095.pub2 }}</ref> A 2004 Cochrane review found that people preferred NSAIDs over paracetamol.<ref name=":10">{{cite journal | vauthors = Wienecke T, Gøtzsche PC | title = Paracetamol versus nonsteroidal anti-inflammatory drugs for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD003789 | date = 2004-01-26 | volume = 2010 | pmid = 14974037 | doi = 10.1002/14651858.cd003789.pub2 | pmc = 8730319 }}</ref> However, it is yet to be clinically determined whether NSAIDs are more effective than paracetamol.<ref name=":10" />

The neuromodulator agents topical [[Chemistry:Capsaicin|capsaicin]] may be reasonable to use in an attempt to reduce pain.<ref name=Ric2012/> [[Chemistry:Nefopam|Nefopam]] by mouth and [[Biology:Cannabis|cannabis]] are not recommended as of 2012 as the risks of use appear to be greater than the benefits.<ref name=Ric2012>{{cite journal | vauthors = Richards BL, Whittle SL, Buchbinder R | title = Neuromodulators for pain management in rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD008921 | date = January 2012 | issue = 1 | pmid = 22258992 | doi = 10.1002/14651858.CD008921.pub2 | pmc = 6956614 }}</ref>

Limited evidence suggests the use of weak oral opioids but the adverse effects may outweigh the benefits.<ref>{{cite journal | vauthors = Whittle SL, Richards BL, Husni E, Buchbinder R | title = Opioid therapy for treating rheumatoid arthritis pain | journal = The Cochrane Database of Systematic Reviews | issue = 11 | pages = CD003113 | date = November 2011 | pmid = 22071805 | doi = 10.1002/14651858.cd003113.pub3 }}</ref>

Alternatively, physical therapy has been tested and shown as an effective aid in reducing pain in patients with RA. As most RA is detected early and treated aggressively, physical therapy plays more of a preventative and compensatory role, aiding in pain management alongside regular rheumatic therapy.<ref name=":13" />

===Surgery===
Especially for affected fingers, hands, and wrists, [[Medicine:Synovectomy|synovectomy]] may be needed to prevent pain or tendon rupture when drug treatment has failed. Severely affected joints may require [[Medicine:Joint replacement|joint replacement]] surgery, such as knee replacement. Postoperatively, physiotherapy is always necessary.<ref name=Davidson2014/>{{rp|1080, 1103}} There is insufficient evidence to support surgical treatment on arthritic shoulders.<ref>{{cite journal | vauthors = Christie A, Dagfinrud H, Engen Matre K, Flaatten HI, Ringen Osnes H, Hagen KB | title = Surgical interventions for the rheumatoid shoulder | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD006188 | date = January 2010 | pmid = 20091587 | doi = 10.1002/14651858.cd006188.pub2 }}</ref>

=== Physiotherapy ===
For people with RA, physiotherapy may be used together with medical management.<ref name=Kav2004/> This may include cold and [[Medicine:Heat therapy|heat]] application, [[Chemistry:Electrotherapy|electronic stimulation]], and [[Unsolved:Hydrotherapy|hydrotherapy]].<ref name=Kav2004>{{cite journal | vauthors = Kavuncu V, Evcik D | title = Physiotherapy in rheumatoid arthritis | journal = MedGenMed | volume = 6 | issue = 2 | pages = 3 | date = May 2004 | pmid = 15266230 | pmc = 1395797 }}</ref> Although medications improve symptoms of RA, muscle function is not regained when disease activity is controlled.<ref name="ReferenceA">{{cite journal | vauthors = Hammond A, Prior Y | title = The effectiveness of home hand exercise programmes in rheumatoid arthritis: a systematic review | journal = British Medical Bulletin | volume = 119 | issue = 1 | pages = 49–62 | date = September 2016 | pmid = 27365455 | doi = 10.1093/bmb/ldw024 | doi-access = free }}</ref>

Physiotherapy promotes physical activity. In RA, physical activity like exercise in the appropriate dosage (frequency, intensity, time, type, volume, progression) and physical activity promotion is effective in improving cardiovascular fitness, muscle strength, and maintaining a long term active lifestyle. In the short term, resistance exercises, with or without range of motion exercises, improve self-reported hand functions.<ref name="ReferenceA"/> Physical activity promotion according to the public health recommendations should be an integral part of standard care for people with RA and other arthritic diseases.<ref name=":12" /> Additionally, the combination of physical activities and [[Unsolved:Cryotherapy|cryotherapy]] show its efficacy on the disease activity and pain relief.<ref name="2017EJPRM">{{cite journal | vauthors = Peres D, Sagawa Y, Dugué B, Domenech SC, Tordi N, Prati C | title = The practice of physical activity and cryotherapy in rheumatoid arthritis: systematic review | journal = European Journal of Physical and Rehabilitation Medicine | volume = 53 | issue = 5 | pages = 775–787 | date = October 2017 | pmid = 27996221 | doi = 10.23736/s1973-9087.16.04534-2 }}</ref> The combination of aerobic activity and [[Unsolved:Cryotherapy|cryotherapy]] may be an innovative therapeutic strategy to improve the aerobic capacity in arthritis patients and consequently reduce their cardiovascular risk while minimizing pain and disease activity.<ref name="2017EJPRM" />

=== Compression gloves ===
[[Engineering:Compression garment|Compression gloves]] are handwear designed to help prevent the occurrence of various medical disorders relating to blood circulation in the wrists and hands. They can be used to treat the symptoms of [[Medicine:Arthritis|arthritis]],<ref>{{cite journal | vauthors = Hammond A, Prior Y |date=1 March 2021 |title=Compression gloves for patients with hand arthritis (C-GLOVES): A feasibility study |journal=Hand Therapy |language=en |volume=26 |issue=1 |pages=26–37 |doi=10.1177/1758998320986829 |pmid=37905193 |pmc=10584057 |s2cid=232050521 |issn=1758-9983 |doi-access=free }}</ref> though the medical benefits may be limited.<ref>{{cite journal | vauthors = Hammond A, Jones V, Prior Y | title = The effects of compression gloves on hand symptoms and hand function in rheumatoid arthritis and hand osteoarthritis: a systematic review | journal = Clinical Rehabilitation | volume = 30 | issue = 3 | pages = 213–224 | date = March 2016 | pmid = 25802424 | doi = 10.1177/0269215515578296 | s2cid = 40742720 | url = http://usir.salford.ac.uk/id/eprint/34121/1/SR%20compression%20gloves%20in%20RA%20HOA%20%20Clin%20Rehab%202015%20FINAL%20word%20version.pdf }}</ref>

===Alternative medicine===
In general, there is not enough evidence to support any complementary health approaches for RA, with safety concerns for some of them. Some mind and body practices and dietary supplements may help people with symptoms and therefore may be beneficial additions to conventional treatments, but there is not enough evidence to draw conclusions.<ref name=NCCIH>{{cite web|title=Rheumatoid Arthritis and Complementary Health Approaches|url=http://nccih.nih.gov/health/RA/getthefacts.htm|publisher=National Center for Complementary and Integrative Health|access-date=July 1, 2015|url-status=live|archive-url=https://web.archive.org/web/20150705082102/https://nccih.nih.gov/health/RA/getthefacts.htm|archive-date=July 5, 2015|date=January 2006}}</ref> A [[Systematic review|systematic review]] of CAM modalities (excluding fish oil) found that " The available evidence does not support their current use in the management of RA."<ref name=Macfarlane>{{cite journal | vauthors = 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 | volume = 50 | issue = 9 | pages = 1672–1683 | date = September 2011 | pmid = 21652584 | doi = 10.1093/rheumatology/ker119 | collaboration = Arthritis Research UK Working Group on Complementary Alternative Medicines | doi-access = free }}</ref> Studies showing beneficial effects in RA on a wide variety of CAM modalities are often affected by [[Publication bias|publication bias]] and are generally not high quality evidence such as [[Randomized controlled trial|randomized controlled trial]]s (RCTs).<ref name=Ef2010>{{cite journal | vauthors = Efthimiou P, Kukar M | s2cid = 21179821 | title = Complementary and alternative medicine use in rheumatoid arthritis: proposed mechanism of action and efficacy of commonly used modalities | journal = Rheumatology International | volume = 30 | issue = 5 | pages = 571–586 | date = March 2010 | pmid = 19876631 | doi = 10.1007/s00296-009-1206-y }}</ref>

A 2005 Cochrane review states that low level laser therapy can be tried to improve pain and morning stiffness due to rheumatoid arthritis as there are few side-effects.<ref>{{cite journal | vauthors = Brosseau L, Robinson V, Wells G, Debie R, Gam A, Harman K, Morin M, Shea B, Tugwell P | title = Low level laser therapy (Classes I, II and III) for treating rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 4 | issue = 4 | pages = CD002049 | date = October 2005 | pmid = 16235295 | doi = 10.1002/14651858.CD002049.pub2 | pmc = 8406947 }}</ref>

There is limited evidence that [[Unsolved:Tai chi|tai chi]] might improve the range of motion of a joint in persons with rheumatoid arthritis.<ref>{{cite journal | vauthors = Mudano AS, Tugwell P, Wells GA, Singh JA | title = Tai Chi for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 9 | pages = CD004849 | date = September 2019 | issue = 9 | pmid = 31553478 | pmc = 6759565 | doi = 10.1002/14651858.CD004849.pub2 }}</ref><ref>{{cite journal | vauthors = Lee MS, Pittler MH, Ernst E | title = Tai chi for rheumatoid arthritis: systematic review | journal = Rheumatology | volume = 46 | issue = 11 | pages = 1648–1651 | date = November 2007 | pmid = 17634188 | doi = 10.1093/rheumatology/kem151 | doi-access = free }}</ref> The evidence for acupuncture is inconclusive<ref>{{cite journal | vauthors = Lee MS, Shin BC, Ernst E | title = Acupuncture for rheumatoid arthritis: a systematic review | journal = Rheumatology | volume = 47 | issue = 12 | pages = 1747–1753 | date = December 2008 | pmid = 18710899 | doi = 10.1093/rheumatology/ken330 | doi-access = free }}</ref> with it appearing to be equivalent to sham acupuncture.<ref>{{cite journal | vauthors = Macfarlane GJ, Paudyal P, Doherty M, Ernst E, Lewith G, MacPherson H, Sim J, Jones GT | title = A systematic review of evidence for the effectiveness of practitioner-based complementary and alternative therapies in the management of rheumatic diseases: rheumatoid arthritis | journal = Rheumatology | volume = 51 | issue = 9 | pages = 1707–1713 | date = September 2012 | pmid = 22661556 | doi = 10.1093/rheumatology/kes133 | collaboration = Arthritis Research UK Working Group on Complementary Alternative Therapies for the Management of the Rheumatic Diseases | doi-access = free }}</ref>

A Cochrane review in 2002 showed some benefits of the electrical stimulation as a rehabilitation intervention to improve the power of the hand grip and help to resist fatigue.<ref>{{cite journal | vauthors = Brosseau LU, Pelland LU, Casimiro LY, Robinson VI, Tugwell PE, Wells GE | title = Electrical stimulation for the treatment of rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD003687 | date = 2002 | volume = 2010 | pmid = 12076504 | doi = 10.1002/14651858.CD003687 | pmc = 8725644 }}</ref> D‐penicillamine may provide similar benefits as DMARDs but it is also highly toxic.<ref>{{cite journal | vauthors = Suarez-Almazor ME, Spooner C, Belseck E | title = Penicillamine for treating rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD001460 | date = 2000-10-23 | volume = 2011 | pmid = 11034719 | doi = 10.1002/14651858.cd001460 | pmc = 8407185 }}</ref> Low-quality evidence suggests the use of therapeutic ultrasound on arthritic hands.<ref name=":6">{{cite journal | vauthors = Casimiro L, Brosseau L, Robinson V, Milne S, Judd M, Well G, Tugwell P, Shea B | title = Therapeutic ultrasound for the treatment of rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD003787 | date = 2002-07-22 | pmid = 12137714 | doi = 10.1002/14651858.cd003787 }}</ref> Potential benefits include increased grip strength, reduced morning stiffness and number of swollen joints.<ref name=":6" /> There is tentative evidence of benefit of [[Biology:Transcutaneous electrical nerve stimulation|transcutaneous electrical nerve stimulation]] (TENS) in RA.<ref name=":7">{{cite journal | vauthors = Johnson MI, Walsh DM | title = Pain: continued uncertainty of TENS' effectiveness for pain relief | journal = Nature Reviews. Rheumatology | volume = 6 | issue = 6 | pages = 314–316 | date = June 2010 | pmid = 20520646 | doi = 10.1002/14651858.cd004377 | pmc = 8826159 }}</ref> Acupuncture‐like TENS (AL-TENS) may decrease pain intensity and improve muscle power scores.<ref name=":7" />

Low-quality evidence suggests people with active RA may benefit from assistive technology.<ref name=":8">{{cite journal | vauthors = Tuntland H, Kjeken I, Nordheim LV, Falzon L, Jamtvedt G, Hagen KB | title = Assistive technology for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD006729 | date = October 2009 | volume = 2009 | pmid = 19821383 | doi = 10.1002/14651858.cd006729.pub2 | pmc = 7389411 }}</ref> This may include less discomfort and difficulty such as when using an eye drop device.<ref name=":8" /> Balance training is of unclear benefits.<ref>{{cite journal | vauthors = Silva KN, Mizusaki Imoto A, Almeida GJ, Atallah AN, Peccin MS, Fernandes Moça Trevisani V | title = Balance training (proprioceptive training) for patients with rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD007648 | date = May 2010 | pmid = 20464755 | doi = 10.1002/14651858.cd007648.pub2 }}</ref>

===Dietary supplements===

====Fatty acids====
There has been a growing interest in the role of long-chain omega-3 polyunsaturated fatty acids to reduce inflammation and alleviate the symptoms of RA. Metabolism of omega-3 polyunsaturated fatty acids produces docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which inhibits pro-inflammatory eicosanoids and cytokines (TNF-a, IL-1b and IL-6), decreasing both lymphocyte proliferation and reactive oxygen species.<ref name=":15">{{cite journal | vauthors = Martin RH | title = The role of nutrition and diet in rheumatoid arthritis | journal = The Proceedings of the Nutrition Society | volume = 57 | issue = 2 | pages = 231–234 | date = May 1998 | pmid = 9656325 | doi = 10.1079/pns19980036 | s2cid = 2000161 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Tedeschi SK, Costenbader KH | title = Is There a Role for Diet in the Therapy of Rheumatoid Arthritis? | journal = Current Rheumatology Reports | volume = 18 | issue = 5 | pages = 23 | date = May 2016 | pmid = 27032786 | doi = 10.1007/s11926-016-0575-y | s2cid = 39883142 }}</ref> These studies showed evidence for significant clinical improvements on RA in inflammatory status and articular index. Gamma-linolenic acid, an omega-6 fatty acid, may reduce pain, tender joint count and stiffness, and is generally safe.<ref>{{cite journal | vauthors = Soeken KL, Miller SA, Ernst E | title = Herbal medicines for the treatment of rheumatoid arthritis: a systematic review | journal = Rheumatology | volume = 42 | issue = 5 | pages = 652–659 | date = May 2003 | pmid = 12709541 | doi = 10.1093/rheumatology/keg183 | url = http://www.crd.york.ac.uk/CRDWeb/ShowRecord.asp?AccessionNumber=12003000980 | access-date = March 23, 2013 | publisher = National Institute for Health and Care Research | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20140116101729/http://www.crd.york.ac.uk/CRDWeb/ShowRecord.asp?AccessionNumber=12003000980 | archive-date = January 16, 2014 }}</ref> For omega-3 polyunsaturated fatty acids (found in fish oil, flax oil and hemp oil), a meta-analysis reported a favorable effect on pain, although confidence in the effect was considered moderate. The same review reported less inflammation but no difference in joint function.<ref name="Senft">{{cite journal | vauthors = Senftleber NK, Nielsen SM, Andersen JR, Bliddal H, Tarp S, Lauritzen L, Furst DE, Suarez-Almazor ME, Lyddiatt A, Christensen R | title = Marine Oil Supplements for Arthritis Pain: A Systematic Review and Meta-Analysis of Randomized Trials | journal = Nutrients | volume = 9 | issue = 1 | pages = 42 | date = January 2017 | pmid = 28067815 | pmc = 5295086 | doi = 10.3390/nu9010042 | doi-access = free }}</ref> A review examined the effect of marine oil omega-3 fatty acids on pro-inflammatory eicosanoid concentrations; leukotriene<sub>4</sub> (LTB<sub>4</sub>) was lowered in people with rheumatoid arthritis but not in those with non-autoimmune chronic diseases.<ref name="Jiang">{{cite journal | vauthors = Jiang J, Li K, Wang F, Yang B, Fu Y, Zheng J, Li D | title = Effect of Marine-Derived n-3 Polyunsaturated Fatty Acids on Major Eicosanoids: A Systematic Review and Meta-Analysis from 18 Randomized Controlled Trials | journal = PLOS ONE | volume = 11 | issue = 1 | pages = e0147351 | year = 2016 | pmid = 26808318 | pmc = 4726565 | doi = 10.1371/journal.pone.0147351 | doi-access = free | bibcode = 2016PLoSO..1147351J }}</ref> Fish consumption has no association with RA.<ref name="DiG">{{cite journal | vauthors = Di Giuseppe D, Crippa A, Orsini N, Wolk A | title = Fish consumption and risk of rheumatoid arthritis: a dose-response meta-analysis | journal = Arthritis Research & Therapy | volume = 16 | issue = 5 | pages = 446 | date = September 2014 | pmid = 25267142 | pmc = 4201724 | doi = 10.1186/s13075-014-0446-8 | doi-access = free }}</ref> A fourth review limited inclusion to trials in which people eat ≥2.7&nbsp;g/day for more than three months. Use of pain relief medication was decreased, but improvements in tender or swollen joints, morning stiffness and physical function were not changed.<ref name="Lee">{{cite journal | vauthors = Lee YH, Bae SC, Song GG | title = Omega-3 polyunsaturated fatty acids and the treatment of rheumatoid arthritis: a meta-analysis | journal = Archives of Medical Research | volume = 43 | issue = 5 | pages = 356–362 | date = July 2012 | pmid = 22835600 | doi = 10.1016/j.arcmed.2012.06.011 }}</ref> Collectively, the current evidence is not strong enough to determine that supplementation with omega-3 fatty acids or regular consumption of fish are effective treatments for rheumatoid arthritis.<ref name="Senft"/><ref name="Jiang"/><ref name="DiG"/><ref name="Lee"/>

====Herbal====
The American College of Rheumatology states that no herbal medicines have health claims supported by high-quality evidence and thus they do not recommend their use.<ref name=ACRCAM/> There is no scientific basis to suggest that herbal supplements advertised as "natural" are safer for use than conventional medications as both are chemicals. Herbal medications, although labelled "natural", may be toxic or fatal if consumed.<ref name=ACRCAM>{{cite web|title=Herbal Remedies, Supplements and Acupuncture for Arthritis|url=http://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Herbal_Remedies,_Supplements_and_Acupuncture_for_Arthritis/|publisher=American College of Rheumatology|access-date=May 3, 2013|url-status=live|archive-url=https://web.archive.org/web/20130505001915/http://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Herbal_Remedies,_Supplements_and_Acupuncture_for_Arthritis/|archive-date=May 5, 2013}}</ref> Due to the false belief that herbal supplements are always safe, there is sometimes a hesitancy to report their use which may increase the risk of adverse reactions.<ref name=Ef2010/>

===Pregnancy===
More than 75% of women with rheumatoid arthritis have symptoms improve during pregnancy but might have symptoms worsen after delivery.<ref name="McGraw Hill"/> [[Chemistry:Methotrexate|Methotrexate]] and [[Chemistry:Leflunomide|leflunomide]] are teratogenic (harmful to foetus) and not used in pregnancy. It is recommended women of childbearing age should use contraceptives to avoid pregnancy and to discontinue its use if pregnancy is planned.<ref name="Wasserman" /><ref name="chapter94" /> Low dose of [[Chemistry:Prednisolone|prednisolone]], [[Chemistry:Hydroxychloroquine|hydroxychloroquine]] and [[Chemistry:Sulfasalazine|sulfasalazine]] are considered safe in pregnant women with rheumatoid arthritis. Prednisolone should be used with caution as the side effects include infections and fractures.<ref>{{cite journal | vauthors = Gotzsche PC, Johansen HK | title = Short-term low-dose corticosteroids vs placebo and nonsteroidal antiinflammatory drugs in rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD000189 | date = 2005-01-24 | volume = 2005 | pmid = 15266426 | doi = 10.1002/14651858.cd000189.pub2 | pmc = 7043293 }}</ref>

===Vaccinations===
People with RA have an increased risk of infections and mortality and recommended vaccinations can reduce these risks.<ref>{{cite journal | vauthors = Perry LM, Winthrop KL, Curtis JR | title = Vaccinations for rheumatoid arthritis | journal = Current Rheumatology Reports | volume = 16 | issue = 8 | pages = 431 | date = August 2014 | pmid = 24925587 | pmc = 4080407 | doi = 10.1007/s11926-014-0431-x }}</ref> The inactivated [[Medicine:Influenza vaccine|influenza vaccine]] should be received annually.<ref>{{cite journal | vauthors = Grohskopf LA, Olsen SJ, Sokolow LZ, Bresee JS, Cox NJ, Broder KR, Karron RA, Walter EB | title = Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP) -- United States, 2014-15 influenza season | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 63 | issue = 32 | pages = 691–697 | date = August 2014 | pmid = 25121712 | pmc = 4584910 }}</ref> The [[Medicine:Pneumococcal vaccine|pneumococcal vaccine]] should be administered twice for people under the age 65 and once for those over 65.<ref>{{cite journal | vauthors = Black CL, Yue X, Ball SW, Donahue SM, Izrael D, de Perio MA, Laney AS, Lindley MC, Graitcer SB, Lu PJ, Williams WW, Bridges CB, DiSogra C, Sokolowski J, Walker DK, Greby SM | title = Influenza vaccination coverage among health care personnel--United States, 2013-14 influenza season | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 63 | issue = 37 | pages = 805–811 | date = September 2014 | pmid = 25233281 | pmc = 5779456 }}</ref> Lastly, the live-attenuated zoster vaccine should be administered once after the age 60, but is not recommended in people on a [[Biology:Tumor necrosis factor alpha|tumor necrosis factor alpha]] blocker.<ref>{{cite journal | vauthors = Hales CM, Harpaz R, Ortega-Sanchez I, Bialek SR | title = Update on recommendations for use of herpes zoster vaccine | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 63 | issue = 33 | pages = 729–731 | date = August 2014 | pmid = 25144544 | pmc = 5779434 }}</ref>

==Prognosis==
[[Image:Rheumatoid arthritis world map - DALY - WHO2004.svg|thumb|upright=1.3|[[Disability-adjusted life year]] for RA per 100,000&nbsp;inhabitants in 2004.<ref>{{cite web |url=https://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html |title=WHO Disease and injury country estimates |year=2009 |website=World Health Organization |access-date=November 11, 2009 |url-status=live |archive-url=https://web.archive.org/web/20091111101009/http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html |archive-date=November 11, 2009 }}</ref>
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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 25% will have subcutaneous nodules (known as [[Medicine:Rheumatoid nodule|rheumatoid nodule]]s);<ref>{{cite book|title=The New Harvard Guide to Women's Health| vauthors = Carlson KJ, Eisenstat SA, Ziporyn TD  |publisher=Harvard University Press|year=2004|location=Cambridge, MA|via=Credo Reference}}</ref> this is associated with a poor prognosis.<ref>{{cite book|title=Arthritis and You| vauthors = Ali N |publisher=Rowman & Littlefield Publishers, Inc.|year=2013|isbn=978-1-4422-1901-4 |location=Lanham, MD|pages=[https://archive.org/details/arthritisyoucomp0000alin/page/138 138]|url=https://archive.org/details/arthritisyoucomp0000alin/page/138}}</ref>

===Prognostic factors===
Poor prognostic factors include,
* Persistent synovitis
* Early erosive disease
* Extra-articular findings (including subcutaneous rheumatoid nodules)
* Positive serum RF findings
* Positive serum anti-CCP autoantibodies
* Positive serum 14-3-3η ([[Biology:YWHAH|YWHAH]]) levels above 0.5&nbsp;ng/ml <ref name="PMC7299510">{{cite journal | vauthors = Carrier N, Brum-Fernanades AJ, Liang P, Masetto A, Roux S, Biln N, Maksymowych WP, Boire G | title = Impending radiographic erosive progression over the following year in a cohort of consecutive patients with inflammatory polyarthritis: prediction by serum biomarkers | journal = RMD Open | volume = 6 | issue = 1 | pages = e001191 | date = April 2020 | pmid = 32371434 | doi = 10.1136/rmdopen-2020-001191 | pmc = 7299510 }}</ref><ref name="PMC4736641">{{cite journal | vauthors = Carrier N, Marotta A, Brum-Fernanades AJ, Liang P, Masetto A, Menard H, Maksymowcych WP, Boire G | title = Serum levels of 14-3-3η protein supplement C-reactive protein and rheumatoid arthritis-associated antibodies to predict clinical and radiographic outcomes in a prospective cohort of patients with recent-onset inflammatory polyarthritis | journal = Arthritis Research & Therapy | volume = 18 | issue = 37 | date = Feb 2016 | page = 37 | pmid = 26832367 | doi = 10.1186/s13075-016-0935-z | doi-broken-date = 2024-01-27 | pmc = 4736641 | doi-access = free }}</ref>
* Carriership of HLA-DR4 "Shared Epitope" alleles
* Family history of RA
* Poor functional status
* Socioeconomic factors<ref name=":17">{{cite book |last1=Donahue |first1=Katrina E. |url=http://www.ncbi.nlm.nih.gov/books/NBK524950/ |title=Drug Therapy for Early Rheumatoid Arthritis: A Systematic Review Update |last2=Gartlehner |first2=Gerald |last3=Schulman |first3=Elizabeth R. |last4=Jonas |first4=Beth |last5=Coker-Schwimmer |first5=Emmanuel |last6=Patel |first6=Sheila V. |last7=Weber |first7=Rachel Palmieri |last8=Lohr |first8=Kathleen N. |last9=Bann |first9=Carla |date=2018 |publisher=Agency for Healthcare Research and Quality (US) |series=AHRQ Comparative Effectiveness Reviews |location=Rockville (MD) |pmid=30199187}}</ref>
* Elevated acute phase response (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP])
* Increased clinical severity.
* Distance from primary care and specialist care in rural communities<ref name=":17" />

===Mortality===
RA reduces lifespan on average from three to twelve years.<ref name="Wasserman"/> Young age at onset, long disease duration, the presence of other health problems, and characteristics of severe RA{{snd}}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{{snd}}have been shown to associate with higher mortality.<ref>Kitas, George (4 April 2006) [https://web.archive.org/web/20060924153339/http://www.rheumatoid.org.uk/article.php?article_id=112 Why is life span shortened by Rheumatoid Arthritis?] National Rheumatoid Arthritis Society</ref> Positive responses to treatment may indicate a better prognosis. A 2005 study by the Mayo Clinic noted that individuals with RA have a doubled risk of heart disease,<ref>[https://web.archive.org/web/20050306030726/http://mayoclinic.org/news2005-rst/2654.html Rheumatoid Arthritis Patients Have Double the Risk of Heart Failure]. mayoclinic.org (3 February 2005).</ref> independent of other risk factors such as [[Medicine:Diabetes|diabetes]], excessive alcohol use, and elevated [[Chemistry:Cholesterol|cholesterol]], blood pressure and [[Body mass index|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 |archive-url=https://web.archive.org/web/20061009112820/http://www.hopkins-arthritis.org/news-archive/2002/cardiac.html |archive-date=October 9, 2006 |title=Cardiac disease in rheumatoid arthritis |publisher=Johns Hopkins University|year=2002}}</ref> It is possible that the use of new biologic drug therapies extend the lifespan of people with RA and reduce the risk and progression of atherosclerosis.<ref name="pmid20678592">{{cite journal | vauthors = Atzeni F, Turiel M, Caporali R, Cavagna L, Tomasoni L, Sitia S, Sarzi-Puttini P | title = The effect of pharmacological therapy on the cardiovascular system of patients with systemic rheumatic diseases | journal = Autoimmunity Reviews | volume = 9 | issue = 12 | pages = 835–839 | date = October 2010 | pmid = 20678592 | doi = 10.1016/j.autrev.2010.07.018 }}</ref> This is based on cohort and registry studies, and still remains hypothetical. It is still uncertain whether biologics improve vascular function in RA or not. There was an increase in total cholesterol and HDLc levels and no improvement of the atherogenic index.<ref name="biologics cv effects/ cancer">{{cite journal | vauthors = Damjanov N, Nurmohamed MT, Szekanecz Z | title = Biologics, cardiovascular effects and cancer | journal = BMC Medicine | volume = 12 | issue = 1 | pages = 48 | date = March 2014 | pmid = 24642038 | pmc = 3984692 | doi = 10.1186/1741-7015-12-48 | doi-access = free }}</ref>

==Epidemiology==
[[File:Rheumatoid arthritis world map-Deaths per million persons-WHO2012.svg|thumb|upright=1.3|Deaths from rheumatoid arthritis per million persons in 2012 {{Div col|small=yes|colwidth=10em}}{{legend|#ffff20|0–0}}{{legend|#ffe820|1–1}}{{legend|#ffd820|2–3}}{{legend|#ffc020|4–5}}{{legend|#ffa020|6–6}}{{legend|#ff9a20|7–8}}{{legend|#f08015|9–9}}{{legend|#e06815|10–12}}{{legend|#d85010|13–20}}{{legend|#d02010|21–55}}{{div col end}}]]

RA affects 0.5–1% of adults in the developed world with between 5 and 50 per 100,000 people newly developing the condition each year.<ref name=Lancet2016/> In 2010 it resulted in about 49,000 deaths globally.<ref name=Loz2012>{{cite journal | vauthors = Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, etal | s2cid = 1541253 | 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 | volume = 380 | issue = 9859 | pages = 2095–2128 | date = December 2012 | pmid = 23245604 | doi = 10.1016/S0140-6736(12)61728-0 | pmc = 10790329 | hdl = 10536/DRO/DU:30050819 | url = https://zenodo.org/record/2557786 | hdl-access = free }}</ref>

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.<ref name="McGraw Hill"/>

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 | vauthors = 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 = Seminars in Arthritis and Rheumatism | volume = 36 | issue = 3 | pages = 182–188 | date = December 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 the persistent symptoms, waxing and waning in intensity, and a progressive deterioration of joint structures leading to deformations and disability.{{citation needed|date=July 2022}}

There is an association between periodontitis and rheumatoid arthritis (RA), hypothesised to lead to enhanced generation of RA-related autoantibodies. Oral bacteria that invade the blood may also contribute to chronic inflammatory responses and generation of autoantibodies.<ref>{{cite journal | vauthors = Cheng Z, Meade J, Mankia K, Emery P, Devine DA | title = Periodontal disease and periodontal bacteria as triggers for rheumatoid arthritis | journal = Best Practice & Research. Clinical Rheumatology | volume = 31 | issue = 1 | pages = 19–30 | date = February 2017 | pmid = 29221594 | doi = 10.1016/j.berh.2017.08.001 | url = http://eprints.whiterose.ac.uk/119931/1/Cheng_et_al_PDRA%20review_final.pdf }}</ref>

==History==
The first recognized description of RA in modern medicine was in 1800 by the French physician Augustin Jacob Landré-Beauvais (1772–1840) who was based in the famed Salpêtrière Hospital in Paris.<ref name=Landre1800/> The name "rheumatoid arthritis" itself was coined in 1859 by British rheumatologist Alfred Baring Garrod.<ref>{{cite book | vauthors = Garrod AB | title=The Nature and Treatment of Gout and Rheumatic Gout | year=1859 | publisher=Walton and Maberly | location=London}}</ref>

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 | vauthors = 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 = 483–486 | date = February 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 | vauthors = Kelly J |date=14 June 2005 |access-date=March 3, 2011 |url-status=live |archive-url=https://web.archive.org/web/20131215072634/http://www.medscape.com/viewarticle/538251 |archive-date=15 December 2013 }}</ref> RA appears to some to have been depicted in 16th-century paintings.<ref>{{cite journal | vauthors = Dequeker J, Rico H | title = Rheumatoid arthritis-like deformities in an early 16th-century painting of the Flemish-Dutch school | journal = JAMA | volume = 268 | issue = 2 | pages = 249–251 | date = July 1992 | pmid = 1608144 | doi = 10.1001/jama.268.2.249 }}</ref> However, it is generally recognized in art historical circles that the painting of hands in the 16th and 17th century followed certain stylized conventions, most clearly seen in the Mannerist movement. It was conventional, for instance, to show the upheld right hand of Christ in what now appears a deformed posture. These conventions are easily misinterpreted as portrayals of disease.{{citation needed|date=July 2022}}

Historic (though not necessarily effective) treatments for RA have also included: [[Medicine:RICE|rest, ice, compression and elevation]], [[Biology:Apple|apple]] diet, [[Biology:Nutmeg|nutmeg]], some light exercise every now and then, [[Biology:Urtica|nettles]], [[Biology:Bee|bee]] venom, [[Chemistry:Copper|copper]] bracelets, rhubarb diet, extractions of teeth, [[Philosophy:Fasting|fasting]], [[Chemistry:Honey|honey]], [[Chemistry:Vitamin|vitamin]]s, [[Biology:Insulin|insulin]], [[Physics:Magnet|magnet]]s, and [[Biology:Electroconvulsive therapy|electroconvulsive therapy]] (ECT).<ref>{{cite journal | vauthors = Hart FD | title = History of the treatment of rheumatoid arthritis | journal = British Medical Journal | volume = 1 | issue = 6012 | pages = 763–765 | date = March 1976 | pmid = 177148 | pmc = 1639217 | doi = 10.1136/bmj.1.6012.763 }}</ref>

===Etymology===
Rheumatoid arthritis is derived from the Greek word ''ῥεύμα-rheuma (nom.), ῥεύματος-rheumatos (gen.)'' ("flow, current"). The suffix -''oid'' ("resembling") gives the translation as ''joint inflammation that resembles [[Medicine:Rheumatic fever|rheumatic fever]]''. Rhuma which means watery discharge might refer to the fact that the joints are swollen or that the disease may be made worse by wet weather.<ref name=Paget2002/>

==Research==

[[Meta-analysis]] found an association between [[Medicine:Periodontal disease|periodontal disease]] and RA, but the mechanism of this association remains unclear.<ref name=Tang2017>{{cite journal | vauthors = Tang Q, Fu H, Qin B, Hu Z, Liu Y, Liang Y, Zhou L, Yang Z, Zhong R | title = A Possible Link Between Rheumatoid Arthritis and Periodontitis: A Systematic Review and Meta-analysis | journal = The International Journal of Periodontics & Restorative Dentistry | volume = 37 | issue = 1 | pages = 79–86 | date = 2017-02-01 | pmid = 27977821 | doi = 10.11607/prd.2656 | doi-access = free }}</ref> Two bacterial species associated with periodontitis are implicated as mediators of protein [[Biology:Citrullination|citrullination]] in the gums of people with RA.<ref name=Lancet2016/>

[[Medicine:Vitamin D deficiency|Vitamin D deficiency]] is more common in people with rheumatoid arthritis than in the general population.<ref name="pmid23370372">{{cite journal | vauthors = Gatenby P, Lucas R, Swaminathan A | s2cid = 10851180 | title = Vitamin D deficiency and risk for rheumatic diseases: an update | journal = Current Opinion in Rheumatology | volume = 25 | issue = 2 | pages = 184–191 | date = March 2013 | pmid = 23370372 | doi = 10.1097/BOR.0b013e32835cfc16 }}</ref><ref name=Wen2011>{{cite journal | vauthors = Wen H, Baker JF | s2cid = 25831521 | title = Vitamin D, immunoregulation, and rheumatoid arthritis | journal = Journal of Clinical Rheumatology | volume = 17 | issue = 2 | pages = 102–107 | date = March 2011 | pmid = 21364350 | doi = 10.1097/RHU.0b013e31820edd18 }}</ref> However, whether vitamin D deficiency is a cause or a consequence of the disease remains unclear.<ref name="pmid21067953">{{cite journal | vauthors = Guillot X, Semerano L, Saidenberg-Kermanac'h N, Falgarone G, Boissier MC | title = Vitamin D and inflammation | journal = Joint, Bone, Spine | volume = 77 | issue = 6 | pages = 552–557 | date = December 2010 | pmid = 21067953 | doi = 10.1016/j.jbspin.2010.09.018 }}</ref> One [[Meta-analysis|meta-analysis]] found that vitamin D levels are low in people with rheumatoid arthritis and that vitamin D status correlates inversely with prevalence of rheumatoid arthritis, suggesting that vitamin D deficiency is associated with susceptibility to rheumatoid arthritis.<ref>{{cite journal | vauthors = Lee YH, Bae SC | title = Vitamin D level in rheumatoid arthritis and its correlation with the disease activity: a meta-analysis | journal = Clinical and Experimental Rheumatology | volume = 34 | issue = 5 | pages = 827–833 | year = 2016 | pmid = 27049238 | url = http://www.clinexprheumatol.org/article.asp?a=10111 | archive-url = https://web.archive.org/web/20170405171050/http://www.clinexprheumatol.org/article.asp?a=10111 | url-status=live | archive-date = 2017-04-05 }}</ref>

The fibroblast-like synoviocytes have a prominent role in the pathogenic processes of the rheumatic joints, and therapies that target these cells are emerging as promising therapeutic tools, raising hope for future applications in rheumatoid arthritis.<ref name=nygaard/>

Possible links with [[Medicine:Coeliac disease|intestinal barrier dysfunction]] are investigated.<ref>{{cite journal | vauthors = Matei DE, Menon M, Alber DG, Smith AM, Nedjat-Shokouhi B, Fasano A, Magill L, Duhlin A, Bitoun S, Gleizes A, Hacein-Bey-Abina S, Manson JJ, Rosser EC, Klein N, Blair PA, Mauri C | title = Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease | journal = Med | volume = 2 | issue = 7 | pages = 864–883.e9 | date = July 2021 | pmid = 34296202 | pmc = 8280953 | doi = 10.1016/j.medj.2021.04.013 }}</ref>

== References ==
{{Reflist}}

== External links ==
{{Medical condition classification and resources
| DiseasesDB = 11506
| ICD10 = {{ICD10|M|05||m|05}}-{{ICD10|M|06||m|05}}, {{ICD10|M45}} (spine)
| ICD9 = {{ICD9|714}}
| OMIM = 180300
| MedlinePlus = 000431
| eMedicineSubj = article
| eMedicineTopic = 331715
| eMedicine_mult = {{eMedicine2|article|1266195}} {{eMedicine2|article|305417}} {{eMedicine2|article|401271}} {{eMedicine2|article|335186}} {{eMedicine2|article|808419}}
| MeshID = D001172
|ICD10CM={{ICD10CM|M05}}-{{ICD10CM|M06}}, {{ICD10CM|M45}} (spine)|ICD11={{ICD11|FA20}}, {{ICD11|FA92.0Z}} (spine)}}
* {{Curlie|Health/Conditions_and_Diseases/Musculoskeletal_Disorders/Arthritis/Rheumatoid|Rheumatoid arthritis}}
* {{cite web | url = https://medlineplus.gov/rheumatoidarthritis.html | publisher = U.S. National Library of Medicine | work = MedlinePlus | title = Rheumatoid Arthritis }}

{{Diseases of the musculoskeletal system and connective tissue}}


{{DEFAULTSORT:Rheumatoid Arthritis}}
[[Category:Rheumatology]]
[[Category:Arthritis]]
[[Category:Autoimmune diseases]]
[[Category:Wikipedia medicine articles ready to translate]]

{{Sourceattribution|Rheumatoid arthritis}}