Editing Rheumatoid arthritis (section)

==Pathophysiology==
RA primarily starts as a state of persistent cellular activation leading to [[autoimmunity]] and [[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 [[T cell]] activation), and chronic inflammatory phase, with tissue injury resulting from the [[cytokines]], [[Interleukin 1|IL–1]], [[TNF-alpha]], and [[Interleukin 6|IL–6]].<ref name="McGraw Hill" />

===Non-specific inflammation===
Factors allowing an abnormal immune response, once initiated, become permanent and chronic. These factors are [[genetic disorder]]s which change regulation of the [[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 [[rheumatoid factor]] and citrullinated fibrinogen bound by [[Anti-citrullinated protein antibody|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>{{rp|10}}

===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|editor-last1=Makowski |editor-first1=Gregory|vauthors=Boldt AB, Goeldner I, de Messias-Reason IJ |pmid=22397030|chapter=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| title = 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"/>{{rp|8}}

This contributes to local inflammation in a joint, specifically the synovium with [[edema]], [[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 [[dendritic cell]]s function as [[antigen-presenting cell]]s by expressing MHC class II molecules, which establishes the immune reaction in the tissue.<ref name=":02" />

===Chronic inflammation===
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| footer            = X-ray of the [[wrist]] of a woman with rheumatoid arthritis, showing unaffected [[carpal bones]] in the left image, and [[Ankylosis|ankylosing]] fusion of the carpal bones eight years later in the right image
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The disease progresses by forming granulation tissue at the edges of the synovial lining, [[pannus]] with extensive [[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 [[calprotectin]] levels serving as a [[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>

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 [[RANKL]] and [[RANK]], they eventually trigger [[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/>