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{{Rheumatoid arthritis}}
{{Rheumatoid arthritis}}
{{CMG}}; {{AE}} {{AN}}
{{CMG}}; {{AE}} {{MKK}}
 
==Overview==
[[Rheumatoid arthritis]] is mediated by the combination of a predisposing [[genotype]] along with which [[genetic]] factors, [[Environmental Lung Diseases|environmental]] factors, and [[Microorganisms|microorganisms]] contribute, resulting in the [[inflammation]] and destruction of the [[synovial membrane]]. These factors lead to [[citrullination]] or [[post-translational modifications]], resulting in the production of altered peptides. The altered [[peptides]] bind to [[MHC]] protein with shared [[epitopes]] which further leads to [[antigen]] presentation to [[T-cells]].
[[T-cells]] further stimulate [[B-cells]] and cytokines which results in cartilage damage. [[Mutation]] of [[human leukocyte antigen]] (HLA) genes on [[chromosome]] 6 is involved in pathogenesis of [[rheumatoid arthritis]]. Various conditions associated with [[RA]] include [[vasculitis]], [[uveitis]], [[scleritis]], peripheral [[ulcerative keratitis]],
[[interstitial fibrosis]], pulmonary [[nodules]], [[bronchiolitis obliterans]], organizing [[pneumonia]], [[venous thromboembolism]], [[pericarditis]], [[myocarditis]], [[congestive heart failure]], [[atrial fibrillation]], [[sjogren's syndrome]], and [[felty's syndrome]].


==Pathophysiology==
==Pathophysiology==
[[Image:Rheumatoid arthritis joint.gif|thumb|left|Joint abnormalities in rheumatoid arthritis]]
[[Rheumatoid arthritis]] is mediated by the combination of a predisposing [[genotype]] along with [[genetic]] factors, [[Environmental Lung Diseases|environmental]] factors, and [[Microorganisms|microorganisms]], resulting in the [[inflammation]] and destruction of the [[synovial membrane]].
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*'''Possible role of infections'''
'''Various factors involved are''':
**Some infectious organisms mentioned in this context have been ''[[Mycoplasma]]'', ''Erysipelothrix'', [[Epstein-Barr virus]], [[parvovirus|parvovirus B19]] and [[rubella]], [[adenovirus]], [[Herpesvirus]], have been implicated in the pathophysiology of RA.<ref name="pmid18484700">{{cite journal |author=Kozireva SV, Zestkova JV, Mikazane HJ, ''et al.'' |title=Incidence and clinical significance of parvovirus B19 infection in patients with rheumatoid arthritis |journal=[[The Journal of Rheumatology]] |volume=35 |issue=7 |pages=1265–70 |year=2008 |month=July |pmid=18484700 |doi= |url=http://www.jrheum.org/cgi/pmidlookup?view=long&pmid=18484700 |accessdate=2012-04-26}}</ref> <ref name="pmid22293286">{{cite journal |author=Davis JM, Knutson KL, Skinner JA, ''et al.'' |title=A profile of immune response to herpesvirus is associated with radiographic joint damage in rheumatoid arthritis |journal=[[Arthritis Research & Therapy]] |volume=14 |issue=1 |pages=R24 |year=2012 |month=January |pmid=22293286 |doi=10.1186/ar3706 |url=http://arthritis-research.com/content/14/1/R24 |accessdate=2012-04-26}}</ref> <ref name="pmid22183424">{{cite journal |author=Pierer M, Rothe K, Quandt D, ''et al.'' |title=Anti-cytomegalovirus seropositivity in rheumatoid arthritis is associated with more severe joint destruction and more frequent joint surgery |journal=[[Arthritis and Rheumatism]] |volume= |issue= |pages= |year=2011 |month=December |pmid=22183424 |doi=10.1002/art.34346 |url=http://dx.doi.org/10.1002/art.34346 |accessdate=2012-04-26}}</ref> <ref name="pmid22011088">{{cite journal |author=Goldstein BL, Chibnik LB, Karlson EW, Costenbader KH |title=Epstein-Barr virus serologic abnormalities and risk of rheumatoid arthritis among women |journal=[[Autoimmunity]] |volume=45 |issue=2 |pages=161–8 |year=2012 |month=March |pmid=22011088 |doi=10.3109/08916934.2011.616557 |url=http://informahealthcare.com/doi/abs/10.3109/08916934.2011.616557 |accessdate=2012-04-26}}</ref>  
 
**[[Periodontitis]] and Rheumatoid arthritis
'''Environmental factors''':
***Various studies have elucidated the co-relation between [[periodontitis]] and Rheumatoid arthritis because of the similarities .<ref name="pmid12956651">{{cite journal |author=Mercado FB, Marshall RI, Bartold PM |title=Inter-relationships between rheumatoid arthritis and periodontal disease. A review |journal=[[Journal of Clinical Periodontology]] |volume=30 |issue=9 |pages=761–72 |year=2003 |month=September |pmid=12956651 |doi= |url=http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0303-6979&date=2003&volume=30&issue=9&spage=761 |accessdate=2012-04-26}}</ref>
* Environmental factors lead to repeated activation of [[innate immunity]] at [[mucosal]] surfaces.
***It was found to be more common and severe in patients with RA, but did not correlate with the disease severity. The presence of [[periodontitis]] in these patients was also associated with seropositivity for [[Rheumatoid factor]], the anti-cyclic citrullinated peptide antibody (anti-CCP)and antibodies to [[Porphyromonas gingivalis]] as well. <ref name="pmid20151800">{{cite journal |author=Dissick A, Redman RS, Jones M, ''et al.'' |title=Association of periodontitis with rheumatoid arthritis: a pilot study |journal=[[Journal of Periodontology]] |volume=81 |issue=2 |pages=223–30 |year=2010 |month=February |pmid=20151800 |doi=10.1902/jop.2009.090309 |url=http://www.joponline.org/doi/abs/10.1902/jop.2009.090309?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed |accessdate=2012-04-26}}</ref> <ref name="pmid18848647">{{cite journal |author=Mikuls TR, Payne JB, Reinhardt RA, ''et al.'' |title=Antibody responses to Porphyromonas gingivalis (P. gingivalis) in subjects with rheumatoid arthritis and periodontitis |journal=[[International Immunopharmacology]] |volume=9 |issue=1 |pages=38–42 |year=2009 |month=January |pmid=18848647 |pmc=2748386 |doi=10.1016/j.intimp.2008.09.008 |url=http://linkinghub.elsevier.com/retrieve/pii/S1567-5769(08)00291-9 |accessdate=2012-04-26}}</ref>
 
*'''[[Smoking]]'''
*[[Smoking]] effects the [[genes]] to increase susceptibility up to 20 to 40 fold.
**[[Smoking]] is one of the most important independent risk factors for radiographic progression of RA. It is associated with an earlier disease onset and shared epitope HLA DRB1.<ref name="pmid22045838">{{cite journal |author=Ruiz-Esquide V, Gómez-Puerta JA, Cañete JD, ''et al.'' |title=Effects of smoking on disease activity and radiographic progression in early rheumatoid arthritis |journal=[[The Journal of Rheumatology]] |volume=38 |issue=12 |pages=2536–9 |year=2011 |month=December |pmid=22045838 |doi=10.3899/jrheum.110410 |url=http://www.jrheum.org/cgi/pmidlookup?view=long&pmid=22045838 |accessdate=2012-04-26}}</ref> <ref name="pmid20112396">{{cite journal |author=Bang SY, Lee KH, Cho SK, Lee HS, Lee KW, Bae SC |title=Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA-DRB1 shared epitope, regardless of rheumatoid factor or anti-cyclic citrullinated peptide antibody status |journal=[[Arthritis and Rheumatism]] |volume=62 |issue=2 |pages=369–77 |year=2010 |month=February |pmid=20112396 |doi=10.1002/art.27272 |url=http://dx.doi.org/10.1002/art.27272 |accessdate=2012-04-26}}</ref> However, short term cessation in smoking does not appear to alter the progression of disease activity over time.<ref name="pmid22422494">{{cite journal |author=Fisher MC, Hochberg MC, El-Taha M, Kremer JM, Peng C, Greenberg JD |title=Smoking, Smoking Cessation, and Disease Activity in a Large Cohort of Patients with Rheumatoid Arthritis |journal=[[The Journal of Rheumatology]] |volume= |issue= |pages= |year=2012 |month=March |pmid=22422494 |doi=10.3899/jrheum.110852 |url=http://www.jrheum.org/cgi/pmidlookup?view=long&pmid=22422494 |accessdate=2012-04-26}}</ref>
**[[Smoking]] causes increased expression of peptidyl arginine deiminase (PAD) in [[alveolar]] [[macrophages]].  
**Genetic variations in NAT2 appear to mediate the risk RA imposed by smoking in African American population.<ref name="pmid21989592">{{cite journal |author=Mikuls TR, Levan T, Gould KA, ''et al.'' |title=Impact of interactions of cigarette smoking with NAT2 polymorphisms on rheumatoid arthritis risk in African Americans |journal=[[Arthritis and Rheumatism]] |volume=64 |issue=3 |pages=655–64 |year=2012 |month=March |pmid=21989592 |doi=10.1002/art.33408 |url=http://dx.doi.org/10.1002/art.33408 |accessdate=2012-04-26}}</ref>
**Peptidyl arginine deiminase converts arginine to [[citrulline]],  the process is known as [[citrullination]], in the airway which further creates neoantigens that can be recognized by the adaptive [[immune system]].<ref name="pmid19479873">{{cite journal |vauthors=Lundström E, Källberg H, Alfredsson L, Klareskog L, Padyukov L |title=Gene-environment interaction between the DRB1 shared epitope and smoking in the risk of anti-citrullinated protein antibody-positive rheumatoid arthritis: all alleles are important |journal=Arthritis Rheum. |volume=60 |issue=6 |pages=1597–603 |date=June 2009 |pmid=19479873 |pmc=2732897 |doi=10.1002/art.24572 |url=}}</ref><ref name="pmid18413445">{{cite journal |vauthors=Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, Grunewald J, Skold CM, Klareskog L, Catrina AI |title=Smoking increases peptidyl arginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells |journal=Ann. Rheum. Dis. |volume=67 |issue=10 |pages=1488–92 |date=October 2008 |pmid=18413445 |doi=10.1136/ard.2007.075192 |url=}}</ref>
*'''Effects of lifestyle'''
'''Genetic factors:'''
**There is also no clear evidence that physical and emotional effects, stress and improper diet could be a trigger for the disease. The many negative findings suggest that either the trigger is different from patient to patient, or that the trigger might in fact be a chance event. <ref>Edwards JC, Cambridge G, Abrahams VM. Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology. 1999;97:188-96.</ref>
*Genetics factors such as [[human leukocyte antigen]] (HLA)-DR.
*'''Genetic associations'''
*These [[genes]] are involved in inducing [[immune response]], [[matrix]] regulation, and [[inflammation]].<ref name="pmid24072602">{{cite journal |vauthors=Bottini N, Firestein GS |title=Epigenetics in rheumatoid arthritis: a primer for rheumatologists |journal=Curr Rheumatol Rep |volume=15 |issue=11 |pages=372 |date=November 2013 |pmid=24072602 |doi=10.1007/s11926-013-0372-9 |url=}}</ref>
**The factors that allow the inflammation, once initiated, to become permanent and chronic, are much more clearly understood. The genetic association with HLA-DR4 is believed to play a major role in this, as well as the newly discovered associations with the gene PTPN22 and with two additional genes <ref>Plenge RM, Seielstad M, Padyukov L et al. TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study. N Engl J Med. 2007;357:1199-209.</ref> <ref name="pmid21752868">{{cite journal |author=Salliot C, Dawidowicz K, Lukas C, ''et al.'' |title=PTPN22 R620W genotype-phenotype correlation analysis and gene-environment interaction study in early rheumatoid arthritis: results from the ESPOIR cohort |journal=[[Rheumatology (Oxford, England)]] |volume=50 |issue=10 |pages=1802–8 |year=2011 |month=October |pmid=21752868 |doi=10.1093/rheumatology/ker224 |url=http://rheumatology.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=21752868 |accessdate=2012-04-26}}</ref>, all involved in regulating immune responses.
'''Microrganisms:'''
**It has also become clear from recent studies that these genetic factors may interact with the most clearly defined environmental risk factor for rheumatoid arthritis, namely cigarette smoking <ref>Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 2004;50:3085-92.</ref>  
*In [[periodontal disease]], P. gingivalis is commonly found, it also expresses peptidyl arginine deiminases.
*'''Hormonal factors'''
*This can lead to [[citrullination]] and thereby promotes anti-citrullinated protein antibodies (ACPA)
**Sex hormones also appear to play a role in pathophysiology of RA, partly the reason for increased incidence of RA in women.
*A. actinomycetemcomitans produces a [[toxin]] that increases [[calcium]] influx into [[neutrophils]] which further leads to [[citrullination]] of [[peptides]] and promotes APCA.
**The symptoms of RA may alleviate during the luteal phase of the [[menstrual cycle]] when the [[progesterone]] levels peak.<ref name="pmid9665348">{{cite journal |author=Case AM, Reid RL |title=Effects of the menstrual cycle on medical disorders |journal=[[Archives of Internal Medicine]] |volume=158 |issue=13 |pages=1405–12 |year=1998 |month=July |pmid=9665348 |doi= |url=http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=9665348 |accessdate=2012-04-26}}</ref>
 
**[[Pregnancy]] is associated with remission of the symptoms of RA throughout the three trimesters, whereas an increase in disease activity is noted in the first three months postpartum.<ref name="pmid1734904">{{cite journal |author=Silman A, Kay A, Brennan P |title=Timing of pregnancy in relation to the onset of rheumatoid arthritis |journal=[[Arthritis and Rheumatism]] |volume=35 |issue=2 |pages=152–5 |year=1992 |month=February |pmid=1734904 |doi= |url= |accessdate=2012-04-26}}</ref>
=== '''Pathogenesis''' ===
**[[Breast feeding]] also appears to exacerbate symptoms. As the immediate [[postnatal|postpartum]] period also imposes a risk for disease activity flare up, the exact role of breast feeding in RA is difficult to delineate.
*All the above factors lead to [[citrullination]] or [[post-translational modifications]].
*'''Occupational risks'''
*The altered [[peptides]] bind to [[MHC]] protein with shared [[epitopes]] which further leads to [[antigen]] presentation to [[T-cells]].
**[[Silicon dioxide|Silica]] and [[asbestos]] exposure have been associated with development of RA.<ref name="pmid19966090">{{cite journal |author=Stolt P, Yahya A, Bengtsson C, ''et al.'' |title=Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis |journal=[[Annals of the Rheumatic Diseases]] |volume=69 |issue=6 |pages=1072–6 |year=2010 |month=June |pmid=19966090 |doi=10.1136/ard.2009.114694 |url=http://ard.bmj.com/cgi/pmidlookup?view=long&pmid=19966090 |accessdate=2012-04-26}}</ref> <ref name="pmid15319232">{{cite journal |author=Stolt P, Källberg H, Lundberg I, Sjögren B, Klareskog L, Alfredsson L |title=Silica exposure is associated with increased risk of developing rheumatoid arthritis: results from the Swedish EIRA study |journal=[[Annals of the Rheumatic Diseases]] |volume=64 |issue=4 |pages=582–6 |year=2005 |month=April |pmid=15319232 |pmc=1755463 |doi=10.1136/ard.2004.022053 |url=http://ard.bmj.com/cgi/pmidlookup?view=long&pmid=15319232 |accessdate=2012-04-26}}</ref>
*[[T cells]] further stimulate [[B cells]] to produce a range of [[antibodies]] that recognize self-[[proteins]], including [[Rheumatoid factor|rheumatoid]] factors and anti-citrullinated protein antibodies (ACPAs).
*'''Other factors'''
*[[Fibroblast]]-like synoviocytes, antigen presenting cells (APCs), and [[macrophages]] are activated locally and produce various [[inflammatory]] factors.
**[[Obesity]] and high consumption of red meat also seems to play a role in increased disease severity.<ref name="pmid22514156">{{cite journal |author=Crowson CS, Matteson EL, Davis JM, Gabriel SE |title=Obesity fuels the upsurge in rheumatoid arthritis |journal=[[Arthritis Care & Research]] |volume= |issue= |pages= |year=2012 |month=April |pmid=22514156 |doi=10.1002/acr.21660 |url=http://dx.doi.org/10.1002/acr.21660 |accessdate=2012-04-26}}</ref> <ref name="pmid19318947">{{cite journal |author=Liao KP, Alfredsson L, Karlson EW |title=Environmental influences on risk for rheumatoid arthritis |journal=[[Current Opinion in Rheumatology]] |volume=21 |issue=3 |pages=279–83 |year=2009 |month=May |pmid=19318947 |pmc=2898190 |doi=10.1097/BOR.0b013e32832a2e16 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1040-8711&volume=21&issue=3&spage=279 |accessdate=2012-04-26}}</ref>
*The [[autoimmune]] response causes [[synovial inflammation]] resulting in [[immune complex]] formation and [[complement]] activation, leading to an increase in [[cytokine]] production and [[synovial]] [[vascular]] leakage.
**Role of [[oral contraceptive]] pills and [[vitamin D]] is found to be equivocal.<ref name="pmid19318947">{{cite journal |author=Liao KP, Alfredsson L, Karlson EW |title=Environmental influences on risk for rheumatoid arthritis |journal=[[Current Opinion in Rheumatology]] |volume=21 |issue=3 |pages=279–83 |year=2009 |month=May |pmid=19318947 |pmc=2898190 |doi=10.1097/BOR.0b013e32832a2e16 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1040-8711&volume=21&issue=3&spage=279 |accessdate=2012-04-26}}</ref>
*[[Cytokine|Cytokines]] lead to [[bone]] and [[cartilage]] destruction.
 
==Genetics==
*The development of [[rheumatoid arthritis]] is the result of [[mutation]] of [[human leukocyte antigen]] (HLA) genes on [[chromosome]] 6.<ref name="pmid9608321">{{cite journal |vauthors=Reveille JD |title=The genetic contribution to the pathogenesis of rheumatoid arthritis |journal=Curr Opin Rheumatol |volume=10 |issue=3 |pages=187–200 |date=May 1998 |pmid=9608321 |doi= |url=}}</ref><ref name="pmid21176794">{{cite journal |vauthors=Entezami P, Fox DA, Clapham PJ, Chung KC |title=Historical perspective on the etiology of rheumatoid arthritis |journal=Hand Clin |volume=27 |issue=1 |pages=1–10 |date=February 2011 |pmid=21176794 |pmc=3119866 |doi=10.1016/j.hcl.2010.09.006 |url=}}</ref>
 
==Associated Conditions==
Conditions associated with rheumatoid arthritis include:<ref name="pmid22527950">{{cite journal |vauthors=Deal C |title=Bone loss in rheumatoid arthritis: systemic, periarticular, and focal |journal=Curr Rheumatol Rep |volume=14 |issue=3 |pages=231–7 |date=June 2012 |pmid=22527950 |doi=10.1007/s11926-012-0253-7 |url=}}</ref><ref name="pmid6378209">{{cite journal |vauthors=Halla JT, Koopman WJ, Fallahi S, Oh SJ, Gay RE, Schrohenloher RE |title=Rheumatoid myositis. Clinical and histologic features and possible pathogenesis |journal=Arthritis Rheum. |volume=27 |issue=7 |pages=737–43 |date=July 1984 |pmid=6378209 |doi= |url=}}</ref>
*[[Osteopenia]]
*[[Myositis]]
*[[Vasculitis]]
*[[Uveitis]]
*[[Scleritis]]
*Peripheral [[ulcerative keratitis]]
*[[Interstitial fibrosis]]
*Pulmonary [[nodules]]
*[[Bronchiolitis obliterans]]
*Organizing [[pneumonia]]
*[[Venous thromboembolism]]
*[[Pericarditis]]
*[[Myocarditis]]
*[[Congestive heart failure]]
*[[Atrial fibrillation]]
*[[Sjogren's syndrome]]
*[[Felty's syndrome]]
 
==Gross Pathology==
On gross pathology of [[rheumatoid arthritis]] the following features may be noticed:<ref name="pmid404905">{{cite journal |vauthors=Resnick D, Niwayama G, Coutts RD |title=Subchondral cysts (geodes) in arthritic disorders: pathologic and radiographic appearance of the hip joint |journal=AJR Am J Roentgenol |volume=128 |issue=5 |pages=799–806 |date=May 1977 |pmid=404905 |doi=10.2214/ajr.128.5.799 |url=}}</ref>
*Irregular surface, seen due to [[synovial]] hyperplasia.
*Subchondral [[cysts]], usually present at the later stage of the disease.
 
==Microscopic Pathology==
On microscopic histopathological analysis:<ref name="pmid14532152">{{cite journal |vauthors=Koch AE |title=Angiogenesis as a target in rheumatoid arthritis |journal=Ann. Rheum. Dis. |volume=62 Suppl 2 |issue= |pages=ii60–7 |date=November 2003 |pmid=14532152 |pmc=1766740 |doi= |url=}}</ref><ref name="pmid9627005">{{cite journal |vauthors=Koch AE |title=Review: angiogenesis: implications for rheumatoid arthritis |journal=Arthritis Rheum. |volume=41 |issue=6 |pages=951–62 |date=June 1998 |pmid=9627005 |doi=10.1002/1529-0131(199806)41:6<951::AID-ART2>3.0.CO;2-D |url=}}</ref>
*The earliest finding is the formation of the new synovial [[blood vessel|blood vessels]].
*Hypertrophy of [[synovial]] lining layer and infiltration of [[mononuclear cells]] may be observed.
*Chronic [[inflammation]] with [[lymphocytic]] [[Infiltration (medical)|infiltration]] may be seen.
*There is [[pannus]] formation which consists of fibrovascular tissue or [[Granulation tissue|granulation]] tissue.
 
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Overview

Rheumatoid arthritis is mediated by the combination of a predisposing genotype along with which genetic factors, environmental factors, and microorganisms contribute, resulting in the inflammation and destruction of the synovial membrane. These factors lead to citrullination or post-translational modifications, resulting in the production of altered peptides. The altered peptides bind to MHC protein with shared epitopes which further leads to antigen presentation to T-cells. T-cells further stimulate B-cells and cytokines which results in cartilage damage. Mutation of human leukocyte antigen (HLA) genes on chromosome 6 is involved in pathogenesis of rheumatoid arthritis. Various conditions associated with RA include vasculitis, uveitis, scleritis, peripheral ulcerative keratitis, interstitial fibrosis, pulmonary nodules, bronchiolitis obliterans, organizing pneumonia, venous thromboembolism, pericarditis, myocarditis, congestive heart failure, atrial fibrillation, sjogren's syndrome, and felty's syndrome.

Pathophysiology

Rheumatoid arthritis is mediated by the combination of a predisposing genotype along with genetic factors, environmental factors, and microorganisms, resulting in the inflammation and destruction of the synovial membrane.

Various factors involved are:

Environmental factors:

Genetic factors:

Microrganisms:

Pathogenesis

Genetics

Associated Conditions

Conditions associated with rheumatoid arthritis include:[6][7]

Gross Pathology

On gross pathology of rheumatoid arthritis the following features may be noticed:[8]

  • Irregular surface, seen due to synovial hyperplasia.
  • Subchondral cysts, usually present at the later stage of the disease.

Microscopic Pathology

On microscopic histopathological analysis:[9][10]

References

  1. ↑ Lundström E, Källberg H, Alfredsson L, Klareskog L, Padyukov L (June 2009). "Gene-environment interaction between the DRB1 shared epitope and smoking in the risk of anti-citrullinated protein antibody-positive rheumatoid arthritis: all alleles are important". Arthritis Rheum. 60 (6): 1597–603. doi:10.1002/art.24572. PMC 2732897. PMID 19479873.
  2. ↑ Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, Grunewald J, Skold CM, Klareskog L, Catrina AI (October 2008). "Smoking increases peptidyl arginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells". Ann. Rheum. Dis. 67 (10): 1488–92. doi:10.1136/ard.2007.075192. PMID 18413445.
  3. ↑ Bottini N, Firestein GS (November 2013). "Epigenetics in rheumatoid arthritis: a primer for rheumatologists". Curr Rheumatol Rep. 15 (11): 372. doi:10.1007/s11926-013-0372-9. PMID 24072602.
  4. ↑ Reveille JD (May 1998). "The genetic contribution to the pathogenesis of rheumatoid arthritis". Curr Opin Rheumatol. 10 (3): 187–200. PMID 9608321.
  5. ↑ Entezami P, Fox DA, Clapham PJ, Chung KC (February 2011). "Historical perspective on the etiology of rheumatoid arthritis". Hand Clin. 27 (1): 1–10. doi:10.1016/j.hcl.2010.09.006. PMC 3119866. PMID 21176794.
  6. ↑ Deal C (June 2012). "Bone loss in rheumatoid arthritis: systemic, periarticular, and focal". Curr Rheumatol Rep. 14 (3): 231–7. doi:10.1007/s11926-012-0253-7. PMID 22527950.
  7. ↑ Halla JT, Koopman WJ, Fallahi S, Oh SJ, Gay RE, Schrohenloher RE (July 1984). "Rheumatoid myositis. Clinical and histologic features and possible pathogenesis". Arthritis Rheum. 27 (7): 737–43. PMID 6378209.
  8. ↑ Resnick D, Niwayama G, Coutts RD (May 1977). "Subchondral cysts (geodes) in arthritic disorders: pathologic and radiographic appearance of the hip joint". AJR Am J Roentgenol. 128 (5): 799–806. doi:10.2214/ajr.128.5.799. PMID 404905.
  9. ↑ Koch AE (November 2003). "Angiogenesis as a target in rheumatoid arthritis". Ann. Rheum. Dis. 62 Suppl 2: ii60–7. PMC 1766740. PMID 14532152.
  10. ↑ Koch AE (June 1998). "Review: angiogenesis: implications for rheumatoid arthritis". Arthritis Rheum. 41 (6): 951–62. doi:10.1002/1529-0131(199806)41:6<951::AID-ART2>3.0.CO;2-D. PMID 9627005.

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