Rheumatoid arthritis pathophysiology: Difference between revisions

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==Overview==
==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==
[[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]].


===Pathogenesis===
'''Various factors involved are''':
[[Rheumatoid arthritis]] is mediated by the combination of a predisposing genotype upon which genetic factors, environmental and microorganism also contribute resulting in the inflammatory and destruction of the synovial membrane.


'''Environmental factors''': It causes repeated activation of innate immunity at mucosal surfaces.
'''Environmental factors''':  
*Smoking interacts with genes to increase susceptibility up to 20- to 40-fold.
* Environmental factors lead to repeated activation of [[innate immunity]] at [[mucosal]] surfaces.
**Smoking causes increased expression of peptidyl arginine deiminase (PAD) in alveolar macrophages.  
 
**Peptidyl arginine deiminase convert arginine to citrulline called 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>
*[[Smoking]] effects the [[genes]] to increase susceptibility up to 20 to 40 fold.
'''Microrganism:'''
**[[Smoking]] causes increased expression of peptidyl arginine deiminase (PAD) in [[alveolar]] [[macrophages]].  
*In periodontal disease, P. gingivalis is commonly found, it also expresses peptidyl arginine deiminases.
**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>
*This can lead to citrullination and thereby promote ACPA.
*A. actinomycetemcomitans produces a toxin that increases calcium influx into neutrophils which further lead to citrullination of peptides and promote APCA.
'''Genetic factors:'''  
'''Genetic factors:'''  
*Genetics factors like class II major histocompatibility complex (MHC), most common human leukocyte antigen (HLA)-DR.
*Genetics factors such as [[human leukocyte antigen]] (HLA)-DR.
*These genes are involved in implicating 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>
*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>
'''Immunologic response'''
'''Microrganisms:'''
*All the above factors lead to citrullination or post-translational modifications, the altered peptides bind to MHC protein with shared epitopes which further lead to antigen presentation to T-cells.
*In [[periodontal disease]], P. gingivalis is commonly found, it also expresses peptidyl arginine deiminases.
*T cells further stimulate B cells to produce a range of antibodies that recognize self-proteins, including Rheumatoid factors and ACPAs (targeting citrullinated proteins).
*This can lead to [[citrullination]] and thereby promotes anti-citrullinated protein antibodies (ACPA)
*Fibroblast-like synoviocytes, APCs, and macrophages are activated locally and produce various inflammatory factors.
*A. actinomycetemcomitans produces a [[toxin]] that increases [[calcium]] influx into [[neutrophils]] which further leads to [[citrullination]] of [[peptides]] and promotes APCA.
*The autoimmune response causes synovial inflammation and there is the formation of an immune complex formation and complement activation, leading to an increase in cytokine production and synovial vascular leakage.
 
*Cytokine leads to bone and cartilage destruction.
=== '''Pathogenesis''' ===
*All the above factors lead to [[citrullination]] or [[post-translational modifications]].
*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]] to produce a range of [[antibodies]] that recognize self-[[proteins]], including [[Rheumatoid factor|rheumatoid]] factors and anti-citrullinated protein antibodies (ACPAs).
*[[Fibroblast]]-like synoviocytes, antigen presenting cells (APCs), and [[macrophages]] are activated locally and produce various [[inflammatory]] factors.
*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.
*[[Cytokine|Cytokines]] lead to [[bone]] and [[cartilage]] destruction.


==Genetics==
==Genetics==
*[Disease name] is transmitted in [mode of genetic transmission] pattern.
*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>
*Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
*The development of [disease name] is the result of multiple genetic mutations.


==Associated Conditions==
==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==
==Gross Pathology==
On gross pathology of rheumatoid arthritis:<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>
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>
*Pannus formation which is made up of fibrovascular tissue or granulation tissue.
*Irregular surface, seen due to [[synovial]] hyperplasia.
*The irregular surface is due to synovial hyperplasia.
*Subchondral [[cysts]], usually present at the later stage of the disease.
*Subchondral cysts usually present at the later stage of the disease.


==Microscopic Pathology==
==Microscopic Pathology==
*On microscopic histopathological analysis:
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>
**On the earliest findings is the formation of the new synovial blood vessel.
*The earliest finding is the formation of the new synovial [[blood vessel|blood vessels]].
**In response to TNF cytokines are produced.
*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==

Latest revision as of 19:54, 23 April 2018

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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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