Rheumatoid arthritis pathophysiology: Difference between revisions
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===Pathogenesis=== | ===Pathogenesis=== | ||
[[Rheumatoid arthritis]] is mediated by the combination of a predisposing genotype upon which genetic factors, environmental and microorganism also contribute resulting in the inflammation and destruction of the synovial membrane. | [[Rheumatoid arthritis]] is mediated by the combination of a predisposing [[genotype]] upon which [[genetic]] factors, [[Environmental Lung Diseases|environmental]] and [[Microorganisms|microorganism]] also contribute resulting in the [[inflammation]] and destruction of the [[synovial membrane]]. | ||
'''Various factors involved are''' | |||
'''Environmental factors''': It causes repeated activation of innate immunity at mucosal surfaces. | '''Various factors involved are''': | ||
*Smoking interacts with genes to increase susceptibility up to 20 | |||
**Smoking causes increased expression of peptidyl arginine deiminase (PAD) in alveolar macrophages. | '''Environmental factors''': | ||
**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> | * It causes repeated activation of [[innate immunity]] at [[mucosal]] surfaces. | ||
*[[Smoking]] interacts with [[genes]] to increase susceptibility up to 20 to 40 fold. | |||
**[[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> | |||
'''Microrganism:''' | '''Microrganism:''' | ||
*In periodontal disease, P. gingivalis is commonly found, it also expresses peptidyl arginine deiminases. | *In [[periodontal disease]], P. gingivalis is commonly found, it also expresses peptidyl arginine deiminases. | ||
*This can lead to citrullination and thereby promote ACPA. | *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. | *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 like class II [[major histocompatibility complex]] (MHC), most common [[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 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> | ||
'''Immunologic response''' | '''Immunologic response''' | ||
*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. | *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]]. | ||
*T cells further stimulate B cells to produce a range of antibodies that recognize self-proteins, including Rheumatoid factors and ACPAs (targeting citrullinated proteins). | *[[T cells]] further stimulate [[B cells]] to produce a range of [[antibodies]] that recognize self-[[proteins]], including [[Rheumatoid factor|rheumatoid]] factors and ACPAs (targeting citrullinated proteins). | ||
*Fibroblast-like synoviocytes, APCs, and macrophages are activated locally and produce various inflammatory factors. | *[[Fibroblast]]-like synoviocytes, APCs, and [[macrophages]] are activated locally and produce various [[inflammatory]] factors. | ||
*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. | *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. | *[[Cytokine]] leads to [[bone]] and [[cartilage]] destruction. | ||
==Genetics== | ==Genetics== | ||
*The development of [[rheumatoid arthritis]] is the result of mutation of human leukocyte antigen (HLA) genes | *The development of [[rheumatoid arthritis]] is the result of [[mutation]] of [[human leukocyte antigen]] (HLA) genes on [[chromosome]] 6. | ||
==Associated Conditions== | ==Associated Conditions== | ||
Conditions associated with rheumatoid arthritis are: | Conditions associated with rheumatoid arthritis are: | ||
*Osteopenia<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> | *[[Osteopenia]]<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> | ||
*Myositis<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> | *[[Myositis]]<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> | ||
*Vasculitis | *[[Vasculitis]] | ||
*Uveitis | *[[Uveitis]] | ||
*Scleritis | *[[Scleritis]] | ||
*Peripheral ulcerative keratitis | *Peripheral [[ulcerative keratitis]] | ||
*Interstitial fibrosis | *[[Interstitial fibrosis]] | ||
*Pulmonary nodules | *Pulmonary [[nodules]] | ||
*Bronchiolitis obliterans | *[[Bronchiolitis obliterans]] | ||
*Organizing pneumonia | *Organizing [[pneumonia]] | ||
*Venous thromboembolism | *[[Venous thromboembolism]] | ||
*Pericarditis | *[[Pericarditis]] | ||
*Myocarditis | *[[Myocarditis]] | ||
*Congestive heart failure | *[[Congestive heart failure]] | ||
*Atrial fibrillation | *[[Atrial fibrillation]] | ||
*Sjogren's syndrome | *[[Sjogren'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]]:<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> | ||
*The irregular surface is 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:<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 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 findings is the formation of the new synovial blood vessel. | *The earliest findings is the formation of the new synovial [[blood vessel]]. | ||
*There is hypertrophy of synovial lining layer and infiltration of mononuclear cells. | *There is hypertrophy of [[synovial]] lining layer and infiltration of [[mononuclear cells]]. | ||
*Chronic inflammation with lymphocytic infiltration. | *Chronic [[inflammation]] with [[lymphocytic]] [[Infiltration (medical)|infiltration]]. | ||
*There is pannus formation which is made up of fibrovascular tissue or granulation tissue. | *There is [[pannus]] formation which is made up of fibrovascular tissue or [[Granulation tissue|granulation]] tissue. | ||
==References== | ==References== | ||
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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
Pathophysiology
Pathogenesis
Rheumatoid arthritis is mediated by the combination of a predisposing genotype upon which genetic factors, environmental and microorganism also contribute resulting in the inflammation and destruction of the synovial membrane.
Various factors involved are:
Environmental factors:
- It causes repeated activation of innate immunity at mucosal surfaces.
- Smoking interacts with genes to increase susceptibility up to 20 to 40 fold.
- 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.[1][2]
Microrganism:
- In periodontal disease, P. gingivalis is commonly found, it also expresses peptidyl arginine deiminases.
- 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:
- Genetics factors like class II major histocompatibility complex (MHC), most common human leukocyte antigen (HLA)-DR.
- These genes are involved in implicating immune response, matrix regulation, and inflammation.[3]
Immunologic response
- 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.
- T cells further stimulate B cells to produce a range of antibodies that recognize self-proteins, including rheumatoid factors and ACPAs (targeting citrullinated proteins).
- Fibroblast-like synoviocytes, APCs, and macrophages are activated locally and produce various inflammatory factors.
- 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.
Genetics
- The development of rheumatoid arthritis is the result of mutation of human leukocyte antigen (HLA) genes on chromosome 6.
Associated Conditions
Conditions associated with rheumatoid arthritis are:
- Osteopenia[4]
- Myositis[5]
- 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
Gross Pathology
On gross pathology of rheumatoid arthritis:[6]
- The irregular surface is due to synovial hyperplasia.
- Subchondral cysts usually present at the later stage of the disease.
Microscopic Pathology
On microscopic histopathological analysis:[7][8]
- The earliest findings is the formation of the new synovial blood vessel.
- There is hypertrophy of synovial lining layer and infiltration of mononuclear cells.
- Chronic inflammation with lymphocytic infiltration.
- There is pannus formation which is made up of fibrovascular tissue or granulation tissue.
References
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Koch AE (November 2003). "Angiogenesis as a target in rheumatoid arthritis". Ann. Rheum. Dis. 62 Suppl 2: ii60–7. PMC 1766740. PMID 14532152.
- ↑ 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.