Rheumatoid arthritis pathophysiology
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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.