Pathophysiology of RA / Flashcards
What is rheumatoid arthritis?
Systemic autoimmune disease that is characterised by chronic inflammation of the synovial joints
Affects multiple small joints
What does RA lead to?
Leads to progressive destruction of the synovial joints through loss of cartilage and bone
Loss in function and disability, comorbidities and reduced QoL, shortened lifespan
What is the incidence and prevalence of RA?
430,000 adults have RA
20,000 new cases diagnosed every year
Who is most likely to have RA, and when is usual onset?
More common in women than men 3:1
Onset often in seen between 30 and 50, but can develop at any age
What is the structure of a synovial joint?
Bone capped with articular cartilage
Synoviocytes around the joint sealing in synovial fluid around the joint
Synovium surrounds the synoviocytes
Joint capsule over the top of this
What is a healthy synovium like?
Synovium is a CT between the joint capsule and and the joint space - lines all joint surface excluding cartilage
Thin layer facing joint space 1-2 cells thick - macrophage-like synovial cells (type 1/A) & fibroblasts-like synovial cells (type 2/B)
Synovial sublining is loose CT with numerous blood and lymphatic vessels, nerves and scattered macrophages and fibroblasts
What is the synovium like in RA?
Lining layer beomes thickened - 6-8 cells thick:
- increased synovial cell proliferation (hyperplasia)
- increased synovial cell size (hypertrophy)
Extensive infiltration of the underlying sublining of synovium by macrophages by macrophages and lymphocytes and plasma cells
What are the general stages of RA development?
Infiltration of synovium by inflammatory cells and proliferation of synovial cells
Increase in blood vessel formation
Increased chemokine production and upregulation of adhesion molecules expression on vascular endothelium
Cytokine production initiates matrix metalloproteinases - MMPs - release leading to degradation of matrix
Pannus formation
How does inflammation start in RA?
Unknown trigger begins initial inflammation of synovial tissue
Infiltration of synovium by inflammatory cells and proliferation of synovial cells
> Trafficking of leukocytes out of blood vessels by leukocyte extravasation
> Which is a response to inflammatory signals produced within synovial tissue - promotes change in adhesiveness of endothelial cells lining the blood vessels
> Leukocytes recruited inc: neutrophils, monocytes, mast cells, T cells, B cells - occurs in 4 stages
What are the 4 steps of leukocyte extravasation?
- Rolling adhesion mediated by E-selectin and its ligand the sialyl-Lewis X; TNF-a activates vascular endothelium
- Tight binding: CXCL8, bound to proteoglycan on surface of endothelium, binds to CXCR8 on leukocyte; LFA interacts with ICAM-1
- Diapedesis (crossing endothelial wall) orchestrated by PECAM (CD31)
- Migration to the tissue along a concentration gradient of chemokines
What happens after initial inflammation of the synovial tissue in RA development?
Increase in blood vessel formation
- Synovial hypoxia in a consequence of the hyperproliferative synovium with increased consumption of oxygen in RA x20 and reduced BF
- Response to hypoxia and increased metabolic demands of synovial tissue activate hypoxia-inducible factor (HIF), leading to the release of pro-angiogenic factors
- Pro-inflammatory cytokines (TNF-a and IL-1B) within RA joint are angiogenic
> Increased angiogenesis in RA
What occurs after angiogenesis in the development of RA?
Increased chemokine production and upregulation of adhesion molecules expression on vascular endothelium
- CXCL8 (IL-8), CXCL5 and CXCL1 are important in RA. Abundant in synovial tissue, synovial fluid and blood. produced by macrophages
- With TNF-a activation of vascular endothelium; E-selectin and ICAM expression upregulated > increased leukocyte recruitment from circulation into RA synovium
- CCL2 (MCP-1) potent chemoattractant for monocytes via CCR2
CCL3 (MIP-1a) recruits monocytes, lymphocytes, basophils and eosinophils via CCR1,5
- CCL5 (RANTES) recruitment of myphocytes and monocytes via CCR1, 3 and 5
What is the stage after increased chemokine production in RA development?
Cytokine production initiates MMPs release leading to degradation of matrix
Major cytokines incl. TNF-a and IL-1B produced mainly by macrophages, as well as T cells, B cells and synovial fibroblasts
TNF-a & IL-1B:
- induce MMP production by chondrocytes
- activate osteoclasts
- increase in adhesion molecule expression on endothelium
What is the stage after MMP release from cytokines production in RA development?
Pannus formation
Hyperproliferative, inflammatory invasive vascularised tissue mass that is a hallmark feature of the joint in RA
- Consists of macrophage-like & fibroblast-like synovial cells in the synovial tissue an dthe large number of infiltrating leukocytes (CD4+ T lymphocytes, B cells, plasma cells and dendritic cells)
Develops from the normal synovium & invades cartilage and bone
Fibroblast-like synovial cells and activated chondrocytes produce MMPs, ADAMTS, pro-inflammatory cytokines and prostaglandins leading to cartilage degradation
Fibroblast-like synovial cells and T-lymphocytes secrete RANKL which activates osteoclasts to destroy bone
What cell types are involved in RA?
T cells
B cells and plasma cells
Macrophages
Dendritic cells
Endothelial cells
Fibroblasts
Osteoclasts
Chondrocytes
Mast cells
Neutrophils
