Rheumatoid arthritis Flashcards
Describe the structure of the normal synovium
It is a connective tissue made of 2 layers which lies between the joint space and joint capsule
Lining layer: Delicate CT facing joint space which is populated by macrophage like Type1/a synoviocytes and fibroblast like Type 2/b synoviocytes
Sublining: Loose CT with neurovasculature populated with macrophages and fibroblasts.
Describe the RA synovium
Angiogenesis and fibrosis - highly vascularised tissue
Hypetrophy of lining layer becomes 6-8 cells thick
Infiltration of tissue with inflammatory cells
Neutrophil extravasation
Joint swelling and distension
Increased chemokine production + upregulation of adhesion molecules on vascular endothelium
Pannus formation - almost metastatic like inflammation in end stage untreated disease
Describe the inflammation in RA
Unknown inflammatory trigger
Inflammatory cells infiltrate the synovium and proliferate, there is leukocyte extravasation mediated by chemotaxis
Inflammatory mediators make cells become more permeable and leaky
Describe leukocyte extravasation
Margination + rolling
E selectin is secreted on the inside of the blood vessel walls which initiates rolling adhesion
Tight binding of leukocytes to CXCL8 on endothelium
Diapedesis : Leukocytes cross and penetrate endothelium mediated by PECAM
Leukocytes migrate out vessel and to areas of inflammation via chemotaxis
How does angiogenesis occur in RA?
= growth of new blood vessels from the host vasculature
- Triggered by hypoxia
- As the synovium becomes hypertrophied + hyper proliferates and grows it requires more O2 to sustain itself it hence becomes hypoxic
- Hyoxia and increased metabolic demand/nutrient demand induces release of HIF which release pro angiogenic factors
Increased chemokine/cytokine production ?
What is the role of TNFalpha?
Up regulation of adhesion molecules on vascular endothelium for rolling adhesion so more leukocyte recruitment
Increased cytokines activates MMPS to degrade matrix + cartilage
TNFalpha - activates vascular endothelium + MMPs, activate bone degradation by osteoclasts
What secretes RANKL?
What is the importance of RANKL?
Fibroblasts
Activates osteoclasts to degrade the bone
What is pannus formation?
Hallmark of chronic RA inflammation, hypertrophied synovium, infiltration of immune cells, vascularised angiogenesis, increased cytokine/chemokines
Metastatic and invasive like process
What is the function of RF?
Clears immune complexes + uptake by B cells
lower specificity
IgM
What are anti CCP antibodies ?
When may citrulline be produced?
90-95% specificity
They are auto antibodies in response to cyclic citrullinated peptides present in keratin, collagen, cartilage, fibrin.
Can be produced in post translational modification when enzyme PAD1 converts arginine -> citrulline
Which HLA allele is associated with RA and what does it encode for?
Where is the shared epitope located?
HLA-DRB1 gene and the DRB1 allele which encodes for the shared epitope
Shared epitope is common to many auto immune disorders
It is common to all HLA-DRB1 alleles
Shared epitope is located in variable region of B1 domain in the cleft of MHCII. Variability in the cleft causes different antigen binding and altered contact strength between antigens and its receptor
What are the typical features of RA?
What can predict RA?
- Symmetrical involvement
- Systemic effects
- Joint swelling, deformity and lack of function
- Better on exercise worse on rest
- Inflammatory - trigger unknown
- MCP + MTP joints
- Early morning stiffness
Family history and prior illness
What are some systemic effects of RA?
- Chest X ray: Sarcoidosis
- Eye disease
- Weight loss
- Skin rashes
- Psoriasis
- Lupus
- Raynauds - loss of vasodilatory NO
What are some clinical features of RA joints?
Pain, swelling and tenderness especially the MCP, MTP joints
Functional impairments: Reduced grip strength, inability to make a fist, incomplete elbow extension
What diagnostic tests can aid RA diagnosis?
Liver function tests
Blood tests
Doppler ultrasounds - vascularised synovium
Ultrasound - synovitis, flexor tenosynovitis, erosions
X rays: Chest + hands/feet to observe erosion
Thyroid + glucose tests - prescribing medication
Urate - gout
Autoantibodies: RF, anti-ccp, anti nuclear antibody ( lupus)
CRP + ESR: Inflammatory markers
