Rheumatoid Arthritis Flashcards
What are the functions of the synovium?
- maintenance of intact tissue surface
- lubrication of cartilage
- nutrition of chondrocytes within joints
- control of synovial fluid volume and composition (hyaluronan, lubricin)
Define Rheumatoid Arthritis
a chronic, symmetrical, polyatricular inflammatory joint disease primarily affecting small joints of hands and feet
What are characteristics of Rheumatoid Arthritis?
Inflammatory cell infiltration, synoviocytes, proliferation and neoangiogenesis
Synovial fluid in joint cavity contains neutrophils especially during acute flares
Synovial pannus causes bone and cartilage destruction
What is pannus?
An abnormal layer of fibrovascular tissue or granulation tissue
What evidence can sometimes be found of autoimmunity in Rheumatoid Arthritis (even before onset)?
Autoantibodies i.e. RFs and anti-citrullinated protein antibodies
Autoantibodies can recognise joint antigens (i.e. type II collagen) or systemic antigens (i.e. glucose phospahte isomerase)
Describe seropositive RA
Most common
Blood tests positive for antibodies hypothesised to cause RA
- Rheumatoid factor
- Anti-citrullinated protein antibody (ACPA)
- Diagnostic anti-Cyclic Citrullinated Peptide assays recognise citrullinated self-proteins
Patients with ACPA+ disease have less favourable prognosis
What does citrullinated mean?
A protein in which AA arginine has been converted to the AA citrulline
Enzymes called peptidylarginine deaminases replace the ketimine group (=NH) with a ketone group (=O)
The immune system recognises these causing autoimmune response
What is rheumatoid factor?
An auto antibody to self IgG Fc
What infectious agents have been associated with RA?
- Viruses i.e. EBV, CMV
- E. Coli
- Mycoplasma
- Periodontal disease (porphyromonas gingivalis)
- Microbiome (gut microbes)
What is synovitis?
Medical term for inflammation of synovial membrane
Describe the pathogenesis of synovitis in RA
Villous hyperplasia
Infiltration of T cells, B cells, macrophages and plasma cells
Intimal cell proliferation (fibroblasts)
Production of cytokines and proteases
Increased vascularity
Self-amplifying process
Describe the roll of inflammatory cytokines in RA
Induce expression endothelial cells adhesion molecules
Activate synovial fibroblasts, chondrocytes, osteoclasts
Promote angiogenesis
Suppress T-regs
Activate leukocytes
Promote autoAb production
Describe neoangiogenesis in RA
Provides nutrients to hyperplastic synovium
Hypoxic conditions and angiogenic factors such as IL-8 and VEGF enhance blood vessel proliferation in the synovium
MIcrovascular endothelia in synovium express adhesion molecules that guide circulating cells into joint under the influence of hemoattractants
Describe cartilage and bone destruction in RA
Distinct mechanisms and cell types regualte this process
Several classes of proteases are produced by FLS in intimal lining layer
Synovial lining cells, especially FLS can attach to and invade cartilage in RA
Bone destruction is mediated by osteoclasts activated under influence of RANKL produced by RA synovium
What is RANKL?
Receptor activator of nuclear factor kappa-B
AKA
osteoclast differentiation factor
Systemic consequences of RA
Vasculitis, nodules, scleritis, amyloidosis
CVD; altered lipid metabolism, elevated acute-phase reactants, increased endothelial activation
Fatigue and reduced cognitive function
Liver; elevate acute-phase response, anaemia/chronic disease
Lungs, muscles, bone (osteoporosis), secondary Sjogren’s syndrome
What is Sjogren’s syndrome?
A condition affecting the parts of the body that produce fluid or fluid-like substances i.e. tear ducts, salivary glands
Symptoms include dry eyes, dry mouth etc.
What are the therapeutic categories for Rheumatoid Arthritis?
1) NSAIDs
2) Disease Modifying anti-Rheumatic Drugs (DMARD)
3) Biologics
4) Corticosteroids (oral, IM, IA)
What are DMARDs?
Disease Modifying Anti-Rheumatic Drugs
A group of structurally unrelated, small molecule drugs which have been demonstrated to have slow onset effect on disease activity and inhibit disease progression
Traditionally assoc. with identifiable toxicity profiles and risk occasional serious adverse event
What are some DMARD drugs?
Methotrexate; effective, well tolerated, cheap
Sulfasalazine
Hydroxychloroquinine
Leflunomide
What are biologic DMARDs?
Drugs which have been developed from understanding inflammatory cascade to target key parts
Typically large complex proteins which need to be given parenterally
Compared to traditional DMARDs they work rapidly, are well tolerated and have high cost
- TNFalpha inhibitors
- IL-1 inhibitors
- anti cell b therapies
- anti cell c therapies
- IL-6 inhibitors
What are some issues with biologic DMARDs?
Efficacy; enhanced response when co-prescribed
TOxicity; minor eg injection site reaction, infection
Cost; expensive compared to non-biologic DMARD
Describe the use of corticosteroids in RA
Can be oral, IA or IM injection and by IV infusion
Short term benefit v long term toxicity
Rarely appropriate as single drug therapy
Describe seronegative RA
Where blood work shows no signs
