genetics of rheumatoid arthritis Flashcards
rheumatoid arthritis
chronic, progressive autoimmune disease in which mormal immune response is directed against an individuals own tissue
including joints, tendons and bones, resulting in inflammation and destruction of these tissues
cause is unknown but usually detected when someone has a lot of joint pain
strong genetic susceptibility - based on pedigree analysis, twin studies etc
prevalence
~1% european + most other populations
~5-7% american indians
prevelence and incidence 2-3 times greater in women than men
increases with age
26,000 new diagnoses per year
autoimmune response
RA causes by inflammatory cascades, lead to persistant synovial inflammation and associated damage to articular cartilage and underlying bone
abnromal interactions between T and B lymphocytes, synovial like fibroblasts and macrophages
leads to overproduction of cytokines such as tumor necrosis factor alpha (TNF-a) + interleukins
T cells and B cells trigger production of autoantibodies- rhemuatoid factors (RF) and anti citrulinnated protein antibidies (ACPA)
autoantibodies go against the body
50-80% of individuals with RA have rheumatoid factor, ACPA or both diagnostic markers
to
RA pathophysiology
function of normal synovium:
- maintenence of intact non adherent tissue surface
- lubrication of cartilage
- nutrition of chondrocytes within joints
joint affected by RA
- inflammatory cell infiltration: T cell, B cell, macrophages and plasma cells
- production of cytokines and proteases
- increased vascularity
- excess synovial fluid production
- swollen joint capsule
- cartilage loss
mechanisms of structural damage
TNF is a central cytokine in the inflammatory cascade, affecting the levels of
other proinflammatory and anti-inflammatory cytokines
- TNF triggers production of a number of other cytokines, including IL-1, IL-6 and IL-8.2,3
- Different cell types and cytokine pathways are believed to be involved in the joint destruction mediated by TNFα and IL-1.3
- these cytokines are stimulators which release matrix metalloproteinases (tissue destroying enzymes)
stages of RA
- thickening of synovial membrane causing inflammation
- cartilage loss
- bones join together over time meaning joint loses function
cytokine disequilbrium in the disease process of RA
more proinflammatory than antiinflammatory, causing the inflammation in the joint
is normally balanced in joints
TNF
pro inflammatory cytokine
helps drive inflammatory cascade- triggers production of other cytokines
causes inflammation, cartilage breakdown and bone reabsorption and erosions
elevated levels cause problems by driving inflammatory response and various types of joint damage
activates monocytes/ macrophages- inflammation
activates chondrocytes - cartilage breakdown
activates osteoclasts (suppresses osteoblasts)- bone reabsorption and erosion
signs and symptoms
joint stiffness
reduced ROM- loss of joint function and muscle pain
starts in smaller joints then spreads to larger joimts
formation of firm lumps called rheumatoid nodes
systemic inflammation may involved other organs, vessels, eyes, blood and lungs
RA diagnosis
radiograph of involved joints
CT/MRI scans
direct athroscopy
synovial membrane biopsy
blood tests- RF, ACPA and C reactive protein
progressive chronic disease
chronic inflammation can lead to joint destruction
muscle weakness and atrophy develop early in the course in many people
progression of disease results in reducible and later fixed deformities
progression
- daily living activities are impaired
- after 5 years- 33% cant work, after 10 years- 50% have substantial functional disability
genetics of RA
~50% genetic contribution + environmental factors (smoking and infection) implicated in disease susceptibility
twin studies- MZ twins 12-15% , DZ twins-5% concordance
many genes involved in pathogenesis- polygenic but contribution is limited
a certain genotype predisposes individual to disease but development of disease isnt a certainty
genetic variation in human leukocyte antigen (HLA) accounts for ~30% of variance in RA susceptibility
other genes like protein tyrosine phosphatase, non receptor (PTPN22), vitamin D receptor and peptidyl arginine deiminases increase suseceptibiltiy
candidate gene associations
associations of genes differs between ethnicities of groups
gene A2M, GST1 - association found in caucasian and asian patients
GWAS
hypothesis free study
common polymorphism is PTPN22 which confers susceptibility to multiple autoummune diseases- including RA, lupus, T1 diabetes + hashmitos thyroiditis
genetic associations with radiological damage in RA- SNPs and radiological progression
RA treatment
resistamce and endurance exercise can help individuals suffering from disease
1. non steroid anti inflammatory drugs (NSAIDs)- treatment of symptoms, lessen pain and stiffness
2. disease modifying anti rheumatic drugs (DMARDs)- diverse mechanisms of actions, reduce joint swelling and pain, limit progressive joint damage and improve joint damage
3. glucocorticoids- reduce inflammation of synovium, can decrease damage but have adverse risks
4. biological agents- selective TNF inhibitors, reduction in underlying inflammation, highly effective
treatments explained
different variations have different SNPs, genes and markers so different medicines will work for different individuals
risk genes have been identified and have corresponding drug target genes - providing successful therapies
control of environmental factors eg physical activity, smoking and nutrition can improve quality of life
