Rheumatoid Arthritis Flashcards
What is Rheumatoid Arthritis (RA)?
= chronic, progressive autoimmune disease
= causes inflammation in joints, often symmetrical in presentation
(esp. hands, wrists and feet)
= systemic condition
= primarily located in lining of the joint
= no cure
What are the good vs bad aspects of inflammation?
Good
= pathogens
= parasites
= tumours
= wound healing
Bad
= myocardial reperfusion injury
= atherosclerosis
= ischaemic heart disease
= asthma
= septic / traumatic shock
= rheumatoid arthritis
Inflammation = essential sometimes BUT when uncontrolled has serious adverse outcomes
What are some changes seen during Inflammation in endothelial cells?
Endothelial cell activation
= exposure of endothelium to IL-1 or TNFα (pro-inflammatory cytokines)
= alters phenotype of endothelial cells
= makes them adhesive for leukocytes
= effect is dependent on protein synthesis
What are some symptoms of RA?
= simultaneous symmetrical joint swelling
= morning joint stiffness (usually lasts for more than 30-40 mins)
also:
= elevated temperature
= unexplained weight loss
= general fatigue (anaemia)
= Raynaud’s phenomenon
= nodules (lumps in skin - often in elbow)
(BUT these symptoms are very general - hard to distinguish)
How is RA diagnosed?
Based on observation of symptoms
Detection of Rheumatoid Factor (RF)
= RF is a group of autoantibodies to the Fc portion of IgG
= found in most (~80%) of RA sufferers
= BUT also found in unaffected people / people with other unrelated autoimmune conditions)
= levels of RF are roughly proportional to disease severity
X-ray
= only at later stages with there be joint erosion visible
EXTRA READING
= also sometimes MRIs
What happens in RA?
= inflammation of the synovial membrane
= untreated inflammation causes joint damage
= systemic condition
(BUT not all joints are affected - notably finger joints are involved)
What is the progression of RA?
Starts with normal knee joint (for example)
= synovial membrane
= synoviocytes
= cartilage
Early Rheumatoid Arthritis
= get capillary formation (vascularisation)
= hyperplastic synovial membrane
= hypertrophic synoviocytes (uncontrolled growth)
= neutrophils
Established Rheumatoid Arthritis
= extensive angiogenesis
= synovial vili
= plasma cell
= eroded bone
= pannus
= neutrophils
What are the end results of RA progression?
Production of cytokines and proteases
Bone destruction
= due to activation of osteoclasts (normal turnover of bone)
= BUT not balanced by osteoblast activity
Cartilage destruction
= elevated production of MMPs and ADAMTS
= OA caused by RA
Who suffers from RA?
= not as common as OA
(less than 1% of UK population)
= gender bias
(2-3x more common in women than men)
= lower prevalence in some ethnic groups
(african american, chinese, japanese)
= generally condition of older age
(age of onset usually 40-60 years old)
(BUT some younger people - 12-15K under 16)
What is the timescale of RA development?
= normally develops over several months
= BUT some cases (~20%) develop over a few weeks
= (~15%) develop over less than a week
= complications arising from RA are the cause of early death by 10-20 years
What are some risk factors of RA?
= age (in older people)
= gender (women more common)
BMI
= higher BMI increased risk of RA
Smoking
= associated with increase risk of RA
What is the Aetiology of RA?
= NOT really known (like OA)
= there are both genetic and environmental aspects
Environmental triggers
= e.g. hormones, smoking, drugs, heavy metals and physical location
Viral / bacterial infections have also been proposed
It is an autoimmune condition
= auto-antibodies are to a range of targets
= e.g. IgG and collagen type II found in cartilage
Also many autoimmune conditions that are rheumatic
= characterised by pain in joints and connective tissues
= different to RA
What is the genetic risk associated with RA?
HLA-DBR1 gene
= associated with increased risk of RA
= ~30% of genetic susceptibility
= codes for part of HLA (human leukocyte antigen) complex = involved in distinguishing self from non-self (auto-immunity)
PTPN22 polymorphism
= protein tyrosine phosphatase, non receptor type 22
= appears to be risk factor for several autoimmune diseases
(e.g. RA, T1DM, Hashimoto’s thyroiditis)
TRAF1
= linked to RA
= encodes factor which interacts with TNF receptor
(but still need an environmental trigger too?)
What are some treatment options for RA?
= 70% of patients likely to improve in first 1-2 years of condition (still NOT a cure)
NSAIDs
= non-steroidal anti-inflammatory drugs
= manage condition
SADMD
= slow acting disease-modifying drugs
= e.g. Gold, hydroxychloroquine, sulfasalazine and penicillaemine
Immunosuppression
= e.g. Methotrexate
= long term use does help but significant side effects
(e.g. liver disease, suppression of bone marrow function, malignancy)
Corticosteroids
= short term relief from symptoms = pain
= potent anti-inflammatory drugs
= BUT effectiveness falls away in time
= can be VERY severe reaction to cessation (become physiologically addicted)
anti-TNF therapy
= regular injections - expensive
= very effective
= e.g. Entanercept - TNF receptor linked to Fc to human IgG (to solubilise)
= e.g. Infliximab - Chimeric monoclonal antibody against TNF alpha
= e.g. Adalimumab - Human monoclonal antibody against TNF alpha
= e.g. Certolizumab pegol - Fab fragment of a human monoclonal antibody against TNF alpha with polyethaleneglycol attached
= e.g. Golimumab - Human monoclonal antibody against TNF alpha
EXTRA READING? Possible involvement of Gut Microbiome?
Precision Medicine
= using patient’s genetics to find most effective treatment
Gut microbiome
= may play role in RA development
= could use probiotics to alter gut microbiome
= people with RA = have fewer beneficial bacteria (e.g. Bifidobacteria and Lactobacilli)
= and may have more potentially harmful bacteria (e.g. Prevotella and Prophyromonas)
= may promote inflammation and immune system dysfunction
= and some bacteria have anti-inflammatory effects - would help treat RA
