Rheumatoid Arthritis Flashcards
Causes of MSK pain?
Joint
Bone
Soft tissue
referred from central region
Two types of RA
1) Degenerative -> OA, degen of the articular cartilage
2) Inflammatory -> RA, degeneration of synovium
Causes of rheumatic disorder?
- Rheumatic disorder broken down into:
- Degenerative -> OA
- Inflammatory -> broken down into INFECTIVE, Crystal, AUTOIMMUNE
- Infective:
- septic arthritis -> streptococcal infection
- post infective arthritis -> no joint sepsis, but arthritis post another infection e.g. STD/ enteric fever (Rheumatic fever)
- viral arthralgia (arthralgia = joint pain) e.g. HEP B/C
- Crystal –> GOUT
- Autoimmune:
- RA
- SLE
- Sjogrens (Connective tissue disease)
- Spondyloarthritis -> affects spine and joints
Synovial joint structure outline
layers of synovium
Role of synovium
Ends of bone covered in layer of hyaline cartilage,
surrounded by outer fibrous membrane forming joint capsule
inner layer of joint capsule formed of synovial membrane (formed of normally of only 1 layer of synoviocytes, no more than 4.)
Synovium secretes synovial fluid: –> lubricates the joint, nourishes the joint by providing medium for nutrient exchange
how do autoantibody levels change through o life?
Increasing levels of autoantibodies detected in healthy people as we age, thought to be due to increasing exposure to infections.
What are the main biological theories of the development of autoimmune disease?
- Failure of T cell central tolerance –> during development immature T lymphocytes in the thymus are exposed to self antigen, those that react are deleted via CLONAL DELETION. Theory that some that react to self antigen weakly are able to leave the thymus –> autoimmune disease.
- Failure of B cell central tolerance –>B cells mature in the bone marrow, if reactive to self antigen they are ANERGISED. Anergy means the cells become unable to mount an immune response, unreactive to the antigen.
- Defect of regulatory T cells –> normally regulatory T cells able to suppress self reactive B/ T lymphocytes
- Polyclonal activation of B cells during infection –> single antigen attacked via multiple B cells synthesising multiple AB’s for the different epitopes on that antigen.
- Linked to Molecular mimicry –> where the pathogenic antigen is similar to a self antigen, leading to production of autoantibody.
- Exposure of immune protected sites -> E.g. in the testes, normally sheilded from immune system -> antisperm AB’s.
What factors make someone susceptible to autoimmune disease?
Genetic susceptibility –>
evidence from the fact that autoimmune disorders tends to run in families.
development of one AutoI disease makes another more likely.
- Female ->
autoimmune disease more likely in women during reproductive cyclic pattern, linked to hormonal cycle.
Cases with hormonal induced sex change and autoimmune disease development
What group of genes are involved in autoimmune disease?
What gene is involved in RA?
What gene is involved in ankylosing spondylolitis?
- HLA genes encode the MHC complexes on chromosome 6
- HLA A/B/C –> MHC class 1 receptor (ubiquitous, present self antigen, activate natural killer cells when absent self antigen.)
- HLA DP/ DQ/ DR –> MHC class 2 receptor (expressed by APC, involved in adaptive response by activating T helper cells which will in turn activate B cells to synthesise AB and T cytotoxic cells.)
- multiple alleles exist for each gene
- RA –> HLA DR1 AND DR4 (also T1DM)
- Ankylosing spondylolitis -> HLA B27
What are rheumatoid factors?
When are they present in what diseases?
When is it tested for?
- Rheumatoid factor = ultimate antibody, is an ANTIBODY against an ANTIBODY.
- RF = IgM against Fc portion of IgG.
- Thought to line vessels at high blood flow regions, therefore more likely to react to circulating antibody.
- RF test 70% positive for RA
- But also in infection/ other rheumatoid diseases and false positives with increasing age
- therefore do not test unless RA strongly suspected.
What are the top 3 autoimmune diseases?
who is affected most?
Top 3 -> Graves, RA, Hashimotos Thyroiditis
Affects women more than men
In RA 2/3 women, 1/3 men.
Key features of RA clinical history?
(differentiates it from OA)
- Onset is usually 20-50 years
- more common in females (F : M 3 : 1)
- develops within weeks - months
-
Symptoms
- 3 S’s –> joint Stiffness, swelling and when Squeezed -> PAIN. (inflammatory signs present.)
- morning stiffness lasting more than an hour
- generalised SX of weight loss, fatigue, anaemia
- low grade fever
- usually symmetrical affecting primarily small joints hands and feet, or larger joints like elbow.
- Often proximal IP joints of hands and MTP joints of feet
- RF commonly present.
- PLUS –> Fam Hx and Smoking = RISK Factor.
Examination features of RA? ( features of the hands)
- Early on –> FUSIFORM swelling –> swelling of dorsum and PIPs of the hands, asymptomatic
- MCP subluxation –> malalignment of the MCP joints
- Ulnar deviation –> MCP joint swelling causes deviation of the fingers towards the ulna.
- Swan neck deformity (hyperextension of proximal IP , flexion of DIP)
- Boutonneire deformity (extended MCP, flexed PIP, hyperextended DIP).
- Rheumatoid nodules –> collections of fibroblasts and fibrin forms nodules
Extraarticular manifestations of RA?
Pathology behind this?
All extrarticular manifestations of RA are due to systemic increase in IL’s (1 & 6) and TNFalpha in the circulation.
- Skin and eyes–> rheumatoid nodules and leg ulcers, scleritis (inflamm sclera) and dryness.
- Liver –> produces more CRP and Hepcidin (inhibits absorption of Iron in gut, leads to anaemia).
- Splenomegaly (Felty’s syndrome).
- Cardiovascular –> inflammation of blood vessel walls (vasculitis), increased risk of atheroma (endothelial dysfunction), MI and stroke.
- Neurological –> nerve compression by C1/C2 subluxation, fatigue and depression
- Lung -> fibrosis and pleural effusion (also linked to glucocorticoid treatment which suppresses immune system).
- MSK -> osteopenia, increased risk osteoporosis and muscle weakness.
Describe the steps of the pathogenesis of RA
- Need to be genetically susceptible (HLA DR1 and HLA DR4 encodes MHC class II)
- Plus Environmental TRIGGER e.g. Smoking or infection
- leads to modification of our own self antigen via CITRULLINATION, e.g. type 2 collagen or fibrin can get citrullinated.
- leads to failure of the immune system to recognise own self antigen
- presentation of modified protein antigen by APC in lymph node
- activation of T helper cell, which activates B cells to become plasma cells, secrete antibody against self antigen.
- T helper and B cell travel within circulation to the joint, enter the joint and secrete cytokines
- recruit macrophages which secrete further cytokines
- stimulates synoviocytes to proliferate and express RANKL and proteases
- Synovitis, osteoclast activation and bone resorption, and protease cartilage breakdown.
- formation of PANNUS = proliferating synoviocytes and immune cells, formation of granuloma tissue.
- within the synovial fluid antibody binding antigen forms immune complexes, activates COMPLEMENT system –> long term inflammation and joint destruction
- chronic inflammation leads to angiogenesis, increase vasc. permeabilty and expression of adhesion molecules.
Key macroscopic changes of arthritic joint?
- Synovium inflammation and proliferation –> Synovitis
- Bone and cartilage erosion –> Pannus filled erosion (pannus = synoviocytes and infammatory cells).
- Angiogenesis
XRAY features of RA?
- Early disease often Xray is normal, detect synovitis on MRI/ Ultrasound
- Established disease: SPUR (E)
- Soft tissue swelling and subluxation
- Periarticular osteopenia
- Ulnar deviation
- Reduced joint space (joint space narrowing)
- Erosion of cartilage and bone
