RA Pathiophysiology Flashcards
Common autoimmune disease
Systemic autoimmune diseases:
*Rheumatoid arthritis
Organ specific autoimmune diseases:
Myasthenia gravis
Grave disease
Autoimmune diabetes
Rheumatoid arthritis
RA is a chronic, progressive, systemic, inflammatory disorder affecting synovial joints.
RA is a chronic systemic autoimmune diseases, which is primarily characterised by proliferative synovitis and inflammatory arthritis with erosions.
24 different types of arthritis, most common is osteoarthritis (joint wearing down/inflammatory based) and rheumatoid arthritis (autoimmune)
The inflammation may also affect eyes, lungs, heart
RA can affect any joint but commonly hand, feet, knee, hip.
The pathogenesis of RA is not fully elucidated but it is multi-factorial. Genetics, environmental and immunological factors play a role. RA has a specific genetic predisposition and approximately 70% of RA patients express HLA-DR4 human leukocyte antigen.
There are other genes related to RA including STAT4 (signal transducer and activator of transcription 4), TRAF1/C5 (tumour necrosis factor receptor associated factor 1/complement component 5) and PTPN22 (protein tyrosine phosphatase, non receptor type 22)
Affects between 0.3 and 1.5%. of the population, affecting 600,000 of the uk
Most sufferers develop RA between age of 25-50yr old more prevalent in women than men.
Pollution, exposure or mineral oil and silica infectious agents and female hormones are involved in RA
Autoimmunity including antibodies such as anti-citrullinated Peptide antibodies (ACPAs) and rheumatoid factor (RFs) is associated with RA.
Immune dysregulation, antibody responses to modified peptides abs increases production of cytokines and chemokine contribute to pathophysiology of RA.
RA genetic and environmental causes
*15% amongst monozygotic twins
MHC allele HLA-DRB1 relative risk 4-12%
*Hormones more in women than men depending on female hormone levels for developing RA
*infections: definite associations lacking, but mycobacterium, streptococcus, mycoplasma, Epstein-Barr virus and parvovirus have been suggest to have a link
Smoking
RA pathophysiology
1- Initiator phase: initiating event unknown and reasons for joint specific localisation is unknown.
Injury, infection, exposure to toxic substances.
APCs and citrillination if proteins means cells are recognised as non-self
2-Inflammation phase:
Self antigens (citrillinated proteins presented)
Clonal expansions of T and B cells and they are insufficiently controlled by T regulatory cells.
3- Self perpetuating phase: inflammatory damage in synovium causes self antigens previously unseen by immune system to be exposed now we have immune response against cartilage and infiltration of immune cells. Self perpetuating this phase further and exposing more self antigens which drives the immune response even further.
4- Destruction phase: synovial fibroblasts and osteoclasts activated by cytokines (TNF,IL-6) which leads to destruction of bones and cartilage.
Pro-inflammatory mediators role in RA pathophysiology
Synovium inflammation is key but systemic at all stages (systemic features link in with co-morbidities
B-cells producer autoantibodies which can activate complement system and also bind to activated macrophages in the synovium. Activated macrophages perpetuate inflammation.
Autoantibodies: RF rheumatoid factor directed against fragment of IgG and anti-citrullinated peptides ( anti-CCP) are directed against antigens commonly present outside the joint.
T-cells potentially activate monocytes, macrophages and synovial fibroblasts which will ridyce TNFalpha and IL-1&6
These cytokines induce the production of matrix metalloproteinases MMPs degrade the cartilage
Joint destruction might be caused by CD4 T-cells cytokine:
RANK ligand belongs to TNF family, this promotes osteoclasts reabsorb bone
Steps of RA development
Induction phase initial activation of the autoimmune system leads to an inflammatory cascade. Possible triggers are injuries, infections and exposure to toxic substances like smoke.
APC gets exposure to self or non-self antigens or become activated and now an inflammation response happens
In inflammation phase where self antigens are present in the context of HLA class II which are characteristic of RA and this leads to polyclonal activation of T & B cells they start to proliferate and become active and now antibodies are produced with cytotoxic T-cells
Self perpetuation phase: tissue damage happening which means antigens not normally seen by immune system are exposed and this drives more inflammatory responses.
Destruction phase: proteases and the cytokines involved there and that rads to osteoclasts which causes the reabsorption of bones and we get destruction of the tissue.
How are these systemic cytokines linked to co-morbidities of RA?
All these cytokines IL-6, TNF alpha and IL-1 are all produced in the joint where this inflammation occurring and they have effects outside the joints so IL-6 can lead to iron redistribution in the liver (hepcidin)
TNF-alpaha and IL-1can lead to insulin resistance in the muscle and we have TNF-alpha & RANK ligand they lead to low bone mineral density and fractures.
IL-6 and TNF-a which play a role in atherogenesis, myocardial infarction and stroke
TNFa & IL6&1 cause low stress tolerance and depression.
So RA has a big impact on the whole body
What is the treatment of RA?
Focus on anti-inflammatory and immunosuppressants
Currently used:
NSAIDs COX-2 inhibitors
DMARDs
Biologics
