The science of Rheumatoid Arthritis Flashcards
What are the functions of the synovium?
Maintenance of intact tissue surface
Production of synovial fluid => lubrication of cartilage
- control of synovial fluid volume and composition (hyaluronan, lubricin)
Nutrition of chondrocytes within joints
What are the 2 layers of the synovium?
Intimal lining – very thin layer - consists of fibroblasts and macrophages
Sub-intimal tissue – contains blood vessels, fat cells, macrophages and fibroblasts
How does rheumatoid arthritis affect a synovial joint?
A trigger (i.e smoking, genetics bacteria or synovial injury / infection of the joint causing inflammation etc) results in modification of auto-antigens (includes citrullination) i.e makes own antigens appear foreign.
APCs recognise these ‘foreign’ cells and trigger an IMMUNE RESPONSE. Plasma cells produce autoantibodies (i.e rheumatoid factor + anti-citrullinated protein antibody) which make their way to the joint + trigger inflammatory process via things like cytokine release (IL-1, IL-6, TNF alpha), activation of Fibroblast-like synoviocytes (Type B) within the synovium causing osteoclast activity (resulting in bone erosion) and production of proteases causing articular cartilage degradation.
Within the synovial fluid in the joint space there are neutrophils which become activated and also produce proteases and reactive O2 species causing bone and articular cartilage degradation too.
What is the definition of RA?
A chronic, symmetric poly-articular inflammatory joint disease, which primarily affects the MCP and PIP joints of the hands and also small joints in the feet
Which autoantibodies are associated with RA and are tested for as part of the diagnostic process? (2)
Rheumatoid factor - in 75% of people with R.A - you could have normal RF levels in R.A though so it is not very accurate / reliable.
Anti-citrullinated protein antibodies (ACPA) - directed against modified auto-antigens (citrullinated auto-antigens) such as fibrin and fillagrin - this is more sensitive and specific test for diagnosing R.A
What are the 2 main classes of Rheumatoid Arthritis that helps to divide R.A patients into?
Seropositive rheumatoid arthritis - RF or ACP antibodies detected - associated with more progressive disease
Seronegative rheumatoid arthritis - antibodies are not detected in the blood - you could still be diagnosed as having R.A based on other symptoms but it could also be that you have another type of inflammatory arthritis
What test is used clinically to detect Anti-citrullinated protein antibodies?
Diagnostic anti-cyclic citrullinated peptide (anti-CCP)
What factors contribute to RA? (6)
Genetics
Smoking
Bacterial infection - Gingivitis
Viruses i.e EBV
Joint problems:
Infection within joint
Synovial injury / hyperplasia
What would happen if a person who is genetically susceptible to RA had repeated insults either by smoking or infection?
The repeated insults can cause modification of auto-antigens which are then picked up by APCs and this triggers an Immune response.
Plasma cells produce auto-antibodies such as RF and ACP antibodies which move into the joint/joint space and creates inflammatory response etc
Define ‘citrullination’
It’s a post-translational modification converting the amino acid arginine in a protein into the amino acid citrulline.
Citrullination happens normally but it can be abnormal in RA patients.
Synovitis is the hallmark of RA, how is it characterised?
Villous hyperplasia
Infiltration of T cells, B cells, macrophages and plasma cells
Fibroblast-like synoviocyte proliferation
Production of cytokines and proteases which cause erosion of bone and articular cartilage
Increased vascularity
Self-amplifying process
What do inflammatory cytokines do? (7)
Induce expression of endothelial-cell adhesion
molecules
Activate synovial fibroblasts, chondrocytes, osteoclasts
Promote angiogenesis
Suppress T-regs
Activate leukocytes
Promote autoAb production
IL-6 mediates systemic effects
What things enhance blood vessel proliferation in the synovium?
Hypoxic conditions and angiogenic factors such as IL-8 and VEGF
Systemic consequences of RA?
Skin - Vasculitis, nodules, scleritis, amyloidosis = secondary to uncontrolled chronic inflammation
CVD - cytokines and inflammation promote atherogenesis (plaque formation) - can lead to MI or stroke
Liver - increased CRP and ESR inflammatory markers and increased Hepcidin - which contributes to Anaemia
Neuro - Fatigue and depression caused by Anaemia
Muscles - inflammation causes insulin resistance - which results in muscle weakness
Bone - osteopenia which progresses to osteoporosis
Bone marrow - anaemia, thrombocytosis
Which genes are associated with RA?
HLA DR4 (a gene often present in RF positive patients) HLA DR1 (a gene occasionally present in RA patients) PTPN22
Which part of the IgG antibody does RF target?
The Fc portion
What is the Fc portion of an antibody?
It is the constant part of antibodies, used to bind to cells of the immune system.
RF targets this portion on IgG causing activation of the immune system against the patients own IgG resulting in systemic inflammation
How does R.A typically present?
It typically presents with a symmetrical distal polyarthropathy. The key symptoms are joint: Pain Swelling Stiffness
These symptoms affect the MCP and PIP joints in the hands. And can also affect smaller joints in hands and feet such as wrist and ankle
What is the key difference between osteoarthritis and rheumatoid arthritis in terms of pain?
Pain from an inflammatory arthritis (R.A) is worse after rest but improves with activity.
Pain from a mechanical problem such as osteoarthritis is worse with activity and improves with rest.
Which joints are almost never affected in R.A?
Distal interphalangeal joints
Key signs of R.A in the hands?
Swan hand - DIP flexed, PIP hyperextended
Boutonniere - DIP hyperextended, PIP flexed
If you are seronegative it may be that you have another type of inflammatory arthritis. What else could you have?
Spondyloarthritis
Psoriasis - related arthritis
What scoring system is useful in monitoring disease activity in R.A and response to treatment?
DAS28 = the Disease Activity Score.
It is based on the assessment for 28 joints and points are given for:
Swollen joints
Tender joints
ESR/CRP result
Other than serology, what is looked for before diagnosing Rheumatoid Arthritis? (3)
The joints that are involved (more and smaller joints score higher)
Inflammatory markers (ESR and CRP)
Duration of symptoms (more or less than 6 weeks)
Which imaging / scans are helpful in diagnosing R.A?
X-rays to see bony changes - look for joint destruction and deformity, soft tissue swelling, periarticular osteopenia and boney erosions
USS of the joints can be used to evaluate and confirm synovitis.
Look
The exact trigger of the inflammation in R.A is unknown. However, we do know which cells are involved.
Role of macrophages and fibroblast like synoviocytes in inflammatory process in R.A?
They secrete cytokines such as: TNF alpha IL-1 IL-6 Which promote inflammation
How do cytokines affect the Fibroblast-like (type B) synoviocytes in the synovium?
They stimulate them which causes them to become activated and they then proliferate. They can also move joint-joint hence why you get symmetrical joint involvement.
At the same time, they begin assisting in RANKL expression which results in osteoclast activity
They also start to produce proteases which cause cartilage degradation. The cartilage then also produces proteases and it becomes a vicious cycle.
RANKL expression together with cytokines stimulates what?
Osteoclast activity
which leads to bone erosion
What is the T-cell involvement in inflammatory process in the joint space in R.A?
Promote inflammation
Secrete IL-17 which promotes macrophage activity as well as stimulate the fibroblast synoviocytes
Help in expression of RANKL which stimulates/speeds up osteoclast activity - bone erosion
What is the plasma cell involvement in inflammatory process in the joint space in R.A?
There aren’t many plasma cells in the joint space in R.A
They assist in inflammation through cytokines and antibodies
Where do you find immune complexes in R.A?
In the synovial fluid in the joint space
They promote inflammation
How is Angiogenesis involved?
New blood vessels form during inflammatory process in order to recruit immune cells and provide nutrients to hyperplastic synovium
Cytokines help increase vascular impermeability etc allowing for more immune cells to migrate into the joints ( this is how the auto-antibodies such as RF and ACP and immune cells produced in lymph nodes elsewhere migrate into the joint)
