Rheumatoid arthritis Flashcards
What is rheumatoid arthritis?
Chronic autoimmune disease characterised by pain, stiffness and symmetrical synovitis (inflammation of the synovial membrane) of synovial (diarthrodial) joints
What are the features of chronic arthritis?
Polyarthritis - swelling of the small joints of the hand and wrists is common Symmetrical Early morning stiffness in and around joints May lead to joint damage and destruction - ‘joint erosions’ on radiographs
What are the features of extra-articular disease?
Rheumatoid nodules and other rarer features like vasculitis and episcleritis
What is the rheumatoid factor that can be detected in blood?
Rheumatoid ‘factor’ may be detected in blood IgM autoantibody against IgG - should really call this rheumatoid ‘antibody’ not ‘factor’
What percentage of the population has rheumatoid arthritis?
1% it is a common cause of significant disability in young adults
What is the gender ratio?
F:M=3:1
Describe the genetic component of rheumatoid arthritis in twins and family
disease concordance rates for twins are 15-30% (monozytic) and 5% (dizygotic). Heritability estimates 60%
What are the specific genes involved with rheumatoid arthritis?
Specific HLA-DRB genes variants mapping to amino acids 70-74 of the BRbeta-chains are strongly associated with rheumatoid arthritis. Ther region encodes conserved amino acid sequence in the HLA-DR antigen-binding groovewhich is common to rheumatoid arthritis-associated DR alleles – termed ‘shared epitope’
Describe the environmental component of rheumatoid arthritis
Smoking- contributes 25% if population attributable risk and interacts with shared epitope to increase risk
What are the most comments effected joints in RA?
Metacarpophalangeal joints (MCP) Proximal interphalangeal joints (PIP) Wrists Knees Ankles Metatarsophalangeal joints (MTP)
What the significance of callous formation under metatarsals?
Callous formation under heads of metatarsals due to joint deformity
what are some of the features of joint deformity and destruction
Swan neck deformity Boutonniere deformity
What is meant by symmetrical polyarthritis?
Damage and destruction tends to occur symmetrically. E.g. symmetrical involvement of the metacarpo-phalangeal joints and the bilateral ulnar deviation of the fingers
What is meant by swan-neck deformity?
there is hyper-extension at the PIP (proximal interphalangeal) joint and hyperflexion and the DIP (distal interphalangeal) joint
What is meant by a Boutonniere deformity?
There is hyperflexion at the PIP joint
What is the primary site of pathology for RA?
synovium
What are some examples of synovium?
- Synovial joints (proximal inter-phalangeal joints)
- Tenosynovium surrounding tendons
- Bursa
What is proximal inter-phalangeal joint synovitis?
What is extensor tenosynovitis?
What are subcutaneous nodules?
Central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue.
What are sub-cutaneous nodules associated with?
- Severe disease
- Extra-articular manifestations
- Rheumatoid factor
Where are subcutanous nodules normally located?
- In the hands- e.g. around the PIP joint
- Rheumatoid nodule- e.g in the ulnar
What are rheumatoid factors?
- Antibodies that recognize the Fc portion of IgG as their target antigen
- Typically IgM antibodies i.e. IgM anti-IgG antibody!
This test is positive in 70% at disease onset and further 10-15% become positive over the first 2 years of diagnosis
What are antibodies to citrullinated protein antigens?
Antibodies to citrullinated peptides are highly specific for rheumatoid arthritis.
What are some of the common extra-articular features?
Common
- Fever, weight loss
- Subcutaneous nodules
What are some uncommon extra-articular features?
Uncommon
- vasculitis (inflammation of blood vessels)
- Ocular inflammation e.g. episcleritis
- Neuropathies
- Amyloidosis
- Lung disease – nodules, fibrosis, pleuritis
- Felty’s syndrome – triad of splenomegaly, leukopenia and rheumatoid arthritis
What does the synovitis cause?
Bone erosion, pannus (abnormal layer of fibrovascular tissue) and cartilage degradation (joint space narrowing)
What can be found inside the synovial joint?
- Synovium
- Synovial fluid
- Articular cartilage
What is in the synovium?
it is 1-3 cells thin
It contains type-A synoviocyte (phagocytic), type-B synoviocytes (producing hyaluronic acid) and Type 1 collagen
What is in synovial fluid?
Hyaluronic acid
What is in articular cartilage?
Type 2 collagen
Proteoglycan- mainly aggrecan
Describe the synovial membrane in rheumatoid arthritis
Synovium beocmes proliferated mass of tissue (pannus) due to:
- Neovascularisation
- Lymphangiogenesis
- inflammatory cells- B/T cells, plasma cells, mast cells and activated macrophages
Why are there so many inflammatory cells in RA?
Due to excess pro-inflammatory cytokine imbalance
Mainly due to actions of TNF-alpha Therapy for rheumatoid arthritis can be inhibited by antibodies and fusion proteins.
What is TNF-alpha?
The cytokine tumour necrosis factor-alpha (TNFα) is the dominant pro-inflammatory cytokine in the rheumatoid synovium and its pleotropic actions are detrimental in this setting
What is TNF alpha inhibition?
TNFα in rheumatoid arthritis validated by the therapeutic success of TNFα inhibition in this condition.
TNFα inhibition is achieved through parenteral administration (most commonly sub-cutaneous injection) of antibodies or fusion proteins
Describe other biological therapy apart form TNF-alpha blockade
Il-6 and IL-1 can also be blockaded
In addition to cytokine blockade, we can also deplete B cells in rheumatoid arthritis by parenteral (intravenous) administration of an antibody against a B cell surface antigen, CD20
What is the management of RA?
Describe the three therapies
Multidisciplinary approach – physio, occupational therapy, hydrotherapy, surgery.
Medication including:
- Drugs – DMARDs – Disease-Modifying Anti-Rheumatic Drugs. Started early in the disease – joint destruction = inflammation x time. DMARDs (“steroid-sparing agents”) are safer and more effective in the long term than steroids since they avoid the long-term side-effects of steroids.
- Biological therapy.
- Glucocorticoid therapy – e.g. prednisolone.
· Avoid long-term use due to side effects but useful in the short term for symtpom relief.
What are DMARDs?
They are disease-modifying anti-rheumatic drugs.
Drugs that induce remission and prevent joint damage- they do not cure.
They do this by reducing inflammation in synovium and slowing/ preventing structural joint damage.
It has a slow onset
Give some examples of DMARDs?
- Methotrexate
- Sulphasalazine
- Hydrochloroquine
Leflunomide, gold and penicillamine (are rarely used)
Everything has signifcant side effects so bloods need to be monitored.
What are the Rituximab and Infliximab management techniques for RA?
Rituximab & Infliximab are chimeric antibodies with Fab mouse regions and human constant regions.
Adalimumab & Golimumab are full human antibodies.
TNFR-Fc is a fusion protein example of TNF-a.
–>Etanercept.
What are the side effects/ cons of biological treatment?
These treatments (including the ones above) are very expensive and limited by NICE.
o Biological therapy involves all the antibody treatments.
o Methotrexate (not biological therapy) is used first and then if this is ineffective, biological therapy is used.
Side effects from biological therapy include an increased infection risk chance.
o TNF-a inhibition =increased susceptibility to mycobacterial infections (screen patients for TB).
o B-cell depletion=(can) to hepatitis B reactivation (so screen patients for Hep B).
o B-cell depletion =(can) to JC virus infection and progressive multifocal leukoencephalopathy (PML).
