RA Flashcards
(34 cards)
1
Q
What is RA?
A
- Rheumatoid arthritis
- chronic AI disease
- characterised by pain, stiffness, symmetrical synovitis of synovial joints
- peak age 30-60
2
Q
What are key features of RA?
A
Chronic arthritis
- Polyarthritis - swelling of the small joints of the hand and wrists is common
- Symmetrical
- Early morning stiffness in and around joints (can last for some hours)
- May lead to joint damage and destruction - ‘joint erosions’ on radiographs
Extra-articular disease can occur
- Rheumatoid nodules
- Others rare e.g. vasculitis, episcleritis
Rheumatoid ‘factor’ may be detected in blood
- IgM autoantibody against IgG - should really call this rheumatoid ‘antibody’ not ‘factor’
3
Q
Morning stiffness in RA and in other arthritis
A
- RA it can last for some h
- in OA it usually resolves in up to 1h
4
Q
Mono-, oligo- and polyarthritis
A
- mono: 1 joint
- oligo: 2-4 joints
- poly: 5+ joints
5
Q
Epidemiology of arthritis
A
- 1% of population has it
- relatively common cause of significant disability in young adults
- 3:1 f:m affected
6
Q
Important genetic components of RA
A
- heritability estimates of 60%
- specific HLA-DRB gene variants (mapping to amino acids 70-74 of the DRb-chains are strongly associated with rheumatoid arthritis) -> Region encodes conserved amino acid sequence in the HLA-DR antigen-binding groove which is common to rheumatoid arthritis-associated DR alleles – termed ‘shared epitope’
- Other genes identified in genome-wide studies exert modest or weak effects
7
Q
Important environmental components of RA
A
Smoking – contributes 25% of population-attributable risk and interacts with shared epitope to increase risk
8
Q
Which joints are most commonly affected in RA?
A
- Metacarpophalangeal joints (MCP)
- Proximal interphalangeal joints (PIP)
- Wrists
- Knees
- Ankles
- Metatarsophalangeal joints (MTP) -> callous may form due to joint deformity
- can also affect shoulders
- MAINLY AFFECTS THE SMALL JOINTS
-> sparing of DIPs (generally)
9
Q
Appearance of hands of patients with RA
A
- joint damage and destruction
- Swan-neck deformity: affecting the ring finger – there is hyper-extension at the PIP joint and hyper-flexion at the DIP joint
- Boutonnière (‘button-like’) deformity affecting little finger – there is hyper-flexion at the PIP joint
- Radiographs of the hands show evidence of joint damage and deformity. Note the symmetrical involvement of the metacarpo-phalangeal joints and the bilateral ULNAR DEVIATION of the fingers
10
Q
What does the synovial include?
A
- synovial joints
- Tenosynovium surrounding tendons (Extensor tenosynovitis – note swelling is not above either the wrist or MCP joints
Note also that the patient has incomplete extension of the little and ring fingers (cannot stick the fingers out straight) – this is consistent with extensor tendon damage by the tenosynovitis) - bursa
11
Q
Sub-cutaneous nodules in RA
A
- Central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue
- Occur in ~30% of patients
- Associated with:
- Severe disease
- Extra-articular manifestations
- Rheumatoid factor
- position e.g. ulnar border of forearm or in the hands
- worse prognosis
- these patients tend to get other extra-articular manifestations e.g. lungs or eyes.
12
Q
Histocytes
A
- macrophage lineage type cells
- found in RA sub-cutaneous nodules
13
Q
Rheumatoid factor
A
- Antibodies that recognize the Fc portion of IgG as their target antigen
- typically IgM antibodies => IgM anti-IgG antibody
- Positive in 70% at disease onset and further 10-15% become positive over the first 2 years of diagnosis
- not specific, not diagnostic, also seen in hepatitis C and TB
- Seronegative vs seropositive patients
14
Q
Seronegative vs seropositive RA patients
A
Seropositive have RF in their blood
15
Q
ACPA
A
= Antibodies to citrullinated protein antigens
- highly specific for RA (anti-CCP ABs)
- arginine -> citrulline (via PAD)
- PADs are present in high concentrations of neutrophils and monocytes -> increased citrullination of autologous peptides in the inflammed synovium
- increased in smoking due to increased citrullination in the lungs
- increased in patients with the shared epitope (shared epitope preferentially binds non-polar amino acids like citrulline but not positively charged amino acids like arginine – so ACPA more likely to develop among individuals with citrulinated autoantigens who have the shared eptiope)
16
Q
PADs
A
= Peptidyl arginine deiminases (PADs)
- arginine -> citrulline (via PAD)
- PADs are present in high concentrations of neutrophils and monocytes -> increased citrullination of autologous peptides in the inflammed synovium
17
Q
Shared epitope
A
The shared epitope [amino acids 70-74 of the HLA-DRb-chains associated with rheumatoid arthritis] preferentially binds non-polar amino acids like citrulline but not positively charged amino acids like arginine – so ACPA more likely to develop among individuals with citrulinated autoantigens who have the shared eptiope
18
Q
HLA molecules and rheumatology
A
- Individual susceptible since they carry conserved amino acid sequence in their HLA-DR antigen-binding groove (‘shared epitope’)
- shared sequence in amino acids 70-74 of the HLA-DRβ chain
- this is why multiple different HLA serotypes were associated with disease (HLA-DR4, -DR1, -DR6, DR10) – all contained the shared epitope and some individuals with HLA-DR4 not at risk – these HLA-DR4 did not contain shared epitope
- This shared epitope preferentially binds non-polar amino acids such as citrulline and citrulline-containing peptide antigens increased during inflammation
- Inflammation and citrullination in rheumatoid arthritis – smoking, changes in microbiota, chronic infections (gingivitis)
- Is the reason that anti-CCP antibodies develop in rheumatoid because of combination of genetic factor (shared epitope) and environmental factor (inflammation resulting in citrullination)?
- HLA-DRbeta is linked to MHC class 2 which suggests T-cell involvement in RA
19
Q
Extra-articular features of RA
A
Common
- Fever, weight loss
- Subcutaneous nodules
Uncommon
- vasculitis (now rare, used to be more common)
- Ocular inflammation e.g. episcleritis
- Neuropathies
- Amyloidosis
- Lung disease – nodules, fibrosis, pleuritis
- Felty’s syndrome – triad of splenomegaly, leukopenia and rheumatoid arthritis
Some people don’t present with joint pain but with systemic features such as malaise.
20
Q
Fibrosis in RA - treatment or disease?
A
- fibrosis can be due to RA
- it can also be due to methotrexate treatment
- CXR in the beginning to have a baseline
21
Q
Felty’s syndrome
A
Felty’s syndrome is a rare, potentially serious disorder that is defined by the presence of three conditions: rheumatoid arthritis (RA), an enlarged spleen (splenomegaly) and a decreased white blood cell count (neutropenia), which causes repeated infections.
22
Q
Radiographic abnormalities in RA
A
- Early: Juxta-articular osteopenia (thinning of the bone, less white and more translucent on the XR)
- Later: Joint erosions at margins of the joint
- Later still: Joint deformity and destruction
23
Q
Pathology in joints in RA
A
- cartilage degradation, joint space narrowing
- synovitis
- bone erosion
- pannus (condition in which a layer of vascular fibrous tissue extends over the surface of an organ or other specialized anatomical structure = gunk of inflammatory tissue)
24
Q
Features of synovial joints
A
- synovium: 1-3 cell deep lining containing macrophage-like phagocytic cells (type A synoviocyte) and fibroblast-like cells that produce hyaluronic acid (type B synoviocyte)
Type I collagen - synovial fluid: Hyaluronic acid-rich viscous fluid
- articular cartilage: Type II collagen
Proteoglycan (aggrecan)
25
What is the most important cytokine in RA?
- 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
- produced mainly by activate macrophages in the rheumatoid synovium
- TNF-alpha has many functions (see slide 19)
- TNF-alpha inhibition is therapeutically successful in RA
26
Biological therapy of RA
- TNF-alpha blockade (SUCCESSFUL!)
- IL-1 and IL-6 inhibition (IL-1 is much less effective than 6 and TNF; IL-1 is not recommended for RA in England)
- B-cell depletion: Rituximab (anti-CD20 AB)
- belimumab, tocilizumab and denosumab are now licenced drugs for SLE, rheumatoid arthritis and osteoporosis respectively.
- both B and T cells are important in this disease!
27
Rituximab
- anti-CD20 AB
- causes depletion of B-cells
- used in some AI diseases incl. RA and SLE and also in lymphoma
28
Management of RA
- MDT: PT, OT, surgery..
- medication: DMARDs (these are started early in the disease because joint destruction = inflammation x time)
- Glucocorticoid Therapy (avoid long term; used in short term treatment)
- Biological therapy
29
DMARDs definition
disease- modifying anti-rheumatic drugs
30
DMARD therapy in RA
- drugs that may induce remission (not cure) and prevent joint damage
- achieve this by:
- reducing the amount of inflammation in the synovium
- slow or prevent structural joint damage e.g. bone erosions
-complex mechanisms of action and relatively slow onset of action i.e. weeks
```
- examples:
methotrexate – commonly used
sulphasalazine – commonly used
hydroxychloroquine – commonly used
leflunomide – uncommon
```
Janus Kinase inhibitors
new and introduced in UK in 2017
Tofacitinib (Xeljanz) – October 2017 NICE appraisal TA480
Baricitinib (Olumiant) - August 2017 NICE appraisal TA466
- gold (rarely used now)
- penicillamine (rarely used now)
all have significant adverse effects and therefore require regular blood test monitoring during therapy
31
Summary of biological therapy in RA
Inhibition of tumour necrosis factor-alpha (‘anti-TNF’)
- antibodies (infliximab, and others)
- fusion proteins (etanercept) -> decoy receptor, mops up TNF-alpha
B cell depletion
- Rituximab – antibody against the B cell antigen, CD20
Modulation of T cell co-stimulation
- Abatacept - fusion protein - extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to modified Fc (hinge, CH2, and CH3 domains) of human immunoglobulin G1
Inhibition of interleukin-6
- Tocilizumab (RoActemra) – antibody against interleukin-6 receptor.
- Sarilumab (Kevzara) – antibody against interleukin-6 receptor.
32
The downside of biological therapy in RA
- very expensive!
- currently it can only be given to patients that failed two standard therapies and still have arthritis.
- Side-effects for all include increased infection risk
- TNFα inhibition is associated with increased susceptibility to mycobacterial infection e.g. tuberculosis so need to screen all patients for tuberculosis before starting treatment and may use prophylactic antibiotics in those at high risk
- B cell depletion therapy can be associated with hepatitis B reactivation so need to screen all patients for hepatitis B before treatment
- B cell depletion therapy can be associated with JC virus infection and progressive multifocal leukoencephalopathy (PML) - rare
33
What is the first line treatment for RA?
Methatrexate
34
Key points to remember
- TNF-alpha is the key cytokine involved
- Smoking and the HLA are features
- Symmetrical polyarthritis and morning stiffness.
