What is the aetiology of RA?
RA is a chronic inflammatory disease of unknown aetiology
It is likely to involve an unknown stimulus which activates the innate immune system triggering cytokines, complements, NK cells and nuts. Dendritic cells present Ag to T cells which proliferate and produce inflammatory cytokines (TNF alpha + others). This stimulates macrophages, fibroblasts to release TNF -alpha, IL-6, IL-15 and 18 which leads to activation of proteases, neutrophils, B cells. Osteoclast are activated by macrophages via RANK-L.
What is the pattern of joint involvement?
symmetric, peripheral polyarthritis
- earliest joints affected are the small joints of the hands and feet
- once RA is established the wrists, MCPs and PIP joints are commonly affected (not DIPs)
- may be monoarticular, oligoarticular (4+) or polyarticular (>5)
- inflammation of joints, tendons and bursa
- flexor tendon synovitis is a hallmark of RA -> decreased ROM, reduced grip strength, trigger fingers
What are the extra-articular features of RA?
- subcutaneous nodules, secondary Sjogrens syndrome (10%), and anaemia are the most common
- also fatigue, lung involvement, pericarditis, peripheral neuropathy, vasculitis, haematological abnormalities
- more likely to develop if Hx of smoking, early onset of significant disability, positive RhF
What are the characteristic symptoms of RA?
Early morning joint stiffness lasting longer than 1 hour which improves with activity.
What are some of the more advanced features of RA
progressive destruction of the joints, soft tissues and tendons lead to deformities
- ulnar deviation from subluxation at the MCPJs
- swan neck deformities - hyperextension of PIPJ with flexion of DIPJ
- boutonniere deformities - flexion of PIPJ with hyperextension of DIPJ
- Z line deformity - subluxation of 1st MCPJ with hyperextension of 1st IPJ
What other joints can be involved?
knees and shoulders in advanced disease
atlantoaxial involvement of the C-spine
- can result in compressive myelopathy and neurological dysfunction
What is the sensitivity and specificity of RF and anti-CCP?
RF occurs in 70-80% patients with RA but also 5-10% of the general population
20-30% of patients with SLE have positive RF
Anti-CCP has specificity of 95-98% and similar sensitivity as RF
Which tests are positive in RA?
RF and anti-CCP - but both tests can be negative in 50% of RA
ESR and CRP are likely to be raised
ANA in 1/3 patients (DDx SLE)
What FBC changes might you see in RA?
anaemia of chronic disease, thrombocytosis
What are the diagnostic criteria for RA
2010 guideline is a scoring system where you get points for number of joints, serology, inflammatory markers and duration of symptoms
- you must score 6+ to achieve diagnosis
What are some Ddx?
Seronegative RA (negative RF and anti-CCP Recent onset RA (
What are the treatment options in RA
NSAIDs Steroids Antimalarials - Hydroxychloroquine DMARDS - MTX, Leflunomide, Salazopyrin Biologics Surgery if requires
What is co-stimulation of the T-cell
Antigen specific binding of T-cell to APC through MHC (major histo-compatibility complex) AND costimulation through the CD28-CD80/86 pathway is required to activate the T-cell (otherwise it dies or doesn’t do anything)
What pathway activates osteoclastogenesis in RA
Driven by macrophages through interaction of RANK and RANK-L (ligand)
What are the main cytokines involved in RA
TNF alpha
IL 1
IL 6
IL 17
What are the t-cell CD4 subsets involved in RA
TH1
TH17
What is pannus?
Pannus is abnormal inflammatory tissue found between cartilage and bone, cells in pannus produce protienases which destroy cartilages
What is VEGF and why important in RA
Vascular endothelial growth factor - enables pannus to obtain its on blood supply through angiogenesis
Why do you get anaemia of chronic disease?
IL-6 causes production of hepcidin (an acute phase protein) which inhibits iron release from macrophages and reduces iron uptake in duodenum = anaemia
What is the genetic contribution to RA?
10-25%
What are some genetic mutations implicated in RA
HLADRB1
STAT 4
PADI 4
PTPN22
Prevalence of RA
1%
Sex distribution of RA
2-3 F: 1M
What are the four categories in the classification criteria for diagnosis of RA?
Joint involvement (number and size) - with synovitis
Serology (RF and anti-ccp)
Acute phase reactants (ESR, CRP)
Duration of symptoms (either less then or greater then 6 weeks)
Score of 6 or greater indicates likely RA
What are some non-pharmacological therapies for RA
PT OT Nutrition Reduce cardiovascular risk Immunisations Smoking cessation
What tests should be performed before commencing treatment of RA
Hepatitis B and C Screen for latent Tb - if present must be treated with Isoniazid for one month prior to initiating treatment and continued for 6 months Ophthalmologist evaluation if using hydroxychloroquine Baseline blood with LFTs Pregnancy test Lipid and glucose testing CXR
What are the four mechanisms by which biological DMARDs work?
TNF alpha inhibition
B-cell depletion
Co-stimulation blockade
Inhibition of IL 1 and IL 6
What is an IL-1 inhibitor used in RA
Anakinra
What is an IL-6 inhibitor used in RA
Tocilizumab
What is a t-cell co-stimulation inhibitor?
Abatacept
What is the main b-cell depleting agent used in RA
Rituximab
What are 4 examples of TNF alpha blockers used in RA
Infliximab Adalimumab Golimumab Certolizumab Ertanercept
What should you screen before staring hydroxychloroquine?
Ophthalmological exam then every 6-12 months on treatment
What is a rare neurological side effect of leflunomide
Peripheral neuropathy
What 4 features most accurately predict a diagnosis of RA?
- arthritis of the hands
- positive RF or anti-CCP
- Morning stiffness for > 1 hour
- MRI bone oedema
Name 4 features that predict a poor outcome in RA (there are more than 4)
- sustained elevation of CRP
- Extra-articular features
- HAQ > 1 at 1 year
- multiple joints involved (>12)
- MRI bone oedema
- Joints with power doppler US signal - these joints tend to erode
- High titres of RF and/or anti-CCP - erosions are more common in seropositive disease
- Low SES/education
- Female
- Advanced age at onset
What is the DAS28?
a scoring system of disease activity which includes:
- number of tender joints (28 joints)
- number of swollen joints (28)
- ESR
- patient rates the global activity of arthritis in the past week out of 100 - 0 = no symptoms, 100 = very severe
the score is calculated using a computer scoring system
DAS28 5.1 = high
DAS28
What pharmacotherapy would you use to manage RA with low disease activity?
DMARD monotherapy
- usually MTX
- if features of poor prognosis present - combination DMARD (double or triple therapy)
- MTX + Leflunomide or Salazopyrin
What pharmacotherapy would you use to manage RA with high disease activity?
DMARD mono therapy or HCQ + MTX
- if features of poor prognosis present
- combination DMARD therapy (double or triple therapy)
or anti-TNF + MTX
in NZ have to have trialled combination DMARD before qualifying for anti-TNF
What 3 anti-TNF drugs are used in RA?
Adalimumab (Humira = humanised mAB, given SC)
Infliximab (chimeric, given IV)
Etancercept (TNFreceptor:Fc fusion protein, given SC)
What are the main side effects of TNF alpha inhibitors
- infection risk: Hazard ratio = 1.2 - 1.5 for serious infection
- susceptibility to intracellular pathogens
- reactivation of latent TB - reactivation of HepB
(TNFaplha suppresses HBV replication)
- monitor serology 3 monthly and consider anti-viral prophylaxis - Risk of cancer is controversial - possible increase risk of lymphomas, although there is a baseline increased risk with RA alone
- consider using rituximab instead of TNF-inhibitors if Hx of malignancy - May worsen CHF - avoid
rare: exacerbation of previous quiescent MS, optic neuritis, ILD
What is the ACR-70?
A standard measure of the number of people who have 70% or greater improvement according to 7 clinical and laboratory measures of disease activity.
What are the benefits of TNF inhibitors?
- reduce erosions
- decrease disability as assessed using HAQ
- improve QOL
Are TNF inhibitors the most effective drug for RA when used alone?
No - trials have shown that TNF inhibitors in combination with MTX are more effective than mono therapy with either MTX or TNF inhibitors.
There has only been one head to head trial of MTX + anti-TNF vs combination DMARD which showed only a modest benefit
What is the main role of steroids in the management of RA?
Disease flares
What vaccinations should be considered?
Inactivated vaccines: Pneumovax Flux Hep B Diphtheria/Pertussis/Tetanus/Polio
Live vaccines:
Zoster
- before starting immunosuppression
What treatment should be used for RA in pregnancy?
May often have lower treatment requirements
- NSAIDs - stop 3rd trimester (closure of ductus)
- DMARDS - Sulphasalazine, hydroxychloroquine and prednisone are probably safe
- anti-TNFs: stop before 30 weeks and do not vaccinate baby with live vaccines
- Rituximab - stope at 12 weeks before delivery (B cell depletion in neonate)