13. RA treatment and DMARDS - Robson Flashcards
What is the prevalence of RA?
1% of the population
How many new cases of RA are diagnosed each year?
Approximately 12,000
What joints in the hands are affected by RA?
MCP joints and proximal IP joints
Is RA symmetrical or non-symmetrical in nature?
RA is symmetrical
Is OA symmetrical or non-symmetrical in nature?
OA is non-symmetrical
In severe cases of RA, which joints will be affected?
In severe cases, most joints will be affected over time
What is the 2010 ACR/EU LAR criteria for diagnosing new patients with RA?
At least one swollen joint - no other explanation
A score of or greater than 6/10
What is the scoring system for the diagnosis of RA?
LOOK AT TABLE IN LECTURE 13/PBL 4
What is the first line of management for RA?
First line is the same as OA - pain relief
How is the first line of management of RA carried out?
Start with the analgesic ladder
Why might a patient not be able to be prescribed standard NSAIDS for pain relief?
What should be prescribed instead?
If they have comorbidites e.g. from cox-1
Cox-2inhibitors
What is the next line of treatment for RA after pain relief?
DMARDs
What are DMARDs?
Disease Modifying Anti-Rheumatics
What are the two different types of DMARDs?
Conventional DMARDs
Biologicals
What is the main mechanism for conventional DMARDs?
Used as immune suppressants
What is the gold standard conventional DMARD?
Methotrexate
How do biologicals (DMARDs) work?
These are TNFa blockers
How should biological DMARDs be used?
These must be used alongside a conventional DMARD as an anchor - typically methotrexate
What is the role of adjunct therapy in the treatment of RA?
Oral corticosteroids may be used only in a particularly bad flare - to get it back under control
When is the best time to initiate treatment of RA?
Want to try and treat it AS SOON AS POSSIBLE for the best prognosis
Ideally start treatment within three months prior to any joint damage
On what kind of dosage of medication should you start for treatment on RA?
VERY HIGH - then once you have control of the disease - reduce the dosage of the drug to be able to maintain the condition
Can then add increased dosage when required e.g. if there is a flare
What is the mechanism of action of methotrexate?
Folate (folic acid) inhibitor (antagonist)
In whom can methotrexate not be used for the treatment of RA?
Pregnant women - folate inhibitor
How frequently must methotrexate be taken?
Take it once a week - same time and day each week
What dosage should initially be taken of methotrexate?
2.5mg tablets
Start between 5-10mg per week (2-4 tablets per week)
How long does it take for methotrexate to have a therapeutic effect?
3-12 weeks
What cells are targeted by methotrexate?
Why does this result in side effects?
Any cells that are proliferating - in RA these are immune cells but there are also many other proliferating cells
What are the common adverse effects of methotrexate treatment?
Liver problems and also haematopoetic stem cells producing RBCs and WBCs - anaemic patients with liver damage
Why should patients taking methotrexate have monthly blood tests?
Methotrexate targets prolfierating cells - liver cells and haematopoetic stem cells producing RBCs and WBCs
Give the mechanism of action of methotrexate
Folic acid antagonist
Uses the same transporter as folate - binds to this and glutamate is added to it - becomes the active drug
Active drug inhibits dihydrofolatereductase and also thymidate synthetase
This inhibition stops the synthesis of DNA and RNA production and so cells requiring this for replication are inhibited
Involves purine metabolism
What is the direct action of methotrexate on?
Dihydrofolate reductase
What is the indirect action of methotrexate on?
Thymidate Synthethase
What is sulfasalazine
Very old antibiotic from 1950s - now used for autoimmune disease treatment
What dosage of sulfasalazine should be administered?
Start with 500mg per day
Over four weeks, gradually increase to 1g twice a day
How long does it take for sulfasalazine to have a therapeutic effect?
12 weeks
Where is the main action of sulfasalazine?
In the gut
Why is the main action of sulfasalazine in the gut?
Not well absorbed across the gut
Gut bacteria break sulfasalazine down into secondary agents - these are also not that well absorbed across the gut
Name a metabolite of sulfasalazine
5-ASA
Where dos 5-ASA have its action?
In the large intestine
What is the association of gastroenteritis with RA?
Gastroenteritis may be an acute trigger of RA
Treatment of what two other conditions may relieve arthritic symptoms?
Ulcerative colitis
Crohn’s disease
What RA treatments can be used for the treatments can be used for the treatment of gastroenteritis, ulcerative colitis and Crohn’s disease and why?
Sulfasalazine
This inhibits folate metabolising enzymes
What is hydroxycholoroquine?
Anti-malarial
What is the action of hydroxycholoroquine?
Accumulates in lysosomes - increases the pH and so decreases protein modifications from occurring
Blocks the toll-like receptor 9 which recognises DNA containing immune complexes - reduces the activation of dendritic cells
Who can hydroxycholoroquine not be given to and why?
Those with psoriatic arthritis - results in a worsening of the skin
What is leflunomide and when is it used?
Similar efficacy to methotrexate - inhibits different pathways
Patients who cannot take methotrexate (pregnancy) should be started on this
How does leflunomide work?
Inhibits pyrimidine biosynthesis through inhibiting dihydroorotate dehydrogenase
How can gold be used to treat RA?
Gold salts - can be injected intramuscularly once a week
Why are gold salts injected?
Oral induction is not as effective
How long does it take for gold to have an effect in the treatment of RA?
4-6 months
Pregnant patients with RA who cannot take methotrexate should be prescribed with conventional DMARD?
Leflunomide
Why do many people induced with gold salts stop treatment?
Relatively large numbers of people experience side effects
How are biological DMARDs made?
Via genetic engineering
What is the target for biologicals?
Specific immune cell or specific inflammatory cytokine
Name three TNF-alpha blockers
Entanercept
Infliximab
Adalimumab
Name an IL-1 blocker
Anakinra
Name a biological that inhibits B cells
Rituximab
Name a biological that blocks T-cell stimulation
Abatacept
Name an IL-6 blocker
Tocilizumab
How does entanercept work?
Acts as a soluble sponge - used as a subcutaneous injection - soaks up all of the TNF-alpha before it can get to the receptor on the cells
How long does it take for entanercept to have an effect?
1-4 weeks
Progressive improvement over 3-6 months
What is the main advantage of TNF-alpha blockers compared to conventional DMARDs?
These have a much quicker onset - get almost instantaneous results
What is infliximab?
Monoclonal antibody against TNF-alpha
Designed against the mouse binding side of the TNF-alpha (255) and human (75%)
What is adalimumab?
Human monoclonal antibody to TNF-alpha
Why are IL-1 inhibitors not used as TNF-alpha inhibitors for the treatment of RA?
IL-inhibitors are not as effective as anti-TNFa agents and are less patient friendly (daily injections)
These are now used for the treatment of other conditions
What is Rituximab?
Monoclonal antibody against CD20
Where is CD20 found?
Primarily found on the surface of B-cells
What is the mode of action of Rituximab?
Destroys both normal and malignant B-cells
What is the advantage of using riutximab for RA treatment?
Could potentially put a patient into complete remission - completely depletes malignant b cells
How long a remission could be obtained from rituximab?
Six months to a year
How long does it take for ritximab to have an effect?
Around three months after infusions
What is abdatacept and how does it work?
Blocks the CD28 receptor found on T-cells
What is the disadvantage of abatacept compared to TNFa blockers?
Slower onset
What is the efficacy of abatacept compared to TNFa blockers?
Similar reports of clinical symptoms BUT radiological results are not as good
What is the advantage of abatacept compared to TNFa blockers?
Fewer adverse effects - not blocking the whole of the immune system - just blocking the t-cells
What is tocilizumab and when should it be used?
IL-6 receptor monocloncal antibody
Used when people do not respond to TNFa blockers
