RA 1 Flashcards
signs and symptoms for Sarah
risk factors
Consider Sarah:
What would you look at to confirm her diagnosis?
signs
- swolen joints, tender joints (bilat)
- baker’s cyst
symp
- morning stiffness, diff in aod
- fatigue
risk factors
- ex-smoker
- post-partum
- genetic link: PMR
Consider Sarah:
What is her DAS28 score?
Try it out! http://www.rheumdas.com
Ø You had most of the information you needed in the slides and
I added that Sarah was rating her global health at 8/10
Considering all of the ways your arthritis has affected
you over the past week, where would you rate yourself
on a scale of 0 to 10?
0 I say is you forgot you had it other than you’re taking these medications. Totally symptom-free,
10, not able to get out of bed. So really struggling with any type of of activity
Sarah does have a high das CRP. Lot of disease activity. And we are going to be very motivated to get that Das 28 down.
Goals of Therapy
● Remission (ultimate goal!)
○ low disease activity if remission not achievable
● Improve (maintain) function
● Maximize quality of life (work, personal)
● Eliminate symptoms, particularly pain
● Prevent erosive damage
● Prevent (minimize) disability
● Reduce complications / co-morbidities
● Prevent early mortality
Treating RA Early
● Window of Opportunity
○ timeframe within which there is a disproportionate response to
therapy, resulting in long-term sustained benefits
■ rapid suppression of disease decreases or resets rate of progression
for extended period of time
■ diminished response to therapy with increasing disease duration
● Tight Control (treat-to-target or T2T)
○ early, aggressive treatment tailored to the disease activity of an
individual patient aimed at achieving remission critical for
optimizing long-term results
Early, Aggressive Treatment
bCalguneri et al.
BeST
Bottom Line:
Ø Combination therapy
resulted in greater
benefit (triple ³
double > mono)
Ø However -
monotherapy will
achieve remission in
1/3 patients!
The more aggressive in terms of early combination therapies, the more people achieved that target
even though combination therapy resulted in greater benefit, triples was better than two, was better than one. A third of patients still achieved remission with just one drug. We think about cost of drugs. We think about adverse effects that patients might encounter if we can keep them just with one that’s better than more.
Bottom Line:
Ø An initial combination
therapy approach, with
or without biologic,
achieved higher
remission rates than a
sequential or step-up
approach, with earlier
functional ability and
less joint damage
(maintained long-term)
Ø However, >50% of
patients still achieved
remission in Gr 1 & 2!
So instead of just one or two or three, they had this step up approach. If one didn’t work, they added another. If two didn’t work, they added another. And then they also looked at an initial combo with a biologic. So infliximab, TNF inhibitor
A more aggressive strategy. Lead to more patients achieving remission. But again, we have to acknowledge that more than 50% of folks still did well with those initial two strategies.
Treat to Target Strategies
Step Up:
Initial monotherapy
Add DMARDs q3-6mo prn
Combination:
Initial combination therapy
Add/switch DMARDs q3-6mo prn
Step Down:
Initial biologic DMARD and/or
prednisone in combination
Add/switch DMARDs q3-6mo prn
The bottom line here is, doesn’t matter how you get there, we just need to get there. So in North America and in Europe, we use in general a step-up approach. So we’re starting with methotrexate monotherapy. We’re adding, we’re reassessing every three months.
Disease Modifying Antirheumatic Drugs
Conventional Synthetic (csDMARDs)
● methotrexate
● leflunomide
● sulfasalazine
● hydroxychloroquine
● (chloroquine)
Targeted Synthetic (tsDMARDs)
● tofacitinib
● baricitinib
● upadacitinib
Biologic (bDMARDs)
● adalimumab
certolizumab
etanercept
golimumab
infliximab
● abatacept
● tocilizumab,
sarilumab
● rituximab
CRA Guideline Recommendations
Initial Treatment Strategy
● DMARDs should be introduced as soon as possible
○ MTX is the preferred agent with respect to efficacy & safety
● Initial combination therapy with csDMARDs should be considered in those
with:
○ Poor prognostic features
○ Moderate-high disease activity
○ Recent onset disease
● When treating with combination therapy, MTX should be used as the
‘anchor drug’ unless contraindicated
○ Combinations of MTX + LEF require caution
● Monitor disease activity every 3 months until remission achieved
○ Adjust DMARD therapy every 3 to 6 months until goal achieved
Approach to Treatment
Canadian Rheumatology Association (2012)
Establish diagnosis (RF, ACPA)
and baseline for follow-up (drug
efficacy and safety monitoring)
Adds measures to ensure safe
to start and baseline for safety
monitoring
ensure that we’re safe to start and to form a baseline for us to move forward with disease-modifying anti rheumatic drugs.
DMARDs
● Mainstay of RA treatment
○ modify disease process
○ prevent/reduce joint damage
● Are ‘immune modulating’ more than ‘immunosuppressive’, by a
variety of mechanisms
● Require months for response
○ should be initiated soon after disease onset, usually in combination
■ commonly co-prescribed with short course of prednisone or NSAID as
‘bridging’ therapy
We need to modify it in order to bring it back down to its baseline level where it can do what it needs to do. So when we modify that immune system, we know that we decrease all of the long-term complications associated with rheumatoid arthritis, including cardiovascular disease, including infections and including the cancers that are associated with it.
disease-modifying drugs that all act on the immune system, it’s like we’re getting at the root of the problem. We’re working on that specific pathophysiology
So things like prednisone, steroids, things like NSAIDS that will help patients but dont deal w root of problem
we’re reassessing folks every three months, It’s because that’s where we’re expecting to see most of the impact already happening in that six-month window.
Methotrexate
Dose: 15-25mg WEEKLY
● initiate as oral, IM or subcut (with rapid dose escalation to 25mg)
○ unpredictable (and poor) oral bioavailability over 15mg
● reduce dose by 50% if CrCl 10-50mL/min (some say avoid if <30)
Efficacy
● onset: 2-4 weeks (rapid); max effect: 3-6 months
● effective in moderate-severe RA
○ ~30% of patients in trials achieved remission/LDA with MTX monotherapy
● no other csDMARD monotherapy has been shown to be superior
○ improves clinical and radiographic outcomes
○ shown in observational studies to reduce mortality
● most often used in combination (Anchor Drug)
○ any of the csDMARDs, bDMARDs, tsDMARDs
SC is used more for RA
It enables us to use the dose range that we want to and feel confident that we’re getting all of that dose absorbed. With the oral bioavailability of methotrexate not being great, maxes out at about 15 mg.
Easy to combine w other drugs
methotrexate was the first drug to show an observational studies that it reduces that early mortality associated with rheumatoid arthritis. And it does that mostly by reducing cardiovascular risk
Methotrexate: MOA
It’s Complicated!
●Inhibits dihydrofolate reductase – inhibiting purine synthesis
○ MOA in cancer chemotherapy
○ unlikely MOA at low doses used in rheumatic disease
■ but does lead to many of the common adverse effects seen
●Stimulates release of adenosine
■ inhibits neutrophils and has potent antiinflammatory properties
○ Clinical Pearl:
■ if MTX is working, MCV will increase by ~5 pg/fL over baseline
Methotrexate: Adverse Effects
● Common:
○ mouth/nose ulcers (3-10%) (folic acid)
○ nausea, vomiting, loss of appetite (>10%) (folic acid) Usualyl right after the 1-2 days after inj
○ fatigue, malaise 24-48h after dose (dextromethorphan)
● Less Common:
○ photosensitivity (sunscreen), rash
○ hair loss (folic acid)
○ ALT/AST elevation (folic acid)
○ ¯WBC, platelets (1%) (folic acid)
● Rare:
○ pneumonitis (hypersensitivity)
○ cancer (reversible lymphoma)
Mouth sores more common than nose ulcers
loss of appetite due to even a change in taste or smell is common for patients with rheumatoid arthritis
Photosensitivity is important for patients with rheumatoid arthritis because methotrexate, sulfasalazine, and hydroxychloroquine can sensitize to the sun. And sometimes patients will have not only a burn but more of a sudden rash.
patients should be going for bloodwork at least every 4 weeks when they first start
actual allergic reaction to methotrexate
if they have new shortness of breath, should definitely be. See a physician for appropriate diagnosis.
Methotrexate: Managing AE
● Folic Acid
○ works as a ‘rescue agent’ for cells that are rapidly dividing and thus are
affected by MTX inhibition of dihydrofolate reductase
■ dose may range from 1-10mg daily to 1-10mg weekly
■ no need to ‘skip the day of MTX’ (but ‘ok’ to do so)
○ use of vitamin B12 may also help reduce these AE
● Dextromethorphan
○ blocks neurostimulation of homocysteine (increased due to MTX) at NMDA
receptor in brain, which leads to headache, lethargy, malaise, memory
impairment/fogginess
■ DM 10mL BID on day of and day after MTX
■ few use this strategy, but may work in up to 50% of patients
Dose may range anywhere 1-10 mg a day to a week.
- some patients might do well and they don’t have many methotrexate related adverse effects. And they’re on 1 mg of folic acid the day after their methotrexate. And that’s it.
- If AE, 10mg/day
- water-soluble vitamin, to worry if it’s too much, patients will just pee it out.
, when you antagonize folic acid, you get an increase in homocysteine. And that is, that is happening because of the methotrexate and it’s binding this NMDA receptor
this is a strategy that’s been used in oncology when we’re using cancer doses of methotrexate, which are much bigger than they are for inflammatory arthritis
Methotrexate: Precautions
● Medication Errors:
○ dose, frequency mistakes still happen
○ missed doses – how would you handle this?
● Alcohol Use:
○ many different recommendations exist
■ 1-2 drinks per week (after safety established)
■ Pearl: avoid binge drinking and consuming alcohol within 24h of MTX
dose
Contraindicated
in pregnancy
I forgot to take my methotrexate. It’s now Thursday. I was supposed to take it on Tuesday. What should I do?
Take it ASAP
if that patient said Thursdays, thursdays are better for me. Great. Keep it on Thursday. What if they wanted to shift back to Tuesday?
I would recommend that folks don’t move it more than one day in any given week. So Thursday this week, Wednesday, next week, Tuesday the week after. So don’t shift it by more than one day
you might see some elevations in ALT that eventually settled down. Following patterns of ALT is as our best indicator for any potential long-term chronic liver issues is our best strategy
