RA 2 Flashcards
DMARD Monitoring
CBC/diff ALT Albumin SCr CXR HBV/HCV
Baseline
q1-3mo
HCQ baseline, annually
ALL Ongoing Signs of infection; serious complications
PFT for MTX: preexisting lung disease or they were someone who presented with new shortness of breath that needed to be investigated, Is this a hypersensitivity to methotrexate
BP for LEF not for everyone ; on the cusp or treated for HTN
Some csDMARD Tips
● Infections
○ usually no increased risk
○ may last a little longer or seem a little worse
○ stop therapy if severe infection (ie, hospitalized) or on advice of
physician only (ideally in consultation with rheumatologist)
● Procedures/Surgery
○ most physicians/dentists will allow ongoing therapy
■ if concern, should speak with rheumatologist
● Utilized in those with an inadequate response to csDMARDs
○ Moderate-high disease activity despite treatment with at least 2
csDMARDs (mono/combo) after 3 months at target dose
○ Co-prescription with MTX recommended for improved efficacy
● TNFi usually recommended as initial ‘advanced therapy’ but could
use any bDMARD or tsDMARD
○ No response to TNFi: switch to alternate bDMARD or tsDMARD
■ called ‘primary failure’
○ Fail TNFi after year(s): switch to alternate TNFi, other b/tsDMARD
■ called ‘secondary failure’
Biologic DMARDs
● “Immune modulating” therapies
○ block specific parts of immune system – targeted therapy
● Highly effective, but also more risks involved compared to traditional
DMARD therapy
○ reduction in damage
○ ¯ symptoms
○ ¯ CV risk
○ But…infection risk
● MTX remains the Anchor:
○ improves effectiveness
○ reduces production of anti-drug Ab ( INFL) (dose ³10mg)
■ Increase risk of infusion/allergic reactions
■ Decrease effectiveness of bDMARD (cleared)
bDMARDs – The Science
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How Effective Are bDMARDs?
bDMARD
Sequence
ACR 20/50/70
Response
1st bDMARD: TNFi
* With MTX
* Alone
60/40/20%
45/25/12%
2nd bDMARD
* TNFi + MTX
* Any other + MTX 50/25/12%
TNFi
● Efficacy
○ Onset: ~2 weeks, peak 3-6 months
○ all have similar efficacy for use in moderate-severe RA
■ ~60% of patients will respond
■ trial of 1 (maybe 2) TNFi agents prior to moving onto alternate bDMARD
● Contraindication
○ HF (NYHA Class III-IV)
○ MS: personal history (and 1st degree relatives?)
○ active cancer (caution: history of lymphoma or skin)
○ [may also trigger lupus-like syndrome, psoriasis]
TNFi
Adalimumab
(Humira®, Abrilada®, Amgevita®, Hyrimoz®,
Hadlima®, Hulio®, Idacio®, Simlandi®,
Yuflyma®)
40mg subcut every other week
± MTX
Certolizumab
(Cimzia®)
400mg subcut @0,2,4wks;
then 400mg q4wks
± MTX
Etanercept
(Enbrel®, Brenzys®, Erelzi®)
50mg subcut weekly
(or 25mg subcut 2x/week)
± MTX
Golimumab
(Simponi®)
50mg subcut monthly
2mg/kg IV @0,4wks; then q8wks with MTX
Infliximab
(Remicade®, Avsola®, Inflectra®, Renflexis®)
(Remsima SC®)
3mg/kg IV @0,2,6wks;
then q8wks (can be to q6wks) x
120mg subcut q2wks
with MTX
Abatacept (Orencia®)
● MOA: T-cell co-stimulation modulator
○ mimics CTLA4, preventing CD28 from binding to its counter-receptor CD80/86, enabling T regulatory activity to continue
● Available both as IV and subcut formulation
● Efficacy:
○ Onset: 2-4 weeks, peak 3-6mo
○ Used in moderate-severe RA who fail TNFi
■ ~50% will respond to abatacept
■ Used preferentially with MTX
● Caution:
○ May ↑ incidence of AECOPD & pneumonia
IL-6i:
Tocilizumab (Actemra®)
Sarilumab (Kevzara®)
● MOA: bind membrane-bound and soluble IL-6 receptors
● TOC available IV and subcut; SAR only subcut
○ ensure ANC >2, platelets >100, ALT/AST <1.5x ULN
● Efficacy:
○ Onset: 2-4 weeks, peak 3-6mo
○ used in moderate-severe RA who fail TNFi
■ 30-50% will achieve response/remission
○ more effective with MTX (good evidence for TOC monotherapy)
● Caution:
○ Risk of GI perforation if history diverticulitis (RF: NSAID, prednisone)
IL-6i: Lab Monitoring
CBC /differential Platelets ALT / AST Lipids
baseline
@4-8 weeks
Every 3-6 months
Periodically
Fun Fact:
● elevated IL-6 (↑↑ CRP) down-regulates CYP enzyme activity
○ monitor drugs with narrow therapeutic index when start IL-6i
Rituximab
(Rituxan®; Truxima®
, Ruxience®
, Riximyo®
, Riabni®)
● MOA: B-cell inhibitor
● Dose: 1000mg IV @0,2wks every ~6 mo
○ patients should not be expected to flare before retreatment
○ always given with MTX
● Efficacy:
○ Onset: 8 weeks, peak 4-6 months
○ used in moderate-severe RA who fail TNFi
■ evidence supports use in Rf+ patients
○ preferred biologic in patients with:
■ B-cell lymphoma
■ latent TB infection
■ multiple sclerosis
■ concomitant vasculitis or overlap syndromes
bDMARD: Adverse Effects
● Infections:
○ URTI, sinusitis, pharyngitis, UTI
■ TNFi: URTI more common in first year
○ RARE: opportunistic infections (PCP, TB, candidiasis)
■ Serious infxn/OI assoc with: age, COPD/asthma, DM, CKD, prednisone
● Allergic Reactions:
○ Infusion reactions: INFL, RTX (£25%)
■ Pre-medicate: acetaminophen, cetirizine/loratadine, ± methylpred
○ Injection reactions (£ 10%)
● Fever, malaise, headache, backache/muscle ache (£ 10%)
● Nausea, diarrhea, GI upset (£ 10%)
Ø Remember to always compare AE rates between drug and placebo/comparator
Ø Consider overlap with s/s of undertreated disease as well
The Cancer Story…
● Historically increased risk of solid tumours (lung, prostate, cervical,
melanoma) and lymphoma in patients with RA
○ Risk correlates with severity and duration of disease activity
■ Which also correlated with use of various DMARDs…
● Most recent systematic review (EULAR 2019):
○ No increased risk with bDMARDs vs. general population or those on
csDMARDs (even if history of cancer)
■ Excluding non-melanoma skin cancer, where:
● MTX and bDMARDs were associated with a small risk compared to the
general population
● ABA (Tcell inhibitor) associated with risk (aHR 2) compared to csDMARDs
and TNF
What are biosimilars?
● Proteins intended to be sufficiently similar to originator product already
approved by a regulatory agency
○ ‘copies’ of originator biologics… similar to ‘generic’ drugs, but…
● Biosimilars are distinct from generics because:
○ generics are identical to the reference product, whereas biosimilars are
‘highly similar’
○ synthesized in living cells, are highly complex, and may have some variation
in each batch that is manufactured
○ at least one clincal study is required to compare the biosimilar to its
reference product
Clinical Development of biosimilars
Used to resolve
uncertainties in the
similarity of the
products
Used to
characterize
changes in
manufacturing
process during
development and
post-approval
Assessment
of biosimilarity
to licensed
reference
‘originator’
product
Companies, researchers are spending most of their time at the bottom part of this pyramid looking at analytical assays and functional assays as the reverse engineer these proteins and figure out exactly how to get the right sequencing. And so it’s binding to the receptor and doing everything that it wants to do.
unlike other studies, when drugs are coming to the market, only one clinical trial needs to be done. And it can be an all encompassing one looking at the kinetics as well as the clinical effects. So unlike a typical randomized control trial for a drug coming to market, their equivalent studies, right?
Equivalence Studies
● No clinically meaningful difference between biosimilar and originator
Originator Better Biosimilar Better
Risk ratio of the point estimate
± 95%CI lies within predefined
equivalence margin
(-! to +!)
Risk ratio of the point estimate
lower 95%CI no less than NI
margin (-!)
Alberta Health: Biosimilars Initiative
AIM: to expand the use of lower cost biosimilars on government
sponsored drug programs
○ savings to help ensure Alberta has a patient-centred health system
focused on providing the high quality care Albertans deserve
○ Reference Based listing: INFL, ETN, RTX, ADA
■ all patients have been switched to biosimilar product
interchangeability vs substituability
Interchangeability
● “Expected to produce the same
clinical result in any given patient”
● Substitution of innovator product
with the new product
○ usually a financial decision (most
cost-effective product)
● For example:
○ hydroxychloroquine for Plaquenil®
○ Inflectra® for Remicade®
Substitutability
● “Expected to produce similar
clinical outcome”
● Substitution of different drug
considered functionally
equivalent to treat a condition
○ usually a formulary or
coverage decision
● For example:
○ Prevacid® for Pantaloc®
○ Inflectra® for Humira®
´ Provincial regulation of a pharmacist’s ability to interchange or substitute an
biosimilar, however Health Canada has recommended against it.
because of that work that’s being done behind the scenes and might already be well in progress for a patient. If there’s some reason why we can’t get a particular biosimilar in. We want to have that conversation with the prescriber so that we move forward together and we’re not duplicating efforts behind the scenes.
Real World Switch Data - FYI
How to Combat the Nocebo Effect
Bottom Line:
* Inflectra found to
be ”similar” to
Remicade from
efficacy and
safety standpoint
* Reassuring data
supported switch
protocols around
the world
Defined: When negative perceptions (based on gaps in knowledge) trigger feelings of uncertainty and
ungrounded negative attitudes toward biosmilars, negatively impacting adherence and treatment outcomes
see slide 68
health care professionals can influence how patients receive medications and decide to be adherent to those medications. S
discussion, joint decision-making, than those patients hopefully feel empowered to move forward with drug therapy.
We have our own patient experiences that we can then share back with patients. So maybe dispel some myths that they’re hearing about, about biosimilars or any other drug product, right? Even methotrexate, there’s so much online about h
JAK Inhibitors
● MOA: Small molecule inhibitor of JAK-induced cytokine production
○ Tofacitinib (Xeljanz®)
○ Baricitinib (Olumiant®)
○ Upadacitinib (Rinvoq®)
● Efficacy:
○ Onset: 2-4 weeks, peak 3-6mo
○ Used in moderate-severe RA who fail csDMARD +/- bDMARD
■ May be used with or without MTX
○ Less likely to lose effect than bDMARDs (no anti-drug Ab)
● Caution:
○ Risk of GI perforation if history diverticulitis (RF: NSAID, prednisone)
stops the down stream cascade of activation of multiple different types of cytokines. They work in some ways very similarly to IL-6 inhibitors because they also drive down that CRP. They’re really good at getting down that systemic inflammation.
we use a lot more tofacitinib and upad than bari
they’re like oral biologic. So this is a pill like biologics. They’re taking that slice out of the immune system. So really specific in how they’re targeting.
How Effective Are tsDMARDs?
csDMARD naïve
* With MTX
* Alone
75/50/25%
70/50/25%
Failed csDMARD (MTX)
* With MTX
* Alone
70/40/25%
60/30/15%
Failed bDMARD
* With MTX 45/25/12%
JAKi: Adverse Effects
● Common (>5%):
○ URTI, nasopharyngitis
○ headache
○ diarrhea (TOF)
● Less Common:
○ serious infections (including opportunistic, TB, herpes zoster)
○ ¯WBC, Hb
○ LDL (0.6mmol/L)
○ ALT/AST elevation (>1x ULN)
○ TOF: bradycardia (¯HR 5-7 beats, lengthen PR interval)
● Caution:
○ VTE (DVT or PE): signal with BAR (close surveillance for all JAKs)
○ Cardiovascular Events / Cancers: post marketing surveillance
Tofa: on rate-limiting medication, something to be aware of that they might have a little bit more symptomatic bradycardia might not be a great medication for them
Bari: signal w/ VTE
TOF Safety: ORAL Surveillance
ORAL-Surveillance
Ann Rheum Dis 2022
Type PROBE (N=4362) NIT
P Active RA ≥50 with ≥1 CV risk factor or CVD
I/C TOF 5mg BID vs.
TNF inhibitor (adalimumab or etanercept)
(+MTX, other csDMARDs)
F/U 4 years (median)
O 1° MACE: 3.2 v 2.5%, HR 1.24 (0.81-1.91) (did not meet NI)
* Hx ASCVD: 8.3 v 4.2%, HR 1.96 (0.87-4.40) (did not meet NI)
* No Hx: 2.4 v 2.3%, HR 1.03 (0.62-1.73) (met NI)
there was a difference. You can see the primary outcome, major adverse cardiovascular events
id not meet non-inferiority. So it wasn’t totally worse than on that side of the line of no effect, but the confidence interval did pass that non-inferiority margin can’t say that they are similar.
those who had a history of atherosclerotic cardiovascular disease were the ones who are driving that outcome. In folks who had no history seemed to be a little bit more similar
Need to be cautious for JAK inhibitor prescribing for over the age of 65 who have multiple cardiovascular risk factors or history of cardiovascular disease
JAKi: Lab Monitoring
Baseline
@4-8 weeks
Every 3 months
Every 6 months (TOF)
Periodically (BAR, UPA)
*BAR contraindicated GFR<60
the lipids not so much related to what’s happening with cardiovascular disease. It’s more that suppression of that systemic inflammation that unmasks the lipids and they increase just a little bit
bDMARD/tsDMARD: Tips
● Infection:
○ Hold until 48h after antibiotics complete &/or symptoms resolved
■ Including topical infections - eye/ear/skin/thrush
■ Do not need to hold for minor illness (cold) – consider delay if bad
○ May not respond the same to infection
■ Including fever, congestion (nose, throat), etc
■ Potential infections need to be assessed and antibiotics started promptly
○ Prevention:
■ Ideally vaccinate 4 weeks prior to initiation; AVOID LIVE vaccines
● Peri-operative
○ Hold pre-op and post-op to decrease risk of infection and ensure
appropriate healing
■ Timing dependent on the bDMARD and the operation
Drug Coverage
ABC Special Authorization / NIHB Requirements
* In severely active rheumatoid arthritis refractory to:
* MTX (3 month trial, ≥20mg dose (≥15mg if >65yo))
* MTX IM or subcut (3 month trial, ≥20mg dose) (if no response; if GI intolerance)
* MTX plus another DMARD (eg. HCQ, SSZ) (4 month trial) (+2 other DMARDs)
* If MTX contraindicated, a combination of 2 csDMARDs (3mo trial)
* leflunomide 20mg/day (10 week trial) (n/a)
* if prescribing rituximab, then antiTNF (n/a)
* For continued coverage must have a good response
* Must be initially prescribed by an authorized prescriber
* Only one biologic covered at a time, cannot switch back to a previously tried biologic
All bDMARD and tsDMARD companies have a ‘support program’ that help patients
manage their therapy & supports acquisition
trying methotrexate ensuring that it’s been done by injection. So either subcutaneous or IM must be used in combination with another conventional synthetic DMARD. For Alberta Blue Cross and specifically for rheumatoid arthritis. Leflunomide needs to have been trialed. And then if rituximab, a TNF inhibitor for Alberto Blue Cross,
for continued coverage, we need to continue to demonstrate that the drug was effective. Disease measures have been reduced so that Das 28 score and that that response is, is continuing and safety is followed as well.
Monitoring for Sarah
Effectiveness
● Signs/Symptoms
○ pain (VAS)
○ duration of morning stiffness
○ fatigue
○ tender & swollen joints
○ activities of daily living (function)
○ (deformities, instability)
○ (EA manifestations)
● Lab/Diagnostic Imaging
○ CRP (preferred to ESR)
○ (X-rays - not generally done)
Safety
● Signs/Symptoms
○ per individual drug (e.g. rash,
injection site reaction)
● Lab
○ per individual drug (e.g.
CBC/diff, lip
CRA Guideline Recommendations
Treatment with Glucocorticoids and NSAIDs
● Steroids can be added to DMARD therapy as part of the initial
treatment strategy
○ oral or intramuscular (or intraarticular)
● Steroids and NSAIDs may be used as an option for:
○ Managing flares
○ As bridging therapy while awaiting DMARD onset
○ Symptom control, if no other options exist
● Should be used in the lowest possible dose and tapered as rapidly as
possible
Oral or IM Steroids, NSAIDs
● Beneficial for managing symptoms affecting many joints
○ decrease pain, inflammation, and stiffness to improve function
○ do NOT alter disease outcomes
● Common regimens:
○ Prednisone 20mg daily x 2wks, taper by 5mg q2wk (8wks total)
○ Methylprednisolone acetate 40-80mg IM
■ self tapering so may help prevent ‘steroid cycling’
○ Naproxen 550mg po BID
● Frequently used in practice
○ use lowest effective dose for shortest duration & as infrequently as possible
naproxen as maybe the more preferred. And said from a cardiovascular risk point of vie
Steroids: Intraarticular
● Useful in controlling residual synovitis in a (single) joint, tendon, or bursa,
with less systemic toxicity
● Dose:
○ Methylprednisolone acetate 10-80 mg IA
○ Triamcinolone acetate 20-80 mg IA
● Efficacy
○ relief onset in few days, lasts weeks to months
● Frequently used in practice
○ most useful when only one or two inflamed joints
○ may help avoid ‘steroid cycling
maybe be the thing that puts them into remission or at least as something that’s effective for four months. I got here may help avoid steroids cycling. So remember people feel good on steroids and they feel not so good when they come off.
not only because they can function with inflammation but because of their mood. So using them through intra-articular injections and or intramuscular injections can help avoid that cycle.
Adjunct Therapy
● May be needed on occasion or for patients with residual pain but no
synovitis (query OA?)
○ help manage symptoms, but do not affect course of disease or
prevent damage to joints
● May include:
○ Analgesics: acetaminophen, opioids, cannabis
○ Anti-inflammatories: NSAIDs (po or topical)
○ NHPs
● Some relief within hours, but may take days or weeks to work fully
○ if it hasn’t worked within a month, it is unlikely to
● Some evidence to support:
○ Omega-3 fatty acids…in a dose of ~3.5g EPA+DHA!
■ anti-inflammatory effect supports DMARD efficacy/regimen longevity
○ Calcium/Vitamin D
■ to modify osteoporosis risk
● Some things to avoid:
○ immune system ‘boosters’ such as ginseng (including ColdFX), echinacea
Patient / healthcare professional arthritis specific monographs available at:
www.albertarheumatology.com
Sarah is prescribed:
MTX 25mg subcut weekly
HCQ 200mg alternating with 400mg po daily
Would you add anything as a ‘bridge’?
we wouldn’t want to do multiple in-charge peculiar injections. We would see that type of steroid use for someone who has one or two joints that are that are being impacted.
Prednisone 20mg daily x 2wks then taper 5mg 12 wks for 8wks total
Role of the Pharmacist
● Empower patients to take an active role in making therapy decisions
● Patient Assessment and Medication Management
○ efficacy measures: components of DAS-28, lab work
■ “How are you managing at home?” (self-care, household chores)
■ “When you wake up in the morning, are you more stiff than later in the day? How long
does it last?”
■ “Considering all of the ways your arthritis has affected you over the past week, how
would you rate yourself on a scale of 0 to 10?”
■ “Is there anything you’re not doing because of your arthritis that you’d like to be?”
○ safety measures: s/s, lab work(!!)
● Management of Complications / Co-Morbidities
○ tobacco cessation
○ screening for cardiovascular risk, modifiable RF
■ 2021 Dyslipidemia guidelines – screen regardless of age
○ osteoporosis
■ 2010 Osteoporosis guidelines
● measure BMD once age ≥50
● prescribe therapy if prednisone ≥7.5mg/day x3mo cumulative dose
○ screening for depression
○ screening for indicated vaccines
Core Vaccine Recommendations
nfluenza Ideally HD (if have coverage) Annually
Pneumococcus
Prevnar-13 (conjugated) * Once
Pneumovax (PPV-23) (polysaccharide) * Given 8 weeks later
(+booster ³5 years later (@age ³65))
Tetanus Tdap Pertussis once as adult
Td Every 10 years
Zoster Shingrix Age >50 ±hx of shingles ³1 year prior
COVID-19 mRNA vaccine: 3 dose primary Boosters as recommended/available
Vaccines for At Risk Groups
Hepatitis A /
Hepatitis B
Twinrix (HAV+HBV)
Recombivax, Engerix-B (HBV only)
0, 6-36 months later
0, 1, 6 months
HPV Gardasil: 3 dose regimen Age >26 and <45
we do want all of our patients to be annually vaccinated for influenza at any age, to be vaccinated with the pneumococcal vaccine. So both Prevnar and Pneumovax 23, ideally, in that order.
Tetanus boosters
Shingrix: rheumatoid arthritis, longstanding, uncontrolled, are at higher risk of shingles and shingles recurrences
- we vaccinate at age 50 rather than at age 60.
- also vaccinate anyone who’s starting on a JAK inhibitor regardless of age
COVID
- 3 dose, 5th dose avail and recommendede
hepatitis a and B and HPV
- if folks haven’t been vaccinated yet in, in schools and are 26-45 years of age, both men and women.
bit more on vaccines
some response is always better than no response.
Caution with respect to the biologics and targeted synthetic. So live vaccines contra indicated for sure. Inactivated vaccines considered safe for all groups.
ooster like MMR would be more likely to be considered safe, buy more health care providers. Something like yellow fever vaccine, which is likely a novel antigen, would be something that we would want to avoid in people who are on any type of disease modifying therapy.
● Immune response when vaccines are administered:
○ May not be as strong; may not last as long
○ Efficacy most reduced by MTX, prednisone, RTX
○ But still 100% WORTH IT!!!!
● csDMARDs
○ inactivated vaccines considered safe
○ some live vaccines considered safe
■ MMR booster
● bDMARDs and tsDMARDs
○ inactivated vaccines considered safe
○ LIVE vaccines CONTRAINDICATED
there is guidance now to hold methotrexate for two weeks after influenza vaccine with the caveat, if disease activity allows
