Rheumatoid Arthritis Flashcards
What is rheumatoid arthritis (RA)?
Systemic autoimmune disease
Is rheumatoid arthritis usually symmetric?
Yes
Does it usually affect multiple joints?
Yes, it’s described as erosive polyarthritis
What are physical symptoms of rheumatoid arthritis?
- pain
- stiffness
-fatigue - morning stiffness greater than 30 min
- multiple swollen joints in a symmetric distribution (including hands and feet)
Can RA affect internal organs?
Yes, it can have systemic manifestations
At what age can RA start?
At what age does it most frequently start?
RA can start at any age (even childhood).
Most commonly starts at age 50-60
Is RA more common in women or men?
Women
What comorbid conditions do those with RA have a higher risk of?
CV disease
CV mortality
Osteoporosis,
Lymphoproliferative disease
Depression
What’s the typical management approach to RA?
Early approach
Start DMARDs as soon as diagnosis of RA is made
What’s a goal of therapy marker?
50% clinical improvement within 3 months and ideally remission
If remission is not possible, target low disease activity within 6 months
What is remission defined as?
Absence of disease activity that is verified by the:
- clinician (swollen and tender joints)
- patient (global assessment of disease activity)
- lab values (CRP and/or ESR)
What non-pharm are usually required for RA patients?
- patient education
- emotional
- psychological support
- physical rehabilitation
Which supplement is beneficial for RA?
Dietary omega-3 PUFA
Does cannabis help with RA management?
No evidence to support
What are the the three types of DMARDs that can be used as treatment for RA?
- Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) -> traditional
- Biologic DMARDs (bDMARDs)
- Targeted synthetic DMARDs (tsDMARDs)
What can biologic DMARDs be further categorized into?
-Bio-originator DMARDs (boDMARDs)
-biosimilar DMARDS (bsDMARDs)
Following diagnosis by rheumatologist, what are patients usually started on?
csDMARD therapy
Where do corticosteroids (IM or PO) come into play?
Early management of RA as bridging therapy (manages the symptoms, as it takes time for DMARDs to start working)
As minor adjustments in between csDMARDs therapy if patient is receiving repetitive flares or progressive joint damage
Also if patient has evidence of drug toxicity
What corticosteroids are often used in RA treatment and what are the doses?
When starting or changing csDMARDs= short-term, low dose therapy (30mg/day of prednisone with tapering)
- If looking for depot options for bridging, there is methylprednisolone and triamcinolone
If using depot preparations of corticosteroids, what s/e must we watch for?
Atrophy of superficial SC soft tissue
Particularly triamcinolone
Therefore, it’s typical to inject into gluteal muscle to lower risk of lipoatrophy
Can increase blood sugars for up to 10 days (counsel)
What other side effects are present for all corticosteroids in general?
Increase blood sugars, increased BP, adrenal suppression
Can increase risk of MI, aggravate osteoporosis and CV disease (which is already worse for RA patients)
Avoid using corticosteroids with NSAID, increased risk of PUD
Where do NSAIDs come into play?
Provide further symptom control
When should we be cautious about using NSAIDs?
Renal impairment
Hypertension
Elderly
History of peptic ulcer disease
If we need to be cautious about NSAIDS, what kind of NSAID would provide a better safety profile?
Topical NSAIDs like diclofenac
When do we expect to see improvement with csDMARDs?
6-8 weeks of therapy following start of therapy
When do csDMARDs reach maximum effect?
3-6 months
When patient’s disease is active, how frequently should they be seen?
At least every 3 months
Once disease is stable, when how often should the patient be seen?
Every 6-12 months
How do we decide how frequent and how much to adjust dosing?
Goal is to have patient in remission or at low disease activity by 3-6 months.
Major changes to therapy (adding or switching agents) can be considered if disease activity is ongoing after 3 months of maximal therapy.
What are some poor prognostic factors that are modifiable?
Smoking
Sedentary lifestyle
Delay in treatment initiations
Which drugs are considered csDMARD therapy?
- Methotrexate
- Sulfasalazine
- Leflunomide
- Hydroxychloroquine
Of the csDMARD drugs, which is considered the gold standard?
Methotrexate (anchor drug)
What is considered an adequate trial of methotrexate
Weekly maximum dose of 25mg (PO or SC) for at least 3 months
While many brands do not like subcutaneous administration as an approved route, it is _______ to administer (in _____ thigh or ______ by the patient themselves), _______ painful, safer, and more effective than IM.
Also provides more __________ blood levels than oral.
easier
upper
abdomen
less
consistent
Is IM methotrexate used often?
No rarely
When should oral doses be split in a 24 hour period to improve absorptions?
When doses are greater than 15mg
What side effects from methotrexate can contribute to discontinuation?
GI adverse effects
Aphthous ulcers
Liver dysfunction
How can these side effects be managed?
Concurrent use of folic acid (at least 5mg/week)
When is this does of folic acid given?
Usually the day after methotrexate administration, but may be administered daily
Avoid on the day of methotrexate
What’s an alternative to folic acid?
Folinic acid 5mg/week, 8-12 hours after methotrexate dose
When do we consider using folinic acid as an alternative to folic acid?
When patient is experiencing methotrexate side effects despite supplementation with folic acid.
When is sulfasalazine monotherapy considered in RA therapy?
- when methotrexate is contraindicated
- if patient has early, very mild disease and absence of poor prognostic factors
Is sulfasalazine equally effective as methotrexate?
No, evidence of effectiveness is limited compared to methotrexate
What’s another csDMARD that can be used as monotherapy?
When does it come into play?
Hydroxychloroquine
Very mild disease
Is hydroxychloroquine as effective as other csDMARDs?
No, it has less impact on joint damage compared with other csDMARDs
What’s a side effect with hydroxychloroquine that we have to monitor for?
Long-term use has risks of retinal toxicity
- patient requires regular eye exams (6-12 months)
Is sulfasalazine and methotrexate commonly used as monotherapy?
No, it’s more often used in combo with methotrexate
What’s the last csDMARD that can also be added to or used instead of methotrexate?
Leflunomide
What’s a bothersome side effect with leflunomide?
What’s a serious adverse event to watch out for with leflunomide?
Loading dose of leflunomide causes significant diarrhea and is no longer recommended
Severe livery injury, and patient with severe side effects require washout
What drug can be used to washout leflunomide?
Cholestyramine
Activated charcoal
When do we begin to consider combination therapy with DMARDS?
When patients have inadequate response to csDMARD monotherapy (usually methotrexate)
If methotrexate monotherapy is not adequate, do we usually stop and switch?
No, we usually keep it and add other agents
What treatment combination has the best evidence to support its use?
Methotrexate + hydroxychloroquine + sulfasalazine
Triple therapy
What’s the efficacy of triple therapy?
Superior to methotrexate alone and similar to methotrexate and a biologic
If patients wonder if triple therapy is safe, what do we say?
Yes. There may higher rates of GI intolerance but usually improves over time.
Methotrexate and leflunomide has not been shown to be superior and is associated with higher toxicity.
If this combo is used, how do we manage?
Higher GI and liver toxicity
Dose of one or both should be reduced if used in combo.
Oral and parenteral gold, minocycline, D-penicillamine, azathioprine, and cyclosporine was once used, but is there still evidence?
No, not part of guideline-recommended therapy?
How do biologic DMARDs work on RA?
Target key mediators of inflammatory synovitis, bone and cartilage destruction (Ex: TNF-alpha)
If patient only has partial response to biologic therapy, how do we adjust therapy?
Maximize the use of methotrexate or add other csDMARDs
What are the different classes of biologic dMARDs (bDMARDs)?
- Tumour necrosis factor inhibitors (TNFi)
- infliximab (IV)
- adalimumab (SC)
- certolizumab (SC)
- etanercept (SC)
- golimumab (SC/IV) - Interleukin inhibitors
- Tocilizumab (IL-6)
- Sarilumab (IL-6)
- Anakinra (IL-1)
Of the two classes of biologic DMARDs, which one is most commonly used? Why?
TNFi are used most commonly as first-line due to long-term safety data
However, other agents are also approved for first-line use
Are TNFi agents more effective as monotherapy or combo?
Most effective when used with methotrexate or another csDMARD
When do we start to see rapid improvement with TNFi?
Within 8-12 weeks
How do we pick and choose between the 5 TNFi agents?
Infliximab
Adalimumab
Certolizumab
Etanercept
Golimumab
Mouse-human monoclonal antibody= infliximab
Fully humanized= adalimumab, certolizumab, golimumab
Certolizumab= pegylated so does not pass into placenta or breast milk
Etanercept= unique mechanism compared to other TNFi
What do we do if the first TNFi is inadequate or loses response?
What if second TNFi does the same?
If first TNFi choice fails, switch to any other biologic.
If second TNFi choice fails, switch to a biologic with a different MOA
When does interleukin inhibitors come into play?
For patients with moderate to severe disease with inadequate response to csDMARDS
Are interleukin inhibitors more effective as monotherapy or combo therapy?
Effective as monotherapy, but preferred to be combined with MTX
What are unique adverse effects to IL-6 therapy?
Drug-induced liver injury, neutropenia, increased risk of bowel perforation
What type of interleukin inhibitor is Anakinra?
Is it effective?
Il-1 receptor inhibitor
Not as effective so rarely used
Higher risk of injection site reactions, but fewer significant infections compared to TNFi therapy
When does abatacept come into play? How does it work?
Natural inhibitor of T-cell to decrease immune response
For when patient have had inadequate response to 1 or more csDMARDs and/or TNFi therapy
What makes rituximab unique?
Chimeric monoclonal antibody that removes memory B cells while leaving plasma B cells intact.
What are biosimilars?
They are biologic drugs that are made by a different manufacturer than their original innovator
Are biosimilar drugs like generic to brand medications? Why
No, because it is impossible to replicate the exact molecule of a biologic. Therefore we can only call them biosimilars.
What drugs are under the category of targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs)?
Tofacitinib
Baricitinib
Upadacitinib
How does tsDMARDs work for RA?
Unlike csDMARDs, they target and inhibit Janus kinases (JAKs)
When do we consider tsDMARDs?
Due to lack of long-term safety data, reasonable to consider them after bDMARD treatment has failed.
Does RA have a cure?
No, it’s a chronic disease. Patient’s require lifelong treatment.
When is discontinuation or dosage reduction of biologic DMARDs considered?
If patient has achieved remission.
Be very careful in those who have been hard to manage or with severe disease.
Biologics and tsDMARDs are innovative, but what’s something we have to watch for?
Increased risk of serious infections including herpes zoster and opportunistic infections.
Should biologics and tsDMARDs be started if patient has serious infection? Can they be continued?
Should not start.
Should pause if already on, and resume once infection has resolved
What are predictors of serious infections while on bDMARDs and tsDMARDs?
- old age
- presence of comorbidities
- higher DAS28 score
- higher physical disability
- higher patient global assessment scores
- higher cumulative corticosteroid exposure
The risk of tuberculosis is increased in patients on ______ therapy and ______ ___________. This risk is less clear with __________.
TNFi
JAK inhibitors
bDMARDS
Prior to starting bDMARD or tsDMARD, patients should be screened for _________ ___________, _____ ____ infection, and _____ ____ infection.
bDMARD
tsDMARD
How do we manage patients who screen positive for TB?
Rule out active TB and offer prophylactic therapy with isoniazid.
If patient has Hep B infection, it could re-activate. Therefore, prophylactic antiviral therapy may be required during treatment and up to ___ months following last dose of ___________.
12
rituximab
What type of vaccines are not recommended in patients taking bDMARD or tsDMARD?
Live vaccines
No evidence that the effectiveness of inactivated vaccines are reduced.
Optimal to receive all vaccines prior to initiation of therapy.
What makes managing methotrexate interactions challenging?
Current resources don’t differentiate between high and low dose therapy of methotrexate
What are three common drug interaction with methotrexate? How do we manage them?
NSAIDs, PPIs, low dose Septra (Ex: 3 times a week for PJP)
Not clinically relevant so no management needed
What is a drug interaction to watch out for with bDMARDs?
Careful if combining two biologic agents or a biologic with a JAK inhibitor
IL-6 inhibitors decrease the number of CYP enzymes. Interaction with any drug that is metabolized by the CYP450 system (dose adjust)
What is a drug interaction to watch for with tsDMARDs (AKA JAK inhibitors)?
JAKi is metabolized by CYP450 system. Caution if there are potent CYP3A4 inhibitors or inducers.
Another route of treatment for RA is surgery, why must careful consideration be given to patients?
They are at higher risk of infection and poor wound healing
If patient is to get surgery, how should their pharmacotherapy be adjusted?
Biologics= discontinued. Surgery should take place at the end of the dosing cycle of bDMARD and restarted once the wound shows evidence of healing (usually 14 days)
tsDMARDs (tofacitinib and baricitnib)= withhold for 7 days prior to surgery
csDMARDs= can be continued at current dose
Which DMARDs class has a warning about increased risk of lymphomas?
Does this warning stand true?
bDMARDs
Based off of earlier studies primarily with TNFi
We must keep in mind that those with RA are at an increased risk of lymphoma in general.
TNFi have been found to have a small increased risk of nonmelanomatous and invasive melanomatous skin cancer
Which DMARD has a Health Canada alert for increase risk of malignancies?
JAK inhibitors (AKA tsDMARDs)
More of a concern with tofacitinib. Risk seems to be higher in those with additional risk factors (current or past smokers). Caution is recommended for those >/= 65 years of age, current or past smokers and those with a history of malignancy.
Which DMARD has the risk of MACE labelled on it?
JAK inhibitor (specifically tofacitinib)
- In patients >/=65, current or past smoker or those with additional CV risk factors, JAKi should be considered when response to TNFi is insufficient
NSAIDs are used as adjunct in relieving pain, but does it stop disease progression?
No
For analgesia, is Tylenol and opioids acceptable?
Tylenol yes -> fewer side effects than NSAIDs
Opioids -> avoid if possible. Limited evidence
How does pregnancy affect RA?
Many experience improvements while pregnant.
Flare ups are common postpartum
How do we manage RA meds in pregnancy?
Methotrexate
Leflunomide
Sulfasalazine
Hydroxychloroquine
Corticosteroids
Folic acid
Biologics
NSAIDs
Methotrexate= stop in both males and females at least 3 months prior to conception attempt
Leflunomide= teratogenic. Avoid use in those of childbearing potential. Require drug elimination protocol with two plasma level tests at least 2 weeks apart to confirm levels. An additional 3 month waiting period is recommended for men
Sulfasalazine= may affect men fertility, wait 3 months
Corticosteroids= Safe at RA doses. At high doses, low birth rate. But no evidence that prednisone or methylprednisolone is teratogenic
Folic acid= 5mg/day supplementation should be continued during pregnancy if used methotrexate within 3 months of conception or if using sulfasalazine
Adalimumab and etanercept= good until end of 2nd trimester
Infliximab= until 16 weeks of pregnancy
Certolizumab= all trimesters ok
Avoid abatacept, anakinra, tocilizumab, and rituximab
NSAID= avoid in third trimester
Hydroxychloroquine= data scarce
How do you manage RA in breastfeeding?
Corticosteroids
NSAIDs
Hydroxychloroquine
Sulfasalazine
Methotrexate
Leflunomide
bDMARDs
tsDMARDs
Corticosteroids= ok
NSAIDs= ok short acting preferred
Hydroxychloroquine= ok
Sulfasalazine= ok
Methotrexate= no
Leflunomide= no
bDMARDs= no evidence
tsDMARDs= no evidence
