Rheumatoid Arthritis Flashcards
What is rheumatoid arthritis?
An autoimmune condition leading to inappropriate immune system activity causing synovial and connective tissue inflammation (antibodies against self develop)
What is the progression in joint damage for patients with rheumatoid arthritis?
Chronic inflammation –> Growth of tissue (pannus) –> Loss of bone and cartilage (the body cannot replace bone and cartilage fast enough, so net loss)
What can trigger rheumatoid arthritis?
Triggered by genetics and by “stochastic” event (smoking is a common trigger, but triggers can be hard to definitively point out as a causative effect)
What are the consequences of inflammation in rheumatoid arthritis?
Can happen within 1 year of onset of RA
- Loss of cartilage
- Formation of scar tissue
- Ligament laxity (they stretch out and no longer able to properly support joint)
- Tendon contractures (they shorten and become tight)
How many people are affected by rheumatoid arthritis?
Affects 1 to 2% of the adult population (more common in women 3:1)
Can occur at any age (most common age for diagnosis is between 30 and 50)
What is the clinical presentation of rheumatoid arthritis?
Symmetrical joint pain and stiffness (lasts longer than 6 weeks)
Muscle pain (early morning stiffness, resolves within 1 hour of waking)
Fatigue, low-grade fever, appetite decrease)
Joint tenderness with warmth and swelling over affected joints
Most commonly a rapid onset starting in peripheral joints
What joints are most likely to be affected by rheumatoid arthritis?
Wrists, nads, elbows, shoulders, knees, and ankles
Review slide 9 for differences between rheumatoid arthritis and osteoarthritis
Review slide 12 for the visual representation of the presentation of symptoms in the hands in each of the three stages of rheumatoid arthritis
What non-joint tissues are affected in rheumatoid arthritis?
- Blood vessels
- Lungs
- Eyes
- Heart
- Muscle
- Bone
- Skin
- Hematological abnormalities
What is the impact of rheumatoid arthritis on blood vessels?
The autoimmune conditions starts impacting the vasculature (occurs with severe, and long-standing RA)
Can affect any blood vessel (especially those that supply/drain the skin and kidneys)
Treated with aggressive treatment of RA
What is the impact of rheumatoid arthritis on the lungs?
Pleuritis, pleural effusion, fibrosis, pulmonary nodules
Drugs used to treat RA may also affect lung function (occasional X-ray is used to monitor condition and therapy)
What is the impact of rheumatoid arthritis in the eyes?
Episcleritis, scleritis, uvetis and iritis (can cause blindness, severity depends on layer affected)
Painful, visual acuity loss
What is the impact of rheumatoid arthritis on the heart?
Pericarditis, myocarditis
Increase risk of CAD, HF, and AF
What is the impact of rheumatoid arthritis on the muscles?
Generalized weakness and pain
From synovial inflammation, myositis, vasculitis
Steroid-induced
What is the impact of rheumatoid arthritis on the bones?
Osteopenia is common
Local bone loss around affected joints
What is the impact of rheumatoid arthritis on the skin?
Rheumatoid nodules
Ulcers
Steroid-induced changes
How is rheumatoid arthritis diagnosed?
Joint involvement
Lab test findings (rheumatoid factor, elevated ESR and CRP, anti-CCP)
Duration of symptoms
What are the goals of treatment for rheumatoid arthritis?
Prevent and control joint damage
Prevent loss of function
Maintain QoL
Decrease pain
Acheive remission or low disease activity (PtGA score below 2)
What are the general principles of management of rheumatoid arthritis?
- Early recognition and diagnosis
- Early use of DMARDs (within 3 months of diagnosis)
- Tight control (treat until remission)
- Responsible NSAIDs and glucocorticoid use
What are some non-pharmacological therapies for rheumatoid arthritis?
- Patient education (goals of therapy, drug safety)
- Rest is important, but balance with activity (need to prevent muscle atrophy)
- Reduce joint stress with RA friendly tools (knee braces)
- Diet/weight loss
- Surgery (fairly complex, associated with complications)
What are the maintenance therapies for rheumatoid arthritis?
- Traditional DMARDs (still used commonly)
- Biologic DMARDs
- Synthetic DMARDs (rarely used)
What are the flare therapies for rheumatoid arthritis?
- Corticosteroids
- NSAIDs/Analgesics
- Combinations
What are some characteristics of traditional DMARDs?
- Slow onset of action
- Controls symptoms
- May delay or stop progression of disease
- Requires regular monitoring (especially Methotrexate)
What are some examples of traditional DMARDs?
Methotrexate
Sulfasalazine
Hydroxychloroquine
Leflunomide
What is the mechanism of action for Methotrexate?
Anti-folate (less DNA synthesis, repair, cellular replication and immune response)
Targets root cause (increases immunosuppression)
What is the mechanism of action for Sulfasalazine?
Prodrug (metabolized into 5-ASA and sulfapyridine)
Modulates mediators of inflammatory response (may inhibit TNF)
What is the mechanism of action for Hydroxychloroquine?
Inhibits neutrophils and chemotaxis (impairs complement system)
What is the mechanism of action for Leflunomide?
Inhibits pyrimidine synthesis, leading to anti-inflammatory effects
Modulates many signalling pathways
What is the onset of effect of traditional DMARDs?
Usually 1-3 months, with hydroxychloroquine taking longer (2-6 months)
What is the methotrexate dosing regimen for rheumatoid arthritis?
Methotrexate 7.5 to 25mg PO weekly
Titrate to target dose (2.5 to 5mg/week increase to at least 15-25mg)
What is the renal dosing for methotrexate?
For eGFR between 10-50mL/min, reduce doses by 50%
Review slide 28 for dosing of traditional DMARDs
What are some commonly experienced side effects associated with Methotrexate?
Nausea
Fatigue
Stomatitis
Photosensitivity
Hair loss
Skin itch/burning/rash
What are some strategies to manage side effects associated with methotrexate use?
A PPI can be given 3 days around methotrexate doses to limit some GI effects
Folic acid can be given to help with methotrexate side effects (1 to 5mg/week)
Methotrexate doses can be split to help with side effects (reduced Gi and muscle fatigue)
What is a serious side effect associated with Hydroxychloroquine?
Ocular toxicity (usually after 1000g lifetime dose has been administered, usually achieved after 5 years of regular use)
What is a serious side effect associated with Methotrexate use?
Pulmonary toxicity (get lung function test to determine baseline)
What are the contraindications associated with hydroxychloroquine?
Pre-existing retinopathy
What are some contraindications for sulfasalazine use?
Hypersensitivity to salicylates or sulfonamides
Asthma attacks precipitated ASA or NSAIDs
Severe renal/hepatic impairment
Existing gastric or duodenal ulcer
What are some contraindications associated with Methotrexate?
- Severe hepatic function
- Severe hepatic impairment
- Current hematologic abnormalities
- Pregnancy/breastfeeding (Category X drug)
What are some contraindications associated with leflunomide?
Moderate-severe renal/hepatic impairment
Current hematological abnormalities or serious infection
Pregnancy/breastfeeding
What are some drug interactions associated with Methotrexate?
NSAIDs (decreased clearance of methotrexate, increased toxicity potential. Only a concern at high doses 500-2000mg weekly)
TMX (methotrexate significantly increases risk of pancytopenia)
PPIs (only in methotrexate dose is above 500mg/week
Loop diuretics (likely only an issue with high methotrexate doses)
How is the efficacy of traditional DMARDs monitored?
- Disease (ESR, CRP) every 1 to 3 months initially
- Radiographs of affected joint every 6-12 months
- Patient assessment (Health Assessment Questionnaire, focus on functional status)
How is the safety of traditional DMARDs monitored?
Hydroxychloroquine (ophthalmic exam to measure ocular toxicity)
Sulfasalazine (CBC and LFTs, creatinine)
Methotrexate (CBCs and LFTs, creatinine & Chest X-rays)
Leflunomide (CBCs and LFTs, creatinine)
Rank traditional DMARDs by potency from highest to lowest
Methotrexate=Leflunomide>Sulfasalazine>Hydrochloroquine
What is the role of hydroxychloroquine in rheumatoid arthritis treatment?
- Useful for early, mild RA
- Best tolerated of the DMARDs
What is the role of sulfasalazine in rheumatoid arthritis treatment?
- Use if other options not tolerated
- Combined with other DMARDs (monotherapy rare)
What is the role of methotrexate in rheumatoid arthritis treatment?
- Highly effective in moderate-severe disease
- Standard therapy (should be used in all RA patients)
What is the role of leflunomide in rheumatoid arthritis treatment?
- Replacement for methotrexate if not tolerated
- May be added in low doses to methotrexate
What are the targets for biologic DMARDs?
Central to the RA inflammatory process, monocytes, macrophages, and fibroblasts within the synovium, which produce cytokines
What are the main classes of biologic DMARDs?
- TNF-alpha inhibitors
- IL-1 and IL-6 inhibitors
- T-Cell Co-stimulation inhibitors
- B-cell depletors
What are some common side effects associated with biologic DMARDs?
Nausea
Headache
Diarrhea
Malaise (most common after administration, usually 1 to 2 days after and resolves on its own)
How are injection site reactions with biologic DMARDs prevented?
Pre-treatment with acetaminophen+antihistamine+steroid
What are some common concerns for biologic DMARD use?
- Elevate infection risk
- Neutropenia
- Malignant disease
- Antibody development
Why does infection risk increase with biologic DMARD therapy?
Increased infection rate (due to immunosuppression MOA of biologic DMARDs)
Common infections: sinusitis, pharyngitis, candidiasis, pneumonia, UTIs
Serious infections: TB, mycobacterial, PCP, CMV, zoster, HepB/C
How is infection risk mitigated when using biologic DMARDs?
- Screen for TB, Hep B/C, HIV prior to therapy
- Up to date on vaccinations
- Educate patient on signs of infection
- Never use two biologics in combination (increased efficacy, but significant infection risk not worth benefit)
What are the characteristics of neutropenia when starting a biologic DMARD?
20% will experience a decrease (important to get baseline prior to initiation of therapy)
Increases severity of infections
Not a reason to d/c therapy
What does the elevated risk for malignant disease in patients on biologic DMARDs look like?
RA patients have higher cancer risk, confounding data
- Avoid biologics in patients with malignancies
- Preferentially avoid if patient has a history with skin cancer
- Use rituximab in those with previous lymphoma
What does antibody development look like in patients on biologic DMARDs?
Usually occurs within 2-6 months of starting therapy (can no longer use biologics from the same class)
Does not occur with IL-6 inhibitors
What biologic DMARD is used if the patient has developed antibodies for multiple classes of biologic DMARDs?
IL-6 inhibitors because they do not cause the formation of antibodies against them
What are some types of TNF-alpha inhibitors (know these)?
- Adalimumab
- Certolizumab
- Etanercept
- Golimumab
- Infliximab
What is the onset of effect for TNF-alpha inhibitors?
within weeks
What are some special instructions for Infliximab/Golimumab?
They are only indicated in combination with methotrexate (reduces chances of biologic antibody formation)
Review slide 52 for details about different types of TNF-alpha inhibitors
Can TNF-alpha inhibitors be renally adjusted?
No, do not use TNF-alpha inhibitors in patients with renal dysfunction
What is the most significant parameter that patients use to pick a preferred TNF-alpha inhibitor?
Usually route of administration (in general, subcutaneous formulations are preferred by patients)
What TNF-alpha inhibitors can be used in pregnant patients?
- Adalimumab
- Infliximab
What are some contraindications for the use of THF-alpha inhibitors?
- Active severe infection
- Moderate to severe HF (use a different type of biologic)
What are some drug interactions associated with TNF-alpha inhibitors?
- Live vaccines
- Additive immunosuppresion
What are some adverse effects associated with TNT-alpha inhibitors?
LFT elevations
HF
Cutaneous
Autoimmune disease
Seizure risk
What are some characteristics of liver enzyme elevations in response to TNF-alpha inhibitor therapy?
- Liver enzyme elevations uncommon
- Concern if ALT are more than 5x beyond upper normal limit
- Requires perioidic monitoring
What are some characteristics of HF in response to TNF-alpha inhibitor therapy?
May cause or worsen existing HF (utilize low doses)
Evidence is not conclusive
What are some characteristics of cutaneous symptoms in response to TNF-alpha inhibitor therapy?
- Cellulitis
- Autoimmune skin diseases
- Skin malignancy
What are some characteristics of auto-immune diseases in response to TNF-alpha inhibitors?
Increased risk of developing autoimmune disease with administration of TNF-alpha inhibitors
ex. Lupus, Vasculitis, Sarcoidosis, Psoriasis
What are some characteristics of seizure risk associated with TNF-a inhibitors?
Avoid in patients with seizure disorder (will exacerbate their seizures)
What are some common variables that are monitored in TNF-alpha inhibitor therapy?
- TB, HIV, Hep B/C screening
- CBCs
- LFTs
- Signs of infection
- Ensure vaccinated
What are some considerations that go into selecting a TNF-alpha inhibitor?
- Frequency of dosing and route
- Cost (consider those with a biosimilar)
- Rheumatologist preference
- If loss of effect experiened o ver time (check for antibodues, and consider switching or adding methadone
What are the IL1 or IL6 and what is their mechanism of action?
IL-1 and Il-6 inhibitors (interleukin) antagonize these receptors and reduce in cytockine activation (less inflammation)
ex. Tocilizumab and Sarilumab (both IL-6 inhibitors)
What is the onset of effect for IL1 or IL6 inhibitors?
Weeks, but reach peak effect at 5 to 6 months
Do IL inhibitors have many contraindications?
No in general, but Tocilizumab is contraindicated in patients with active infections
What is the efficacy of IL-1 inhibitor (Anakinra) in rheumatoid arthritis treatment?
Less effective than other biologics (used less often)
What is the efficacy of IL-6 inhibitors (Tocilizumab/Sarilumab) in rheumatoid arthritis treatment?
40% acheive ACR50 (comparable to TNF-alpha inhibitors)
How often is Ankinra (IL-1 inhibitor) dosed?
SC once daily
How often is Tocilizumab/Sarilumab (IL-6 inhibitors) dosed?
Tocilizumab (IV every 4 weeks)
Sarilumab (SC every 2 weeks)
What is an advantage of IL-6 inhibitors over most biologic DMARDs?
They are the only biologics that have good renal dysfunction dosing data (no need to adjust dose in patients with CrCl values abover 30mL/min)
What are some adverse effects associated with IL-6 inhibitors?
GI perforation (rare)
Dyslipidemia (consider caution in patients that already are struggling to maintain good cholesterol management)
Antibody development not linked to decreased effect (unlike other biologics)
HTN
What are are some drug interactions associated with interleukin inhibitors?
Increased CYP activity due to interleukin supression
Additive immunosuppression
Tocilizumab (simvastatin increased 4-10x, switch to a different statin)
How are patients on IL-6 inhibitors monitored for safety?
- Baseline CBC, LFTs, creatinine (then repeat in 4-8 weeks after starting, then every 3 to 6 months)
- Lipid panel
- BP
- Latent/active TB, HepB/C screening
What are some characteristics of T-cell Co-stimulation inhibitors in rheumatoid arthritis?
They inhibit T-cell activation (immunosupression)
Used if inadequate response to other DMARDs or TNF inhibitors
What is the efficacy of T-cell co-stimulation inhibitors in treating rheumatoid arthritis?
41% acheived ACR50 (clinical response), on par compared to other DMARDs
What are some adverse effects associated with T-cell co-stimulation inhibitor?
COPD exacerbations (contraindication, other options exist)
HTN and increased blood glucose (can be managed with monitoring or drug therapy)
What is the impact of T-cell co-stimulation inhibitors on liver function?
None, unlike other DMARDs
Good for patients with hepatic dysfunction
What are some monitoring parameters for T-cell co-stimulation inhibitors?
- Signs and symptoms of infection
- TB and hepatitis screening
- CBCs, creatinine
- Blood pressure
- Blood glucose
What are some characteristics associated with B-cell depletors in rheumatoid arthritis treatment?
They are a last-line option (used when other options have failed)
Directly prevent the formation of antibodies
ex. Rituximab
Are B-cell depletors ever used as monotherapy for rheumatoid arthritis?
No, they are always in combination with methotrexate and following failure on a TNF inhibitor
What are some dosing instructions associated with B-cell depletors?
2 dose course (1g IV infusion given two weeks apart)
Pretreat with steroid, acetaminophen, and diphenhydramine
Re-treat when needed (every 6 months)
What are some adverse effects associated with B-cell depletors?
Infusion reactions tend to be more rapid (mild and brief)
Serious infection rate is non-existent initially, then increases on repeat courses
Mucocutaneous reactions (SJS, and TENS)
Antibody formation likely leads to increased infusion reactions and decreased efficacy
What are some monitoring parameters for B-cell depletors?
Baseline CBC, LFTs, creatinine
TB, Hepatitis B/C screening
Review slide 77 for a good summary of general concerns with all biologics
What is an example of a T-cell inhibitor?
Abatacept
Review slide 78 for what biologic to avoid when choosing an agent for rheumatoid arthritis in patients with comorbidities
What is the place of biologics in therapy?
They are considered once traditional DMARDs have been tried and are not sufficient to see clinical response.
It is expected that most patients will start on methotrexate, but a biologic is added eventually
What are Janus Kinase inhibitors?
They are a group of enzymes responsibles for enabling interleukin signalling
Indicated in combination with methotrexate
Last line options
ex. Tofacitinib, Baricitinib, Upadacitinib
What are some adverse effects associated with Janus Kinase inhibitors?
Similar to TNF inhibitors and other biologics, including the following:
- HTN
- Infections/cytopenia
- LFTs/hepatoxicity
- Bradycardia
- GI perforation
No concern about antibody development
What are some monitoring tips for Janus Kinase inhibitors?
- Latent TB testing
- Lipid profile
- CBCs every 3-6 months
- LFTs
Limited evidence for use in pregnancy/lactation
What is the role of corticosteroids in rheumatoid arthritis?
It is used for flare management (most patients have been on multiple courses of steroid therapy)
Likely has DMARD properties and decreases early progression of RA
What is the efficacy of corticosteroids in rheumatoid arthritis?
Subjective symptomatic improvement (more than the other drugs thet have used, increased risk of corticosteroid overuse)
Reduces joint tenderness more than placebo and NSAIDs
Reduces pain more than NSAIDs
What is the most common treatment modality used in flare management?
Short-term use (doses of 10-15mg prednisone equivalent/day for 1 to 2 months per course)
What is the purpose of chronic corticosteroid use in rheumatoid arthritis treatment?
Some severely affected patients may require long-term steroid dosing (benefits outweigh risk)
5-10mg prednisone equivalent per day indefinitely (osteoporosis and GI bleed risk)
What is the purpose of pulse corticosteroid therapy in the treatment of rheumatoid arthritis?
Rare, more specialist territory
Safety issues (CV collapse, hypokalemia, MI, severe infection)
Considered a last resort option in RA
What are some characteristics of intra-articular corticosteroid injections?
An option for patients who have oral corticosteroid overuse (needs to be administered by a MD
Effects are dramatic but temporary
Same joint should not be done more than once per 3 months
Considered palliative
What are some issues with intra-articular corticosteroid injections for rheumatoid arthritis?
Tendon rupture
Acute synovitis
Localized skin hypopigmentation
Septic arthritis
What are some guideline reccomendations associated with corticosteroid use in rheumatoid arthritis?
Consider for flares or as bridging (symptom relief as DMARD takes a few months to acheive full onset of action)
Aim for a max dose of 10mg prednisone/day
Never use as monotherapy (increase DMARD dose before corticosteroid dose)
FInd minimum dose/duration
What are some reccomendations about NSAIDs in rheumatoid arthritis?
Provide a high NSAID dose at initial diagnosis
Use for at least 2 weeks for maximum benefit
Cautiously combined with other treatments
Considering providing GI protection
Should not be used chronically
Should multiple biologics be used concurrently in rheumatoid arthritis treatment?
No, recommend against multiple biologics
Should biologic or targeted sythetic DMARDs be tapered in patients who are in sustained remission or low disease activity (longer than 6 months)?
Stepwise reduction in the dose of DMARDs without d/c is recommended
For patients that do not have rapid access to care or gaining access to medication is challenging, tapering down is not recommended
What should patients who are unsucessful in a TNF inhibitor trial for rheumatoid arthritis?
Try a different TNF inihibitor
Non-TNF biologic
JAK inhibitor (not reccomeded if patient has higher risk of CV morbidity)
What is the intital therapy approach for low disease activity rheumatoid arthritis?
Try lowest potency traditional DMARDs first (monotherapy preferred)
(HCQ>SSZ>MTX>LEF)
What are some initial first-line therapy approach for patients with moderate to high disease activity?
Methotrexate stronhly recommended over other traditional DMARDs
Methotrexate monotherapy recommended over multi-traditonal DMARD therapy
Methotrexate monotherapy recommended over combo with biologics
What is the next step after methotrexate monotherapy fails to acheive goal of therapy?
Preferentially add a biologic DMARD instead of SSZ/HCQ
What is the next step for when a biologic in rheumatoid arthritis therapy fails?
Switch to a biologic of a different class, rather than the same class
When should rheumatoid arthritis therapy be escalated?
Failure to achieve remission or acceptable disease activity after 3 to 6 months at optimal doses
What are some precautions for patients on methotrexate thinking about conceiving?
Males and females should stop methotrexate for at least 3 months prior to conception
What DMARDs can be used safely during pregnancy?
All biologic agents, except b-cell depletors (rituximab) have favourable safety profiles
What are some safe rheumatoid arthritis therapies for lactating mother?
NSAID use (ibuprofen) is acceptable
Low dose prednisone (less than 20mg/day)
HCQ and SSZ are safe (only traditional DMARDs that are safe, avoid methotrexate and leflunomide)
TNF inhibitors and IL-6 inhibitors are safe
What are some characteristics of juvenile rheumatoid arthritis?
Defined as persistent arthritis in more than one joint for at least 6 weeks
Most common rheumatic condition in kids
Review slide 111
What are the goals of treatment for juvenile rheumatoid arthritis?
Decrease chronic joint pain
Suppress inflammatory process
Maintain normal growth and development
What are some treatment options for juvenile rheumatoid arthritis?
Physical Therapy
Ophthalmologic surveillance
NSAIDs
Corticosteroids
DMARDs/biologics (Tocilizumab preferred)
Review slides 116 to 118 for a summary of rheumatoid arthritis agents
