Rheumatoid Arthritis (2) Flashcards
In which patients is RA more common in?
Women of child bearing age (25-55)
-important to consider when thinking about therapy options
Increased risk with smoking and family history
RA vs OA
Osteoarthritis occurs due to mechanical damage (wear/tare of joints)
Rheumatoid arthritis is caused by immune mediated inflammatory reaction that causes damage to joints
Hands and feet/ankles are classic signs of RA - more of a clue that its RA not OA
RA pathophysiology
CD4 T cells initiated autoimmune response by reacting with self antigen (perhaps chemically modified) - B and T cells then get activated against self antigen, and b cells produce antibodies towards self antigen
Then T cells produce cytokines that generate inflammation causing damage to joint
Cytokines and other inflammatory mediators released include…
-TNF-alpha and IL-1
-RANKL
-IL-17
-INF-gamma
Chronic inflammation in the synovial tissue lining causes proliferation of a tissue called the pannus, which invades cartilage and bone surface causing erosion and destruction of joint
RA autoantibodies
B cells will make antibodies toward self antigen - autoantibodies
Many of the autoantibodies detected in patients are specific for citrullinated peptides (deaminated arginine)
-Evidence suggests that the anti-citrullinated protein antibodies (ACPA) in combination with a T cell response to the citrullinated proteins contribute to disease chronicity.
Majority of patients will have serum IgA, IgG, or IgM autoantibodies that bind to the Fc portions of their own IgG antibodies … these are called rheumatoid factor … these antibody-autoantibody complex deposits in tissues and generates the immune response (compliment cascade and recruits inflammatory mediators causing inflammation)
RA diagnosis
Difficult to diagnose, diagnosis criteria are used… a score of 6 or higher is diagnostic of RA
Score is based on…
-joint involvement - how many and what type - small joints have higher score
-serology - present of autoantibodies (more = higher score)
-acute phase reactants - elevated CRP and ESR (indicated inflammation)
-Duration of symptoms - RA is a chronic disease, so if symptoms present for 6 weeks or longer, that is a point
RA typical patient presentation
Symptoms develop insidiously (over weeks to months)
Prodromal symptoms: fatigue (more in the afternoon and during flares), weakness, low grade fever, loss of appetite, joint pain
Stiffness and myalgias may precede joint swelling
Joint involvement is usually symmetrical (in early disease some patients may have asymmetrical pattern) - but it is not limited to one joint (more holistic presentation)
Extraarticular manifestations of RA
These occur in 40% of patients
-Subcutaneous nodules (rheumatoid nodules)
-Sjogren’s syndrome - another autoimmune disease that may present with RA, effects ability to produce tears and saliva
-interstitial lung disease (ILD)
-pulmonary nodules
-vasculitis
-anemia
-Felty syndrome: RA in association with splenomegaly and neutropenia
RA clinical course
Majority will have persistent and progressive disease that waxes and wanes with intensity (remissions/flares)
Only 10% undergo spontaneous remission
Few have progressive form that results in severe erosive joint disease (less common now with treatment)
RA mortality
Patients with RA have a mortality rate 2x greater than the general population
Most common cause of mortality is ischemic heart disease, followed by infection
What is the goal of therapy for RA
Prevent joint damage disability (not just relieve pain)
Note - joint damage that already occurred cannot be reversed
Bridge therapy
The drugs used for chronic RA therapy take a while to kick in, so in the meantime we can use bridge therapy to provide rapid relief …
Corticosteroids
-slow progression of RA
-never use as monotherapy due to ADRs with long term use
-use lowest effective dose for the shortest duration possible (less than 3 months, 10 mg prednisone or less)
NSAIDs/APAP
-these do not slow progression of RA, only provide symptomatic relief, so they are recommended as PRN dosing for pain/stiffness (that may not be stopped by chronic therapy)
Which drugs are used for chronic RA therapy?
DMARDs - disease modifying antirheumatic drugs…
Conventional DMARDs
-Methotrexate
-Hydroxychloroquine
-Sulfasalazine
-Leflunomide
Biological DMARDs
-TNF-alpha inhibitors (adalimumab, certolizumab, etanercept, golimumab, infliximab)
-Non TNF alpha biologics (abatacept, tocilizumab, sarilumab, anakinra, rituximab)
Tofacitinib
Methotrexate MOA
Methotrexate is an analog of folic acid, which is an important substrate of dihydrofolic acid reductase (DHFR) - this enzyme is important for single carbon transfer which is important for synthesis of essential nucleotides and amino acids
Methotrexate inhibits DHFR, inhibiting the synthesis of nucleotides
Methotrexate route of administration
Available oral, SQ, and IM
(also available IV and intrathecal, but this is not used for RA)
Methotrexate ADRs
Dose dependent toxicities (so consider potential for toxicity with organ dysfunction)
-diarrhea, stomatitis, vomiting
-severe GI toxicity, hepatotoxicity, pulmonary toxicity, severe dermatological reaction, severe renal toxicity, serious infection, neurotoxicity
Hematologic toxicity:
-blood count decrease (discontinue if significant)
-myelosuppression
What should be given with methotrexate?
Folic acid (to reduce ADRs)
How is methotrexate excreted?
Renally
(keep renal function in mind when thinking about potential toxicity)
Methotrexate and pregnancy
Contraindicated for use in pregnancy
Methotrexate monitoring parameters
CBC
Serum creatinine
LFTs
Prior to initiation:
-Chest X ray (within 1 year prior to initiation) - to check for pulmonary toxicity
-Hep B and C serology, TB testing annually for patients who travel to high risk areas
Liver biopsy…
- at baseline (for patients with abnormal baseline LFTs, alcoholism, or chronic hep B or C) … MTX should NOT be used on patients with alcoholism or untreated liver disease
- or during treatment if LFT elevations persist
Methotrexate place in therapy for RA
Drug of choice for most patients (unless contraindicated)
Methotrexate dosing for RA
Oral/SQ/IM all weekly dosing
Contraindications to methotrexate
Pregnancy
Alcoholism
Liver disease
Immunodeficiency or pre-existing hematologic disorders (leukopenia, thrombocytopenia)
Hydroxychloroquine/chloroquine MOA
Mechanism is not fully understood
Inhibit certain cellular pathways in immune activation by changing pH concentrations (inhibit immune response)
Hydroxychloroquine/chloroquine PK considerations
Both have a large volume of distribution
And a long half life
Also have a slow onset (like other DMARDs, may take several weeks)
Hydroxychloroquine and pregnancy
Recommended and safe for pregnant patients
Hydroxychloroquine ADRs (3)
Cardiovascular effects including prolonged QT interval and risk of torsades
-increased risk with other QT prolonging medications and in patients with renal insufficiency
-don’t exceed QTc > 500 msec
Retinopathy
-especially in those with low body weight and renal/hepatic impairment
Also effects muscle strength
Hydroxychloroquine monitoring parameters
CBC, liver function, renal function - baseline and throughout therapy
Monitor muscle strength
For patients at increased risk of QTC prolongation - ECG at baselines and as clinically indicated
Ophthalmology exam at baseline and annually after 5 years of use (or sooner if risk factors are present)
Hydroxychloroquine place in therapy
Typically used in combination with other DMARDs
Can be used as monotherapy in mild cases (or pregnancy)
Sulfasalazine MOA
This is a prodrug that is metabolized to 5-ASA (bacteria in colon cleave azo bond to form 5-ASA)
Exact mechanism is not understood
-modulates chemical mediators of the inflammatory response - leukotrienes, free radical, TNF alpha inhibition
Sulfasalazine ADRs
Skin rash
Gastric distress
N/v, dyspepsia
Oligospermia (reversible)
Less common:
-leukopenia, thrombocytopenia, increased LFTs
-hemolytic anemia (increased risk if G6PD deficiency)
Sulfasalazine pregnancy
Can be used in women planning pregnancy
But, effects sperm production in males (so don’t use if they plan on becoming a father, note the oligospermia is reversible)
Sulfasalazine place in therapy
Can be used as monotherapy or in combination with other DMARDs for RA
-use is limited by GI effects
Sulfasalazine is contraindicated with…
TRUE sulfonamide or salicylate allergy
Leflunomide MOA
Inhibits synthesis of pyrimidine
It is a prodrug, the active form inhibits dihydroorotate dehydrogenase (DHODH) which is an essential enzyme needed for pyrimidine synthesis
Leflunomide PK and toxicity considerations
Highly protein bound
Has a very long half life (2 weeks)
-this is important to consider, if patient is experiencing toxicity or has an incidental pregnancy we need to “washout” with cholestyramine
-goes through biliary excretion and enterohepatic recirculation, cholestyramine interrupts enterohepatic recirculation (decreasing the half life)
Excreted by kidneys and through direct biliary excretion
Leflunomide ADRs
Increased LFTs (liver toxicity)
-discontinue if ALT > 3x of ULN
Others
-alopecia
-headache
-skin rash
-diarrhea, nausea, vomiting
-hypertension
-dizziness
-GI pain
-oral mucosal ulcer
Leflunomide and pregnancy
Contraindicated in pregnancy
Leflunomide 2 BBWs
Pregnancy - fetal harm
Hepatoxicity
Leflunomide monitoring parameters
Pregnancy test to rule out pregnancy before starting (if female of reproductive age/potential)
Active/latent TB and signs/symptoms of other severe infections or pulmonary symptoms
Blood pressure (baseline and periodically)
CBC
LFTs
Serum creatinine
Leflunomide place in therapy
Monotherapy or combination with other DMARDs
-use is limited to side effects (we have better agents)
Which 2 conventional DMARDs can NOT be used in pregnancy
Methotrexate
Leflunomide
(hydroxychloroquine and sulfasalazine can be used)
Note - methotrexate and leflunomide are antimetabolites, so it makes sense that they cannot be used in pregnancy
Which drugs are TNF alpha inhibitors (5)
“additional tanning certainly goes to inflammation”
Adalimumab
Etanercept
Certolizumab
Golimumab
Infliximab
TNF alpha inhibitor MOA
These drugs bind to TNF alpha and prevent it from binding to its receptor - blocking its inflammatory effects (suppressing downstream cytokines IL-1 and IL-6)
They are all protein drugs and do this, but are slightly different in their form…
Adalimumab, golimumab and infliximab are monoclonal antibodies
Etanercept is a fusion protein - fc domain fused with TNF alpha receptor
Certolizumab is a PEGylated monoclonal antibody (PEGylated to increase its size)
TNF alpha and immunogenicity
-formation of antibodies against drugs
-this is a potential for any biologic drug, but the chance of this is less with these drugs because they suppress the immune response
-methotrexate inhibits the formation of antibodies against these drugs
Theoretically the human antibodies should cause the least ADA (but it can still occur)
TNF alpha inhibitor onset
Can take up to 3 months to achieve full benefit
(several weeks for clinical benefit)
TNF alpha inhibitor place in therapy
Used when disease remains moderate or high despite conventional DMARD therapy (MTX)
or contraindication to conventional DMARD therapy
TNF alpha inhibitor side effects/contraindications
Do NOT use in patients with mod/severe heart failure (NYA class III/IV) (worsens heart failure)
Increases risk of serious infection
Increases risk of malignancy (lymphoma and skin cancer)
TNF alpha monitoring
Before starting therapy:
screen for TB and hep b
During therapy: CBC, signs/symptoms of malignancy and serious infection
TNF alpha inhibitors and pregnancy
Most data is seen with certolizumab for continuing throughout pregnancy
Etanercept and adalimumab have theoretical risk for newborn infection, but are sometimes continued
Which TNF alpha inhibitor is IV only
Infliximab
-IV and needs to be premedicated with methylprednisolone, acetaminophen, and antihistamine to avoid infusion related reactions
(the rest are subq, so that is more convenient for the patient)
What are the non-tnf alpha biologics that can be used for RA? (5)
- Abatacept
- Tocilizumab
- Sarilumab
- Anakinra
- Rituximab
Abatacept MOA
Fusion protein - inhibits T cell activation, by inhibiting costimulation
Binds to CD80/86… stopping the interaction between CD28 and B7 which activates the t cell -
Abatacept place in therapy
used in moderate/severe RA as monotherapy or in conjunction to conventional DMARDs
-note - biologics cannot be combined together (infection risk)
-alternative to TNF alpha inhibitor therapy, usually reserved if that didn’t work
Abatacept ADR
COPD exacerbations
-not the best choice for patients with COPD
Others:
-headache, URTI, nasopharyngitis, nausea, infusion reactions, serious infections, malignancy
Abatacept monitoring
Signs/symptoms of infection or hypersensitivity reaction
Hepatitis and TB screening before therapy initiation
Periodic skin exams
Abatacept and pregnancy
Limited data - so should be discontinued if pregnant
Tocilizumab and Sarilumab MOA
Antibodies that bind to the IL-6 receptor - inhibit the binding of IL-6 and the inflammatory function of it
Also effects the liver, causing secretion of CRP in response to inflammation
-and induces CYP3A4 (decreasing concentrations of CYP3A4 substrates - important consideration)
Tocilizumab and Sarilumab ADRs
infections, headache, hypertension, increased liver enzymes, injection site reactions, infusion reactions can also occur, gastrointestinal perforation, neutropenia, thrombocytopenia, serious infections, and malignancy
Tocilizumab and Sarilumab DDI consideration
CYP3A4 inducers
decrease concentration of CYP3A4 substrates - including oral contraceptives (important counseling point)
Tocilizumab and Sarilumab monitoring
Neutrophils, platelet
Lipid panel and AST/ALT (since they effect the liver)
Baseline TB screening
Tocilizumab and Sarilumab in pregnancy
Limited data- so use should be discontinued if pregnant
Tocilizumab and Sarilumab place in therapy
Reserved for patients who had an incomplete response to one or more conventional DMRADs and/or TNF alpha inhibitor
Can be used as monotherapy or in combination with conventional DMRAD
(biologics can NOT be used together - infection risk)
Anakinra MOA
antagonist of the interleukin 1 receptor
Anakinra side effects
Gastrointestinal (N/v/d)
infection, fever, injection site reaction, headache, hematologic & oncologic abnormalities
Anakinra monitoring
CBC
Serum creatinine (renal dose adjustment required)
Signs/symptoms of infection - TB test at baseline
Anakinra and pregnancy
Limited data- discontinue if pregnant
Anakinra place in therapy
Not included in the most recent guidelines
Reserved for moderate/severe RA if all else has failed
Rituximab MOA
Monoclonal antibody binds to CD20 on B cells causing ADCC, CDC, and apoptosis
Killing the b cells decreases the antibodies present in circulation
Rituximab ADRs
Infusion reactions (IV only)
-need to premedicate with methylprednisolone, acetaminophen, and antihistamine before infusion moderate-to-severe RA who have failed one or more DMARD
Bowel obstruction/perforation
Blood cell disorders
Cardiovascular events
Rituximab monitoring parameters
CBC should be obtained before each infusion (and every 2-4 months)
Hep B screening prior to initiation
Rituximab pregnancy
Do not use in pregnancy
Rituximab place in therapy
Reserved for patients who have failed TNF alpha inhibitors
-can be used as monotherapy or with methotrexate
Limited use by the fact this it is IV only, needs to be premedicated for infusion reactions and need CBC before each infusion
Tofacitinib MOA
JAK tyrosine kinase inhibitor
-JAK is an essential tyrosine kinase involved in signal transduction (extracellular information to the cell nucleus) inhibiting its activity shuts down signal transduction - influencing DNA transcription
_______________ should be avoided in patients taking tofacitinib
Live vaccines
Tofacitinib ADRs
There are many tyrosine kinases, so has broad side effects
-infection
-lymphoma and other malignancies
-cardiovascular effects
-GI perforation
-diarrhea
-headache
-hepatotoxicity
-bone marrow suppression
Tofacitinib monitoring
●Lymphocyte count baseline and every 3 months thereafter
●ANA, platelet counts, and hemoglobin should be monitored at baseline, after 4 to 8 weeks of therapy, and every 3 months thereafter
●Lipids 4 to 8 weeks after starting therapy and periodically thereafter
●Liver function tests at baseline and periodically
●Screening for viral hepatitis (prior to initiating therapy)
●Heart rate and blood pressure at baseline and periodically thereafter
Tofacitinib and pregnancy
Data is limited - do NOT use
How is disease activity determined?
Using activity scales (differ in practice)
determined to be Low or moderate activity - this is important because it determines what treatment we use
Low disease activity treatment
First line: hydroxychloroquine
-then sulfasalazine, then methotrexate
But, methotrexate is preferred if patient has poor prognostic factors …
-presence of autoantibody
-presence of early erosions (confirmed by x ray)
(on exam will be told if disease activity is low)
Nonpharm therapy for RA
Rest - balance … we want to relieve stress on joints, but too much rest can cause damage
Occupational/physical therapy
Use of assistive devices
Weight reduction
Surgery
Which drugs are JAK inhibitors? When are they used
Tofacitinib (Xeljanz)
Upadacitinib (Rinvoq)
Baricitinib (Olumiant)
Place in therapy for RA is unclear, reserved for if all else fails
___________ can NEVER be used together. Why? (other considerations related to this)
More than 1 biologic can NEVER be used together
-due to infection risk
-biologics have the biggest infection risk of DMARDs, so patients with Hep C or skin cancer history should get conventional DMARD
-if they are getting surgery, may consider holding biologic to allow for proper healing
-live vaccines should not be given to patients taking biologics
Treatment algorithm for moderate/high disease activity
Methotrexate monotherapy - first line
-titrate to highest dose (remember dosing is weekly)
-switch to SQ administration from oral if not at target
If still not at goal…
Add biologic DMARD
-if patient cannot afford biologic consider double or triple therapy of MTX +/- sulfasalazine +/- hydroxychloroquine
Can therapy be discontinued?
Consider tapering if low disease activity for 6 months
Can consider stopping one agent, but continue at least 1 DMARD (even if disease activity is low)
-guidelines don’t specify which DMARD should be continued, doesn’t have to be MTX, consider patient preference and ADRs
How long can it take for maximal DMARD benefit?
up to 12 weeks - so this is when we should re-assess
(biologics work a bit faster than conventional DMARDs)
Which drugs should NOT be used in patients with moderate/severe HF?
TNF alpha inhibitors
2 big side effects of hydroxychloroquine
Retinopathy
QT prolongation (risk of torsades)
The big ADR with methotrexate is…
Hepatotoxicity
Which drug can cause COPD exacerbations?
Abatacept
Which drug causes oligospermia?
Sulfasalazine
Which drugs are CYP3A4 inducers?
Tocilizumab and Sarilumab
Which 2 drugs require pretreatment with methylprednisolone, acetaminophen, and an antihistamine
Infliximab
Rituximab
