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Imm/Musculoskel/Skin > Rheumatoid Arthritis (2) > Flashcards

Rheumatoid Arthritis (2) Flashcards

1
Q

In which patients is RA more common in?

A

Women of child bearing age (25-55)
-important to consider when thinking about therapy options

Increased risk with smoking and family history

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2
Q

RA vs OA

A

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

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3
Q

RA pathophysiology

A

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

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4
Q

RA autoantibodies

A

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)

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5
Q

RA diagnosis

A

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

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6
Q

RA typical patient presentation

A

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)

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7
Q

Extraarticular manifestations of RA

A

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

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8
Q

RA clinical course

A

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)

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9
Q

RA mortality

A

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

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10
Q

What is the goal of therapy for RA

A

Prevent joint damage disability (not just relieve pain)

Note - joint damage that already occurred cannot be reversed

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11
Q

Bridge therapy

A

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)

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12
Q

Which drugs are used for chronic RA therapy?

A

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

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13
Q

Methotrexate MOA

A

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

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14
Q

Methotrexate route of administration

A

Available oral, SQ, and IM
(also available IV and intrathecal, but this is not used for RA)

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15
Q

Methotrexate ADRs

A

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

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16
Q

What should be given with methotrexate?

A

Folic acid (to reduce ADRs)

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17
Q

How is methotrexate excreted?

A

Renally
(keep renal function in mind when thinking about potential toxicity)

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18
Q

Methotrexate and pregnancy

A

Contraindicated for use in pregnancy

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19
Q

Methotrexate monitoring parameters

A

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

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20
Q

Methotrexate place in therapy for RA

A

Drug of choice for most patients (unless contraindicated)

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21
Q

Methotrexate dosing for RA

A

Oral/SQ/IM all weekly dosing

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22
Q

Contraindications to methotrexate

A

Pregnancy
Alcoholism
Liver disease
Immunodeficiency or pre-existing hematologic disorders (leukopenia, thrombocytopenia)

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23
Q

Hydroxychloroquine/chloroquine MOA

A

Mechanism is not fully understood
Inhibit certain cellular pathways in immune activation by changing pH concentrations (inhibit immune response)

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24
Q

Hydroxychloroquine/chloroquine PK considerations

A

Both have a large volume of distribution
And a long half life
Also have a slow onset (like other DMARDs, may take several weeks)

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25
Hydroxychloroquine and pregnancy
Recommended and safe for pregnant patients
26
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
27
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)
28
Hydroxychloroquine place in therapy
Typically used in combination with other DMARDs Can be used as monotherapy in mild cases (or pregnancy)
29
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
30
Sulfasalazine ADRs
Skin rash Gastric distress N/v, dyspepsia Oligospermia (reversible) Less common: -leukopenia, thrombocytopenia, increased LFTs -hemolytic anemia (increased risk if G6PD deficiency)
31
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)
32
Sulfasalazine place in therapy
Can be used as monotherapy or in combination with other DMARDs for RA -use is limited by GI effects
33
Sulfasalazine is contraindicated with...
TRUE sulfonamide or salicylate allergy
34
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
35
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
36
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
37
Leflunomide and pregnancy
Contraindicated in pregnancy
38
Leflunomide 2 BBWs
Pregnancy - fetal harm Hepatoxicity
39
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
40
Leflunomide place in therapy
Monotherapy or combination with other DMARDs -use is limited to side effects (we have better agents)
41
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
42
Which drugs are TNF alpha inhibitors (5)
"additional tanning certainly goes to inflammation" Adalimumab Etanercept Certolizumab Golimumab Infliximab
43
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)
44
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)
45
TNF alpha inhibitor onset
Can take up to 3 months to achieve full benefit (several weeks for clinical benefit)
46
TNF alpha inhibitor place in therapy
Used when disease remains moderate or high despite conventional DMARD therapy (MTX) or contraindication to conventional DMARD therapy
47
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)
48
TNF alpha monitoring
Before starting therapy: screen for TB and hep b During therapy: CBC, signs/symptoms of malignancy and serious infection
49
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
50
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)
51
What are the non-tnf alpha biologics that can be used for RA? (5)
1. Abatacept 2. Tocilizumab 3. Sarilumab 4. Anakinra 5. Rituximab
52
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 -
53
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
54
Abatacept ADR
COPD exacerbations -not the best choice for patients with COPD Others: -headache, URTI, nasopharyngitis, nausea, infusion reactions, serious infections, malignancy
55
Abatacept monitoring
Signs/symptoms of infection or hypersensitivity reaction Hepatitis and TB screening before therapy initiation Periodic skin exams
56
Abatacept and pregnancy
Limited data - so should be discontinued if pregnant
57
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)
58
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
59
Tocilizumab and Sarilumab DDI consideration
CYP3A4 inducers decrease concentration of CYP3A4 substrates - including oral contraceptives (important counseling point)
60
Tocilizumab and Sarilumab monitoring
Neutrophils, platelet Lipid panel and AST/ALT (since they effect the liver) Baseline TB screening
61
Tocilizumab and Sarilumab in pregnancy
Limited data- so use should be discontinued if pregnant
62
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)
63
Anakinra MOA
antagonist of the interleukin 1 receptor
64
Anakinra side effects
Gastrointestinal (N/v/d) infection, fever, injection site reaction, headache, hematologic & oncologic abnormalities
65
Anakinra monitoring
CBC Serum creatinine (renal dose adjustment required) Signs/symptoms of infection - TB test at baseline
66
Anakinra and pregnancy
Limited data- discontinue if pregnant
67
Anakinra place in therapy
Not included in the most recent guidelines Reserved for moderate/severe RA if all else has failed
68
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
69
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
70
Rituximab monitoring parameters
CBC should be obtained before each infusion (and every 2-4 months) Hep B screening prior to initiation
71
Rituximab pregnancy
Do not use in pregnancy
72
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
73
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
74
_______________ should be avoided in patients taking tofacitinib
Live vaccines
75
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
76
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
77
Tofacitinib and pregnancy
Data is limited - do NOT use
78
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
79
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)
80
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
81
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
82
___________ 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
83
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
84
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
85
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)
86
Which drugs should NOT be used in patients with moderate/severe HF?
TNF alpha inhibitors
87
2 big side effects of hydroxychloroquine
Retinopathy QT prolongation (risk of torsades)
88
The big ADR with methotrexate is...
Hepatotoxicity
89
Which drug can cause COPD exacerbations?
Abatacept
90
Which drug causes oligospermia?
Sulfasalazine
91
Which drugs are CYP3A4 inducers?
Tocilizumab and Sarilumab
92
Which 2 drugs require pretreatment with methylprednisolone, acetaminophen, and an antihistamine
Infliximab Rituximab

Imm/Musculoskel/Skin (16 decks)

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