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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
Q

Hydroxychloroquine and pregnancy

A

Recommended and safe for pregnant patients

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26
Q

Hydroxychloroquine ADRs (3)

A

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

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27
Q

Hydroxychloroquine monitoring parameters

A

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)

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28
Q

Hydroxychloroquine place in therapy

A

Typically used in combination with other DMARDs
Can be used as monotherapy in mild cases (or pregnancy)

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29
Q

Sulfasalazine MOA

A

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

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30
Q

Sulfasalazine ADRs

A

Skin rash
Gastric distress
N/v, dyspepsia
Oligospermia (reversible)

Less common:
-leukopenia, thrombocytopenia, increased LFTs
-hemolytic anemia (increased risk if G6PD deficiency)

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31
Q

Sulfasalazine pregnancy

A

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)

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32
Q

Sulfasalazine place in therapy

A

Can be used as monotherapy or in combination with other DMARDs for RA
-use is limited by GI effects

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33
Q

Sulfasalazine is contraindicated with…

A

TRUE sulfonamide or salicylate allergy

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34
Q

Leflunomide MOA

A

Inhibits synthesis of pyrimidine

It is a prodrug, the active form inhibits dihydroorotate dehydrogenase (DHODH) which is an essential enzyme needed for pyrimidine synthesis

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35
Q

Leflunomide PK and toxicity considerations

A

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

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36
Q

Leflunomide ADRs

A

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

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37
Q

Leflunomide and pregnancy

A

Contraindicated in pregnancy

38
Q

Leflunomide 2 BBWs

A

Pregnancy - fetal harm
Hepatoxicity

39
Q

Leflunomide monitoring parameters

A

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
Q

Leflunomide place in therapy

A

Monotherapy or combination with other DMARDs
-use is limited to side effects (we have better agents)

41
Q

Which 2 conventional DMARDs can NOT be used in pregnancy

A

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
Q

Which drugs are TNF alpha inhibitors (5)

A

“additional tanning certainly goes to inflammation”

Adalimumab
Etanercept
Certolizumab
Golimumab
Infliximab

43
Q

TNF alpha inhibitor MOA

A

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
Q

TNF alpha and immunogenicity

A

-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
Q

TNF alpha inhibitor onset

A

Can take up to 3 months to achieve full benefit
(several weeks for clinical benefit)

46
Q

TNF alpha inhibitor place in therapy

A

Used when disease remains moderate or high despite conventional DMARD therapy (MTX)
or contraindication to conventional DMARD therapy

47
Q

TNF alpha inhibitor side effects/contraindications

A

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
Q

TNF alpha monitoring

A

Before starting therapy:
screen for TB and hep b

During therapy: CBC, signs/symptoms of malignancy and serious infection

49
Q

TNF alpha inhibitors and pregnancy

A

Most data is seen with certolizumab for continuing throughout pregnancy

Etanercept and adalimumab have theoretical risk for newborn infection, but are sometimes continued

50
Q

Which TNF alpha inhibitor is IV only

A

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
Q

What are the non-tnf alpha biologics that can be used for RA? (5)

A
  1. Abatacept
  2. Tocilizumab
  3. Sarilumab
  4. Anakinra
  5. Rituximab
52
Q

Abatacept MOA

A

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
Q

Abatacept place in therapy

A

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
Q

Abatacept ADR

A

COPD exacerbations
-not the best choice for patients with COPD

Others:
-headache, URTI, nasopharyngitis, nausea, infusion reactions, serious infections, malignancy

55
Q

Abatacept monitoring

A

Signs/symptoms of infection or hypersensitivity reaction

Hepatitis and TB screening before therapy initiation

Periodic skin exams

56
Q

Abatacept and pregnancy

A

Limited data - so should be discontinued if pregnant

57
Q

Tocilizumab and Sarilumab MOA

A

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
Q

Tocilizumab and Sarilumab ADRs

A

infections, headache, hypertension, increased liver enzymes, injection site reactions, infusion reactions can also occur, gastrointestinal perforation, neutropenia, thrombocytopenia, serious infections, and malignancy

59
Q

Tocilizumab and Sarilumab DDI consideration

A

CYP3A4 inducers
decrease concentration of CYP3A4 substrates - including oral contraceptives (important counseling point)

60
Q

Tocilizumab and Sarilumab monitoring

A

Neutrophils, platelet
Lipid panel and AST/ALT (since they effect the liver)

Baseline TB screening

61
Q

Tocilizumab and Sarilumab in pregnancy

A

Limited data- so use should be discontinued if pregnant

62
Q

Tocilizumab and Sarilumab place in therapy

A

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
Q

Anakinra MOA

A

antagonist of the interleukin 1 receptor

64
Q

Anakinra side effects

A

Gastrointestinal (N/v/d)
infection, fever, injection site reaction, headache, hematologic & oncologic abnormalities

65
Q

Anakinra monitoring

A

CBC
Serum creatinine (renal dose adjustment required)
Signs/symptoms of infection - TB test at baseline

66
Q

Anakinra and pregnancy

A

Limited data- discontinue if pregnant

67
Q

Anakinra place in therapy

A

Not included in the most recent guidelines
Reserved for moderate/severe RA if all else has failed

68
Q

Rituximab MOA

A

Monoclonal antibody binds to CD20 on B cells causing ADCC, CDC, and apoptosis
Killing the b cells decreases the antibodies present in circulation

69
Q

Rituximab ADRs

A

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
Q

Rituximab monitoring parameters

A

CBC should be obtained before each infusion (and every 2-4 months)

Hep B screening prior to initiation

71
Q

Rituximab pregnancy

A

Do not use in pregnancy

72
Q

Rituximab place in therapy

A

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
Q

Tofacitinib MOA

A

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
Q

_______________ should be avoided in patients taking tofacitinib

A

Live vaccines

75
Q

Tofacitinib ADRs

A

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
Q

Tofacitinib monitoring

A

●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
Q

Tofacitinib and pregnancy

A

Data is limited - do NOT use

78
Q

How is disease activity determined?

A

Using activity scales (differ in practice)
determined to be Low or moderate activity - this is important because it determines what treatment we use

79
Q

Low disease activity treatment

A

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
Q

Nonpharm therapy for RA

A

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
Q

Which drugs are JAK inhibitors? When are they used

A

Tofacitinib (Xeljanz)
Upadacitinib (Rinvoq)
Baricitinib (Olumiant)

Place in therapy for RA is unclear, reserved for if all else fails

82
Q

___________ can NEVER be used together. Why? (other considerations related to this)

A

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
Q

Treatment algorithm for moderate/high disease activity

A

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
Q

Can therapy be discontinued?

A

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
Q

How long can it take for maximal DMARD benefit?

A

up to 12 weeks - so this is when we should re-assess

(biologics work a bit faster than conventional DMARDs)

86
Q

Which drugs should NOT be used in patients with moderate/severe HF?

A

TNF alpha inhibitors

87
Q

2 big side effects of hydroxychloroquine

A

Retinopathy
QT prolongation (risk of torsades)

88
Q

The big ADR with methotrexate is…

A

Hepatotoxicity

89
Q

Which drug can cause COPD exacerbations?

A

Abatacept

90
Q

Which drug causes oligospermia?

A

Sulfasalazine

91
Q

Which drugs are CYP3A4 inducers?

A

Tocilizumab and Sarilumab

92
Q

Which 2 drugs require pretreatment with methylprednisolone, acetaminophen, and an antihistamine

A

Infliximab
Rituximab

Imm/Musculoskel/Skin (16 decks)

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