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📖PHARM: Psych, RA & Gout > 3-2 Rheumatoid Arthritis & Gout > Flashcards

3-2 Rheumatoid Arthritis & Gout Flashcards

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1
Q

What is Rheumatoid arthritis?

A

Chronic, system autoimmune disease of unknown etiology

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2
Q

What characterizes rheumatoid arthritis? (2)

A

-inflammation and pain in the joints -progressive joint destruction (can also involve extra-articular sites)

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3
Q

What are the mediators of rheumatoid arthritis? (6)

A
  1. T cells
  2. B cells
  3. TNF alpha
  4. IL-6
  5. IL-1
  6. Prostaglandin
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4
Q

What are the treatment goals for Rheumatoid Arthritis? (2)

A
  1. Decrease ACUTE joint pain
  2. Prevent/control joint damage
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5
Q

What are the classes of drugs to decrease acute joint pain? (3)

A
  1. NSAIDs
  2. Analgesics
  3. Glucocorticoids

*Symptomatic relief only!

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6
Q

What are the classes of drugs to prevent/control joint damage? (2)

A
  1. Disease-Modifying anti-Rheumatic drugs (DMARDs)
  2. Biological Response Modifiers (BRMs)
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7
Q

When would you normally use the drugs to reduce ACUTE joint pain?

A

Typically used to minimize symptomatics effects of RA while waiting for the clinical effects of the slow acting DMARDS and BRMs

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8
Q

What are some examples of analgesics? (3)

A
  1. Acetominophen
  2. Capsacin
  3. Opioids
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9
Q

What is an example of a Glucocorticoid?

A

Dexamethasone

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10
Q

What are some examples of NSAIDS? (2)

A
  1. ibuprofen
  2. naproxen
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11
Q

What are some DMARDs? (4)

A
  1. hydroxychloroquine
  2. sulfasalazine
  3. methotrexate
  4. leflunomide
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12
Q

What are some classes of BRMs/Biologics? (5)

A
  1. anti-TNF drugs
  2. other anti-cytokine drugs
  3. drugs that inhibit T cells
  4. drugs that inhibits B cells
  5. Chemical inhibitors of cytokine signaling
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13
Q

How long does it take for DMARDs to show efficacy?

A

weeks to months

*slow acting anti rheumatic drugs

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14
Q

How long are DMARDs typically taken?

A

Long periods

such as, months to years

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15
Q

What are some less commonly used DMARDs? (5)

A
  1. Azathioprine
  2. D-Penicillamine
  3. Gold Salts
  4. Cyclosporin
  5. Cyclophosphamide
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16
Q

What is hydroxychloroquine?

A

Anti-malarial drug that is moderately effective for mild Rheumatic Arthritis

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17
Q

What is the mechanism of Hydroxychloroquine?

A

Thought to involve

  1. inhibition of TLR signaling in dendritic/B cells
  2. inhibition of antigen presentation to T cells

*Low yield (unlikely to be a test question)

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18
Q

How long does it take for hydroxychloroquine to take effect?

A

3 - 6 months

*Low yield (unlikely to be a test question)

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19
Q

What is the side effect of Hydroxychloroquine?

A
  • Occular Toxicity that can result in permanent visual loss RARE (1/40,000)
    • Risk factors
      • Length of treatment > 5 yrs
      • Age > 60 yrs
      • High dose

Safe during pregnancy and lactation

Generally well tolerated

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20
Q

What is a drug considered to be a Sulfasalazine?

A

Azulifidine

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21
Q

How efficacious is sulfasalazine compared to methotrexate?

A

Similar efficacy

*Effective in up to 50% of patients

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22
Q

How does Sulfasalazine become active?

A

Begins as a prodrug (5-aminosalicyclic acid) covalently linked to sulfapyridine

Cleaved to active components by bacteria in the gut THEN sulfapyridine is absorbed and is the active component in RA

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23
Q

Mechanism of action of Sulfasalazine

A

thought to interfere with T and B cell immune responses

possibly inhibits activation of NF-kB

*low yield

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24
Q

When will you see the effects of Sulfasalazine?

A

1 - 3 months

*Low yield

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25
Q

Side effects of Sulfasalazine (2)

A
  1. Agranulocytosis within 2 weeks
  2. fully reversible Hepatotoxity

More toxic than hydroxychloroquine

Safe during Pregnancy

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26
Q

How is it often prescribed?

A

In combination with other DMARDs (e.g. Hydroxychloroquine)

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27
Q

Indication for Methotrexate

A

Drug of choice for patients with patients with active moderate/severe disease (60% of RA patients)

-used at 10-1000X lower dose than that used in cancer treatment

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28
Q

Results of Methotrexate use (3)

A
  1. decreases appearance of new bone erosions
  2. improves the long term clinical outcome
  3. up to 70% of patietns experience some response to the drug
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29
Q

How long does it take for Methotrexate to take effect?

A

4 - 6 weeks

*low yield

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30
Q

Mechanism of Methotrexate

A

In Powerpoint FYI only

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31
Q

Side effects fo Methotrexate (4)

A

Common SE - dose related hepatotoxicity (abstain from alcohol)

Rare SE

  1. Pulmonary toxicity
  2. Bone Marrow suppression
  3. Increased risk of lymphoma

Generally well tolerated (>50% of pts continue taken for over 3 years)

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32
Q

How is methotrexate excreted?

A

MTX is 80 - 90% renally excreted

*adverse effects frequently observed in patients with renal impairment

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33
Q

What are the contraindications for Methotrexate? (3)

A
  1. Pregnancy/breast feeding (used as abortifacient)
  2. Not recommended for patients with pre-existing liver disease
  3. Not recommended for patients with renal impairment
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34
Q

When would you use Leflunomide?

A

Alternative for those unable to take or non responsive to MTX

Low cost alternative to TNF inhibitors or those with preference for oral <–(*whistle*)

As effective as either sulfasalazine or MTX

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35
Q

How long does it take for Leflunomide to take effect?

A

1 - 2 months

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36
Q

Mechanism of Action for Leflunomide(4)

A

“U GLaD Leflunomide is Low cost! “

  1. Inhibits Uridine synthesis
  2. Inhibits G1 cell cycle (arrest)
  3. Inhibits Lymphocytes
  4. Inhibits Dihydroororate Dehydrogenase

Inhibitis [Dihydroororate Dehydrogenase] –> DEC Uridine synthesis –> [Inhibits G1 Cell cycle arrest]

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37
Q

Side effects for Leflunomide (4)

A
  1. Hypertension (especially with concurrent NSAIDs)
  2. Diarrhea/nausea
  3. rash (10 - 15% of patients)
  4. Hepatotoxicity (10 - 13%)
    1. more severe in presence of methotrexate requiring liver enzyme monitoring
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38
Q

Contraindications for Leflunomide (2)

A
  1. Pregnancy/Breast feeding
  2. Pre-existing liver diease
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39
Q

What are Biological Response Modifiers/Biologics?

A

Recombinant drugs that are specifically designed to inhibit either cytokines or cell types involved in the autoimmune response in RA

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40
Q

What are the pathways TNF alpha controls? (3)

A
  1. Activated Endothelial cells –> Leukocyte recruitment –> Joint inflammation
  2. Synoviocyte/Chondrocyte –> Cartilage breakdown
  3. Osteoclast Different –> Bone resorption –> Bone Erosion

It is synthesized by activated CD4+ T cells, macrophages and mast cells

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41
Q

What are some [TNF Alpha] drugs? (3)

A

“TNF-(A)IE”

  1. Etanercept
  2. Infliximab
  3. Adalimumab
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42
Q

Administration of anti-TNF alpha drugs (2)

A
  1. given either subQ or IV
  2. administered weekly/bi-weekly

as effective as methotrexate

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43
Q

How long does it take for [TNF alpha] drugs to take effect?

A

1 - 4 weeks

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44
Q

Clinical outcomes of anti-TNF alpha drugs (3)

A
  1. decreased joint pain and swell
  2. decreased formation of new bone erosions
  3. decreased progression of structural joint damage

~30 - 60% of patients will exhibit a 20 - 50% improvement in their syptoms

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45
Q

Clinical use of Anti-TNF alpha drugs

A

Monotherapy

*combination therapy with methotrexate [often added to patients not responding adequately to methotrexate monotherapy

46
Q

Side effects of TNF alpha blockers? (5)

A

[DICC: Demyelination / Infection / CHF / CA]

  1. increased risk of opportunistic infx (bact. and fungal)
  2. potential reactivation of latent TB and latent HBV)
  3. Exacerbation of pre-existing CHF (Rare)
  4. Developement of demyelinating diseases (e.g. multple sclerosis) (Rare)
  5. Appearance of malignancies, especially lymphoma (Rare)
47
Q

Contraindication for TNF alpha blockers

A

Should not be given to patients with either acute or chronic infx

*treatment should be discontinued if a serious infx or sepsis develops

48
Q

Name a T cell inhibitor.

A

AbaTacept

49
Q

What are T cell inhibitors?

A

Recombinant fusion protein of CTLA-4 and human IgG1

*binds with high affinity to CD80/CD co-stimulatory molecules on APC

50
Q

Mechanism of Action for T cell inihibitor

A

Inhibits T cell activation by blocking the delivery of CD 28 co-stimulatory signals that are essential for efficient T cell activation

51
Q

Who are T cell inhibitors effective for?

A

Effective in patients non-responsive to TNF alpha inhibitors

~30 - 60% of patients will exhibit a 20 - 50% improvement in their symptoms

52
Q

Side effect of T cell inhibitors

A

Increased risk of serious infx

*screen for latent TB and HBV

53
Q

Contraindication for T cell inihibitors

A

should not be given in combination with a TNF alpha blocker

54
Q

Name one B cell inihibitor

A

RituximaB

55
Q

A: [B cell inhibitor] MOA

B: SE

A

A: Chimeric Ab that binds to [B-cell CD20]

B: Can Deplete Serum B-cells if given IV!!

CD20 molecule expressed exclusively on B lymphcytes

56
Q

What role do B cells play in the etiology of RA? (2)

A
  1. antigen presentation to T cells
  2. formation of autoantibodies

Depletion reduces disease progression

57
Q

What are the effects of B cell inhibitors? (2)

How long do they last?

A
  1. Decrease signs/symptoms of disease
  2. Reduces disease progression

Effects not seen for 3 months, although effects may last 6 months to 2 years

58
Q

Who are B cell inhibitors effective in?

A

patients not responsive to TNF alpha inhibitors

59
Q

Side effects of B cell inhibitors (3)

A
  1. Increased infx
  2. Reactivation of latent viruses
  3. Progressive multifocal leukoencephalopathy (PML) -RARE fatal demyelinating disease associated with reactivation of JC virus
60
Q

Name one anti-cytokine agent

A

Anakinra

61
Q

What are anti-cytokine agents?

A

Recombinant version of an endogenous IL-1 receptor antagonist (IL-1RA)

62
Q

How effective are anti-cytokine agents compared to anti-TNF agents?

A

Less effective

63
Q

What is the half life of Anakinra?

A

short half life of 4 - 6 hours

*must be given SubQ once/day

64
Q

MOA of Anakinra

A

Competitively inhibits the pro-inflammatory effects of IL-1

65
Q

Side effects of Anakinra (2)

A
  1. Increased of neutropenia
  2. Increased of serious infx

*complications more frequent when given together with an anti-TNF alpha drug

66
Q

Contraindication for Anakinra

A

Do not give to patient with acute/chronic infx

67
Q

Name one cytokine Receptor (R) antagonist

A

Tocilizumab

68
Q

What are cytokine R antagonists?

A

Chimeric humanized antibody directed against the IL-6 cytokine receptor

69
Q

How is Tocilizumab used clinically? (2)

A
  1. Used in patients non-responsive to TNF inhibitors
  2. combination Tx with MTX
70
Q

Side effects of Tocilizumab (5)

A

“When I Tock up…I want CHIPC”

  1. CA (Malignancy)
  2. Hepatotoxic
  3. Infection (serious)
  4. Pancytopenia
  5. Cholesterol INC
71
Q

Contraindications for Tocilizumab (4)

A
  1. Patients with acute/chronic infx
  2. Should NOT be combined with other BRM drugs
  3. Patients with pre-existing liver disease
  4. Patients with low blood counts or on immunosuppressive therapy
72
Q

Name one small molecule inhibitor of cytokine signaling

A

Tofacitinib

73
Q

What are small molecule inhibitors of cytokine signaling?

A

Small molecule inhibitor that inhibits JAK tyrosine kinases involved in immune cell cytokine signaling

*new class of anti-rheumatic drug

74
Q

MOA of Tofacitinib

A

See Powerpoint for details

75
Q

Side effects of Tofacitinib (4)

A

[CHIP: Cholesterol / Hepatotoxic / Infection / Pancytopenia]

“To Fat only get 1 CHIP!”

  1. Pancytopenia (Lymphocytopenia, neutropenia, and anemia)
  2. Increased risk of serious infx
  3. Lipid abnormalities (increased cholesterol)
  4. Increased Liver enzymes
76
Q

Treatment Strategy for Rheumatoid Arthritis (by severity)

A

MILD dz: Hydroxychloroquine or Sulfasalazine or combination therapy

Moderate dz: Methotrexate (alternative - Leflunomide)

or Combination Therapy - DMARDs +/- TNF inhibitors

Severe dz: BRMs/Biologics

or Combination Therapy - DMARDs +/- TNF inhibitors (Resistance to TNF inh. –> switch to other BRM

77
Q

What is Gout?

A

Extremely painful form of arthritis

*linked to a purine rich diet and excessive alcohol consumption

78
Q

What is Gout associated with? (5)

A
  1. Obesity
  2. Hypertension
  3. Hyperlipidemia
  4. type - 2 diabetes
  5. HYPERURICEMIA
79
Q

What are the causes of Hyperuricemia in Gout? (2)

A

Hyperuricemia - high serum uric acid (>7 mg/dL)

  1. overproduction of uric acid (10% of patients)
  2. decreased excretion of uric acid by the kidney (90% of patients)
80
Q

Disease course of Gout

A

Asymptomatic hyperuricemia –> Acute Gouty Attack –> Intercritical phase –> Multiple Acute Gouty Attacks –> Chronic Gout

Intercritical phase - Hyperuricemia without symptoms (10% patients never experience 2nd attack)

81
Q

A: Signs of an Acute Gouty Attack (2)

B: When does this resolve

A
  1. Rapid onset of intense pain
  2. swelling in a single joint

e.g. first metatarsophalangeal joint

B: typically resolves in 3 - 10 days

82
Q

What characterizes Chronic Gout? (5)

A
  1. Recurrent attacks
  2. Increased Freq of attacks
  3. Increased severity of attacks
  4. Increased Joint Involvement
  5. Formation of TOPHI

*TOPHI - urate deposits around the joint that promote inflammation and joint destruction

83
Q

In what ways can different drugs treat Gout? (4)

A
  1. Relieve symptoms of acute gouty attack
  2. Lower uric acid levels by promoting uric acid excretion
  3. Lower uric acid levels by inhibiting uric acid synthesis
  4. Directly degrade Uric acid
84
Q

Name two drugs that relieve the symptoms of a Gouty Attack (2)

A
  1. NSAIDs
  2. Colchicine (traditional treatment)
85
Q

A: Indications for NSAIDs (2)

B: What drug is NOT used for Gout Tx

A
  1. Acute Gouty attack - Lowers pain and disability due to acute attack
  2. Prophylactic treatment with other anti-GOUT drugs

*Aspirin/Salicylates are NOT used - both inhibit uric acid at low doses and can induce gout

86
Q

MOA of Colchicine?

A

plant alkaloid that prevents tubulin polymerization into microtubules

87
Q

Effects of Colchicine (2)

A
  1. lowers leukocyte migration and phagocytosis
  2. anti-inflammatory, but NO analgesic properties
88
Q

When to use Colchicine?

A
  • effective when given during the first 24 - 48 hours of the attack
  • can also be used in prophylaxis with other anti-GOUT drugs

*very narrow therapeutic window - limited by side effects (especially at high doses/ 80% of patients develop NVD)

89
Q

Name one Uricosuric agent

A

Probenecid

Uricosuric agent - drug that enhances uric acid excretion

*Lesinurad newly approved Dec 2015

90
Q

MOA of Probenecid

A

weak organic acid inhibits anion transporters in the proximal renal tubules involved in the reabsorption of Uric Acid

91
Q

Outcomes of Probenecid usage

A

INC Uric Acid Excretion

92
Q

A: Indication for Probenecid

B: When is it given

A

patients that under excrete uric acid (90% of patients)

*should not be given until 2 -3 weeks after initial attack. Drug can initiate and/or prolong the symptoms of an acute gouty attack (by affecting uric acid homeostasis)

Prophylactic NSAID Tx should be provided to dec. risk of attack

93
Q

Contraindications for Probenecid (2)

A
  1. Patients that overproduce Uric acid (inc. risk of kidney stones)
  2. Patients with kidney stones and/or renal insufficiency
94
Q

Drug Interactions for Probenecid

A

Many drugs that are normally reabsorbed in the kidney by URAT1

*Dec. Clinical efficacy

Examples of drugs using URAT1 - Indomethacin, naproxen, lorazepam, cephalosporins, methotrexate, captopril, AZT, and ganiciclovir

95
Q

Name two drugs that decrease uric acid synthesis (2)

A
  1. Allopurinol
  2. Febuxostat
96
Q

Indication for Allopurinol/Februxostat

Which patients are they particularly useful for? (3)

A

Used in the treatment of chronic gout to block overproduction of uric acid

  1. high level of endogenous uric acid synthesis
  2. recurrent kidney stones
  3. renal imairment
97
Q

MOA for Allopurinol/Februxostat

A

Inhibitors of Xanthine Oxidase, an enzyme that catalyzes the final two steps in purine degradation

98
Q

Side effects of Allopurinol/Februxostat (5)

A

FLAG and Rash!

  1. Fever
  2. Leukopenia and Thrombocytopenia
  3. [Allopurinol Hypersensitivity Syndrome]
  4. Gouty attack-Acute if NSAID px is not given
  5. Rash

The last 3 can occur in 3 - 5 % of patients

99
Q

Symptoms of Allopurinol hypersensitivity syndrome (RARE)(5)

A

Potentially life threatening reaction (25% mortality)

  1. erythematous rash
  2. fever
  3. hepatitis
  4. eosinophilia
  5. acute renal failure
100
Q

When is the allopurinol hypersensitivity syndrome most likely to hapen?

A

most likely to occur in patients taking excessive doses of drug in the presense of pre-existing renal failure and/or diuretics

*dosage reduction required in renal impairment

101
Q

What is the characteristic genetics of the allopurinol hypersensitivity syndrome?

A

HLA-B*5801 allele

  • more common in Korean, Han Chinese, Thai ancestry
102
Q

Important drug Interaction with allopurinol/Febuxostat

What drug(s)?

What is the drug(s) used for?

A

6-mercaptopurine and azathioprine (prodrug)

  • purine synthesis inhibitors
  • used in immunosuppression and in treatment of leukemia/lymphoma
  • metabolized by Xanthine Oxidase (allopurinol blocks this) to inactive metabolite

The blockage of Xanthine oxidase decreases conversion of 6-mercaptopurine into Inactive metabolite leading to Toxicity

103
Q

A: Which chronic gout patients are indicated for treatment? (3)

B: Tx goal

A
  1. Patients with multiple gouty attacks
  2. Those that are more susceptible to future attacks (e.g. renal insuffciency)
  3. Patients with very high levels of uric acid (>12 mg/dL)

B: reduce serum uric acid levels to <6 mg/dL

104
Q

Criteria to categorize patient as over-producer or an under-secretor of uric acid

A
  • Underexcretion (Probenecid) = 24 hour urinary uric acid excretion <700 mg/dL [90% of patients]
  • Overproducer (Allopurinol vs. Febuxostat) = 24 hour urinary uric acid excretion >700 mg/dL [10% of patients]
105
Q

How long is effective therapy for Chronic Gout?

A

LIFELONG

106
Q

Name one drug used to treat drug resistant Chronic Gout

A

Pegloticase

107
Q

MOA of Pegloticase

A

Porcine uricase linked to PEG (polyethylene glycol)

Enzymatic conversion of Uric Acid to soluble metabolite

*Humans lack Uricase enzyme

108
Q

Indication for Pegloticase

A

Advanced, actively symptomatic gout which is uncontrolled with other uric acid lowering drugs

  • presence of frequent flares
  • presence of TOPHI
  • contraindications to other GOUT drugs
109
Q

Clinical use of Pegloticase

A: Dosage Timing

B: Caveot

A

A: administration by IV infusion every 2 weeks

B: requires NSAID/Colchicine prophylaxis

effective in months vs. years with oral agents?

110
Q

Side effects of Pegloticase (0)

A

Generally well tolerated

GENERATION OF ANTI-DRUG ANTIBODIES LIMITS TREATMENT

📖PHARM: Psych, RA & Gout (6 decks)

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