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4. HDS Multisystem > Rheumatoid Arthritis Treatment > Flashcards

Rheumatoid Arthritis Treatment Flashcards

1
Q

Rheumatoid Arthritis

Treatment

A
  • Two drug classes used to ↓ inflammation ⇒ NSAIDs and glucocorticoids
    • ↓ inflammation but do not slow disease process
  • Long-term use of corticosteroids ⇒ weight gain, diabetes, cataracts, osteoporosis
  • Low dose corticosteroids ↓ joint destruction
  • Disease Modifying Anti-Rheumatic Drugs (DMARDS) can slow progression
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2
Q

Disease Modifying Anti-Rheumatic Drugs

(DMARDS)

A
  • Slow disease progression
  • Take some time to exert their action
  • Fall into two major categories
    • Older agents ⇒ non-biologics
    • Newer agents ⇒ mostly, but not exclusively Ab’s or recombinant proteins (“biologics”)
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3
Q

Rheumatoid Arthritis

Older Pharmacological Agents

A
  • Methotrexate
    • Most commonly used
  • Hydroxychloroquine
    • Second most commonly used
  • Sulfasalazine
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4
Q

Methotrexate

MOA

A

Folic acid analogue:

⊗ dihydrofolate reductase ⇒ ↓ dTMP ⇒ ↓ DNA and protein synthesis

  • Likely not mech. by which methotrexate exerts its action in RA
  • Therapeutic effect is not reversed by folic acid
  • May work by ↑ release of adenosine ⇒ anti-inflammatory mediator
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5
Q

Methotrexate

Pharmacokinetics

A
  • Methotrexate is polyglutamated
  • Methotrexate → 7-hydroxymethotrexate (active metabolite) in the liver
    • Longer half-life than methotrexate
    • Given once a week either PO or IM
  • Primary excretion pathway via kidneys ⇒ weak acid secretory pathway in proximal tubule
  • Aspirin or probenecid can compete for excretion ⇒ methotrexate toxicity
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6
Q

Methotrexate

Adverse Effects

A
  • Most common adverse reactions:
    • Mucosal ulcers
    • Nausea
    • Diarrhea
    • Can be ↓ w/ leucovorin or by using folic acid
  • Abnormal liver enzymes do occur
    • Liver disease is uncommon
    • Liver function should be monitored
    • Liver complications more likely in alcoholics and pts w/ pre-existing liver problem
  • At higher concentrations used for cancer tx ⇒ bone marrow suppression
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7
Q

Methotrexate

Indications

A
  • Most widely used for RA due to:
    • Favorable efficacy and toxicity profile
    • Rapid onset and offset of action
    • Improvement can be seen w/in weeks
  • Effect stabilizes by 6 months
  • Can last as long as 7 yrs
  • Contraindicated in pregnancy
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8
Q

Hydroxychloroquine

MOA

A

Drug is a base ⇒ accumulates in lysosomal compartment of CT and WBCs

Thought to ⊗ intracellular Ag processing & loading of peptides onto MHC class II molecules in endosomes ⇒ ⊗ T-cell activation

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9
Q

Hydroxychloroquine

Pharmacokinetics

A
  • Given PO once a day
  • T½ is 40 days ⇒ steady state not reached for months
  • Long latency (12-24 wks) period before it exerts its action
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10
Q

Hydroxychloroquine

Adverse Effects

A
  • Majority of adverse effects are transient and not serious:
    • Rashes
    • GI upset
    • Leukopenia
    • Peripheral neuropathy
    • Ocular effects
  • Admin w/ food controls adverse GI affects
    • Bioavailability is not affected
  • Eye exam @ beginning of therapy to establish a baseline ⇒ ∆ in ocular function can be assessed
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11
Q

Hydroxychloroquine

Indications

A
  • Used for pts not responding adequately to NSAIDs
  • May be used along w/ NSAIDs
  • ↓ Rheumatoid factor
  • Does not affect erosive bony lesions
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12
Q

Sulfasalazine

MOA

A

MOA is unknown

  • ↓ Rheumatoid factor
  • ⊗ T-cell activation
  • ⊗ Release of inflammatory cytokines
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13
Q

Sulfasalazine

Pharmacokinetics

A
  • Administered PO
  • Sulfapyridine moiety important in RA
  • Salicylic acid component more important in ulcerative colitis
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14
Q

Sulfasalazine

Adverse Effects

A
  • GI or CNS complications
  • Neutropenia
    • ☑︎ CBC every 2 to 4 weeks for 3 months then every 3 months thereafter
    • Drug should be stopped if WBC count < 3.5x109/l or platelets < 120x109/l
  • Skin rashes
  • Hepatotoxicity
    • ☑︎ LFTs monthly for first 3 months and every 3-6 months thereafter
    • Drug should be stopped if LFTs ↑ to 3x baseline value
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15
Q

Sulfasalazine

Indications

A

Now more commonly used early in tx of arthritis

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16
Q

Biological Response Modifiers

A
  • Most have HMW ⇒ must be given IV
  • MΦ and T-cells contact each other w/in joint lining
  • MΦ releases TNF-α and IL-1 among other inflammatory mediators
  • Interact w/ T-cell ⇒ release additional mediators
  • Drugs modify this process
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17
Q

TNF-α Inhibitors

A
  • Drugs ⇒ Etanercept, Infliximab, Adalimumab
  • Can cause serious infections
  • Need TB screening b/c drugs may reactivate latent TB
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18
Q

Adalimumab (Humira)

MOA

A

TNF-α Inhibitor

  • Fully human anti-TNF-α Ab
  • ⊗ ability of TNF-α to interact w/ p55 and p75 cell-surface TNF receptors
  • Used subQ
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19
Q

Etanercept (Enbrel)

MOA

A

TNF-α Inhibitor

Two soluble TNF p75 receptor moieties linked to Fc portion of human IgG-1

  • Binds two TNF molecules
    • Not specific for α form ⇒ also binds β form
  • ⊗ TNF actions ⇒
    • ↓ expression of adhesion molecules responsible for leukocyte migration
    • ↓ serum levels of cytokines and metalloproteinase
  • Used subQ
20
Q

Infliximab (Remicade)

MOA

A

TNF-α Inhibitor

Chimeric mAb that binds w/ high affinity to TNF-α

  • 2/3 human and 1/3 mouse ⇒ Ab may develop to it
  • Binds specifically to TNF-α
  • Used IV
21
Q

TNF-α Inhibitors

Indications

A
  • Can be used alone or in combo w/ methotrexate
    • Combo usually more effective than methotrexate alone
  • Can be used for:
    • Rheumatoid arthritis
    • Ankylosing spondylitis
    • Juvenile idiopathic arthritis
    • Psoriatic arthritis
    • Plaque psoriasis
    • Moderate to severe Crohn’s disease/ulcerative colitis (except etanercept)
22
Q

TNF-α Inhibitors

Common Adverse Effects

A
  • Common to all TNF inhibitors:
    • ↑ in serious infections
      • Activation of latent TB and respiratory infection
    • Rash
    • Headache
    • GI disturbances
    • Rhinitis
    • Pharyngitis
  • Injection site reactions to etanercept and adalimumab
  • Infusion reactions to infliximab ⇒ includes fevers and chills
  • Ab develop to etanercept and infliximab
  • Do not affect the response to the drug
23
Q

TNF-α Inhibitors

Contraindications

A

Multiple sclerosis

Congestive heart failure

Many other precautions

24
Q

Anakinra (Kineret)

MOA

A

Interleukin-1 Inhibitor

Recombinant form of human IL-1 receptor antagonist

  • ⊗ actions of IL- 1
  • IL-1 ⇒ cartilage degradation
    • ⊕ proteoglycans loss
    • ⊕ bone resorption
25
Q

Anakinra (Kineret)

Pharmacokinetics

A

Given as a daily subQ injection

Can cause injection site reactions

26
Q

Anakinra (Kineret)

Adverse Effects

A
  • Injection site reaction
  • Serious infections
  • Neutropenia
27
Q

Anakinra (Kineret)

Indications

A
  • Used for pts 18 yrs and older who have failed one or more DMARDS
  • Can be used alone or in combo w/ other non-biologic DMARDS
  • But not w/ anti-TNF drugs
28
Q

Tocilizumab (Actemra)

MOA

A

Interleukin-6 Inhibitor

Human Ab

  • Binds to soluble and membrane bound IL-6 receptors ⇒ ⊗ IL-6 signaling
  • IL-6 produced locally by synovial cells in the joints in response to inflammatory processes
29
Q

Tocilizumab (Actemra)

Pharmacokinetics

A

IV or subQ administration

Once every four weeks

30
Q

Tocilizumab (Actemra)

Adverse Effects

A
  • Injection site reactions
  • Infusion reactions
  • Rash
  • GI sx
  • Headache
  • Respiratory tract infections
  • Nasopharyngitis
  • Activation of latent TB
  • ↑ liver enzymes
31
Q

Tocilizumab (Actemra)

Indications

A
  • Juvenile idiopathic arthritis
  • Rheumatoid arthritis ⇒ if pt has not been responsive to other biologics
  • May be used in combo w/ other non-biologic DMARDS
32
Q

Leflunomide

MOA

A

Lymphocyte antagonist

  • Leflunomide ⊗ dihydroorotate dehydrogenase ⇒ ↓ UMP ⇒ cells arrested in G1 phase
  • Activated lymphocytes require ↑ DNA/RNA synthesis
  • Depends on de novo synthesis of nucleotides
  • Mostly ↓ B-cells but also has significant effect on T-cells
33
Q

Leflunomide

Pharmacokinetics

A
  • PO administration
  • Leflunomide converted to active drug in intestinal mucosa and liver
  • Average plasma T½ of 15 days d/t plasma protein binding and enterohepatic recirculation
  • Cholestyramine can interrupt enterohepatic recirculation ⇒ ↑ rate of elimination
34
Q

Leflunomide

Adverse Effects

A
  • Diarrhea
  • Reversible alopecia
  • Rash
  • Headache
  • Dizziness
  • Respiratory tract infection
  • Elevation of liver enzymes and hepatoxicity
  • Contraindicated in pregnancy
35
Q

Leflunomide

Indications

A
  • Efficacy of leflunomide similar to methotrexate
  • Can be used in combo w/ it
  • May be combined w/ biologic DMARDS
36
Q

Abatacept

MOA

A

Lymphocyte antagonist

  • Recombinant fusion protein
  • Binds to CD80 and CD86 on APCs
  • ⊗ molecules from binding CD28 on T-cells ⇒ prevents co-stimulatory signal ⇒ ⊗ T-cell activation
37
Q

Abatacept

Pharmacokinetics

A

Administered by IV or subQ every two weeks

38
Q

Abatacept

Adverse Effects

A
  • ↑ in infections
  • Nasopharyngitis
  • Exacerbates COPD
  • Headache
  • Nausea
39
Q

Abatacept

Indications

A

Moderate to severe active RA w/ inadequate response to 2 or more DMARDS

May be used alone or w/ non-biologic DMARD but not w/ a biologic

40
Q

Tofacitinib

MOA

A

Janus kinase (jak) pathway inhibitor

41
Q

Janus Kinase (JAK) Pathway

A
  • Janus kinases are intracellular tyrosine kinases
  • Phosphorylate cytokine receptor when it is activated
  • Recruits signal transducers and activators of transcription (stats)
  • Become phosphorylated then dimerize
  • Dimers enter nucleus and ∆ gene expression
  • Signals important in inflammation
42
Q

Tofacitinib

Pharmacokinetics

A

Administered PO 2x/day

43
Q

Tofacitinib

Adverse Effects

A
  • Potential for cytochrome p450 interactions
  • ↑ risk of infections
  • Headache
  • Diarrhea
  • Nasopharyngitis
44
Q

Tofacitinib

Indications

A
  • RA in pts who have not responded to methotrexate
  • Used alone or in combo w/ methotrexate or other non-biologic DMARDS
  • Should not be used in combo w/ biologics such as TNF or IL inhibitor
  • Considered to be an oral molecule w/ biologic-like efficacy
45
Q

DMARDS

Table 1

A
46
Q

DMARDS

Table 2

A

4. HDS Multisystem (43 decks)

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