Rheumatoid Arthritis Treatment

Question 1

Rheumatoid Arthritis

Treatment

Answer 1

• 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

Question 2

Disease Modifying Anti-Rheumatic Drugs

(DMARDS)

Answer 2

• 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”)

Question 3

Rheumatoid Arthritis

Older Pharmacological Agents

Answer 3

• Methotrexate
  
  • Most commonly used
• Hydroxychloroquine
  
  • Second most commonly used
• Sulfasalazine

Question 4

Methotrexate

MOA

Answer 4

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

Question 5

Methotrexate

Pharmacokinetics

Answer 5

• 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

Question 6

Methotrexate

Adverse Effects

Answer 6

• 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

Question 7

Methotrexate

Indications

Answer 7

• 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

Question 8

Hydroxychloroquine

MOA

Answer 8

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

Question 9

Hydroxychloroquine

Pharmacokinetics

Answer 9

• Given PO once a day
• T_½ is 40 days ⇒ steady state not reached for months
• Long latency (12-24 wks) period before it exerts its action

Question 10

Hydroxychloroquine

Adverse Effects

Answer 10

• 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

Question 11

Hydroxychloroquine

Indications

Answer 11

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

Question 12

Sulfasalazine

MOA

Answer 12

MOA is unknown

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

Question 13

Sulfasalazine

Pharmacokinetics

Answer 13

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

Question 14

Sulfasalazine

Adverse Effects

Answer 14

• 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

Question 15

Sulfasalazine

Indications

Answer 15

Now more commonly used early in tx of arthritis

Question 16

Biological Response Modifiers

Answer 16

• 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

Question 17

TNF-α Inhibitors

Answer 17

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

Question 18

Adalimumab (Humira)

MOA

Answer 18

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

Question 19

Etanercept (Enbrel)

MOA

Answer 19

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

Question 20

Infliximab (Remicade)

MOA

Answer 20

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

Question 21

TNF-α Inhibitors

Indications

Answer 21

• 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)

Question 22

TNF-α Inhibitors

Common Adverse Effects

Answer 22

• 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

Question 23

TNF-α Inhibitors

Contraindications

Answer 23

Multiple sclerosis

Congestive heart failure

Many other precautions

Question 24

Anakinra (Kineret)

MOA

Answer 24

Interleukin-1 Inhibitor

Recombinant form of human IL-1 receptor antagonist

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

Question 25

Anakinra (Kineret) Pharmacokinetics

Answer 25

Given as a daily subQ injection Can cause injection site reactions

Question 26

Anakinra (Kineret) Adverse Effects

Answer 26

* Injection site reaction * Serious infections * Neutropenia

Question 27

Anakinra (Kineret) Indications

Answer 27

* **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

Question 28

Tocilizumab (Actemra) MOA

Answer 28

**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

Question 29

Tocilizumab (Actemra) Pharmacokinetics

Answer 29

IV or subQ administration Once every four weeks

Question 30

Tocilizumab (Actemra) Adverse Effects

Answer 30

* **Injection site reactions** * **Infusion reactions** * **Rash** * **GI sx** * **Headache** * Respiratory tract infections * **Nasopharyngitis** * Activation of latent TB * **↑ liver enzymes**

Question 31

Tocilizumab (Actemra) Indications

Answer 31

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

Question 32

Leflunomide MOA

Answer 32

_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**

Question 33

Leflunomide Pharmacokinetics

Answer 33

* PO administration * **Leflunomide converted to active drug in intestinal mucosa and liver** * Average plasma T_½ of 15 days d/t **plasma protein binding** and **enterohepatic recirculation** * Cholestyramine can interrupt enterohepatic recirculation ⇒ ↑ rate of elimination

Question 34

Leflunomide Adverse Effects

Answer 34

* Diarrhea * **Reversible alopecia** * Rash * Headache * Dizziness * Respiratory tract infection * **Elevation of liver enzymes and hepatoxicity** * **Contraindicated in pregnancy**

Question 35

Leflunomide Indications

Answer 35

* Efficacy of leflunomide similar to methotrexate * Can be used in combo w/ it * May be combined w/ biologic DMARDS

Question 36

Abatacept MOA

Answer 36

_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**

Question 37

Abatacept Pharmacokinetics

Answer 37

Administered by IV or subQ every two weeks

Question 38

Abatacept Adverse Effects

Answer 38

* ↑ in infections * Nasopharyngitis * Exacerbates COPD * Headache * Nausea

Question 39

Abatacept Indications

Answer 39

**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

Question 40

Tofacitinib MOA

Answer 40

Janus kinase (jak) pathway inhibitor

Question 41

Janus Kinase (JAK) Pathway

Answer 41

* 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

Question 42

Tofacitinib Pharmacokinetics

Answer 42

Administered PO 2x/day

Question 43

Tofacitinib Adverse Effects

Answer 43

* **Potential for cytochrome p450 interactions** * ↑ risk of infections * Headache * Diarrhea * Nasopharyngitis

Question 44

Tofacitinib Indications

Answer 44

* **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

Question 45

DMARDS Table 1

Answer 45

Question 46

DMARDS Table 2

Answer 46