Rheumatoid Arthritis Treatment Flashcards
Rheumatoid Arthritis
Treatment
-
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
Disease Modifying Anti-Rheumatic Drugs
(DMARDS)
- 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”)
Rheumatoid Arthritis
Older Pharmacological Agents
- Methotrexate
- Most commonly used
- Hydroxychloroquine
- Second most commonly used
- Sulfasalazine
Methotrexate
MOA
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
Methotrexate
Pharmacokinetics
- 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
Methotrexate
Adverse Effects
-
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
Methotrexate
Indications
-
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
Hydroxychloroquine
MOA
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
Hydroxychloroquine
Pharmacokinetics
- 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
Hydroxychloroquine
Adverse Effects
- 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
Hydroxychloroquine
Indications
- Used for pts not responding adequately to NSAIDs
- May be used along w/ NSAIDs
- ↓ Rheumatoid factor
- Does not affect erosive bony lesions
Sulfasalazine
MOA
MOA is unknown
- ↓ Rheumatoid factor
- ⊗ T-cell activation
- ⊗ Release of inflammatory cytokines
Sulfasalazine
Pharmacokinetics
- Administered PO
- Sulfapyridine moiety important in RA
- Salicylic acid component more important in ulcerative colitis
Sulfasalazine
Adverse Effects
- 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
Sulfasalazine
Indications
Now more commonly used early in tx of arthritis
Biological Response Modifiers
- 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
TNF-α Inhibitors
- Drugs ⇒ Etanercept, Infliximab, Adalimumab
- Can cause serious infections
- Need TB screening b/c drugs may reactivate latent TB
Adalimumab (Humira)
MOA
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
Etanercept (Enbrel)
MOA
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
Infliximab (Remicade)
MOA
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
TNF-α Inhibitors
Indications
-
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)
TNF-α Inhibitors
Common Adverse Effects
- Common to all TNF inhibitors:
-
↑ in serious infections
- Activation of latent TB and respiratory infection
- Rash
- Headache
- GI disturbances
- Rhinitis
- Pharyngitis
-
↑ in serious infections
- 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
TNF-α Inhibitors
Contraindications
Multiple sclerosis
Congestive heart failure
Many other precautions
Anakinra (Kineret)
MOA
Interleukin-1 Inhibitor
Recombinant form of human IL-1 receptor antagonist
- ⊗ actions of IL- 1
- IL-1 ⇒ cartilage degradation
- ⊕ proteoglycans loss
- ⊕ bone resorption
Anakinra (Kineret)
Pharmacokinetics
Given as a daily subQ injection
Can cause injection site reactions
Anakinra (Kineret)
Adverse Effects
- Injection site reaction
- Serious infections
- Neutropenia
Anakinra (Kineret)
Indications
- 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
Tocilizumab (Actemra)
MOA
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
Tocilizumab (Actemra)
Pharmacokinetics
IV or subQ administration
Once every four weeks
Tocilizumab (Actemra)
Adverse Effects
- Injection site reactions
- Infusion reactions
- Rash
- GI sx
- Headache
- Respiratory tract infections
- Nasopharyngitis
- Activation of latent TB
- ↑ liver enzymes
Tocilizumab (Actemra)
Indications
- Juvenile idiopathic arthritis
- Rheumatoid arthritis ⇒ if pt has not been responsive to other biologics
- May be used in combo w/ other non-biologic DMARDS
Leflunomide
MOA
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
Leflunomide
Pharmacokinetics
- 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
Leflunomide
Adverse Effects
- Diarrhea
- Reversible alopecia
- Rash
- Headache
- Dizziness
- Respiratory tract infection
- Elevation of liver enzymes and hepatoxicity
- Contraindicated in pregnancy
Leflunomide
Indications
- Efficacy of leflunomide similar to methotrexate
- Can be used in combo w/ it
- May be combined w/ biologic DMARDS
Abatacept
MOA
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
Abatacept
Pharmacokinetics
Administered by IV or subQ every two weeks
Abatacept
Adverse Effects
- ↑ in infections
- Nasopharyngitis
- Exacerbates COPD
- Headache
- Nausea
Abatacept
Indications
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
Tofacitinib
MOA
Janus kinase (jak) pathway inhibitor
Janus Kinase (JAK) Pathway
- 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
Tofacitinib
Pharmacokinetics
Administered PO 2x/day
Tofacitinib
Adverse Effects
- Potential for cytochrome p450 interactions
- ↑ risk of infections
- Headache
- Diarrhea
- Nasopharyngitis
Tofacitinib
Indications
- 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
DMARDS
Table 1
DMARDS
Table 2
