Rheumatoid Arthritis and DMARDs

Question 1

Drug:

• frequently used in early stages of RA
  
  • including RA with poor prognostic features
  • also used at later stages
• generally the first-choice drug for intial therapy; used in over 50% of patients
• a folic acid analog that is also used in cancer chemotherapy
• ACTIVE HALF-LIFE is much LONGER than PLASMA half lfie–> because active drug gets trapped in cell

Answer 1

Methotrexate (MTX)

• Rapid immune cell proliferation depends on purines nad pyrimidines–methotrexate inhibits both, but also increases adenosine, which is anti-inflammatory
• Can do oral but often by SC injection because of better bioavailabilty and fewer side effects
• usually administered once a week
• effects take 4-6 weeks as drug builds up in tissues
• can reduce side effects by giving replacement folic acid; daily 1-3 mg

Question 2

Drug:

• antimalarial drug that is also effective anti-inflammatory
• commonly used with MTX, sulfasalazine, other DMARDs rather than alone
• orally effective–> taken daily–> slow onset of effects –>very long half-life (45 days)

Answer 2

Hydroxycloroquine

Adverse Effects:

• possible retinal damage–> drug accumulates in melanin-containing tissues like the eye
• do not use when psoriasis or porphyria is present

Question 3

Drug:

• an immune-suprressive drug
• inhibition of multiple immune cells and cytokines by poorly defined mechanisms
• often together with hrydroxychloroquine and/or MTX
• orally effective, taken daily
• Concerns:
  
  • blood dyscrasias; agranulocytosis, aplasitc anemia
    
    • killing of the wrong kind of blood cells
  • can reduce folate reabsorption
  • do not use in those with sulfa or celcoxib allergy–because of cross reactivity

Answer 3

Sulfsalazine

Question 4

Explain triple drug therapy for RA

Answer 4

• Start with MXT, weekly
• Try hydroxychloroquine plus sulfasalazine, daily
  
  • Try all three in combination
  • Can add NSAIDs and/or prednisone to the above
• multiple drugs with synergistic effects; reduced side effects compared to increasing dose of any one drug
• championed at UNMC

Question 5

Drug:

• an immunosupressive agent;
• inhibits pyrimidine synthesis
• inhibits T cell prolideration and reduces auto-antibody formation by B cells
• an extremely long half life–> due to repeated enterohepatic recirculation
• inhibits CYP P450s, so increases many drug concentrations

Answer 5

Leflunomide

• is a prodrug–> converted to teriflunomide, the active agent in cells

Question 6

Drug:

• well-established tetracycline antibiotic
• inhibits matrix metalloproteinases, including collagenase–>collagen gets degraded
  
  • inhibits the degeneration of collagen and bone
• specific action to decrease the collagen degradation component of RA
• effective in for use in early disease progression
• minimal side effects, dizziness and hyperpigmentation

Answer 6

Minocycline

Question 7

What are side effects common to nearly all immunosurpressive agents, including biologics

Answer 7

• increased risk of infections:
  
  • upper respiratory, TB, herpes zoster, fungal, others
• Blood dyscrasias
  
  • agranulocytosis, aplastic anemia, others
• increased cancer incidence
  
  • non-melanoma skin cancer
  • non-hodgkin’s lymphoma
  • particular concerns in children and adolescents
• GI problems, headache, skin rash, sinusitis, cough

Question 8

Drug

• anti-TNF drug
• soluble p75 subunit of the human TNF receptor used as a drug
• a recombiant protein with two p75 receptors linked to the Fc domain of IgG1
• binds to TNF, prevents TNF from binding to cellular receptors
• inhibits all steps toward inflammation that are downstream of TNF
  *

Answer 8

Etanercept

• a protein–> so injected weekly
• shortest duration of all the anti-TNF agents
• an advantage in case of adverse reaction
• Side effects:
  
  • headaches, sinusitis, allergic reactions–> its a protien

Question 9

Drug

• Binds TNF
• but is a monoclonal antibody against TNF, not part of the TNF receptor
• a partially humanized mouse antibody, a mouse-human chimera
• administered IV, every 4-8 weeks, after initial loading dose
• always combined with MTX or other DMARDs
• can cause hypotension

Answer 9

Infliximab

Question 10

Drug:

• anti-TNF antibodies
• But FULLY humanized proteins
• injected SC; every two weeks
• Similar side effects as other anti-TNF drugs but this also casues deylination

Answer 10

Adalimumab

Question 11

Drug:

• CTLA-4 analog, a fusion protein of IgG1 and the extracellular binding domain of CTLA-4
• thus it is a CD28 receptor anatgonist, and thus a T cell activation inhibitor
• injected SC weekly or given IV monthly
• for moderate to severe RA that is not responsive to other DMARDs

Answer 11

Abatacept

• Side effects:
• serious infections in 3% of patients
• infusion reactions– bronchospasm, angioedema, hypotension
• should not be combined with TNF inhibitors
  
  • because of increased infection risk
• should not be used in people with COPD
  
  • because of pulmonary infection and other risks

Question 12

Drug:

• is an anti-CD20 monoclonal antibody, therefore a B cell inhibitor
• binds CD20 and depletes CD20+ B cells thar are critical in RA
• administerd IV, two injections two weeks apart
• then not again for at least 6 months
• used in combination with MXT
• in those not treated well with TNF inhibitors

Answer 12

Rituximab

• increased risk and infusion reactions, sometimes severe and life threatening
• some PML cases have occured already–>fatal viral infection