Wolff: DMARDs

Question 1

What are the drugs of first choice for RA due to efficacy and rapid onset of action?

Answer 1

NSAIDs

Question 2

What is important to remember about using NSAIDs for RA?

Answer 2

Do NOT alter disease progression

Question 3

What is the important role of using glucocorticoids in managment of RA; which have longer half-lifes and potency?

Answer 3

• Relieves pain and inflammation while waiting for DMARD effects
• Fluorinated prednisolones: Betamethasone, Dexamethasone, Triamcinolone

Question 4

How can exogenous glucocorticoids be fatal?

Answer 4

If abruptly stopped, rather than discontinuing slowly

Question 5

Which DMARD is the drug of first-choice for RA?

Answer 5

Methotrexate

Question 6

RA pt’s taking low doses of methotrexate should also take what?

Answer 6

Weekly folate supplements

Question 7

What are the life-threatening major toxicities associated with higher doses of Methotrexate?

Answer 7

• Bone marrow suppression
• Hepatic fibrosis
• GI ulceration
• Pneumonitis

Question 8

What is the MOA of low-dose Methotrexate used for RA?

Answer 8

• Polyglutamation –> MTX-(glu)_n which accumulates in cells
• Blocks thymidylate synthase and AICAR
• AICAR causes Adenosine efflux which binds purinergic GPCRs –> anti-inflammatory effect

Question 9

What is the MOA of Hydroxycloroquine used in RA; how quick is onset?

Answer 9

• Lipophilic weak base –> accumulates in lysosomes –> ↑ pH
• ↑ pH of lysosome in APC’s limits the assoc. of peptides w/ class II MHC
• Can slow disease progression, but delayed onset (3-6 mo.)

Question 10

Which DMARD can a pregnant mother with RA use safely?

Answer 10

Hydroxychloroquine

Question 11

What is a rare dose-related, but serious, AE of Hydroxychloroquine?

Answer 11

Retinal damage

Question 12

What is the active metabolie of the DMARD Sulfasalazine when used for RA?

Answer 12

Sulfapyridine

Question 13

What is the MOA of the DMARD, Leflunomide?

Answer 13

• Inhibition of mitochondrial enzyme dihydroorotate dehydrogenase to block synthesis of rUMP and pyrimidine synthesis
• Inhibits T cell proliferation (especially memory T cells)

Question 14

Which traditional DMARD disrupts pyrimidine synthesis and is a 2nd choice due to more common serious AE’s?

Answer 14

Leflunomide

Question 15

5 most common AE’s assoc. w/ the DMARD, Leflunomide?

Answer 15

• Diarrhea
• Respiratory infection
• Reversible alopecia
• Rash
• Nausea

Question 16

The DMARD, leflunomide is toxic to which organ?

Answer 16

Hepatotoxic –> ↑ risk of serious infections

Question 17

What is the rule for using biologic and non-biologic DMARDs together?

Answer 17

• CAN combine biologics and non-biologics
• Biologics should NEVER be combined w/ other biologics

Question 18

What are the 3 TNF-α blockers used for RA?

Answer 18

• Etanercept
• Infliximab
• Adalimumab

Question 19

What is the clinical indication for using the TNF-α blockers (etanercept, infliximab, and adalimumab) for RA?

Answer 19

Moderate to severe RA, gen. after traditional DMARDs have been ineffective

Question 20

What are some of the serious AE’s associated with the TNF-α blockers used for RA?

Answer 20

• Serious infections: including tuberculosis
• Pt’s may also experience severe allergic reactions

Question 21

Which drug targets CD20 antigen of B cells to cause a B cell ‘do-over,’ and is used to treat HL and CLL + in combo with MTX for RA in those who have no responded to TNF-blockers?

Answer 21

Rituximab

Question 22

What testing in a pt with RA would indicate a greater likelihood of response to Rituximab?

Answer 22

(+) testing for rheumatoid factor or anti-cyclic citrullinate peptide (CCP)

Question 23

Rituximab is associated with what serious AE?

Answer 23

Severe infusion related hypersensitivity rxns

Question 24

What is the MOA of Abatacept used for RA?

Answer 24

Prevents CD28 from binding to its counter-receptor, CD80/CD86

Question 25

What is the MOA and effects of Tocilizumab used for RA?

Answer 25

• Humanized anti-human IL-6 receptor antibody
• Limits hepatic acute phase response and activation of T cell, B cells, macrophages, and osteoclasts

Question 26

What is the most common AE and a serious AE of Tocilizumab?

Answer 26

• Most common = upper respiratory tract infections
• Serious = life-threatening infections (TB, invasive fungal infections, opportunistic, etc.)

Question 27

Which biologic DMARD used for RA stands out due to it being available as an oral formulation?

Answer 27

Tofacitinib - JAK3 antagonist

Question 28

What is the MOA of Tofacitinib used for RA?

Answer 28

Inhibitor of JAK3 –> directly suppresses the prod. of IL-17 and IFN-y and the proliferation of CD4+ T cells

Question 29

What are AE’s associated with Tofacitinib and which warning comes with this drug?

Answer 29

• Serious and sometimes fatal infections due to bacteria, mycobacterial, invasive fungal and other opportunistic pathogens
• Warning = ↑ risk of malignancies (i.e., lymphoma)

Question 30

What is the MOA of Anakinra used for RA; clinical indication?

Answer 30

• A recombinant non-glycosylated version of human IL-1 receptor antagonist–> blocks the pro-inflammatory activity of naturally occurring IL-1
• Less efficacious than others, so used as late choice

Question 31

Which TNF-antagonist consists of two TNF receptors bound to Fc portion of IgG and is administered 1-2x/weekly by SQ injection?

Answer 31

Etanercept

Question 32

The TNF-antagonist, Etanercept is effective in treating what conditions?

Answer 32

RA + psoriatic arthritis + ankylosing spondylitis