Rheumatoid arthritis and gout

Question 1

____ and ____ play a central role in rheumatoid arthritis; what cell tends to make these? All this leads to what?

Answer 1

TNF-alpha and IL-1; activated macrophages;
synovial fibroblasts activated and other inflamm cells recruited and MMPs released, leading to bone and cartilage destruction

Question 2

Conservative approach of giving aspirin and NSAIDs first followed by DMARDs is questioned because of what?

Answer 2

1. Joint damage most rapid early in the disease and cannot be reversed
2. DMARD given early retard joint damage
3. rheumatoid patients have multiple health problems and reduced life expectancy

Question 3

Indomethacin (Indocin)

Answer 3

Class: Non-selective NSAID
Mech: Eliminate pain; reduce inflammation (but does not slow disease progression)
Thera: Rheumatoid arthritis; acute gouty arthritis
Important SE’s: Gastric and duodenal ulcers

Question 4

Naproxen (Aleve)

Answer 4

SAME AS INDOMETHACIN

Question 5

COX-2 inhibitors

Answer 5

Class: Selective NSAID
Mech: Eliminate pain; reduce inflammation (but does not slow disease progression)
Thera: Superseding conventional NSAIDs for rheumatoid arthritis
Important SE’s: 50% fewer gastric and duodenal ulcers than traditional NSAIDs

Question 6

Quinolones

Answer 6

Class: DMARD (antimalarial)
Mech: Reduces T-cell activation & chemotaxis
Important SE’s: Rheumatoid arthritis, SLE
Important SE’s: Retinal damage (chloroquine)
Misc: Used for patients who no longer respond to NSAIDS or can’t tolerate other DMARDs

Question 7

“Glucocorticoids

(Corticosteroids)”

Answer 7

Class: DMARD
Mech: “1. Inhibits phospholipase A2 (inhibiting release of arachidonic acid and, thus, formation of prostaglandins)
2. Inhibits cytokine production (which prevents induction of COX-2)”
Thera: Rheumatoid arthritis; acute gouty arthritis (intraarticular injection for relief of acute monoarticular gout)
Important SE’s: Cushingoid symptoms
Misc: “Started initially (fast acting) before other drugs become effective
Can give orally or intra-articularly”

Question 8

Sulfasalazine (Azulfidine)

Answer 8

Class: DMARD
Mech: Likely inhibition of IL-1 & TNF-alpha release
Thera: Rheumatoid arthritis
Important SE’s: N/V, skin rashes, neutropenia (30% of patient discontinue drug)
Other SE’s: Headaches
Misc: Acts more quickly than other drugs

Question 9

Methotrexate (Trexall)

Answer 9

Class: “DMARD
(Immunosuppressive)”
Mech: “1. Inhibition of aminoimidazolecarboxamide (AICAR) transformylase and
thymidylate synthetase, with secondary effects on PMN chemotaxis
2. Causes adenosine accumulation, which inhibits inflammation”
Thera: Rheumatoid arthritis
Important SE’s: Nausea, stomatitis, hepatotoxicity (rare)
Misc: Takes several weeks to start working; “gold standard” of therapy

Question 10

Leflunomide (Arava)

Answer 10

Class: “DMARD
(Immunosuppressive)”
Mech: Inhibits dihydroorotate dehydrogenase (DHODH), which inhibits T-lymphocyte response to stimuli
Thera: Rheumatoid arthritis
Important SE’s: Diarrhea, hepatotoxity
Misc: Takes several weeks to start working; oral prodrug

Question 11

Etanercept (Enbrel)

Answer 11

Class: Biologic Response Modifiers
Mech: Blocks binding of TNF to TNF receptors
Important SE’s: Rheumatoid arthritis
Misc: Twice weekly subcutaneous injections

Question 12

Infliximab (Remicade)

Answer 12

Class: Biologic Response Modifiers
Mech: Blocks binding of TNF to TNF receptors
Thera: Rheumatoid arthritis
Important Se’s: Antigenic response to murine monoclonal Ab

Question 13

Adalimumab (Humira)

Answer 13

Class: Biologic Response Modifiers
Mech: Blocks binding of TNF to TNF receptors
Thera: Rheumatoid arthritis
Misc: Fully human, so no antigenic response; twice monthly injections

Question 14

Golimumab

Answer 14

Class: Biologic Response Modifiers
Mech: Blocks binding of TNF to TNF receptors
Thera: Rheumatoid arthritis
Important SE’s: Risk of serious infections

Question 15

Certolizumab

Answer 15

Class: Biologic Response Modifiers
Mech: Blocks binding of TNF to TNF receptors
Thera: Rheumatoid arthritis
Important SE’s: Risk of serious infections
Misc: Conjugated to PEG for stabilization

Question 16

Anakinra (Kineret)

Answer 16

Class: Biologic Response Modifiers
Mech: IL-1 Receptor Antagonist
Thera: Rheumatoid arthritis
Misc: Short (6 hr) plasma half-life; daily treatment with high doses

Question 17

Tocilizumab (Actemra)

Answer 17

Class: Biologic Response Modifiers
Mech: IL-6 Receptor Antagonist
Thera: Rheumatoid arthritis

Question 18

Rituximab (Rituxan)

Answer 18

Class: Biologic Response Modifiers
Mech: Anti-CD20 mAb, reduces circulating B cells
Thera: Rheumatoid arthritis
Important SE’s: Infections; hypersensitivity reactions
Misc: Used for RA refractory to TNF-alpha inhibitors

Question 19

Abatacept (Orencia)

Answer 19

Class: Biologic Response Modifiers
Mech: Inhibits T-cell activation and induces T-cell apoptosis
Thera: Rheumatoid arthritis
Important SE’s: Headaches; infections
Misc: Used in patients for RA refractory to MTX or TNF-alpha inhibitors

Question 20

Colchicine (Colcrys)

Answer 20

Mech: Prevents tubulin polymerization & leads to inibition of leukocyte migration, phagocytosis, and release of cytokines
Thera: Acute gouty arthritis
Important SE’s: Long-term use causes peripheral neuropathy & neutropenia
Other SE’s: Nausea, vomiting, abdominal pain, troublesome diarrhea
Misc: Works in 12-24 hours!

Question 21

Probenecid (Benemid)

Answer 21

Class: Uricosuric Agent
Mech: Compete with urate at the anionic transport site of the renal tubule and inhibit urate reabsorption
Thera: Chronic tophaceous gout
Important SE’s: Urate crystal mobilization and acute gouty arthritis
Other SE’s: Gastrointestinal irritation
Misc: Secretion of some weak acids (e.g., penicillin) is reduced

Question 22

Allopurinol (Zyloprim)

Answer 22

Mech: “1. Reduces uric acid synthesis by inhibiting xanthine oxidase (competitive inhibition) –> alloxanthine
2. Alloxanthine is a non-competitive inhibitor of xanthine oxidase”
Thera: Chronic tophaceous gout
Important SE’s: Acute attacks of gouty arthritis early in treatment due to mobilization of urate crystals

Question 23

Febuxostat (Uloric)

Answer 23

Mech: Non-purine, non-competitive antagonist of xanthine oxidase
Thera: Chronic tophaceous gout
Important SE’s: Nausea, rash, arthralgias
Misc: Expensive

Question 24

Pegloticase (Krystexxa)

Answer 24

Class: Recombinant, stabilized uricase
Mech: Converts uric acid to allantoin
Thera: Chronic tophaceous gout

Question 25

What enzyme is present in most mammals that is lacking in humans and great apes?

Answer 25

Uricase

Question 26

When can uric acid crystals form?

Answer 26

At moderately elevated concentration (>100 mg/L)

Question 27

What can lead to high rate of urate production? Low rate of urate excretion?

Answer 27

1. Disease states (e.g. Hodgkin’s, lymphomas, leukemia, MM where cells are rapidly produced and destroyed)
2. Metabolism (like ketosis, lactic acidosis)
3. Drug induced (e.g. antineoplastic agents, radiation therapy, alcohol)
4. Diet (high purine intake, like beer, animal muscle, seafood);
5. Renal problems (decreased rates of renal urate clearance)
6. Supoptimal urine volumes
7. Drugs (e.g. thiazide diuretics)