Rheumatoid Arthritis and DMARDs

Question 1

How do you treat osteoarthritis?

Answer 1

acetaminophen

Question 2

describe osteoarthritis:

Answer 2

associated with age, immune system is NOT involved, treatment is acetaminophen, not an NSAID, good for analgesic purposes

Question 3

T/F. Rheumatoid arthritis is an autoimmune disease.

Answer 3

TRUE, with immune system drug targets.

Question 4

First approach of treatment for RA:

Answer 4

physical therapy; rest and splitting to prevent muscular atrophy

Question 5

Second approach for treatment of RA:

Answer 5

drugs; to relieve symptoms, MINIMIZE TISSUE DESTRUCTION CAUSED BY INFLAMMATION

Question 6

T/F. Aggressive treatment very early to halt disease progression is now common.

Answer 6

TRUE.

Question 7

What does DMARDs stand for?

Answer 7

Disease-Modifying Anti-Rheumatic Drugs: slowing or stopping disease progression

Question 8

Third approach to treatment of RA:

Answer 8

surgery if drugs inadequate

Question 9

Three groups that help treat RA:

Answer 9

NSAIDs and GCs, “Traditional” DMARDs, and Biologic Response Modifies or Biologics

Question 10

Group of drugs that is generally a broad immune-toxic mechanism:

Answer 10

Traditional DMARDs

Question 11

What does traditional mean?

Answer 11

oral

Question 12

Group of drugs that target individual specific signaling molecules:

Answer 12

Biologic Response Modifiers or Biologics

Question 13

Protein or peptide drugs:

Answer 13

Biologic response modifiers

Question 14

Small molecule drugs, brand and can do all types of things:

Answer 14

Traditional DMARDs (and oral)

Question 15

NSAID used for RA:

Answer 15

Naproxen.

Question 16

Why is NSAID never mono therapy?

Answer 16

It provides just a bandaid, but does not fix problem, not sufficient enough; only provides initial relief

Question 17

GC stands for:

Answer 17

glucocorticoids

Question 18

What is a glucocorticoid?

Answer 18

anti-inflammatory steroids

Question 19

What is the most commonly used GC?

Answer 19

Prednisone

Question 20

Characteristics of Prednisone:

Answer 20

highly effective, but long term toxicity effects; not used as a mono therapy, rapid acting bridge agent

Question 21

Traditional DMARDs:

Answer 21

methotrexate, hydroxychloroquine, sulfasalazine, triple drug therapy, leflunomide, minocycline

Question 22

Biologic DMARDs

Answer 22

ANTI-TNF drugs, etanercept, infliximab

Question 23

The first choice DMARDs drug for initial therapy of RA and used in early stages of RA (but can be used in late stages too:

Answer 23

Methotrexate, also called MTX

Question 24

Do we use Methotrexate with other drugs?

Answer 24

Yes, very often. Also use in more than 50% of RA patients

Question 25

Dose of methotrexate?

Answer 25

once per week, mat take up to 4-6 weeks to see effects

Question 26

Structure and mechanism of methotrexate:

Answer 26

FOLIC ACID analog; folate transporters.

Question 27

Does methotrexate have a long half life in the cell than plasma?

Answer 27

Yes, much longer than plasma half-life.

Question 28

What is mechanism 1 of methotrexate?

Answer 28

acts as anti-metabolite (anti-folate) to inhibit PURINE and PYRIMIDINE synthesis; inhibits DHFR and FH4; anti-cancer mechanism

Question 29

What is mechanism 2 of methotrexate?

Answer 29

inhibits enzyme AICAR; inhibits purine synthesis; increase anti-inflammatory mediate ADENOSINE outside cells; doesn't just slow but REVERSES; MAJOR MECHANISM in RA

Question 30

What is mechanism 3 of methotrexate?

Answer 30

reduce pyrimidine synthesis, inhibits proliferation of inflammatory cells

Question 31

Overall the mechanisms for methotrexate rely on what?

Answer 31

rapid immune cell proliferation depends on purines and pyramids; methotrexate inhibits both, but increases adenosine (anti-inflammatory)

Question 32

Side effects of methotrexate:

Answer 32

minor GI problems, rare hepatotoxicity with high doses, elevation of liver enzyme levels at high doses, USE ONCE A WEEK to avoid high doses, avoid alcohol, avoid patients with liver failure

Question 33

Many side effects of methotrexate or due to what?

Answer 33

induced folate deficiency

Question 34

How can you reduce folate deficiency?

Answer 34

REPLACEMENT FOLIC ACID DAILY (1-3 mg)

Question 35

What are CONTRAINDICATIONS of methotrexate?

Answer 35

renal insufficiency; pregnancy or those planning for pregnancy (teratogenic), nursing mothers, abortifacient with misoprostol

Question 36

What is a less common complication but signs need to be watched when administering MTX?

Answer 36

increased infections, including upper respiratory, TB, fungal

Question 37

Anti-malarial drug that is anti-inflammatory:

Answer 37

hydroxychloroquine

Question 38

What drugs do we use hydroxychloroquine with?

Answer 38

MTX, sulfasalazine

Question 39

How is hydroxychloroquine thought to work?

Answer 39

altering cellular pH

Question 40

T/F. hydroxychloroquine has a slow onset and very long half-life (45 days). And skin is reservoir.

Answer 40

TRUE.

Question 41

Side effects of hydroxychloroquine:

Answer 41

Retinal damage (melanin contains tissues such as eye), decreased blood glucose, increased risk of hypoglycemia in diabetics; NO adverse effects in pregnancy/breast feeding

Question 42

is another traditional DMARD and immune-suppressive drug, it has poorly defined mechanisms but is thought to:

Answer 42

inhibition of multiple immune cells and cytokines

Question 43

What drugs do we give Sulfasalazine with?

Answer 43

Hydroxychloroquine and/or MTX

Question 44

Where is Sulfasalazine metabolized and what is it metabolized to?

Answer 44

metabolized in gut; metabolized to salicylate and sulfapyridine

Question 45

Sulfasalazine is known to have anti-inflammatory effects where?

Answer 45

In the bowel

Question 46

Common side effects of Sulfasalazine:

Answer 46

GI issues, anorexia, headache, skin irritation

Question 47

Most significant concerns with Sulfasalazine:

Answer 47

blood dycrasias; reduce folate absorption; do not use in those with sulfa or CELEBREX allergy (cross-reactivity)

Question 48

Another name for Triple drug therapy:

Answer 48

Nebraska therapy (UNMC)

Question 49

Process of triple drug therapy:

Answer 49

start with MTX weekly, then try hydroxychloroquine plus Sulfasalazine daily; then try all three in combo; can add NSAIDs or prednisone

Question 50

Inhibits digydro-orotate dehydrogenase which inhibits pyrite synthesis; also inhibits tyrosine kinases at higher doses:

Answer 50

Leflunomide

Question 51

What is overall effect of Leflunomide?

Answer 51

INHIBIT T-CELL proliferation, reduces antibody production by B-Cells

Question 52

T/F. Leflunomide is a pro-drug.

Answer 52

TRUE

Question 53

Why does Leflunomide have an extremely long effective half-life with significant consequences?

Answer 53

due to repeated entero-heptatic recirculation; active agent can remain in body long after last administration

Question 54

Side effects of Leflunomide:

Answer 54

diarrhea, and hair loss (alopecia), carcinogenic and teratogenic, CONTRAINDICATED before and during pregnancy, cholestyramine WASHOUT if needed prior to stopping birth control

Question 55

Well established tetracycline antibiotic that inhibits collagenase; specific action to decrease collagen degradation component of RA:

Answer 55

minocycline

Question 56

minocycline administration and use:

Answer 56

oral, once or twice a day. use in early disease progression

Question 57

Side effects of minocycline:

Answer 57

dizziness and hyper pigmentation

Question 58

Biologic DMARDs:

Answer 58

newer drugs that are peptides or proteins (NOT small molecules)

Question 59

How to biologic DMARDs act?

Answer 59

all are immuno-suppresive but act by targeting INDIVIDUAL SPECIFIC MEDIATORS; target mediators early in inflammation signaling cascades

Question 60

What types of drugs prevent auto-antibody production and release and subsequent inflammation?

Answer 60

biologic DMARDs

Question 61

T/F. Biologic DMARD block signaling molecules.

Answer 61

TRUE, these signaling factors drive inflammation and damage to synovial cells and structures

Question 62

Difference between murine, chimeric, and humanized:

Answer 62

0%, 65%, 90%

Question 63

What does "mib" and "nib" stand for?

Answer 63

Mib = protease/proteosome inhibitors; nib = (inhibit) kinase inhibitors

Question 64

T/F. All of the biologics are more effective when used in combination with methotrexate/

Answer 64

TRUE.

Question 65

Side effects for biologics:

Answer 65

increased risk of infections, blood dycrasias, increased cancer incidence (non-Hodgkins, non-melanoma skin), GI problems, headache, skin rash, cough

Question 66

Examples of Anti-Tumore Necrosis Factor drugs (ANTI-TNF):

Answer 66

EtanerCEPT, InflixiMAB

Question 67

Which of the biologics is most commonly used?

Answer 67

Anti-TNFs

Question 68

What does TNF-alpha do?

Answer 68

upstream regulator of many other immune and inflammatory cytokines; TNF receptors p55 and p75

Question 69

One of the first anti-TNF drugs:

Answer 69

Etanercept

Question 70

The soluble p75 subunit of the TNF reCEPTor used as a drug:

Answer 70

Etanercept

Question 71

Mechanism by which Etanercept works:

Answer 71

bings to and prevents TNF from binding to its cellular receptor

Question 72

Administration and use of Etanercept:

Answer 72

given weekly, shortest duration, used in combo with MTX

Question 73

Side effects of Etanercept:

Answer 73

headaches, sinus issues, allergies, PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) (rare untreatable viral infection of CNS); black box warning for lymphomas

Question 74

T/F. Etanercept is not a protein.

Answer 74

FALSE, it IS a protein.

Question 75

A Monoclonal AntiBody against TNF (not part of the receptor), a mouse-human chimera (xi), bings to TNF:

Answer 75

InfliXImab

Question 76

Another anti-TNF drug that is monoclonal antibody against TNF:

Answer 76

InfliXImab

Question 77

Administration and use of InfliXImab:

Answer 77

IV, every 4-8 weeks, after initial loading dose; ALWAYS COMBINED WITH MTX or other t-DMARDs

Question 78

Side effects of InfliXImab:

Answer 78

similar to Etanercept; can cause HYPOTENSION (do not use in heart failure patients)