Anti-Rheumatics

Question 1

What is the inherent contracdiction involved in initiating DMARD treatment early?

Answer 1

The contradiction is that Disease Modifying anti-rheumatic drugs work better when given earlier because they do not reverse the damage, but are usually given after other treatments such as NSAIDs. This is because of the toxic effects of the DMARDs.

Question 2

2. Explain why the term DMARD is a misnomer.

Answer 2

Disease-modifying anti-rheumatic drugs (DMARDs) may be a misnomer as no drug reverses damage to bone and cartilage.

Question 3

Explain how its MOA makes methotrexate a DMARD and an anti-cancer agent.

Answer 3

Methotrexate inhbits dehydrofolate reductase which is needed for the formation of thymidine nucleotides for DNA synthesis.

This inhibition has two affects. It inhibits immune cell proliferation and stimulates apoptosis in them, plus because rapidly replicating cancer cells need nucleotides as well it inhibits their replication.

Question 4

4. Apply the dosing of leflunomide (a DMARDs) to a clinically-relevant case study.

Answer 4

Active metabolite, A77-1726, inhibits dihydroorotate dehydrogenase, leading to arrest of stimulated cells in the G1 phase; inhibits T-cell proliferation and B-cell antibodies.

Leflunamide is given 10-20 mg 2x a day but after a loading dose of 100 mg/day for 3 days. Then it is given at 20 mg/day.

The reason for the large loading dose is the half-life of M1 metabolites (metabolite of leflunomide) is 2 weeks.

If you have an active metabolite with a long half life, you have to give a loading dose, a higher than normal dose.

Adverse effects:
Diarrhea (25%).
Elevated liver enzymes (dose dependent).
Increased blood pressure.
Contraindications: pregnancy

Question 5

What is Methotrexate indicated for?

Answer 5

Immunosuppresant SAARD. Inhibits dihydrofolate reductase (DHFR) preventing tetrahydrofolate regeneration.

RA

juvenile chronic arthritis

psoriasis

ankylosing spondylitis

polymyositis

systemic lupus erythematosus

vasculitis

Question 6

What are the long term complications to using Glucocorticoids?

Answer 6

Long term effect of glucocorticoids could cause a negative feedback on the anterior pituitary shutting down production.

Question 7

What is the relation of monocloncal antibodies to immune components?

Answer 7

A number of monoclonal antibodies have recently been developed to target
specific proteins involved in immune-system elements
particularly cell-surface proteins on T cells.

Question 8

Abatacept

Answer 8

Mab that targets the CD80/86 receptor of the antigen presenting cell.

Prevents T cell activation

Question 9

Alefacept

Answer 9

Mimics the LFA protein from the APC and binds to CD2 on the T cell, preventing its activation

Question 10

Where does Adalimumab act?

Answer 10

A TNF alpha specific antibody

Forms complexes with TNF alpha itself. Prevents activation of macrophages and interupts T-cell function

It decreases the rate of formation of NEW lesions

Indicated for:

RA

ankylosing spondylitis

psoriatic arthritis

Question 11

Infliximab

Answer 11

A TNF alpha Antibody that may bind to TNF alpha

Indications:

Crohn’s disease

Combined with methotrexate reduced new erosions over 52-104 weeks

Question 12

Etanercept

Answer 12

Antiboides from the moieties of the TNF receptor. Also a TNF-alpha Antibody.

Inidcated:

Juvenile chronic arthritis

Psoriasis

Can be combined with methotrexate

Question 13

Apply one advantage and one disadvantage of treating RA with glucocorticoids to a clinically-relevant case scenario

Answer 13

Advantage: Glucocorticoids have prompt and dramatic effects on RA

Inhibit phospholipase A2, which prevents the release of arachidonic acid.

Indacations:

• RA,
• vasculitis,
• SLE,
• Wegner’s granulomatosis,
• psoriatic arthritis,
• sarcoidosis,
• gout.
• Given intra-articular to
• alleviate pain (preferable to systemic dose)

Disadvantage:

Insomnia, hypomania, acute peptic ulcers are occasionally seen after only a few days.

Treating for more than 2 weeks can result in adrenal suppression. A marked decrease in ACTH production of the anterior pituitary

Question 14

Rituximib

Answer 14

A non-TNF-directed Antibody

A monoclonal antibody targeting CD20 on B cells.
Used for RA that does not respond to anti-TNF agents. Combined with methotrexate. Given in IV infusions (two, 2 weeks
apart).

Question 15

Apply the length of time that DMARDs and Mabs need to show effects of reducing new lesions to a clinically-relevant case scenario.

Answer 15

DMARDs and Mabs take 4 weeks to 1 year to work.

For instance, infliximab and methotrexate was better than methotrexate alone in reducing new erosions over 52-104 weeks.

Question 16

Describe one dose-related toxicity of methotrexate and how it is detected.

Answer 16

• Progressive dose-related hepatotoxicity

Testing: Liver enzymes

Question 17

Give the antidote to methotrexate overdose

Answer 17

Leucovorin:.

Question 18

Apply the latent disease that is activated by the TNF-mabs and what should be done about it to a clinically-relevant case scenario.

Answer 18

Adverse effects of TNF-α directed MABs

• Can activate latent tuberculosis, so screen for TB before prescribing.
• In rare cases, double-stranded DNAs and anti-nuclear antibodies appear, incurring lupus erythematosus, although this is very rare.

Patients should be screened before given treatment of TNFmabs

Tumor Necrosis Factor-Alpha (TNF) blockers have an increased risk of lymphomas in children and adolescents and leukemia in all patients, including adults.

the FDA is also notifying healthcare professionals of an increased risk of new-onset psoriasis in all patients, including adults.

Question 19

Apply the specific indication for which penicillamine is reserved to a clinically-relevant case scenario.

Answer 19

Reserved for patients with active progressive-erosive rheumatoid disease not controlled by conservative therapy.

Question 20

Apply both the use of acetaminophen in RA and its limitations to a clinically-relevant case scenario

Answer 20

• May be used as an analgesic adjunct to an anti-inflammatory for RA.
• It has virtually no anti-inflammatory effect, but does help with mild to moderate pain.
• It is a weak prostaglandin inhibitor in peripheral tissues.
• Unlike aspirin it does not antagonize uricosuric agents (for gout).

Question 21

Apply the mechanism of action and indication for tofacitinib to a clinically-relevant case scenario.

Answer 21

Tofacitinib is a Janus kinase (JAK) inhibitor used to treat adults with moderately to severely active rheumatoid arthritis in which methotrexate did not work well.