PHR 937 Rheumatology Med Chem: DMARDs & JAK Pathway Insights

What are DMARDs?

disease modifying anti-rheumatic drugs

slow down disease progression

Do NSAIDs and steroids help slow RA?

No, NSAIDs decrease inflammation and steroids decrease immune response, but not the disease itself

What do all DMARDs put the patient at risk for?

increased risk of infection

Why does blocking/decreasing folic acid lead to better outcomes in cancer and RA?

folic acid is necessary for cell division

Where does MTX act?

MTX works at

1. DHFR to prevent folic acid from becoming dihydrofolate

2. DHFR to prevent dihydrofolate from becoming tetrahydrofolate

3. TYMS to prevent dUMP from becoming dTMP

What is the affinity MTX has for DHFR and TYMS versus folic acid?

MX has a 1000 fold higher affinity than FA

What are ADEs of MTX?

hepatotoxicity, leukopenia, increased infection risk, nausea, abdominal pain, fatigue, fever, dizziness, teratogenic, neurological damage, memory loss

Who and when was JAK3 pathway discovered?

John O'Shea discovered JAK3 pathway in immune cells in 1994

Why is inhibiting JAK effective?

it inhibits further downstream activation that is responsible for gene regulation, apoptosis, and most important cell division; limits immune cell activation

Why is etanercept different than other TNF-alpha inhibitors?

Etanercept is biologically engineered