Biologics (mabs) and Gout

Okay heads up. I love immunology so have fun bb girls

cancer, autoimmune diseases, CVD, transplant rejection

Biologics and Disease modifying anti-rheumatic drugs (DMARDs) can be used for what?

Disease modifying anti-rheumatic drugs (DMARDs)

Any drugs that interrupts or slows the progression of RA when NSAIDs are ineffective

Methotrexate, leflunomide, hydroxychloroquine, gold salts

Examples of DMARDs

Blocks AICAR transformylase (no purine or thymidylic acid - reduces ICAM and interferes wit IL-1B binding), interferes with DNA synthesis (specific to S phase - DHFR inhibition)

MOA for methotrexate (MTX)

1/week (15-20% discontinue due to ADRs)

Describe the dosing regimen for MTX

Dose dependent hepatotoxicity (leads to fibrosis/cirrhosis), stomatitis, immunosuppression (neutropenia), C/I in pregnancy (interferes with folate)

ADRs of MTX

leflunomide (still teratogenic)

For people who can’t tolerate MTX what is another option?

immunosuppresion

ADRs for gold salts and hydroxychloroquine

Competes with SARS-CoV for the ACE-2 receptor (blocking entry)

What is the thought behind using hydroxychloroquine for COVID-19? note: all papers have been retracted

2 heavy chains, 2 light chains connected by disulfide bonds

Describe the structure of an antibody

harvested blood/plasma from someone who has survived whatever, give it to folks who currently have the disease

Describe the OG antibody therapy (convalescent serum/plasma)

Etanercept (2/week), indliximab (IV at 1,2, and 6 weeks then q8 weeks), adalimumab (q2 week), certolizimab (q 2 week), gloimumab (q month)

Give me some examples of drugs that bind TNF (inflammatory cytokine in the joints)

psoriasis, RA, psoriatic arthritis, ankylosing spondylitis, Crohn’s

Indications for TNF mabs

Snatches TNF out of the plasma (it’s literally just a receptor attached to an Fc chain)

MOA for etanercept

IL-6 receptor binding (neutralizes the receptor - IV q month)

MOA for tocilizumab (actemra)

immunosuppression, activation of latent TB

ADRs for TNF Mabs and IL-6 receptor mabs

Blocks the CD8 costimulatory signal

MOA for abatacept - used for peeps who have failed other DMARDs

immunosuppression

ADRs for abatacept

Bind CD25 subunit of IL-2 receptor (no activation of Ts)

MOA for basiliximab

Bind CD3 receptor on Ts

MOA of Moromonab

Naked antibodies, conjugated antibodies (suicide bombers), CAR-T cells, bridging antibodies to recruit CD8S

Ways to used Mabs in chemo?

Activate NK cells (ADCC), compliment, block the binding of other molecules, induce apoptosis, inhibit receptor dimerization (activation)

How can naked antibodies be used in chemo

IL-1 receptor antagonist (competes with IL-1 (inflammatory, causes fevers) for the receptor)

MOA for Anakinra (not an antibody)

Inhibits the JAK cascade by blocking phosphorylation (JAK 3 signalling in particular)

MOA for tofacitinib (oral BID)

Neutropenia, elevated cholesterol

ADRs for tofactinib

leads to B-cell apoptosis

MOA for rituximab

RA, non-hodkins lymphoma

indications for rituximab

increased infection risk, reactivation of viral infections

ADRs for rituximab

A biologic dupe after the patent expires

What is a biosimilar (mab-random letters)

Gout

A genetic metabolic disease in which urate crystals work their way into the joints

leukocyte suppression, increasing renal excretion, reducing urate production

Gout therapy is aimed at

binds tubulin to prevent polymerization (inhibits leukocyte migration)

MOA of colchicine

Acute gout attacks when uricosuric drugs + allopurinol aren’t working

indications for colchicine

Diarrhea (used indomethacin), abdominal pain. alopecia, neutropenia

ADRs for colchicine

prevent phagocytosis of crystals, inflammation blockage (IKb)

MOA of NSAIDs (1st line) in gout

increase renal excretion of gout (reduce reabsorption, increase net excretion) - combine with acetazolamide (make urine alkaline)

MOA for uricosuric drugs (probenicid)

inhibits xanthine oxidase (no urate synthesis)

MOA for allopurinal

chronic tophaceous gout, grossly elevated plasma urate, recurrent urate stones, poor renal function, patients with leukemias/lymphomas

Indications for allopurinal

no response to allopurinal

Febuxostate indications (more effective that allopurinol just )