Immunotherapeutic Agents Flashcards
How should corticosteroids be chosen if they are being used for their systemic anti-inflammatory and immunosuppressive properties?
Should be chosen based on relative mineralocorticoid and glucocorticoid activity
Agent with least mineralocorticoid activity should be used
What are the corticosteroids with the most and least mineralocorticoid activity?
Hydrocortisone - most activity, least relative anti-inflammatory potency
Betamethasone / Dexamethasone - least mineralocorticoid activity, most relative anti-inflammatory potency
What is the role of corticosteroids in treating patients with long-term systemic diseases, generally?
- Used as bridge therapy when awating slower onset of clinical infects of DMARDs
- Low dose may be used adjunctively with other therapies
- Intra-articular injections can provide long-term pain relief
What connective tissue conditions is methotrexate used for and what is its mechanism of action in these conditions?
Severe rheumatoid arthritis (first line), psoriasis / psoriatic arthritis (think of the girls with skater pads on extensor surfaces), and SLE.
Mechanism of action as an anti-neoplastic is inhibition of dihydrofolate reductase and thus reduction of DNA synthesis.
Mechanism of action as an immunosuppressive / anti-inflammatory is not well understood.
What are the adverse effects of methotrexate? Is it safe in pregnancy?
GI intolerance
Oral mucositis
(two rapidly dividing membranes)
Hepatotoxicity - guy helping cook
No, it is pregnancy category X
Who is methotrexate contraindicated in?
Contraindicated in alcoholics and those with pre-existing liver disease
Increased risk of hepatotoxicity also in diabetes, renal disease, and obesity
What are the indications for hydroxychloroquine? What is its mechanism of action?
Malaria, RA, and SLE. Useful in mild lupus or RA, or severe disease in combination with other DMARDs.
It is a DMARD which probably works by suppressing T cell response to mitogens and stabilizing lysosomal enzymes, inhibiting immune activation.
What are the adverse effects of hydrochloroquine?
Retinal toxicity! (Same as chloroquine, pg 196). Also have been some reports of neuromyopathy.
Generally well tolerated.
What is the mechanism of action of Sulfasalazine and what is it used for in connective tissue diseases?
Likely its sulfa moiety suppresses natural killer cells and impairs lymphocyte transformation, used for RA / JRA (note: in ulcerative colitis it is a 5-ASA which makes it useful as an anti-inflammatory)
Uses as a DMARD in mild disease
What are the adverse effects of sulfasalazine?
Yellow-orange discoloration of skin
Rash is common since it’s a sulfa drug
What is the mechanism of action of leflunomide and its clinical indication?
Inhibits dihydroorotate reductase -> decreases pyrimidine synthesis. This suppresses T cell proliferation.
Clinical use: DMARD in rheumatoid arthritis.
What are the adverse effects of leflunomide?
Diarrhea, hypertension, hepatotoxic (monitor liver enzymes)
Note: very teratogenic. Issue because it has a long half-life due to enterohepatic cycling
How should you handle it if you find out your patient on leflunomide got pregnant?
Give them activated charcoal or cholestyramine -> reduce enterohepatic cycling to decrease the half-life of the drug (normally around 20 days)
What drug is a janus kinase inhibitor? What is its indication? Can it be used with biologics?
Tofacitinib - JAK3 antagonist which prevents cytokine signalling
Think “Two Faced Jak”
Indication: Moderate to severe RA as a monotherapy or with another traditional DMARD
Although it is an oral agent, it CANNOT be used with biologics.
What should be monitored when using tofacitinib and pretty much all DMARDs?
Monitor LFTs and CBCs (absolute neutrophil count)
- > black box warning for serious infections and reactivation TB
- > known to cause hepatotoxicity
What are the black box warnings for the TNFa inhibitors?
- Increased risk of reactivation TB
- Increased risk of malignancy (TNF needed to suppress tumors)
- Reactivation hepatitis B
- Exacerbation of heart failure in many people
Which TNF inhibitors is anti-drug antibody production most and least likely?
Most likely: Infliximab -> chimeric
Least likely: Etanercept - bivalent decoy receptor which isn’t even an antibody
What conditions do the TNF inhibitors have use in?
Crohn’s disease, ulcerative colitis, rheumatoid arthritis, psoriasis, and ANKYLOSING SPONDYLITIS
How are most of the TNF inhibitors used in combination?
Generally they are given in combination with methotrexate.
Remember, you cannot mix biologics
What special considerations should be given to infliximab?
- It is chimeric, so it has the highest chance of infusion reactions -> give with benadryl / corticosteroids
- Patient MUST be on MTX as well, as it gives the highest risk of anti-drug antibodies
What is the main advantage of certolizumab and golimumab over other TNF inhibitors?
They are pegylated or formulated in such a way that they can be given much more infrequently (i.e. monthly)
What is the mechanism of action of Abatacept and what is its indication?
AbaTacept = intercepts T cell activation by binding CD80/86 (B7) on antigen presenting calls so that it can’t interact with CD28 on T cells (7*4 = 28)
Indicated for severe RA or psoriatic arthritis who have failed anti-TNF therapy
What is the mechanism of action of anakinra and its indication?
Indicated for rheumatoid arthritis
AnakInra = IL-1 antagonist
What biologic drug has similar adverse effects as tofacitinib and even a similar name? What is its mechanism?
Tocilizumab - IL-6 inhibitor. Kinda makes sense because tofacitinib also blocks acute phase cytokines.
Adverse effects are same:
hepatotoxicity, decreased absolute neutrophil count, and GI perforation (tofacitinib had all these)
Mechanism of action of Sarilumab? Adverse effects?
Sarilumab = I give Saara a 6/10. = IL-6 inhibitor, like tocilizumab. Same adverse effects.
What is the mechanism of action of belimumab? What condition is it used in?
BeLim think B-Lymph -> blocks B lymphocyte stimulator protein (BLyS), thus inducing B cell apoptosis. Used only in the treatment of mild to moderate SLE where B cells mediate the disease.
When can belimumab not be used?
Cannot be used in severe disease (i.e. lupus nephritis, CNS lupus) since it cannot be used in combination with other strong immunosuppressants (i.e. cyclophosphamide)
When is rituximab used in connective tissue disease? What is its mechanism?
Used for treatment of rhuematoid arthritis patients refractory to TNFa antagonists
Mechanism - anti-CD20 (anti-B cell only, not plasma cell)
What are the adverse effects of Rituximab?
chimeric, so infusion reactions are common -> should premiedicate.
Also known to cause hepatitis B reactivation and PML
What are the two IL-17 receptor antagonists worth remembering? What is their primary indication?
Secukinumab
Ixekizumab
“Isaac” in an in”secure” 17 year old
Primarily used in psoriatic arthritis
What are the adverse effects of the IL-17 antagonists?
Upper respiratory infections and candidiasis
-> just remember that yeast infections are common in teenagers like isaac
What is the IL-12/23 inhibitor and what conditions is it used in?
Ustekinumab
Psoriasis / psoriatic arthritis, Crohn’s disease (which makes sense cuz it’s granulomatous)
What is the mechanism of action of mycophenate and what is it used for?
Inhibits IMP dehydrogenase
Used for treatment of lupus nephritis
What is cyclophosphamide used for in connective tissue disease? Side effects?
Severe lupus -> lupus nephritis induction therapy
Side effects include bone marrow suppression and hemorrhagic cystitis (give MESNA)
