DMARDs and Immunosuppressives Flashcards by Caroline Motschwiller

What are the

(a) uses
(b) limitations

of NSAID tx for RA

NSAIDs for RA

(a) Uses = anti-inflammatory and analgesic, it will help w/ the pain and inflammation
(b) Not addressing the underlying autoimmunity

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What is the gold standard DMARD drug?

Methotrexate = most efficacious

Efficacy

mild-moderate = hydroxychloroquine
moderate = sulfasalazine
moderate-excellent = methotrexate

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Toxicity of Hydroxychloroquine

Hydroxychloroquine = DMARD
Only mildly effective, but very well tolerated

-rare toxicity = retinal disease

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Mechanism of hydroxychloroquine

-inhibits toll like receptors
Exact mechanism not known, but works far up in the line to prevent autoimmunity (before the disease gets fully going)

-alters antigen presentation and TLRs

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Sulfasalazine toxicity

GI intolerance
liver toxicity
marrow suppression

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Indications for sulfasalazine

RA, psoriatic arthritis, IBD

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Which DMARD is the most toxic? What should be monitored?

MTX (methotrexate) = most effective, most toxic

Monitoring necessary for
-liver and marrow function

Also can cause rheuamtoid nodules

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Mechanism of methotrexate usage in cancer vs. RA

Cancer = very high dose MTX (comparatively): mechanism of MTX is to inhibit DNA synthesis by inhibiting folate synthesis

RA = lower doses, not used to inhibit folate (sometimes even give RA pts on MTX folate supplements)

MTX promotes release of adenosine into the extracellular space
Adenosine binds to receptor and generates anti-inflammatory effects inside the cell

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What is the next step in therapy after trying MTX?

Multidrug therapy

-use a combo of the DMARDS (even all 3 at once) => superior/additive benefit

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Metalloproteinase

(a) fxn
(b) what cells produce it
(c) release stimulated by what

Metalloproteinase

(a) enzyme that when released enzymatically degrades articular cartilage
(b) produced by synoviocytes
(c) stimulated by TNFalpha and IL-1

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Infliximab

‘mab’ = monoclonal antibody

Infliximab = Remicade = partially humanized anti-TNF antibody
-deliver intravenously

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Entanercept

‘cept’ = uses receptor

Entanercept = Enbrel = TNF-receptor fused to IgG Fc
-subQ injection

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Adalimumab

Adalimumab = Humira = fully humalized anti-TNF anitbody

-subQ injection

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Limitations of TNF blockers

Infliximab, Entanercept, Adalimumab

All proteins => can’t be taken orally
Large molecules => only work extracellularly

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Response to TNF blockers

Great response, huge decrease in radiologic progression

-prevents erosion

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Toxicity of TNF blockers

Pretty well tolerated (low toxicity) but MUST screen first for Tb

-TNF blockers increase risk of reactivation of latent Tb infection

Anakinra

Anakinra = IL-1Ra = IL-1 receptor antagonist

-endogenously produced IL-1 blocker

Compare efficacy of anakinra and infliximab

Anakinra (IL-1Ra) is much less efficacious then infliximab (anti-TNF antibody) in RA

-shows us that TNF is a much more potent disease/inflammatory mediator than IL-1 in rheumatoid arthritis

What is anakinra first line of therapy for?

Anakinra (IL-1 receptor antagonist) is extremely beneficial against inflammasome mediated rheumatic disease = gout!

Tocilizumab

Tocilizumab = Anti-IL-6 receptor antibody

antibody against the receptor blocks access of IL-6 ligand
Tocilizumab often used in combination w/ MTX in RA treatment

Name four biologic targets for RA treatment

4 things that are very involved in the pathophysiology of RA = good treatment targets

cytokines (TNF, IL-1, IL-6)
T-cells
B-cells
antigen presenting

Why would targeting T cells be effective against TA?

T-cells are crucial to accept antigen presentation and activate B cells to produce autoantibodies

Explain how Leflunomide targets T cells

Leflunomide = blocks T-cell proliferation by inhibiting pyrimidine synthesis
-targets T cells b/c they lack salvage pathways, specifically lacking pyrimidine (and purine) salvage pathways

What are the shared toxicities of Leflunomide and MTX

Leflunomide (block pyrimidine synthesis which targets T cells b/c they lack salvage pathways) and MTX

hepatotoxicity
teratogenicity

Why does rituximab not permanently wipe out the body's B cell population?

Rituximab = anti-CD20 antibody which is on only certain parts of the B cell lineage => stem cells and plasma cells are spared - stem cells are spared so once you stop the medication in about 6 months the entire B cell supply can be restored - important that plasma cells aren't affected b/c prevents infection

What is a rare toxicity of rituximab?

PML = progressive multifocal leukoencephalopy due to activation of latent JC virus

Why are B-cells a good target for RA therapy?

B cells produce plasma cells that produce antibodies (so also produce the autoantibodies involved in RA) => B-cells are what produce anti-CCP and rheuamtoid factor

How does CTLA4-Ig Abatacept help against the immune response?

CTLA-4 = T-cell protein that has a very high affinity for CD86 on APCs which needs to bind to CD28 for costimulation to elicit an immune response => CTLA-4 blocks CD86 (on APCs) from binding to CD28 (on T-cells) which blocks the co-stimulation needed to cause immune response

Name three limitation of anti-rheumatologic biologics

- cost - IV or subQ (not oral) b/c they're proteins - can only act extracellularly (b/c they're large) => can't attack any intracellular activity

Describe how JAK inhibitor Tofacitinib works against RA

Tofacitinib = directly inhibits JAK1 and JAK3 inside T cells - oral medication - small molecule => acts intracellularly - inhibiting JAK => STAT (transcription factor) activation blocked => blocks upregulation of transcription of pro-inflammatory molecules -hit a lot of bird w/ one stone b/c JAK kinase signaling induces production of a lot of cytokines

Describe how PKA activation by Apremilast helps against psoriatic arthritis

Apremilast = PDE4 inhibitor, PDE4 breaks down cAMP and cAMP activates PKA which has anti-inflammatory and immunomodulatory effects Blocking PDE4 => more cAMP around => more PKA activation => anti-inflammation and immunomodulatory effects

Name 2 indications for PKA stimulating drug Apremilast

1. Moderately effective for psoriatic arthritis and psoriasis 2. Helps decrease oral ulcers in rare immune mediated vasculitis Behcet's syndrome

What 3 classes of drugs are used to treat lupus?

1. Glucocorticoids 2. DMARDS such as hydroxychloroquine and MTX 3. Immunsuppressants: cyclophosphamide, mycophenolate motefil, belimumab

What is cyclophosphamide? (a) Mechanism (b) Indication

Cyclophosphamide = the big guns for RA (a) Alkalting agent to kill rapidly dividing cells (basically ties up DNA) (b) Used in cancer and severe RA cases (only used in severe cases b/c of the toxicity)

Toxicity of Cyclophosphamide

Very high toxicity | N/V, marrow suppression, stomach ache, severe immunosuppression => infection, alopecia, infertility

MMF (mycophenolate motefil) vs. Leflunomide (a) Mechanism (b) Indication

MMF vs. Leflunomide (a) Both take advantage of T-cell's lack of salvage pathways. MMF by blocking guanine (purine) synthesis and Leflunomide by blocking pyrimidine synthesis (b) MMF used in lupus tx, leflunomide used in RA

When to use cylcophosphamide vs. MMF

Cyclophosphamide is more effective but much more toxic => use in severe and acute situations -MMF has good efficacy and it a lot better tolerated => often tried first

Describe how blocking BLyS (Belimumab) helps treat lupus

Belimumab = antibody against BLyS (B-lymphocyte stimualtor) ``` B cells (which are key in lupus b/c they make autoantibodies) need constant BLyS (released by macrophages) stimulation to remain active -blocking BLyS w/ Belimumab helps prevent autoantibody production => modestly effective in lupus, some help in preventing flare ups ```