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HemeDermMSK 2 > DMARDs and Immunosuppressives > Flashcards

DMARDs and Immunosuppressives Flashcards

1
Q

What are the

(a) uses
(b) limitations

of NSAID tx for RA

A

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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2
Q

What is the gold standard DMARD drug?

A

Methotrexate = most efficacious

Efficacy

  • mild-moderate = hydroxychloroquine
  • moderate = sulfasalazine
  • moderate-excellent = methotrexate
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3
Q

Toxicity of Hydroxychloroquine

A

Hydroxychloroquine = DMARD
Only mildly effective, but very well tolerated

-rare toxicity = retinal disease

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4
Q

Mechanism of hydroxychloroquine

A

-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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5
Q

Sulfasalazine toxicity

A
  • GI intolerance
  • liver toxicity
  • marrow suppression
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6
Q

Indications for sulfasalazine

A

RA, psoriatic arthritis, IBD

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7
Q

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

A

MTX (methotrexate) = most effective, most toxic

Monitoring necessary for
-liver and marrow function

Also can cause rheuamtoid nodules

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8
Q

Mechanism of methotrexate usage in cancer vs. RA

A

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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9
Q

What is the next step in therapy after trying MTX?

A

Multidrug therapy

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

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10
Q

Metalloproteinase

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

A

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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11
Q

Infliximab

A

‘mab’ = monoclonal antibody

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

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12
Q

Entanercept

A

‘cept’ = uses receptor

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

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13
Q

Adalimumab

A

Adalimumab = Humira = fully humalized anti-TNF anitbody

-subQ injection

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14
Q

Limitations of TNF blockers

A

Infliximab, Entanercept, Adalimumab

  • All proteins => can’t be taken orally
  • Large molecules => only work extracellularly
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15
Q

Response to TNF blockers

A

Great response, huge decrease in radiologic progression

-prevents erosion

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16
Q

Toxicity of TNF blockers

A

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

-TNF blockers increase risk of reactivation of latent Tb infection

17
Q

Anakinra

A

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

-endogenously produced IL-1 blocker

18
Q

Compare efficacy of anakinra and infliximab

A

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

19
Q

What is anakinra first line of therapy for?

A

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

20
Q

Tocilizumab

A

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
21
Q

Name four biologic targets for RA treatment

A

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

  1. cytokines (TNF, IL-1, IL-6)
  2. T-cells
  3. B-cells
  4. antigen presenting
22
Q

Why would targeting T cells be effective against TA?

A

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

23
Q

Explain how Leflunomide targets T cells

A

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

24
Q

What are the shared toxicities of Leflunomide and MTX

A

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

  • hepatotoxicity
  • teratogenicity
25
Q

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

A

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
26
Q

What is a rare toxicity of rituximab?

A

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

27
Q

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

A

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

28
Q

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

A

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

29
Q

Name three limitation of anti-rheumatologic biologics

A
  • 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
30
Q

Describe how JAK inhibitor Tofacitinib works against RA

A

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

31
Q

Describe how PKA activation by Apremilast helps against psoriatic arthritis

A

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

32
Q

Name 2 indications for PKA stimulating drug Apremilast

A
  1. Moderately effective for psoriatic arthritis and psoriasis
  2. Helps decrease oral ulcers in rare immune mediated vasculitis Behcet’s syndrome
33
Q

What 3 classes of drugs are used to treat lupus?

A
  1. Glucocorticoids
  2. DMARDS such as hydroxychloroquine and MTX
  3. Immunsuppressants: cyclophosphamide, mycophenolate motefil, belimumab
34
Q

What is cyclophosphamide?

(a) Mechanism
(b) Indication

A

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)

35
Q

Toxicity of Cyclophosphamide

A

Very high toxicity

N/V, marrow suppression, stomach ache, severe immunosuppression => infection, alopecia, infertility

36
Q

MMF (mycophenolate motefil) vs. Leflunomide

(a) Mechanism
(b) Indication

A

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

37
Q

When to use cylcophosphamide vs. MMF

A

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

38
Q

Describe how blocking BLyS (Belimumab) helps treat lupus

A

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

HemeDermMSK 2 (11 decks)

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