Rheumatoid Arthritis and DMARDs

Question 1

Hydroxychloroquine

Answer 1

Antimalarial drug. Anti-inflammatory agent.
Alters cellular pH.
Oral. Very long half life (45 days)
Combined with other DMARDs. (often with MTX and/or sulfasalazine)
Adverse: GI, skin, POSSIBLE RETINAL DAMAGE (accumulates in melanin-containing tissues, baseline eye exam, repeat at 5y and then annually); DECREASED BLOOD GLUCOSE
Do not give if psoriasis or porphyria present
Caution in liver damage, neuro or hematologic d/o, alcoholism
Ocular toxicity more common in those with renal dz

Question 2

Sulfasalazine

Answer 2

Immune-suppressive drug
Oral.
Metabolized in gut –> salicylate and sulfapyridine
–both poorly absorbed
–benefit from modifying the GI immune system?!
SALICYLATE metabolite: RA benefit
Sulfapyridine has anti-infl effect (for bowel infl)
Combined with hydroxychloroquine and/or MTX
Adverse: blood dycrasias, agranulocytosis, aplastic anemia, reduced folate absorption
DO NOT USE if sulfa or celebrex allergy (cross-reactivity)

Question 3

Methotrexate (MTX)

Answer 3

Early stages of RA. First choice drug initially.
Oral. SubQ (better bioavailability, fewer side effects)
Once per week.
Effects may take 4-6 weeks (use prednisone bridge)
Folic acid analog. (membrane folate transporters)
Poly-Glutamated inside cells (traps active drug in cell, prolongs action)
Plasma t1/2 shorter than action t1/2.
Effective inhibitor of multiple types of immune and inflammatory cells
1. “anti-metabolite” (anti-folate): inhibit purine synthesis
–INHIBITS dihydrofolate reductase (DHFR) and tetrahydrofolate (FH4) formation
–main anti-CA mechanims
2. inhibits AICAR transformylase
–INCREASE anti-inflammatory mediator ADENOSINE
–Adenosine–> resolution of inflammation
–major part of RA benefit
3. Inhibits thymidylate synthetase (reduces thymidine (pryimidine) levels)
–inhibits proliferation of infl cells
Overall effect: inhibit purine/pyrimidine synthesis, increase adenosine
Adverse: rare hepatotoxicity (high doses) (minimize EtOH), kidney elimination (c/i in renal insufficiency), teratogenic (abortifacient), pulmonary toxicity, increased infection, lymphoma
Give supplemental folic acid 24h after each weekly dose.

Question 4

Leflunomide

Answer 4

Immunosuppressive
Inhibits dihydro-orotate dehydrogenase (inhibits pyrimidine synthesis)
Inhibits tyrosine kinases
[[Inhibits T cell proliferation and reduces auto-antibody formation by B cells]]
Oral. Prodrug –> teriflunomide.
Extremely long half life (2 years)
–repeated enterohepatic recirculation
–cleared by cholestyramine (ex for pregnancy)
Adverse: inhibits CYPs, carcinogenic, teratogenic

Question 5

Minocycline

Answer 5

Tetracycline antibiotic. Inhibits matrix metalloproteinases (incl collagenase) .
Decreases collagen degradation (part of RA)
Oral. Experimental.
Minimal side effects (dizziness, hyperpigmentation)

Question 6

Entanercept

Answer 6

Anti-TNF alpha
TNF (cytokine, immune and infl responses, up-stream regulator, promotes infl/joint destruction, TNF-R: p55, p75)
Soluble p75 subunit of human receptor
two p75 receptors linked to Fc of IgG1
p75: natural endogenous circulating TNF antagonist
Prevents TNF from binding to CELLULAR receptors (inhibits all steps toward inflammation)
Protein = injected (subQ q week)
Short duration. Combo with MTX.
–good to start with b/c of short duration
Adverse: PML (progressive multifocal leukoencephalopathy)

Question 7

Infliximab

Answer 7

Monoclonal Ab against TNF
Partially humanized mouse Ab (mouse-human chimera)
IV q 4-8 weeks
Combined with MTX
Adverse: hypotension (don’t use if heart failure)

Question 8

Adalimumab

Answer 8

Anti-TNF aut-Ab (fully humanized)
Injected subQ q 2 weeks
JUVENILE IDIOPATHIC ARTHRITIS
Adverse: demyelination (c/i if has demyelinating dz)

Question 9

Abatacept

Answer 9

CTLA-4 analog (CD28 receptor antagonist) (T cell activation inhibitor)
Peptide. SubQ weekly. IV monthly.
Mod to severe RA (not responsive to others)
Adverse: serious infection (3%), infusion reactions, DO NOT COMBINE WITH TNF INHIBITORS, don’t use in COPD

Question 10

Rituximab

Answer 10

anti-CD20 monoclonal Ab = B cell inhibitor
–CD20: B cell surface protein. B cell activation.
–Binds to CD20. Depletes CD20+ B cells.
IV. 2 injections 2 weeks apart. Not again for 6 months.
Combo with MTX.
If not treated well with TNF inhibitors.
Adverse: infection risk, infusion reactions.

Question 11

Biological DMARDs

Answer 11

Immuno-suppressive
Target EARLY inflammatory signals.
Prevent auto-Ab production.
Block SIGNALING MOLECULES
More effective if used with MTX
Side effects:
–Risk of infection (URI, TB, herpes zoster, fungal..)
–Blood dyscrasias (agranulocytosis, aplastic anemia)
–Cancer (non-melanoma skin CA, non-Hodgkin lymphoma)
–GI prob, HA, skin rash, sinusitis, cough

Question 12

CD28 and CTLA-4

Answer 12

CD28: T cell surface protein. Recognizes activated APCs.
CD80/86: on APCs form CD28 receptor
CD28: drives T cell activation and infl.
CTLA-4: T cell protein. binds CD80/86 –> blocks binding to CD28 (ligand)
–“like” an endogenous antagonist for CD28
–inhibits T cell activation, immunity, infl.