PHR 937 - RA Pharmacology kaitlyn

non-pharm treatments

- patient and family education

- exercise (PT/OT)

- weight loss (decreases pressure on joints)

- ambulatory devices

- surgery

pharm treatments (overview)

- NSAIDs, COX-2 inhibitors

- salicylates

- corticosteroids

- DMARDs

> synthetic (conventional)

> biologics

> target specific

non-selective NSAIDs

ibuprofen, naproxen, diclofenac

use: reduce joint pain & swelling, improve joint function

- does NOT slow progression - sx relief only!!

MOA: inhibit COX-1 and COX-2

caution: renal dysfunction, CHF

ADE: GI toxicity, edema, HTN, renal impairment

monitoring: SCr, BP, GI symptoms, edema

corticosteroids

prednisone, methylprednisolone

use: reduce joint pain and swelling

- bridge therapy ONLY, not for long term!!

MOA: potent anti-inflammatory and immunosuppressive effects

caution: DM, HTN, CHF

ADE: (Cushings) osteoporosis, HTN, weight gain, edema, hyperglycemia, skin thinning

monitoring: CBC, BP, DEXA scans (bone density)

DMARDs

use: reduces / prevents joint damage

- should be started within 3 months of diagnosis!!

3 types:

> synthetic (conventional)

> biologics

> target specific

concerns: takes weeks to months for benefit; women can NOT get pregnant on most

synthetic DMARDs

hydroxychloroquine

sulfasalazine

methotrexate

leflunomide

(there are a few more, but these are most used)

hydroxychlorquine

Plaquenil

synthetic DMARD

use: mild-moderate RA without poor prognostic features

MOA: unclear - thought to affect antigen presentation

time to benefit: 2-4 months

ADE: macular damage, retinopathy

monitoring: annual eye exam

dose: 200-400 mg PO daily

notes: safe in pregnancy; may be used in triple DMARD with sulfasalazine + MTX/LEF

sulfasalazine

synthetic DMARD

use: mild-moderate RA without poor prognostic features

MOA: unknown - has antimicrobial and anti-inflammatory effects

time to benefit: 1-3 months

CI: sulfa allergy or G6PD deficiency, liver disease

toxicities: dose dependent; myelosuppression, GI effects

monitoring: CBC, AST/ALT Q2-4 weeks, then Q3 months after stable dose for 3 months

dose: 1000 - 1500 mg PO BID

methotrexate

synthetic DMARD

use: ALL levels of disease

MOA: anti-inflammatory and immunosuppresive DHF reductase inhibitor

- inhibits purine biosynthesis and proliferation of inflammatory cytokines

time to benefit: 1-3 months

CI: pregnancy, chronic liver disease, CrCl <30

toxicities: stomatitis, GI, myelosuppression, pulmonary fibrosis, hepatic fibrosis

monitoring: CBC, SCr, liver enzymes monthly; then CBC monthly + SCr/ liver panel Q2-3 months once dose is stable for 1 year

dose: 7.5-10 mg PO/ SQ QW -> 25 mg max

notes: often 1st line, superior efficacy; must co-admin with folic acid 1 mg QD

leflunomide

synthetic DMARD

use: ALL levels of disease

MOA: inhibits pyrimidine biosynthesis

- disrupts DNA synthesis + impacts proliferation/ activation of lymphocytes

- selectively target autoimmune lymphocytes (reduces ADEs)

time to benefit: 1-2 months

CI: liver disease, pregnancy

toxicities: GI, hepatotoxicity

monitoring: CBC, liver enzymes monthly; then every 3 months once dose is stable for 3 months

dose: 10-20 mg PO QD

biologic DMARDs

TNF-a inhibitors

JAK inhibitors

B-cell depletion

T-cell inhibitor

IL-6 receptor antagonist

IL-1 antagonist

- screen for TB/ hepatitis for all

TNF-a inhibitors

use: an alternative to methotrexate in DMARD-naive patients with moderate to high disease activity OR as an adjunctive therapy in pts not at treatment goals with methotrexate

MOA: binds soluble and membrane bound TNF-a

ADE: injection site rxn, increased risk of infection, headache, N/V

[box warning]: increased risk of infection, malignancy

CI: heart failure, lupus

- not recommended in MS

adalimumab

Humira

TNF-a inhibitor

40 mg Q 2 weeks

- alt: 40 mg Q weekly if not on MTX

etanercept

Enbrel

TNF-a inhibitor

- "safer" for the liver

certolizumab

Cimzia

TNF-a inhibitor

- only pregnancy safe biologic!!!!!

golimumab

Simponi

TNF-a inhibitor

infliximab

Remicade

TNF-a inhibitor

IL-6 receptor antagonists

tocilizumab (Actemra)

sarilumab (Kevzara)

- both self injectable

use: moderate to severe active RA in pts who have had an inadequate response OR contraindication to 1+ TNF-a therapies

MOA: binds soluble and membrane bound IL-6 receptors

ADE: increased liver enzymes, thrombocytopenia, neutropenia, lipid effects

caution with GI perforation

monitoring: CBC, AST, ALT, lipid panel

JAK inhibitors

use: moderate to severe active RA who have had an inadequate response OR intolerance to methotrexate

MOA: prevents activation of cytokine signaling pathways

ADE: increased ALTs, elevated lipids, UTIs, headache, diarrhea, nasopharyngitis

[black box]: thrombosis, serious infections, GI perforations, lymphomas

monitoring: CBC, LFT, FLP

- oral!

tofacitinib

Xeljanz

JAK inhibitors

- non selective JAK

upadacitinib

Rinvoq

JAK inhibitors

- higher selectivity for JAK 1

baracitinib

Olumiant

JAK inhibitors

- higher selectivity for JAK 1 and 2

T cell costimulation inhibitor

abatacept (Orencia)

- self injectable or IV infusion

MOA: inhibits T cell activation by binding CD80 and CD86 on the APC, blocking the required interaction with CD28

ADE: URIs

CI: precaution in COPD pts

B cell depletion

rituximab (Rituxan)

- IV

use: patients with moderate to severe RA with inadequate response to 1+ TNF-a inhibitors

MOA: chimeric monoclonal anti-CD20 antibody that selectively depletes B cells

ADE: infusion site reactions (premedication REQUIRED)

caution with GI perforation and history of arrythmia

monitoring: CBC and platelets

IL-1 receptor antagonist

anakinra (Kineret)

- subq daily

- LAST RESORT

MOA: competitively inhibits binding of IL-1 to the IL-1 type receptor

- mono or in combo with MTX

ADE: injection site reactionsm increased infection risk

CI: hypersensitivity to E coli derived proteins

monitoring: CBC