Pharm E2- Rheum

What is a chronic inflammatory disease characterized by symmetrical joint involvement and extra-articular manifestations, with inflammation of synovial lining (pannus)?

Rheumatoid arthritis (RA)

What condition involves damage to articular cartilage, joint narrowing/erosion, and pain due to activation of nociceptive nerve ending in joint by mechanical/chemical irritants?

Osteoarthritis (OA)

What are non pharmacological treatment options for RA and OA?

PT/OT, wt loss, moist heat, ice, rest, surgery

The following treatment options are for RA or OA?

• chronic: NSAIDs, low dose steroids

• acute exacerbation: steroids

• DMARDs

• knee effusion: aspirate & steroid injection

RA

The following treatment options are for RA or OA?

• chronic: APAP, NSAIDs, topical analgesics

• acute exacerbations: opioid analgesics

• knee effusion: aspirate & steroid injection

OA

What is the cornerstone of therapy for RA and should be initiated as early as possible?

disease modifying anti rheumatic drugs (DMARDs)

What are the traditional DMARDs?

MTX, HCQ, sulfasalazine, leflunomide

What biologic DMARDs are anti-TNF?

Infliximab

Certolizumab

Etanercept

Adalimumab

Golimumab

What biologic DMARD is a co-stimulation modulator?

Abatacept (Orencia)

What biologic DMARD is an IL-6 receptor antagonist?

Tocilizumab (Actemra)

What biologic DMARD is a CD20 inhibitor?

Rituximab (Rituxan)

What DMARD is a JAK inhibitor used in severe-moderate RA treatment when MTX therapy failed?

Tofacitinib (Xeljanz)

Which DMARDs have the best efficacy-toxicity ratios?

MTX and HCQ

What drug should be started first in most patients with RA?

MTX

Which has a faster onset of action- traditional DMARDs or biologic DMARDS?

biologic

What should be done before treatment for RA, especially if using biological DMARDs, due to immunosuppression?

test for TB & get up to date vaccines

Which vaccines can NOT be given to patients taking biologics?

live vaccines

The herpes zoster vaccine is normally recommended at age 60, but when should RA patients receive it?

50

What drug?

• inhibits cytokine & purine biosynthesis, stimulates adenosine

• analog of folic acid w/ high affinity for dihydrofolate reductase

• (works against folic acid; stifles reproduction of immune cells & dec inflammation)

MTX (Trexall, Rheumatrex)

What SEs are seen with MTX?

BM suppression, stomatitis, GI / oral ulceration, N/V/D, hepatotoxicity, alopecia, pulm fibrosis, pneumonitis

*monitor renal function

What are CIs to MTX?

pregnancy, renal insufficiency (CrCl < 40), chronic liver dz, blood dyscrasias

What drug?

• MC DMARD; tx for RA

• fairly rapid onset of action (1-2mos)

• acceptable incidence of SEs

• monitoring - CBC, LFTs, SCr at baseline, monthly for 6 mos then every 1-2 mos

MTX

What should be given with MTX?

folic acid (1 mg daily or 7 mg once weekly)

What drug?

• prodrug inhibits pyrimidine synthesis → dec lymphocyte proliferation

• used in RA tx- benefits in 1 month

• dec sx, inflammation, and joint damage

Leflunomide (Arava)

What drug has at the following adverse effects?

• MC diarrhea

• most significant: hepatotoxicity, immunosuppression, hematologic toxicity

  • **dont use w/ other hepatotoxins (ex- MTX)

• teratogenic (need cholestyramine washout)

• monitor- LFTs, CBC, pregnancy

Leflunomide

What drug?

• least toxic & potent DMARD; less monitoring

  • no myelosuppression, hepatotoxicity, renal insufficiency

• for mild RA dz or use in combo regimen

• onset- 2-4 mos

Hydroxychloroquine (HCQ)

What drug has the following MOA?

• inhibit neutrophil locomotion, chemotaxis eosinophils, & impairs complement dependent ag-ab rxns

• (prevents ability of immune cells to get to site of inflammation → can’t cause inflammation → less joint damage over time)

HCQ

What SEs are seen with hydroxychloroquine (HCQ)?

GI: N/V/D (take w/ food)

retinopathy: blurry vision, scotomas, accommodation effects

derm: rash, alopecia, inc skin pigmentation

What drug?

• DMARD used in RA tx

• prodrug cleaved by colonic bacteria into sulfapyridine & 5 amino salicylic acid

• unknown MOA- modulate inflam mediators, TNFi, see radical scavenger

• onset 1-4 mos

Sulfasalazine

What SEs are seen with sulfasalazine?

N/V/D, rash, elevated LFTs, alopecia, leukopenia or thrombocytopenia (rare), yellow or orange urine/stools

What drug interactions are seen with sulfasalazine and should be separated out when taking?

abx, iron supplements, warfarin (protein binding)

What drug?

• DMARD- available PO

• RA monotherapy or in combo with other DMARDS

  • *dont use w/ biologics

• dec dose w/ significant renal dysfunction, hepatic dysfunction, or CYP3A4 inhibitors

• BBW: serious infx, lymphomas, malignancies

• Test for latent TB before starting!

Tofacitinib

Which type of DMARDs?

• very little monitoring needed

• very expensive

• inc risk of infx & TB (test before!!)

• dont give live vaccines

• discontinue while pt has infx

Biologics

What BBW is seen with TNF-⍺ inhibitors?

lymphoproliferative cancer

What are relative CIs to TNF-⍺ inhibitors?

CHF (EF < 50% or NHYA class II or IV) & MS (can induce sx)

What drug?

• bind & inhibit TNF linked to Fc fragment of IgG → dec sx, inflammation, and joint damage

• 2nd line DMARD in RA; use alone or w/ MTX

• inc risk of infx & injection site rxns

Etanercept (Enbrel)

What drug?

• chimeric ab that binds & inhibits TNF-⍺ → dec sx, inflammation, & joint damage

• 2nd line for RA if MTX inadequate

  • combo w/ leflunomide

  • combo w/ MTX to prevent infusion rxn to foreign protein (flu like sx, rash, etc) & improve efficacy

Infliximab (Remicade)

What should be used as pretreatment prior to an infusion of chimeric proteins like Infliximab?

antihistamine/bendaryl, corticosteroids, tylenol

(have EPI on hand in case of reaction)

What drug?

• human monoclonal ab binds & inhibits TNF → dec sx, inflam, & joint damage

• human = less allergy risk

• monotherapy for RA if inadequate response to other DMARDs

  • SQ injection at home

• SE: infx, injection site rxn, rash, HA, pruritus, N, V

Adalimumab (Humira)

What drug?

• mod-severe RA tx when other therapies failed

• binds to CD80-CD86 receptions → prevent interactions bt ag presenting cells & T cells → prevent T cell activation

• weight based design q 4 wks

• SE: HA, infx, injection rxn, extremity pain

Abatacept

What drug?

• chimeric antibody against CD20 protein on B cells → binding almost completely depletes B cells → dec ag presentation to T cells

• RA tx when MTX or TNFi failed

• needs to be pretreated!

Rituximab (Rituxan)

What drug?

• humanized mab against IL-6 (promotes inflammation in RA)

• used after TNFi failure

• SE: infusion rxn, infx, hyperlipidemia, elevated transaminases, GI perforation

• CYP3A4 inducer

  • (lowers levels of other drugs like warfarin, birth control, statins, etc)

Tocilizumab (Actemra)

If biologic agents fail, can you use a combination of biologics?

no- too much immunosuppression

What should be done if biological agents fail in RA treatment, either primary lack of efficacy (no response in 3-6 mos, never really worked) or secondary lack of efficacy (failure after initial response, neutralizing abs formed against drug & stopped working)?

add on non biological DMARD or switch between MOAs

What drug?

• used in RA treatment- antiinflammatory & immunosuppressive

  • chronic tx, bridge therapy (allow DMARD to start working), & disease flare ups

• interfere w/ ag presentation to T cells

• inhibit free radical generation

• impair cell migration & chemotaxis

corticosteroids

What dosage form of corticosteroids allows for a natural taper and less withdrawal / adrenal insufficiency?

intramuscular long acting depot

What dosage form of corticosteroids is good for a small number of joints but should not be administered more than 2-3x per year due to joint destruction and tendon atrophy?

intra-articular injection

What SEs are seen with corticosteroids?

HPA axis suppression, osteoporosis (give Ca and vit D), myopathies, cataracts, hirsutism, hyperglycemia, hyperlipidemia, ulcers, infx

What drug?

• RA- mainstay of chronic tx

• OA- adjunctive to analgesics or used alone

• does not modify dz progression

NSAIDs

RA algorithm

What DMARD combinations are acceptable for treatment of RA?

(*** Test Q)

2 Traditionals

Traditional + Biologic

Traditional + Jak inhibitor

What combination of DMARDs should be AVOIDED in RA treatment due to high risk of hepatotoxicity?

(***Test Q)

MTX + Leflunomide

What DMARDs combos should be avoided due to high infection risk?

2 biologics

Jak inhibitor + biologics

What is the max dose of acetaminophen per day?

4 g

What drug?

• first line for OA

  • (not good for RA bc no anti-inflammatory properties)

• less effective than NSAIDs but also less toxic

• hepatotoxicity, inc bleeding risk if taken w/ warfarin

Acetaminophen (APAP)

What drug?

• first line for knee OA if APAP failed

• fewer systemic SEs

Topical NSAIDs (Diclofenac, Aspercreme, etc)

Which is preferred in OA patients over age 75?

Topical NSAIDs

What drug?

• topical analgesic used in adjunct to analgesics & NSAIDs in OA treatment

• need to be consistent- results in several weeks after depletion of substance P

• wash hands w/ soap & water after

Capsaicin

What are examples of counter-irritants used in OA treatment that work by creating cold/heave over the sore surface drawing the pain?

menthol, camphor, oil of wintergreen

What is the alternative first line tx for knee and hip OA when uncontrolled by NSAIDs & APAP?

(*dont give more than every 3 mos - tendon atrophy)

Intraarticular corticosteroids

What is second line tx for OA and should be used short term for pain?

Opioids

What dietary supplement (found in cartilage and synovial fluid) can be given for OA & work by increasing proteoglycan synthesis in articular cartilage to repair and prevent further breakdown?

Glucosamine & Chondroitin

What is a contraindication to glucosamine and chondroitin?

shellfish allergy

What drug?

• constituent of synovial fluid; used for pain associated with knee OA

• antiinflammatory, reduces pain, & improves jt mobility

• relatively free of SEs

Hyaluronate injections

Hip & Knee OA algorithm

Hand OA algorithm

What bone disorder is characterized by low bone density, impaired bone architecture, & compromised bone strength?

Osteoporosis

What drugs are associated with osteoporosis?

aromatase inhibitors (dec estrogen), long term PO glucocorticoids (inc bone resorption & dec formation), long term PPIs (Ca malabsorption)

Estrogen & testosterone increase bone ______ ; PTH increases bone ______

formation ; resorption

What is the active form of vit D (activated in liver & kidneys) that stimulates Ca absorption/retention?

Calcitriol (1,25 dihydroxy)

What factors are seen in the pathophysiology of osteoporosis?

low vit D → low serum Ca → parathyroid releases PTH → stimulates Ca resorption in kidney & osteoclast activity (bone resorption)

estrogen deficiency → inc osteoclast activity

What are non pharmacological options for osteoporosis?

Calcium (carbonate, tums) & Vitamin D

What SEs are seen with calcium?

constipation, hypercalcemia, nephrolithiasis, can bind to other drugs (iron, thyroid supplements, FQs, tetracyclines, bisphosphonates)

What patients would vitamin D supplementation not be efficient?

hepatic / renal impairment (can’t activate)

Who is prescription tx for osteoporosis prevention recommended in?

postmenopausal women or men > 50 y/o with

• osteoporosis

• low bone mass + 10 yr hip fx risk ≥3%

• 10 yr risk of any osteoporosis related fx ≥20%

Are the following drugs antiresorptive or anabolic?

• Ca, Vit D, bisphosphanates, SERMs, calcitonin, denosumab, estrogen, testosterone

Antiresorptive

What agents are bisphosphonates?

Alendronate (Fosamax)

Ibandronate (Boniva)

Risedronate (Actonael)

Zoledronic acid (Recast) - IV

What agents mimic pyrophosphate (endogenous bone resorption inhibitor) and reduces osteoclast maturation, number, adhesion, & lifespan to allow osteoblasts to function?

Bisphosphonates

What drugs require specific administration for absorption to occur due to < 1 % oral bioavailability; but has a half life of up to 10 years once absorbed?

Bisphosphonates

What SEs are seen with bisphosphonates?

GI (heartburn, dyspepsia), esophageal erosion/ulcer, osteonecrosis of jaw

How should oral bisphosphonates be administered?

take tablet w/ 6 oz water (no other liquid) atleast 30 min before consuming other foods or liquids

remain upright for atleast 30 min

Which bisphosphonate can be dosed yearly?

Zoledronic acid

Which drug?

• binds to RANKL → prevents binding on surface of osteoclast precursor cells → never gets signal to mature, fewer osteoclasts resorbing bone

• 25 day half life; peak concentration 10 days

• dosed every 6 mos

• ADR: local derm rxn, skin infx, bone turnover suppression

Denosumab (Prolia)

What mixed estrogen agonist/antagonist (SERM) can be used for treatment and prevention of osteoporosis in women?

Raloxifene (Evista)

What drug?

• endogenous hormone released from thyroid gland when Ca elevated (opposes actions of PTH)

• produced from salmon sperm

• Intranasal administration

• not recommended osteoporosis but can be used if other tx not appropriate

  • only evidence for vertebral fx reduction, not hip fx

Calcitonin

What drug?

• used in osteoporosis pts who are high risk for fx but failed bisphosphonates

• mimics PTH - stimulate bone formation, remodeling rate, osteoblast number & activity (anabolic agent)

• REMS program- bone cancer risk; take less than 2 years

Teriparatide (Forteo)

What are treatment options for acute gouty arthritis?

Ice, NSAIDs, corticosteroids, colchicine

begin w/in 24 hrs; combo if severe

When would systemic steroids be used instead of intraaritcular injections (kenalog) for acute gouty arthritis?

> 2 joints are affected

When do corticosteroids need to be tapered?

duration > 1 wk

What drug?

• antimitotic - prevents cell replication in rapidly dividing cells

• in gout- binds microtubule proteins in neutrophils inhibiting migration & limiting inflam response

• only used for acute gouty arthritis w/in 36 hours or will lose efficacy

Colchicine (Colcrys)

What SEs are seen with colchicine?

dose dependent GI sx (N/V/D), axonal neuromyopathy, neutropenia

What are non pharmacological options to prevent recurrent gout attacks?

maintain lower uric acid levels, limit alcohol intake, limit meds that raise uric acid (thizaide/loop diuretics, niacin, low dose ASA)

What treatment options for hyperuricemia are considered with two or more gout attacks per year, one or more typhus is present, chronic kidney disease, or history urolithiasis?

urate lowering therapy (XOIs or uricosurics)

What drugs?

• lowers uric acid- impairs xanthine oxidase to convert hypoxanthine → xanthine & xanthine → uric acid

• most widely used for prevention of gouty attacks

Xanthine Oxidase Inhibitors (XOIs)

What drugs are XOIs?

Allopurinol & Febuxostat

what SEs are seen with allopurinol?

rash, leukopenia, GI upset

rare- TEN, exfoliative dermatitis

what SEs are seen with febuxostat?

N, arthralgias, transaminitis

What drug?

• uricosuric: inc renal clearance of uric acid by inhibiting post secretory renal tubular absorption

• ADR: nephrolithiasis, rash, GI sx, precipitation of gouty arthritis

• may inc levels of drugs by inhibiting renal secretion (extending half life)

  • PCNs, cephalosporins

• CI in renal impairment (*watch kidneys)

Probenecid

What drug?

• recombinant form of urate oxidase → catalyzes breakdown of uric acid into soluble allantoin

• reserved; used for tumor lysis syndrome

• can form abs that make drug less effective if given again or develop allergy

• SE: may cause hemolysis and methemoglobinemia (blue/cyanotic look) in patients w/ G6PD deficiency

Rasburicase (Elitek)