Drugs for rheumatoid arthritis

Some DMARDs and Biologic Agents Page 39 Treatment Guidelines Published by The Medical Letter, Inc.. • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication Volume 10 Issu

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Drugs for Rheumatoid Arthritis

Table

1 Some DMARDs and Biologic Agents Page 39

Treatment Guidelines

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Volume 10 (Issue 117) May 2012

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Disease-modifying anti-rheumatic drugs (DMARDs)

are now used early in the treatment of rheumatoid

arthritis (RA) to achieve clinical remission, prevent

irreversible damage to joints, and minimize toxicity

associated with nonsteroidal anti-inflammatory drugs

(NSAIDs) and corticosteroids.1 DMARDs (Table 1)

generally do not have an immediate analgesic effect,

but over time can control symptoms and have been

shown to delay and possibly stop progression of the

disease NSAIDs have immediate analgesic and anti-inflammatory effects, but may not affect the disease process Oral corticosteroids can relieve joint symp-toms and control systemic manifestations, but their chronic use can cause many complications Judicious use of intra-articular corticosteroids can rapidly decrease inflammation in acute joints with few, if any, adverse effects

DMARDs

Most DMARDs have a slow onset of action and require regular monitoring for adverse effects

Methotrexate (Rheumatrex, and others) is generally

the first DMARD prescribed; it can be used in mild, moderate or severe RA For mild disease, some clini-cians prefer to start with hydroxychloroquine

(Plaquenil, and others) or sulfasalazine (Azulfidine,

and others)

METHOTREXATE — Methotrexate is usually the

standard of care for initial DMARD therapy Even in low doses, it can decrease symptoms, limit joint dam-age, and improve long-term outcomes Methotrexate can induce a sustained clinical remission and has been reported to prolong survival in patients with RA, pos-sibly by a beneficial effect on cardiovascular disease.2 The anti-rheumatic effect of methotrexate is usually apparent within 4-6 weeks, but sometimes not for sev-eral months

Dosage – Many rheumatologists recommend starting

with a single dose of oral methotrexate 7.5-15 mg once a week In patients who cannot tolerate the single dose, methotrexate can be given in 3 divided doses at 12-hour intervals The dosage can be increased over 1-2 months to 25 mg once a week Intramuscular (IM)

or subcutaneous (SC) methotrexate once weekly (in the same dose as the oral formulation) may be helpful for patients who have adverse gastrointestinal (GI)

RECOMMENDATIONS: For initial treatment of

rheumatoid arthritis, most Medical Letter

consult-ants prescribe a disease-modifying anti-rheumatic

drug (DMARD), and add a nonsteroidal

anti-inflammatory drug (NSAID) with or without a

corticosteroid to control symptoms Methotrexate is

generally the DMARD of choice;

hydroxychloro-quine is a safer alternative that may be appropriate

in the mildest cases

Tumor necrosis factor (TNF) inhibitors (etanercept,

infliximab, adalimumab, golimumab, and

certolizu-mab pegol) are typically the first-line biologic agents

prescribed after an inadequate response to a DMARD;

they may be given as monotherapy or in combination

with methotrexate For patients who do not respond

adequately to a TNF inhibitor, switching to a second

TNF inhibitor may be effective, but with the

availability of non-TNF biologic agents, many

rheumatologists change to a biologic agent with a

dif-ferent mechanism of action

The combination of a biologic agent with a DMARD

(usually methotrexate) offers better disease control

without a substantial increase in toxicity and is now

commonly used to achieve remission Aggressive

early therapy with methotrexate and/or a biologic

agent results in longer disease-free remissions, less

joint destruction, and a better quality of life

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effects from the oral formulation or lose benefit over

time because of poor absorption Supplements

contain-ing folic acid (1-4 mg daily) or folinic acid (2.5-10 mg

weekly 24 hours after the methotrexate dose) are

rec-ommended to decrease methotrexate’s adverse effects

Adverse Effects – In low doses, methotrexate is

usu-ally well tolerated, but it can cause stomatitis, anorexia,

nausea, abdominal cramps, increased aminotransferase

activity and, rarely, hepatic fibrosis Parenteral

admin-istration decreases the GI effects of the drug Many

rheumatologists would not prescribe methotrexate for

patients with pre-existing liver disease or for those

who consume large amounts of alcohol All patients

taking methotrexate should be discouraged from

drink-ing alcohol Hepatic transaminases should be

monitored before and during treatment and patients at

risk for hepatitis B and C should be screened before

starting the drug

Methotrexate is an antifolate that is toxic to all rapidly

dividing cells; even in low doses it can suppress the

bone marrow, and peripheral blood counts should be

monitored periodically Bone marrow suppression can

be treated with leucovorin rescue Infections such as

herpes zoster may be more common in patients taking

the drug A rare association has been reported between

methotrexate use and localized lymphoma, which

often regresses when methotrexate is discontinued

Hypersensitivity pneumonitis, which can be severe,

occurs in 1-2% of patients and may be more common

in those with antecedent lung disease An increase in

rheumatoid skin nodules and (rarely) cutaneous

necro-tizing vasculitis has been reported

Since methotrexate is eliminated primarily by renal

excretion, serious toxicity is more likely in patients

with decreased creatinine clearance (CrCl)

Methotrexate is not recommended for use in patients

with CrCl <30 mL/min

Pregnancy – Methotrexate is teratogenic and should not

be prescribed for women who are or may become

preg-nant It is also an abortifacient and can decrease fertility

in both men and women The drug should be stopped in

both sexes at least 3 months before conception.3

Drug Interactions – Trimethoprim/sulfamethoxazole

(Bactrim, and others), trimethoprim (Proloprim, and

others) and other drugs that interfere with folate

metabolism may increase bone marrow suppression

caused by methotrexate NSAIDs decrease the renal

tubular secretion of methotrexate and may increase its

toxicity, but many patients take both drugs without

adverse effects

LEFLUNOMIDE — An oral inhibitor of pyrimidine

synthesis, leflunomide (Arava, and others) can be

used as initial monotherapy instead of methotrexate or can replace methotrexate in patients who do not toler-ate it Like methotrextoler-ate, leflunomide can reduce symptoms, limit damage to joints, and improve func-tion.4 Leflunomide and methotrexate have been used together, but their hepatotoxicity may be additive

Dosage – The maintenance dose of leflunomide is 20

mg daily; if not well tolerated, the dose can be reduced to 10 mg daily A loading dose of 100 mg daily for 3 days is sometimes recommended, but many clinicians omit this because of a high incidence

of GI intolerability

Adverse Effects – Diarrhea occurs frequently with

leflunomide and is sometimes debilitating Reversible alopecia, rash, myelosuppression, and increases in aminotransferase activity can also occur; complete blood counts and liver function tests should be moni-tored The risk of severe liver toxicity may be greater in patients taking leflunomide and methotrexate concur-rently Anaphylaxis, Stevens-Johnson syndrome, weight loss, interstitial lung disease, peripheral neuropathy and leukocytoclastic vasculitis have occurred rarely

Pregnancy – Leflunomide is carcinogenic and

terato-genic in animals and is contraindicated during pregnancy Women who want to become pregnant and men who want to father a child after beginning treat-ment with leflunomide should discontinue it and take

cholestyramine (Questran, and others) 8 g three times

a day for 11 days to bind and eliminate the drug;

plas-ma levels of the active metabolite should then be checked to verify that they are <0.02 mg/L The same detoxification protocol can be used for acute toxic effects of leflunomide Without cholestyramine, it could take up to 2 years for serum concentrations of the drug to become undetectable

HYDROXYCHLOROQUINE — The antimalarial

hydroxychloroquine is moderately effective for mild

RA and is usually well tolerated It is now often used with other drugs, particularly methotrexate and sul-fasalazine It may require 3-6 months for the drug’s effectiveness to become apparent

Adverse Effects – Nausea and epigastric pain can

occur, but serious adverse effects are rare Hemolysis may occur in patients with glucose-6-phosphate dehy-drogenase (G6PD) deficiency Some patients report immediate blurred vision or difficulty seeing at night that reverses upon discontinuation of the drug Retinal damage is a rare complication that can be avoided if vision is monitored (visual fields, color vision), dosage

Drugs for Rheumatoid Arthritis

Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 117) • May 2012

is kept below 6.5 mg/kg/day, and the drug is

discontin-ued promptly when signs of retinal toxicity first

appear; it should not be used in patients with

signifi-cant renal insufficiency A complete ophthalmologic

exam is recommended before treatment and annually

for those at high risk (age >60, hepatic or renal disease,

retinal disease); patients at low risk may be examined

less frequently Use of hydroxychloroquine during

pregnancy is thought to be relatively safe.5

SULFASALAZINE — Sulfasalazine (Azulfidine, and

others) has been shown to prevent joint erosions It

often requires 2-3 months of therapy for beneficial

effects to become apparent Sulfasalazine causes more toxicity than hydroxychloroquine

Adverse Effects – Nausea, anorexia and rash are

fair-ly common with sulfasalazine Use of enteric-coated tablets may decrease GI toxicity Serious reactions such as hepatitis, leukopenia and agranulocytosis are rare and usually occur within the first 2-3 months of treatment A lupus-like syndrome has been reported Hemolysis may occur in patients with G6PD

deficien-cy Sperm counts may decrease, but return to normal after withdrawal of the drug Sulfasalazine is probably safe for use during pregnancy

39

DMARDs

Rheumatrex (DAVA)

(25 mg/mL)

Plaquenil (sanofi)

Azulfidine (Pfizer)

Azulfidine EN-tabs

Arava (sanofi)

Minocycline – generic 50, 75, 100 mg caps, tabs 50 to 200 mg/d in divided doses PO

BIOLOGIC AGENTS

TNF Inhibitors

Certolizumab pegol – Cimzia (UCB) 200 mg vial; 400 mg 2 SC at 0, 2, and 4 wks, then

200 mg/mL syringe 200 mg every other week or 400 mg

q4 weeks Etanercept – Enbrel (Immunex) 25 mg vial; 25, 50 mg/mL 25 mg 2x/wk or 50 mg once/wk SC

syringe

6 wks, then q8 wks IV

Non-TNF Inhibitors

Rituximab 4 – Rituxan (Genentech) 100, 500 mg vials 1000 mg IV twice, 2 weeks apart 5

Tocilizumab – Actemra (Genentech) 80, 200, 400 mg single-use vials 4-8 mg/kg IV q4 weeks

(20 mg/mL) Abatacept – Orencia (BMS) 15 mL (250-mg vial) 500, 750, or 1000 mg at 0, 2 and 4

weeks, then q4 weeks IV 6

1 mL (125 mg syringe) 125 mg once/wk SC 7

1 The manufacturer recommends a loading dose of 100 mg/day for the first three days, but many clinicians omit it due to GI intolerability.

2 Given as 2 SC injections of 200 mg.

3 Approved for use only in combination with methotrexate.

4 FDA-approved only for use with methotrexate in patients with an inadequate response to at least one TNF antagonist.

5 To reduce the incidence and severity of infusion reactions, IV methylprednisolone 50-100 mg or equivalent infused 30 minutes before rituximab is recommended.

6 Dose is 500 mg for patients weighing <60 kg, 750 mg for patients 60-100 kg, and 1000 mg for patients >100 kg.

7 The first 125-mg SC injection is given within a day of an IV loading dose (see footnote 6).

Table 1 Some DMARDs and Biologic Agents

MINOCYCLINE — The antibiotic minocycline

(Minocin, and others) may offer some benefit in the

mildest cases of RA; it is relatively safe, but can cause

drug-induced lupus and is contraindicated for use in

young children and in women during pregnancy and

when breastfeeding

RARELY USED DMARDs — Gold salts, although

now used infrequently, can induce a complete

remis-sion in RA Injectable gold, which is much more

effec-tive than oral gold, is an alternaeffec-tive for patients who

cannot tolerate methotrexate or the biologic agents It

has numerous adverse effects, particularly stomatitis,

rash, proteinuria and, less commonly, leukopenia and

thrombocytopenia Enterocolitis, aplastic anemia and

interstitial pneumonitis are rare serious adverse effects

of injectable gold Gold therapy is not recommended

for use during pregnancy

Azathioprine (Imuran, and others) is an

immunosup-pressive purine analog sometimes used for patients

with refractory RA or systemic involvement such as

rheumatoid vasculitis GI intolerance, hepatitis and

bone marrow suppression can occur, and an increased

risk of lymphoma has been reported Azathioprine is

contraindicated for use during pregnancy

Cyclosporine (Neoral, and others) is an inhibitor of

T-cell activation that can be helpful in some patients with

RA, but nephrotoxicity and many interactions with

drugs and foods have limited its use Cyclosporine

should not be used during pregnancy

BIOLOGIC AGENTS

Biologic agents are generally reserved for use in

patients with moderate to severe disease

TNF INHIBITORS — Tumor necrosis factor (TNF)

is a pro-inflammatory cytokine present in the

synovi-um of patients with RA Five parenteral drugs that bind

to TNF and block its activity are approved for

treat-ment of RA They relieve symptoms and may be more

effective than methotrexate and other DMARDs in

limiting joint destruction TNF inhibitors also act more

quickly than DMARDs; some patients report

substan-tial improvement after the first dose Use of a TNF

inhibitor in combination with methotrexate has

syner-gistic beneficial effects

Etanercept (Enbrel) is a subcutaneously (SC)

admin-istered recombinant human fusion protein consisting

of a soluble TNF receptor covalently linked to a human

IgG1 Fc fragment In patients who do not respond

ade-quately to methotrexate alone, addition of etanercept

has been effective in improving signs and symptoms of

RA and slowing joint damage It is also FDA-approved for monotherapy The dose of etanercept is 25 mg SC twice weekly or 50 mg once weekly

Infliximab (Remicade), which is given intravenously

(IV), is a chimeric human/mouse anti-TNF monoclonal antibody Infliximab is not approved for monotherapy Concurrent methotrexate therapy enhances its efficacy, possibly by inhibiting formation of neutralizing anti-bodies against infliximab In patients with persistently active RA, addition of infliximab 3 mg/kg IV every 8 weeks to methotrexate has improved symptoms and slowed progression of joint damage Some patients may require higher (up to 10 mg/kg every 8 weeks) or more frequent (up to every 4 weeks) doses

Adalimumab (Humira) is a recombinant human

monoclonal anti-TNF antibody It can be injected sub-cutaneously in a dose of 40 mg once a week or (more commonly) every other week Adalimumab appears to

be about as effective as etanercept or infliximab when used with methotrexate.6

Golimumab (Simponi) is a high-affinity human

monoclonal antibody approved as monotherapy or in combination with methotrexate.7It is available as a

50-mg SC injection administered monthly

Certolizumab pegol (Cimzia) is a humanized

pegylat-ed, anti-TNF monoclonal antibody approved for monotherapy or in combination with DMARDs.8The pegylated structure increases the biologic half-life of the medication and may possibly help target it to sites

of inflammation The recommended dosage of cer-tolizumab is 400 mg SC every other week for three doses, followed by a maintenance dose of 200 mg every other week; monthly injections of 400 mg are an alter-native maintenance regimen

Injection-site reactions are common with etanercept, golimumab, certolizumab pegol and adalimumab Infusion reactions can occur with infliximab and may include severe back pain, fever, urticaria, dyspnea and hypotension Cytopenias can occur with any anti-TNF therapy; complete blood counts should be monitored regularly

Serious infections, including bacterial sepsis and tuber-culosis (usually reactivation and often disseminated), are the most important potential adverse effects of TNF inhibition These drugs should not be given to patients with an active infection Patients should be screened for latent tuberculosis infection before and during treat-ment with a TNF inhibitor Appropriate treattreat-ment for latent tuberculosis reduces the risk of reactivation TNF inhibitors also increase the risk of invasive and

dissem-Drugs for Rheumatoid Arthritis

Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 117) • May 2012

inated infections caused by viral, fungal and other

opportunistic pathogens such as histoplasmosis,

candidiasis, aspergillosis, coccidioidomycosis,

blasto-mycosis, pneumocystosis and toxoplasmosis Serious

infection with Legionella and Listeria have also been

reported Reactivation of hepatitis B can occur

Malignancies, especially lymphomas, have been

reported in association with TNF inhibitors, but a

cause-and-effect relationship has not been established;

patients with RA in general have an increased risk of

lymphoma TNF inhibitors should not be used in

patients with a recent history of malignancy

TNF inhibitors may rarely induce new-onset or

exacer-bate pre-existing congestive heart failure or induce a

reversible lupus-like syndrome Demyelinating

condi-tions, including multiple sclerosis, have occurred in

patients being treated with these agents Patients with

pre-existing demyelinating disorders should not receive

anti-TNF therapy The manufacturer of infliximab has

issued a warning about possible hepatotoxicity, including

jaundice, hepatitis, cholestasis and acute liver failure

Pregnancy – TNF inhibitors are classified as category

B for use in pregnancy, but serious congenital

anom-alies have been reported in the offspring of women

tak-ing TNF inhibitors durtak-ing pregnancy.9

Choice of a TNF Inhibitor – Patients who do not

respond to one TNF inhibitor may respond to another

Some clinicians would use etanercept first because it

has a rapid onset of action and a short half-life that

makes toxicity, if it occurs, relatively short-lived

Others would start with infliximab, and if it proves

ineffective, would try etanercept or adalimumab next

NON-TNF BIOLOGICS — Rituximab (Rituxan) is a

genetically engineered chimeric monoclonal antibody

against CD20, a B-cell specific surface antigen It has

been effective in patients with RA who have had

inade-quate responses to methotrexate and/or anti-TNF

agents.10,11Rituximab is commonly given concurrently

with methotrexate or another DMARD; concomitant use

of another biologic agent is not recommended It is

administered as two IV infusions given 2 weeks apart

IV methylprednisolone 50-100 mg or its equivalent

infused 30 minutes before rituximab can reduce the

incidence and severity of infusion reactions Patients

can be retreated every 6 months

Anaphylaxis and anaphylactoid reactions can occur

within 2 hours of a rituximab infusion; fatalities have

been reported Late adverse effects of the drug include

progressive multifocal leukoencephalopathy (PML)

due to JC virus infection, which often causes death or

severe neurological disability, and reactivation of hep-atitis B infection Screening patients at high risk of hepatitis B is recommended before treatment An increased risk of tuberculosis has not been observed with rituximab

Abatacept (Orencia) is a genetically engineered fusion

protein that interferes with T-cell activation.12It is avail-able in both IV and SC formulations, with no apparent difference in efficacy between the two formulations.13 Abatacept can be used as monotherapy or in combina-tion with a DMARD, but should not be used concur-rently with other biologic agents After an initial IV dose, subsequent doses are given at weeks 2 and 4, fol-lowed by monthly maintenance dosing Alternatively, after an initial IV loading dose, subcutaneous abata-cept can be administered weekly starting the day after

IV induction Some prescribers omit the IV dose and start directly with the subcutaneous weekly regimen Adverse events occurring within an hour after the start

of an abatacept infusion can include hypertension, headache, dizziness, and, rarely, anaphylactoid reac-tions Abatacept probably increases the risk of serious infections such as pneumonia, pyelonephritis, cellulitis and diverticulitis, but no clear association with tuber-culosis has been demonstrated

Tocilizumab (Actemra) is a humanized monoclonal

antibody that competitively inhibits the binding of the pro-inflammatory cytokine interleukin-6 (IL-6) to its receptors.14 It has been shown to achieve clinical improvement in some RA patients as early as two weeks after start of therapy Tocilizumab is given as a monthly IV infusion

Infusion reactions, hypertension, neutropenia, elevated serum transaminases, and dyslipidemia can occur Severe complications including GI perforation, serious infections, and hypersensitivity with anaphylaxis have been reported in clinical trials

Anakinra (Kineret) is a genetically engineered IL-1

receptor antagonist that competitively inhibits the pro-inflammatory effects of IL-1 It is considered the least effective biologic DMARD for RA and is not recommended.1

COMBINATION THERAPY

A combination of 2 or even 3 DMARDs or a DMARD with a biologic agent may be more effective than monotherapy without causing a significant increase in toxicity Combinations are used particularly for patients with highly active disease, a long duration of disease, or with clinical features that indicate a poor

41

prognosis, such as a positive rheumatoid factor or

anti-CCP test, functional limitations, extra-articular disease,

or bony erosions In one study in

methotrexate-refrac-tory patients randomized to addition of infliximab or

addition of sulfasalazine and hydroxychloroquine,

radiographic progression after 24 months was slower in

the infliximab group.15 The combination of

methotrex-ate with a biologic agent has been more efficacious

than methotrexate alone in achieving and maintaining

remission.16Concurrent use of methotrexate and a TNF

inhibitor has been more effective than either one alone

and in early RA can induce a clinical response in up to

50% of patients.17,18Leflunomide used in combination

with methotrexate increases the risk of hepatotoxicity;

patients must be monitored closely Combining

differ-ent biologic agdiffer-ents increases the risk of infections

without providing any appreciable additional benefit

and is not recommended

VACCINATIONS

All patients starting therapy with a DMARD or

bio-logic agent should be immunized against influenza,

pneumococcal disease, hepatitis B, and herpes zoster.19

Live virus vaccines, such as herpes zoster, MMR

(measles, mumps, rubella), varicella or intranasal

influenza, should not be used in patients taking a

bio-logic agent If needed, they should be given at least one

month before initiating treatment

NONSTEROIDAL ANTI-INFLAMMATORY

DRUGS

Because of the efficacy of methotrexate alone or in

combination with a biologic, NSAIDs now are used

mainly as bridge drugs for relief of pain No oral

NSAID is consistently more effective than any other

for treatment of RA, but some patients who do not

respond to or tolerate one may respond to or tolerate

another.20Aspirin in high doses is as effective as any

other NSAID, but may have more GI toxicity

Non-acetylated salicylates have less GI toxicity than

aspirin Although approved only for use in

osteoarthri-tis, topical diclofenac 1% gel (Voltaren Gel) could be

helpful in some patients with RA who have isolated

symptomatic joints.21

Mechanism of Action – The physiologic effects of

NSAIDs are due mainly to inhibition of the two

iso-forms of cyclooxygenase, COX-1 and COX-2 COX-1

is expressed in most tissues and is thought to protect

the gastric mucosa COX-2 is expressed in various

tis-sues, especially in the kidney, where it helps to

main-tain perfusion, and is inducible at sites of

inflamma-tion Inhibition of COX-1 decreases synthesis of

thromboxane in platelets and interferes with their

aggregation, a cardioprotective effect Inhibition of COX-2 is responsible for the anti-inflammatory effect

of NSAIDs At therapeutic doses, the older traditional

NSAIDs such as ibuprofen (Advil, and others) or naproxen (Naprosyn, and others, and others) block

both isoforms to varying degrees, while COX-2-selec-tive inhibitors (“coxibs”) selecCOX-2-selec-tively inhibit COX-2 At

present, celecoxib (Celebrex) is the only

FDA-approved coxib on the market; its potential for cardiovascular toxicity has limited its use.22

Gastrointestinal Adverse Effects – All NSAIDs can

cause dyspepsia and more serious GI toxicity, including gastric and duodenal ulceration, perforation and bleed-ing (with or without warnbleed-ing symptoms), especially in elderly patients, those with a previous GI bleed, and those receiving anticoagulants or systemic cortico-steroids Celecoxib has been shown to have less upper

GI toxicity than some of the nonselective NSAIDs Concurrent use of a proton pump inhibitor such as

omeprazole (Prilosec, and others), a double dose of a

histamine H2-receptor antagonist such as ranitidine

(Zantac, and others), or the prostaglandin analog miso-prostol (Cytotec, and others), may decrease the

incidence of GI toxicity caused by NSAIDs.23 Arthrotec

(diclofenac/misoprostol), Vimovo (naproxen/esomepra-zole) and Duexis (ibuprofen/famotidine) are three

commercially available NSAID preparations combined with an agent for gastrointestinal protection.24,25 Concurrent use of even low doses of aspirin increases the risk of NSAID GI toxicity

Effects on Bleeding – All NSAIDs, with the exception

of celecoxib, non-acetylated salicylates and, to a lesser

extent, meloxicam (Mobic, and others) and nabumetone (Relafen, and others), can interfere with platelet

func-tion and prolong bleeding time This effect is reversible when the drug is cleared, except with aspirin, which has

an irreversible inhibitory effect on platelets that persists for the life of the platelet (7-10 days)

Cardiovascular Risk – NSAIDs in general have

under-gone scrutiny of their cardiovascular safety.26 According to a meta-analysis of controlled clinical tri-als, the thrombotic risk increased with diclofenac

(Voltaren, and others), meloxicam and indomethacin (Indocin, and others), increased slightly with high-dose

ibuprofen (>1200 mg/d), and did not increase with naproxen Celecoxib did not appear to increase the inci-dence of cardiovascular events compared to placebo or non-selective NSAIDs.27,28

Renal Toxicity – Because of their inhibition of renal

prostaglandins, all NSAIDs, including celecoxib, decrease renal blood flow, cause fluid retention, and may cause hypertension and renal failure in some

Drugs for Rheumatoid Arthritis

Treatment Guidelines from The Medical Letter • Vol 10 ( Issue 117) • May 2012

patients, particularly the elderly Diminished renal

function or decreased effective intravascular volume

due to diuretic therapy, cirrhosis or congestive heart

failure increases the risk of NSAID renal toxicity

Other Effects – NSAIDs can cause central nervous

system effects such as dizziness, anxiety, drowsiness,

confusion, depression, disorientation, severe headache

and aseptic meningitis

NSAIDs frequently cause small increases in

amino-transferase activity; serious hepatic toxicity is rare, but

may occur more frequently with diclofenac

Pancreatitis has been reported Cholestatic hepatitis

has occurred with celecoxib, possibly related to

sul-fonamide allergy; celecoxib is contraindicated in

patients allergic to sulfonamides

NSAIDs rarely cause blood dyscrasias; aplastic

ane-mia has been reported with ibuprofen, fenoprofen

(Nalfon, and others), naproxen, indomethacin,

tol-metin and piroxicam (Feldene, and others).

Asthmatic patients sensitive to aspirin could develop

severe bronchospasm and anaphylactoid reactions with

any NSAID; non-acetylated salicylates and possibly

coxibs are less likely to cause these reactions

NSAIDs have been associated with both mild and severe

skin reactions, including exfoliative dermatitis,

Stevens-Johnson syndrome and toxic epidermal necrolysis

Pregnancy – Exposure to NSAIDs during pregnancy

or around the time of conception has been associated

with an increased risk of miscarriage, but the data are

weak Use of NSAIDs during the third trimester of

pregnancy may cause premature closure of the ductus

arteriosus and persistent pulmonary hypertension in

the neonate, but these effects appear to be uncommon

if the drug is discontinued 6-8 weeks before delivery

Drug Interactions – NSAIDs may decrease the

effec-tiveness of diuretics, beta-blockers, ACE inhibitors

and some other antihypertensive drugs, and may

increase the toxicity of lithium and methotrexate

Celecoxib and other NSAIDs can increase the

interna-tional normalized ratio (INR) if given with warfarin

(Coumadin, and others) and might increase the risk of

bleeding Patients taking aspirin for cardiovascular

protection should not take ibuprofen because it can

interfere with aspirin’s antiplatelet effect

CORTICOSTEROIDS

Use of oral corticosteroids in RA remains

controver-sial Many rheumatologists use short courses of

low-dose corticosteroids for symptomatic relief until the beneficial effects of DMARDs become apparent In patients with early RA, prednisone 7.5 mg daily has been reported to reduce radiographic progression, and the addition of daily prednisone 10 mg to methotrexate has been shown to reduce erosive joint damage and increase the likelihood of remission compared to methotrexate alone,29 but most clini-cians do not use corticosteroids as DMARDs because

of the complications associated with long-term use Use of corticosteroids in higher doses may be required to control severe systemic manifestations of

RA, such as pericarditis or vasculitis, but with the use

of methotrexate and the biologics, these are now uncommon

Intra-articular injection of a corticosteroid such as

triamcinolone (Aristospan) often can relieve an

acute-ly inflamed rheumatoid joint with minimal adverse effects; injecting 1 or 2 joints to control a patient who does not have generalized disease is an underutilized way of controlling the inflammatory process.30

Adverse Effects – Intra-articular corticosteroids cause

few, if any, adverse effects The adverse effects of sys-temic corticosteroids include osteoporosis, weight gain, fluid retention, cataracts, glaucoma, poor wound healing, gastric ulcers and GI bleeding, hyper-glycemia, hypertension, adrenal suppression and increased risk of infection Even short-term cortico-steroid use in low doses can cause bone loss; calcium and vitamin D supplements should be given concur-rently Using a bisphosphonate, such as alendronate

(Fosamax, and others) or risedronate (Actonel), or the

parathyroid hormone formulation teriparatide

(Forteo)31 can help to prevent corticosteroid-induced osteoporosis Prophylactic antibiotic therapy against

Pneumocystis jiroveci (formerly carinii) pneumonia is

recommended for patients receiving prolonged moder-ate or high-dose corticosteroid therapy (>20 mg daily prednisone or equivalent), especially when combined with an immunosuppressive DMARD

1 JA Singh et al 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis Arthritis Care Res 2012; 64:625.

2 SL Westlake et al.The effect of methotrexate on cardiovascular disease

in patients with rheumatoid arthritis: a systematic literature review Rheumatology 2010; 49:295.

3 A Golding et al Rheumatoid arthritis and reproduction Rheum Dis Clin North Am 2007; 33:319.

4 N Alcorn et al Benefit-risk assessment of leflunomide: an appraisal of leflunomide in rheumatoid arthritis 10 years after licensing Drug Saf 2009; 32:1123.

5 F Vroom et al Disease modifying antirheumatic drugs in pregnancy: current status and implications for the future Drug Saf 2006; 29:845.

6 YF Chen et al A systematic review of the effectiveness of

adalimum-ab, etanercept and infliximab for the treatment of rheumatoid arthritis

43

in adults and an economic evaluation of their cost-effectiveness.

Health Technol Assess 2006; 10:iii.

7 Golimumab (Simponi) for inflammatory arthritis Med Lett Drugs

Ther 2009; 51:55.

8 Certolizumab (Cimzia) for Crohn’s disease Med Lett Drugs Ther

2008; 50:81.

9 JD Carter et al A safety assessment of tumor necrosis factor

antago-nists during pregnancy: a review of the Food and Drug Administration

database J Rheumatol 2009; 36:635.

10 Rituximab (Rituxan) for rheumatoid arthritis Med Lett Drugs Ther

2006; 48:34.

11 SB Cohen et al Rituximab for rheumatoid arthritis refractory to

anti-tumor necrosis factor therapy: results of a multicenter, randomized,

dou-ble-blind, placebo-controlled, phase III trial evaluating primary efficacy

and safety at twenty-four weeks Arthritis Rheum 2006; 54:2793.

12 Abatacept (Orencia) for rheumatoid arthritis Med Lett Drugs Ther

2006; 48:17.

13 MC Genovese et al Subcutaneous abatacept versus intravenous

abat-acept: a phase IIIb noninferiority study in patients with an inadequate

response to methotrexate Arthritis Rheum 2011; 63:2854.

14 Tocilizumab (Actemra) for rheumatoid arthritis Med Lett Drugs Ther

2010; 52:47.

15 RF van Vollenhover et al Conventional combination treatment versus

biological treatment in methotrexate-refractory early rheumatoid

arthritis: 2 year follow-up of the randomised, non-blinded,

parallel-group Swefot trial Lancet 2012 Epub ahead of print.

16 B Kuriya et al Efficacy of initial methotrexate monotherapy versus

combination therapy with a biological agent in early rheumatoid

arthritis: a meta-analysis of clinical and radiographic remission Ann

Rheum Dis 2010; 69:1298.

17 YH Lee et al Meta-analysis of the combination of TNF inhibitors plus

MTX compared to MTX monotherapy, and the adjusted indirect

com-parison of TNF inhibitors in patients suffering from active rheumatoid

arthritis Rheumatol Int 2008; 28:553.

18 KE Donahue et al Systemic review: comparative effectiveness and

harms of disease-modifying medications for rheumatoid arthritis Ann

Intern Med 2008; 148:124.

19 Adult immunization Treat Guidel Med Lett 2011; 9:75.

20 Drugs for pain Treat Guidel Med Lett 2010; 8:25.

21 Diclofenac gel for osteoarthritis Med Lett Drugs Ther 2008; 50:31.

22 PL McCormack Celecoxib: a review of its use for symptomatic relief

in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing

spondylitis Drugs 2011; 71:2457.

23 Primary prevention of ulcers in patients taking aspirin or NSAIDs.

Med Lett Drugs Ther 2010; 52:17.

24 Naproxen/esomeprazole (Vimovo) Med Lett Drugs Ther 2010; 52:74.

25 A fixed-dose combination of ibuprofen and famotidine (Duexis) Med

Lett Drugs Ther 2011; 53:85.

26 ME Farkouh and BP Greenberg An evidence-based review of the

car-diovascular risks of nonsteroidal anti-inflammatory drugs Am J

Cardiol 2009; 103:1227.

27 P McGettigan and D Henry Cardiovascular risk with non-steroidal

anti-inflammatory drugs: systematic review of population-based

con-trolled observational studies PLoS Med 2011; 8:e1001098.

28 WB White et al Risk of cardiovascular events in patients receiving

celecoxib: a meta-analysis of randomized clinical trials Am J Cardiol

2007; 99:91.

29 MF Bakker et al Low-dose prednisone inclusion in a

methotrexate-based, tight control strategy for early rheumatoid arthritis: a

random-ized trial Ann Intern Med 2012; 156:329.

30 E Dernis et al Use of glucocorticoids in rheumatoid arthritis -

practi-cal modalities of glucocorticoid therapy: recommendations for

clini-cal practice based on data from the literature and expert opinion Joint

Bone Spine 2010; 77:451.

31 Drugs for postmenopausal osteoporosis Treat Guidel Med Lett 2011;

9:67.

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Treatment Guidelines

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