The medical letter on drugs and therapeutics december 22 2014

The Medical Letter

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IN THIS ISSUE

Drugs for Rheumatoid Arthritis .................................................................................. p 127

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The Medical Letter

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on Drugs and Therapeutics
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Volume 56

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ISSUE No.

December 22, 2014
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IN THIS ISSUE

1433
1458 Drugs for Rheumatoid Arthritis
Volume 56
Related article(s) since publication

RECOMMENDATIONS
For initial treatment of rheumatoid arthritis, most
expert clinicians prescribe a disease-modifying antirheumatic drug (DMARD) and add a nonsteroidal
anti-inflammatory drug (NSAID) or a corticosteroid
to control symptoms. Methotrexate is generally the
DMARD of choice; hydroxychloroquine and sulfasalazine
are safer alternatives that may be appropriate in the
mildest cases. In patients with moderate to severe
disease, combining a biologic agent with a DMARD
(usually methotrexate) for initial treatment may provide
better disease control than a DMARD alone.

can be used to treat mild, moderate, or severe RA.
For mild disease, some clinicians prefer to start
with hydroxychloroquine (Plaquenil, and generics)
and/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 damage,
and improve long-term outcomes. The antirheumatic
effect of methotrexate is usually apparent within 4-6
weeks, but sometimes can take several months.

DMARDs

Adverse Effects – In low doses, methotrexate is

usually well tolerated, but it can cause stomatitis,
anorexia, nausea, vomiting, abdominal cramps,
aminotransferase elevations and, rarely, hepatic
fibrosis. Parenteral administration can decrease
the GI adverse effects associated with oral
administration 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. 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.

Disease-modifying antirheumatic drugs (DMARDs)
are 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
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. Methotrexate (Rheumatrex, and
others) is generally the first DMARD prescribed; it

Methotrexate is an antifolate that is toxic to all rapidly
dividing cells; complete blood counts should be
monitored monthly. Supplements containing folic acid
(1-4 mg daily) or folinic acid (2.5-10 mg weekly, 24
hours after the methotrexate dose) are recommended

to decrease adverse effects. Bone marrow suppression
can be treated with leucovorin rescue. Infections such
as herpes zoster may be more common in patients
taking the drug. Methotrexate use has rarely been
associated with localized lymphoma, which often
regresses when methotrexate is discontinued.

Tumor necrosis factor (TNF) inhibitors are typically
the first-line biologic agents prescribed after an
inadequate response to DMARD therapy, often in
combination with methotrexate. For patients who do
not respond adequately to one TNF inhibitor, switching
to another TNF inhibitor or a non-TNF biologic agent
may be effective.

127

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December 22, 2014

Table 1. Some DMARDs for Rheumatoid Arthritis
Drug

Some Available Formulations

Usual Adult Dosage1

Methotrexate, oral – generic
Rheumatrex (Dava)
Trexall (Duramed/Barr)

2.5 mg tabs

Induction: 7.5-10 mg PO once/wk
Maintenance: 7.5-25 mg PO once/wk3

$ 33.30
134.50
65.60

Methotrexate, injectable – generic
Otrexup (Antares)

2, 4, 10 mL vials (25 mg/mL)
10, 15, 20, 25 mg in 0.4 mL
auto-injectors
7.5 mg-30 mg auto-injectors7

Induction: 7.5 mg PO once/wk4,5
Maintenance: 10-25 mg IM or SC once/wk5,6

5.80

548.00

Hydroxychloroquine sulfate - generic
Plaquenil (Covis)

200 mg tabs

Induction: 400-600 mg/day PO x 4-12 wks
Maintenance: 200-400 mg/day PO

57.20
128.20

Sulfasalazine – generic8
Azufidine (Pfizer)8
enteric-coated – generic
Azulfidine EN-tabs

500 mg tabs

Induction: 3-4 g/day in divided doses PO
Maintenance: 2 g/day in divided doses PO

22.30
98.90
27.90
129.10

Rasuvo (Medac)

Leflunomide – generic
Arava (Sanofi)

Cost2
3

5, 7.5, 10, 15 mg tabs

448.00

500 mg tabs
10, 20 mg tabs
10, 20, 100 mg tabs

Induction: 100 mg/day PO x 3 days9
Maintenance: 10-20 mg/day PO

41.50
1066.50

1. Dosage adjustment may be needed for hepatic or renal impairment.
2. Approximate WAC for 30 days’ treatment with the lowest usual maintenance dosage. WAC = wholesaler acquisition cost or manufacturer’s published price to
wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. December 5, 2014. Reprinted with permission by First Databank, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy.
3. In patients who cannot tolerate the single dose, methotrexate can be given in 3 divided doses. The dosage can be increased over 1-2 months to 25 mg once/wk.
4. An oral formulation of methotrexate should be used for induction therapy with Otrexup and an oral or SC formulation of methotrexate can be used with Rasuvo.
5. 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 effects from the oral formulation or lose benefit over time because of poor absorption. Otrexup and Rasuvo are only for subcutaneous use.
6. Maintenance dosage for Rasuvo is 7.5-30 mg/wk.
7. Rasuvo is available in 7.5 mg/0.15 mL, 10 mg/0.2 mL, 12.5 mg/0.25 mL, 15 mg/0.3 mL, 17.5 mg/0.35 mL, 20 mg/0.4 mL, 22.5 mg/0.45 mL, 25 mg/0.5 mL,
27.5 mg/0.55 mL, and 30 mg/0.6 mL single-use auto-injectors.

8. Not FDA-approved for treatment of rheumatoid arthritis.
9. Some expert clinicians omit induction therapy because of GI intolerability.

Interstitial pneumonitis, which can be severe, occurs
in <1% of patients, but may be more common in
those with antecedent lung disease. An increase
in rheumatoid skin nodules and (rarely) cutaneous
necrotizing vasculitis have 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 patients with a
CrCl <30 mL/min.
Pregnancy – Methotrexate is teratogenic and should
not be prescribed for women who are or may become
pregnant. It is also an abortifacient and can decrease
fertility in both men and women. The drug should
be stopped for at least one ovulatory cycle before
conception in women and for at least 3 months in men.
HYDROXYCHLOROQUINE — The antimalarial hydroxychloroquine is moderately effective for mild RA and
is generally well tolerated. It is often used with other
drugs, particularly methotrexate and sulfasalazine.
A 48-week, randomized, double-blind trial in 353
patients with active RA despite methotrexate
therapy found that adding hydroxychloroquine and
sulfasalazine was noninferior to adding etanercept
(Enbrel) in improving disease activity scores.2
128

Adverse Effects – Nausea and epigastric pain can

occur, but serious adverse effects are rare. Hemolysis
may occur in patients with G6PD deficiency.
The most serious adverse effect of hydroxychloroquine is retinal toxicity with long-term use.
The risk is low in the first 5 years of use if the daily dose is ≤5 mg/kg.3 A complete ophthalmologic
exam is recommended before treatment to rule out
underlying retinal disease, and annual screening
should begin after 5 years.4 Early detection of toxicity can prevent loss of central vision.5
SULFASALAZINE — Sulfasalazine has been shown to
prevent joint erosions. It often requires 2-3 months
of therapy for beneficial effects to become apparent.
Sulfasalazine is frequently used with hydroxychloroquine
and methotrexate.
Adverse Effects – Nausea, anorexia, and rash are fairly
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 deficiency.
Sperm counts may decrease, but return to normal after
withdrawal of the drug.


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LEFLUNOMIDE — An oral inhibitor of pyrimidine
synthesis, leflunomide (Arava, and generics) can reduce
symptoms, limit joint damage, and improve function.6

Leflunomide and methotrexate have been used together,
but both are hepatotoxic, and concurrent use may
increase the risk.
Adverse Effects – Diarrhea occurs frequently
with leflunomide and is sometimes debilitating.
Reversible alopecia, rash, myelosuppression, and
aminotransferase elevations can also occur; complete
blood counts and liver function tests should be
monitored. Anaphylaxis, Stevens-Johnson syndrome,
weight loss, interstitial lung disease, peripheral
neuropathy, and leukocytoclastic vasculitis have
occurred rarely.
Pregnancy – Leflunomide is carcinogenic and
teratogenic in animals and is contraindicated for
use during pregnancy. Women who want to become
pregnant and men who want to father a child after
beginning treatment 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; plasma levels of the
active metabolite should then be checked to verify
that they are <0.02 mg/L. The same 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.
AZATHIOPRINE (Imuran, and others) is an
immunosuppressive 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.
BIOLOGIC AGENTS
Biologic agents are generally reserved for use in
patients with moderate to severe RA.
TNF INHIBITORS — Tumor necrosis factor (TNF) is a
pro-inflammatory cytokine present in the synovium of
patients with RA. Five parenteral drugs that bind to TNF
and block its activity are approved for treatment of RA
(Table 2). They relieve symptoms and are more effective
than methotrexate monotherapy in limiting joint
destruction. TNF inhibitors also act more quickly than
DMARDs; some patients report substantial improvement
after the first dose. Use of a TNF inhibitor in combination
with methotrexate has synergistic beneficial effects.

Vol. 56 (1458)

December 22, 2014

Adalimumab (Humira) is a recombinant human monoclonal antibody. It appears to be about as effective as
etanercept or infliximab when used with methotrexate.
Certolizumab pegol (Cimzia) is a pegylated Fab'
fragment of a humanized monoclonal antibody.7 The
pegylated structure increases its biologic half-life and
may possibly help target it to sites of inflammation.
Etanercept (Enbrel) is a recombinant human
fusion protein consisting of a soluble TNF receptor
covalently linked to a human IgG1 Fc fragment.

In patients who do not respond adequately to
methotrexate alone, addition of etanercept has been
effective in improving signs and symptoms of RA
and slowing joint damage.
Golimumab (Simponi, Simponi Aria) is a high-affinity
human monoclonal antibody.8 No clinical trials are
available comparing it directly with other TNF inhibitors
that have been in use longer, but it has been effective
in some patients who had not responded adequately
to infliximab or etanercept.9
Infliximab (Remicade) is a chimeric human/mouse
monoclonal antibody. Concurrent use of methotrexate
enhances its efficacy, possibly by inhibiting formation
of neutralizing antibodies against infliximab.
Adverse Effects – 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.
Patients treated with TNF inhibitors are at
increased risk for serious infections, including
reactivated
and
disseminated
tuberculosis,
invasive or disseminated fungal infection, and other
opportunistic infections, such as those caused by
Legionella and Listeria. Tuberculin skin testing

and chest radiography are recommended before
starting therapy. Inhibition of TNF has also been
associated with reactivation of hepatitis B virus in
patients who are chronic carriers; serologic testing
for active hepatitis B infection is recommended
before treatment.
Malignancies, especially lymphomas, have been
reported 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.
129


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December 22, 2014

Table 2. Some Biologic Agents for Rheumatoid Arthritis
Drug

Some Available Formulations

Usual Adult Dosage1

Cost2

Adalimumab – Humira (Abbvie)

10 mg/0.2 mL, 20 mg/0.4 mL syringe;
40 mg/0.8 mL prefilled pen and syringe

40 mg SC once/wk or q2 wks

$2913.60

Certolizumab pegol – Cimzia (UCB)

200 mg vial; 200 mg/mL syringe

Induction: 400 mg SC at 0, 2, and 4 wks
Maintenance: 200 mg SC every other
week or 400 mg q4 wks

2769.20

Etanercept – Enbrel (Amgen)

25 mg vial; 25, 50 mg/mL syringe;
50 mg/mL auto-injector

25 mg SC 2x/wk or 50 mg SC once/wk

2914.20

Golimumab3 – Simponi (Janssen)

50 mg/0.5 mL, 100 mg/mL syringe
and auto-injector
50 mg vial

50 mg SC once/month

2978.90

Induction: 2 mg/kg IV at 0 and 4 wks
Maintenance: 2 mg/kg IV q8 wks

1265.504

100 mg vial

Induction: 3 mg/kg IV at 0, 2, and 6 wks
Maintenance: 3 mg/kg IV q8 wks5

2784.704

Rituximab6 – Rituxan (Genentech)

100, 500 mg vials

1000 mg IV twice, 2 weeks apart7

14,099.20

Tocilizumab – Actemra (Genentech)

80, 200, 400 mg single-use vials

Induction: 4 mg/kg IV q4 wks
Maintenance: 8 mg/kg IV q4 wks

2251.00

162 mg/0.9 mL syringe

Induction: 162 mg SC every other week8
Maintenance: 162 mg SC once/wk

2728.40

250 mg vial

500, 750, or 1000 mg IV at 0, 2,
and 4 wks, then q4 wks9

125 mg/mL syringe

125 mg SC once/wk10

2914.70

Anakinra – Kineret (Sobi)

100 mg/0.67 mL syringe

100 mg SC once/d

3284.10

Tofacitinib11 – Xeljanz (Pfizer)

5 mg tabs

5 mg PO bid

2348.50

TNF Inhibitors

Simponi Aria
Infliximab3 – Remicade (Janssen)
Others

Abatacept – Orencia (BMS)

701.60

1. Dosage adjustment may be needed for hepatic or renal impairment.
2. Approximate WAC for 30 days’ treatment with the lowest usual maintenance dosage, and for a 70-kg patient treated with some parenteral drugs. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual
transactional price. Source: AnalySource® Monthly. December 5, 2014. Reprinted with permission by First Databank, Inc. All rights reserved. ©2014. www.
fdbhealth.com/policies/drug-pricing-policy.
3. FDA-approved only for use in combination with methotrexate.
4. Cost for 2 months' treatment.
5. Some patients may require higher doses (up to 10 mg/kg every 8 weeks) or more frequent (up to every 4 weeks) doses.

6. FDA-approved only for use with methotrexate in patients who have inadequate response to at least one TNF antagonist.
7. Patients can be retreated every 4-6 months. IV methylprednisolone 100 mg or its equivalent infused 30 minutes before rituximab can reduce the incidence and
severity of infusion reactions.
8. Every week for patients weighing ≥100 kg.
9. Dose is 500 mg for patients weighing <60 kg, 750 mg for patients 60-100 kg, and 1000 mg for patients >100 kg.
10. The first 125-mg SC injection is given within a day of an IV loading dose (see footnote 9).
11. A synthetic janus kinase inhibitor, technically not a biologic.

TNF inhibitors may rarely induce new-onset or
exacerbate pre-existing heart failure or induce a
reversible lupus-like syndrome. Demyelinating
conditions, 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.
Choice of a TNF Inhibitor – Patients who do not
respond to one TNF inhibitor may respond to another.
Some expert 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
130

short-lived. Others would start with infliximab,
and if it proves ineffective, would try etanercept or
adalimumab next.
OTHERS — 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 inadequate
responses to methotrexate and/or anti-TNF agents.10,11
Rituximab is FDA-approved for treatment of RA only
for use with methotrexate; concomitant use of another
biologic agent is not recommended.
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 leukoencephalo-


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pathy (PML) due to JC virus infection, which often
causes death or severe neurological disability,
and reactivation of hepatitis B infection. Patients
at high risk for hepatitis B should be screened for
the disease before starting treatment. An increased
risk of tuberculosis has not been observed
with rituximab.
Tocilizumab (Actemra) is a humanized monoclonal
antibody that competitively inhibits the binding of
the pro-inflammatory cytokine interleukin-6 (IL-6)
to its receptors.12 Clinical improvement has occurred
in some RA patients as early as two weeks after
the start of therapy. Tocilizumab monotherapy was
superior to adalimumab monotherapy in reducing
disease activity scores in one clinical trial.13 In

patients who have not responded adequately to
methotrexate, tocilizumab may be as effective as
combination therapy with methotrexate.14
Infusion reactions, hypertension, neutropenia, elevated
serum transaminases, and dyslipidemia can occur;
monitoring of blood counts and liver enzymes is
recommended. Severe complications including GI
perforation, serious infections, and hypersensitivity
with anaphylaxis have been reported in clinical trials.
Abatacept (Orencia) is a genetically engineered fusion
protein that interferes with T-cell activation.15 It can
be used as monotherapy or in combination with a
DMARD, but it should not be used concurrently with
other biologic agents.
Adverse events occurring within an hour after the
start of an abatacept infusion can include hypertension, headache, dizziness, and, rarely, anaphylactoid
reactions. Abatacept may increase the risk of serious
infections such as pneumonia, pyelonephritis,
cellulitis, and diverticulitis, but no clear association
with tuberculosis has been demonstrated.
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.1
Tofacitinib (Xeljanz), technically not a biologic, is an
oral inhibitor of Janus kinase (JAK), an important
signaling mediator in various immune activation
pathways.16 Added to methotrexate, its efficacy
appears to be comparable to that of adalimumab plus
methotrexate.17 In one clinical trial in 958 patients,

first-line treatment with tofacitinib monotherapy was
superior to methotrexate monotherapy in reducing
signs and symptoms of RA and in slowing the

Vol. 56 (1458)

December 22, 2014

progression of joint damage.18 Tofacitinib should not
be used concurrently with biologic agents.
Diarrhea, nasopharyngitis, upper respiratory infections, headache, and hypertension are the most
commonly reported adverse effects. Elevated hepatic
transaminases, dyslipidemia, and cytopenias have
been reported; periodic monitoring is recommended.
As with all immunosuppressive drugs, infections can
occur. Screening for tuberculosis infection is recommended before treatment. An increased incidence
of solid cancers was detected in short-term (≤12
months) clinical trials; the clinical significance of this
observation is unclear.
COMBINATION THERAPY
A combination of 2 or even 3 DMARDs or a DMARD
plus 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 clinical features that indicate a poor
prognosis, such as a positive rheumatoid factor
or anti-CCP test, functional limitations, extraarticular disease, or bony erosions. In one study in
methotrexate-refractory patients randomized to
addition of infliximab or addition of sulfasalazine and

hydroxychloroquine, radiographic progression after
24 months was less in the infliximab group.19 The
combination of methotrexate with a biologic agent
has been more efficacious than methotrexate alone in
achieving and maintaining remission.
Leflunomide used in combination with methotrexate
increases the risk of hepatotoxicity. Combining
different biologic agents increases the risk of infection
and is not recommended.
CORTICOSTEROIDS
Oral corticosteroids can relieve joint symptoms
and control systemic manifestations, but their
chronic use can cause many complications. 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,20 but most
clinicians do not use corticosteroids as DMARDs
because of the complications associated with long131


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term use. Use of corticosteroids in high doses may be
needed to control severe systemic manifestations of
RA, such as pericarditis or vasculitis, but with the use
of methotrexate and biologic agents, these are now
uncommon.
Intra-articular injection of a corticosteroid such as
triamcinolone (Aristospan) can often relieve an acutely
inflamed rheumatoid joint with minimal adverse
effects; injecting 1 or 2 joints in a patient who does
not have generalized disease is an underutilized way
of controlling the inflammatory process.
NSAIDS
NSAIDs have immediate analgesic and antiinflammatory effects. Because of the efficacy
of methotrexate alone or in combination with
a biologic agent, NSAIDs are now used mainly
as bridge drugs for relief of symptoms. 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.21 Aspirin 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 osteoarthritis, topical diclofenac 1% gel
(Voltaren Gel) may be helpful in some patients with
RA who have isolated symptomatic joints.22
VACCINATIONS
Before starting therapy with a DMARD or biologic
agent, all patients should be immunized against
influenza, pneumococcal disease, hepatitis B, and

herpes zoster.23 Live virus vaccines generally should
not be administered to patients taking a biologic
agent. ■
1. JA Singh et al. 2012 update of the 2008 American College
of Rheumatology recommendations for the use of diseasemodifying antirheumatic drugs and biologic agents in the
treatment of rheumatoid arthritis. Arthritis Care Res 2012;
64:625.
2. JR O’Dell et al. Therapies for active rheumatoid arthritis after
methotrexate failure. N Engl J Med 2013; 369:307.
3. RB Melles and MF Marmor. The risk of toxic retinopathy in
patients on long-term hydroxychloroquine therapy. JAMA
Ophthalmol 2014 October 2 (epub).
4. MF Marmor et al. Revised recommendations on screening
for chloroquine and hydroxychloroquine retinopathy.
Ophthalmology 2011; 118:415.
5. MF Marmor. Comparison of screening procedures in
hydroxychloroquine toxicity. Arch Ophthalmol 2012; 130:461.
6. 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.

132

Vol. 56 (1458)

December 22, 2014

7. Certolizumab (Cimzia) for Crohn’s disease. Med Lett Drugs
Ther 2008; 50:81.
8. Golimumab (Simponi) for inflammatory arthritis. Med Lett

Drugs Ther 2009; 51:55.
9. JS Smolen et al. Insights into the efficacy of golimumab plus
methotrexate in patients with active rheumatoid arthritis who
discontinued prior anti-tumour necrosis factor therapy: posthoc analyses from the GO-AFTER study. Ann Rheum Dis 2014;
73:1811.
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, double-blind, placebo-controlled, phase III trial
evaluating primary efficacy and safety at twenty-four weeks.
Arthritis Rheum 2006; 54:2793.
12. Tocilizumab (Actemra) for rheumatoid arthritis. Med Lett Drugs
Ther 2010; 52:47.
13. C Gabay et al. Tocilizumab monotherapy versus adalimumab
monotherapy for treatment of rheumatoid arthritis (ADACTA):
a randomised, double-blind, controlled phase 4 trial. Lancet
2013; 381:1541.
14. M Dougados et al. Adding tocilizumab or switching to
tocilizumab monotherapy in methotrexate inadequate
responders: 24-week symptomatic and structural results of
a 2-year randomised controlled strategy trial in rheumatoid
arthritis (ACT-RAY). Ann Rheum Dis 2013; 72:43.
15. Abatacept (Orencia) for rheumatoid arthritis. Med Lett Drugs
Ther 2006; 48:17.
16. Tofacitinib (Xeljanz) for rheumatoid arthritis. Med Lett Drugs
Ther 2013; 55:1.
17. RF van Vollenhoven et al. Tofacitinib or adalimumab versus
placebo in rheumatoid arthritis. N Engl J Med 2012; 367:508.
18. EB Lee et al. Tofacitinib versus methotrexate in rheumatoid

arthritis. N Engl J Med 2014; 370:2377.
19. RF van Vollenhoven et al. Conventional combination
treatment versus biological treatment in methotrexaterefractory early rheumatoid arthritis: 2 year follow-up of
the randomised, non-blinded, parallel-group Swefot trial.
Lancet 2012; 379:1712.
20. MF Bakker et al. Low-dose prednisone inclusion in a
methotrexate-based, tight control strategy for early rheumatoid
arthritis: a randomized trial. Ann Intern Med 2012; 156:329.
21. Drugs for pain. Treat Guidel Med Lett 2013; 11:32.
22. Diclofenac gel for osteoarthritis. Med Lett Drugs Ther 2008;
50:31.
23. Adult immunization. Treat Guidel Med Lett 2014; 12:39.

Coming Soon in The Medical Letter:
In Brief: Influenza in 2015
Oritavancin (Orbactiv) for Skin and Skin Structure Infections
Olodaterol (Striverdi Respimat) for COPD
A 3-Drug Combination (Triumeq) for HIV
In Brief: Siltuximab (Sylvant) for Treatment of Multicentric
Castleman’s Disease
Drugs for Chronic Heart Failure

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Issue 1458 Questions

(Correspond to questions #121-130 in Comprehensive Exam #71, available January 2015)
1. The DMARD generally used first to treat rheumatoid arthritis is:
a. methotrexate
b. hydroxychloroquine
c. sulfasalazine
d. leflunomide

6. Patients treated with TNF inhibitors are at risk for:
a. interstitial pneumonitis
b. pulmonary fibrosis
c. serious infections
d. all of the above

2. Methotrexate can cause:
a. hepatotoxicity
b. bone marrow suppression
c. interstitial pneumonitis
d. all of the above

7. A 44-year-old man with rheumatoid arthritis has not responded
to treatment with methotrexate plus etanercept (Enbrel). A
reasonable option for this patient would be to:
a. stop methotrexate and increase the dose of etanercept
b. continue methotrexate and substitute adalimumab
(Humira)
c. double the dose of methotrexate and monitor for hepatic
toxicity
d. none of the above

3. The most serious adverse effect of hydroxychloroquine is:
a. progressive multifocal leukoencephalopathy
b. retinal toxicity
c. bone marrow suppression
d. increased susceptibility to malaria
4. A 36-year-old woman with newly diagnosed rheumatoid arthritis
is 8 weeks pregnant. You would like to treat her with a DMARD.
Which of the following DMARDs should not be taken during
pregnancy?
a. methotrexate
b. leflunomide
c. azathioprine
d. all of the above

5. TNF inhibitors:
a. are more effective than methotrexate in limiting joint
destruction
b. have a slower onset of action than DMARDs
c. are unlikely to relieve symptoms
d. all of the above

8. Biologic agents other than TNF inhibitors:
a. should not be used concurrently with methotrexate
b. have been shown to increase the risk of leukemia
c. can be used instead of a TNF inhibitor in patients
who have not responded adequately to methotrexate
monotherapy
d. none of the above
9. Combinations of DMARDs or a DMARD plus a biologic agent are
used particularly for patients with:
a. highly active disease
b. recent onset of disease
c. a good prognosis
d. all of the above
10. Corticosteroids are used in rheumatoid arthritis:
a. in low doses for symptomatic relief until the beneficial
effects of DMARDs become apparent
b. in higher doses to control severe systemic manifestations
of RA
c. as intra-articular injections to relieve an acutely inflamed
rheumatoid joint
d. all of the above

ACPE UPN: Per Issue Exam: 0379-0000-14-458-H01-P; Release: December 22, 2014, Expire: December 22, 2015

Comprehensive Exam 71: 0379-0000-15-071-H01-P; Release: January 2015, Expire: January 2016

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical
School; Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller
University; David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital,
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Harvard Medical School; F. Estelle R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R.,
Weill Medical College of Cornell University
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