bDMARD according to the EULAR guidelines. However, TNF inhibitors have

been available on the market for longer and thus have more robust long-term safety

data, which may influence prescribers’ confidence in these agents. A TNF-α inhibitor

would be an appropriate choice in therapy for B.W. Her MTX therapy should be

continued with the selected anti-TNF agent.

CASE 44-7, QUESTION 7: Which TNF-α inhibitor should be started in patient B.W.?

There are five TNF-α inhibitors available for the treatment of RA including

etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab. While there

are multiple studies describing the efficacy and safety of these agents, there is no

consensus on the preferred initial TNF-α inhibitor. The use of each of these

medications as well as comparisons between them will be explored here.

TNF-α Inhibitors: Place in Therapy and Dosing

Etanercept (ETA) is the first biologic response modifier to be approved by the FDA

for reducing the signs and symptoms of moderate to severe active RA, either alone or

in combination with MTX.

44 ETA is a soluble TNF receptor that competitively binds

two TNF molecules, rendering both molecules inactive. It is self-administered once

weekly by subcutaneous injection at a dose of 50 mg.

44 ETA provides rapid and

significant improvement in subjective and objective measures of RA, either alone or

in combination with MTX.

43,137 The addition of ETA to MTX therapy has shown

greater clinical efficacy when compared with MTX monotherapy.

138 ETA has also

been shown to be superior to MTX as monotherapy in the reduction of RA symptoms

and disease activity.

139,140 ETA has demonstrated decreased radiographic progression

of RA as well as long-term safety and efficacy.

141,142 Etanercept is a reasonable

choice for B.W. and should be used in combination with MTX for best results.

Adalimumab (ADA) is a genetically engineered, fully humanized IgG1 monoclonal

antibody that has been shown to inhibit the structural damage of RA while reducing

clinical signs and symptoms. The recommended dose is 40 mg administered by

subcutaneous injection every other week. It is recommended to give ADA in

combination with MTX.

45 Patients who cannot or choose not to take MTX may

benefit from weekly dosing.

45 When ADA 40 mg every other week was added to the

treatment regimen of RA patients receiving stable MTX doses, significantly more

ADA-treated patients (67%) achieved an ACR-20 response than those receiving only

MTX (14.5%, p < 0.001) after 24 weeks.

143 Combination therapy with ADA and

MTX was shown to be superior to either MTX or ADA monotherapy for RA

symptoms and disease progression.

144

In radiographic data reflecting 1 or 2 years of

treatment, ADA has been shown to slow the progression of joint damage. Data also

support the long-term efficacy and safety of ADA for more than 8 years.

145 ADA

would also be an appropriate choice for B.W. and would require less frequent

injections than ETA.

Infliximab (IFX) is a chimeric (mouse–human) IgG antibody directed against TNF.

Specifically, IFX is approved in combination with MTX for the treatment of

moderate to severe active RA. The recommended dose is 3 mg/kg via intravenous

infusion at weeks 0, 2, and 6, then every 8 weeks thereafter. Some patients may

benefit from an increase in dose up to 10 mg/kg or a decrease in treatment interval to

as often as every 4 weeks.

46

IFX should be given with MTX therapy to prevent the

formation of antibodies to infliximab. In a randomized, double-blind, multicenter,

placebo-controlled trial of active RA patients who failed to respond adequately to at

least 12.5 mg/week of MTX, IFX 3 or 10 mg/kg or placebo was administered every

4 or 8 weeks along with MTX therapy. The signs and symptoms of RA were

improved in the IFX groups versus MTX alone. This study was unblinded after 1

year because of radiographic evidence of disease modification in patients receiving

IFX. Analysis of radiographic results after 2 years demonstrated that IFX

significantly protected against joint erosion.

146

IFX would also be an appropriate

bDMARD for B.W., particularly if she prefers less frequent intravenous infusions to

self-administration of subcutaneous injections. Patient preferences are an important

factor to consider when choosing between the anti-TNF agents.

Certolizumab pegol (CZP) consists of a Fab attached to a 40-kDa PEG moiety.

The attachment to the PEG moiety increases the half-life of CZP to approximately 2

weeks, which allows dosing every 2 to 4 weeks.

147 The recommended dosing

regimen is 400 mg initially and at weeks 2 and 4 followed by 200 mg every other

week or 400 mg every 4 weeks by subcutaneous injection.

47 CZP’s unique structure

lacks an Fc region, so it may not induce complement- or antibody-dependent cellmediated cytotoxicity, which has been observed in vitro with adalimumab,

etanercept, and infliximab.

148 The efficacy of CZP has been demonstrated in patients

with moderate to severe active RA in combination with MTX and as

monotherapy.

149–151

In a randomized, double-blind, placebo-controlled study in 619

patients with active RA, significantly more patients met ACR response rates with

CZP plus MTX than patients treated with placebo plus MTX (p < 0.001).

150 Physical

function, as evidenced by the mean change in the HAQ disability index (DI) score,

DAS28 remission, and radiographic progression of RA were all improved in the

CZP plus MTX group.

150 CZP has shown sustained efficacy and safety over 5 years in

patients with active RA.

152 Patient B.W. would also be a candidate for CZP. As with

ETA and ADA, CZP is self-administered by subcutaneous injection.

Golimumab (GLM) is a human IgG1 monoclonal antibody specific for human

TNF-α. It was created using genetically engineered mice immunized with human

TNF. GLM binds to both the soluble and the transmembrane bioactive forms of

human TNF. This binding prevents the binding of TNF-α to its receptors, thus

inhibiting the biologic activity of TNF-α.

49 GLM shares common characteristics with

both adalimumab and infliximab. Similar to adalimumab, GLM is a fully humanized

bivalent immunoglobulin monoclonal antibody.

153 GLM is made up of light and heavy

chains, which are identical to infliximab, but whereas infliximab is derived from

both mice and humans, GLM is completely humanized. GLM is approved for the

treatment of moderate-to-severe active RA in combination with MTX.

49

It can be

administered by subcutaneous injection or intravenous infusion. The subcutaneous

injection is a 50 mg injection dosed every 4 weeks.

49 The dose of the intravenous

infusion is 2 mg/kg over 30 minutes as weeks 0 and 4, then every 8 weeks

thereafter.

154 Clinical trials have demonstrated GLM efficacy in patients with no

previous MTX use and in patients with an inadequate response to MTX or a TNF-α

inhibitor.

155–157 A randomized, placebo-controlled trial conducted in 444 patients

examined the efficacy of GLM in patients with active RA despite concomitant MTX

use.

158 Significantly, more patients in the combined GLM plus MTX group achieved

an ACR-20 response compared with the MTX plus placebo group (55.6% vs. 33.1%,

respectively, p < 0.001), and these results were sustained at 52 weeks.

158

In another

study assessing the long-term safety and efficacy of GLM in RA patients who

discontinued previous TNF-α inhibitors, GLM treatment resulted in sustained

efficacy and safety through 5 years.

158 Given this information, GLM would also be an

appropriate treatment option for B.W., and she would have the option of choosing

between intravenous or subcutaneous dosing.

There are currently no definitive guidelines recommending one TNF-α inhibitor

over another. Direct head-to-head comparisons between the anti-TNF agents are

lacking; therefore, prescribers must depend on surveillance data, systematic reviews,

and meta-analyses to make clinical decisions regarding comparative efficacy and

safety.

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Table 44-7

Biologic Disease-Modifying Antirheumatic Drug Dosing Information

Generic

(Brand)

Mechanism of

Action Dosage Range

Administration

Schedule

Routes of

Administration

Can Be SelfAdministered?

Infliximab

(Remicade)

TNF-α inhibitor 3 mg/kg

a Weeks 0, 2, and

6 and then every

8 weeks

IV No

Etanercept

(Enbrel)

TNF-α inhibitor 50 mg Weekly SC Yes

Adalimumab

(Humira)

TNF-α inhibitor 40 mg Every 14 days SC Yes

Certolizumab

pegol (Cimzia)

TNF-α inhibitor Initial: 400 mg

SC on weeks 0,

2, 4

Subsequent: 200

mg every 2

weeks or 400 mg

Weeks 0, 2, and

4, then every 2 or

4 weeks

SC Yes

every 4 weeks

Golimumab

(Simponi)

TNF-α inhibitor 50 mg Every 4 weeks SC Yes

Golimumab

(Simponi Aria)

TNF-α inhibitor 2 mg/kg infusion

over 30 minutes

Weeks 0 and 4,

then every 8

weeks

IV No

Abatacept

(Orencia)

Costimulation

modulator, T cell

activation

inhibitor

Weight based:

<60 kg = 500 mg

60–100 kg = 750

mg

>100 kg = 1,000

mg

Weeks 0, 2, and

4 and then every

4 weeks

IV No

Or

125 mg Once weekly

(may be initiated

with or without

IV loading dose)

SC Yes

Rituximab

(Rituxan)

CD20+ B-cell

inhibitor

1,000 mg IV

infusion:

Initial: 50

mg/hour, may

increase every

30 minutes to a

maximum rate of

400 mg/hour

Subsequent: 100

mg/hour, may

increase every

30 minutes to

maximum rate of

400 mg/hour

b

Repeat in 14

days, then

discontinue

IV No

Tocilizumab

(Actemra)

IL-6 inhibitor Initial: 4 mg/kg

every 4 weeks

Subsequent:

Titrate to 8

mg/kg based on

clinical response

Max: 800

mg/dose (8

mg/kg)

Every 4 weeks IV No

Or

Weight based SC

dosing:

<100 kg= 162 mg

every other

week, followed

by an increase to

every week

based on clinic

response

≥100 kg = 162

mg every week

SC Yes

Anakinra

(Kineret)

IL-1 inhibitor 100 mg Once daily SC Yes

aFor incomplete response, may increase dose to 10 mg/kg or decrease dosing interval to every 4 weeks.

bPremedicate with corticosteroid, acetaminophen, and an antihistamine before each dose.

Source: Drug Facts and Comparisons. Facts & Comparisons eAnswers [database online]. St. Louis, MO: Wolters

Kluwer Health, Inc. Updated periodically. Accessed August 4, 2015.

IL, interleukin; IV, intravenous; SC, subcutaneous; TNF, tumor necrosis factor.

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In a mixed treatment comparison of the anti-TNF agents, all of the agents

demonstrated significant improvement in clinical response across all outcome

measures. However, etanercept and certolizumab demonstrated improved outcomes

compared to infliximab, adalimumab, and golimumab. All anti-TNF agents were

found to be superior to infliximab.

160 Evidence from national registries have also

provided insight into the differences among TNF-α inhibitors in clinical practice.

Patients in the Czech National Registry had higher survival rates when treated with

adalimumab and etanercept compared to infliximab.

161 Data from the Danish and

Swedish national registries have shown the drug continuation rates were significantly

higher with etanercept and adalimumab than with infliximab.

145,162,163

In a metaanalysis of Cochrane reviews of six biologics for RA (abatacept, adalimumab,

anakinra, etanercept, infliximab, and rituximab), it was found that etanercept was

associated with lower rates of withdrawal because of adverse events than either

adalimumab or infliximab, and the survival rates with adalimumab and etanercept

were better than with infliximab.

164 Given this data, etanercept would be an

appropriate choice for B.W. as initial therapy with a bDMARD. Systematic reviews

seem to demonstrate that etanercept is well-tolerated in comparison to other

bDMARDs and has been associated with superior efficacy. Given no other patient

specific factors to guide therapy toward another agent, etanercept would be an

appropriate option. (Dosing information for the TNF-α inhibitors can be found in

Table 44-7.)

CASE 44-7, QUESTION 8: What side effects will need to be monitored when starting B.W. on etanercept?

TNF-α Inhibitors: Side Effects and Monitoring

The greatest concern with etanercept therapy is the risk of immunosuppression and

subsequent serious infections, including sepsis. TNF-α is a key mediator of

inflammation and plays a major role in immune system regulation. Post-marketing

reports of infections, such as TB, mycobacterial infections, and fungal infections,

further reinforce the strong recommendation against the initiation of etanercept

therapy in patients with sepsis or any chronic or localized active infection.

44

Mycobacterium tuberculosis skin testing and a baseline chest radiograph should be

undertaken before initiation of anti-TNF therapy. Therapy should be postponed for

patients identified as having latent TB until appropriate antituberculosis therapy has

been completed.

28 Clinicians also must be cautious when prescribing etanercept (or

any bDMARD) to patients with a history of recurring infection or with underlying

illnesses that predispose them to infection (i.e., diabetes). B.W. should receive a TB

skin test, undergo a chest radiograph, and be warned of the potential adverse effects

of etanercept, particularly the risk of immunosuppression and subsequent infection.

Any sign of infection must be reported immediately to her health care provider.

TNF-α has been implicated in the pathophysiology of heart failure, and increased

serum levels of TNF-α seem to be associated with worsening heart failure.

165

Proposed mechanisms contributing to the onset or worsening of heart failure include

accelerated left ventricular remodeling, negative inotropic effects, and increased

apoptosis of myocytes and endothelial cells. However, despite the association

between TNF-α and worsening of heart failure, clinical trials with anti-TNF therapy

(which have included etanercept and infliximab) have not reduced mortality and heart

failure–related hospitalizations. Furthermore, some trials have shown increased

cardiovascular risk.

165 As a result, anti-TNF therapy is not recommended for RA

patients with moderate-to-severe (New York Heart Association [NYHA] class III

and IV) heart failure. Anti-TNF therapy can be used with caution in patients with

mild (NYHA class I and II) heart failure, but patients should be closely monitored for

cardiac decompensation.

26,28

Included in the labeling for all anti-TNF bDMARDs is a warning for increased

risk of lymphoma. An increased incidence of lymphoma has been observed among

patients with RA receiving any of the available anti-TNF agents; however, causation

has not been established because both RA and MTX are associated with an increased

rate of lymphoma. In an observational study assessing the risk of lymphoma in

patients treated with csDMARDs compared to patients treated with anti-TNF agents,

there was no evidence of an increased risk in the anti-TNF cohort.

166 A meta-analysis

of patients receiving anti-TNF agents suggested a possible increase in incidence of

lymphoma; however, given the low incidence of lymphoma overall, this failed to

reach statistical significance.

167 Additionally, the FDA has issued a warning

following reports of hepatosplenic T-cell lymphoma, a rare cancer of the white

blood cells, in patients being treated with TNF blockers, AZA, or mercaptopurine.

168

The majority of these cases were found in adolescents and young adults with Crohn’s

disease or ulcerative colitis. Incidence was also more common in patients on a

combination of immunosuppressive agents. Although it is difficult to measure the

added risk associated with anti-TNF agents, caution and monitoring is advised.

168

Other adverse effects, in order of decreasing frequency, include headache, rhinitis,

dizziness, pharyngitis, cough, asthenia, abdominal pain, and rash.

CASE 44-8

QUESTION 1: S.K., a 71-year-old woman, was diagnosed with RA approximately 15 years ago. Her initial

drug therapy included MTX, followed by the addition of SSZ and HCQ, which seemed to keep her RA in nearremission for 5 years. She then began etanercept along with MTX (without SSZ and HCQ) with good results

until 1 year ago. In response to declining disease control, infliximab was substituted for etanercept with

excellent results. Then last month, she experienced a flare in RA activity. At that time, her CRP was 5.1

mg/dL, ESR was 90 mm/hour, and anti-CCP was positive at 112 units. She also experienced morning stiffness

lasting several hours and multiple joints with swelling (n = 26) and tenderness (n = 38). Of note, S.K. has a

history of treated skin melanoma 2 years ago. What are the reasonable treatment options for S.K. at this stage

of her disease?

Clinical studies have consistently demonstrated that bDMARDs improve the signs

and symptoms of RA as well as slow the progression of structural damage. TNF-α

inhibitors have long been considered first-line bDMARDs given the availability of

long-term data and clinical experience compared to the non-TNF bDMARDs.

However, ongoing registry and trial data suggests that the safety profiles of the nonTNF bDMARDs, abatacept, rituximab, and tocilizumab, are consistent with clinical

trial results.

26 Some trials have shown superiority of some of these agents over

TNF-α inhibitors. TNF-α inhibitors also fail to produce an ACR-20 response in

approximately 30% of patients, which is known as primary failure. Even more

patients experience acquired resistance to treatment, known as secondary failure,

which is defined as a loss of response with time and is illustrated by S.K.

169 Many

patients who lose responsiveness to an initial trial of anti-TNF therapy can be

successfully treated with an alternative anti-TNF agent.

170 However, studies have

also shown that response rates with sequential anti-TNF therapy may be lower and

the reasons for initial anti-TNF failure (inefficacy or adverse effects) may be

recurrent.

170,171 Therefore, it is important to consider alternative options for the

treatment of patients like S.K. with anti-TNF treatment failure.

170,171

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Abatacept (inhibitor of T-cell activation), rituximab (selective depletor of CD20+

B cells), and tocilizumab (anti-IL-6 receptor antibody) have demonstrated excellent

efficacy in patients with inadequate response to csDMARDs (e.g., MTX) as well as

to anti-TNF therapy.

26,28 Owing to their differing mechanisms of action, each of these

agents possesses unique qualities with regard to efficacy and safety. (Detailed dosing

information for the bDMARDs can be found in Table 44-7.)

Abatacept

Abatacept (ABT) is a selective costimulation inhibitor of T-cell activation indicated

for the treatment of moderate to severe active RA.

52 ABT may be prescribed as

monotherapy or in combination with csDMARDs. It can be administered

intravenously or subcutaneously. ABT intravenous dosing is based on body weight

(500 mg for patients <60 kg, 750 mg for patients 60–100 kg, and 1,000 mg for

patients >100 kg) and should be infused over 30 minutes at weeks 2 and 4 after the

first dose, then every 4 weeks thereafter.

52 The dose for the subcutaneous injection is

125 mg weekly. The efficacy and safety profiles have been shown to be comparable

between the two preparations.

172

Abatacept has demonstrated efficacy in patients with an inadequate response to

MTX as well as in patients with an inadequate response or adverse reactions to

TNF-α inhibitors.

52

In a study comparing ABT plus MTX to placebo plus MTX,

significantly more patients in the ABT plus MTX group attained ACR-20 response

when compared with the ABT plus placebo group (73.1% vs. 39.7%, respectively, p

< 0.001) and had significant slowing of structural damage progression compared to

the patients treated with placebo at 12-month follow-up.

53 ABT efficacy was

maintained in the 5-year open-label extension of this trial. Structural damage

progression was reduced by 50% in the second year relative to the first year, with

approximately half of the patients who completed all 5 years of ABT treatment

exhibiting no structural damage progression.

173 Efficacy and safety data from 7 years

of ABT therapy indicate that ABT maintains sustained improvements in disease

activity and ACR-70 scores during this period, with no change in safety profile.

174

ABT has also demonstrated efficacy in patients with an inadequate response to one

or more TNF-α inhibitors, such as S.K.

175,176

Finally, ABT has also been compared head-to-head with the TNF-α inhibitor

adalimumab. In a 2-year study in RA patients with an inadequate response to MTX,

ABT and ADA were found to be similar in both efficacy and safety. Overall, patients

experienced similar improvement in clinical markers of disease control and

progression. While rates of adverse events in both groups were similar, there were

more discontinuations because of adverse events in the ADA group (9.5%) compared

to the ABT group (3.8%) (95% CI −9.5 to −1.9).

177

The side effects of greatest concern with ABT include infections such as

pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, and acute

pyelonephritis. Infections are significantly more common when ABT is combined

with anti-TNF therapy; thus, this combination is not recommended.

52 A few case

reports of malignancy have been associated with ABT, and patients with chronic

obstructive pulmonary disease are noted to suffer from more respiratory-related and

nonrespiratory-related adverse effects than patients with chronic obstructive

pulmonary disease treated with placebo.

52

Rituximab

Rituximab (RXB) is a chimeric monoclonal antibody that binds to the antigen CD20

on B cells. It is approved in combination with MTX for the treatment of moderate to

severe active RA in patients who have had an inadequate response to one or more

TNF antagonist medications.

54 However, according to the EULAR guidelines,

rituximab may be considered as a first-line bDMARD in patients with

contraindications to other bDMARDs, such as recent history of lymphoma, latent TB

with contraindications to chemoprophylaxis, living in a TB-endemic areas or a

previous history of demyelinating disease.

26 RXB, provided in 100- and 500-mg

single-use vials at a concentration of 10 mg/mL, is administered as two 1,000-mg IV

infusions separated by 2 weeks.

54 RXB must be diluted to a final concentration of 1

to 4 mg/mLwith either 0.9% sodium chloride or 5% dextrose in water. To reduce the

incidence and severity of infusion-related adverse effects, premedication with IV

methylprednisolone 100 mg, or its equivalent, 30 minutes before each infusion is

strongly recommended; other premedications (e.g., acetaminophen and antihistamine)

may also be beneficial. Antihypertensive medications should be discontinued 12

hours before RXB administration to avoid transient hypotension, which has been

reported during RXB infusions. RXB must be given with MTX for maximal efficacy

based on clinical trials and to help reduce the risk of developing HACA, which

occurs in approximately 9% of patients receiving RXB. It is recommended that

subsequent courses of RXB be given every 24 weeks. The dosing interval may be

decreased on the basis of clinical evaluation, but must be no less than every 16

weeks.

54

Rituximab has been shown to be effective in patients who have responded

inadequately to MTX therapy as well as in patients who have responded

inadequately to anti-TNF medications.

178 The REFLEX (Randomized Evaluation of

Long-Term Efficacy of Rituximab in RA) trial evaluated the use of RXB plus MTX

versus placebo plus MTX in 499 patients with active, long-standing RA who

responded inadequately to one or more anti-TNF medications, such as S.K.

179 At 24-

week follow-up, significantly more patients in the RXB group demonstrated an ACR20 response than those in the placebo group (51% vs. 18%, respectively). And in a

56-week follow-up report of the REFLEX trial, RXB significantly inhibited

radiographic progression of joint damage.

180

In the 2-year extension of this trial, RXB

showed significant and sustained inhibition of joint damage. These findings support

the efficacy and appropriateness of RXB for RA patients, such as S.K., who are

refractory to anti-TNF therapy.

In the case of failure with one TNF-α inhibitor, patients may be switched to

another anti-TNF agent or to a non-TNF agent. While there are no randomized

controlled trials providing head-to-head comparisons between switching to rituximab

versus a second anti-TNF agent, there are some observational studies to guide

therapy. In the SWITCH-RA trial, a global, observational, comparative effectiveness

study, rituximab was compared to an alternative TNF inhibitor in patients with RA

with a previous inadequate response to one TNF inhibitor. It was found that the

change in DAS28-3-ESR at 6 months was significantly greater in the rituximab

patients versus the second TNF inhibitor patients (−1.5 vs. −1.1; p = 0.007).

However, this difference only remained significant for the patients who discontinued

the initial TNF inhibitor because of inefficacy, but not in those who discontinued

because of intolerance.

181 Similar results have been found in other observational

studies of initial TNF nonresponders.

182 Clinicians should consider reasons for

treatment failure, potential side effects, route of administration, ease of use, cost and

patient specific factors when choosing an appropriate therapeutic regimen. There is

currently no definitive investigation or recommendation for sequencing of

bDMARDs. There is a randomized controlled trial underway comparing ABT, RXB,

and other anti-TNF therapy following anti-TNF failure, which is expected to provide

further insight upon completion.

183

Infusion reactions, including severe reactions, can be caused by RXB. Severe

reactions typically occur with the first infusion; thus, careful monitoring is warranted

and premedication with methylprednisolone 100 mg or its equivalent is

recommended 30 minutes prior to each infusion. RXB should be discontinued if

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a serious reaction occurs. Severe mucocutaneous reactions may also occur in

patients receiving RXB. Finally, hepatitis B (HBV) reactivation may occur in

patients receiving RXB. Therefore, all patients should be screened for HBV infection

prior to initiation. The most common adverse reactions in RA patients receiving

RXB include upper respiratory tract infections, nasopharyngitis, urinary tract

infections, and bronchitis.

54 RXB has not been associated with any increase in

malignancy; therefore, it is preferred over anti-TNF agents in patients with a recent

history of cancer.

26

Since S.K. failed two TNF- inhibitors because of inefficacy, either ABT or RXB

would be an appropriate choice. Given S.K.’s history of skin melanoma 2 years ago,

RXB would be the preferred agent over ABT in this patient.

CASE 44-9

QUESTION 1: Q.O. is a 55-year-old woman with highly active RA for the past year who cannot tolerate

MTX therapy. Her doctor would like to start a bDMARD as monotherapy and would like to know which

medication would be best?

Tocilizumab

Tocilizumab is a humanized anti-IL-6 receptor antibody indicated for the treatment of

adult patients with moderate to severe active RA, who have had an inadequate

response to one or more csDMARDs.

57 TCZ may be administered intravenously or

subcutaneously. For the intravenous infusion, the recommended dosage is 4 mg/kg,

infused IV every 4 weeks with an increase to 8 mg/kg as needed based on clinical

response. The dosing for the subcutaneous formulation is 162 mg per injection either

weekly or every other week depending on patient weight and response.

57 The safety

and efficacy of the intravenous and subcutaneous formulations have been studied and

appear to be comparable. However, an increase in injection site reactions in the

subcutaneous TCZ group has been seen.

184 TCZ should not be initiated in patients

with an absolute neutrophil count less than 2,000 cells/μL, platelet count less than

100,000 platelets/μL, or in patients who have an ALT or AST value greater than 1.5

times the ULN.

57 TCZ treatment should be interrupted if a patient experiences a

serious infection; therapy may be resumed once the infection is controlled.

57

TCZ has demonstrated efficacy in the treatment of RA as monotherapy, in

combination with csDMARDs, and in patients who are refractory to anti-TNF

medications.

185,186

In a systematic review of eight RCTS, TCZ at a dose of 8 mg/kg in

combination with MTX was shown to statistically significantly decrease disease

activity and improve physical function when compared to MTX plus placebo.

187 TCZ

has also shown decreased radiographic progression of RA compared to

csDMARDs.

185,188

In the RADIATE trial, patients with an inadequate response to one

or more TNF-α inhibitors were randomly assigned to receive 8 or 4 mg/kg of TCZ or

placebo every 4 weeks for 24 weeks.

186 An ACR-20 response was achieved at 24

weeks by 50.0%, 30.4%, and 10.1% of patients in the TCZ 8 mg/kg, 4 mg/kg, and

placebo arms, respectively (p < 0.001).

186 Given this information, TCZ would also

be a reasonable option for patients who have failed one or more TNF inhibitors, like

S.K. from Case 44-8.

Tocilizumab is also approved as monotherapy for RA. In the AMBITION trial,

TCZ monotherapy compared to MTX monotherapy and TCZ therapy was found to

have a superior ACR 20 response (69.9% vs. 52.5%; p < 0.001) and DAS28 <2.6

rate (33.6 vs. 12.1%) at week 24.84. In a study comparing TCZ 8 mg/kg plus MTX,

TCZ 4 mg/kg plus MTX, TCZ 8 mg/kg monotherapy, and MTX monotherapy, all

groups containing TCZ showed superior DAS28 remission compared to MTX alone.

However, only the TCZ 8 mg/kg plus MTX group had consistent superiority in

clinical, functional, and radiographic outcomes.

85

According to the ACR and EULAR treatment guidelines, the standard of care

indicates that patients should maintain MTX or csDMARD therapy when a bDMARD

is added.

26,28 However, for up to 40% of patients, MTX therapy is discontinued

because of intolerance or patient preference and as many as one-third of patients may

be taking bDMARDs as monotherapy.

86 Three of the TNF inhibitors (etanercept,

adalimumab, and certolizumab pegol) and two of the non-TNF bDMARDs (abatacept

and tocilizumab) are approved as monotherapy. In a study comparing ADA and TCZ

monotherapy in patients who were either intolerant to MTX or MTX was not an

appropriate treatment option, patients in the TCZ group were found to have

significantly greater improvement in DAS28 as well as most clinical endpoints when

compared to the ADA group.

86 Therefore, TCZ is a reasonable therapeutic option for

Q.O. as monotherapy for RA and has demonstrated superiority over at least one antiTNF agent.

186,188

When starting TCZ, Q.O. should be monitored for potential side effects. The most

serious side effects associated with TCZ therapy include severe infections, GI

perforation, and laboratory abnormalities. As with the TNF-α inhibitors, TCZ has a

boxed warning for increased risk of developing serious infections, especially those

caused by opportunistic pathogens. The risk for infection is increased when TCZ is

taken in combination with other immunosuppressant agents (e.g., MTX and

corticosteroids). As with the anti-TNF agents, a TB skin test result and chest

radiograph must be obtained before initiating treatment. In clinical studies the overall

rate of fatal serious infections was low at 0.13/100 patient-years.

57

TCZ has also been associated with a number of blood chemistry changes including

neutropenia, thrombocytopenia, elevated LFTs, and lipid changes. Increases in lipids

(total cholesterol, low-density lipoprotein, high-density lipoprotein, and

triglycerides) have been shown in clinical trials. Increase in lipids may be caused in

part by the decrease in inflammatory activity with TCZ use. Lipid elevations respond

to lipid-lowering agents. While clinical trials do not indicate an increase in

cardiovascular risk, further studies are necessary to assess the effects of TCZ on

cardiovascular risk factors.

189,190

CORTICOSTEROIDS

CASE 44-10

QUESTION 1: W.M., a 57-year-old man, has progressive RA that has not been responsive to SSZ. He is

having difficulty working a full day and is seeking an alternative medication. After a discussion of therapeutic

options, W.M. declines MTX therapy and asks to start HCQ. Would it be appropriate to initiate corticosteroids

concurrently? And if so, at what dose?

Despite the potential for serious adverse effects with long-term therapy, the

judicious use of low-dose corticosteroids represents an important component of

treatment during the course of unremitting disease. In addition, low-dose

corticosteroids may offer some disease-modifying properties, although this is

controversial because of the long-term negative effects of corticosteroid use.

65 The

benefit of low-dose glucocorticoid therapy is favorable as long as the course of

therapy is short.

28 Considering that W.M.’s RA is sufficiently active to compromise

his ability to earn an income, MTX is a much better DMARD selection. Regardless,

concurrent initiation of a DMARD and an intermediate-acting corticosteroid (e.g.,

prednisone in a daily or divided dose of 5–10 mg) is justified.

191 A Cochrane review

showed that corticosteroid doses equivalent to ≤15 mg of prednisolone were

superior to placebo and NSAIDS for joint tenderness and pain in RA.

192

In large

cohort studies, prednisone doses greater than 7.5 mg/day

p. 899

p. 900