TNF Inhibitors vs New Biologics for the Treatment of Inflammatory Joint Diseases - An Expert Interview With Kay, MD

[Guest guest]

Tumor Necrosis Factor Inhibitors vs New Biologics for the Treatment of

Inflammatory Joint Diseases: Evidence on Safety and Efficacy -- An Expert

Interview With Kay, MD

NOTE: To view the article with Web enhancements, go to:

http://www.medscape.com/viewarticle/578027

Kay, MD, FACP, FACR

Medscape Rheumatology. 2008; ©2008 Medscape Posted 07/31/2008

Editor's Note:

The clinical picture seen in rheumatoid arthritis (RA) is the result of a

complex cascade involving antigen-presenting cells, the major

histocompatibility complex class II proteins, and a complex set of

costimulation signals, which lead to the production of proinflammatory

cytokines. Biologic therapies targeted at tumor necrosis factor (TNF)-alpha

were the first generation of biologic therapies for RA. Due to shortcomings

of anti-TNF-alpha therapies, recent advances have witnessed the development

of new biologic therapies that target different components of the

intracellular cascade as well as a new generation of anti-TNF agents. New

therapies offer increased therapeutic choices for all patients with RA.

In this interview, Helen Fosam, PhD, Medscape Rheumatology, spoke with

Kay, MD, FACP, FACR, Associate Clinical Professor of Medicine,

Harvard Medical School, Boston, Massachusetts, on the recent advances with

biologic agents targeted at TNF, as illustrated by data presented at the

2008 European League Against Rheumatism (EULAR) meeting.

Medscape: Since the US Food and Drug Administration (FDA) approval and

introduction of anti-TNF agents in the clinical setting, what is your

perspective on their significance and contribution to the treatment of RA?

Dr. Kay: Prior to the availability of anti-TNF agents, patients with RA were

treated with methotrexate and other disease-modifying antirheumatic drugs.

Many patients with RA responded quite well to methotrexate; at that time,

the doses of methotrexate used were lower than the typical doses used today.

However, there were still patients with RA who did not respond adequately to

methotrexate or other available options.

Before anti-TNF therapies were available, these patients had no effective

alternative treatment for their disease. However, with the availability of

anti-TNF therapies infliximab and etanercept and then subsequently

adalimumab, drugs were available that allowed control of disease activity in

more patients with RA. The anti-TNF agents are extremely effective agents

for the treatment of RA, they are relatively safe and well tolerated, and

these agents have dramatically revolutionized the treatment of patients who

responded inadequately to methotrexate. They have also shown significant

benefit in limiting radiographic progression of disease above and beyond

that which has been achievable with methotrexate alone and other traditional

disease-modifying antirheumatic drugs.

Medscape: Of the 3 anti-TNF agents currently FDA-approved for RA, what is

the latest on their long-term safety and efficacy as presented by data at

EULAR 2008?

Dr. Kay: At the EULAR meeting in Paris, data were presented that showed

continued efficacy of each of the 3 anti-TNF agents over the long term.

There were interesting data presented about safety. For example, the

meta-analysis presented by Mines and colleagues[1] demonstrated that there

was an increased relative risk of malignancy in patients treated with

etanercept. But this was comparable to the increased risk of malignancy that

was observed in the meta-analysis by Bongartz and colleagues[2] of

infliximab and adalimumab published in 2006.

The study by Mines and coworkers[1] showed that there was an increased

occurrence of tuberculosis among patients with RA who were not being treated

with TNF antagonists. The significance of this is that the reactivation of

tuberculosis may not be an effect only occurring with TNF antagonists.

However, the risk of reactivation of tuberculosis certainly is increased

when patients are treated with any of the TNF antagonists.

The study by -Zafrilla and colleagues,[3] looking at the Biobadaser

Spanish registry, compared the incidence of herpes zoster in patients with

RA treated with biologic agents vs other registries of patients not treated

with biologic agents. The results showed a higher incidence of herpes zoster

among patients treated with biologic agents. This finding is of relevance to

rheumatologists because the older RA patient population is at greater risk

for herpes zoster, and we have to be careful and vigilant for this potential

complication when we use anti-TNF therapy in these patients.

Finally, the study presented by Bongartz and colleagues[4] investigating the

incidence of malignancy with etanercept showed that there was an increased

occurrence of lymphoma among patients treated with etanercept, but it was

not clearly different from the incidence of lymphoma in patients with RA not

treated with a biologic agent. The study also showed that there was an

increased occurrence of squamous cell carcinoma among patients with

psoriasis who were treated with etanercept, but again nothing unexpected was

uncovered.

Medscape: What are the limitations of current FDA-approved anti-TNF agents

that have led to the development of new anti-TNF agents?

Dr. Kay: Each of the currently available anti-TNF agents are effective in

many patients, but not in all patients with RA. Each of the agents at best

achieves about a 70% ACR-20 clinical response in clinical trials when used

in patients who have responded inadequately to methotrexate.

There is a need for other agents to treat RA disease activity, particularly

among patients who are inadequately responsive to each of the currently

available anti-TNF agents. Also, the administration of the currently

available agents requires either weekly or every-other-week subcutaneous

dosing, or intravenous dosing every 4-8 weeks. This dosing schedule can be

relatively inconvenient for some patients, so newer therapies can offer the

opportunity for less frequently dosed medications with similar efficacy in

patients who have not adequately responded to the currently available

agents.

Medscape: With regard to safety and efficacy, were there new data presented?

Dr. Kay: Very much so. Efficacy data on certolizumab pegol, or Cimzia, were

presented last year at EULAR and the ACR meeting; the RAPID I and RAPID II

trials[5,6] demonstrated that certolizumab pegol in methotrexate-inadequate

responders was more effective than placebo, with ACR-20 response of

approximately 32% greater for certolizumab pegol compared with placebo.

Several data were presented this year at EULAR that showed that at 24 weeks

and at 52 weeks, certolizumab pegol in combination with methotrexate was

effective in significantly reducing the progression of structural joint

damage as well as improving physical function and work performance in RA

patients.[7-10] Furthermore, the safety and efficacy of certolizumab pegol

as monotherapy or in combination with methotrexate was

demonstrated.[6,11,12]

The EULAR meeting was also notable for the data presented for golimumab,

which is a fully human monoclonal antibody against TNF. The potential

advantage of golimumab is that it is being dosed subcutaneously once monthly

in clinical trials and in patients who were previously using but had

discontinued anti-TNF-alpha therapy.[13]

Several clinical trials with golimumab are in progress; for example, the

GO-BEFORE trial investigates the benefit of golimumab monotherapy or in

combination with methotrexate vs methotrexate alone in RA patients who were

naive to methotrexate.[14] The GO-FORWARD study investigates the efficacy

and safety of golimumab in patients with active RA who were inadequately

responsive to methotrexate.[15] And the GO-AFTER trial investigated

golimumab in patients with RA who had previously been treated with another

anti-TNF agent.[16]

The significance of the GO-AFTER trial is that this is the first randomized

controlled trial of anti-TNF therapy in patients who had previously been

treated with anti-TNF therapy. Other studies have looked at switching

between anti-TNF agents, but they have not necessarily been randomized in a

controlled fashion with placebo or a new drug. In those other studies,

patients were continued on the anti-TNF agent to which they had been

inadequately responsive or switched to another drug. In contrast, in the

GO-AFTER study, this is the first time in a randomized, double-blinded,

placebo-controlled trial that an anti-TNF agent has been shown to be more

effective than placebo in treating patients who have previously been

inadequately responsive to another anti-TNF agent. As expected, the

GO-FORWARD study showed that golimumab was effective in patients

inadequately responsive to methotrexate; this finding essentially confirms a

previously published study.[17]

The GO-BEFORE study, which was a study looking at golimumab in patients with

RA who had not yet been treated with methotrexate, compared golimumab with

methotrexate and showed that golimumab was neither inferior nor superior to

methotrexate. The authors of this study suggested that the intent-to-treat

analysis, which was the prespecified endpoint, failed because there were 3

patients who were randomized but did not receive the study drug. Of note,

when a modified intent-to-treat analysis was done, excluding those 3

patients who never received drug, superiority of golimumab to methotrexate

was demonstrated.

Monitoring of patients treated with certolizumab pegol and with golimumab is

ongoing. The safety profile for golimumab is comparable to that of the

currently available anti-TNFs.

Medscape: Despite the lack of head-to-head studies, how well do the

long-term safety and efficacy of approved anti-TNF agents compare with other

approved biologic agents such as abatacept and rituximab?

Dr. Kay: It is very difficult to compare the ACR-20, 50, and 70 responses

among the various trials because the patient populations are very different.

The response to abatacept or rituximab in patients who have not previously

received anti-TNF therapy is relatively similar to that of patients who were

given an anti-TNF agent but demonstrated inadequate response. Both abatacept

and rituximab have about a 50% ACR-20, a 20% ACR-50, and a 10% ACR-70, which

is lower than the typical 60% ACR-20, 40% ACR-50, and 20% ACR-70 that you

see with an anti-TNF agent in methotrexate-inadequate responders. But it is

very difficult to compare the degree of response of each of these agents to

one another.

Certainly there are RA patients who have not been previously treated with an

anti-TNF agent and respond to abatacept or rituximab, and there are patients

who were given anti-TNF agents in clinical practice who have an inadequate

response to the anti-TNF agent but then respond to abatacept or rituximab.

Furthermore, there are patients who do not respond to anti-TNF agents,

abatacept, or rituximab.

So I guess, in summary, one cannot directly compare the efficacy of one

agent to another except in a head-to-head study. In terms of long-term

safety, abatacept and rituximab do not seem to have as much risk in the

reactivation of tuberculosis. However, rituximab in diseases other than RA

has been associated with cases of progressive multifocal encephalopathy,

which has not been observed to date in anti-TNF-treated patients. So there

are differences in toxicities among the different biologic agents that will

need to be evaluated carefully in long-term postmarketing surveillance

studies. The cumulative information gathered will need to be assessed in the

context of the efficacy of these individual agents.

Medscape: Based on the data presented at this meeting, what is your

take-home message for clinicians who use anti-TNF biologic therapy for RA?

Dr. Kay: The combination of methotrexate and etanercept in active, early,

moderate-to-severe RA (COMET study) was presented at EULAR and has recently

been published,[18] which shows that in early RA, combination therapy with

etanercept plus methotrexate is more effective than treatment with

methotrexate alone in inducing remission.

So the data presented at EULAR indicate that anti-TNF agents are as

effective as we have always recognized them to be and are no less safe than

we have acknowledged them to be over the nearly 10 years of experience that

we have had since the FDA approval of anti-TNF-alpha agents. We learned that

there is an increased risk for herpes zoster infection in patients treated

with anti-TNF agents. Clinicians need to be aware of this potential

infectious complication of anti-TNF therapy.

We also learned that tuberculosis is more prevalent among patients with RA

than in patients without RA, which makes the need for purified protein

derivative (PPD) screening and vigilance for reactivation of tuberculosis

more important among patients treated with anti-TNF agents. No new safety

signals have come out over the past year with anti-TNF therapy so that there

should be continued confidence in the use of these agents to treat those

patients who are inadequately responsive to methotrexate.

Perhaps one can take an approach of considering the use of these agents in

combination with methotrexate to induce a remission in RA. The economic

issues associated with long-term anti-TNF therapy should prompt further

studies to look at whether remission can be maintained without continuation

of the anti-TNF agent and the continuation of methotrexate alone rather than

withdrawal of methotrexate and continuation of the anti-TNF agent, as the

design of the COMET study is investigating.

Medscape: What do you see as the key educational needs to improve the

implementation of biologic agents for RA in the clinical setting?

Dr. Kay: I think most rheumatologists are quite familiar with the safety and

efficacy of the currently available anti-TNF agents. There needs to be more

discussion of the algorithms by which one chooses to use these agents and

when to use these agents in the treatment of patients with RA based upon

clinical evidence. Discussion of quantitatively driven management of RA,

such as that espoused by the TIght COntrol for Rheumatoid Arthritis

(TICORA), the Bethandel Strategieen (BeSt), and the Computer Assisted

Management for Early Rheumatoid Arthritis (CAMERA) studies, should be

disseminated widely among rheumatologists.

Rheumatologists should also be familiarized with the use of the DAS-28 and

the HAQ or the MD HAQ in clinical practice so that patients are closely

monitored and are not left inadequately treated with agents to which they

are not showing optimal response. Educational initiatives should be focused

on informing rheumatologists of the best practice by which to use

methotrexate, TNF antagonists, and other therapies for RA. Patients with RA

will benefit most and will have the greatest chance of optimal clinical

outcomes with the least possible structural damage.