EXPERT INTERVIEW - Biologic therapies for RA: current challenges, future direction

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Medscape Rheumatology

Expert Interview

Posted 12/01/2005

Biologic Therapies for RA: Current Challenges, Future Direction -- An

Expert Interview With Stanley Cohen, MD

Editor's Note:

Rheumatoid arthritis (RA) is a common disease that affects approximately 2

million people in the United States and is prevalent across all ethnic

groups. It can occur at any age, although most cases are seen in adults

between the ages of 30 and 60 years. Women make up 75% of all cases. The

disease accounts for more than 9 million physician visits and 250,000

hospitalizations annually, presenting a huge economic burden to society. RA

is a chronic, progressive, autoimmune inflammatory disease of unknown

etiology that attacks the synovial tissue and leads to irreversible joint

damage, chronic pain, stiffness, and functional impairment.[2-4] Without

treatment, most RA patients develop permanent bone erosions and joint space

narrowing and, with time, many are disabled and may require joint

replacement surgery. RA can reduce the average life expectancy by about a

decade.

This past decade has seen rapid advances in the understanding of the

pathogenesis of many musculoskeletal disorders. Parallel to these events,

there have been remarkable advances in therapeutic options for many

patients. However, not all patients respond to current therapies, and the

challenge of patient selection for maximum therapeutic outcome remains. In

addition, due to lack of controlled studies focused on children with RA,

optimal treatment of this patient group has not been established.

Helen Fosam, PhD, Medscape Rheumatology, interviewed Stanley Cohen, MD, on

the current challenges and future direction in treating adults and children

with RA. Stanley Cohen is Clinical Professor at the University of Texas

Southwestern Medical Center at Dallas. He is also the Medical Director at

Radiant Research, Dallas, Texas.

Medscape: Dramatic advances have been made in the treatment of RA since the

introduction of biologic therapy. Can you summarize some of the evidence

that shows the added benefit of biologic therapy over traditional therapy

for RA?

Dr. Cohen: A number of clinical trials have evaluated the new biologics, the

tumor necrosis factor (TNF) inhibitors as well as interleukin-1 inhibitor in

RA. Most of the initial trial designs included patients who had active

disease despite receiving methotrexate therapy. In these studies, a biologic

was added to methotrexate, and these outcomes were compared to those of

patients who continued methotrexate alone. Results showed addition of a

biologic response modifier to methotrexate very significantly improved

patient outcomes. Recent studies, primarily looking at patients with early

RA (ie, < 3 years' duration) have compared methotrexate directly to

biologics. Another study, the TEMPO trial,[1,2] compared methotrexate to

etanercept and to the combination of etanercept plus methotrexate. This

study demonstrated that monotherapy with biologics, whether it be adalimumab

(Humira) or etanercept (Enbrel), when compared to methotrexate, demonstrates

comparable improvement in signs and symptoms of the disease as well as

health-related quality-of-life outcomes.

For example, improvements in the American College of Rheumatology (ACR)

response criteria (ACR 20, 50, and 70) and the disease activity score, the

DAS 28, were similar for methotrexate and the biologics used. However, these

studies demonstrated a superiority of the biologics in preventing both

structure damage and radiographic progression. So, even though there were

similar improvements in signs and symptoms and similar improvements in

physical function and disability, biologics were superior in preventing

x-ray progression and structural damage in comparison to methotrexate. I

think these results echo what we have seen in the clinic over the last 20

years. We have had very good luck with methotrexate as a disease-modifying

drug. In our experience, about a third of patients have an excellent

response, a third of patients have a good response, and about a third do not

respond very well or cannot tolerate the medication. Even in those patients

with a good to excellent response, over time the majority of these patients

generally would develop further x-ray damage. We hope and think, at least on

the basis of short-term, 52-week, and104-week follow-up of the clinical

trials, that the biologics, and primarily the TNF inhibitors, will prevent

structural damage -- which, in the long term, correlates very well with

impaired physical dysfunction and disability.

The other very important take-home point of the last 10 years is that it

looks like the combination of a disease-modifying antirheumatic drug (DMARD)

such as methotrexate plus a biologic, whether it be etanercept, adalimumab,

or infliximab, is superior to either monotherapy with a biologic or

methotrexate. That has been borne out in 3 separate data sets: first, the

ASPIRE trial[3] evaluated infliximab in early RA; second the PREMIER

study,[4] which again focused on early using adalimumab; and last, the TEMPO

trial, which I mentioned earlier.

Medscape: You mentioned that about a third of the patients do not actually

respond or respond inadequately to methotrexate. Is this also true for TNF

inhibitors?

Dr. Cohen: Indeed that is correct with TNF inhibitors, as you see when you

take a look at the ACR responses. What we in the clinic think is a

substantial response probably equates to an ACR 50, a 50% response, and only

about 35%-45% of patients achieve that response. So there is still a large

number of patients that have an incomplete response, and a small

percentage -- probably in the range of 5%-10% -- have no response to TNF

inhibitors.

We are very concerned about those patients who do not respond to treatment

at this point. We hoped we could use combination biologic therapy for those

patients. However, so far, the data with anakinra (Kineret) plus etanercept

and now with abatacept (Orencia) plus other biologics have shown that these

combinations of therapy do significantly increase the risk of serious

infections. So, for now, we are cautious about the combination of biologics.

I'm not saying that we are not going to go back and look at this again as

newer therapies are developed, but it is something that I would not

recommend clinicians pursue at this time because of the higher risk of

serious infections.

Medscape: On the basis of these statistics, would you agree that the current

challenge to clinicians is identifying those patients who are most likely to

benefit or respond to treatment?

Dr. Cohen: I think there are several challenges, but that is one of them.

One of the challenges is to make sure that we use these medicines properly

and that we evaluate the benefits of these medications and their risks to

the individual. These medicines can have side effects. Rare, serious

infections can occur. These therapies do compromise the immune system, not

to mention their very high cost. First thing that we want to do is identify

the patients who are more likely to progress, more likely to have active

disease, and these are the patients who are rheumatoid factor positive,

patients who have antibodies to anticyclic citrullinated peptide (CCP),

elevated acute-phase reactants, such as C-reactive protein (CRP) and

erythrocyte sedimentation rate (ESR), or patients who have baseline

radiographic damage. Those people have a worse prognosis and are more likely

to have impaired physical function, and they are the ones that especially

should be treated with biologics. However, we cannot tell for sure who is

going to respond to the biologics, but we certainly can pick out the

patients who are more likely to do worse if they do not receive a biologic,

and those are the patients I've just described. What I should emphasize is

that it does not matter if you have 15 years of disease or 1 year of

disease; it is clear from the clinical trials that duration of the disease

has no impact on the likelihood to respond.

Medscape: Would you recommend these biologics as first-line, or as

subsequent therapy?

Dr. Cohen: Well, no. I do not use them first line. What we do in our

practice, in accordance with evidenced-based medicine, is to start with a

disease-modifying agent, generally methotrexate. Within 3 to 6 months, if

the patient has not had close to a 100% response, is continuing to have

swollen or tender joints, with abnormal ESR or CRP; we will give strong

consideration to adding combination therapy, which is generally going to be

a biologic.

There are studies currently ongoing to determine whether the 6-month period

before starting a patient on a biologic will have any long-term impact on

overall outcomes. If the cost of these therapies was significantly less and

we could have a better way of delineating who is going to have adverse

reactions, then we would be in a better position to more appropriately use

these therapies in patients who are most likely to benefit. I think that,

for now, most rheumatologists have adopted using a DMARD such as

methotrexate or occasionally leflunomide initially and then adding a

biologic after 3 to 6 months.

Medscape: The evidence so far has been gathered from studies done on adults.

However, children do suffer from RA. Can you comment on the major challenges

physicians face when treating children with RA, particularly in the absence

of controlled clinical studies?

Dr. Cohen: Well, there are clinical trials in children that are ongoing but

there are very few published studies. We are now trying to shift from the

terminology " juvenile rheumatoid arthritis " to " juvenile inflammatory

arthritis " because it is a slightly different disease from adult RA. The

polyarticular juvenile disease is one that looks the most like the

rheumatoid disease that tends to occur in older children and persists into

adulthood. There have been studies with etanercept with the standard

pediatric clinical trial design. It is very difficult to put adults on

placebo in a clinical trial, and you can imagine trying to do a clinical

trial where children with active disease are put on placebo. It is just

something that children and their parents will not stand for. So, clinical

trial design involving children is typically a trial in which all patients

receive therapy initially. One such study has been done with etanercept.

Patients who demonstrated a significant response to etanercept were then

entered into the second portion of the protocol, where the etanercept was

discontinued and patients received a placebo. If disease subsequently flared

in these patients now on placebo, ., etanercept was re-introduced. In a

clinical trial utilizing this design, etanercept was found to be effective

and is approved by the US Food and Drug Administration (FDA) for the

treatment of juvenile inflammatory arthritis.

My understanding from pediatric rheumatology colleagues is that methotrexate

is the first DMARD used in the majority of these patients and, as with

adults, in cases of nonresponse, biologics are considered. As far as

infliximab and adalimumab are concerned, there are no published clinical

trials yet that I am aware of, although, to my knowledge, those trials are

ongoing. Again, the same concerns about costs and the risk for serious

infection exist for children as for adults.

To summarize, these therapies have been quite effective in treating juvenile

inflammatory arthritis, and those patients who have been on methotrexate and

have not had a significant response are potential candidates for these

therapies. The only FDA-approved therapy to my knowledge at this point is

etanercept.

Medscape: What about the long-term prognosis for these children -- is it

quite good?

Dr. Cohen: I think the prognosis is probably in line with what we have seen

in adults. There are no long-term follow-up studies in the juveniles I have

seen to date. Again, you know, it is a much more variable disease. The

pauciarticular juvenile inflammatory arthritis often runs its course over a

few years. I believe these therapies will allow for preservation of joint

integrity and joint function and therefore prevent some of the disability or

problems that these kids have when they move on to adulthood. I am

optimistic that these biologic therapies will do that, but, again, we have

not had long enough follow-up. These drugs have only been available for 7

years.

Medscape: According to published data, there is a consistent finding that RA

patients tend to have a shortened life span due to increase of

cardiovascular events. Can you comment on whether the disease-modifying

drugs or the move toward early and aggressive treatment have an impact on

cardiovascular outcome?

Dr. Cohen: I think it is clear from several epidemiologic studies that RA

patients have a shortened life span and that one of the more frequent causes

of mortality is cardiovascular disease. There are many theories about this,

but one of these pertains to the ongoing inflammation that occurs in RA, and

Dr. Weyend and colleagues as well as others have reported experimental data

suggesting the presence of activated or altered T-lymphocytes in coronary

plaques.[5-7] That has stimulated a great deal of interest in how our

therapies may impact mortality. The National Database from Wichita, Kansas,

as well as studies by Frederick Wolfe and colleague, and by Kaleb

Michaud,[8,9] demonstrated that methotrexate reduced overall mortality in RA

patients and seemed to reduce cardiovascular mortality. Recent abstracts

were presented at the Annual European Congress of Rheumatology 2005 (EULAR

2005) suggesting that the biologics may also have the same impact on

cardiovascular outcomes.[10] We are optimistic that the newer therapies that

can systemically lower inflammation may reduce inflammation in the coronary

arteries and therefore reduce cardiovascular mortality.

It is clear that the biologics have an effect outside the clinical

improvement seen, in that they suppress CRP levels, and recent studies have

suggested that CRP is an independent risk factor for coronary artery disease

that normalizes or reduces CRP in such a way that we may subsequently lower

cardiovascular risk in patients with RA. We are very optimistic about that.

In addition to our standard arthritis therapies, I think it is incumbent

upon the rheumatologist as well as the internists or family physicians

managing these patients to treat the risk factors that can be modified, such

as cholesterol or hypertension, and to instruct patients to avoid smoking.

Smoking itself has been shown to aggravate RA and possibly make its symptoms

worse, so we need to take care of the standard risk factors that can be

associated with coronary artery disease as well.

Medscape: Moving on to some of the more recent studies on statins and their

possible role in anti-inflammation, can you comment on the evidence for this

and their potential role for treating RA?

Dr. Cohen: There is some suggestion that statins, devoid of their

lipid-lowering capabilities, have some anti-inflammatory capability; however

the data are not conclusive at this point. I do not foresee statins ever

being used as a primary treatment for RA. I think that the majority of our

RA patients who are hyperlipidemic are on statins. We have never really seen

or perceived any significant clinical effect. A study was published

suggesting a modest effect of statins in the management of RA[11,12];

however, I think there are some questions about the methodology of the

trial. My personal feeling is that I do not think that we will ever see

statins as a treatment for RA, certainly not in the scope of DMARDs or the

biologics that we have presently. I am unaware of any rheumatologists

instituting statins at this point for the treatment of RA outside of

treating hyperlipidemia.

Medscape: How do you see the landscape of managing patients with RA changing

in 2006 and beyond?

Dr. Cohen: I think that there has been a major shift in the last several

years, which I think you pointed out in one of your questions, and that is

that we are very aggressive with early intervention. Clinics have been

developed around the country for the management of early RA to encourage

patients who have evidence of joint swelling to see a specialist as soon as

possible so that therapy can be initiated. We learned during the mid '90s,

using some of our weaker therapies, such as hydroxychloroquine or

sulfasalazine, that even a delay of 3 months would have an impact on

radiographic disease progression over 2-year follow-up. Early intervention

with a DMARD is a necessity, so we want to get the RA patient in to see the

rheumatologist as soon as possible. That is one area we are already moving

toward.

One approach that has been of interest is , the assessment of objective

outcomes, so that we can modify our therapies more closely to disease

activity. Some rheumatologists are now using the DAS-28 score to monitor

disease activity and as a basis for altering therapy. We are also looking at

monitoring structure progression with radiographs and, eventually, with MRI

technology. We need to be aggressive in treating those patients who fail TNF

therapies. I still think that the general treatment order for now is to

initiate a DMARD such as methotrexate. For the 50%-60% of patients who have

an incomplete response or fail to respond, combination therapy, usually with

a biologic, is initiated within 3 to 6 months. Nonresponders will continue

to be a difficult group of patients to treat. Abatacept, a modulator of

T-cell function, will soon be on the market. The clinical trial evidence for

the effectiveness of abatacept looks robust, and in time we will develop

experience with this new therapy. We are also working with rituximab, which

is a treatment for B-cell non-Hodgkin's lymphoma. There have been several

data sets now suggesting it may be of benefit in RA.

Our ultimate primary goal is to cure these patients, even though we never

would have said this in the past. Our secondary goal is to put the patient

into remission and prevent progression of disease. We need to get to

patients at some point before they actually develop RA. With further

unraveling of the human genome, and knowing that CCP antibodies and

rheumatoid factor may be present years before the onset of disease, we may

be able to identify those at greatest risk and prevent them from developing

the disease. For now, the approach is to administer very early, aggressive

therapy, closely follow up with a specialist, and closely monitor features

of the disease to modify your therapy accordingly.

Medscape: Although the push now is for early, aggressive treatment, what

about those patients who do present late, who already have the deformity in

place? Are current therapies still beneficial?

Dr. Cohen: Absolutely, and I made that point earlier. We want to prevent the

deformities from occurring, because when you already have structural damage

that is going to affect the physical function, it is not reversible -- but

that does not mean that the disease will not respond to these therapies.

They will, and that has been shown over and over in the clinical trials. The

majority of the clinical trials, except the ones that are designated as

early-stage RA trials, involve patients with disease of 9 to13 years'

duration, and they frequently have wonderful responses to these therapies.

So, certainly, long-standing disease is not a reason to withhold these

therapies.

Medscape: In terms of educational need, what do you see as the main issues

for clinicians and patients alike?

Dr. Cohen: Well, I think that the field is rapidly changing, and so

clinicians and patients need to receive this information in a timely manner,

and need to take a well-balanced and unbiased approach. It has to be

communicated through a CME-type venue, rather than a promotional one. I

think we need to provide summaries of what the state of the literature is at

a particular time, perhaps through Web-based educational programs. It is

interesting that the most-read journal articles by clinicians are review

articles, not new research studies. So, I think we need to continue to be

diligent in providing clinicians -- both through printed publications and

the Web -- with the latest information on new developments in therapeutics

for RA.

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