A Glimpse of Rheumatoid Arthritis Research at HSS

Hospital for Special Surgery, founded in 1863, is dedicated to rheumatology and orthopedics. In particular, the hospital has had a very active research program since 1945. We now have some 30 rheumatologists involved in basic and/or clinical research, making ours one of the largest such research programs in the country. Between 1997 and 2001, we published 210 articles in peer-reviewed journals; last year we had 25 presentations at the American College of Rheumatology scientific sessions and 11 presentations at the European League Against Rheumatism annual meeting.

Review of Rheumatoid Arthritis

RA is a systemic, inflammatory, autoimmune disease. Systemic means that it can cause generalized symptoms like fever, weight loss, fatigue and can affect any organ in the body, including the heart, lungs, eyes, skin, blood, kidney, and liver. Inflammatory means it can cause swelling, redness, and warmth of joints, which is symmetrical (on both sides of the body), most commonly in the small joints of the hands and feet, although, as noted, inflammation can cause damage elsewhere in the body. Autoimmune means that your immune system attacks your own body.

RA affects 1% of the population, occurs more commonly in women, and has a peak age of onset between 45 and 65. It is most commonly characterized by progressive destruction of the joints, with loss of cartilage, bone, physical function, and quality of life.

The goals of rheumatologists are to: relieve symptoms; prevent joint destruction and loss of joint function, deformity and disability; achieve quality of life; and achieve clinical remission, in other words, no evidence of disease. To help us achieve these goals, we have many medication options: non-steroidal anti-inflammatory drugs (NSAIDs) and painkillers; the older disease-modifying anti-rheumatic agents (DMARDs), such as sulfasalazine, methotrexate, and hydroxychloroquine (Plaquenil), as well as exciting newer ones in the last few years, including leflunomide (Arava), etanercept (Enbrel), infliximab (Remicade), and anakinra (Kineret). (The last three of these are also called biologic drugs because they interfere with specific biologic activities.)

Types of Research

Basic research is laboratory research that uses cells (animal or human) and animals. It investigates cellular mechanisms, genetic causes of autoimmune disease, and regulation of the immune system.

Clinical research involves patients in studies of the safety and effectiveness of new drugs, largely in order to obtain approval from the Food and Drug Administration (FDA) before the drug can be made available to the general public. Clinical research trials are usually done in three phases.

• Phase 1 trials are the first use of a medication in humans simply to determine its safety. This phase usually involves healthy volunteers. However, it may involve people with end-stage cancer, when all other treatments have failed to help them. -
• Phase II trials are designed to detect the effectiveness of the drugs, as well as the drugs effect on the body (how it is absorbed and eliminated and the optimal doses), while continuing to monitor safety. Volunteer patients who have the disease are studied.
• Phase III trials compare the effectiveness of the new drug to the prior standard of treatment or, in some cases, to a placebo (inactive pill). Again, volunteer patients who have the disease are studied. (Methotrexate is the gold standard of treatment in rheumatoid arthritis and, despite the development of newer medications, is still the most commonly used. Thus, as newer agents are evaluated, they are usually compared to methotrexate.)

In addition, even after a drug is approved by the FDA for one disease, further research may be conducted to evaluate the use of the drug in different doses, or in patients with different diseases, etc. These are apt to be conducted in the style of a Phase III trial.

Every clinical trial has inclusion criteria, such as that you have to have rheumatoid arthritis and be in a certain age group, and exclusion criteria, such as that you do not have kidney problems. These criteria are different for every clinical trial.

The "gold standard" design of clinical trials is:

• randomized and controlled, in which half of the patients are randomly chosen to get the new drug, while the other half, receiving an older drug or a placebo, serves as the control group;
• double-blinded, in which neither the physician nor the patient knows who is getting the new vs the old or placebo drug, so that they won't be biased in their reporting.

Another form of clinical research involves outcome studies, which look at how the patient does as a result of the treatment, what their final outcome is - not just in terms of their X-rays and joint movement, but in terms of the patient's quality of life.

Yet another form of clinical research is the patient registry, in which we collect clinical data and blood samples from people with a particular disease so that we can do retrospective sub-group analyses. For example, we can compare groups of people taking different drugs or with different disease characteristics.

Basic Research at HSS

A review of the body's immune system can help you understand basic research. The immune system is designed to protect us from foreign invaders, such as a virus or bacteria. Any such substance that provokes the immune system is called an antigen. When provoked, the immune system has three lines of defense:

• first line are the white blood cells (neutrophils, basophils, eosinophils, monocytes, macrophages);
• second line brings in two types of lymphocytes - B cells and T cells;
• third line consists of two types of T cells (T helper and T killer) and antibodies, which the B cells stimulate plasma cells to produce.

For example, a macrophage, nicknamed the "big eater," captures and eats antigens in a process called phagocytosis. The antigen is chopped up inside the macrophage, and some parts of it are displayed on the macrophage cell surface. Then T-helper cells from the second line of defense attach themselves to the macrophage. This attachment causes an increase in the T-killer cells or the antibody-producing B cells. The increased antibodies then attack the antigen and clear the infection. But in rheumatoid arthritis, the immune system becomes confused and fails to recognize the joint as "self." Instead, for reasons we do not understand, these immune cells attack the joint as if it were a foreigner, causing inflammation and swelling of the joint space.

All of these immune cells "talk" with each other - via chemical messengers, called cytokines - which regulate their activities (The cytokines use particular signaling pathways to communicate). TNF-alpha and IL-1 are key cytokines involved in rheumatoid arthritis. Their levels are increased in joint spaces and in the blood.

When you understand the immune system, you can understand how some of our newer therapies work. One of the cytokines that immune cells use to communicate is TNF, so there are receptors on the inflammatory cell for TNF. When TNF comes along and binds to those receptors, it activates the inflammatory response. Etanercept (brand named Enbrel) has a fake receptor that binds to TNF, which prevents the TNF from binding to the inflammatory cells and activating the system; that's why etanercept is called a TNF inhibitor. Another approach is injecting an antibody to the bad guy, which is the approach with infliximab (Remicade).

One example of basic research at HSS is a project focusing on these chemical messengers to explore why they are inappropriately activated in rheumatoid arthritis. Can we shut down this communication and decrease immune activity? Although the research is looking at many cytokines, it is particularly focused on IL-10. They are trying to identify molecular mechanisms that inhibit the signaling pathway - in order to shut down communication between the cytokines. They have discovered a system to inhibit this signaling and stop the communication, and they are trying to develop a treatment based on this signaling system.

Another research group is focusing on the receptors on each T cell surface that identify the antigen. They have identified a molecule, CD-29, and they are seeking therapies that will shut down signaling there.

Clinical Research at HSS

We are conducting a number of Phase II and III studies. For example, HSS is one of the centers for a Phase II study of H5gG.1/mab, which is an antibody to one of the components of the immune system, in volunteers who have RA. It is believed to shut down one of the mechanisms between the immune cells. This is a double-blind, placebo-controlled trial for patients who have continued to have active disease, despite use of methotrexate and leflunomide for at least three months. Patients are followed for 28 weeks.

Etanercept has been approved by the FDA for subcutaneous injections of 25 mg twice a week. We are now doing a Phase III study to explore whether a higher dose at a longer interval will be equally effective and safe. So one group is taking etanercept at 50 mg once a week, while the other is on placebo.

Another Phase III study of ours looked at an off-label use of etanercept. That is, the drug had been approved only for rheumatoid arthritis, and we were one of only two centers reporting study of it for psoriatic arthritis. After two years, 80% of our psoriatic arthritis patients are still on etanercept and doing well. The FDA recently approved etancercept for this new application.

One of the Outcome Studies projects at HSS is exploring whether people with RA have cardiovascular disease more commonly than the general population and how it develops. They are evaluating levels of atherosclerosis, which is a thickening/hardening of artery walls caused by cholesterol plaque inside the vessels. This research is collecting blood to check for the inflammatory markers and doing echocardiograms of the heart and ultrasound of the carotid arteries to look for plaque, and the results in people with RA will be compared to those of people with lupus and to healthy volunteers.

Our Rheumatoid Arthritis Registry is a collection of medically important information on patients that enables us to study subgroups of RA patients with different characteristics, such as different age, medications, and clinical manifestations. We now have more than 700 patients in the registry. Initial intake only requires about 30 mintues of your time, and follow-ups ever six months take about 10 minutes - just providing some blood and answering a questionnaire. If you would like to participate in the registry, please call 212-774- 2760.

One of our recent studies demonstrates to value of having a registry. A common side effect of methotrexate is liver toxicity; therefore, the American College of Rheumatology (ACR) recommends doing liver function tests every 4 to 8 weeks. However, we have observed that liver function abnormality is very rare. Indeed, in a study of 222 patients in our registry who were using methotrexate, after checking all of their blood tests (some going as far back as 10 years), we noticed very few therapy-altering liver function test abnormalities. As a result, we published an editorial in the Journal of Rheumatology recommending that the ACR reassess its guidelines to extend liver function testing to every 3 months, which would be a more cost-effective approach.

Another registry study looked at whether it is necessary to take methotrexate with infliximab, which is the current recommendation. We compared the records of patients who take infliximab and methotrexate together to those who take infliximab alone (because they are unable to take methotrexate due to past side effects or allergies). After one year, benefits were similar with either regimen.

Another registry study looked at whether there is a difference in effectiveness between etanercept and infliximab - and ours was the first head-to-head outcome study of these two drugs in the U.S. We have found no difference in benefits on RA activity.

Pharmacoeconomic Studies are another area of our research. One study, for example, relates to the huge price difference between the old and new DMARDs: $600 a year for methotrexate, compared to $14,000 for etanercept. In the last few years, many insurance companies have been requiring that physicians demonstrate that methotrexate has failed to provide adequate benefit for their patients before approving coverage of the newer, more expensive drugs, such as etanercept. We have surveyed American rheumatologists based on three different case scenarios - mild, moderate, and severe RA - each being treated for the first time after six months of disease. First we asked what they would prescribe if cost were not a consideration. Second, we asked what they would prescribe taking cost into consideration. We just published our results for the year 2000 in Arthritis Care and Research, showing that 65% would start treatment with leflunomide, etanercept, or infliximab if cost were no object, but that drops to 14% when cost factors are taken into consideration; instead, most are prescribing methotrexate, hydroxychloroquine, or sulfasalazine. We concluded that pharmaceutical companies and third party payers should make efforts to decrease the expense of these highly effective medications. This is an ongoing study, which is showing an increasing physician preference for the newer drugs and for starting them earlier in the course of disease.

If you are interested in participating in a research study at HSS, call 212-774-2500.

Dr. Erkan's Recent Publications

Learn about HSS' Rheumatology Clinical Research Center

Learn about the Living with RA Workshop at HSS

---

posted 6/20/2002