Rheumatoid Arthritis Treatments on the Horizon

Physicians do not allow chronic diseases such as asthma, hypertension, or diabetes to exist uncontrolled. They consistently give medications to control the disorder so people can live the lives they want to lead. In the past, that was not possible with rheumatoid arthritis (RA). Now it is. With some of our new medications and a better understanding of some of the older ones, we can make a tremendous difference in people's lives - and prevent joint damage.

We are at the very beginning of an exciting era of biological medications, stimulated by our new understandings of what causes RA and how we can suppress it. We are looking for the same model we use in infectious disease: an infection causes some inflammation or a fever; the doctor takes some fluid from the infected area and has it cultured in the lab; bacterial plates are placed in the culture to determine which antibiotic works against that infection; and then we give the right antibiotic and the infection is gone. That's the model we're aiming for now in RA - individualizing care for each patient depending on what immune cells are causing the problem and then getting rid of all symptoms of the disease.

Understanding Rheumatoid Arthritis

RA is a systemic inflammatory autoimmune disorder.

• Systemic means that it causes generalized symptoms such as fatigue, fever, and joint swelling, in contrast to osteoarthritis, which is just a localized process in the joint.
• Inflammatory means that the joints get red, warm, and swollen, which may cause limitations in range of motion and problems with function. Joint pain comes directly from this inflammation.
• Autoimmune means that the body's immune response reacts against itself. We have an army of immunologically active cells that protect us. You get a flu and your body takes care of it. You feel terrible for a few days, because a battle is going on in your body, and then you feel better when it's over. For unknown reasons, in patients with RA, that same immunological system that battles viruses and bacteria instead attacks the body itself - and that's why we have to use immunosuppressive therapy to try to control the overactive immune system.

RA has a specific personality that is individual to each person, although some things overlap and allow us to make the diagnosis. For example, typically, it causes inflammation that is symmetrical - i.e. in the same joint on both sides of the body, such as both wrists or both knees. And it typically affects the small joints of the hands and feet, sometimes the knees and elbows. After three to four months of such inflammation, changes in the joint may occur - although we now have drugs to help prevent such changes.

The Normal Joint

A joint is a mobile area where two bones connect. Within the bone is bone marrow, which can produce cells that can cause irritation, damage or erosions to the joint. At the tip of the bone is cartilage, the substance that cushions bone ends. Between the bones is a synovial space that allows the joint to move. Lining the joint is a synovial membrane, which produces synovial fluid that lubricates the joint. Surrounding the joint are thick tissues, which stabilize and support it, as well as tendons and muscles, which are important for stability and ability to move.

The Joint in Rheumatoid Arthritis

In early RA, the synovial membrane thickens because cells invade it. Something in the joint makes the cells come into the area; the body knows there is something going on - an inflammatory trigger - and sends troops into the synovial membrane to fight off this process. Over time, as RA becomes established, the synovial membrane becomes much larger and filled with these cells - cells that used to be dedicated to fighting off viruses and are now fighting off something in the inflamed area. The innocent bystander to this battle is the cartilage, which gets damaged. And unless we suppress the inflammation, it can go on to produce other changes in the joint.

In joints that have been damaged, you see on X-rays that the space between the bones (called the joint space) has narrowed because bone cartilage and bone has been damaged. Such damage, alone with bony erosions, are the major "bad guys" of RA that we have to make sure don't happen - and that don't have to happen with our new medications.

What causes the inflammation in RA?

We believe that at least two causative factors are involved. First, there is a genetic predisposition; we each have an individual gene pool that stimulates certain types of immune responses. Second, there is likely some type of viral or bacterial exposure, called an environmental trigger, although no specific one has been identified. Although certain types of viruses can trigger rheumatoid-like illnesses, they are usually self-limited. However, in people with the genetic predisposition, we believe these environmental triggers cause an inflammatory process. You know that if you get a viral illness, you sometimes get a flare; but, in contrast, sometimes your joints may feel their best ever during a cold or flu, as if the immunological system were busy elsewhere fighting off that infection

What is the body's reaction to this trigger?

Immune cells enter into the joints or tendons, yielding enlargement of the lining cell layer and increased fluid and blood vessels in the joint. That's why it gets red, warm and swollen. All these immune cells produce and secrete chemicals; these then trigger responses in other immune cells, which then produce cytokines - proteins that can damage joints and cause fever and fatigue. These cytokines are the chemical messengers by which immune cells communicate. Much of our battle with the immune system is trying to stop those cells from such communication. However, we want to stop the communication sufficiently to block RA inflammation, but so greatly that the system can no longer fight infection.

Thus, we need to reset the immune response - so that the inflammatory response in RA won't make you feel sick all the time because of the battle going on as the immune system fights your own tissue in the same way as it fights off a flu.

How is the severity of RA measured?

A symptom is what you tell the physician: "I have pain, fever, weight loss, fatigue, am unable to work and socialize." A sign is what the physician finds upon examination: a joint is red, warm and swollen or has limited range of motion; you have fever, rash, or hypertension. Lab tests provide further information: blood tests to check the sedimentation rate (a sign of inflammation) and to look for anemia or an elevated platelet count - which can all be changed by cytokines.

Doctors use all of this information to determine what's going on - how high the inflammatory thermostat is - and then turn down that thermostat as low as it can safely be turned down without placing you at risk of failed defenses against infections.

What is the goal of RA therapy?

On a scale of one to ten, if ten is the worst you have ever felt with RA, my goal is to achieve at least a 70 to 80% reduction in symptoms. But my real goal is what cancer therapists call NED - no evidence of disease. We must accept no less in rheumatology because redness, warmth and swelling can beget erosions and joint damage. So we face the inflammation as aggressively as it presents to us. In a safe, responsible way, we raise the medication level to bring the thermostat of the inflammation down - until we see no redness, warmth, or swelling. If a medication regimen does not achieve that goal, it's not working, and we have to try another regimen. Different institutions have different approaches, but here at Hospital for Special Surgery we are very aggressive because RA is an aggressive disorder.

How do we effectively combat RA?

We combat every phase of the immunological process. The cells that are part of the immune response are very complex in their types, in what stimulates them, and how much they react. Just like cancer chemotherapy uses different combinations of drugs to hit different components of the cell cycle of a tumor cell, we want to control different parts of the immune response. But, again, we must do it safely so that we don't take away your immune protection. It's important to strike the right balance, to calm the inflammation down but assure that you can still fight infection. Here are the drugs we use.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) control inflammation in general. They include naproxen (brand named Naprosyn), piroxicam (Feldene), sulindac (Clinoril), rofecoxib (Vioxx), celecoxib (Celebrex), and many others, even aspirin in high doses. While they are effective against inflammation and pain, they don't get at the basic process of RA. They don't modify the disease.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs) are drugs that change the course of the disease. Disease modifiers combat the overactive immune cells and their products in a very specific way. With some of these drugs, this means that if you don't have an erosion in your joint now, you won't develop one. These include: hydroxychloroquine (Plaquenil), sulfasalazine (Azulfidine), methotrexate (Rheumatrex), cyclosporine (Sandimmune or Neoral), leflunomide (Arava).

Biological Response Modifiers (biologics) are the latest of the DMARDs. They are called biologics because they are directed at specific parts of the immune system and are made in the test tube with recombinant types of technology. They include: etanercept (Enbrel), infliximab (Remicade), and anakinra (Kineret).

Unfortunately, we can't yet predict which of these drugs will work best for your biochemistry and physiology, as we can in treating infections with antibiotics. So the physician and patient have to work together in a process of trial-and-error. If a drug does not improve your condition within a few months, we either have to add something to it or replace it.

How is a medication selected for a person with RA?

Generally, medications are selected based on the severity of the disease - mild, moderate or severe - which means the level of inflammation, the level of erosions or bone deformities that may already exist, and the systemic manifestations, such as fatigue and fever. We try to fine tune the type of medication to the severity of inflammation, while keeping in mind that the "personality" of the inflammation can change over time, requiring a different medication regimen.

In milder RA, we use hydroxychloroquine, sulfasalazine and, sometimes, tetracycline minocycline, which is a tetracycline antibiotic. When this antibiotic works in people with RA, it does not necessarily mean that the RA has been caused by a bacterial infection. Rather, in most patients, the effectiveness of minocycline may be because it blocks the enzymes that cause the damage - that is, another characteristic of the drug, not its antibiotic benefits.

In moderate to severe RA, we tend to use methotrexate (one of the most widely used for more than 25 years and relatively safe), leflunomide (a cousin of methotrexate), or one of the biologics. In the most severe RA, we also may also use cyclosporine or even certain types of processes that can take out the chemicals in the body that can cause damage.

How do the new biologics work?

To understand the new biologics, first you need to understand how various cells in the body play a role in the body in fighting off infection.

Macrophages are the early sentinels that gobble up a virus or other environmental factors, change its structure into a small protein component, and then display that protein on their surface to T-lymphocytes. They tell the T-lymphocytes what bad guys are in the neighborhood.

T-lymphocytes are the central cells of the immune response, produced in the thymus gland when you were born. Your body already has T-lymphocytes ready that are specific for nearly every invader. But in order to act, they have to be alerted by the macrophages as to what bad guys are in the neighborhood. This sets up the battlefront, causing the T-lymphocytes to multiply for action.

These cells communicate through chemicals called cytokines, which can be good guys or bad guys. (Some are called interleukin - which means "in between white cells.") So one cell produces a cytokine that goes through the fluid in the joint and sends a message by touching the surface of another cell; this tells the gene in the cell's nucleus to produce a certain protein. A protein can be many things, including an enzyme that breaks down your joint and causes erosions.

How do we stop the T-cell from producing the bad-guy cytokines that lead to joint damage? First, we can suppress the inflammatory response. Or, if the macrophage produces a chemical, we can produce a decoy for it - an anti-missile missile. Thus, we either take out these cells, or take out their products so they can't do their dirty deeds downstream.

Etanercept and infliximab are called anti-tumor necrosis factor (anti-TNF) medications. Among the cytokines that the macrophages can produce is TNF, which got its name from its ability to break down tumors. It was discovered when some people with lung cancer had their cancers get better after they developed lung infections. The chemical that doctors called tumor necrosis (killing) factor was found in their lungs. Thus, TNF can help protect us against tumors and infections, but it also has a down side - damaging tissue, eroding joints, and leading to fever, fatigue, and weight loss. So a main area of research has been to suppress the negative actions of TNF.

We now have two different types of medications that block TNF. Etanercept decoys the TNF in the blood; the TNF attaches to it, thinking it's attaching to a joint, and the decoy takes it out of the system, so it can't do its dirty deed. Infliximab blocks TNF directly; it's an antibody that aims right at TNF and takes it out of the system. So it's a missile against a missile.

Anakinra is a third biologic, and it works as a decoy to interleukin 1, a different cytokine that causes damage and fatigue. It is called interleukin-1ra, which stands for receptor antagonist.

Etanercept is given as a subcutaneous injection twice a week, and anakinra is given as a subcutaneous injection daily. Infliximab is given intravenously (called an infusion therapy) in the clinic or doctor's office; after the first infusion, it is given two weeks later, then six weeks later, and then every eight weeks. These biologics cost about $12,000 per year. Almost invariably, they are paid for by managed care, Medicaid, and Medicare, with the exception that Medicare only covers infusion therapies, not those given by subcutaneous injection.

How effective and safe are the new biologics?

These biologics are extraordinarily effective at controlling inflammation and preventing joint damage, although only about 70% of patients respond to them. They have the ability to make a quantum leap over drugs such as methotrexate and possibly even leflunomide.

However, they have only been studied for about five years, and we are very careful to watch for any potential problems with them. Here at HSS, we have more than 500 people on these biologics, more than any other institution. So we have a lot of experience. We also do a lot of studies, and we are doing a lot of the post-marketing surveillance because the FDA's system is not very good. We have seen some infections in people who have been treated with them but, in general, their effectiveness is so significantly greater than medications such as methotrexate that more and more people we will be using them in the future.

What more is on the horizon?

We have come a long way in the past 30 years. We now have specific targets that we focus our therapies on. Our therapies are amazingly effective and safe. The world has changed for people with RA. However, these three new biologics are just the beginning. We have many more coming down the road over the next few years that will be even more effective, as well as less expensive, and which we will be able to use in combination with each other for even better results.

About the Living with RA Workshop at HSS.