Reports From National Arthritis Meeting

Dr. Shiel Gives Perspectives Of Interest On Rheumatoid Arthritis From
2001 Annual Scientific Meeting Of The American College Of Rheumatology

• Introduction
  
• New Treatments
  
• Associated Conditions
  
• Patient Education
  
• Complications

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease that can cause chronic inflammation of the joints and other areas of the body. Rheumatoid arthritis can affect persons of all ages. Its cause is unknown. Rheumatoid arthritis is a chronic disease that is characterized by periods of disease flares and remissions. In RA, multiple joints are usually, but not always, affected in a symmetrical pattern (affecting both sides of the body). The chronic inflammation of RA can cause permanent joint destruction and deformity. The "rheumatoid factor" is an antibody blood test that can be found in 80 percent of patients with RA.

Rheumatoid arthritis is a common rheumatic disease, affecting more than two million people in the United States. The disease is three times more common in women than in men. It afflicts people of all races equally. The disease can begin at any age, but most often starts after age forty and before sixty. In some families, multiple members can be affected, suggesting a genetic basis for the disorder.

There is no known cure for RA. The treatment of RA optimally involves a combination of patient education, rest and exercise, joint protection, medications, and occasionally, surgery. Currently, doctors feel that the earlier patients with RA receive aggressive treatment, the better their long-term outcome.

Below are perspectives on key reports presented at the recent national meeting of the American College of Rheumatology:

New Treatments

Some of the biggest new from this year's meeting related to the newer medications used to treat RA. Here are summaries in this area:

Remicade (infliximab)

Remicade (infliximab) is an antibody that blocks the effects of tumor necrosis factor alpha (TNF-alpha). TNF-alpha is a substance made by cells of the body that has an important role in promoting inflammation. By blocking the action of TNF-alpha, infliximab reduces the signs and symptoms of inflammation.

Remicade was a topic in over 100 papers presented at the meeting, most of which related to RA. Remicade, an approved treatment for RA, is given by intravenous infusion every 2 months.

Researchers at this meeting reported Remicade to be effective and safe in treating RA. Some reported an 80% significant response rate in the first year of use.

Dr. Shiel's Perspective: This is my experience with this medication. Very effective in calming the pain, stiffness, and swelling from the inflammation due to arthritis in a high percentage of patients.

It was also reported by researchers from the Netherlands that a combination of Remicade/methotrexate prevents structural damage to the joints of patients with RA, regardless of whether or not the patient was feeling better!

Dr. Shiel's Perspective: The fact that blocking TNF with drugs like Remicade and Enbrel stops disease progression has already been shown. The interesting point of this study is that they seem to prevent joint damage irrespective of whether patients' signs and symptoms of arthritis were improving. This seems to imply that the drug has an essential effect in stopping the rheumatoid disease.

Remicade or Enbrel treatments resulted in the increased ability of patients to work.

Dr. Shiel's Perspective: While it seems patently logical that controlling a disease that results in loss of function would help people return to the work place, it is good to see it documented.

Remicade was also effective for treating juvenile rheumatoid arthritis, thereby resulting in a significant and prompt reduction in disease activity and improved quality of life. And, another paper presented data demonstrating that doses of Remicade that are higher than currently recommended doses could be effective and necessary in juvenile rheumatoid arthritis.

Dr. Shiel's Perspective: This does not surprise me, since it is the same situation for adults with RA.

Remicade treatment allowed for the reduction in the use of simultaneous arthritis medications over time in 40% of patients. In fact, in many instances, patients were able to fully withdraw from other medications to the use of Remicade alone. This included tapering completely off of steroids (such as prednisone) and methotrexate.

Dr. Shiel's Perspective: I have been lowering doses of methotrexate and weaning off of steroids in my patients that have stable disease.

Remicade was reported as safe in 2 patients with RA who also had chronic hepatitis C.

Dr. Shiel's Perspective: I have treated patients with both conditions, but not yet with Remicade. This is may be a reasonable option for certain patients.

QUESTION

The term arthritis refers to stiffness in the joints. See Answer

Remicade is frequently given together with weekly methotrexate, since this has previously been shown to be helpful in preventing immune reactions to the Remicade. Research was presented that demonstrated the safety and effectiveness of Remicade alone. Also, at this meeting, papers were presented that demonstrated the safety and effectiveness of Arava in combination with Remicade as an alternative to methotrexate/Remicade combination in the treatment of RA.

Dr. Shiel's Perspective: I have treated patients with the Arava/Remicade combination successfully after hearing of previous preliminary reports. It is a treatment option for certain patients, such as those who could not tolerate methotrexate.

Both increasing the dose of Remicade and decreasing the interval between infusions were shown to be effective methods in capturing control of RA in several studies.

Dr. Shiel's Perspective: This is something I have already been doing in practice for the past 2 years. While it does not always work for those resistant cases, it can be very effective.

If Remicade is stopped, it was reported to result in a flare of the RA in an average of 4 months in 2/3 of patients.

Dr. Shiel's Perspective: This makes complete sense since Remicade is basically a powerful antiinflammation drug that only works when it is blocking the inflammation promoting protein, tumor necrosis factor (TNF). When it is out of the system, eventually the inflammation of the RA should return--(and does, on the average of about 4 months, as was shown at this meeting).

Three papers reported reactions to the Remicade infusions at rates of 4.3%, 5.5%, and 5.7%. They were generally reported between the second and fifth infusions of Remicade.

Dr. Shiel's Perspective: This is in line with previous reports and seems to be the most significant of the reactions to Remicade. These can often be prevented or minimized by pretreatment with antihistamine drugs and/or cortisone injections. Aspirin use also seem to have a preventative effect against infusion reactions, but the researchers I spoke with were really not certain as to why this happened.

Patients taking Remicade developed DNA antibodies (known to be associated with lupus) in 16% of patients. These antibodies were not felt to significant as they were not related to the development of lupus disease.

Dr. Shiel's Perspective: This has been my experience. I have been monitoring my patients closely for signs of lupus, but have never had any develop it. In fact, I have used Remicade in a number of patients who's conditions were originally lupus, but who transitioned into classical RA without lupus features. None of those patients again developed lupus symptoms and their RA was controlled.

Remicade also was shown to be effective in patients who had previously tried and failed Enbrel. One study reported Remicade and Enbrel as equally effective.

Dr. Shiel's Perspective: I have had some successes here as well. I have also had successes using Enbrel in patients who had failed Remicade. I agree that both drugs are similarly effective.

Enbrel (etanercept)

Enbrel is an injectable anti-tumor necrosis factor for treating rheumatoid arthritis. Tumor necrosis factor (TNF) is a protein that the body produces during the inflammatory response, the body's reaction to injury. TNF promotes the inflammation and its associated fever and signs (pain, tenderness, and swelling) in several inflammatory conditions, including rheumatoid arthritis. Enbrel is a synthetic (man-made) protein that binds to TNF. Enbrel thereby acts like a sponge to remove most of the TNF molecules from the joints and blood. This prevents TNF from promoting inflammation and the fever, pain, tenderness, and swelling of joints in patients with RA.

Enbrel plus methotrexate was reported at this meeting to be more effective than Enbrel alone.

Dr. Shiel's Perspective: This may be true, to a degree, for both Enbrel and Remicade, but I use them individually or with methotrexate or other drugs on a case by case basis.

The long-term safety of Enbrel in more than 2,600 patients over 5 years was reported. There was no cumulative toxicity with extended use and the clinical response was sustained for up to 5 years of the study.

Dr. Shiel's Perspective: These long-term statistics are very helpful for doctors who are assessing the value of this relatively new treatment for rheumatoid arthritis.

Enbrel was found to be safe when used in combination with Kineret (see below).

Dr. Shiel's Perspective: Combination therapy using more than one antirheumatic drug is commonly necessary in the treatment of certain patients with RA. This combination awaits further studies of Kineret before it is used commercially.

Enbrel increases general functioning of patients with RA.

Dr. Shiel's Perspective: This is important for doctors in office practice because we want to help our patients get to their optimal functional status.

Enbrel was found to be effective in patients with juvenile RA.

Dr. Shiel's Perspective: Enbrel is already approved for the use in treating juvenile rheumatoid arthritis that has not responded to other disease-modifying rheumatic drugs.

Arava (leflunomide)

Arava reduces inflammation by suppressing the immune cells responsible for the inflammation. It does this by preventing the formation of DNA and RNA in the immune cells by inhibiting an enzyme (dihydroorotate dehydrogenase) that is necessary for the production of a critical component of DNA and RNA, pyrimidine (a nucleic acid).

Arava plus methotrexate was reported as helpful and safe in patients with RA who had failed treatment with methotrexate alone. Elevations in liver function test were reversible with either a dose reduction or discontinuation of Arava.

Dr. Shiel's Perspective: This is a combination that I have not yet used. Both drugs have similar potential side effects in the liver and bone marrow.

Remicade is frequently given together with weekly methotrexate as this has previously been shown to be helpful in preventing immune reactions to the Remicade. At this meeting, papers were presented that demonstrated the safety and effectiveness of Arava in combination with Remicade as an alternative to methotrexate/Remicade combination in the treatment of RA.

Dr. Shiel's Perspective: I have already been using this combination effectively in my practice based on preliminary reports already published.

Arava was documented to be as safe after 2 years as in previously published studies of 1 year of use in patients with RA.

Arava's main side effects involve liver inflammation, skin rash, diarrhea, and reversible hair loss. Dr. Shiel's Perspective: These all seem to be relatively uncommon and seem to usually improve or resolve with adjustments of the dosage of the drug.

Arava was shown to be well tolerated and effective in treating children with RA who had failed or were intolerant of methotrexate.

Dr. Shiel's Perspective: This appears to be an important alternative it appears in juvenile rheumatoid arthritis treatment.

Kineret (anakinra)

This is the first in a new drug class that has just become commercially available for the treatment of moderate to severe RA, in patients 18 years of age or older, who have failed treatment with other disease-modifying drugs. It works by blocking the action of a chemical, interleukin-1, that is important in promoting inflammation. Kineret's safety and effectiveness has previously been documented in studies of over 1,300 patients with rheumatoid arthritis.

Kineret was shown to improve the functional status of patients with RA. In another study, Kineret was demonstrated to significantly improve the number of productive days at work and domestic home activity in patients with RA.

Dr. Shiel's Perspective: These are important because, after all, these are critical measures of successful treatment.

Kineret was found to be safe in patients when used in combination with Enbrel (see above). The safety of Kineret in over 1,100 patients was demonstrated as being similar to a placebo.

Dr. Shiel's Perspective: Combination therapy using more than one antirheumatic drug is commonly necessary in the treatment of certain patients with RA. This combination awaits further studies of Kineret before it is used commercially. Low white blood cell counts have previously been reported when combining Kineret with TNF-blocking drugs, such as Enbrel and Remicade. Kineret was also reported to reduce the inflammation of joints when used in combination with other arthritis drugs, such as indocin and methotrexate, but this was in rats. This drug appears relatively safe, but previous reports showed a small increase in infections as compared to the placebo. This drug must be injected into the skin daily. Local skin reactions (usually mild redness and irritation) at the site of the injections is the most common adverse reaction with the drug.

Kineret decreased signs of inflammatory arthritis in rats.

Dr. Shiel's Perspective: Well, this actually was a significant study because it demonstrated the beneficial effects of Kineret in reducing inflammation in the joints when used in combination with other arthritis medications, such as methotrexate.

The rate of side effects of Kineret was only slightly increased in regard to serious infections in comparison with the placebo.

Dr. Shiel's Perspective: I would like to see further side effect studies with this treatment. Preliminarily, these results are very encouraging.

Adalimumab

This is a new drug that is not commercially available. Adalimumab (D2E7) is the first fully human, monoclonal antibody in development. Adalimumab is an investigational agent designed to block the activity of tumor necrosis factor alpha (TNF-a), which contributes to the inflammation in autoimmune diseases such as RA. This drug, which is given by subcutaneous injection every 2 weeks, was effective in combination with methotrexate and seems to be well tolerated other than occasional injection site reactions. It is not yet commercially available, but is worth keeping an eye on.

Dr. Shiel's Perspective: Well, here comes a new kid on the block. It will be important to watch for further research on this drug. It may well be an effective addition to our current treatments. Injecting only every 2 weeks would be relatively convenient.

Valdecoxib

Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that is being studied for use in the treatment of RA. It is not yet commercially available. Prostaglandins are chemicals that are important contributors to the inflammation of arthritis, which causes the pain, fever, swelling, and tenderness. Valdecoxib blocks the enzyme that makes prostaglandins (specifically, cyclooxygenase 2 or Cox-2), resulting in lower concentrations of prostaglandins. As a consequence, inflammation and its accompanying pain, fever, swelling, and tenderness are reduced. Cox-2 Inhibitors differ from traditional NSAIDs in that they cause less inflammation and ulceration of the stomach and intestine and do not interfere with the clotting of blood.

Valdecoxib was superior to the placebo and similar to naproxen (at 500mg twice daily) in effectiveness. At the lower doses, it showed less stomach irritation than Naprosyn.

Dr. Shiel's Perspective: This would be a welcome addition to Celebrex, which is the Cox-2 NSAID currently available for the treatment of RA.

Etoricoxib

Etoricoxib is another Cox-2 NSAID that is being investigated for the treatment of RA (see Valdecoxib above). Previous studies have demonstrated its effectiveness in relieving the signs and symptoms of joint inflammation.

Fewer patients treated with etoricoxib had to discontinue the medication because of gastrointestinal complications as compared with the traditional NSAIDs, Voltaren, and Naprosyn.

Dr. Shiel's Perspective: This is an example of a safety study that must be performed before a drug is approved to demonstrate its value. Because it is billed as a Cox-2 inhibitor, etoricoxib should and apparently does, have advantages with regard to the stomach and intestines.

Associated Conditions

Early treatment of RA was clearly reported to have the best outcome.

Dr. Shiel's Perspective: This has long been believed to be true and arthritis specialists (rheumatologists) are treating RA more aggressively and earlier now than in past decades.

Sjogren's Syndrome

An increased bladder irritability was reported in patients with Sjogren's syndrome.

Dr. Shiel's Perspective: This seems to be an under-recognized complication of Sjogren's syndrome. Doctors will have to be vigilant in monitoring this symptom. Patients with symptoms of an overactive bladder should always report them to their doctor.

Smoking and Diet Risks

Heavy smoking was statistically shown to significantly increase the risk of developing RA.

Dr. Shiel's Perspective: As if we needed another reason NOT to smoke!

Researchers from the Universities of Alabama, Iowa, and San Francisco found that decaffeinated coffee intake was associated with an increased risk for the development of RA. Women drinking more than three cups of decaf coffee were at more than twice the risk of developing RA. Women drinking regular coffee were at no increased risk, while women drinking tea were had a 60% decreased risk!

Dr. Shiel's Perspective: This study requires further follow-up studies to confirm these preliminary results, as suggested by the authors of the study.

Patient Education

Education of patients with RA about their disease significantly improved their overall function, according to a paper reported from Canada.

Dr. Shiel's Perspective: Well, this is how I am devoting a major part of my life now here with MedicineNet.com. The reason is because I clearly see the benefits of education in my patients. (I wonder how much, in part, this has to do with being compliant about taking the medications regularly for the RA!)

Education of patients in Korea with RA about their disease significantly improved their fatigue and reduced pain, while improving self-care activities.

Dr. Shiel's Perspective: This was an 8 week intensive course with patients in small groups who were interacting to understand their disease. It would probably apply to anyone with RA who was interested in independently educating him or herself, say via the Internet!

The perceived quality of life of patients with RA improved significantly as a result of an after-day hospital education program.

Dr. Shiel's Perspective: Again, education proves to be a key to providing a higher quality of life for patients with RA.

Complications

Tuberculosis was reported to occur in RA patients four times more frequently than the general population.

Dr. Shiel's Perspective: While tuberculosis in the U.S. is not extremely common, this report is important. The reason is because the new "TNF-blocking" drugs, such as Remicade and Enbrel, have been documented to be associated with rare episodes of reactivation of tuberculosis. It seems that there is some increased risk simply from the rheumatoid condition itself. Currently, patients taking Remicade are recommended to be screened for tuberculosis with a skin test (PPD test) prior to starting the treatment.

For more, please visit MedicineNet.com' s Rheumatoid Arthritis Center.

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