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About RA

The Treatment of Rheumatoid Arthritis

Since the cause of rheumatoid arthritis is still unknown, one cannot expect to be completely cured of the disease while undergoing treatment. However, by aggressively using anti-rheumatic drugs such as methotrexate and biological products, QOL can be maintained while working towards the goal of remission.

Drug Therapy

1-1. Non-steroidal anti-inflammatory drugs (anti-inflammatory drugs)

By suppressing the production of substances called prostaglandins which cause inflammation, joint pain and swelling can be reduced. Although the medication cannot stop the progression of the disease or bone and joint destruction, it takes effect quickly; therefore it’s useful for patients in maintaining their daily lives. However, this treatment can cause side effects such as stomach ulcers or reduced kidney function. To counteract these problems, supplemental medications are available. Since ulcers induced by nonsteroidal anti-inflammatory drugs generally have no recognizable symptoms in nearly half of the patients, it is recommended that upper endoscopy or fecal occult blood test should be done on a regular basis.

1-2. Corticosteroid (steroids):

At one time corticosteroids were used as the wonder drug for rheumatoid arthritis because of their superior ability to suppress inflammation. Originally discovered in the 1950s, their developers (Hench, Kendall, Reichstein) received a Nobel Prize. Later, however, many side effects were discovered, and they are now used mainly as adjuvant therapy. A regular dosage is 5mg best taken in the morning to match the body’s natural rhythm. As a side effect, taking the drug lowers the body’s natural production of steroid hormones. So patients must not change their dosage independently. It’s important to follow doctor’s instructions while under treatment.

1-3. Anti-rheumatic drugs and immunosuppressive drugs:

Anti-rheumatic drugs work to improve abnormalities in the immune system. They are referred disease modifying anti-rheumatic drugs because the may stop progression of the disease. Now they are actively used in treatment with in the first three month of onset.

Characteristics of anti-rheumatic drugs:

1. They are essential to the treatment of rheumatoid arthritis.
2. They are generally slow-acting but the effects are sustainable.
3. Some patients respond to treatment while do not.
4. While complete remission is rare they may slow the progression of joint damage.
5. If the efficacy of one drug diminishes, a doctor may consider changing or combining medications for treatment.
6. Side effects vary depending upon the medicine, caution should be used because some side effects are quite severe.
• Bucillamine (trade name Rimachiru) the 
SH compound, tectonically similar to penicillamine. It was developed in Japan. Efficacy is relatively high and it tends to be used first due to its less serious side effects.
• Salazosulfapyridine (trade name Azarufijin EN) efficacy is good, particularly in early stages some patients respond well. Especially in Europe it is used as a standard anti-rheumatic drug, along with methotrexate.
• Methotrexate (trade name Riumatorekkusu, Metoreto, etc.) is the standard treatment in the United States
. It was approved in Japan in August of 1999 for the treatment of rheumatoid arthritis. In the United States the average dosage is 15mg per week, but because of its side effects, in Japan the dosage is limited to 8mg per week. Methotrexate has a rapid therapeutic effect as compared to other anti-rheumatic medications, and the effects are long lasting. The most notable side effects are bone marrow suppression and acute interstitial pneumonia, so blood tests and regular chest X-rays are required.
• Leflunomide (trade name Arava) is an immunosuppressive drug which was approved for use in Japan in April of 2003. Reports from abroad indicate efficacy similar to or higher than methotrexate. As for dosage, for the first three days, 100mg is taken orally once in the morning. After that, a dosage of 4-10mg is taken once in the morning. Unlike methotrexate, because the dosage is the same for Japanese regardless of their weight difference as compared with Europeans and North Americans there are many side effects, particularly severe interstitial pneumonia.
• Tacrolimus (trade name Prograf) was approved for use in Japan in April of 2005. As side effects, kidney damage and abnormal glucose tolerance are reported often. However hepatic damage is rare. The difference of the side effect from the other anti-rheumatoid drug is that there are fewer reports of interstitial pneumonia.

Other medications are also available, though at present, are not widely used:

• Gold compounds: injection (trade name Shiozoru) oral (trade name Ridora)
• Penicillamine (trade name Metarukaputaze)
• Lobenzarit (trade name Karufeniru)
• Mizoribine (trade name Buredinin)
• Actarit (trade name Ochre, Mobar)

1-4. Biological Products:

Biological products are drugs (injectable formulations) developed with genetic engineering techniques. Currently there are four of them available for RA treatment in Japan. Three of them inhibit the action of the molecules for tumor necrosis factor (TNF) by combining with them, they are remicade (trade name Remicade), etanercept (trade name Enbrel) and adalimumab (trade name Humira). The fourth, tocilizumab (trade name Actemra) is an antibody drug which works against IL-6 receptors.
Remicade needs to be used with methotrexate (MTX; trade name Riumatorekkusu / Metoreto) to inhibit the production of neutralizing antibodies. Usually one to two weeks after the initiation of the treatment, inflammation reactions (CRP levels) and joint pain and swelling start to improve. As the drugs are known to stop bone destruction, one can expect the prevention of joint deformation. If patients stop taking treatment after conditions improve, remission may be sustainable, meaning the disease could almost be cured. The method of administration is intravenous infusion and each takes about two hours. The second infusion is done two weeks after the first, the third is done four weeks after the second, and the four is done eight weeks after the third. Subsequent infusions are also done at eight week intervals.
Enbrel is a subcutaneous injection formulation, injected twice a week. With proper practice, it is possible for patients to perform self-administration. Although combination use of methotrexate is not always necessary, it may improve the efficacy. Like remicade, enbrel has an efficacy that can prevent joint destruction.
Although humira is also administered by subcutaneous injection, the frequency is only once every two week. Self administration is also possible with proper practice. Like enbrel, the combination use of methotrexate is not necessarily required, though higher efficacy can be expected. Humira, also like remicade, can prevent joint destruction.
Actemra is an intravenous formulation. Intravenous infusions are done every four weeks and each one takes about an hour. Actemra doesn’t need to be used with methotrexate. Like remicade, actemra has the efficacy that can prevent joint destruction.
These biological products have some side effects which require caution during treatment. The most severe side effects are infections and allergic reactions. For example, tuberculosis is a severe side effect and patients such as tuberculin reactors or those who have a history of tuberculosis should take an antitubercular agent during the treatment. By taking that precaution, tuberculosis can be prevented. Another side effect is pneumonia caused by various pathogenic microbes, which occurs in 3 % of the patients(3 out of 100 patients). Recently, as opportunistic infections become progressively more severe, if one has cough or has fever a chest X-ray should be taken immediately. Vaccinations against influenza or pneumococcus are recommended. As for allergic reactions, there is a severe reaction again intravenous fluid preparation called anaphylaxis. Also injection site reactions (redness or itching at the injection site) are often seen after administrating the treatment intravenously. Usually the treatment continues with the use of allergy medication. However, these biological products are thought to be safe in a sense because organ damage (reduced blood cells, liver or kidney damage, etc.) usually caused by the other conventional anti-rheumatoid drug is very rare when using them.
Unfortunately though, these four biological agents are very expensive. For example one infusion of remicade costs about two hundred twenty thousand yen (about seventy thousand yen with regular medical insurance that covers 70 percent of the cost) for a patient of average constitution (weighing 34~67 kilos). One injection of enbrel is about fifteen thousand yen, meaning 8 injections which is supposed to be necessary for one month’s treatment cost one hundred twenty thousand yen (thirty six thousand yen for those with 30 percent self-pay health insurance). Humira is about seventy thousand yen, meaning about one hundred forty thousand yen every month (forty two thousand yen with 30 percent self-pay health insurance). The dosage of actemra is 8 mg based on weight meaning 400mg should be given to a 50kg-patient, which cost more than one hundred twenty thousand yen (about forty thousand yen with 30 percent self-pay health insurance). Such high medical expenses have been a problem in applying biological products.