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[E381]Exercises For Rheumatoid Arthritis

by Nathan Wei, Nat

The most widely prescribed disease-modifying anti-rheumatic drug (DMARD) for rheumatoid arthritis is methotrexate.

It has been in use since the early 1980's and is the “gold standard” by which rheumatologists judge all other DMARDS. It is also the drug upon which other medicines such as biologic response modifiers (BRMS) are added.

Methotrexate interferes with folic acid metabolism by blocking a specific enzyme called dihydrofolate reductase. Dihydrofolate reductase is required for the growth of actively dividing cells. Since inflammation is perpetuated by rapidly growing cells, methotrexate is felt to exert its effects by blocking the multiplication or proliferation of these cells.

As a result of its actions, methotrexate reduces the swelling and pain associated with rheumatoid arthritis and also decreases the risk of long term disability. It takes roughly 4-12 weeks to see the maximum effects of methotrexate. During this short period of time, the dose of methotrexate is started at a low dose and gradually increased.

The drug can be administered in several ways. Patients who have extremely active disease can be treated intravenously to help with induction of remission. Patients can then be treated with oral tablets. The tablets come in a dose of 2.5 mgs per tablet. Methotrexate is taken as a single dose of medicine once a week. That means that if a patient is taking the drug either intravenously or in tablet form, they take all their medicine at one time once a week. Some patients who have difficulty taking oral tablets because of nausea may be able to take their methotrexate as a subcutaneous injection.

The dose of methotrexate varies from a low of 5 mgs per week to as high as 25 mgs per week. Higher doses tend to be poorly tolerated.

Potential side effects include mouth sores, gastrointestinal problems such as nausea, vomiting, and diarrhea, shortness of breath, cough, liver function abnormalities, hair loss, sun sensitivity, and drops in white blood cell count or platelet count. Rarely, cirrhosis of the liver can occur. Older people who have dietary deficiencies are at particular risk for methotrexate side effects.

Patients should have laboratory testing of blood counts and liver function tests once a month.

Patients are usually given supplemental folic acid in a dose of 1-2 mgs per day to counteract some of the side effects of methotrexate.

Methotrexate is terribly teratogenic (capable of causing birth defects). Therefore, in women, as well as men, who are contemplating having children, patients need to hold their methotrexate for at least 3 months prior to attempting conception.

Since methotrexate is capable of damaging the liver, patients should be counseled about limiting or eliminating alcohol ingestion.

Furthermore, methotrexate can interact with a number of other medicines including antibiotics such as sulfa drugs as well as non-steroidal anti-inflammatory drugs.

Methotrexate is often used in combination with biologic drugs such as Enbrel, Humira, and Remicade.

Gold was used extensively until the early 1980's when it was supplanted by methotrexate as the disease-modifying anti-rheumatic drug (DMARD) of choice. (DMARDS are drugs that actually slow down the progression of rheumatoid arthritis (RA) as opposed to non-steroidal anti-inflammatory drugs that merely help with symptoms.) More recently, biologic treatments have also entered the arena and are capable of putting RA into remission.

Gold treatment, while often effective, also was associated with a host of problems. The shots took months to take effect and side effects included rashes, mouth sores, kidney damage, inflammation of the lung, and occasionally, damage to the bone marrow causing life-threatening reductions in the number of red and white blood cell counts and platelet counts.

Dr. David Pisetsky, chief of the division of rheumatology at Duke University School of Medicine, says " We rheumatologists have really never understood how gold works." His hope is that once the mechanism of action is understood, then it might be possible to create new and better gold-like drugs to treat arthritis.

Pisetsky's interest in gold comes from his work with a particular molecule, HMBG1, which causes inflammation, the linchpin to the development of rheumatoid arthritis. He states, "HMBG1 is a molecule which has two functions; it behaves one way when it's inside the nucleus of a cell, and ...another way when it's released from a cell."

Inside the nucleus, HMGB1 acts as a messenger and is responsible for converting genetic information from DNA to RNA. But when HMGB1 is released from the cell, for whatever reason, it stimulates the immune system and promotes inflammation...

Pisetsky feels that if HMGB1 were kept within the nucleus, it would help reduce the inflammation associated with arthritis.

HMGB1 prodcution in the body is heterogenous- it is not produced in the same concentration in every tissue of the body. There is an unusually high amount of it present within joints where arthritis occurs.

The experiments went like this... researchers at the University of Pittsburgh, the Karolinska Institute in Sweden, and Duke stimulated mouse and human immune system cells to make HMGB1, then treated the cells with gold. They found that the gold blocked release of HMGB1 from the nucleus. Theoretically, that should lessen the amount of HMGB1 available to promote an inflammatory response.

Pisetsky feels that gold works by interfering with the action of interferon beta and nitric oxide. These two substances help control the release of HMGB1.

(The study will appear in the January, 2008 issue of the Journal of Leukocyte Biology, but will be available ahead of print on the journal's website. Co-authors of the study include lead investigators Weiwen Jiang, from Duke University, and Cecilia Zetterstrom, from the Karolinska Institute; Heidi Wahamaa, Therese Ostberg, Ann-Charlotte Aveberger, Hanna Schierback and Ufl Anderson from the Karolinska Institute; Helena Erlandersson Harris, senior co-author, from the Medicine and Rheumatology Unit of the Karolinksa University Hospital and Michael Lotze, from the University of Pittsburgh.)

This description about how gold may work is fascinating to an arthritis specialist who started practice in 1981. At that time we had hydroxychloroquine, gold, and d-penicillamine. None of these treatments was ideal and both gold and d-penicillamine were very toxic. Our treatment options have increased greatly and we are now able to get many patients with RA into remission. However, we still have a ways to go. Research into the mechanisms of disease will help us find better therapies in the future. It may be that some of the older therapies like gold- if we can develop drugs that have the good effects... without the bad, may be very useful.

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Nathan Wei has sinced written about articles on various topics from Arthritis Pain, Health and Arthritis Signs. Nathan Wei, MD FACP FACR is a rheumatologist. For more info: or. Nathan Wei's top article generates over 550000 views. to your Favourites.