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[R315]Rheumatoid Arthritis Drug Treatment

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.

These drugs are targeted therapies that act on tumor necrosis factor, a cytokine, to block its action in the immune response that is out of whack in patients with RA. Cytokines are chemical messengers that are produced by cells to permit signaling among each other.

TNF-inhibitors may be used in conjunction with disease modifying anti-rheumatic drugs (DMARDS) such as methotrexate, although they may also be used alone.

Since their first use approximately fifteen years ago, much information has become gleaned from clinical experience as well as clinical research trials.

About one-third of patients with RA treated with anti-TNF drugs fail to respond. This failure of response is called primary treatment failure.

And another significant percentage of patients lose response over time. This phenomenon is termed secondary treatment failure.

Patients with primary treatment failure are generally switched to another anti-TNF drug with a different mechanism of action.

Patients who experience secondary failure can have their dose of drug increased either by increasing the amount of drug given or by decreasing the interval between doses of drug.

Anti-TNF drugs do come with potential serious side effects that must be monitored for.

These include an increased risk of infection as well as a possible increase in risk of cancer reoccurrence (although this is highly speculative). TNF-inhibitors can also increase the risk of tuberculosis.In addition, an increased incidence of other fungal infections such as histoplasmosis and coccidiodomycosis has also been noted.

Other potential side effects include a risk of neurological syndromes that mimic multiple sclerosis and injection site reactions.

Options for patients who have developed failure to TNF-inhibitor treatment include switching to either abatacept (Orencia) or rituximab (Rituxan).

Abatacept acts to block the activation of T-cells which are felt to play a significant role in the immune response.

Rituximab acts by depleting B-cells, which are also felt to be a significant contributor to the role of RA progression.

Another drug that is waiting in the wings is tocilizumab (Actemra). This drug inhibits the action of interleukin-6, another cytokine that has multiple effects on the immune system. Actemra has many desirable effects but because interleukin-6 is so ubiquitous, it also has some undesirable effects as well. These include elevation of liver enzymes as well as elevation of lipids.

Other drugs that have even different mechanisms of action include the various protein kinase inhibitors such as the Syk and JAK inhibitors that are currently being studied. These drugs have multiple effects on the immune system and are attractive because unlike anti-TNF drugs, protein kinase drugs are taken orally. However, they too have potentially undesirable side effects that must be accounted for.

The current buzz is the development of biomarker profiles that will potentially allow customized therapies for RA patients. By biopsying the synovium (lining of the joint)and identifying the biomarkers that are present within the synovium, it may be possible to "customize" the correct drug or combination of drugs that will get a patient into remission.

This will provide a much more targeted approach to treatment and may potentially lead to a cure for this devastating disease.

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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.