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Rheumatoid arthritis (RA) is a chronic systemic disease characterized by inflammation and multiplication of inflammation causing cells within the lining of the joints. This leads to progressive damage and bone destruction. In addition, because it is systemic disease, the same type of inflammatory changes are seen in other organ systems of the body.
It is the consensus of most researchers that RA is driven by chemical messengers called cytokines. These cytokines activate immune cells to attack the synovial lining of the joint. Among the most important cytokines are tumor necrosis- α (TNF) and interleukin -1β (IL-1).
These two cytokines have been the prime targets for the development of different therapies for RA. Drugs like Enbrel, Humira, and Remicade block the effects of TNF while Kineret blocks the effects of IL-1.
Another interesting cytokine that seems to play a significant role is interleukin-6. Studies have demonstrated that the fluid obtained from the inflamed joints of patients with RA have an increased level of IL-6. The increase in IL-6 correlates with laboratory signs of inflammation such as elevated erythrocyte sedimentation rate (ESR) as well as with clinical signs such as fever and anemia.
IL-6 is made by a number of different cells that are involved in the immune response. These include, among others, T cells and B cells. T cells and B cells are lymphocytes, a type of white blood cell, that is responsible for many immune functions. Another major source of IL-6 in RA is the synovial cell fibroblast, a type of cell that is found in the lining of the joint of patients with RA.
In laboratory experiments, it appears that IL-6 is necessary for the production of antibodies by B cells. IL-6 also activates T-cells, ie. makes them more likely to participate in the immune response.
A number of studies have shown that IL-6 is a major player in causing and perpetuating inflammation. What seems to be the primary process within the joint is the production of IL-6 by synovial fibroblasts (SF). The IL-6 then causes more SF to grow. Thus a cycle of SF growth leading to more IL-6, leading to more SF growth takes place.
Il-6 may also cause another type of cell, the osteoclast, to multiply. Osteoclasts chew away bone. This chewing away of bone leads to erosions, the hallmark of RA within the joint.
Because IL-6 has such a large role in destructive inflammation, it has been an attractive target for drug development.
Attempts to create an antibody against IL-6 have been successful. Tociluzamab is a humanized mouse antibody directed against human IL-6. Experiments have clearly shown that this product binds to and inhibits the inflammatory capability of IL-6. The tradename of tociluzamab is Actemra.
Clinical trials are ongoing investigating the safety, tolerability, and efficacy of this new compound.
This window last perhaps 2-3 months following the development of symptoms. It is critical that a patient be started on a disease-modifying anti-rheumatic drug as soon as possible.
Methotrexate is the drug that is most commonly prescribed in patients with newly diagnosed rheumatoid arthritis. It is the disease modifying anti-rheumatic drug (DMARD)of choice for most patients. This means it has an effect of slowing down the progression of disease.
Methotrexate has the potential for significant side effects. The word "potential" needs to be stressed. Most patients take methotrexate without any significant problems. Safety warnings about methotrexate should be heeded. To improve patient safety, methotrexate must be taken according to directions. Patients should undergo teaching before starting the drug. In our clinic, all patients started on methotrexate go through a teaching process with our nurses.
Methotrexate is classified as a DMARD because it decreases pain and swelling associated with arthritis, and also, methotrexate can slow down the rate of and lower the risk of long-term disability.
Improvement from methotrexate may be seen at anywhere from 4 to 12 weeks. If a patient has not improved by twelve weeks, they are not going to respond.
Methotrexate blocks the enzyme dihydrofolate reductase. By doing so, it affects production of a form of folic acid, which is needed for actively growing cells. It remains unclear exactly how methotrexate decreases arthritis activity. However, it appears to have both anti-inflammatory as well as disease-modifying effects.
Methotrexate is available in 2.5 mg tablets. The starting dose for most adults with rheumatoid arthritis is 7.5 to 10 mg (i.e. 3 or 4 pills). The 3 or 4 pills are taken together once a week (i.e. the same day each week is advised). The dose of methotrexate can be increased to 20 to 25 mg each week. Methotrexate is also available in an injectable form. Methotrexate injection given as 12.5 to 50 mgs is sometimes used as induction therapy for RA patients who have severe disease. After 6 weeks of intravenous therapy, they can be switched to oral therapy. The injectable form of the drug is sometimes given subcutaneously by patients who have problems tolerating the oral tablets.
Methotrexate can cause abnormal liver function. It's important to routinely have blood drawn for complete blood counts as well as liver function so the doctor can monitor for unwanted side effects.
In our clinic, we monitor patients on a monthly basis. There are many places that monitor patients less frequently; however, we have had at least five cases over the last three years where if the patient wasn't not monitored monthly, a serious potentially dangerous side-effect would have been missed.
The increased risk of liver damage is significant for people who drink alcohol excessively while taking methotrexate. While no alcohol is unrealistic, we do advise that patients curtail their alcohol intake. If they continue to ingest more than 1 drink a day, we discontinue the methotrexate. Long term studies have not been done; however, in patients with abnormal liver function test, we will do liver biopsies.
Nausea, vomiting, and severe fatigue may occur and be dose-dependent. If you have any of these side effects, adjusting the dose may eliminate the problem. Many patients experience no significant side effects while taking methotrexate. Other possible side effects include:
•Mouth sores
•rash
•diarrhea
•blood count abnormalities
•cirrhosis of liver (rare)
•persistent cough
•unexplained shortness of breath
•hair loss
•sensitivity to sunlight
Methotrexate should not be taken by people with significant liver or kidney disease and may need to be temporarily stopped before having surgery.
Since methotrexate is a folic acid antagonist, patients should take folic acid supplements daily. Folic acid supplementation minimizes the side effects associated with taking methotrexate. The dose of folic acid is generally 1-3 mgs per day.
Methotrexate can cause serious birth defects. Patients should use some form of contraception while taking methotrexate and for 3 months after they stop taking methotrexate. It's important to note that although a woman should not take methotrexate during pregnancy, taking the drug does not decrease the chance for future pregnancies.
Men who take methotrexate should also stop the drug about three months before attempting conception.
Drugs known to increase methotrexate toxicity include the sulfa antibiotics and non-steroidal anti-inflammatory drugs (NSAIDS). These drugs should be used cautiously in patients taking methotrexate.
Methotrexate is often used as a "base" drug in that other medications such as anti-tumor necrosis factor medicines such as Enbrel, Humira, or Remicade are added to it to induce remission.