Antirheumatic

There is no known cure for rheumatoid arthritis. To date, the goal of treatment in rheumatoid arthritis is to reduce joint inflammation and pain, maximize joint function, and prevent joint destruction and deformity. Early medical intervention has been shown to be important in improving outcomes. Aggressive management can improve function, stop damage to joints as seen on x-rays, and prevent work disability. Optimal treatment for the disease involves a combination of medications, rest, joint strengthening exercises, joint protection, and patient (and family) education. Treatment is customized according to many factors such as disease activity, types of joints involved, general health, age, and patient occupation. Treatment is most successful when there is close cooperation between the doctor, patient, and family members.
Two classes of medications are used in treating rheumatoid arthritis: fast-acting "first-line drugs," and slow-acting "second-line drugs (also referred to as Disease-Modifying Antirheumatic Drugs or DMARDs)." The first-line drugs, such as aspirin and cortisone (corticosteroids), are used to reduce pain and inflammation. The slow-acting second-line drugs, such as gold, methotrexate and hydroxychloroquine (Plaquenil) promote disease remission and prevent progressive joint destruction, but they are not anti-inflammatory agents.
The degree of destructiveness of rheumatoid arthritis varies from patient to patient. Patients with uncommon, less destructive forms of the disease or disease that has quieted after years of activity ("burned out" rheumatoid arthritis) can be managed with rest, pain and anti-inflammatory medications alone. In general, however, patients improve function and minimize disability and joint destruction when treated earlier with second-line drugs (disease-modifying antirheumatic drugs), even within months of the diagnosis. Most patients require more aggressive second-line drugs, such as methotrexate, in addition to anti-inflammatory agents. Sometimes these second-line drugs are used in combination. In some patients with severe joint deformity, surgery may be necessary.

"First-line" Drugs
Acetylsalicylate (Aspirin), naproxen (Naprosyn), ibuprofen (Advil, Medipren, Motrin), and etodolac (Lodine) are examples of nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are medications that can reduce tissue inflammation, pain and swelling. NSAIDs are not cortisone. Aspirin, in doses higher than that used in treating headaches and fever, is an effective antiinflammatory medication for rheumatoid arthritis. Aspirin has been used for joint problems since the ancient Egyptian era. The newer NSAIDs are just as effective as aspirin in reducing inflammation and pain, and require fewer dosages per day. Patients' responses to different NSAID medications vary. Therefore, it is not unusual for a doctor to try several NSAID drugs in order to identify the most effective agent with the fewest side effects. The most common side effects of aspirin and other NSAIDs include stomach upset, abdominal pain, ulcers, and even gastrointestinal bleeding. In order to reduce stomach side effects, NSAIDs are usually taken with food. Additional medications are frequently recommended to protect the stomach from the ulcer effects of NSAIDs. These medications include antacids, sucralfate (Carafate), proton-pump inhibitors (Prevacid, and others), and misoprostol (Cytotec).
Corticosteroid medications can be given orally or injected directly into tissues and joints. They are more potent than NSAIDs in reducing inflammation, and in restoring joint mobility and function. Corticosteroids are useful for short periods during severe flares of disease activity, or when the disease is not responding to NSAIDs. However, corticosteroids can have serious side effects, especially when given in high doses for long periods of time. These side effects include weight gain, facial puffiness, thinning of the skin and bone, easy bruising, cataracts, risk of infection, muscle wasting, and destruction of large joints, such as the hips. Corticosteroids also carry some increased risk of contracting infections. These side effects can be partially avoided by gradually tapering the doses of corticosteroids as the patient achieves improvement of the disease. Abruptly discontinuing corticosteroids can lead to flares of the disease or other symptoms of corticosteroid withdrawal, and is discouraged. Thinning of the bones due to osteoporosis may be prevented by calcium and vitamin D supplements. For further information on corticosteroids, please read the article on prednisone.

"Second-line" or "Slow-acting" Drugs
(Disease-modifying Anti-rheumatic Drugs or DMARDs)
While "first-line" medications (NSAIDs and corticosteroids) can relieve joint inflammation and pain, they do not necessarily prevent joint destruction or deformity. Rheumatoid arthritis requires medications other than NSAIDs and corticosteroids to stop progressive damage to cartilage, bone, and adjacent soft tissues. The medications needed for ideal management of the disease are also referred to as Disease-modifying Anti-rheumatic Drugs or DMARDs. They come in a variety of forms and are listed below. These "second-line" or "slow-acting" medicines may take weeks to months to become effective. They are used for long periods of time, even years, at varying doses. If effective, DMARDs can promote remission, thereby retarding the progression of joint destruction and deformity. Sometimes a number of second-line medications are used together as combination therapy. As with the first-line medications, the doctor may need to use different second-line medications before treatment is optimal.
Recent research suggests that patients who respond to a DMARD with control of the rheumatoid disease may actually decrease the known risk (small, but real) of lymphoma that exists from simply having rheumatoid arthritis.
Hydroxychloroquine (Plaquenil) is related to quinine, and is also used in the treatment of malaria. It is used over long periods for the treatment of rheumatoid arthritis. Possible side effects include upset stomach, skin rashes, muscle weakness, and vision changes. Even though vision changes are rare, patients taking Plaquenil should be monitored by an eye doctor (ophthalmologist).
Sulfasalazine (Azulfidine) is an oral medication traditionally used in the treatment of mild to moderately severe inflammatory bowel diseases, such as ulcerative colitis and Crohn's colitis. Azulfidine is used to treat rheumatoid arthritis in combination with antiinflammatory medications. Azulfidine is generally well tolerated. Common side effects include rash and upset stomach. Because Azulfidine is made up of sulfa and salicylate compounds, it should be avoided by patients with known sulfa allergies.
Methotrexate has gained popularity among doctors as an initial second-line drug because of both its effectiveness and relatively infrequent side effects. It also has an advantage in dose flexibility (dosages can be adjusted according to needs). Methotrexate is an immune suppression drug. It can affect the bone marrow and the liver, even rarely causing cirrhosis. All patients taking methotrexate require regular blood test monitoring of blood counts and liver function blood tests.
Gold salts have been used to treat rheumatoid arthritis throughout most of the past century. Gold thioglucose (Solganal) and gold thiomalate (Myochrysine) are given by injection, initially on a weekly basis for months to years. Oral gold, auranofin (Ridaura) was introduced in the 1980's. Side effects of gold (oral and injectable) include skin rash, mouth sores, kidney damage with leakage of protein in the urine, and bone marrow damage with anemia and low white cell count. Patients receiving gold treatment are regularly monitored with blood and urine tests. Oral gold can cause diarrhea. These gold drugs have lost such favor that many companies no longer manufacture them.
D-penicillamine (Depen, Cuprimine) can be helpful in selected patients with progressive forms of rheumatoid arthritis. Side effects are similar to those of gold. They include fever, chills, mouth sores, a metallic taste in the mouth, skin rash, kidney and bone marrow damage, stomach upset, and easy bruising. Patients on this medication require routine blood and urine tests. D-penicillamine can rarely cause symptoms of other autoimmune diseases.
Immunosuppressive medicines are powerful medications that suppress the body's immune system. A number of immunosuppressive drugs are used to treat rheumatoid arthritis. They include methotrexate (Rheumatrex, Trexall) as described above, azathioprine (Imuran), cyclophosphamide (Cytoxan), chlorambucil (Leukeran), and cyclosporine (Sandimmune). Because of potentially serious side effects, immunosuppressive medicines are generally reserved for patients with very aggressive disease, or those with serious complications of rheumatoid inflammation, such as blood vessel inflammation (vasculitis). The exception is methotrexate, which is not frequently associated with serious side effects and can be carefully monitored with blood testing. Methotrexate has become a preferred second-line medication as a result.
Immunosuppressive medications can depress bone marrow function and cause anemia, a low white cell count and low platelets counts. A low white count can increase the risk of infections, while a low platelet count can increase the risk of bleeding. Methotrexate can also lead to liver cirrhosis and allergic reactions in the lung. Cyclosporin can cause kidney damage and high blood pressure. Because of potentially serious side effects, immunosuppressive medications are used in low doses, usually in combination with anti-inflammatory agents.

Newer Treatments
Newer "second-line" drugs for the treatment of rheumatoid arthritis include leflunomide (Arava), and the "biologic" medications etanercept (Enbrel), infliximab (Remicade), anakinra (Kineret), and adalimumab (Humira).
Leflunomide (Arava) is available to relieve the symptoms and halt the progression of the disease. It seems to work by blocking the action of an important enzyme that has a role in immune activation. Arava can cause liver disease, diarrhea, hair loss, and/or rash in some patients. It should not be taken just before or during pregnancy because of possible birth defects.
Other medications that represent a novel approach to the treatment of rheumatoid arthritis and are the products of modern biotechnology. These are referred to as the biologic medications or biological response modifiers. In comparison with traditional DMARDs, the biologic medications have a much more rapid onset of action and can have powerful effects on stopping progressive joint damage.
Etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira) are biologic medications. These medications intercept a protein in the joints (tumor necrosis factor, or TNF) that causes inflammation before it can act on its natural receptor to "switch on " inflammation. This effectively blocks the TNF inflammation messenger from calling out to the cells of inflammation. Symptoms can be significantly, and often rapidly, improved in patients using these drugs. Etanercept (Enbrel) must be injected subcutaneously once or twice a week. Infliximab (Remicade) is given by infusion directly into a vein (intravenously). Adalimumab (Humira) is injected subcutaneously either every other week or weekly. Each of these medications will be evaluated by doctors in practice to determine what role they may have in treating various stages of rheumatoid arthritis. Recent studies demonstrate that biological response modifiers also prevent the progressive joint destruction of rheumatoid arthritis. They are currently recommended for use after other medications have not been effective. The biological response modifiers (TNF-inhibitors) are expensive treatments. They are also frequently used in combination with methotrexate and other DMARDs.
Anakinra (Kineret) is another biologic treatment that is used to treat moderate to severe rheumatoid arthritis. Anakinra (Kineret) works by binding to a cell messenger protein (IL-1, a proinflammation cytokine). Anakinra (Kineret) is injected under the skin daily. Anakinra (Kineret) can be used alone or with other DMARDs. The response rate of anakinra (Kineret) does not seem to be as high as with other biologic medications.
While biologic medications are often combined with traditional DMARDs in the treatment of rheumatoid arthritis, they are generally not used with other biologic medications because of unacceptible risk for serious infections.
The Prosorba column therapy involves pumping blood drawn from a vein in the arm into an apheresis machine, or cell separator. This machine separates the liquid part of the blood (the plasma) from the blood cells. The Prosorba column is a plastic cylinder about the size of a coffee mug that contains a sand-like substance coated with a special material called Protein A. Protein A is unique in that it binds unwanted antibodies from the blood that promote the arthritis. The Prosorba column works to counter the effect of these harmful antibodies. The Prosorba column is indicated to reduce the signs and symptoms of moderate to severe rheumatoid arthritis in adult patients with long standing disease who have failed or are intolerant to disease-modifying anti-rheumatic drugs (DMARDs). The exact role of this treatment is being evaluated by doctors and it is not commonly used currently.

OBJECTIVES: Although cyclooxygenase-2 inhibitors (coxibs) were developed to cause less gastrointestinal hemorrhage than nonselective nonsterodial antiinflammatory drugs (NSAIDs), there has been concern about their cardiovascular safety. The relative risk of acute myocardial infarction (AMI) was studied among users of celecoxib, rofecoxib, and NSAIDs in Medicare beneficiaries with a comprehensive drug benefit. METHODS: A matched case-control study was conducted of 54,475 patients 65 years of age or older who received their medications through two state-sponsored pharmaceutical benefits programs in the United States. All healthcare use encounters were examined to identify hospitalizations for AMI. Each of the 10,895 cases of AMI were matched to four controls on the basis of age, gender, and the month of index date. A matched logistic regression model was constructed, including indicators for patient demographics, healthcare use, medication use, and cardiovascular risk factors to assess the relative risk of AMI in patients who used rofecoxib compared with persons taking no NSAID, taking celecoxib, or taking NSAIDs. RESULTS: Current use of rofecoxib was associated with an elevated relative risk of AMI compared with celecoxib (OR 1.14; 95% CI, 1.05-1.46; P = 0.011), and with no NSAID (OR, 1.14; 95% CI, 1.00-1.31; P = 0.054). The adjusted relative risk of AMI was also elevated in dose-specific comparasions; rofecoxib < or = 25 mg versus celecoxib < or = 200 mg (OR 1.21; 95% CI, 1.01-1.44; P = 0.036) and rofecoxib > 25 mg versus celecoxib > 200 mg (OR 1.70; 95% CI, 1.07-2.71; P = 0.026). The adjusted relative risks of AMI associated with rofecoxib use of 1 to 30 days (OR, 1.40; 95% CI, 1.12-1.75; P = 0.005) and 31 to 90 days (OR, 1.38; 95% CI, 1.11-1.72; P = 0.003) were higher than > 90 days (OR, 0.96; 95% CI, 0.72-1.25; P = 0.8) compared with celecoxib use of similar duration. Celecoxib was not associated with an increased relative risk of AMI in these comparisions. CONCLUSIONS: In this study, current rofecoxib use was associated with an elevated relative risk of AMI compared with celecoxib use and no NSAID use. Dosages of rofecoxib greater than 25 mg were associated with a higher risk than dosages of 25 mg or less. The risk was elevated in the first 90 days of use, but not thereafter.

BACKGROUND: Oxygen free radicals have been implicated as mediators of tissue damage in patients of rheumatoid arthritis (RA). This study was designed to elucidate plasma oxidant/antioxidant status in rheumatoid arthritis, with the aim of evaluating the importance of antioxidant therapy in the management of this disease. METHODS: The study included 40 patients of rheumatoid arthritis who were randomly divided into two subgroups of 20 each. One group received conventional treatment for 12 weeks and in the other group conventional treatment was supplemented with antioxidants for the same duration. Twenty age- and sex-matched normal individuals constituted the control group. Blood samples of controls and patients were collected at the time of presentation and analyzed for total thiols, glutathione, vitamin C and malondialdehyde (MDA-marker of oxidative stress). The investigations were repeated in the patients after 12 weeks. RESULTS: The blood concentrations of total thiols, glutathione and vitamin C were found to be significantly lower in rheumatoid arthritis patients as compared to healthy controls, while the concentrations of MDA were much higher. There was a statistically significant increase in the posttreatment concentrations of these antioxidants, along with a decrease in the concentrations of MDA. CONCLUSIONS: The antioxidant defense system is compromised in rheumatoid arthritis patients. There is a shift in the oxidant/antioxidant balance in favor of lipid peroxidation, which could lead to the tissue damage observed in the disease. The results suggest the necessity for therapeutic co-administration of antioxidants along with conventional drugs to such patients. However, due to the limited number of cases included in this study, more studies may be required to substantiate the results and arrive at a definite conclusion, in terms of safety and efficacy of adding on antioxidant therapy for the treatment of RA.

Nippon Rinsho. 2002 Dec;60(12):2351-6.
Combination therapy of disease-modifying antirheumatic drugs(DMARDs) in rheumatoid arthritis
Kobayashi S, Kanai Y.
Department of Rheumatology, Juntendo University, School of Medicine.

The early suppression of disease activity during the first 2 years in rheumatoid arthritis (RA) has been reported to be exclusively important to prevent joint destruction and functional decline. Since single disease-modifying antirheumatic drugs(DMARDs) therapy is still disappointing, many rheumatologists today advocated a more aggressive approach using combinations of classic DMARDs. Many clinical trials on combination therapy have been reported and most studies of combination therapy focused on the efficacy of a treatment strategy. Therefore, the possible synergistic action of combination of drugs has not been demonstrated. Among combination of therapy of classical DMARDs, only few trials demonstrated the efficacy of combination therapy. The incidence of adverse effects among 341 RA patients was investigated by our department. The incidence of adverse effect in combination therapy revealed 36.4% which was not statistically different from that in monotherapy(33.6%, p = 0.41). The recent studies on combination therapy on classical DMARDs are not encouraging, however, the combination therapy for patients with early RA, drugs utilizing immunosuppressant, biologics and other newly developed drugs will still have a chance to expect a potent efficacy for RA.

Longterm safety and efficacy of disease modifying antirheumatic drugs (DMARD) have been challenging to assess. There are few studies that have evaluated patient outcome beyond 5 years. As patients may receive several DMARD over the course of their disease a long with nonsteroidal antiinflammatory drugs, corticosteroids, and other drugs for comorbidities, it is difficult to design and implement a trial to define a specific drug's longterm effect. Based on the findings of several key studies, however, it does appear that DMARD are safe when taken longterm, and that they are more likely to be discontinued because of inefficacy than toxicity. Although DMARD are often discontinued because of lack of efficacy, 12 year data suggest that DMARD can provide benefit over this period. The toxicity profiles vary significantly between DMARD. In addition, the time during therapy when the majority of these adverse effects most frequently appear is DMARD-specific. Prospective studies are needed to further clarify longterm safety and efficacy of the newer DMARD.