Drugs II

Methotrexate: Committee on Rheumatologic Care; J. Michael Condit, MD, Chair;FOR DISTRIBUTION TO: Members of the American College of Rheumatology; People with Arthritis; Primary Care Physicians; Medical Societies; Media Representatives:

BACKGROUND: Low-dose methotrexate has been approved by the Food and Drug Administration for use in the treatment of rheumatoid arthritis and psoriasis. It may be used alone or in combination with other disease-modifying agents or anti-inflammatory agents. For more than twenty-five years, the drug has been the subject of clinical trials in people with rheumatoid arthritis and has proven to be beneficial in both short- and long-term management of rheumatoid arthritis.

As an antirheumatic drug, methotrexate is used as a disease modifying treatment second-line treatment for rheumatoid arthritis. It is also used by rheumatologists for other rheumatic diseases, including juvenile arthritis and psoriatic arthritis.

It is not ordinarily prescribed until other forms of anti-inflammatory treatment have proven inadequate. It should only be prescribed by physicians who are experienced in initiating and monitoring such antirheumatic therapy. The drug is appropriate therapy for selected people with rheumatoid arthritis.

Methotrexate has multiple mechanisms of action, but sites of activity; its exact mechanism of action in rheumatoid arthritis is not known. Clinical studies with methotrexate have demonstrated that a majority of people who take the drug have less joint pain and swelling, reduced morning stiffness, less fatigue, improvement in functional status, and a slowing of the rate of radiographic progression.

Improvement usually occurs between three and six weeks after treatment is initiated. Methotrexate is taken once a week in a single or divided dose; it can be taken by mouth or given by injection. The dosage averages between 7.5 and 25 mg. per week and may be adjusted depending on individual response.

The most common side effects of methotrexate include loss of appetite, nausea, diarrhea, sores or ulcers in the mouth, hair loss, and decreases in the platelets, white blood cell or red blood cell counts. Potential for liver toxicity exists, specifically in people with preexisting liver disease or who are heavy users of alcohol.

Rare but serious side effects include fibrosis and cirrhosis of the liver, bone marrow suppression, a reaction similar to pneumonia, usually indicated by fever, cough and severe shortness of breath, and rarely, lymphoma which may resolves with discontinuation. Folic acid and folinic acid can be used to reduce many of the side effects.

Blood tests should be conducted to detect potential bone marrow and liver problems. In some patients, liver biopsies may be indicated prior to initiating therapy or during the course of therapy to determine if fibrosis of the liver is present. Guidelines for monitoring have been established.

Pregnant women should not take methotrexate because it is known to cause birth defects, miscarriages, and stillbirths. Pregnancy should not be attempted until the drug is stopped in males for three months and at least one ovulation cycle in females. Women who are breast feeding should not take methotrexate

Methotrexate is a relatively safe and effective treatment for rheumatoid arthritis. and other autoimmune diseases. Individuals who believe they are candidates for methotrexate treatment should contact their family physician or rheumatologist.

Only physicians, such as rheumatologists, who are experienced in treating rheumatoid arthritis and who are fully aware of its potential toxicity, should prescribe methotrexate.

Careful monitoring and patient education are essential to reduce the potential for side effects of methotrexate, which include nausea, diarrhea, loss of appetite, suppression of blood cell production, inflammation of the lungs, and liver damage. Appropriate monitoring of a patient taking methotrexate may include a baseline chest x-ray and periodic determination of WBC, RBC, platelets, and renal and liver function studies.

To study the efficacy of leflunomide in RA: This drug has been compared in clinical trials to the gold standard of DMARDs - methotrexate, as well as to placebo and sulfasalazine (another second line agent).

In a randomized, double blind, controlled study, 482 patients with active RA in the US and Canada were treated with methotrexate (182 patients), placebo (118 patients) and leflunomide (182 patients).

After 52 weeks of treatment, leflunomide and methotrexate each significantly increased the rate of patients meeting ACR criteria for a 20 percent response (a common standard used in RA drug trials) versus placebo. No significant differences were found between the responses to methotrexate and leflunomide.

Significantly, patients on leflunomide not only improved clinically, but also had slowing of disease progression, as shown by analysis of bony erosions on X-rays. Diarrhea occurred in about one-quarter of the patients on leflunomide, and elevated liver function tests in 15 percent.

In another study, 358 patients received leflunomide, sulfasalazine, or placebo. Leflunomide was significantly more effective than placebo in the treatment of RA and demonstrated comparable efficacy to sulfasalazine.5 Significant improvements in measurements of disease activity were found already four weeks after initiating leflunomide therapy.

Finally, in a small multicenter open label study, adding leflunomide to methotrexate had significant benefit in patients that remained active on methotrexate alone, without excessive toxicity. After one year, 16 patients (53%) met ACR 20 response criteria.

Leflunomide is indicated for patients with active RA to reduce signs and symptoms of disease and to retard disease progression. In practical terms, leflunomide should be considered in those situations in which a DMARD is being added to the therapeutic regimen. Overall, the efficacy of leflunomide seems comparable to methotrexate.

The side effect profile of these medications also has many areas of overlap. Therefore, many rheumatologists would still choose methotrexate as the first DMARD to be used in a patient with RA, based on many accumulated patient-years of positive experience with this drug. Patients with inadequate benefit from methotrexate, unacceptable toxicity or contraindications to methotrexate use may be considered for leflunomide therapy.

Hydroxychloroquine is used for several forms of malaria attacks. It is also useful in treating patients with the local skin (discoid) and systemic forms of lupus erythematosus. In those with systemic disease, it has been found to particularly relieve skin inflammation, hair loss, mouth sores, fatigue, and joint pains. It has also been found helpful in preventing relapses of active disease. Hydroxychloroquine is also useful in treating rheumatoid arthritis.

DOSING: Should be taken with food or milk.

DRUG INTERACTIONS: All patients who take long-term hydroxychloroquine require regular special eye examinations to monitor for signs of a rare, but potentially serious eye toxicity. The toxicity can affect the back of the eye, called the retina, and can lead to visual disturbances, color blindness, and even loss of vision. The eye doctor can often detect changes that suggest toxicity before serious damage occurs, so regular eye checks, even when feeling normal, are mandatory. Patients who are genetically deficient in a certain enzyme, called G6PD, can develop a severe anemia resulting from the rupture of red blood cells. This enzyme deficiency is more common in persons of African descent, and can be measured by blood testing.

SIDE EFFECTS: Side effects when treating patients with lupus erythematosus and rheumatoid arthritis are not common. The most serious reaction can involve the eyes, as described above. Other reported reactions include irritability, headache, weakness, hair bleaching or loss, nausea, and itching. Rarely, hydroxychloroquine can affect the bone marrow. In patients being treated for malaria, temporary headache, dizziness, and stomach upset can occur.

Sulfasalazine is a pro-drug, that is, it is not active in its ingested form. It is broken down by bacteria in the colon into two products: 5-aminosalicylic acid (5ASA), and sulfapyridine. There is some controversy as to which of these two products are responsible for the activity of azulfidine. Whereas it is known that 5ASA has therapeutic benefit, it is not clear whether sulfapyridine adds any further benefit. In the colon, the products created by the breakdown of sulfasalazine work as anti-inflammatory agents for treating inflammation of the colon.

The beneficial effect of sulfasalazine is believed to be due to a local effect on the bowel, although there may also be a beneficial systemic immune-suppressant effect as well. Following oral administration, 33% of the sulfasalazine is absorbed, all of the sulfapyridine is absorbed, and about 33% of the 5ASA is absorbed. Sulfasalazine was approved by the FDA in 1950.

Uncoated and enteric coated tablets, each containing 500mg. The tablets should be kept at room temperature, 15-30°C (59-86°F).

Sulfasalazine is used for the treatment of mild to moderate ulcerative colitis; as adjunctive therapy (i.e. with other medications) in the treatment of severe ulcerative colitis; for the treatment of Crohn's disease; for the treatment of rheumatoid arthritis or ankylosing spondylitis.

DOSING: Doses range from 500mg to 2000mg, and dosing intervals range from every 6 hours to every 12 hours, depending on the clinical condition of the patient. Higher doses have also been used.

Sulfasalazine should be taken with a full glass of water after meals or with food to minimize stomach upset. Patients with kidney diseases may need to use lower doses of sulfasalazine.

Sulfasalazine may cause reduced absorption of folic acid and of digoxin. In hundreds of pregnant women with ulcerative colitis or Crohn's disease treated with sulfasalazine, there has been no increase in the risk of fetal malformations relative to other women with these illnesses who have not been treated with sulfasalazine. Additionally, there have not been ill effects on pregnant animals given high doses of sulfasalazine. Thus, sulfasalazine may be used during pregnancy if the physician feels the benefit outweighs the possible risk.

Biologic Therapy:

Like TNFa, IL-1b is a proinflammatory cytokine produced and secreted by activated macrophages, as well as by endothelial cells, chondrocytes and osteoclasts. One of the activating signals for transcription of IL-1b is the linkage of TNFa with their respective cell membrane receptors.

Interleukin-1b appears to be more active than TNFa mediating the irreversible structural changes in articular cartilage and bone seen in RA. IL-1b stimulates chondrocytes to release proteolytic enzymes that degrade cartilage matrix, while at the same time it inhibits these cells from synthesizing the macromolecular proteoglycans that are critical to the structure and function of articular cartilage.

In addition, IL-1b activates osteoclasts that resorb bone and are important in the development of the characteristic subarticular erosions of bone seen in RA. Levels of IL-1b are elevated in rheumatoid synovium and synovial fluid and the level of IL-1b correlates with disease activity.

Like TNFa, IL-1b acts by attaching to specific cell membrane receptors on the surface of the target cells, leading to crosslinking of the membrane receptors with other cell membrane proteins. Once this crosslinking occurs, the intracellular portions of the receptors act as kinases which catalyze the phosphorylation of cytoplasmic proteins which eventually activate nuclear transcription factors that result in new messenger RNA synthesis, thereby altering cell function.

The actions of IL-1b are kept in check by at least two other molecules secreted by macrophages. One of these is a soluble form of the IL-1b receptor and the other is a molecule known as IL-1 receptor antagonist (IL-1RA) that can attach to the IL-1b receptor but prevents crosslinking and cell activation.

Anakinra (Kineret®) is a recombinant non-glycosylated form of IL-1RA to which methionine has been added to its N-terminal end. When given parenterally, anakinra enters inflamed joints and inhibits IL-1b activity.

Dosage and Administration: Anakinra is supplied in preloaded syringes for subcutaneous administration, along with a unique automated injector system, Simpleject, from the drug manufacturer (Amgen). Because of its relatively short half-life, the drug is administered daily at a dose of 100 mg.

It is approved for use in patients with moderate to severe RA who have not had an adequate response to other DMARD's -- usually methotrexate or leflunomide (Arava®). The drug has not been studied in patients who have failed to respond to TNFa inhibition. However, anecdotally, some of these patients have responded to IL-1b inhibition. Amgen is reported to be developing a form of the molecule polymerized to polyethylene glycol that has a significantly longer half-life.

Anakinra has been studied in clinical trials involving 2932 RA patients. The drug has usually been given in conjunction with methotrexate and compared with patients on methotrexate and placebo followed for 6-12 months. In these trials, the ACR20 response rate has been approximately 45% for the anakinra group compared with 13% in the placebo group.

Nineteen per cent of the patients receiving anakinra achieved an ACR50 response as compared 4% of the controls. Anakinra has been used as monotherapy in a trial of 472 RA patients. There was a significant reduction in radiological progression in these patients compared with the placebo group. Anakinra has also been studied in a small number of patients in conjunction with leflunomide (Arava®) responded comparably to patients given methotrexate and anakinra.

A trial of anakinra with etanercept was halted because of a high rate of infection.

Adverse Reactions: The most frequent adverse reaction seen with anakinra has been local injection site inflammation. These reactions appear to diminish after the first several weeks of administration and have been a rare cause of drug discontinuation. Opportunistic and severe systemic infections, as well as malignancies, bone marrow dyscrasias, autoimmune syndromes and demyelinating syndromes, have not been reported to date.

Anakinra appears to be an effective second-line agent in the treatment of RA which may retard the structural damage to the joints associated with this disease. The drug appears to be relatively safe. Because of its short half-life, anakinra has to be given by daily injections. Conversely, because of its rapid metabolism, it can be withdrawn quickly in the event of an adverse reaction or if patients develop an infection. Like the other biological agents for RA, anakinra is quite expensive.

Etanercept is an injectable drug that blocks tumor necrosis factor alpha (TNF alpha) and is used for treating rheumatoid arthritis. TNF alpha is a protein that the body produces during the inflammatory response, the bodys reaction to injury. TNF alpha promotes the inflammation and its associated fever and signs (pain, tenderness, and swelling) in several inflammatory conditions including rheumatoid arthritis.

Etanercept is a synthetic (man-made) protein that binds to TNF alpha. It thereby acts like a sponge to remove most of the TNF alpha molecules from the joints and blood. This prevents TNF alpha from promoting inflammation and the fever, pain, tenderness and swelling of joints in patients with rheumatoid arthritis.

Enbrel is prepared as white preservative-free powder in 25mg vials. Before injection, etanercept is mixed with 1 milliliter of sterile water to form a clear colorless solution.

Sterile powder should be refrigerated at 2-8°C (36- 46°F). Solutions should be used as soon as possible but may be stored in the vial at 2-8°C (36-46°F) for up to six hours.

Etanercept is used to reduce the pain, swelling and tenderness of the joints resulting from moderate to severe rheumatoid arthritis in adults that has not adequately responded to other drugs (called disease-modifying medicine(s) for rheumatoid arthritis). Etanercept reduces the signs and symptoms arthritis and prevents the progressive destruction of the joints in patients with rheumatoid arthritis

Etanercept can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone. Etanercept also is used for reduction in signs and symptoms of moderately to severely active polyarticular-course juvenile rheumatoid arthritis in patients who have had an inadequate response to one or more disease-modifying medicine(s).

Etanercept is approved for the treatment of the arthritis of psoriasis and is reported to be of benefit in ankylosing spondylitis, psoriasis, and uveitis.

Etanercept is not recommended for persons with preexisting disease of the central nervous system (brain and/or spinal cord) or for those with multiple sclerosis, myelitis, or optic neuritis.

Etanercept is injected under the skin. Adults usually inject 25mg twice weekly. Children 4 to 17 years old should receive 0.4mg/kg (maximum 25mg) twice weekly. Etanercept has not been studied in children younger than 4 years.

Drug interaction studies have not been conducted. Because etanercept may reduce the response of the immune system, etanercept should not be administered with live vaccines. Studies have not been conducted in pregnant women. Etanercept is not recommended in pregnant women. It is unknown whether etanercept is excreted in human breast milk. Etanercept is not recommended in nursing women.

The most common side effects are mild to moderate itching, pain, swelling and redness at the site of injection. Headache, dizziness, nasal and throat irritation also occur. TNF alpha has an important role in the responses of the immune system to infections. Thus, blocking the action of TNF alpha with etanercept may worsen or increase the occurrence of infections, and patients with serious infections should not receive etanercept. Moreover, etanercept should be discontinued if a patient develops a serious infection.

It is not initiated in patients with active infections or allergy to its components. In addition, children should receive their recommended immunizations before treatment with etanercept. Etanercept should be used with caution in patients prone to infection, such as those with advanced or poorly controlled diabetes.

Some reported associated conditions may or may not be related to etanercept. Since etanercept has been on the market, there have been reports of multiple sclerosis, myelitis, optic neuritis in patients using the drug.

Etanercept is not recommended for persons with preexisting disease of the central nervous system (brain and/or spinal cord) or for those with multiple sclerosis, myelitis, or optic neuritis. Additionally, rare cases of seriously low blood counts (pancytopenia) have been reported in patients using etanercept.

Since etanercept is a relatively new drug, there is limited information on long-term risks.

Infliximab is an injectible antibody that blocks the effects of tumor necrosis factor alpha (TNF alpha). There are two other injectible drugs that block TNF alpha--infliximab (Remicade) and etancercept (Enbrel). is a substance made by cells of the body which has an important role in promoting inflammation.

Specifically, infliximab is used for treating the inflammation of Crohns disease and rheumatoid arthritis. By blocking the action of TNF-alpha, infliximab reduces the signs and symptoms of inflammation. Infliximab does not cure Crohns disease or rheumatoid arthritis; however, preliminary studies have demonstrated that infliximab can retard the destruction of joints by rheumatoid arthritis.

Infliximab,usually,is combined with methotrexate for treating rheumatoid arthritis in patients who do not have an adequate response to methotrexate alone. In these patients it is used for reduction of joint damage caused by the rheumatoid arthritis.

Infliximab is also used for reducing the signs and symptoms of inflammation in moderate to severe Crohns disease and Crohns disease in which there are fistulas (passageways created when the inflammation penetrates beyond the wall of the intestine).

Infliximab has also been reported to be helpful in reducing the joint inflammation of juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, uveitis, psoriasis, and for sarcoidosis that is not responding to traditional therapies.

Infliximab is administered intravenously. For moderate to severe Crohns disease the dose is 5 mg/kg administered as a single dose. For fistulizing Crohns disease, the dose is 5mg/kg followed by additional doses of 5mg/kg two and six week after the first dose.

The recommended dose for the treatment of rheumatoid arthritis is 3 mg/kg as a single dose. The initial dose should be followed by additional 3 mg/kg doses two and six weeks after the first dose.

Thereafter, the maintenance dose is 3 mg/kg every eight weeks.

The interaction of infliximab with other drugs has not been studied.

Use of infliximab in pregnant women has not been adequately evaluated. It is not known if infliximab is secreted in breast milk, and, therefore, if there is the potential for effects on the nursing infant.

The most common side effects of infliximab are upper respiratory tract infections, urinary tract infections, cough, rash, back pain, nausea, vomiting, abdominal pain, headache, weakness and fever.

Side effects such as low or high blood pressure, chest pain, difficulty breathing, rash, itching, fever and chills may occur during or shortly after administration. These reactions could indicate an allergy to the drug. They are more common among patients who develop antibodies to infliximab and are less likely to occur in patients who are taking drugs that suppress the immune system, such as methotrexate.

Infliximab should be discontinued if serious reactions occur. Serious infections have been reported with other drugs that block TNF- alpha, and infections have been reported during treatment with infliximab. Therefore, infliximab should not be used in patients with serious infections. Moreover, infliximab should be discontinued if a serious infection develops during treatment.

Before starting infliximab, persons are recommended to have tuberculosis skin testing (PPD tests for TB), because of reports of reactivation of tuberculosis in patients taking infliximab.

Adalimumab is an injectable protein that blocks the inflammatory effects of tumor necrosis factor alpha(TNF alpha). Two other injectable drugs--infliximab (Remicade) and (Enbrel)--also block TNF alpha.

Inflammation is the bodys reaction to injury and is a necessary process for the repair of injury. TNF is a protein that the body produces when there is inflammation. The TNF promotes inflammation and the signs of inflammation, which, include fever as well as pain, tenderness, and swelling of joints.

The unchecked inflammation of rheumatoid arthritis eventually leads to destruction of the joints. Adalimumab is a synthetic (man-made) protein, similar to human protein, that binds to TNF in the body and thereby blocks the effects of TNF. As a result, inflammation and fever as well as the pain, tenderness and swelling of joints are reduced in patients with rheumatoid arthritis. In addition, the progressive destruction of the joints is slowed or prevented. Adalimumab was approved by the FDA in December, 2002.

Prefilled glass syringe: 40 mg (0.8 ml); glass vial : 40 mg (0.8 ml)Adalimumab should be refrigerated at 2-8°C (36-46°F). Adalimumab is used for reducing the signs and symptoms of rheumatoid arthritis. It also slows the progression (destruction of the joints) in moderate to severe rheumatoid arthritis. It is used after one or more other drugs that slow the destruction of the joints (referred to as disease modifying anti-rheumatic drugs or DMARDs) have failed. Adalimumab can be used alone or in combination with other DMARDs, such as MTX.

Adalimumab is injected under the skin. The recommended dose for adults is 40 mg every other week, but some patients may need weekly administration.

Methotrexate reduces the absorption of adalimumab by 29-49%, but no adjustments to the dose of adalimumab need to be made when methotrexate is given concomitantly.

Adalimumab has not been adequately studied in pregnant women. Use of adalimumab by nursing mothers has not been adequately evaluated.

The most common side effects are nausea and stomach upset. Adalimumab may cause swelling, redness, pain and itching at the site of injection . Adalimumab suppresses the immune system and is therefore associated with minor infections of the urinary tract, respiratory tract and sinuses. Like other drugs that block TNF, use of adalimumab also has been associated with serious infections such as sepsis (bacteria in the blood) and fungal infections.

Individuals with active infections should not be treated with adalimumab. Adalamimumab also may worsen the symptoms of diseases of the nervous system. In studies some patients who used adalimumab developed cancer.

Since patients with rheumatoid arthritis have a higher rate of cancers than the general population, the connection between cancer and use of adalimumab is unclear.Adalimumab is an injectable protein that blocks the inflammatory effects of tumor necrosis factor alpha(TNF alpha).

Inflammation is the bodys reaction to injury and is a necessary process for the repair of injury. TNF is a protein that the body produces when there is inflammation. The TNF promotes inflammation and the signs of inflammation, include fever as well as pain, tenderness, and swelling of joints. The unchecked inflammation of rheumatoid arthritis eventually leads to destruction of the joints.

Adalimumab is a synthetic (man-made) protein, similar to human protein, that binds to TNF in the body and thereby blocks the effects of TNF. As a result, inflammation and fever as well as the pain, tenderness and swelling of joints are reduced in patients with rheumatoid arthritis. In addition, the progressive destruction of the joints is slowed or prevented. Adalimumab was approved by the FDA in December, 2002.

Prefilled glass syringe: 40 mg (0.8 ml); glass vial : 40 mg (0.8 ml Adalimumab should be refrigerated at 2-8°C (36-46°F).

Adalimumab is used for reducing the signs and symptoms of rheumatoid arthritis. It also slows the progression (destruction of the joints) in moderate to severe rheumatoid arthritis. It is used after one or more other drugs that slow the destruction of the joints (referred to as disease modifying anti-rheumatic drugs or DMARDs) have failed. Adalimumab can be used alone or in combination.

Adalimumab is injected under the skin. The recommended dose for adults is 40 mg every other week, but some patients may need weekly administration.

Methotrexate reduces the absorption of adalimumab by 29-49%, but no adjustments to the dose of adalimumab need to be made when methotrexate is given concomitantly. Adalimumab has not been adequately studied in pregnant women. Use of adalimumab by nursing mothers has not been adequately evaluated.

Like other drugs that block TNF, use of adalimumab also has been associated with serious infections such as sepsis (bacteria in the blood) and fungal infections. Individuals with active infections should not be treated with adalimumab. Adalamimumab also may worsen the symptoms of diseases of the nervous system.

In studies some patients who used adalimumab or other TNF blocking drugs developed cancer. Since patients with rheumatoid arthritis have a higher rate of cancers than the general population, the connection between cancer and use of adalimumab is unclear.