Psoriasis

Description

Alternative Names

Other Medications

Systemic treatments involve oral or injected drugs, which affect the entire body. Many of the systemic drugs used for psoriasis are also used for other severe diseases, including autoimmune diseases (especially rheumatoid arthritis) and cancer. Nearly all are powerful medications with potentially serious side effects. These drugs should be used only for severe incapacitating cases of psoriasis that do not respond to lifestyle changes or topical (or other less potent) therapies. And they should be used only in very extreme circumstances in children.

As with all medications for psoriasis, the least potent agents should be used first:

• Methotrexate and oral retinoids are the first-line, or primary, systemic drugs for adults with severe psoriasis. Cyclosporine is also an option.
• Second-line drugs include hydroxyurea, sulfasalazine, and thioguanine.
• Third-line agents include tacrolimus.

At this time, the only agents specifically approved for psoriasis are methotrexate, the retinoids, and cyclosporine.

Systemic Regimens. As with all psoriasis treatments, combinations are often used. The following is an example of a systemic regimen with combination treatments:

• The patient starts with an immunosuppressant, such as cyclosporine.
• Acitretin, a vitamin A derivative, is then added (the transitional phase).
• If the drugs are effective, the cyclosporine is withdrawn gradually after a few months and acitretin continues at as low a dose as possible as maintenance.
• Phototherapy using PUVA is added if acitretin cannot control psoriasis.

Methotrexate

Methotrexate (Rheumatrex) is very effective for severe psoriasis. Despite its adverse effects, some experts view methotrexate as the best therapy for widespread plaque psoriasis. It may also be effective for some patients with other severe forms of the disease, including psoriatic arthritis, generalized erythrodermic and pustular psoriasis. For example, one center reported that 80% of patients reported prolonged improvement. Methotrexate appears to be effective in children, but more safety research is needed.

It has the following beneficial properties:

• It interferes with cell reproduction.
• It has anti-inflammatory properties.
• It is one of the few systemic agents proven to help patients with psoriatic arthritis.

It is important to note that the recommended dose is taken weekly, not daily. Fatal toxicities have been reported in people who mistakenly took it once a day.

Side Effects. Common side effects of methotrexate are nausea and vomiting, rash, mild hair loss, headache, and mouth sores. It may also cause muscle aches. Many of these side effects as well as anemia, a more serious complication are due to folic acid deficiency. Patients should ask their physician about supplements (generally recommended at 1 to 5 mg of folic acid daily). Patients who experience severe nausea may opt for injections, which are effective and less expensive than oral agents.

More serious complications include the following:

• Liver damage. (In one study, 25% of patients taking methotrexate for five years developed cirrhosis, liver scarring.) People with existing liver problems should not take it, if possible. Regular monitoring for liver toxicity, including blood tests and liver biopsies, is important in patients who take the drug. Timing of biopsies depends on any risk factors for liver damage.
• Toxic effects on bone marrow, which can cause suppression of blood cell production.
• Osteoporosis. (Low doses do not appear to have any significant affect on bone loss, but long-term studies are needed to confirm this.)
• Kidney complications.
• Increased risk for infections, particularly herpes zoster (shingles) and pneumonia. Methotrexate suppresses the immune system and so should be avoided in patients with active infections.
• Lung disease. This side effect can be sudden and severe, and occurs in up to 5% of people who take methotrexate. It deserves special mention. There are five key risk factors for methotrexate-induced lung diseases: age, diabetes, existing rheumatoid involvement in the lung, protein in the urine, and previous use of rheumatoid arthritis drugs called DMARDs (particularly sulfasalazine, oral gold, and d-penicillamine). Patients should report any symptoms, such as coughing or shortness of breath, that might indicate lung injury.
• Severe anemia from folic acid deficiencies. (Folic acid supplements can offset this effect).
• Negative effects on reproduction. In pregnant women the drug can cause miscarriages and birth defects in the offspring. It may impair fertility in men.
• Lymphomas. A few cases have been reported, which are most likely related to the drugs immune-suppressing effects. In most instances, the disease has gone into remission when the drug was stopped. Most studies have found no significant risk for cancers in patients taking methotrexate.
• Radiation recall. An uncommon side effect in patients who have previously been burned by radiation cancer treatments or by sunburns. In such cases, a flare-up of symptoms occurs in the previously affected skin areas.

Drug and Alcohol Interactions. Alcohol and many drugs interact with methotrexate, and in some cases the combinations can be toxic. Patients should discuss with their physicians any other medications they are taking. The following are just a few examples:

• Many of the common nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen (Advil), or naproxen, cause serious toxic interactions. Some NSAIDs, namely ketoprofen, fluorobiprofen, and piroxicam, appear to be safe when given with methotrexate and may be used in patients with psoriatic arthritis. (Rheumatoid arthritis patients who take methotrexate often take NSAIDs as well, but methotrexate doses in psoriasis patients are usually much higher than those in RA.)
• Specific antibiotics interact with methotrexate. Of note, the antibiotic trimethoprim-sulfamethoxazole increases the toxicity of methotrexate.

People Who Should Avoid Methotrexate. Pregnant and nursing mothers should never take methotrexate because it increases the risk for severe, even fatal, birth defects and miscarriage. The drug should be discontinued several months before planning a pregnancy. It may also cause temporary impairment of fertility in men. Other people who should avoid methotrexate are alcoholics, those who also have kidney or liver abnormalities (such as hepatitis), who have active infections, and patients with impaired immune systems. Patients at risk for liver complications include diabetes and people who are obese. Anyone with a previous history of hepatitis should have a biopsy before treatment. Others who might avoid methotrexate are people with peptic ulcers, rheumatoid arthritis, anemia, or other blood abnormalities.

Oral Retinoids

Oral retinoids are derivatives of vitamin A. Those used for psoriasis include acitretin (Soriatane) and isotretinoin (Accutane). Acitretin is the retinoid of choice and may be dramatically effective for severe psoriasis, particularly pustular or erythrodermic variants. When used alone, it is much less effective against more common forms, such plaque or guttate psoriasis. However, combinations with PUVA phototherapy can markedly improve the response even in these patients. Accutane, more commonly used to treat acne, is generally far less potent than acitretin, but may still be effective against pustular psoriasis and also be effective with phototherapy. An older agent, etretinate (Tegison) was very effective but produced severe side effects and has been withdrawn from the market. It still may be useful for HIV patients. Oral tazarotene will likely gain FDA approval in the summer of 2004. It is not yet known how it will compare in efficacy to the existing choices, but experts consider it to be a very safe medication. Studies have shown that instead of accumulating in the body, it clears rapidly upon cessation of treatment, making it a potentially better choice for women of childbearing years. Oral tazarotene may be used in combination with light therapy and other medications, and it is relatively inexpensive.

Benefits. Oral retinoids have the following beneficial properties for patients with psoriasis:

• They have anti-inflammatory actions.
• They help regulate cell reproduction.
• They may even improve arthritis that accompanies psoriasis.

Combinations. Acitretin may be most effective in combination with other agents, usually topical agents and especially with phototherapy. The drug results in faster and more complete responses to PUVA and UBV treatments. Acitretin and phototherapy, in fact, have some of the highest clearance rates of any treatment. Furthermore, lower radiation doses can be used, which may decrease the risk of skin cancers, and some research suggests that retinoids may temporarily suppress the development of these malignancies. Combination therapy also allows lower doses of oral retinoids to be used, which diminishes many skin and mucous membrane side effects. In addition to combination treatments, some experts recommend the following to reduce the toxic effects of acitretin:

• Maintenance doses should be as low as possible and should be taken every second or third day.
• Patients should eat a low-fat diet and get daily aerobic exercise to maintain healthy triglyceride levels.

Side Effects. All retinoids have the same potentially serious toxicities as do high doses of vitamin A:

• Of special note, retinoids pose a significant risk for birth defects when taken by pregnant women. Children and women who wish to bear children should not take these agents.
• Skin and mucous membrane problems are common. These include dry nose, nosebleeds, dry eyes, chapped lips, thinning hair, dry or sticky feeling skin, and peeling of the palms and soles. Nail problems may also develop. Studies on isotretinoin indicate that many of these side effects may be relieved with vitamin E supplements (800 IU daily), but studies on acitretin have not been done.
• Bone and joint pain, fatigue, bruising, and headaches may also occur.
• The drugs may cause eye problems, including blurred vision, cataracts, conjunctivitis, and a sudden deterioration in night vision.
• Retinoids carry a high risk for increased bone growth, particularly in the ankles, pelvic area, and knees.
• They increase levels of triglycerides, which are lipids (fatty molecules in the blood) that are proving to be danger for the heart. Certain cholesterol-lowering agents, including gemfibrozil (Lopid) or statins, such as atorvastatin (Lipitor), may prevent this.
• In rare cases, retinoids, particularly isotretinoin, may cause a condition called benign intracranial hypertension (pseudotumor cerebri), which occurs in the brain. Symptoms include headache, nausea, vomiting, and blurred vision. Patients experiencing these symptoms should call the physician immediately and stop taking the drug.
• The drugs also can cause damage to the liver, so patients should be monitored regularly.
• Isotretinoin has been associated with depression and possible risk for suicide in some people.

Despite these side effects, oral retinoids remain among the safest systemic therapies for psoriasis. A low-fat diet, aerobic exercise, and fish oil supplements may help reduce the side effects.

Cyclosporine

Cyclosporine (Neoral, Sandimmune, SangCya) blocks certain immune factors and may be effective for all forms of psoriasis. Neoral is the preparation used most often for psoriasis and clears psoriasis in between 60% and 91% of patients within eight to 12 weeks. Cyclosporine has significant side effects if used for a long time, notably kidney problems and nonmelanoma skin cancers. It should be reserved for patients who do not respond to phototherapy or less potent systemic agents (e.g., methotrexate or acitretin).

Side Effects. Common and temporary side effects include headaches, gingivitis, joint pain, gout, body hair growth, tremor, and fatigue.

More serious complications may include the following.

• Kidney damage. This is a significant complication and prolonged use always causes some kidney injury.
• High blood pressure (occurring in up to 30% of patients). Some experts advise treating high blood pressure with calcium-channel blockers, since other standard anti-hypertensive drugs may worsen psoriasis. Calcium channel blockers also help prevent kidney problems.
• Unhealthy cholesterol and lipid levels. Patients may need to take cholesterol-lowering agents.
• Abnormalities in the liver.
• Increased risk for infections.
• Skin cancers. Patients who have taken cyclosporine after PUVA therapy have a higher incidence of squamous cell carcinoma. According to a 2003 study, the risk is six times that of the general population. The risks are highest with long duration and previous use of PUVA, methotrexate, or other immunosuppressants.
• Lymphomas. The use of cyclosporine after transplantation has been associated with a higher risk for lymphomas, although whether cyclosporine used for skin diseases poses any higher risk is unknown.
• High levels of calcium and low levels of magnesium. These effects can usually be offset with magnesium supplements and eating potassium rich foods.

To minimize complications of cyclosporine, the dosage is reduced after improvement occurs. Maintenance therapy is usually limited to a year, although some experts believe that a microemulsion form of Neoral (Neoral-Neo) may safe for up to two years. Patients should be monitored regularly for hypertension and signs of kidney or liver abnormalities and evaluated for skin cancers.

Patients Who Should not Use Cyclosporine. Because the drug suppresses the immune system, people with active infections or cancer should avoid it. Patients with uncontrolled high blood pressure and impaired kidney function should also not use this agent. Cyclosporine therapy for children with psoriasis has not been well-studied.

Drug and Food Interactions. Cyclosporine interacts with numerous drugs--both prescription and over-the-counter preparations--and also grapefruit and grapefruit juice.

Second- and Third-Line Systemic Agents

Second- or third-line agents are used alone or sometimes in combination with first-line systemic drugs if those medications fail. Most are investigative and are generally less safe than first-line agents.

Sulfasalazine. Sulfasalazine (Azulfidine) sometimes used for psoriasis. In one major analysis, sulfasalazine and methotrexate were the only agents proven to help patients with psoriatic arthritis. Many people, however, stop taking the drug because of common side effects that include headaches, gastrointestinal complaints, and rash. Benefits, if any, should be apparent in four to six weeks.

Macrolides. Macrolides are agents that fight bacteria and also have immunosuppressant properties. (Their actions are similar to those of cyclosporine.) Some macrolides being studied for psoriasis include tacrolimus (Prograf), pimecrolium, and sirolimus. In one study, for example, tacrolimus showed an 83% reduction in symptoms in patients with psoriasis who used the drug. Studies have been limited, however. Side effects of these agents are similar to those of cyclosporine. Pimecrolimus may specifically target the skin and so have fewer side effects. (Some macrolides are also being studied as topical treatments.)

Biologic Response Modifiers

Biologic response modifiers, sometimes called biologics, belong to a new class of drugs that are considered the most exciting development in psoriasis treatment. Three such drugs have been approved since 2003. Biologics are genetically engineered drugs that interfere with specific components of the autoimmune response. Because of their precise targets, these drugs do not damage the entire immune system the way that general immunosuppressants do. They are producing dramatic results in some studies.

T-Cells-Blockers. Alefacept (Amevive) blocks overactive T-cells, but appears to leave other immune factors alone. Alefacept received FDA approval in January 2003 for moderate to severe plaque psoriasis. Studies report that between 40% to 71% of patients experience at least a 50% improvement in symptoms, and the response appears to persist and even improve in many people. (In a few patients the psoriasis worsened.) Response rates have been better than those observed with methotrexate. Alefacept is administered by weekly intramuscular injection in 12-week courses, although longer courses are often more successful. Early evidence suggests it works more slowly than Enbrel and Raptiva, and may be slightly less effective than these two agents. Alefacept may pose less risk for infections than the other biologic agents or immunosuppressants, however. Further research is needed to determine long-term risks including liver toxicity and infections.

Efalizumab (Raptiva) was FDA approved in December 2003. In one study, up to 58% of patients achieved a 75% or greater improvement in symptoms. Administered by subcutaneous injection, Raptiva takes effect quickly and is comparable to Enbrel in efficacy. Withdrawal from Raptiva may cause flare-ups of psoriatic lesions.

Tumor Necrosis Factor Blockers. Etanercept (Enbrel) and infliximab (Remicade) block tumor necrosis factor (TNF), an inflammatory immune factor called a cytokine that is very important in the psoriasis disease process. Both TNF-blocking agents are given by injection.

Enbrel is now approved for both plaque psoriasis (moderate to severe) and psoriatic arthritis. Remicade is awaiting approval. Both agents are proving to be effective for moderate-to-severe psoriasis. In a 2003 study of infliximab, by week 10 up to 88% of patient who took the drug experienced improvement that was equal or greater than 75%. (Higher rates were observed with higher doses.) Studies also report that about half of patients taking etanercept show significant improvement.

Side effects of the biologic response modifiers (usually reported in studies of patients taking these agents for rheumatoid arthritis) include the following:

• The most common adverse effects of all three are minor reactions at the injection site, but there are few other immediate side effects.
• Because these agents affect immune factors, there is some risk for severe infections particularly in susceptible individuals, such as those with uncontrolled diabetes, people taking other immunosuppressants, or anyone with a current active infection. For example, cases of tuberculosis and histoplasmosis (a fungal infection in the lungs) have been reported in patients taking TNF-modifiers. (While millions of healthy people unknowingly carry the TB organism, it does not become active in most people with healthy immune systems.) Patients should be tested for TB before initiating treatment.
• There have been a few reports of aplastic anemia.
• In rare cases, both etanercept and infliximab have been associated with nerve damage that resembles the disease process in multiple sclerosis. This involves demyelination (the loss of myelin, the insulation coat over nerve fibers) and can result in confusion, numbness, changes in vision, and difficulty walking.
• There have been reports of a lupus-like symptoms in a few patients taking these drugs, but it is not clear if such findings are significant. To date, the symptoms have resolved when patients stopped taking the drugs.
• Many patients develop an immune reaction to infliximab itself, which makes the drug less effective overtime. Nevertheless, in one study, benefits persisted for at least two years after stopping the drug.
• Infliximab has been linked to a few deaths in patients with pre-existing congestive heart failure.
• There is some suggestion that anti-TNF drugs increase the risk for lymphomas.

Leflunomide. Leflunomide (Arava) blocks autoimmune antibodies and is a powerful anti-inflammatory agent. It is proving to be active against psoriatic arthritis. Reports of adverse effects are comparable to those with methotrexate. Common problems include nausea, diarrhea, hair loss, and rash. Potentially serious side effects include infections and liver injury.

Interleukins. Interleukins are other powerful inflammatory agents of the immune system. Interleukins being investigated as sources or targets of therapy include IL-4, IL-2, IL-8, IL-11, and IL-12. For example, in a 2003 study, 75% of patients with severe psoriasis who were treated with interleukin-4 (rhuIL-4) experienced improvement rates of more than 68%.