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Psoriasis

Description

An in-depth report on the causes, diagnosis, treatment, and prevention of psoriasis.

Other Medications

Other treatments for psoriasis may be taken by mouth (oral) or given by an injection (injected). These drugs are called "systemic" because they 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 severely incapacitating cases of psoriasis, which do not respond to lifestyle changes or topical treatments. 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• If the drugs are effective, the cyclosporine is withdrawn gradually after a few months and acitretin continues at as low a dose as possible for maintenance.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. One center reported that 80% of patients reported prolonged improvement. Methotrexate appears to be effective in children, but more safety research is needed.

Methotrexate 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. Deadly reactions 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. Anemia is a condition where there is a low level of red blood cells in the body. As a result, less oxygen reaches the organs in the body. Patients should ask their doctor about folic acid supplements (generally recommended at 1 - 5 mg daily). Patients who experience severe nausea may choose injections, which are as effective and less expensive than oral drugs.

More serious complications of methotrexate include the following:

• Liver damage: In one study, 25% of patients taking methotrexate for 5 years developed cirrhosis, liver scarring. People with existing liver problems should not take this medicine, 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 reduced blood cell production
• Osteoporosis: Low doses of methotrexate 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. Patients with active infections should avoid this drug.
• 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, which 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, or birth defects in the baby. It may harm fertility in men.
• Lymphomas: A few cases have been reported, which are most likely related to the drug's immune-suppressing (lowering) 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 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, occasionally with toxic results. Patients should tell their doctor about 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 (Aleve), 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), people 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 related to 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 as 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.

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 treatments, usually topical drugs and especially 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. Triglycerides are a type of fat molecules in the blood. They may cause heart disease.

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. Certain cholesterol-lowering agents, including gemfibrozil (Lopid) or statins, such as atorvastatin (Lipitor), may prevent this problem.
• 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 a doctor 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.

Oral Retinoids and Pregnancy Retinoids taken by pregnant women pose a significant risk for severe birth defects in the unborn child. Pregnant or nursing women or those planning to become pregnant should not use these drugs. Women of childbearing age who take retinoids should have regular pregnancy tests. There are some differences in retinoid effects, however. Acitretin is cleared from the body in about 3 - 4 weeks, so the drug does not appear to pose a risk for birth defects beyond that time. There is one important exception: Drinking alcohol converts acitretin to etretinate, which is a retinoid that is stored in fat cells for 3 years. It may have the potential for causing birth defects during that time. Therefore, if a woman drinks alcohol while taking acitretin or any time during the 2 months after she stops, she must wait 3 years to conceive. Note: Some cooking products and over-the-counter preparations, such as cough syrup, may contain alcohol and be inadvertently ingested. Some experts, then, advise that acitretin not be given to any woman, regardless of alcohol use, who may become pregnant within 3 years of taking it. Isotretinoin (Accutane) can cause birth defects. It should not be used by women who are pregnant or plan to become pregnant. As of December 31, 2005, everyone who takes, prescribes, or dispenses the drug must enroll in a national registry called iPLEDGE. Accutane has also been linked to suicide and suicidal attempts. Patients who take the drug should be closely watched for signs of depression.

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 - 91% of patients within 8 - 12 weeks. Cyclosporine has significant side effects if used for a long time, notably kidney problems and non-melanoma skin cancers. It should be reserved for patients who do not respond to phototherapy or less potent systemic agents (for example, 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 blood-pressure 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 by 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 be safe for up to 2 years. Patients should be monitored regularly for high blood pressure and signs of kidney or liver problems, 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 investigational and are generally less safe than first-line agents.

Sulfasalazine. Sulfasalazine (Azulfidine) is 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 4 - 6 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.)

Biological Response Modifiers

Biological response modifiers, sometimes called "biologics," belong to a new class of drugs that are considered the most exciting development in psoriasis treatment. Four 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.

T-Cell Blockers. In psoriasis, and other inflammatory diseases, T cells (a type of immune cells) become overactive. Drugs that block T cell activation can help prevent psoriasis flare-ups and reduce symptoms.

• Alefacept (Amevive) received FDA approval in January 2003 for treatment of moderate-to-severe plaque psoriasis. It was the first biologic drug approved for psoriasis. Studies suggest that the drug produces 50 - 75% improvement in symptoms. Alefacept is given in a doctor's office or clinic. Patients receive weekly injections for 12 weeks. Blood tests are also done weekly to make sure that T cell levels do not drop too low. Alefacept's side effects are generally mild and include sore throat, dizziness, and cough. There have been a few reports of serious infection and cancer.
• Efalizumab (Raptiva) was FDA-approved in December 2003 for treatment of moderate-to-severe plaque psoriasis. Many patients experience 50 - 75% improvement in symptoms within 4 - 6 weeks of starting the drug. Unlike alefacept, patients can inject efalizumab by themselves at home. Weekly subcutaneous (under the skin) injections are given for 12 weeks. Recent clinical trials suggest that a longer course of treatment (24 weeks) may also be safe and effective for patients with chronic plaque psoriasis. Some patients experience flare-ups of psoriatic lesions after stopping efalizumab. Very serious, but rare, side effects include hemolytic anemia (due to red blood cell destruction), and antibiotic-resistant infections.

Tumor Necrosis Factor (TNF) Blockers. Activated T cells release chemical messengers that cause an inflammatory response. This inflammatory response can increase skin cells in psoriasis and cause joint pain in psoriatic arthritis. The TNF blockers used to treat psoriasis target the chemical messenger TNF-alpha.

• Etanercept (Enbrel) was approved in 2002 for treatment of psoriatic arthritis, and in 2004 for treatment of moderate-to-severe plaque psoriasis. In 2005, etanercept was also approved to improve physical function in patients with psoriatic arthritis. The drug is given either alone or in combination with methotrexate. Patients inject themselves under the skin, once or twice a week for 12 weeks. Etanercept can cause infections and should not be used by patients with weakened immune systems or heart failure. TNF-blockers have also been associated with increased risk of developing lymphomas (a type of cancer).
• Infliximab (Remicade) was approved in 2005 for treatment of psoriatic arthritis. Patients receive three intravenous infusions during the first 6 weeks of treatment. After this initial treatment period, patients receive an infusion every 8 weeks. The infusions take 2 hours and are given in a doctor’s office or clinic. Patients with a history of infection or heart failure should not take this drug.
• Adalimumab (Humira) is another TNF-blocker. It is being tested in clinical trials for treatment of psoriasis and psoriatic arthritis. Results from a Phase III (late-stage) study show that adalimumab (Humira) is more effective than methotrexate in the treatment of moderate-to-severe psoriasis. In the study, 80% of patients treated for 16 weeks with adalimumab reported a 75% or better improvement, compared with 36% of patients treated with methotrexate.

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 (IL) 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%.

• Review Date: 10/30/2006
• Reviewed By: Harvey Simon, M.D., Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

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