Systemic Medications:

Systemic treatment uses various medications that affect the whole body, not just the skin. Many systemic drugs used for psoriasis are also used for other severe diseases, including autoimmune diseases (especially rheumatoid arthritis) and cancer.

Systemic treatments for psoriasis may be taken by mouth or injection. The medicines can have significant side effects and are generally reserved for severe psoriasis.

At this time, the only systemic medications specifically approved for psoriasis are:

• Cyclosporine
• Methotrexate
• Retinoids

As with all medications for psoriasis, patients should use the lowest strength medication first. The primary treatment is called a first-line treatment, the next is known as a second-line treatment, and so on. Combinations of medications are often used.

Methotrexate

Methotrexate (Rheumatrex) is a biologic drug that interferes with cell reproduction and has anti-inflammatory properties. It is a first-line, or primary, systemic drug used to treat adults with severe psoriasis. The medicine is one of the few systemic drugs that has been proven to help patients with psoriatic arthritis.

The drug 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 include:

• Anemia
• Headache
• Mild hair loss
• Mouth sores
• Nausea
• Possible muscle aches
• Rash
• Vomiting

Many of these side effects are due to folic acid deficiency. Patients should ask their doctor if they should take folic acid supplements (generally recommended at 1 mg daily).

More serious side effects include:

• Increased risk for infections, particularly shingles and pneumonia. Methotrexate suppresses the immune system. Patients with active infections should avoid this drug.
• Infertility, miscarriage, and birth defects. This drug should not be used during pregnancy, because it can cause miscarriages or birth defects in the baby. It may harm fertility in men.
• Kidney complications.
• Liver damage. This drug may cause scarring of the liver. Those 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.
• Lung disease. This side effect can be sudden and severe, and occurs in up to 5% of people who take methotrexate. Risk factors include diabetes, existing lung inflammation, protein in the urine, and use of rheumatoid arthritis drugs called DMARDs.
• Lymphomas. A few cases of lymphoma have been reported, which are most likely related to the drug's immune-suppressing (lowering) effects. In most instances, the disease went into remission when the drug was stopped. Most studies have found no significant risk for cancers in patients taking methotrexate.
• Osteoporosis. Low doses of methotrexate do not appear to have any significant effect on bone loss, but long-term studies are needed to confirm this.
• Radiation recall. This is an uncommon side effect in patients who have been burned by radiation cancer treatments or sunburns. In such cases, a flare-up of symptoms occurs in the previously affected skin areas.
• Severe anemia. Folic acid supplements can offset this effect.
• Toxic effects on bone marrow. This can cause reduced blood cell production.

Despite methotrexate's side effects, some experts view it as the best therapy for widespread plaque psoriasis. It may also be effective for some patients with generalized erythrodermic and pustular psoriasis, as well as psoriatic arthritis.

Methotrexate appears to be effective in children, but more safety research is needed.

Drug Interactions. Many drugs interact with methotrexate, occasionally with harmful results. For example, the antibiotic trimethoprim-sulfamethoxazole increases the toxicity of methotrexate.

A serious, harmful reaction can occur if methotrexate is taken with common, nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, or naproxen. Other NSAIDs, namely ketoprofen, flurbiprofen, and piroxicam, appear to be safe when given with methotrexate and may be used in patients with psoriatic arthritis. Rheumatoid arthritis (RA) patients who take methotrexate often take NSAIDs as well, but methotrexate doses in psoriasis patients are usually much higher than those in RA.

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.

People with the following conditions should also avoid taking methotrexate:

• Alcoholism
• Anemia or other blood abnormalities
• Immunosuppression
• Kidney problems
• Liver problems (including hepatitis)
• Peptic ulcers
• Rheumatoid arthritis

Patients at risk for liver complications include those with diabetes and obesity. Anyone with a history of hepatitis should have a liver biopsy before taking methotrexate.

Oral Retinoids

Oral retinoids are vitamin A-related medications taken by mouth. This group of medicines is also a first-line treatment for adults with severe psoriasis. Oral retinoids 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 types. When used alone, it is much less effective against more common forms of psoriasis, such as plaque or guttate psoriasis. However, when combined with PUVA phototherapy it can markedly improve the response, even in patients with these forms of psoriasis.

Accutane, more commonly used to treat acne, is far less potent than acitretin, but it may still be effective against pustular psoriasis. The drug may also be effective with phototherapy.

Oral retinoids help control cell reproduction and have anti-inflammatory properties. They may even improve arthritis that accompanies psoriasis.

Combination therapy. Acitretin may work best when combined with other treatments, usually topical drugs and especially phototherapy. Combination therapy allows lower doses of oral retinoids to be used, which diminishes many skin and mucus membrane side effects. Acitretin combined with phototherapy has some of the highest clearance rates of any treatment.

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

• Bone and joint pain
• Bruising
• Depression and possible suicide risk (with isotretinoin)
• Eye problems, including blurred vision, cataracts, conjunctivitis, and a sudden deterioration in night vision
• Fatigue
• Headache
• Increased bone growth, particularly in the ankles, pelvic area, and knees
• Increased triglyceride levels
• Liver damage
• Nail problems
• Skin and mucus membrane problems, including dry nose, nosebleeds, dry eyes, chapped lips, thinning hair, dry or "sticky" feeling skin, and peeling of the palms and soles

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.

Oral retinoids should not be taken during pregnancy.

Despite these side effects, oral retinoids remain among the safest whole-body therapies for psoriasis. A low-fat diet, aerobic exercise, and fish oil supplements may help reduce the side effects. Certain cholesterol-lowering drugs, including gemfibrozil (Lopid) or certain statins, such as atorvastatin (Lipitor), may help control triglyceride levels.

Maintenance doses should be as low as possible and should be taken every second or third day.

Oral Retinoids and Pregnancy

Taking retinoids during pregnancy significantly increases the 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.

• Acitretin should not be given to any woman who may become pregnant within 3 years of taking it. Drinking alcohol changes acitretin to a retinoid that is stored in fat cells for 3 years. It may have the potential to cause birth defects during that time. Be cautious about cooking products and over-the-counter preparations, such as cough syrup, which may contain alcohol.
• Women who are pregnant or who plan to become pregnant should not use isotretinoin. Everyone who takes, prescribes, or dispenses the drug must enroll in a national registry called iPLEDGE, which ensures that no woman starts retinoid therapy while pregnant or trying to get pregnant.

Cyclosporine

Cyclosporine (Neoral, Sandimmune, SangCya) blocks certain immune factors and may be effective for all forms of psoriasis. It is also a first-line, or primary, systemic drug used to treat adults with severe psoriasis. Neoral is the preparation used most often for psoriasis, and it clears psoriasis in many patients within 8 - 12 weeks.

Side Effects. 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 medications (for example, methotrexate or acitretin).

Common and temporary side effects include:

• Fatigue
• Gingivitis
• Gout
• Hair growth
• Headaches
• Joint pain
• Tremor

More serious complications may include:

• Kidney damage
• High blood pressure (Some doctors advise treating high blood pressure with calcium channel blockers, because other standard blood pressure drugs may worsen psoriasis. Calcium channel blockers also help prevent kidney problems.)
• High cholesterol and lipid levels
• High levels of calcium and low levels of magnesium
• Increased risk for infections
• Liver problems
• Lymphomas
• Skin cancers (Patients who take cyclosporine after PUVA therapy have a higher incidence of squamous cell skin cancer. The risks are greatest with long use and previous use of PUVA, methotrexate, or other immunosuppressants.)

To reduce complications of cyclosporine, the dosage is decreased 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 to use for up to 2 years. Patients should be monitored regularly for high blood pressure and signs of kidney or liver problems and 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 medication. 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.

Newer forms of cyclosporine that have fewer side effects are being investigated.

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. 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.

Biologics are traditionally second- or third-line treatments, and may be used alone or in combination with first-line systemic drugs. Depending on the severity of psoriasis, some of these drugs may be used earlier in the course of treatment. Studies of these medications have primarily been done on patients who are over 18 years old.

There are different types of biologics used to treat psoriasis:

• T cell blockers block immune cells linked to inflammation.
• Tumor necrosis factor (TNF) blockers target the chemical messenger TNF-alpha, which is released during the inflammatory response.

Types of T-cell blockers:

• Alefacept (Amevive). This drug is approved for the treatment of moderate-to-severe plaque psoriasis. It is very effective for psoriasis of the scalp. However, it doesn't work for all patients. Alefacept is given in a doctor's office or clinic. Patients receive weekly injections for 12 weeks. They need weekly blood tests to make sure T cell levels do not drop too low. Side effects are generally mild and include sore throat, dizziness, and cough. There have been a few reports of serious infection and cancer.

Types of TNF blockers:

• Etanercept (Enbrel) is approved for the treatment of psoriatic arthritis and moderate-to-severe plaque psoriasis. The drug is given either alone or in combination with methotrexate. Side effects include infections and lymphoma (a type of cancer). Patients inject themselves under the skin once or twice a week for 12 weeks. Continuing etanercept after 12 weeks may lower the severity of disease without increasing infections or side effects. Although etanercept has not been studied in children who have psoriasis, it has been shown to be safe and effective for treating children with rheumatoid arthritis.
• Infliximab (Remicade) is approved for the treatment of psoriatic arthritis. Patients receive three intravenous infusions during the first 6 weeks of treatment. After the initial treatment period, patients receive an infusion every 8 weeks. Therapy takes 2 hours and is given in a doctor's office or clinic. Patients with a history of infection or heart failure should not take this drug. Several studies have shown that symptoms improve significiantly by week 10 in most patients with severe psoriasis who are treated with infliximab.
• Adalimumab (Humira) has been approved for moderate-to-severe chronic plaque psoriasis. It is given by injection weekly at first, and then bi-weekly.

Investigational Biologics

Interleukins (IL) being investigated as sources or targets of therapy include IL-4, IL-2, IL-8, IL-11, and IL-12. The investigational biologic drug, ustekinumab, which targets IL-12 and IL-23, has been shown to reduce or clear symptoms in some patients with psoriasis. The drug's manufacturer has applied for FDA approval.

Another investigational medicine called ABT-874 has greatly reduced symptoms in most patients studied. ABT-874 targets proteins that are responsible for psoriasis-related inflammation.

Other Second- and Third-Line Treatments

Sulfasalazine. Sulfasalazine (Azulfidine) is sometimes used for psoriasis. In one major analysis, sulfasalazine and methotrexate were the only medications 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.

Immunosuppressants. Some immunosuppressants being studied for psoriasis include tacrolimus (Prograf), pimecrolium, and sirolimus. Studies have been limited, however. Side effects of these medications are similar to those of cyclosporine. Pimecrolimus may specifically target the skin and have fewer side effects. (Some immunosuppressants are also being studied as topical treatments.)