People whose psoriasis cannot be controlled by topical medications applied directly to affected areas of the skin may turn to systemic, or internally administered, drugs, to ultraviolet light treatments, 
to biologic therapies, or to some combination of them. In the United States, the three most common systemic medications for psoriasis are cyclosporine, methotrexate, and acitretin (Soriatane). Each can be very effective, but each can also cause serious side effects. Therefore, patients must decide together with their doctors whether to take a systemic medication and which one to choose based on careful consideration of factors including psoriasis severity, overall health, and lifestyle.
Read on for more information on cyclosporine, methotrexate and acitretin.
Cyclosporine (Neoral and others)
What is it?
Cyclosporine is an immunosuppressant medication that has been widely used since the early 1980’s to prevent rejection of organ transplants. In 1997, one particular formulation of cyclosporine, Neoral, gained FDA approval for the treatment of severe psoriasis.
How is it administered?
Psoriasis patients usually take cyclosporine in pill form, twice a day. Because long-term use of cyclosporine damages the kidneys (see below, Drawbacks), patients normally receive multiple short courses of cyclosporine therapy, each lasting about 12 weeks, with “rest” periods in between.
How well does it work?
Cyclosporine is highly effective at controlling psoriasis. Overall, about 70% of patients in clinical trials experienced at least a 75% improvement in their psoriasis symptoms as measured by the Psoriasis Area and Severity Index (PASI). The PASI takes into account both the fraction of the body surface area covered by psoriasis plaques and the severity of the plaques (e.g. the degree of redness and scaling). “PASI 75,” as this level of improvement is known, is the standard typically used by the U.S. Food and Drug Administration (FDA) in evaluating the effectiveness of potential psoriasis treatments.
Advantages
Although Cyclosporine cannot be used long-term, it can be very helpful as an initial therapy to bring severe psoriasis under control or to treat periodic flares. Patients can combine intermittent short-term courses of cyclosporine with long-term use of a less toxic medication. Although cyclosporine is considered less harmful to a developing fetus/child than methotrexate or acitretin, this advantage may no longer be as important since the advent of the biologics, which may be a better choice for women who are or may become pregnant. But this is a complex question that should be discussed with a physician in advance of a pregnancy.
Drawbacks
The most serious problem with cyclosporine is that long-term use almost inevitably leads to kidney damage, although the damage is often reversible if patients stop taking the medication. Therefore, psoriasis patients should not use cyclosporine continuously for more than 1-2 years. The preferred treatment strategy is give multiple short courses of cyclosporine therapy with breaks in between to allow the kidneys to recover from the drug’s toxic effects. Patients receiving cyclosporine need to undergo regular blood tests to monitor their kidney function. Those with pre-existing kidney disease are generally advised not to use cyclosporine.
Psoriasis patients taking cyclosporine also often develop high blood pressure. Usually, the increase in blood pressure is mild to moderate, does not require treatment, and resolves when the course of cyclosporine therapy ends.
Due to its immunosuppressant effects, cyclosporine can increase the risk of infection and cancer. So far, these problems have only been clearly demonstrated in transplant patients who take higher doses of cyclosporine for longer periods of time than psoriasis patients. Still, because of the potential risk, cyclosporine is not generally considered safe for psoriasis patients who have a history of cancer or for those whose immune system is impaired, for example by HIV infection.
How does it work?
Cyclosporine inhibits the production of a chemical called interleukin-2 (Il-2) inside certain immune cells, particularly T lymphocytes. T lymphocytes need Il-2 to become fully active and without it, their ability to mount an immune response is severely impaired. Psoriasis may be caused by hyperactive, mis-regulated T lymphocytes, so the dampening effect of cyclosporine on T lymphocytes could explain why the drug is effective against psoriasis.
Methotrexate (Rheumatrex and various generics)
What is it?
Methotrexate was developed as an anti-cancer drug and received FDA approval for the treatment of cancer in 1953. Not long afterward, doctors noticed that methotrexate also effectively controlled severe psoriasis and have prescribed it for that purpose ever since. The FDA officially approved methotrexate as a psoriasis treatment in the early 1970’s. Today, methotrexate is used to treat cancer and several immune system diseases, including psoriasis, psoriatic arthritis, rheumatoid arthritis and Crohn’s disease.
How is it administered? Methotrexate is typically taken in pill form, but it can also be administered by injection into the muscle, or intravenously. A typical dose would range from 10 mg to 25 mg weekly. Sometimes your physician will advise you to split the weekly dose into three segments taken over a 24-hour period (i.e., you take the first third of the total weekly dose, wait 12 hours, take the second third, wait 12 hours, then take the final third of the dose). As long as there are no signs of severe side effects, methotrexate can be taken for years. Some patients take a folic acid supplement along with methotrexate to reduce some of methotrexate’s side effects.
How well does it work?
Even though methotrexate has been used to treat psoriasis for decades, it has not been thoroughly tested for effectiveness in large clinical trials. Data from several small studies suggest that psoriasis improves by 50% (as measured by the PASI) in approximately three-quarters of patients taking methotrexate. In one study that compared cyclosporine and methotrexate “head to head,” both drugs performed well. (Seventy-one percent of patients taking cyclosporine and 60% of patients taking methotrexate experienced at least a 75% improvement in PASI score; the difference was not statistically significant.) Methotrexate continues to be widely prescribed for psoriasis and psoriatic arthritis, alone or in combination with other treatments.
Advantages
Methotrexate is effective, relatively inexpensive, and convenient to take. Unlike cyclosporine, methotrexate can be used for longer periods of time, as long as patients are monitored for liver damage and other potentially serious side effects.
Drawbacks
Methotrexate can cause serious liver damage. The damage is not always evident in blood tests for liver function, so liver biopsy, a procedure during which a small sample of liver tissue is collected and examined in a laboratory, is recommended after every 1 ½-2 years of methotrexate treatment. According to one study, 14% of patients who had been taking methotrexate for an average of 237 weeks had to stop because of liver problems. To lessen the risk, patients should not drink alcohol while taking methotrexate and those who already have liver disease should not use the drug. Folic acid supplements may help protect the liver. If patients follow the recommended monitoring scheme and stop using methotrexate at the first sign of liver problems, the damage is usually reversible.
Other serious potential side effects of methotrexate include a drop in white blood cell production, lung disease, and skin reactions, so patients should be carefully checked for these conditions during treatment.
The most common less serious side effect of methotrexate use is nausea. Taking supplemental folic acid or anti-nausea medications can help control this symptom.
Methotrexate causes birth defects and miscarriages, so women taking the drug must be careful to avoid conception. Further, it is advisable for women to wait six months after stopping methotrexate before trying to conceive. Men are also typically advised to stop using methotrexate and wait three-to-six months before trying to conceive, due to risk of temporary infertility and/or risk to the fetus/baby, but a study that reviewed available data found the risks largely theoretical, and men have fathered healthy children while taking methotrexate during conception.
How does it work?
At the high doses used to treat cancer, methotrexate blocks synthesis of DNA and RNA, thereby preventing tumor cells from dividing. Interestingly, methotrexate can control psoriasis at a 100-fold lower dosage, suggesting that it may be working by a different mechanism. According to one theory, methotrexate prevents immune cells from displaying certain molecules on their outer surfaces that are necessary for cell-to-cell communication and interaction. Without these molecules, the cells are unable to congregate in the skin or trigger the inflammatory reaction that leads to the formation of psoriasis plaques.
Acitretin (Soriatane)
What is it?
Acitretin belongs to a class of drugs called retinoids, which are derivatives of vitamin A. It received FDA approval in 1996 and currently is the only orally administered retinoid approved for the treatment of psoriasis in the United States. A closely related retinoid, etretinate (Tegison), was used to treat psoriasis, but was withdrawn from the U.S. market in 1998. A third retinoid, isotretinoin (Accutane), is primarily used to treat severe acne. It is less effective against psoriasis than acitretin, but is still prescribed in some cases.
How is it administered?
Acitretin is usually taken in pill form once a day.
How well does it work?
There is a lot of variability in study results, but acitretin appears to be somewhat less effective than cyclosporine or methotrexate at controlling plaque psoriasis, the most common form of the disease. Acitretin clears psoriasis completely in about 30% of patients and improves symptoms significantly in another 50%. Many patients get the best results by combining acitretin with PUVA. The drug is also especially beneficial for patients with pustular or erythrodermic psoriasis.
Advantages
Aside from the fact that it causes serious birth defects (see below, Drawbacks), acitretin is a relatively safe medication. Unlike cyclosporine and methotrexate, acitretin usually does not cause cumulative organ damage, so in patients who can reliably avoid pregnancy, it can be a good long-term maintenance therapy. For example, patients can take acitretin during the gaps between short courses of cyclosporine treatment. Acitretin is also the only one of the three systemic therapies that does not suppress the immune system, so patients with immunodeficiency disorders, such as HIV infection, can use it. Finally, acitretin is particularly effective against pustular and erythrodermic psoriasis and is considered a first choice treatment for patients with those rarer forms of the disease.
Drawbacks
Acitretin causes severe birth defects and can be converted to a form that takes a very long time to clear from the body. Therefore, female patients must absolutely avoid pregnancy while taking the drug and for three years after stopping treatment. Because alcohol consumption promotes the conversion of acitretin to the long-lasting form, women of child-bearing age are advised not to drink any alcohol while taking acitretin.
In many patients, acitretin use leads to an increase in triglyceride levels in the blood, a risk factor for heart attacks. Triglyceride levels should be monitored during treatment and acitretin is not recommended for patients with pre-existing abnormal triglyceride levels. Because of rare reports of serious effects on the liver, liver function should also be monitored.
Acitretin also commonly causes hair loss; hair grows back after stopping treatment.
How does it work?
It is not yet clear how acitretin controls psoriasis. In general, retinoids activate molecules in cell nuclei called retinoic acid receptors. The active receptors regulate the output of many different genes, which influence cellular behavior in complex ways. Retinoids have been shown to reduce inflammation and affect the division rate of cells in the skin. A better understanding of how retinoids work will hopefully lead to the development of more specific and effective psoriasis medications.
