The History of Treatments for Psoriasis

In 1775 Sir Percival Potts described coal tar as a human carcinogen, having observed that chimney sweeps, boys who were small enough to slide down chimneys to remove the soot, developed scrotal cancer. When he provided an opportunity for these boys to bathe routinely, the incidence of the malignant lesions decreased. This represented the first example in the medical literature of an agent that was capable of causing cancer, but was certainly not the last mention of coal tar, because for many decades coal tar has been, and still is, the mainstay of topical therapy for psoriasis. No one knew why or how it worked, but there are many medical treatments that enjoyed wide use and clinical success long before anyone knew how or why (aspirin, for example).

Another example of a treatment that developed without knowing why it worked is ultraviolet therapy. Most psoriasis patients improve in the summer when they are exposed to the sun, so the role of UV exposure became obvious many years ago. Indeed, in 1925 Goeckerman introduced a protocol for using gradually increased doses of ultraviolet B (UVB) radiation together with the classic treatment – topical applications of coal tar. This treatment regimen has had many modifications over the years, but still remains the mainstay of therapy for patients with extensive, severe psoriasis. An average of 20 to 30 treatments are required for successful clearing (complete resolution of 90% of plaques), and this is followed by maintenance therapy consisting of a decreasing number of lower dose of UVB radiation once a week, unless relapse occurs, in which case the treatment schedule must be increased. Aside from the staining and unpleasantness of coal tar ointments, and the discomfort (sunburn) associated with the UVB (plus the inconvenience of many visits to the dermatologist), this regimen marks the successful use of two known carcinogens – coal tar and UVB, the main agent in sunlight that is now known to be responsible for skin cancer in humans.

As if that were not enough, along came the use of UVA radiation therapy with Psoralen, a photosensitizing drug. UVA is the longer wave length of sunlight that has a stronger role in skin wrinkling than in causing skin cancer, but it also thought to play a major role in skin cancer duet to the increase that followed the introduction of sun screen in 1935, since it enabled persons to stay in the sun longer without the burning caused by UVB. In the U.S., Psoralen is usually taken orally, although in Europe topical forms tend to be more frequent. Psoralen from plant sources were first reported as being effective for psoriasis in the early 1970s, with the first use of Psoralen with UVA (PUVA) for the treatment of psoriasis in 1974. As with the coal tars and UVB radiation, the mechanism of PUVA was not understood at the time; indeed, many medical breakthroughs before the recent emergence of modern insights from biotechnology research were based on empirical observation – i.e. it worked. In any case, PUVA is effective and widely used in patients with severe psoriasis or those who no longer respond to coal tar and UVA, although PUVA has been associated with an increased risk of non-melanoma skin cancer.

The next class of drugs for therapy of psoriasis, antimetabolites, began with the use of Aminopterin for treatment of childhood leukemia in the late 1940s. Methotrexate is metabolized from Aminopterin, and when used on patients with arthritis was shown to result in the clearing of psoriatic plaques. Methotrexate is now approved by the FDA for use in severe psoriasis as well as rheumatoid arthritis and certain cancers.

Although the exact mechanism of action of Methotrexate in psoriasis is unknown, it was the first effective systemic medication used in the treatment of psoriasis, and continues to be the standard of therapy against which other therapies are compared. It is used in patients with extensive psoriasis that does not respond to topical therapy, and a “reasonable” goal is to achieve 75% clearing of the involved area.
This goal is accomplished in 60% to 75% of patients (in 3 months), using a range of doses of Methotrexate. When the cumulative dose of Methotrexate reaches 1500 mg, all patients should have liver biopsies with
subsequent biopsies at intervals thereafter, since psoriasis patients have a 2.5 to 5 fold increased risk of developing liver fibrosis and cirrhosis from treatment with Methotrexate than patients with rheumatoid arthritis treated with similar doses. Although there are many side effects such as nausea or diarrhea, severe hematological effects can occur in 25% of the patients; even those taking low weekly doses can develop severe and sometimes life-threatening decrease in their blood cell counts.

Other systemic cytotoxic drugs have also been used for treatment of severe psoriasis, such as Azathioprine, which is a drug used to prevent rejection of organ transplants. However, its use for psoriasis has been limited due to the fact that is causes severe depression of blood formation by the bone marrow and is also associated with an increased risk of malignancies such as lymphoma or squamous cell carcinoma. A metabolite of Azathioprine, Thioguanine, has been shown to cause cell death of activated T lymphocytes, with the depletion of these lymphocytes from psoriatic plaques resulting in clearing of the lesions. Thioguanine appears to be successful in patients who could not continue Methotrexate therapy due to liver damage, and an effective response rate of 48.8% was reported in one study of 80 patients. However, bone marrow suppression occurs in 22-68% of cases, depending on dosage schedules and cumulative doses.

In 1979 it was reported that Cyclosporine, another anti-rejection drug, improved psoriasis. This was discovered serendipitously in patients undergoing transplantation, with the first prospective study not reported until 1986. Prior to this time, psoriasis research had been focused mostly on trying to determine why the keratinocytes demonstrated such abnormal growth and differentiation. Finding that Cyclosporine reduced the number of T lymphocytes in psoriatic lesions, thereby leading to a significant remission, led researchers to recognize that psoriasis was an immunologic disorder. Cyclosporine is approved by the FDA for use in psoriasis, and it is indicated in patients who have failed to respond to at least one systemic therapy, or who cannot tolerate other systemic therapies. With this treatment, about 65% of the patients achieve clearance or near clearance, although not without side effects such as hypertension, which is not dose dependent, and renal dysfunction, which is. Despite these 2 serious complications, Cyclosporine has proved effective with long term administration using low concentration maintenance doses, although most patients relapse and require higher doses over time. Relapse after discontinuation of Cyclosporine is usually seen within 8 to 12 weeks. The incidence of cancer in patients taking Cyclosporine is similar to that of Methotrexate, with about 1% of patients developing malignancies of which 50% are skin cancers. Oral Tacrimilus, another anti-rejection drug, has also been used for the treatment of psoriasis but it has side effects similar to Cyclosporine. Topical Tacrimulus ointment has been tried but although there were no symptomatic side effects, is it not significantly effective.

Another category of oral therapies for psoriasis include those derived from vitamin A. Etretinate was used in the U.S., and proved most effective for postular psoriasis. However, Etretinate has teratogenic (birth defect causing) potential, so its use is not indicated for women of childbearing age, especially since after long term administration it can be stored in fatty tissue, leading to detectable serum levels for more than two years after discontinuation. Acitretin, a metabolite of Etretinate, is less lipophilic and is cleared from the body more rapidly than Etretinate, so is considered to pose less of a risk of birth defects. In the U.S., Acitretin has been approved by the FDA for treatment of psoriasis although it is less effective than etretinate, which it has replaced. Systemic retinoids can enhance the effects of many other topical and systemic anti-psoriasis therapies, and are often used in association with topical agents and phototherapy, but are not without significant side effects with long-term therapy, which require periodic monitoring for skeletal toxicity.

A topical retinoid, Tazarotene, was recently introduced for the treatment of psoriasis, but it can irritate normal skin, causing pruritis and erythema. With this topical therapy, in patients with a successful response to therapy (defined as a 50% or greater clearing of psoriasis), relapse occurred within three months of discontinuation in 37% of the patients. The effect of Tazarotene may be enhanced when combined with UVB or UVA radiation.

Another vitamin-derived therapy is Calciprotol, a topical vitamin D analogue that came into use in 1992. However, it is mildly irritating and hypercalcemia can results if the recommended dose is exceeded. When Calciprotol is used after PUVA and UVB therapy, a lower does of radiation may be needed.

Despite the extensive array of treatments used for psoriasis, topical corticosteroids are the most widely used treatment in the U.S., because of their short-term efficacy leading to better patient compliance. They have been used since the introduction of hydrocortisone in 1952. However, long-term therapy with topical steroids can cause thinning of the skin, striae, skin discolorations, masking of local infections and hypo-pigmentation.

There are many new drugs in development that target T-lymphocytes. In one trial, 39% of patients treated weekly with the Genentech drug for 12 weeks showed improvement of at least 75%, with side effects including headache, chills and fever (side effects are said to diminish after the first dose). Another genetically engineered drug from Biogen, Amevive, saw a similar improvement after 12 weeks of weekly injections into muscle with side effects ranging from headache to common-cold infections. However, although discontinuation of therapy allows patients to remain in remission for an average of 10 months, withdrawing the Genentech drug causes a rapid relapse (half of the patients relapse in less than 64-70 days), while one of the patients testing the Biogen therapy developed cancer. Many drugs in this category are currently in development, but it remains to be seen if their effects are long lasting and without undesirable side effects.

All of the treatments described above, and derivatives of the agents mentioned, may treat psoriasis successfully but none are without undesirable and sometimes severe side effects requiring monitoring and balancing the use of one against the use of another therapy with respect to which has the most tolerable side effect. The only agent not yet mentioned is a class of more benign drugs used for psoriasis, the keratolytics that assist in removing the scales associated with psoriasis. Salicylic acid is the most commonly used keratolytic agent, with prescription strengths ranging from 3% to 10% and it is essentially without side effects when used appropriately.

Because of the efficacy plus relative safety of salicylic acid, a low concentration (1.8%), which is recognized as effective by the FDA has been used in the Miraderm cream, in which it is formulated in a base which aids the keratolytic effect of salicylic acid by formulating it in a soothing base with bioflavenoids (plant derived) anti-inflammatory agents and emollients to counteract skin dryness.

Compared to all other treatments, Miraderm may appear to be too benign to be effective, but it can be used to give your body a rest from steroids or systemic therapy. When used in new patients, its results are rapid (well below the 3 usual months required for efficacy of the other treatments) and long lasting, and if there is a recurrence of plaques, these respond even more rapidly to Miraderm than do the original lesions.

If you have had many different treatments for psoriasis, we recommend that you give the big guns a rest and yourself a treat. What have you got to lose?