Choosing therapy: Weigh options carefully for immunocompromised patients

September 1, 2008

As immunocompromised patients, and those with genodermatoses, have a significantly increased risk of developing skin cancer, physicians should carefully weigh their choices of therapy from the start, to avoid precluding future therapies when these patients may need them most.

Key Points

Amsterdam, Netherlands - Immunocompromised patients, and those with a specific genodermatoses, have an increased risk of developing skin cancer compared to the normal population.

Chronically immunocompromised patients, such as transplant recipients, are at high risk because of the medications that these patients receive.

"We see an increased risk of skin cancer in transplant patients, especially in those who have had high levels of sun exposure (e.g., outdoor workers and 'sun worshippers').

"These patients have acquired DNA damage throughout their lives prior to the transplant, accumulating DNA damage from the UV radiation they expose themselves to.

"This damage is, in part, repaired or removed; however, histochemical studies prove that several UV-induced mutations remain in the skin ('p53 islets') and is seen later in the form of a higher susceptibility to develop skin cancers," says Tamar Nijsten, M.D., department of dermatology, Erasmus Medical Center, Rotterdam, the Netherlands.

Immune surveillance

The body has different kinds of repair systems that control the progression of UV-damaged cells into skin cancer, such as the DNA repair system, as well as the immune system, constituting the body's immune surveillance.

Dr. Nijsten says if the immune system is wiped out with immunosuppressive drugs, such as cyclosporine, the body's immune surveillance is compromised to varying degrees.

A transplant is overwhelmingly important and can be crucial to the survival and quality of life of the patient, but a significantly increased risk of developing skin cancers is a common sequela of the immunosuppressing medications that physicians use in these patients, according to Dr. Nijsten.

"It is like taking the bad with the good," he says.

Light therapy

"In contrast to transplant recipients, psoriasis patients are commonly, and often successfully, treated with ultraviolet radiation such as PUVA and UVB; however, these therapies are known to be carcinogenic and increase skin cancer risk.

"Both of these approaches expose patients to UV light, inducing a similar DNA damage as seen in people who expose themselves to UV radiation at the beach. The difference is that this DNA damage is iatrogenic," Dr. Nijsten tells Dermatology Times.

Biologics

Dr. Nijsten says the problem is that if the light therapy proves to be ineffective after a while, or the patient cannot complete the suggested UV therapy protocol, physicians then start the patient on other therapies, including cyclosporine and biologics.

This creates a situation similar to that of transplant patients, in which there is substantial UV exposure followed by an immunosuppression, which leads to a substantial increase in risk of skin cancer.

"This important sequence of detrimental effects in respect to the increase of skin cancers does not seem to be fully accepted by the dermatologic community. They do realize that there is DNA damage, but the impact of the negative synergy of UV therapy and cyclosporine has not been fully recognized by dermatologists," Dr. Nijsten says.

According to Dr. Nijsten, in order to receive reimbursement for biologic therapy in Europe, a patient needs to fulfill a set of criteria: Patients should have failed or have contraindications for UV therapy, methotrexate and cyclosporine.

This implies that before a patient is eligible to use a biologic, he or she must have received high doses of UV and cyclosporine, which is not ideal from a safety perspective.

Moreover, it implies that patients on biologics all have had either the maximum or at least high UV exposure.

'Systematic intoxication'

"This amounts to the common scenario of a patient receiving maximum UV therapy for years, then maximum cyclosporine therapy, and then the commencement of a biologic therapy, which is almost like a systematic intoxication of your patients.

"Because of this paradoxical situation, I believe that it is crucial to choose the avenue of therapy very wisely from the get-go," Dr. Nijsten says.

He says most of the therapies available will weaken the immune system. Therefore, it should not be compulsory to use cyclosporine as a reimbursement criterion before moving on to another therapeutic approach, such as a biologic.

"The dermatologist's hands are effectively tied, and you are basically systematically putting patients at high risk of (skin) cancer without being allowed to individualize treatment regimens and carefully step forward therapeutically for the good of each patient, individually," he says.

According to Dr. Nijsten, PUVA should be reserved as the last option and should be given only after cyclosporine, methotrexate and the biologics have failed, because the resultant cumulative DNA damage leads to an increased susceptibility of developing skin cancers. He says UVB therapy has only one-seventh the carcinogenicity of PUVA and seems to be more advantageous at the initiation of treatment.

Dr. Nijsten says that after topical therapy, UVB could be used as a first-choice therapy, but the total number of treatments should be relatively limited.

Physicians could then be able to switch their patients sooner to systemic therapies to minimize the UV-induced damage to the DNA and its possible consequences.

"Physicians often mercilessly expose their psoriasis patients to PUVA, and this is an approach that needs to be controlled and/or changed for the benefit of our patients in terms of the increase in risk of developing skin cancers," Dr. Nijsten says.

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