Principle 1. Systemic Drugs with an Element of Risk Are Essential in the Management of Numerous Dermatoses

Many dermatologic therapies are administered through relatively safe topical routes. In addition, there are a number of systemic drugs for which there are few significant risks and which therefore require little or no routine monitoring for adverse effects ( Table 48-1 ). This chapter focuses on the systemic drugs with a significant element of risk that are commonly used to treat more serious dermatologic conditions ( Table 48-2 ).

Principle 2. It Is Important Initially to Make a Reasonable Estimation of the Cutaneous Disease “Severity”

There are a number of dermatologic conditions in which disease severity and associated risks are self-evident. Blistering diseases such as pemphigus vulgaris and blistering drug reactions such as toxic epidermal necrolysis (TEN) have well-established risks. Malignancies that are multicentric at the outset, such as cutaneous T-cell lymphoma (mycosis fungoides), represent another example of high-risk dermatoses. At times, the dermatologic risk is a function of the systemic findings associated with the dermatologic signs of internal disease. Systemic lupus erythematosus, sarcoidosis, drug reaction with eosinophilia and systemic symptoms (DRESS), and dermatomyositis are appropriate examples. The severe irreversible ocular mucosal morbidity with mucous membrane pemphigoid also presents a noteworthy risk.

It is more difficult to determine disease severity and risk in conditions without life-threatening potential and without severe irreversible morbidity. Dermatologists are commonly confronted with the psychosocial risk and/or functional impairment presented by patients with severe acne vulgaris or psoriasis. In these cases the patient and physician collectively will have to determine if appropriate systemic drug therapy with an element of risk is warranted.

Dermatologic conditions in which the morbidity results in a loss of work can also justify potentially risky systemic therapy. Pyoderma gangrenosum is an example of such a condition.

Principle 3. “Risk–Risk” Analysis Is Performed by Comparing the Risk(s) of a Given Disease (As Defined Earlier) with the Inherent Risk(s) of the Proposed Systemic Drug Therapy. The Treatment Risks Should Not Exceed the Inherent Untreated Disease Risk

The risk–risk analysis may be preferable to the risk–benefit ratio, which is traditionally discussed. Even after considering conditions deemed severe by the criteria cited earlier, dermatologists predominantly face conditions with less risk of death and severe morbidity than do most other specialists in medicine. In most cases, there is a significant subjective element to this risk–risk analysis. The patient has a central role in this decision-making process.

Principle 4. It Is Important to Be Aware of a Given Drug’s Official Food and Drug Administration (FDA)-Approved Indications, and the Generally Accepted but “Unapproved” or “Off-Label” Indications for That Drug

Official FDA approval means that there has been an application for a specific use of a drug and that sufficient safety and efficacy data have been presented to warrant use of the drug for that specific disease indication. Safety data are usually applicable to generally accepted but “off-label” indications. What is lacking in these off-label indications is efficacy data officially submitted by the pharmaceutical company to the FDA. Considerable expense is associated with applications for each “new use.” Usually, the decision to use systemic medications for off-label indications is based either on significant personal experience or evidence from the medical literature.

Systemic drug therapy is commonly associated with some element of risk. The patient ideally should be notified when the drug will be used for an off-label indication.

Principle 5. The Priority Sequence of Systemic Drug Choices Should Be Individualized for Each Specific Patient. Factors Such As Drug Cost, Simplicity of the Therapeutic Regimen, Inherent Drug Risk, and Patient Preference Enter into the Decision

When all other factors are equal, a drug that is relatively inexpensive, simple to use, and relatively safe should be prescribed. Ideally, such a drug should be supported by an FDA indication or sufficient clinical data and experience to justify its use. If such therapy is not appropriate or is not successful, then more costly, complicated, or novel treatments with an element of risk can be tried. Frequently, patient preferences are shaped by logistics, such as drug cost, patient income, time, travel, and the patient’s tolerance of risk.

For female patients of childbearing potential, plans for pregnancy should be discussed before prescribing systemic medications. For potentially teratogenic medications, birth control methods should be discussed and documented in the chart. Physicians should also inquire if the patient is breastfeeding prior to initiating systemic therapy.

Principle 6. Be Aware of Pharmacogenomics Biomarkers Required to Assess Drug Safety for Individual Patients

Pharmacogenomics plays an important role in identifying patients at risk for specific adverse events and in identifying potential nonresponders. Two examples of important pharmacogenomics tests in dermatology are glucose-6-phosphodehydrogenase (G6PD) level to assess for G6PD deficiency in patients prescribed dapsone, and thiopurine methyltransferase testing to assess for intermediate or poor metabolizers in patients prescribed azathioprine (see the FDA website listed in Suggested Readings for available pharmacogenomics biomarkers).

Principle 7. Be Cognizant of Important Drug–Drug Interactions when Prescribing Systemic Therapy for Cutaneous Diseases

An increasing number of patients who present to the dermatologist are already receiving a wide variety of systemic medications for nondermatologic medical problems. An awareness of the patient’s complete medication profile helps enhance the safety of prescribing systemic drugs, particularly for patients who are receiving cyclosporine or methotrexate. A systematic way of recording and updating the patient’s complete medication profile helps minimize the risk of these potential interactions. It is our suggestion that current drug therapy be monitored and recorded at each patient visit. Electronic medical records have helped decrease the risk of drug–drug interactions by alerting physicians to potential interactions between medications prescribed and those recorded in the chart. This should not replace an effort on the part of the dermatologist to be alert to potential drug–drug interactions when prescribing systemic medications. It is also important to notify the patient of key interactions and medications to avoid during therapy.