In the United States, approximately 1.5 million hospitalizations every year are due to adverse drug reactions, and an estimated 100,000 people die from them. Cutaneous drug reactions account for a large proportion of all adverse drug reactions and present a unique set of diagnostic challenges. This data underscores the need for clinicians to carefully weigh which drugs they prescribe for their patients, according to Neil H. Shear, M.D., F.R.C.P.C., F.A.C.P., professor and chief of dermatology, University of Toronto, and director of the Drug Safety Clinic at Sunnybrook Health Sciences Centre, Toronto, Canada.
Although many approved medications have excellent safety profiles, adverse drug reactions can be caused by most any drug. These can range from a fixed eruption to systemic manifestations, which can be very severe. These reactions may mimic a large variety of skin diseases, including viral exanthems, collagen vascular disease, neoplasia, bacterial infection, psoriasis, and autoimmune blistering diseases, Dr. Shear points out. This can confound even the most astute clinician. A better understanding of which medications can cause these adverse drug reactions and how to best find the potential offenders is key to managing patients, he says.
“Many patients are often on multiple medications for their disease or condition, which can make it much more difficult to determine which drug could be the potential offender in a patient with a suspected adverse drug reaction,” Dr. Shear says.
“When approaching a patient with cutaneous symptoms that appear to be in line with an adverse drug reaction, it is important that the clinician carefully weigh the potential differential diagnoses that fit the clinical picture and not quickly assume that the cutaneous symptoms seen are a direct result of a drug or drugs that the patient is on,” he adds.
“Automatically assuming that a drug is the cause of cutaneous symptoms seen in patients is a mistake,” Dr. Shear says. “Unwary clinicians can fall into this trap, which is almost impossible not to be drawn into, as many cutaneous manifestations can look very much like adverse drug reactions.”
On the flip side, Dr. Shear explains that it is also important to consider that cutaneous symptoms seen in a patient, such as a skin exanthema or other cutaneous eruptions, could be a reaction to a drug taken by the patient.
In an attempt to help clinicians better manage patients with a suspected cutaneous drug eruption, Dr. Shear developed the acronym STOP (Suspect systemic syndromes, Therapeutic tally, Other causes of the disease, and Probabilities), which can be used to more quickly and systematically identify a potential drug offender.
When approaching a patient with a skin exanthema or other cutaneous eruption, Dr. Shear explains that it is of paramount importance to first be clear about what one is seeing and establish a working diagnosis.
A very detailed drug history can be extremely helpful in incriminating or ruling out a
variety of potential offending drugs. Clearly, patients on multiple drugs can complicate the weeding-out process of potential offenders.
“Drug reactions, especially the severe ones, can sometimes take four to six weeks before patients present with any systemic symptoms,” Dr. Shear says, adding that a clinician “thinking that the potential drug eruption was caused by the last medication patients took could be incorrect, as it may be due to a drug they took weeks before they came in to see you. These things have a tipping point; sometimes it can take several weeks for drug reactions to show themselves clinically.”
Dr. Shear emphasizes that clinicians should first try to discontinue certain medications that the patient may not need or, if possible, replace them with other longer-standing agents that could have a more favorable safety profile.
“Often you go through the list of drugs patients are on and find that a lot of those drugs are not needed,” he says. “The first thing you want to do is treat the patient, and then you want to stop the drug that you think could have caused the drug eruption. It’s amazing how many drugs we can take away and patients do not fall apart because we took them away.”
Physicians also have to consider the probability a drug may have in causing a drug eruption. According to Dr. Shear, the timing of a cutaneous manifestation is critical because a specific adverse reaction can occur with a very specific timing after exposure to certain drugs, which impacts the probability of potential drug offenders that the patient may be on.
Some drugs and drug groups are more frequently associated with adverse drug reactions than others, Dr. Shear explains. These include the “antis” such as antibiotic, antigout, anticonvulsant, and anti-inflammatory medications.
Drug reactions may be exanthematous or urticarial and can sometimes be very severe, such as hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Although the more severe conditions are rare, these can be lethal, underscoring the urgency to find or rule out a potential drug offender.
“Shear’s Diagnostic Triangle” is another acronym tool designed to help clinicians consider the different diagnostic components simultaneously rather than as a list. Dermatologists can remember the word RASH for Remember, Appearance, Systemic, Histology.
The rash seen in a patient could be exanthematous, urticarial, bullous, or pustular, Dr. Shear explains. Systemic symptoms could include fever, lymphadenopathy, pharyngitis, hepatitis, or arthritis. In the histology, clinicians could look for vasculitis, interface dermatitis, CD8 predominance, apoptosis, or blistering.
READ: What is the culprit?
“All three parameters are important,” Dr. Shear says. “In an ideal scenario, you would find aspects of all three components in the patient. Fever is perhaps one of the most telltale features indicating that a drug is likely at fault. Fever usually changes everything, particularly when associated with other systemic features,” he explains.
According to Dr. Shear, toxicity assays or genetic testing can be used to find some potential drug offenders including allopurinol and carbamazepine. Other diagnostic evaluations include patch testing, the results of which can prove valuable in determining the potential drug at fault.
“Finding the offending drug using these diagnostic paths is crucial, particularly in the more severe drug reactions. If a patient has a very severe reaction, even a 5% likelihood that it could have been due to ibuprofen or another medication would not make you want to use that drug again, unless you can prove it wasn’t at fault,” Dr. Shear says.
Approval does not equal full safety
“It is important that physicians recognize the strengths, limitations, and sources of error when assessing drug safety, whether dealing with longer standing drugs or newer agents that come to market,” says Joel M. Gelfand, M.D., M.S.C.E., associate professor of dermatology and epidemiology, medical director of the Clinical Studies Unit, and senior scholar at the Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Penn.
In the FDA drug approval process, drugs are studied in relatively small numbers of people for short periods of time. As a result, Dr. Gelfand explains, one can only be certain of safety from common side effects, which may occur in approximately 1% of the patient population and can occur after short-term exposure to the drug. Clinical trials are generally unable to properly determine the risk of serious but less common events, such as cardiovascular events, risk of cancer, or risk of new morbidities.
“Many of these are things that are not picked up in the initial studies used to prove efficacy, but instead often become evident in the post-marketing setting. It is not possible to completely rule out any side effect in any drug that has gone through the FDA, which highlights the need for ongoing risk assessment throughout the life cycle of a drug,” Dr. Gelfand says.
Clinicians need to understand that, when a drug is approved, the benefits are generally well proven but the safety is not as well understood. When a brand new drug is approved, Dr. Gelfand explains, it takes time to completely understand if there are rare but serious side effects that could sideline the drug.
One classic example would be efalizumab (Raptiva, Genentech, Merck Serono), which showed PML (progressive multifocal leukoencephalopathy) side effects years after the drug came to market, ultimately resulting in the drug’s discontinuation.
Finding the balance
There is always a tension between bringing the new drugs to market that patients need and fully understanding their safety profile. According to Dr. Gelfand, 51% of approved drugs have serious adverse effects that are not detected before approval and 7.5% of drugs have a black box warning added after approval. Roughly 3% of drugs are withdrawn from the market because of safety issues that weren’t discovered during the development process.
Dr. Gelfand comments that, for a brand new drug that just received approval, physicians should be aware that the full safety profile is not available yet and they should counsel their patients accordingly. Physicians may also want to consider not using a newer drug as a first-line therapy if it does not offer patients any major advantages to more established drugs.
“On one hand, a brand new drug may have issues that we don’t know about, but on the other, we need to move away from older drugs because they are being surpassed by better drugs in terms of efficacy and improved safety profiles. Moving forward, physicians can be cautiously optimistic when prescribing medications for their patients,” Dr. Gelfand says.
Disclosures: Dr. Shear reports no relevant financial interests. Dr. Gelfand has been an investigator and/or consultant for Amgen, Abbvie, Jansen, Merck (DSMB), Pfizer, Lilly, Celgene, Coherus (DSMB), and Novartis.