Dr. Benjamin Kaffenberger discusses three high-yield updates in managing and treating severe cutaneous adverse reactions, including differentiating high-risk drug eruptions from low-risk drug eruptions, the use of validated instruments for their diagnosis and drug attribution, and SJS controversies.
Benjamin Kaffenberger, MD, MS, is Clinical Associate Professor of Dermatology, The Ohio State University, Columbus, Ohio
“Drug eruptions are by far and away the most common single entity that are seen by dermatologists in the hospital setting but are also seen in the outpatient setting too,” said Benjamin Kaffenberger, MD, who presented “Severe Cutaneous Adverse Reactions” at the Congress of Clinical Dermatology presented by the Georgia Society of Dermatology and Dermatologic Surgery.
According to Dr. Kaffenberger, to effectively manage and treat those severe cutaneous adverse reactions (SCARs), dermatologists need to know how to distinguish low-risk from high-risk drug eruptions, be aware of validated diagnostic and drug attribution criteria to confirm the diagnosis and specific drug causing the SCAR, and carefully consider some of the existing controversies in Stevens-Johnson Syndrome (SJS).
Eruption Areas Matter
“Initially, when looking at a patient with a morbilliform eruption, [ask yourself], ‘do they have facial involvement?’ because this is a very early sign that differentiates patients.”
Both low-risk and high-risk drug eruptions appear on the trunk, but low-risk eruptions don’t typically involve the face, said Dr. Kaffenberger.
“Whereas patients with high-risk eruptions (and viral eruptions also that are morbilliform pattern) do tend to have facial involvement early on in the disease course.”
If the face is involved, dermatologists should perform additional testing and monitor the patient for later signs more specific to SJS, acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, said Dr. Kaffenberger.
“We look at something specifically called the oblique earlobe crease for our patients with DRESS syndrome.”
DRESS Syndrome can be characterized by facial swelling, which is sometimes not easy to determine, especially in overweight patients, he said.
“So we look for this oblique earlobe crease where the earlobe swells and bends upwards.”
A recent paper his team published in the Journal of the European Academy of Dermatology and Venereology1includes representative photos and sensitivity and specificity data for the crease, said Dr. Kaffenberger.
“So we presented that as a relatively specific sign for DRESS syndrome, and we think it’s a valuable diagnostic sign.”
Other known features that indicate high-risk drug eruptions are pustules, dusky skin, and morbilliform eruption on the palms and soles, said Dr. Kaffenberger.
“If you’re seeing pustules on top of the base of a morbilliform eruption, strongly push towards acute generalized exanthematous pustulosis, although it could also be a viral eruption.”
“Similarly… early signs of duskiness on the skin is going to be highly indicative of Stevens Johnson Syndrome although acute generalized exanthematous pustulosis can also have that same keratinocyte necrosis, although to a smaller extent.”
Finally, look at the hands and feet. If a physical examination reveals morbilliform eruption on the palms and soles, it’s not a low-risk drug eruption, said Dr. Kaffenberger.
“…that has to be one of the high-risk drug eruptions. And your job, then, is additional lab testing, monitoring, looking for these other symptoms to push yourself from not just a high-risk drug eruption, but specifically into the DRESS category, AGEP category, or Stevens Johnson Syndrome category.”
These high-risk drug eruption indicators are generally visible early during the disease course, said Dr. Kaffenberger.
“So those can be the clues to say this is the patient that needs to be monitored more closely or this is the patient that needs to have the lab testing. I’m going to monitor this patient for liver abnormalities and eosinophilia development.”
Using Validated Diagnostic and Drug Attribution Criteria
It’s critical to get the right diagnosis and drug on the patient’s allergy list, said Dr. Kaffenberger.
While diagnostic systems such as the REGISCAR criteria are well known and cited for DRESS syndrome, “In particular, with Stevens Johnson Syndrome, something that dermatologists may not be as familiar with (because it wasn’t published in our in our journals) is the ALDEN criteria.”2
The ALDEN criteria have been validated for consistently attributing a drug causing SJS, said Dr. Kaffenberger.
Although it often is not needed to determine the specific drug causing the SCAR, “…when dermatologists are having difficulty, I strongly recommend looking at this ALDEN criteria and using it in those situations… otherwise that patient can redevelop it, and even worse in a faster time course, and even die from the disease.”
SJS Treatment Controversies
Stevens Johnson Syndrome is one of the most severe diseases treated by dermatologists, yet strong treatment guidance is lacking, said Dr. Kaffenberger.
As a result, it’s not uncommon for treatments to vary completely among different dermatologists and institutions.
His advice: “…think about the literature. Think about the patients. Think about the drug. In particular, think about the mechanism of action.”
Medications with a narrow therapeutic index, including methotrexate, colchicine, and many chemotherapies, cause direct toxicity of the skin and may look like SJS, said Dr. Kaffenberger.
Make sure you have the right diagnosis as extensive keratinocyte necrosis can also cause direct toxicity.
“I think you have to really consider this and, if it’s not immune-mediated disease and this is a direct side effect of a drug within a narrow therapeutic index, is immunologically suppressing that patient going to benefit that patient?”
“There’s not evidence to say but my inclination is, it doesn’t make that much sense if it’s not mediated by the immune system.”
Another immunological treatment consideration is skin current condition and salvageability.
“If they have widespread dusky disease or an early morbilliform eruption, they have [a lot of] skin that’s salvageable. On the flipside, if their skin is already nearly completely eroded on day 0 when you’re first meeting this patient, meaning it’s sloughed off or [there are] extensive blisters in a large surface area, there’s not much skin to salvage.”
Thus, said Dr. Kaffenberger, why immunologically suppress that patient?
“There’s no clear answer in terms of where that cut off is and in terms of treating the patient with immunosuppressants, but it’s definitely something that I think that we have to consider.”
Finally, approach existing data for SJS treatment with caution, said Dr. Kaffenberger.
“One study that people are excited about recently used reepithelization as an endpoint.3 I’m not certain that most dermatologists can differentiate reepithelization consistently in this disease. I think that’s an endpoint that needs significant validation before…we all buy into it.”
References
- Gilkey TW, Amigo MA, Himed S, Rojek NW, Milani-Nejad N, Korman AM, Trinidad JC, Kaffenberger BH. Oblique earlobe crease as a novel physical examination finding in drug reaction with eosinophilia and systemic symptoms: a retrospective study. J Eur Acad Dermatol Venereol. 2022 May 26. doi: 10.1111/jdv.18270. Epub ahead of print. PMID: 35617202.
- Sassolas B, Haddad C, Mockenhaupt M, et al. ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis. Clin Pharmacol Ther. 2010 Jul;88(1):60-8. doi: 10.1038/clpt.2009.252. Epub 2010 Apr 7. PMID: 20375998.
- Wang CW, Yang LY, Chen CB, et al. Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions. J Clin Invest. 2018 Mar 1;128(3):985-996. doi: 10.1172/JCI93349. Epub 2018 Feb 5. PMID: 29400697; PMCID: PMC5824923.
