What role should high-dose isotretinoin have in acne treatment?

Acta Eruditorum

Abby Van Voorhees

Dr. Van Voorhees is the physician editor of Dermatology World. She interviews the author of a recent study each month.

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In this month’s Acta Eruditorum column, Physician Editor Abby S. Van Voorhees, MD, talks with Dean Morrell, MD, about his recent JAMA Dermatology article, “High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris.” 

Dr. Van Voorhees: Isotretinoin has been used for the treatment of acne for many years. What made you decide to look at the use of high-dose isotretinoin?

Dr. Morrell: Due to its profound positive effect on patients, isotretinoin is one of my favorite medications. As I gained more clinical experience with isotretinoin, I noticed that some people required longer courses to reach total acne clearance. I also noticed that those who had overall higher cumulative doses tended to have better long-term outcomes and be less likely to require a second course of medication. Although not officially tracked, it was my impression that the adverse events with higher dosing seemed similar to patients with traditional lower dosing. With the outstanding assistance of Dr. Jackie Coloe Dosal, we performed a retrospective review of my patients’ outcomes, including reported adverse effects relative to their total cumulative dose. Statistically, we found that patients receiving cumulative dose greater than 219mg/kg were less likely to require an additional course of isotretinoin. In addition, adverse effects were not different in lower versus higher doses.

Since there are obvious issues with retrospective studies, several UNC Dermatology faculty members and resident physicians joined me to perform a prospective study to look at outcomes and potential adverse events. We gathered the information prospectively in a systematic format after which UNC medical students Rachel Blasiak and Christopher Stamey crunched the numbers to yield the results.

Dr. Van Voorhees: How was this higher dose of isotretinoin administered? In a larger daily dose? In a more prolonged course of treatment? How did you determine which patients were in the lower dose course versus those in the higher dose course? What criteria were used to determine when a single course of isotretinoin was completed?

Dr. Morrell: In the years prior to our study, my faculty colleagues Drs. Aida Lugo-Somolinos and Craig Burkhart were traditional isotretinoin dose prescribers. For the study, we decided to treat our patients in our own clinical patterns: Aida and Craig as traditional dose prescribers and me as the high dose prescriber. Otherwise, the laboratory monitoring and documentation of potential adverse events were identical.

My higher dose approach starts the same as traditional dosing as I start all patients at 40mg per day. During the second month, patients’ doses are increased to slightly greater than 1mg/kg/day (a 70kg patient would take 80mg each day; a 150kg patient would be increased to 160mg per day). Through the course of a high dose patient, I push the daily dose toward 2mg/kg/day (a 70kg patient would receive 120-140mg/day for the last two to three months of therapy). As a patient enters into months four to six of therapy, I calculate the total cumulative dose at monthly visits and watch for clearance of acne lesions. In the study, the definition of a completed course was similar: patients had completed a course of isotretinoin when they had achieved the targeted total dose (120mg/kg or 220mg/kg) AND were clear of all acne lesions for one month. The average total dose for our high dose group was 310mg/kg. Because we defined clearance of acne for one month on the medication plus the target dose as completion of a course of medication, our low dose group drifted a little higher (171mg/kg total dose) than traditional dosing (120mg/kg).[pagebreak]

Dr. Van Voorhees: What did you find? Was the higher dose course of isotretinoin more efficacious in your acne patients? How about the relapse rate—did the higher dose course of isotretinoin make a difference in the need for post-treatment therapy for acne?

Dr. Morrell: The higher dose regimen had superior and safe results. At one year after last dose of medication, 73 percent of the higher dose group was clear of acne and not using any acne medication versus only 53 percent of the lower dose group. Retinoid dermatitis (dry skin usually of the forearms) was the only adverse event that was statistically more present in the higher dose group (54 percent versus 32 percent). All measures of laboratory and other potential adverse events were similar when comparing the groups. I was excited to see that the results confirmed my previously unmeasured experience with isotretinoin in the clinical setting.

Dr. Van Voorhees: What about the need for an additional course of isotretinoin—did that vary as well between the two groups?

Dr. Morrell: In our previous study, there was a significant difference between patients that received greater versus less than 219mg/kg total dose. In the higher dose group, only 8 percent of patients required a repeat course of isotretinoin versus 37 percent in the lower dose group. The average time to repeat course of isotretinoin in these patients was 10 months. For the prospective study and based upon our prior study, we decided to use one year after completion of the medication to measure need for acne treatment. In these patients, there was no statistical difference between the groups for need for additional isotretinoin courses. There are potential reasons behind this result:

  1. Maybe we needed a larger group of patients;
  2. Maybe we needed to have a longer follow-up period of time;
  3. Our lower dose group was not the traditional 120mg/kg cumulative dose and actually drifted up to 171mg/kg.

[pagebreak]Dr. Van Voorhees: Were there any notable differences in the frequency of adverse events between the higher and lower dose courses of isotretinoin?

Dr. Morrell: Everyone has unproven concerns about higher dosing. Other dermatologists frequently say to me: “Oh, the side effects must be much worse,” or, “We could never do that dosing with our patients.” As demonstrated by our two isotretinoin studies, there are no major differences in adverse events when comparing high versus lower dose isotretinoin. Patients receiving higher doses may have more retinoid dermatitis of the forearms which is easily managed by more frequent moisturization or low-potency topical steroids. Otherwise, all laboratory results and other potential effects are comparable.

Dr. Van Voorhees: Are there practical suggestions that you would recommend to the practicing dermatologist as a result of what you’ve learned from this study? Should we all be using more isotretinoin than we’ve been led to believe for our patients with recalcitrant acne?

Dr. Morrell: I am a firm believer in the notion that higher dosing is the best way to treat patients with recalcitrant acne. I recommend starting at 40mg per day and then increasing to at least 1mg/kg/d during the second month. For the last two to three months of therapy, I increase the dose toward 2mg/kg/d and continue until the patient is clear of all acne lesions for a minimum of one month on therapy. I have a calculator handy for these visits to make sure that we are over 220mg/kg total dose. With this approach, patients receive better long-term outcomes without increases in adverse effects. If we can obtain better and equally as safe outcomes and decrease future topical and oral acne treatments, we all win. Physicians are more confident in the medication’s effect and patients are more satisfied in the results. With better long-term results and less return of acne, we save money in the practice of medicine. 

Dr. Morrell is professor, director of dermatology residency training program, and director of pediatric and adolescent dermatology in the University of North Carolina department of dermatology. His article appeared in the December 2013 issue of JAMA Dermatology; JAMA Dermatol 2013: 149(12); 1392-1398. doi: 10.1001/jamadermatol.2013.6746.