Laboratory Monitoring guidelines for Isotretinoin- A Delphi Consensus

Isotretinoin is a potent vitamin A derivative which has been one of the most effective treatment option for acne resulting in long-term remission after approximately 6 months of therapy. The associations between isotretinoin and hypertriglyceridemia, transaminitis, thrombocytopenia, and leukopenia have led to guidelines for frequent monitoring of patients' laboratory values. However, recent findings suggest there is little evidence supporting frequent routine monitoring thus the optimal laboratory monitoring required is uncertain. Recently a Delphi consensus statement on laboratory monitoring in patents on isotretinoin was published in the Journal of the American Medical Association Dermatology.

Methods

The modified electronic Delphi survey technique is an established, iterative process in which several rounds of anonymous surveys are presented to guide health care decision-making. Twenty two board-certified dermatologists participated on a voluntary basis from diverse places including North America, South America, Europe, Australia, and Asia. A series of anonymous electronic surveys via Research Electronic Data Capture (REDCap) tools were administered using encrypted email with an overarching goal of achieving consensus among dermatologist acne experts.

The study consisted of a total of 4 rounds. All were asked to rank whether they would perform core laboratory values at given treatment times on a scale from 1 to 9, with 1 meaning strongly disagree and 9 meaning strongly agree. Responses were aggregated using a standardized scoring system in which having at least 70% of responses scoring 7 to 9 indicated consensus in agreement with the statement, at least 70%of responses scoring 1 to 3 indicated consensus in disagreement with the statement, and responses not reaching the 70% threshold indicated no consensus.

For statements lacking consensus, aggregated scores and feedback from participants were presented in the subsequent round for review, and participants were asked to rescore that statement. If consensus was still not reached after 2 iterations, the authors concluded that there was no consensus regarding that laboratory value. However, laboratory tests in round 3 close to reaching consensus, denoted by at least 60% consensus, were presented again in the fourth and final round. Because many items that did not reach consensus were related to liver function testing, after the second round, a hepatology specialist was recruited to provide additional feedback to the participants.

Results

Out of the 22 survey participants, the mean (SD) time in practice was 23.7 (11.6) years with a median (IQR) of 25.5(15.0-30.0) years; 12(54.5%) practiced in an academic setting, 7(31.8%) practiced in private practice, 14(63.6%) were based in North America and 4(18.2%) were based in Europe. After 4 rounds, consensus was reached for most of the laboratory tests.

The only tests that reached consensus for inclusion were alanine aminotransferase (ALT) and triglycerides, which should both be tested once within a month of starting isotretinoin treatment (89.5%for ALT; 89.5%for triglycerides) and a second time at peak dose (89.5%for ALT; 78.9% for triglycerides). For ALT and triglycerides, testing monthly (76.2% not for ALT; 84.2% not for triglycerides) and after treatment completion (73.7%not for ALT; 73.7% not for triglycerides) reached consensus for exclusion.

Among the liver function tests, there was consensus around excluding gamma-glutamyl transferase (GGT) (78.9%), serum bilirubin (81.0%), total protein (72.7%), and serum albumin (72.7%).

Metabolic laboratory tests that reached consensus for exclusion included sodium (81.8%), potassium (81.8%), calcium (81.8%), bicarbonate (81.8%), chloride (81.8%), fasting blood glucose (76.2%), blood urea nitrogen (77.3%), and creatinine (81.8%).

The other tests with consensus for exclusion were low-density lipoprotein (LDL) (73.7%), high-density lipoprotein (HDL) (73.7%), all hematologic laboratory tests, and C-reactive protein (77.3%). The tests with no consensus were aspartate aminotransferase (AST), alkaline phosphatase, creatine kinase, and total cholesterol.

The authors recommend that for generally healthy patients without underlying abnormalities or pre-existing conditions warranting further investigation, it is sufficient to test ALT and triglycerides once at baseline, ideally within a month prior to treatment initiation and a second time at peak dose. Other tests such as complete blood cell counts and basic metabolic panels as well as specific laboratory tests such as GGT, serum bilirubin, total protein, serum albumin, LDL, HDL, and C-reactive protein should not be routinely monitored.

Given the longstanding ambivalence surrounding isotretinoin laboratory monitoring, this study provides an integral step forward in the lab testing of patents on oral isotretinoin therapy.

References

1. Xia E, Han J, Faletsky A, Baldwin H, Beleznay K, Bettoli V, Dréno B, Goh CL, Stein Gold L, Gollnick H, Herane MI, Kang S, Kircik L, Mann J, Nast A, Oon HH, See JA, Tollefson M, Webster G, Zip C, Tan J, Tapper EB, Thiboutot D, Zaenglein A, Barbieri J, Mostaghimi A. Isotretinoin Laboratory Monitoring in Acne Treatment: A Delphi Consensus Study. JAMA Dermatol. 2022 Jun 15. doi: 10.1001/jamadermatol.2022.2044. Epub ahead of print. PMID: 35704293.