Speaker: Prof Alison Layton (University of York, United Kingdom)

Published guidelines recommend a variety of different dosing schedule for isotretinoin ranging from 0.3 to 1 mg/kg/day, with a threshold cumulative dose of 120 to 150 mg/kg. Some also suggest that the duration of treatment is important rather than the cumulative dose.

The concept of cumulative dose lacks physiological justification, especially when compared to other drugs. Short-term treatment success with isotretinoin primarily focuses on acne clearance. Initial studies indicated that significant success could be achieved with daily doses of 0.1, 0.5, or 1 mg/kg/day. These studies revealed a higher relapse rate in patients receiving lower doses, leading to suggestion for a dosage range of 0.5 to 1 mg/kg/day over a treatment period of 12 to 14 weeks. 

The underlying mechanism of action of isotretinoin remains partially understood, although it is known to induce apoptosis in sebocytes and sebaceous glands. Genetic variability is an essential consideration, and it may influence the response to isotretinoin among patients. The extent of isotretinoin-induced apoptosis likely varies among individuals, although the correlation with dose or duration remains unclear. 

Early studies on cumulative dosing have significant limitations, primarily due to their retrospective design. These studies were uncontrolled and lacked comparators. An early retrospective analysis involved 88 patients and suggested cumulative dosing. In this specific cohort, patients had chronic, severe nodulocystic acne that differs substantially from the patient population treated today.

A longitudinal, retrospective study conducted in 1999 investigated the prognostic factors for relapse in acne patients undergoing isotretinoin therapy. This study found no significant correlation between relapse and either mean cumulative dose, mean daily dose, or total cumulative dose. The only predictive factors identified for relapse were patient age and the severity of facial acne. 

A decade later, a large-scale retrospective analysis including 17,351 first-time isotretinoin users were assembled between 1984 and 2003 utilizing administrative databases to examine the predictors of acne relapse following isotretinoin treatment. This study employed a nested case-control design and identified that longer treatment durations of isotretinoin were associated with a lower incidence of relapse. Cumulative dose appeared to influence outcomes, but patients achieving optimal results often received cumulative doses exceeding the established threshold of 120 to 150 mg/kg. Therefore, this threshold may not be as relevant as previously thought.

Another investigation focused on the impact of higher isotretinoin doses on treatment failure rates among acne patients. Despite being a smaller retrospective study (n=102), it monitored patients for 12 months post-treatment. The findings revealed no significant differences in relapse rates between patients based on cumulative dose. Notably, those who received cumulative doses below 220 mg/kg had a higher likelihood of relapse and required subsequent isotretinoin courses. This suggests that severe acne may necessitate higher doses for effective management. Furthermore, a gender-based analysis within the same study indicated that female patients had an increased need for retreatment with isotretinoin, independent of cumulative dose (p=0.018). This observation contrasts with findings from other studies that suggest males with severe acne are more prone to treatment challenges. This raises questions about potential pharmacokinetic differences and dietary influences that might affect treatment response

In another study that aimed to validate the established threshold of 120 mg/kg, researchers treated patients to this cumulative dose and monitored them for relapse within a 24-month period. The results demonstrated that male sex was a significant prognostic factor for relapse, as has been consistently reported in prior studies, with males exhibiting higher relapse rates than females (32% vs 17%). However, the authors found no statistically significant therapeutic difference in mean total doses between patients who relapsed and those who did not, further questioning the relevance of cumulative dosing. 

The 2021 study compared 83 patients requiring a second course of isotretinoin to a control group that had only received one course. It found that patients likely needing a subsequent course had a cumulative dose of 128 mg/kg, suggesting that the traditional threshold of 120 to 150 mg/kg may be inadequate. These patients had shorter treatment durations post-acne clearance and tended to discontinue treatment about a month earlier. The results supported the idea of extending isotretinoin treatment beyond the point of acne clearance, effectively increasing the cumulative dose received. When analyzing relapse rates, younger patients with macromodonal acne who still had lesions at the end of treatment were more prone to relapses, with cumulative dose not significantly influencing relapse. Another study suggested aiming for full clearance and extending treatment by an additional month, irrespective of cumulative dose. 

Despite these insights, many studies are small, retrospective, and uncontrolled, with varied inclusion criteria. They also have differing definitions of relapse, inconsistent treatment regimens and inconsistent follow-up periods. They often lack consideration of dietary factors, which can influence isotretinoin absorption due to its lipophilic nature. Additionally, there are indications that bioequivalence between generic formulations and innovative drugs may differ, leading to potential dosing discrepancies.

A study by Jim Layton highlighted that younger patients are particularly susceptible to relapse, with nearly 100% relapsing within two years if treated at ages 10 to 12. The likelihood of relapse decreases with age but remains high. In a longitudinal study conducted in Leeds, it was shown that sebaceous follicles in younger patients activate asynchronously, leading to increased sebum production and potential relapse after treatment. Lastly, the consideration of cumulative dose is evolving, particularly as isotretinoin is used to treat moderate acne cases at risk for permanent scarring. These cases may need lower cumulative doses. Overall, the evidence suggests a need for a more nuanced understanding of isotretinoin therapy, emphasizing individual patient characteristics and treatment duration alongside cumulative dosing.

Several studies have shown that smaller cumulative doses of isotretinoin can help achieve clearance and lower relapse rates in patients with moderate disease. Conversely, patients with severe disease may require significantly higher cumulative doses; some studies indicated thresholds over 250 mg/kg and even up to 290 mg/kg. One prospective study using 220 mg/kg as a threshold still found a quarter of patients relapsed, which was higher than those receiving lower doses, although only two in the higher dose group needed re-treatment with isotretinoin. This suggests that severity should inform dosing strategies.

Historically, studies from the 1990s were poorly designed and utilized different patient cohorts. Current evidence shows a strong correlation between high doses and severe disease. However, contradictions exist; some studies have indicated that high doses lead to fewer re-trials despite equal relapse rates. 

In summary, relapse occurs in about 40% of patients (p=0.03), with some evidence indicating that a higher cumulative dose may reduce the likelihood of relapse, particularly in severe cases. Complete clearance before discontinuation and prolonging treatment beyond initial clearance may improve outcomes. 

Relapse definitions for isotretinoin treatment can vary, with retrial specifically indicating the need for additional treatment. Older studies focused on nodulocystic acne recommended cumulative doses of 120-150 mg/kg, with a 2007 study highlighting significant relapse and retrial rates. Research in 2011 found that doses over 220 mg/kg reduced re-trials but did not significantly lower relapse rates, while a 2013 study suggested fewer relapses with the same higher doses, albeit with increased re-trials. Overall, relapse occurs in approximately 40% of patients, and higher cumulative doses may reduce relapse in severe cases, exceeding the recommended threshold. Partial remission raises relapse risk, emphasizing the importance of full clearance, ideally followed by 1-2 months of continued treatment. 

Risk factors such as younger age and female gender contribute to relapse rates, while the treatment duration may be more influential than cumulative doses. Extended treatment may lead to longer intervals before re-treatment with isotretinoin is necessary. According to a 2023 systematic review on isotretinoin dosing in acne vulgaris, higher cumulative doses of isotretinoin were not linked to increased efficacy in studies involving mild to moderate acne, particularly when isotretinoin is potentially used off-label. The review also noted that findings remain conflicting regarding the effectiveness of isotretinoin in cases of severe acne. 

In conclusion, there's a need for a re-evaluation of treatment protocols, as higher cumulative doses are required for inducing remission in severe disease compared to moderate cases. Tailoring treatment to individual patients, aiming for complete clearance, and addressing clinical factors impacting decision-making are essential.

33, European Academy of Dermatology and Venereology Congress, 25-28 September 2024, Amsterdam.