Speaker: Vincenzo Bettoli (Bologna, Italy)

The total cumulative dose of isotretinoin refers to the total amount of mg of isotretinoin taken by a patient per kilogram of body weight at the end of the treatment. The primary goal of achieving a total cumulative dose is to minimize the risk of relapse. Relapse is variably defined in the literature, as recurrence of a few acne lesions, or return to pre-isotretinoin acne severity, or patient request of a second course of isotretinoin.

One of the frequently cited study in this area was published in 1984 by Johnson and Bill Cunliffe. They treated patients over 16 weeks with isotretinoin at three different dosages: 0.1, 0.5, and 1.0 mg/kg/day. The results indicated that all dosages were equally effective in achieving patient clearance, but the rate of relapse varied significantly with dosage. After 88 weeks, 77% of the patients treated with 0.1 mg/kg/day relapsed, compared to 50% in the 0.5 mg/kg/day group and 42% in the 1.0 mg/kg/day group. This study highlighted that relapse is more frequent in patients treated with lower doses of isotretinoin.

A subsequent study by Professor Allison Layton in 1993 also examined the relationship between dosage and relapse rates. In this study, 88 patients were treated with either 0.5 mg/kg/day or 1.0 mg/kg/day for an average duration of 4 months and followed up for 10 years. The relapse rate was 39% in the 0.5 mg/kg/day group and 22% in the 1.0 mg/kg/day group. Importantly, the study found that 82% of patients with a total cumulative dose of less than 120 mg/kg experienced relapse, compared to only 30% of patients who received more than 120 mg/kg. This finding underscored the significance of achieving a higher total cumulative dose to reduce relapse risk. Further research introduced the concept of a 150 mg/kg threshold for the total cumulative dose. A study involving 237 patients found that beyond this dose, there were no additional benefits in preventing relapse. This finding suggested that 150 mg/kg could be considered the maximum total cumulative dose.

However, challenges have arisen in clinical practice when treating patients with moderate or mild-to-moderate acne. In some cases, patients achieved full clearance with total cumulative doses lower than 120 mg/kg, raising the question of whether treatment should be continued for three months in fully cleared patients.

A study was conducted to explore the effectiveness of an isotretinoin-sparing protocol in preventing relapse and maintaining remission. This open, prospective, non-comparative study of 139 patients used a low starting dose of isotretinoin, progressively increasing to the highest dose tolerated by the patient. Treatment continued until full clearance was achieved, regardless of the total cumulative dose, and isotretinoin was continued for one additional month after clearance. As maintenance therapy, adapalene 0.1% cream was prescribed for one year. Results show that the mean total cumulative dose was 92 mg/kg, with a range from 18 to 168 mg/kg. Notably, 89% of patients achieved full clearance with less than 120 mg/kg, while only about 10% received a cumulative dose higher than 120 mg/kg. The recurrence rate in this cohort was 9.35%. The study concluded that treating patients until full clearance, followed by one additional month of isotretinoin, could provide prolonged remission without the need to exceed a total cumulative dose of 120 mg/kg in mild - moderate acne cases. There was no significant correlation between total cumulative dose and relapse, and relapse rates in patients with cumulative doses lower than 120 mg/kg were comparable to those reported in the literature for severe acne patients treated with 120–150 mg/kg.

In 2015, Jerry Tan and colleagues published a systematic literature review to evaluate the evidence supporting the concept of dosing isotretinoin based on total cumulative dose. Their review included 20 studies that explored this concept, contributing valuable insight into the ongoing debate about optimal dosing strategies for minimizing acne relapse while ensuring patient safety. However, only four studies were graded as moderate quality, with the majority classified as low quality. Importantly, none of the moderate-quality studies specifically addressed the total cumulative dose of isotretinoin, while the two studies that did were categorized as very low quality. Consequently, the concept of a total cumulative dose in the range of 120–150 mg/kg is based on weak parameters, both in terms of methodology and clinical definitions of clearance and remission. The definition of these clinical outcomes in the studies was often vague, further undermining the strength of the evidence. The conclusion from Tan’s review was that the optimal cumulative dose should be adjusted according to the severity of acne. This contrasts with earlier studies, which supported the notion of a standard cumulative dose.

In 2016, a study from New Zealand also challenged the importance of total cumulative dose, concluding that neither daily nor cumulative dosing significantly influenced the relapse rate of acne vulgaris. The historical support for total cumulative dose has been questioned in recent publications. Earlier studies backed the use of total cumulative dose in isotretinoin treatment, but recent critiques have highlighted methodological and clinical shortcomings. It is now evident that cumulative dosing should be adapted based on the severity of the condition

In summary, while the methodology of older studies supporting total cumulative dosing is weak, there is insufficient evidence to categorically dismiss the concept. More well-designed and robust studies are required before any definitive conclusions can be made regarding the utility of total cumulative dose in the treatment of acne. At this point, it would be premature to exclude total cumulative dose as a relevant treatment parameter, and further research is needed to clarify its role in acne management.

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