Acne is a common complaint among adolescents, although onset can occur at other stages of life. In fact, acne affects to a greater or lesser extent between 80 and 85% of individuals aged between 12 and 25 years1 and in addition to the potential physical discomfort (for example, pain, itching, superinfection, and scarring), serious psychological repercussions may occur as the face is often targeted by this disease.

We can classify acne into different types according to the predominant lesion, with classic forms including papulopustular, comedonal, and nodulocystic acne.1 There are several classes of therapeutic drugs used to tackle different types of acne. One of the most widely used medications is oral isotretinoin as it targets all levels of acne pathogenesis. According to expert consensus, the recommended dose is 0.3–0.5mg/kg/d for moderate papulopustular or nodular acne and more than 0.5mg/kg/d for at least 6 months (with a mean total cumulative dose of 120–150mg/kg) for acne conglobata. Other authors, however, recommend lower or pulsed doses for longer periods in cases of moderate acne.2–4

Regardless of the dosage regimen used, at the end of treatment most patients show substantial improvement in acne lesions, although this is coupled with erythema and deterioration in the quality of skin due to the extreme cutaneous dryness induced by the treatment. Moreover, recurrence of acne lesions following isotretinoin treatment remains an unsolved problem. According to recent studies, the percentage of patients with relapses is very variable and ranges between 10 and 61% depending on the cumulative dose,5 population characteristics, and duration of follow-up.6 There is some debate as to whether failure to reach the target dose leads to the early onset of acne relapse.7,8 To establish a basis for comparison of the mean relapse rate, the study with the greatest number of patients (17351), which described a mean relapse rate of 41%, can be taken as a reference.8 However, there are no specific data on relapse percentages over short periods of time after discontinuing isotretinoin administered at the standard dose of 120–150mg/kg.

To avoid relapses after isotretinoin administration, topical retinoids have been used for many years in patients with acne due to their capacity to reduce hyperseborrhea (by inhibiting the proliferation and differentiation of sebocytes) and normalize keratinization.3 Some authors have suggested that their use at the end of treatment with oral isotretinoin may help prevent future relapses.3,9–12 Consequently, the main objective of the present study is to demonstrate that a new product, whose main component is Retinsphere technology, is effective for reducing acne relapses or maintaining the results obtained by acne patients after treatment with oral isotretinoin. Furthermore, we will determine tolerance to the new product in these patients, without the usual adverse events seen with other retinoids.

A prospective, randomized, double-blind, placebo-controlled (vehicle) study was carried out on both sides of the face. Thirty-two patients were recruited. Treatment with the retinoid combination was applied on a split-face model, applying the active product to one side of the face and the vehicle to the other, once daily for 3 months.

The assessments were carried out at baseline (T0) then after 1.5 months (T1) and 3 months (T2) by the same, blinded investigator. A physical examination was carried out together with a standard photographic record with RBX technology (Reveal, Canfield Inc., Fairfield, NJ, USA) on each visit.

Statistical analysis was performed with SPSS v18.0 software (Chicago, IL, USA). Results are presented as mean (SD) values. The Wilcoxon nonparametric test for paired data, as the comparisons were paired both in time and between treatments. In the subsection where the isotretinoin dose was analyzed for influence on the response to the product compared to vehicle, the Mann–Whitney non-parametric test was used, as they are two independent groups. The percentages of patients with deterioration and improvement were calculated for each group, and the McNemar test was used to determine the statistical significance of the difference between 2 percentages.

Before initiating the study and based on previous studies,16 in which the number of lesions decreased 90% after 3 months, assuming 10% rate of recurrent or persistent lesions, the statistical software estimated a sample size of 30 patients, assuming an SD of 3. Statistical significance was set to P≤0.05.

Thirty-two patients who completed treatment with isotretinoin in the last year were included. Of these, 40.6% were male (mean age, 18.4±5.2 years) and 59.4% female (mean age, 23.5±5.6 years). Two patients did not complete the study due to work commitments.

The mean period from discontinuation of treatment with isotretinoin until initiation of the study was 2 months (range, 2 weeks to 6 months). Of the 30 patients who completed the study, 7 (23%) had reached the standard cumulative target dose of isotretinoin (mean dose for these patients, 147.71mg/kg). Twenty-three of the 30 patients (77%) had not reached the target dose but had reached a mean of 68.34mg/kg by the time they suspended oral isotretinoin due to the arrival of summer, intolerance or clearance of lesions. Thus, the majority of our patients had not reached the total cumulative target dose of 120–150mg/kg.

The percentage of relapses on the side treated with the retinoid combination was almost 17% compared to 43% on the vehicle side; this difference was statistically significant (P=0.021) (Table 1).

There were no statistically significant differences in the number of relapses (regardless of whether they were inflammatory or non-inflammatory lesions) between those who stopped treatment with isotretinoin after reaching the target dose and those who stopped due to the arrival of summer, and therefore did not reach the total cumulative dose (data not shown).

The mean quality-of-life score, as measured by the SOQOL scale at baseline (T0) after discontinuation of isotretinoin treatment, was 3.8 (n=27) while the impact after topical treatment with the study product further improved this quality-of-life data by reducing the SOQOL score to 1.8 (n=27) at T2, after 3 months. The increase in overall satisfaction indicated an improvement in the perception of skin appearance described by the patient.

Overall, 90% of patients who received treatment experienced some degree of improvement during the treatment and almost 50% showed good or excellent improvement.

There were no differences between either side of the face in the scoring of shineness or scaling, either at the beginning or the end of the treatment. The mean baseline hydration was 0.53 (between non-existent and mild) with no differences between treated and untreated sides of the face. At T2, significant differences were observed (P=0.02) with a score of 1.3 (mild) on the side treated with the combination of retinoids versus 0.2 (non-existent) on the side treated with vehicle. In the case of erythema, on T2 the mean erythema showed no significant differences between either treatments indicating an excellent tolerance to retinoids.

No significant differences were registered at any time regarding subjective discomfort perceived by the patient (scaling, dryness, itching, burning and erythema). Only one case of pruritus was described on visit T1, which disappeared by visit T2.

At the end of the study (T2), a significant improvement in extent of scarring was observed on the treated side compared with the vehicle side (P=0.002).

No statistical differences in the PGA were found after the treatment compared with baseline.

In this study we have demonstrated the efficacy of a new product in decreasing the number of relapses following isotretinoin treatment compared to vehicle, while showing excellent tolerance and no adverse events. Although a significant reduction in the total number of lesions was found on the treated side compared to the vehicle side, when individual lesions were studied this difference was not statistically significant. This effect may be due to the small sample size and low number of total lesions at the beginning of the study (T0).

At the end of the treatment, the vehicle side showed a trend toward relapse of 43%, similar to that observed in literature in the follow-up of groups without post-isotretinoin treatment.8 Interestingly, the side treated with Retinsphere technology showed a significantly lower relapse rate (17%), demonstrating the efficacy of maintenance treatment with these topical retinoids. Although we did not find any significant differences between the target dose and onset of relapse, among patients with relapse (16 subjects), just 25% (4/16) had reached the target dose of 120mg/kg.

These results are consistent with those reported in some other published studies 5,6 but could also be due to the small sample size.

The mean follow-up time from suspension of oral isotretinoin to the end of the study was 6 months, which may appear short but given that the majority of patients (77%) in our study had not reached the target dose at the time of discontinuation (due to the arrival of summer, intolerance or clearance of lesions), in theory we expected an early relapse, although this latter point is controversial.7

Quereux et al.17 defined a maintenance treatment with topical retinoids as the most important protective factor for the prevention of relapse. Borghi et al.3 described the use of maintenance therapy with topical retinoids for 1 year after discontinuation of oral isotretinoin, with a very low relapse rate (9%) in spite of having used low doses of oral isotretinoin.

In our study, investigator-reported improvement was observed in 60% of patients treated with topical retinoids compared with an improvement of 30% on the vehicle side, demonstrating that Retinsphere technology is effective in improving acne lesions that persist after treatment with isotretinoin. Improvement on the vehicle side in our study can be attributed to long-term improvements induced by cumulative isotretinoin dose and the effect of the vehicle in improving skin quality after treatment with oral isotretinoin. According to our results, topical retinoids are useful in improving persistent non-inflammatory and inflammatory lesions.

The excellent tolerance and cutaneous compatibility of the product is supported by the immunomodulatory role of retinoids,1 their theoretical capacity for accelerated cutaneous regeneration18 attributed to the stimulation of neocollagenesis,19 as well as to the possible role, yet to be confirmed, of transforming growth factor β.20 Topical retinoids can be associated with skin irritation but this innovative retinoid combination maintained the efficacy of topical retinoids without observing associated dermatitis.

The new product is based on Retinsphere technology, which combines 2 topical retinoids, retinol encapsulated in glycospheres and hydroxypinacolone retinoate. This combination has been used previously in patients with active acne, with an improvement in the lesion count (macrocomedones and microcomedones), follicular keratinization, and measures of seborrhoea and acne severity according to the Global Acne Grading System with few side effects, all mild.21 The ester of retinoic acid, hydroxypinacolone retinoate, acts in a similar way to tretinoin but does not cause the irritation observed with this retinoid. Recently, Veraldi22 showed that the use of this new combination for 2 weeks in patients improved skin roughness by 50% and scaling by 40%. Unlike retinol and other derivatives that need to be converted to the biologically active form of retinoic acid, hydroxypinacolone retinoate binds directly to retinoic acid receptors.20,23

Some limitations of the study were that the time lapse between finishing oral isotretinoin and starting with topical treatment was very variable, ranging from 2 weeks to 6 months, possibly leading to increased variability of the results. In addition, the patients had received different total doses of oral isotretinoin. These limitations hinder assessment of whether the emergence of relapses is related to the total cumulative dose and/or to the small sample size.

The importance of maintenance treatment with retinoids is noteworthy from a psychological standpoint, as it helps to sustain an improved quality-of-life after use of oral isotretinoin, as well as the perception of improvement and satisfaction described by the patient.

Avoidance of a relapse after treatment with isotretinoin, especially if the target dose is not reached, has not been studied in depth. To prevent such relapses, this new retinoid combination has proven effective and is able to significantly improve acne lesions compared with baseline and with treatment with vehicle. In conclusion, the use of topical retinoids, after suspending isotretinoin either in the initial months or during the post-treatment year, when relapse rates are higher, could be a protective factor to prevent relapse, with efficacy and tolerance statistically demonstrated in this and previous studies.3,11,12 Likewise, this study confirms that maintenance therapy with retinoids after discontinuation of oral isotretinoin with residual acne lesions can reduce both non-inflammatory and inflammatory lesions.

Retinsphere technology has proven effective and safe in the maintenance treatment after oral isotretinoin in patients with acne, although future studies with a longer follow-up period may confirm the results observed.

The conduct of the present study was funded by Industrial Farmaceutica Cantabria S.A. (IFC S.A., Madrid, Spain).

M.T. Truchuelo receive economic compensation of IFC laboratories for external advice. The remaining authors declare that they have no conflict of interest.