Predictive factors for acne flare during isotretinoin treatment

ARTICLE

Auteur(s) : Zeynep Demircay¹, Sadiye Kus², Haydar Sur³

¹Department of Dermatology, Marmara University School of Medicine, Istanbul, Turkey
²Department of Dermatology, Acibadem Hospital, Istanbul, Turkey
³Department of Health Management, Marmara University Health Education Faculty, Istanbul, Turkey

accepté le 27 Février 2008

Isotretinoin is an effective agent for the treatment of acne and has been widely used since it was first introduced in 1979 [1]. Most of the adverse effects due to isotretinoin are tolerable, treatable, dose dependent and self-limited [2]. Flare of acne is an expected event at the beginning of isotretinoin treatment. However, severe flare, which necessitates treatment with systemic steroids or discontinuation of the drug, is rare [3-5]. In fact severe flare has been reported in less than 6% of the acne patients treated with isotretinoin [2, 6].

Acne is a distressing condition which may lead to psychosocial problems such as depression, anxiety and social inhibition [7-11]. During exacerbations, the inflammatory acne lesions may become suppurative or ulcerative and result in permanent scars [4, 12]. Solid facial edema of acne, an uncommon skin condition, may also occur as a complication of acne vulgaris [13]. These painful and disfiguring lesions of severe flare not only increase the psychosocial impact of acne, but also impair our relationship with patients. Therefore, it is important to recognize the predictive factors to be able to introduce early interventions and to prevent severe flares.

The presence of multiple large comedones, male gender and young age are reported to be promoting factors for flare [4-6]. However, detailed information regarding flare of acne during isotretinoin treatment is still limited. Consequently, the target of this study was to investigate the incidence, types and course of acne flare and the predictive factors for its occurrence during isotretinoin treatment.

Material and methods

Patients

Treatment and evaluations

Patients were evaluated by the same investigator (ZD) at the baseline, at weeks 2 and 4 and then once in every four weeks until the completion of cumulative dose of isotretinoin (120-150 mg/kg). The grading of acne was defined according to global acne grading system (GAGS) score (table 1) [14]. Based on GAGS, “0” was considered none, “1-18” as mild, “19-30” as moderate and “≥ 31” as severe acne. At each visit, comedones and inflammatory lesions (papules, pustules and nodules) were also counted on the forehead, right cheek, left cheek, nose, chin, chest and upper back.

Flare was classified according to the increase in number of inflammatory nodules when compared to the previous visit and treatment requirements of the patients. Flare was graded as mild, when there were less than 5 new nodules that resolved without any change in the treatment; moderate when the number of new nodules was between 5 and 10 and necessitated dose reduction and/or addition of oral antibiotics (azithromycin or clindamycin); severe, when there were 10 or more new nodules and besides dose reduction or cessation of isotretinoin, addition of oral steroids were required (figure 2).

In patients with mild flare no additional treatment was required and the lesions resolved within four weeks. In patients with moderate flare the dose of isotretinoin was reduced to 0.1 mg/kg and an oral antibiotic was added until the flare subsided. Azithromycin was preferred in majority of the patients. As previously described in a report on the treatment of acne [15], the dose of azithromycin was 500 mg/day for three consecutive days (days 1, 2, and 3) for the first week, two consecutive days (days 1, 2) for the second week and 500 mg/week (day 1) for the following 2-4 weeks until the flare subsided. In agreement with the previous reports, our treatment approach in severe flare was to start systemic steroids and to reduce the dose of isotretinoin to 0.1 mg/kg [4-7]. In our patients prednisone was given at a dose of 0.5-1 mg/kg for two weeks and then gradually tapered. It was generally continued for two months until the flare subsided. During this period the dose of isotretinoin was cautiously increased. Our experience was that flare frequently relapsed especially if the steroid dose was reduced or stopped quickly.

Remission has been defined as total clearance of inflammatory acne lesions. The duration of flare was recorded for each patient. All of the possible risk factors for flare such as; age, sex, duration of acne, basal acne grade, baseline numbers of comedones, papule-pustules, nodules, hyperandrogenism, and presence of sinuses were all investigated.
Table 1 Global acne grading system (GAGS) [12]

Statistical analysis

The distribution of quantitative data did not generally match with the normal distribution rules. Thus, the distributions were summarized in terms of median and range scales rather than mean and standard deviations. Chi square tests were carried out for proportion comparisons.

Cut off values for age, comedones, papules, pustules and nodule counts were determined as median values of the variables. For truncal comedones and nodules, the median was < 1, so the presence or absence of nodules was used as a criteria.

Statistical analysis was performed using the SPSS 11.5 software.

Results

From a total of 244 patients, 161 patients completed the study. Ten patients had side effects that required stopping isotretinoin (elevated blood liver enzymes in five patients, elevated blood lipid levels in three patients, headache in one patient and arthralgia in one patient). The study flow chart is given in figure 1.

Seventy nine patients (32%) had facial and/or truncal flare (including the patients who left the study due to flare). Flare was mild in 18% (n = 44), moderate in 10% (n = 24), and severe in 4.5% (n = 11) of the patients. The distribution of patients who experienced flare in terms of severity and location is indicated in table 2.

Severe flare with systemic signs and symptoms was present in only one male patient.

The median time to flare was 4 weeks (range: 2-16). The median duration of flare was 5 weeks (range: 2-20). For severe flare, the median time to flare was 2 weeks (range: 2-12), and the median duration of flare was 8 weeks (range: 2-20) under treatment. The percentage of completion of treatment was significantly higher (p < 0.05) in patients who had flare.

Predictive factors for acne flare (mild, moderate, severe) is given in table 3 and table 4 (severe flare). The presence of severe acne, macrocomedones, truncal nodules and facial comedones counted as greater than 44 were determined as the statistically significant patient characteristics that were predictive for flare (mild to severe).

For severe flare, male sex, severe acne, GAGS cut-off score greater than 28, presence of more than 44 facial comedones and 2 facial nodules and presence of truncal nodules were found to be the predictive factors.

The rate of flare in patients with hyperandrogenism and without hyperandrogenism was 35.1% and 28.3%, respectively (p > 0.05). Severe flare was only seen in 2 females, who both had untreated hyperandrogenism.
Table 2 The distribution of patients who experienced flare in terms of severity and location (facial or truncal)

^**Cut-off values.

Table 4 Predictive factors for severe acne flare (n = 244)

^**Cut-off value.

Discussion

• 1. Inflammatory attacks which resolve spontaneously at the end of the first month.
• 2. Recurring inflammatory attacks in the following months that may show a progressive course, especially if the dose of isotretinoin is increased.
• 3. Explosive inflammatory attacks seen in the second and third months in which the clinical picture is similar to acne fulminans, with or without systemic signs. Such a flare requires 0.5-1 mg/kg of prednisolone daily for two or three weeks with gradual tapering thereafter [2, 6].

In our study, we graded flare according to the number of new inflammatory nodules and the treatment requirements of the patients, to be able to classify patients more accurately. Regarding the clinical course of patients with different grades of flare, our grading system was comparable with the one defined by Chivot [4, 16].

In the present study, 32% of the patients experienced flare, beginning at week four and lasting for 5 weeks. Flare was mild in 18% (n: 44), moderate in 10% (n: 24), and severe in 4.5% (n: 11) of the patients. In most of the patients, flare was mild and localized on the face. We observed that the occurrence of flare was related to the presence of severe acne, macrocomedones, sinus and a high total number of comedones and nodules.

In the present study, we especially focused on defining the predictive factors for severe flare, which may be disfiguring and lead to permanent scars. Severe flare is reported in 3 to 6% of acne patients treated with isotretinoin [2, 6]. Similarly, severe flare was seen in 4.5% of our acne patients. Clark et al. observed that severe flare developed within the first 3 to 5 weeks of isotretinoin treatment, while Chivot et al. reported that it usually had occurred in the second or third months of the treatment [4, 6]. In our study, despite treatment, severe flare appeared at week 2 and continued for 8 weeks which is a longer duration than milder intensities of flare.

The presence of macrocomedones and male sex are reported to be related to severity of flares [4-6]. In our study, male sex was also an important predictive factor for severe flare. In fact, severe flare was only observed in two female patients with untreated hyperandrogenism. According to our results, the presence of facial macrocomedones and truncal comedones, severe acne, a high number of facial comedones and presence of more than 2 facial nodules were other risk factors for severe flare. Although we could not find a statistically significant relationship between presence of sinus and severe flare, we observed that 4 of 5 patients with sinus had flare, three of whom were severe.

Rarely, severe flare with systemic signs simulating acne fulminans may be observed in association with isotretinoin treatment [17-20]. Leyden reported that this clinical picture generally develops in male patients with crusted lesions on the chest prior to treatment [5]. We had only one male patient who experienced acne fulminans with fever and joint pain. His symptoms were managed by reduction the dose of isotretinoin to 0.1 mg/kg and the addition of systemic antibiotics and 1 mg/kg prednisolone. Prior to therapy, he had multiple macrocomedones and severe cystic acne.

Severe flare is reported to be more frequent at a dose of 1 mg/kg [5]. We could not evaluate the role of isotretinoin dose on acne flare because we started with a standard dose of 0.5 mg/kg in all patients. The pathogenesis of acne flare during isotretinoin treatment is unknown. Recent data suggests that the mechanism of the inflammatory effect is complex. It has an anti-inflammatory action by inhibition of inflammatory cytokines, and a pro-inflammatory action, probably related to a release of P acnes antigens and/or antigens of the pilosebaceous follicle. These antigens could induce intense inflammation, notably by a mechanism involving super antigens and/or Toll-like receptors. It may also have a modulating effect on many inflammation factors [21, 22]. The study of Perkins et al. supported that isotretinoin may enhance neutrophil responses to pro-inflammatory stimuli [23].

Surprisingly, we observed that in patients who experienced flare, adherence to treatment was better. Since they had more severe acne, this result was probably due to these patients’ belief in the necessity of an ongoing treatment.

Conclusion

Acknowledgements

References

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