Isotretinoin

Abstract

A total of 160 patients (59 male and 101 female) ages varying from 13 to 28 years (mean age 20 years) with moderate to severe acne were treated with isotretinoin in the doses ranging from 0.5 mg/kg/day to 1 mg/kg/day. The drug was given for a period ranging from 6 to 28 weeks. The patients were followed up regularly for a period of 12 months after stoppage of isotretinoin for any evidence of relapse. In the event of a recurrence greater than mild acne after 8 weeks of stoppage of isotretinoin therapy, the patients were given another course of the drug. Patients were considered to be non-relapsing if they had no evidence of recurrence after 12 months of follow-up. Twenty seven patients were excluded from the study. Of the remaining 133 patients (51 male and 82 female) only 117 patients (36 male and 81 female) could follow up for at least 12 months after stopping therapy. Of the 133 patients, a total of 127 patients (95.5%) achieved complete or partial clearance. Forty two percent (total 49 patients: 20 male and 29 female) experienced relapse after stopping therapy. Of these, 21 (42.85%) were given a second course of the drug. None of the patients developed a rise in lipids levels significant enough to warrant stoppage of the drug.

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Introduction

Isotretinoin, after being synthesized in 1955, (1) has been studied in Europe since 1971 for acne. In the late 1970s, isotretinoin was confirmed to be highly effective in the treatment of acne vulgaris and cystic conglobate acne. (2) With years of experience this drug has been used to treat less severe and long-standing acne unresponsive to conventional treatments. However, because of its non-availability in many developing nations and high cost, it has not been that widely used in third world countries. Therefore, there is very little data available on the use of isotretinoin in acne vulgaris from developing nations. Isotretinoin is freely available in Kuwait and is supplied to the local population free of cost from all the major government hospitals. Therefore, we had an opportunity to study large number of acne patients treated with isotretinoin. The aim of this study was to identify the most suitable types of acne for isotretinoin therapy; to determine the relationship between age, sex, type, and severity of acne, cumulative dose of isotretinoin and presence of endocrinologic abnormalities to the incidence of relapse after isotretinoin therapy; to observe the influence of repeated courses of isotretinoin on the disease progression, and also to determine the optimum dosage and duration of treatment that would ensure complete, stable remission with a minimum of side effects.

Patients and Methods

Out of the 160 patients initially enrolled for the study, 27 patients were excluded from the study because of following reasons: presence of a photosensitive disorder, renal or hepatic compromise, pre-existing hyperlipidemias, family history of hyperlipidemias or premature atherosclerosis, and females who were planning a family or were pregnant. All the patients were educated on compliance, regular follow-up, side effects, avoidance of other oral medication and importance of contraception whilst on treatment. Written consent for the treatment with isotretinoin was obtained from all the patients. The following parameters of the consented patients were then recorded: age, sex, duration and severity of acne, site of acne, treatment received in the past with degree of response, indications for isotretinoin therapy, average daily dose of isotretinoin, response, relapse, time taken to relapse, and subsequent treatment were recorded for each patient. Grading of the acne was done as mild, moderate, and severe depending upon the number of inflammatory lesions. (3) Baseline complete and differential blood counts, liver function tests, renal function tests, complete lipid profile and urine pregnancy test (for female patients) were done for all the patients before starting isotretinoin. These tests were then repeated every month for the whole duration of isotretinoin therapy. Before starting isotretinoin, a pelvic ultrasound was done (for female patients) to rule out polycystic ovarian disease and endocrinal studies to check for raised androgen levels.

The patients were then started on isotretinoin at the dosage of 0.5 mg/kg/day and later increased to 1 mg/kg/day (depending on the severity of acne and tolerability). The drug was given after food in two equal divided dosages for a duration till the cumulative dose 120 to 150 mg/kg was reached. The duration of treatment varied from 4 to 8 months depending on the dose used and clinical response. These patients were then followed up every 4 weeks and were evaluated clinically and monitored biochemically for side effects of the drug. Relapse was defined as the recurrence in the form of intermittent or permanent papular, pustular, and nodular acne of moderate to severe grade noted after 8 weeks of stopping isotretinoin therapy. In those patients who required a further course of isotretinoin it was instituted with the same treatment modalities being used as in the first course.

Results

A total of 133 patients with acne vulgaris were enrolled in this study between January 2001 and July 2002. There were 51 male (38.3%), and 82 (61.7%) female with a mean age of 20 years (range: 13 to 28 years). The patients enrolled had either moderate to severe acne or scarring or psychologically disturbing disease not responsive to conventional anti-acne medications (Table 1). The duration of illness ranged from 1 to 10 years (mean duration: 3.5 years). One hundred (75.18%) of the patients had only facial lesions, 5 (3.75%) had only truncal lesions and the remaining 28 (21.05%) had both truncal and facial lesions. All the patients had received anti-acne treatment in the past with minimal results. The details of past treatments received are shown in Table 2. The patients were given isotretinoin in the doses varying from 0.5 mg/kg/d to 1 mg/kg/d for a period varying from 6 weeks to 28 weeks (Table 3). Out of the total 133 patients, 127 (95.5%) achieved complete or partial remission. The remaining 6 (4.5%) patients had a poor response to isotretinoin, including 3 (2 female and 1 male) patients with truncal acne. These 3 patients did not respond in spite of having received a total cumulative dose of 120 mg/kg each. Three other patients had experienced severe nausea with isotretinoin therapy and dropped out. The rest of the 127 patients tolerated the drug well. Severe dryness (especially of the lips and face) associated with dermatitic changes was noticed in almost all the patients. But the dryness could be controlled easily by liberal use of moisturizers and sun screens. Only 3 patients showed a transient rise in serum lipids, especially triglycerides. But none of the patients had levels high enough to warrant stoppage of the drug. Lipid levels in all of them returned to normal limits within 4 weeks of completion of isotretinoin therapy. Side effects observed in the patients along with there incidence are shown in Table 4. Forty nine (42%) of the 117 patients experienced relapse within 2 to 12 months after stopping isotretinoin therapy. Those patients with a poor response (n = 6) and those who had not relapsed but did not follow up for 12 months (n = 10) were excluded from the subsequent analyses pertaining to the relapse rate. There was no significant difference in age, sex, duration of acne, average daily dose, and duration of treatment between those who relapsed and those who did not. There was no correlation between the total cumulative dose and the duration of time before relapse. However, with increasing cumulative dose, the relapse rate became progressively lower (Table 5). Out of the 49 cases of relapse, 21 (42.85%) patients were treated with another course of isotretinoin. All of the 21 patients who were given a second course of isotretinoin cleared completely.

Discussion

Isotretinoin has been used for more than 30 years as an effective treatment for patients with severe nodular acne unresponsive to conventional therapy, including systemic antibiotics. Overall, the use of isotretinoin for severe recalcitrant nodular acne is accepted as the most effective treatment modality available today. The effect of isotretinoin in severe nodular acne has been described as one of the greatest successes in dermatology.

Isotretinoin exerts its effect on sebum production and, therefore, on acne. (4) The most likely mechanism by which isotretinoin leads to clinical improvement in acne is by reducing sebaceous gland size (up to 90%) by decreasing proliferation of basal sebocytes, suppressing sebum production and inhibiting sebocyte differentiation. There is also a modulation in keratinocytes maturation and adhesion, which reduces the formation of comedones. The inflammatory component of acne is reduced, as well.

The response rate of 95.5% obtained in our study is comparable with other studies carried out in the past both in Western (5) as well as Asian populations. (6) Some of the earlier studies have found that a younger age, shorter duration of treatment, (7) truncal acne, (7,8) and lower daily dosage (9) were associated with higher incidences of relapses. But in the present study, we could not find any such correlation. Generally, our relapse rate became progressively lower with an increasing cumulative dose of isotretinoin. The overall relapse rate in this study was 42%, which is also comparable with the relapse rates of 47.7% (6) and 13% to 42% (7) reported in previous studies. A poor response rate of 50% (3 of 6 patients) seen in patients with only truncal lesions could be because of concomitant diseases like Pityrosporum folliculitis.

In the present study, the incidence of adverse effects on liver function test (n = 3) and lipid metabolism (n = 2) was low in comparison with the rates reported in earlier studies.

Conclusion

After noticing the miraculous effect of isotretinoin in severe nodular acne, and also the low incidence of significant side effects seen in our study. We have concluded that all the severe acne patients deserving systemic therapy may benefit from isotretinoin. We completely agree with Layton et al that oral isotretinoin provides a very effective means of therapy to prevent a patient being "scarred for life." (10) But to achieve this, the patients have to be prescribed isotretinoin sooner rather than later. Considering the high incidence of complete cure and prolonged remissions associated with isotretinoin therapy, isotretinoin seems to be cost effective in the long run in the acne patients requiring systemic therapy.

Considering the low incidence and milder nature of the biochemical adverse effects of isotretinoin noticed in our study, and also keeping in mind the short-term use of the drug for acne vulgaris, we believe that the patients with normal laboratory parameters at baseline need not be monitored so frequently. If the laboratory tests are normal after 4 weeks of isotretinoin therapy, they need not be repeated. Also, isotretinoin should be used at 1 mg/kg/day in all patients to achieve the total effective cumulative dose faster. Both these measures would definitely increase the patient compliance.

References

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2. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis retinoic acid. N Eng J Med. 1979;300:329-333.

3. Pochi PE, Shalita AR, Strauss JS, et al. Report of the consensus conference on acne classification. J Am Acad Dermatol. 1991;24:495-500.

4. Saurat JH. Oral Isotretinoin. Where now, where next? Dermatology. 1997;195;Suppl 1(1-3):38-40.

5. Lehucher-Ceyrac D, Weber-Buisset MJ. Isotretinoin and acne in practice: a prospective analysis of 188 cases over 9 years. Dermatology. 1993;186:123-128.

6. Ng PPL, Goh CL. Treatment outcome of acne vulgaris with oral isotretinoin in 89 patients. Int J Dermatol. 1999;38(3):213-216.

7. Cunliffe WJ, Norris, JF. Isotretinoin an explanation for its long term benefit. Dermatologica. 1987;175(suppl 1):133-137.

8. Chivot M, Midoun, H. Isotretinoin and acne a study of relapses. Dermatologica, 1990;180:240-243.

9. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol. 1984;10:490-496.

10. Layton AM, Seukeran D, Cunliffe WJ. Scarred for life? Dermatology. 1997;195(Suppl 1):15-21.

Nawaf Al-Mutairi MD FRCPC, Y. Manchanda MD DNB, Osama Nour-Eldin MSc, Amani Sultan MB BCH

Department of Dermatology and Venereology, Farwaniya Hospital, Farwaniya, Kuwait

Address for Correspondence

Nawaf Al-Mutairi MD

Department of Dermatology

Farwaniya Hospital, Kuwait

Phone: 0965-9370203

Fax: 0965-4808167

e-mail:nalmut@usa.net

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