Efficacy and adverse effects of systemic isotretinoin therapy.
To determine the efficacy and frequency of adverse effects of systemic isotretinoin therapy in patients of acne vulgaris.
Patients and methods All acne patients attending OPD from January, 2007 to December, 2009 at WAPDA Hospital Complex, Lahore fulfilling the inclusion criteria were enrolled and treated with isotretinoin 1mg/kg after baseline investigations. Patients were followed up fortnightly for clinical improvement and side effects.
Out of 250 patients, there were 112 (44-8%) males and 138 (55.2%) females; age range 18-30 years. Two patients discontinued therapy due to drug-related side effects so that 248 patients were evaluable. Clinical improvement was 100% at end of 16 weeks. Similarly, all patients (100%) had suffered from some adverse effects.
Isotretinoin is a very effective therapy for moderate to severe acne; however, treated patients suffer from bearable side effects.
Key words: Isotretinoin, acne vulgaris, efficacy, adverse effects.
Acne is a chronic inflammatory disease of pilosebaceous unit, clinically characterized by comedones, papules, pustules, nodules, cysts and in some cases scarring.1 It is the most common dermatological disorder affecting approximately 85% of individuals between 12-24 year of age.2 There is no mortality associated with this disease but often there is significant psychological morbidity.3 Propionibacterium acnes is now believed to contribute to inflammatory stages of the condition.
Treatment of acne depends on the type and severity of disease and includes topical and oral medications. Topical compounds are retinoids, benzoyl peroxide and antibiotics while antibiotics, isotretinoin and cyproterone acetate are commonly used oral compounds.
Effective treatment in acne is important to prevent scarring and psychological distresses. Conventional topical and systemic anti-acne medicines in use are not much effective in relapsing and nodulocystic acne (with consequent complications like scarring and pigmentation). Modalities like anti-androgens play a role but there use is gender limited.
Isotretinoin, 13-cis-retinoic acid, is a retinoid which produces miraculous response in a short period and can prevent complications.6 It counteracts the pathogenic factors that contribute to development of acne.7,8 Studies show that it produces changes in surface skin lipids composition9 due to marked inhibition of sebaceous gland activity.10 It reduces sebaceous gland size up to 90% by decreasing proliferation of basal sebocytes, suppressing sebum production and inhibiting sebocytes differentiation in vivo. It also causes significant reduction in microbial flora which persists for sometime even after discontinuation of therapy.11,12 All these effects make it an effective treatment for acne refractory to other therapies.
It is a far safer compound13 but sometimes can cause serious side effects.14 Adverse effects appear intermittently, are reversible and are dose related.15,16 Some of the most common ones are dryness of skin, lips, mouth and nasal mucosa. Other side effects are facial or body rash, dryness of skin, itching, peeling of palms and soles, increased photosensitivity, epistaxis, cheilitis, bleeding and inflammation of gums, easily injured skin and increased fatigue. There may be some redness, dryness or irritation of eyes. There have been reports of depression, suicidal ideation, suicidal attempts and suicide in patients treated with isotretinoin.9 Teratogenic potential necessitates cautious use in females of child bearing age.
The current study was aimed to determine the efficacy and frequency of adverse effects of isotretinoin in moderate to severe acne.
Patients and methods
The current study was carried out in outpatient Department of WAPDA Teaching Hospital Complex Lahore (affiliated with Central Park Medical College, Lahore) from January, 2007 to December, 2009. All patients of both sexes having moderate to severe acne, according to Global acne grading system,17 who were not on other medications for last three months were enrolled. Children were ruled out. Written consent was taken from married ladies regarding contraception and side effects were explained. A daily dose of 1 mg/kg body weight was started. Dose calculated nearest to multiple of 20s according to age and was continued for 16 weeks. All possible effects and side effects were explained.
Baseline investigations like complete blood count, liver function tests, lipid profile and renal function tests were done and were repeated on monthly basis. Patients were followed up every four weeks for sixteen weeks. Topical adjuvant therapy, adapalene was also given at night time.
Assessment of patients was done every four weeks till 16 weeks. Every patient continued using the drug and the dose was not reduced in case of early improvement. Clinical improvement was graded as: 1-excelent [100% clearance of lesions], 2-good [75% clearance of lesion], 3-moderate [50-75% clearance of lesions], 4-slight [ less than 50% clearance of lesions].
In total, 250 patients were enrolled. There were 138 females (55.2%) and 112 (44.8) males. Age range was from 18-30 years. Mean age for males was 21.46 years and for females was 21.13 years. There were two dropouts due to drug- induced adverse effects so the results were evaluated in 248 patients.
Efficacy of the treatment is shown in Table 1. A continuous improvement was noticed and by the end of study period 100% of patients were free of their disease. Side effects were seen in 248 patients (100%). The frequency of encountered adverse effects is shown in Table 2. The vast majority had mucocutaneous reactions.
Table 1 Efficacy of isotretinoin therapy in 248
Week###Mean improvement in acne lesions
Table 2 Frequency of side effects seen in the study
Dryness face###200 (80.64)
Erythema face###98 (39.51)
Skin dryness###84 (33.87)
Thinning of hair###52 (20.96)
Dry oral mucosa###35 (14.11)
Visual disturbances including###10 (4.03)
blurring and problems with
Red eyes###2 (0.80)
Dropouts due to head ache###2 (0.80)
Musculoskeletal pains###24 (9.67)
Impaired lipids###4 (1.61)
Mild diarrhea###1 (0.40)
In our study, 100% of patients showed improvement of acne by 16 weeks of treatment. This testifies the notion that oral isotretinoin therapy remains the gold standard treatment for severe acne.18 Many previous studies reported similar results. Ghaffarpour et al.19 noted a cure rate of 96.7%, Nawaf-al-Mutairi et al.20 had a cure rate of 95.5% while Md Abdul Wahab et al.21 reported 100% cure rate in moderate to severe acne with isotretinoin. Our results confirm this, as cure rate was 100% in this study.
Isotretinoin induces a dramatic reduction in size and output of sebaceous glands, modulates keratinocyte maturation and adhesion and reduces the inflammatory component of acne as well.22 It has been used safely and effectively to treat acneiform eruptions even in elderly patients.23 There may be recurrences in one quarter of the patients which are responsive to repeat course of therapy.24
Because isotretinoin is a vitamin A analogue, many of the side effects seen with this drug are similar to the clinical findings in hypervitaminosis A syndrome.25 Adverse effects observed in this study were similar to those previously reported by Kapadia et al.6 Mucocutaneous toxicity is the most common and frequent adverse reaction associated with isotretinoin. Monitoring is also required for liver function tests, lipid levels and other blood parameters. In two large clinical trials with isotretinoin, mainly mucocutaneous adverse events were observed. Other significant adverse events (psychiatric disorders, pseudotumour cerebri, decreased night vision, corneal opacities, inflammatory bowel disease, hyperostosis, hepatotoxicity and hypertriglyceridemia) have also been reported.26
Flare of the acne is a commonly reported side effect and was observed in 80 (32.25%) patients while it was observed in 87% of the patients by Ahmed et al.(32)27, 94% by Goulden et al.15 and 99% by Al-Khawajah.
As regards cheilitis, chapped lips are expected to occur in every patient26,27 as occurred in 100% of our patients. It is also comparable with that by Amichai et al.16 where cheilitis was seen in 91% of cases. Dry skin and facial rash or irritation are reported in 50% of patients16,26,27 while in our study dry skin was seen in 33.9% and facial erythema in 39.5%. These findings correlate with study by Ahmed et al.27
Dry nose is a problem for 30-50% of cases29 while in our study dry nasal mucosa was seen in 14% and epistaxis in 1.6% of patients. In the study by Amichai et al.16 2.5% of patients had epistaxis. Similarly, dry eyes were reported to be seen in one fifth of patient26 but visual disturbances including blurring of vision and problem with contact lenses was seen in only 10 cases (4%).
Headaches were reported by 18 (7.25%) patients while 5.2% of the patients experienced headache in the study by Ahmed et al.27 There were two dropouts due to persistent and severe headache in our study.
Musculoskeletal aches and pains were seen in 24 (9.7%) patients while it was reported in 15% of cases by Mclane.26 Impotence has been reported previously15,30 but none of our patient reported this adverse effect. Impaired LFTs and lipid levels were relatively rare and seen in 4 (1.6%) and 3 (1.2%) patients, respectively. This is comparable with Jacobs et al.31
Insomnia was reported in only two cases while depression was seen in 10 (4.03%) patients. Given the prevalence of depressive symptoms in dermatological population, it is important to be aware of the risk factor for suicide. There is no evidence to support a causal connection between isotretinoin and major depression or suicide.30,31
Isotretinoin is a very effective therapy for nodulocystic acne; however, all patients suffer from some sort of side effects which usually do not warrant discontinuation of therapy.
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Ch. Muhammad Tahir Department of Dermatology, WAPDA Teaching Hospital Complex, Lahore. Address for correspondence Dr. Ch. Muhammad Tahir Head Department of Dermatology, Wapda Teaching Hospital Complex,210-Ferozepur Road Lahore.
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|Publication:||Journal of Pakistan Association of Dermatologists|
|Date:||Mar 31, 2011|
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