Isotretinoin: An Indian experience

Introduction

The last two decades have seen the emergence of synthetic retinoids as a major milestone in dermatotherapeutics. We retrospectively analysed the unique efficacy of isotretinoin, and studied the incidence of its side-effects on an Indian population.

Oral isotretinoin (13 cis-retinoic acid/roaccutane) is an isomer of all-trans retinoic acid, a metabolite of retinol (vitamin A).[1] The absorption is enhanced when the drug is taken with food. There is no progressive accumulation of the drug in the skin during long term administration. It has a very short half-life compared to etretinate (7-37 hours). It crosses the placenta and is a known teratogen. It is rapidly eliminated by the liver and kidneys, with the main mechanism of excretion being hepatic clearance. No parent drug is identified in the urine.

A major breakthrough in the understanding of retinoid action came from the discovery of nuclear receptors for retinoids (retinoic acid receptors - RARs and retinoid x receptors - RXRs).[2] The former binds all-trans retinoic acid and the latter binds 9-cis retinoic acid. In the presence of retinoids, the RARs and RXRs can bind specific DNA regulatory sequences and alter the expression of other genes by increasing or suppressing the expression of other regulatory proteins for example - growth factors, oncogenes, keratins or transglutamines which control several body processes.

Amongst both synthetic (such a etretinate, acitretin, arotinoids) and natural retinoids (such as all - trans retinoic acid and 13-cis retinoic acid), only 13-cis retinoic acid exerts its effect on sebum production and therefore on acne.[3] 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. Sebocyte lipid synthesis is reduced by 75% with daily doses as low as 0.1 mg/kg after four weeks.[4] The cause of this specificity is still intriguing. Other mechanisms include anti-inflammatory, anti-bacterial, inhibition of microbial enzyme activity and desquamation of poral occlusion.[2]

Isotretinoin is associated with a high incidence of a number of minor annoying side-effects.[2],[4],[5],[6],[7] They appear to be dose related and are largely cutaneous.

A group of internationally known experts proposed a treatment guideline for isotretinoin.[8],[9] According to them, acne vulgaris warranting oral therapy include:

• nodulocystic or severe inflammatory acne.
• acne causing severe scarring or pigmentation
• acne that relapses or does not respond to conventional therapy.
• affects the social existence, in a high profile job or adolescence.

Other indications are gram negative folliculitis, inflammatory rosacea- rhinophyma, pyoderma faciale, acne fulminans and hidradenitis suppurativa.

Materials and Methods

Thirty-two patients were included in the trial9 males (5< 20 years and 4> 20 years) and 23 females (9< 20 years and 14>20 years). See [Table - 1].

Before initiating therapy, the patients were educated on compliance, regular follow-up, sideeffects, cost of treatment, avoidance of other oral medications (to prevent drug interaction) and importance of contraception whilst on treatment. Those individuals who suffered from photosensitive disorders, renal or hepatic compromise, economically non-affording, uneducated, unable to follow-up, with pre-existing hyperlipidemia, family history of hyperlipidemia or premature atherosclerosis, and females who were planning a family or pregnant were not considered.[2]

A pelvic ultrasonography to rule out polycystic ovaries syndrome (pcos) and endocrinal studies to pickup raised androgen levels, was performed to avoid treatment relapses.

11 female patients were detected to have pcos and were put on diane (a combination pill containing cyproterone acetate and estrogen) and isotretinoin.

Isotretinoin tablets are available in the strength of 20 milligrams. We started with 0.5 mg/kg/day and increased it to 1 mg/kg/day (depending on the severity of acne and tolerability). The standard cumulative dose for isotretinoin is 120-150 mg/kg/treatment course to prevent relapse.[8] The same dosage guidelines were applicable to repeated courses of isotretinoin. Treatment course lasted for 4-7 months depending on daily dose and clinical progress. See [Table - 2].

Results

Generally patients were able to tolerate isotretinoin. In those whom the tolerability was poor, such as extreme dryness of the lips and face, dosage adjustments along with liberal use of moisturizers and sunscreens sufficed. Two female patients complained of severe nausea causing them to drop out. Those who had raised serum levels in the laboratory tests were advised to stop the treatment temporarily till repeat levels were within normal limits before they were restarted on a lower dosage schedule.

Side effects observed and outcome of treatment are given in [Table - 3] and [Table - 4].

Discussion

The dramatic clinical response observed in this case study made us realise that acne patients should, where appropriate, be prescribed isotretinoin sooner rather than later. It normally results in complete clearance of nodulocystic acne followed by prolonged remission and many patients remain free from the disease.

The cost of isotretinoin was the main drawback. However considering the long term advantages which include physical and emotional relief, these expenses are negligible. In addition, society benefits from limiting the evolution of bacterial resistance and reducing health care costs.[9]

The cost can be lowered by considering the following options.

• It has been observed that healing continues for some time after the discontinuation of therapy. Therefore whether treatment should be maintained until total clearance is observed is debatable.[2]
• Treatment schedules currently in use were developed in experimental protocols conducted in the late 1970′s and early 1980′s, before the marketing of isotretinoin, and included paients with severe cystic acne. Patients being treated at present times often have less severe cystic acne, limited to the face and may respond comparably and with less toxicity to lower doses, such as 0.5 mg/kg/day.[2]
• Monitoring a young healthy patient′s blood triglyceride and cholesterol levels throughout the course of treatment is not essential unless indicated, that is, positive family history or obese habitat.

A number of patients benefited by combining isotretinoin with diane. Since both these drugs target different mechanisms in acne pathogenesis, they act synergistically. No drug interaction between the two have been reported.[7] Regular use of sunscreen helped the patients to increase his/her tolerance, compliance and avoid photosensitisation to isotretinoin.

In conclusion we agree whole heartedly with Layton et al, that oral isotretinoin provides a very effective means of therapy to prevent a patient being "scarred for life".[12]