Description of the condition

Acne vulgaris is a chronic, inflammatory disease of the pilosebaceous unit, which consists of a hair shaft, hair follicle, erector pili muscle, and sebaceous gland. Acne lesions predominantly affect the face and, to a lesser extent, the back and chest. The cause of this disease is attributed to four major factors that interact in complex ways to result in the appearance of acne lesions:

1. increased excretion of sebum by sebaceous glands inside the hair follicle (seborrhoea);

2. follicular hyperkeratinization, which results in the formation of a plug of sebum and keratin called a microcomedone;

3. bacterial hypercolonization within the pilosebaceous unit (mainly by the micro‐organism Propionibacterium acnes); and

4. consequent innate and acquired immune reactions triggering inflammation in affected follicles (Gollnick 2003; Kim 2005; Kurokawa 2009).

Although it is well‐established that microcomedones precede all acne lesions and the general causal mechanisms have been identified, the initial trigger for acne is not fully understood (Gollnick 2003). It is only known that inflammatory events precede hyperkeratinization (Thiboutot 2009).

The diagnosis is clinical. Acne lesions are polymorphic and characterised by open comedones (blackheads), closed comedones (whiteheads), and inflammatory lesions. Inflammatory lesions are more severe lesions and may take the form of papules (pinheads), pustules (pimples), or nodulocystic lesions (large nodules). The latter lesion‐type develops deeper within the dermis than the first two. Inflammatory lesions occur in acne when, due to extensive and continuous sebum production and inflammation, the follicular sac of the microcomedone ruptures into adjacent tissue. The surrounding dermis is affected by inflammation and becomes damaged (Gollnick 2003). Hyperpigmentation and scarring usually follows more severe acne lesions, but this may happen even after superficial lesions in those with scar‐prone skin. Grading is useful in the clinical assessment of acne, and there are many grading scales, though none are universally accepted. Lesion counts are usually essential for clinical trials, but not for daily clinical practice (Layton 2010).

A person is more likely to develop acne than any other skin disease; acne affects up to 85% of teenage boys and 80% of teenage girls (Simpson 1994). The detrimental effects on quality of life in those with acne are now well‐recognised, and they are comparable to those caused by other chronic diseases, such as diabetes, asthma, and arthritis (Mallon 1999). Mental health problems, social impairment, depression symptoms, and even suicidal thoughts have been described in association with acne, mainly in older adolescents with severe forms of the disease (Halvorsen 2011; Yazici 2004). A peak in prevalence and severity of acne appears between 14 and 17 years in girls, when 40% are affected; and between 16 and 19 years in boys, when 35% are affected (Burton 1971). However, recent prevalence studies emphasise that acne vulgaris should no longer be considered a disease restricted to teenagers. Currently, there is good evidence that acne can be a problem beyond the teenage years in as many as 50% of individuals, and women are more affected than men in groups aged 20 years or older (Collier 2008; Thiboutot 2009). Heredity not only influences susceptibility to acne, but it is also a prognostic factor. Family history of acne is associated with earlier occurrence, increased number of retention lesions (comedones), and treatment difficulties (Ballanger 2006). Ethnicity plays a role in the frequency and severity of acne. In studies involving ethnic groups, adolescent Caucasians have more evident acne than those of African or Asian descent (Cheng 2010).

Description of the intervention

The drug isotretinoin (13‐cis‐retinoic acid) is derived from vitamin A. It is available for topical and oral administration. Oral isotretinoin was approved by the U.S. Food and Drug Administration for nodulocystic acne in 1982 and introduced into the United Kingdom in 1983. Since then, it has revolutionised the treatment of acne and, almost three decades later, remains the most clinically effective anti‐acne therapy (Layton 2010). When isotretinoin was first introduced, it was almost exclusively used in those with severe nodular acne (Jones 1983). Nowadays, with the experience acquired in clinical management of oral isotretinoin, use of the drug has been widened to include those with a tendency to scarring and those who show no improvement with appropriate topical antimicrobial or retinoid‐like therapies and long‐term oral antibiotics (Cunliffe 1997; Layton 2010).

Most physicians prescribe a daily dose of oral isotretinoin that varies from 0.5 to 1.0 mg/kg body weight. This dose results in approximately 85% of people who receive it being clear of acne within 16 weeks. The remaining 15% of people who receive it need about 5 or 6 months to achieve a complete response at this dose, and less than 1% of them may require up to 12 months of continuous treatment to be clear of their acne. Treatment regimens usually begin at 0.5 mg/kg/day and may be increased to 1.0 mg/kg/day, but some centres start the treatment at the higher dose, which provides the optimal benefit (Layton 2010).

Because pharmacokinetic evaluations showed that the absorption rate can be doubled with the concomitant presence of fat in the intestine, the advice is to take the capsules together with the main meal of the day (Colburn 1983). Whether starting on a higher or lower dose, physicians usually adjust the dose over the course of the treatment, considering the response and the presence of side‐effects. The treatment duration varies from 16 to 30 weeks, with a mean of between 16 and 20 weeks. There is no cumulative dose effect, but there is a definite effect of both dose and therapy duration: post‐therapy relapse is minimised by doses that reach a total of at least 120 mg/kg. There is no added benefit of exceeding 150 mg/kg. The duration of therapy is adjusted to produce a 90% clearance of acne lesions, which is followed by 4 weeks of maintenance with the aim of consolidating the treatment before withdrawing the drug (Harms 1986).

How the intervention might work

Isotretinoin is the only therapy that targets all of the primary causal factors involved in acne. Oral isotretinoin, unlike antibiotics, does not act directly on microbial cells. It markedly reduces the sebum excretion rate and the sebaceous gland size (King 1982). By reducing sebum secretion, the drug consequently decreases the follicular hyperkeratinization and alters the microenvironment within the duct, providing greater Propionibacterium acnes (P. acnes) suppression than that seen with topical or oral antibiotics. The drastic reduction in the P. acnes population contributes to the reduction in acne inflammation (Coates 1997). Oral isotretinoin also modifies inflammatory effects at the cellular level (Falcon 1986).

Why it is important to do this review

Oral isotretinoin has many side‐effects. Soon after its launch on the market, the use of isotretinoin was associated with a number of psychiatric side‐effects: mood changes, depression, suicidal thoughts, and psychoses (Hazen 1983). Although some studies have attempted to explain these adverse effects, they remain controversial and unclear. Psychiatric events associated with isotretinoin are considered by other authors to be rare and no greater than the background incidence (Ferahbas 2004). The occurrence of idiosyncratic reactions, however, persists as a possibility (Magin 2005).

Mucocutaneous and cutaneous changes are the most frequent clinical adverse events during isotretinoin therapy. They are expected, dose‐dependent, and seldom interfere with the physician’s management of the condition. Cheilitis, xeroderma, facial dermatitis, discoid dermatitis, and blepharoconjunctivitis can usually be minimised by regular use of lip balms, eye lubricants, and moisturisers (Layton 2010). Flaring of acne lesions may occur in up to 6% of people early in the course of treatment with isotretinoin, with clinical importance in half of these (Clark 1995). Elevation of liver enzymes in liver function tests and lipids are seen in almost all those treated with isotretinoin, but discontinuation of the drug promotes a rapid return to pretreatment levels (Jones 1983; Scheinfeld 2006).

More uncommon side‐effects are headache (which may uncommonly be an early symptom of idiopathic intracranial hypertension) as well as muscle and joint pain (Hull 2000). Recently the association of oral isotretinoin with the development of inflammatory bowel disease has been raised. Case‐control studies, however, could not consistently confirm this association (Bernstein 2009; Crockett 2010). Among its many other side‐effects, isotretinoin is teratogenic, which means that exposure to it during pregnancy can induce abnormalities of physiological development. Approximately 20% of foetal exposures to isotretinoin may result in spontaneous abortion. The risk of mental and physical birth defects associated with oral isotretinoin is 18% to 28%. Any level of exposure seems to be a potential cause of malformation since there is no safe level of exposure. The most common deformities are craniofacial and cardiac (Sladden 2007).

Due to the issue of isotretinoin teratogenicity, a Cochane review on the efficacy and safety of minocycline in acne (Garner 2011), which analysed an open randomised controlled trial comparing oral isotretinoin with a combined oral minocycline and topical azelaic acid regimen, has suggested that the minocycline and azelaic acid regimen is a safer option for women with acne nodular. In the reviewed trial, though isotretinoin was more efficacious by some measures, percentage reductions in all types of lesion count were very high for both therapies, and the onset of improvement with the minocycline/azelaic acid combination was rapid and equivalent to oral isotretinoin.

Although isotretinoin is currently widely‐used in the treatment of acne, its real efficacy and safety have not yet been assessed in a Cochrane systematic review.