bs_bs_banner Australasian Journal of Dermatology (2012) ••, ••–•• doi: 10.1111/j.1440-0960.2012.00947.x REVIEW ARTICLE Isotretinoin: dose, duration and relapse. What does 30 years of usage tell us? Marius Rademaker Dermatology Department, Waikato Hospital, Hamilton, New Zealand ABSTRACT and extrinsic (photo) aging. Teratogenicity however, remains a very significant concern. With 30 years of clinical use, it is appropriate to review the use of isotretinoin. We now understand Key words: acne vulgaris, adverse effects, dose, that retinoids influence cellular growth, differentia- isotretinoin, relapse, retinoid. tion, morphogenesis and apoptosis, inhibit tumour promotion and malignant cell growth, exert immuno- modulatory actions and alter cellular cohesiveness. INTRODUCTION This has expanded the indications of isotretinoin from just acne and rosacea to a wide range of inflammatory Since achieving registration in the USA in 1982, isotretinoin and malignant skin disorders. While the standard has truly revolutionised the management of acne vulgaris,1 dose of 0.5 to 1 mg/kg per day for 4 months to a as well as finding a place in the treatment of a number of cumulative dose of 120–140 mg/kg per day has served other dermatological conditions. Peck and colleagues2 pub- us well in the management of acne vulgaris, there is lished the first study of oral 13-cis-retinoic acid (isotretin- emerging evidence that much lower dosages (as low oin) for acne vulgaris in 1979, although initial research had as 5 mg/day) are just as effective but have signifi- started a decade earlier in several Austrian and German cantly fewer adverse effects. Relapse of acne vulgaris dermatology departments. continues to be a problem but we are beginning to Early dose ranging studies3–8 showed there was no dose recognise that this is related less to the cumulative effect in the range of 0.1 to 1.0 mg/kg per day, with both the dose and more to the length of sebaceous gland sup- rate of improvement, and the total clearance of acne, being pression. Other factors important for relapse include the same for 0.1 mg/kg per day as for 1.0 mg/kg per day. a macrocomedonal pattern of acne, smoking and age, However, a number of subsequent studies suggested that both younger (under 14 years) and older (over 25 relapse 1–2 years after a single 16-week course of isotretin- years). After 30 years of use, we now understand why oin was greater in those treated with 0.1 mg/kg per day than isotretinoin is such an effective drug. Not only does it with 1.0 mg/kg per day.9 This was interpreted to indicate clear acne in almost all patients, long-term remission that the best long-term response from isotretinoin was can be achieved in 70–80% of patients with a single obtained if the patient achieved a cumulative dose of 120– course. Important changes in the use of isotretinoin 140 mg/kg.10,11 include using a lower daily dose for a longer period Now 30 years on, it is timely to review what we have of time. New indications continue to emerge, parti- learned over this period. This includes re-evaluating the cularly as a potential treatment for both intrinsic evidence for the daily dose, the duration of treatment, cumulative dose, relapse, non-responsiveness and indica- tions for isotretinoin. THE PATHOPHYSIOLOGY OF ACNE First, though, it is opportune to review our understanding Correspondence: Dr Marius Rademaker, Dermatology Depart- of the pathophysiology of acne. The current model of acne ment, Waikato Hospital, Private Bag, Hamilton, New Zealand. Email: [email protected] Abbreviations: Marius Rademaker, DM. Conflicts of interest: The author was the principal investigator for atRA all-trans retinoic acid a pharmaceutical company (Douglas Pharmaceuticals, Auckland, IL interleukin New Zealand) sponsored trial of very low dose isotretinoin (5 mg/ RAR retinoic acid receptors day) for persistent low-grade adult acne vulgaris. RARE retinoic acid response element Submitted 28 June 2012; accepted 17 July 2012. © 2012 The Author Australasian Journal of Dermatology © 2012 The Australasian College of Dermatologists 2 M Rademaker vulgaris includes a hormonally induced alteration in sebum tin. In other words, there is an initial induction of apoptosis production, abnormal growth and differentiation of epider- and cell cycle arrest, particularly in the sebaceous gland, mal cells leading to hypercornification of the pilosebaceous followed by the skin adopting a wound–healing-like pattern duct, abnormal growth of Propionibacterium acnes and of gene expression, with subsequent repair and remodel- a subsequent auto-immune response. This auto-immune ling.16,17 Clinical experience suggest this may be dose- response appears to be mediated via Toll-like receptor 2 and dependent with reduced scarring at 0.1 mg/kg per day but 4 and the release of pro-inflammatory mediators (inter- hypertrophic scarring at 1–2 mg/kg per day. leukin [IL]-1a, IL-8 and tumor necrosis factor-a).12 These result in neutrophil recruitment, the release of lysosomal enzymes and subsequent disruption of the follicular epithe- DAILY DOSE OF ISOTRETINOIN lium. In addition, there is upregulation of human beta defensin-1 and -2.13 The dose of isotretinoin has been well established at 0.5– 1.0 mg/kg per day for 16–20 weeks to a cumulative dose of 120–140 mg/kg.15 We know this is effective, so why change? RETINOIDS: HOW THEY WORK The main reason is that, while 1 mg/kg per day is as effec- Retinoids, including isotretinoin, can influence cellular tive as 0.1 mg/kg per day in clearing acne, the adverse growth, differentiation, morphogenesis and apoptosis, effects are very much greater. At 1 mg/kg per day, 98% of inhibit tumour promotion and malignant cell growth, exert patients complain of adverse events, while at doses below immuno-modulatory actions and alter cellular cohesive- 0.25 mg/kg per day, half the patients experience no adverse ness.14 They do so through a number of mechanisms, the effects at all, and in those who do, the effects are signifi- most important being their ability to influence gene tran- cantly less severe.18 While the evidence for an association scription. Retinoids exert some of their physiological effects between isotretinoin and psychiatric or gastrointestinal by binding to two distinct families of nuclear receptors: RAR adverse effects remains controversial, a reduction in daily (retinoic acid receptors) and retinoid X receptors, which dose can only be regarded as being of potential benefit. belong to the superfamily of nuclear receptors (that also A further advantage of using a lower dose is the differen- include vitamin D3 receptors, thyroid hormone receptors tial effect on acne scarring. At 1 mg/kg per day there is a and peroxisome proliferator-activated receptors).14 well-established risk of excessive scarring, yet at doses of The direct effects of isotretinoin are mediated through 0.1 mg/kg per day acne scarring is generally much less (see binding to a specific retinoic acid response element (RARE) above). in the promoter region of target genes, whose transcrip- The first published study of isotretinoin for acne used a tion is then activated (this, for example, mediates the dosage range of 1.0–3.3 mg/kg per day.2 However, subse- differentiation-inducing actions of isotretinoin). In contrast, quent dose-ranging studies indicated that there was no dose the anti-proliferative and anti-inflammatory actions of effect in the 0.1–3.0 mg/kg per day range, in that all dosages isotretinoin are believed to be mediated by a negative, indi- cleared acne in equal measure and at the same rate.3–8,19 rect regulatory mechanism. These indirect effects result Plewig and colleagues20 demonstrated that a single from the downregulation of genes that do not contain RARE 10–20-mg daily dose of isotretinoin over 6 months reduced in their promoter region, by antagonising other transcrip- inflammatory lesions by 87–94% and non-inflammatory tion factors, such as activator protein-1 and nuclear factor- lesions by 81–88%. In addition, sebaceous gland size was IL6 through competition for co-activator proteins. In reduced by 35–58%, sebum production by 90–95%, follicu- addition all-trans retinoic acid or tretinoin (atRA) has lar keratinization by 55–70% and Propionibacterium acnes recently been shown to regulate the expression and activa- by 33–73%. Skin surface lipids, however, were reduced tion of Toll-like receptors. by only 6%. Geissler and colleagues21 showed, albeit in It is estimated that isotretinoin affects over 500 genes; 300 patients with seborrhoea, that doses as low as 2.5 mg thrice being upregulated and 200 downregulated, although only weekly were effective in reducing sebum production, imply- 27 of these seem to be mediated via the classic RAR/RARE ing the minimal effective daily dose of isotretinoin is in the pathway. Isotretinoin itself does not bind to retinoic acid order of 2 mg/day, irrespective of bodyweight. receptors, but atRA and 13-cis RA are geometric isomers A recent, as yet unpublished, study (Rademaker and col- and show reversible interconversion. Isotretinoin therefore leagues) of persisting acne vulgaris in adults has shown that acts largely as a pro-drug for atRA, although its metabolites 5 mg/day clears acne very effectively compared to placebo, may also play a significant role.15 with minimal adverse effects.22 Of note, the pattern of gene expression induced by A further disadvantage of higher dosage isotretinoin is the isotretinoin changes over time. Immediately following the well-recognised flare of acne after 3–6 weeks of treatment. commencement of isotretinoin there is upregulation of This may relate to the degree of sebaceous cell apoptosis, tumour suppressor genes, protein processors and genes which can largely be avoided by using doses of below involved in the transfer or binding of ions and small mol- 0.2 mg/kg per day.23,24 The larger the dose of isotretinoin, ecules.16,17 After 8 weeks of treatment there is downregula- the greater the apoptosis of sebocytes and thereby the tion of the genes involved in the metabolism of steroids, greater antigen load to drive the auto-immune response.