Overview of New Therapeutic Developments for Acne

Anja Thielitz; Harald Gollnick


April 13, 2009

In This Article

Oral Isotretinoin

Oral isotretinoin is unique among acne treatments because it exhibits activity against all major etiologic factors involved in the pathogenesis of acne. It significantly reduces the size and sebum production of sebaceous glands and induces apoptosis in sebocytes,[72] normalizes follicular keratinization and prevents the development of microcomedones and comedones, indirectly inhibits P. acnes growth by changing the follicular milieu and upregulation of antimicrobial factors (neutrophil gelatinase-associated lipocalin)[72] and exerts direct anti-inflammatory activity. In 2003, the European Agency for the Evaluation of Medicinal Products amended the summary product characteristics for oral isotretinoin to standardize information provided from the different countries of the European Community and recommended that exclusively severe forms of acne (e.g., nodular or conglobate acne or acne at risk of permanent scarring) resistant to adequate courses of standard therapy with systemic antibacterials and local therapy should benefit from oral isotretinoin, which degraded the substance to a second-line medication. However, several acne expert groups emphasized that a number of prognostic factors, as well as psychosocial morbidity, should be taken into account when choosing the regimen and that these factors may influence the use of oral isotretinoin as first-line therapy.[73,74,75]

The recommended dose to start isotretinoin therapy is now 0.5 mg/kg, normally divided in two daily doses taken with food. Dosing can be adjusted after 1 month according to individual response and side effects, but should not usually exceed 1 mg/kg. Most cases of severe acne respond to a single 4-6-month therapeutic course that should ideally reach a cumulative dose between 120 and 150 mg/kg to reduce relapse rates.[6] A second course of isotretinoin is needed in approximately 20% of patients; factors linked with relapse are younger age, female history of acne, prepubertal acne or truncal acne and a high score of inflammatory lesions at the end of treatment.[76] Side effects of isotretinoin include those of the mucocutaneous, musculoskeletal and ophthalmic systems, as well headaches. These side effects are usually dose-dependent and resolve after discontinuation of the drug.

Hypertriglyceridemia, hypercholesterolemia and elevated liver enzymes occur in 15-25% of patients but are rarely of clinical significance or severe enough to require dose reduction or discontinuation of treatment. Lipids rapidly drop to pretreatment levels after cessation of therapy. Monitoring of liver enzymes and lipids is now recommended before and 1 month after starting treatment and every 3 months thereafter.[6,75]

The most-severe safety issue concerning oral isotetinoin is teratogenicity as isotretinoin is highly potent in inducing fetal abortions and malformations of the brain, face and cardiovascular system.[77] Therefore, women of child-bearing potential must be treated adhering the to the pregnancy-prevention program implemented in the UK and other countries. In the USA, prescribers, patients, pharmacies and manufacturers must comply with the iPLEDGE program, approved by the FDA in 2005, which requires mandatory registration of all patients receiving the drug. With regard to these regulatory issues, the use of several propagated low-dose isotretinoin or intermittent regimens, which are undoubtedly clinically effective,[78,79,80] is inadvisable and 'off label'. A recently published study investigating the effect of intermittent isotretinoin revealed that this dosage regimen might be useful for patients not tolerating the classical dose and is equal to the normal dose after follow-up of 12 months in patients with moderate acne.[79] However, in severe acne, the intermittent dose regimen was inferior, which supports the fact that relapse occurs more frequently after lower cumulative doses. In addition, moderate acne cases are normally no indication for oral isotretinoin according to the new prescription regulations, which makes the low-dose/intermittent regimens largely dispensable.

Treatment with oral isotretinoin has also been associated with suicidal ideation, mood alterations and depression. Although case reports suggested such an association, the current literature reviewing the results of epidemiologic data and several retrospective studies does not support nor disprove a causative link between depression and isotretinoin,[81,82] neither has a molecular mechanism been established linking the two. Summarizing the available evidence, there is no need to discourage the use of isotretinoin in severe acne patients who will normally benefit from the treatment in terms of physical and psychological improvement. To rule out the few cases with adverse reactions, careful history taking and patient information and that of his relatives regarding the problem, as well as assessment of psychiatric symptoms at each visit, should be performed and, if necessary, referral to a psychiatrist and discontinuation of isotretinoin should be considered.


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