Retinoids in Acne Management: Review of Current Understanding, Future Considerations, and Focus on Topical Treatments

December 2018 | Volume 17 | Issue 12 | Supplement Individual Articles | 51 | Copyright © December 2018

Anna L. Chien MD

Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD

induced reduction in sebum production.42 Diffuse or localized hair loss, nail thinning, and paronychia-like changes may also occur.43 Central nervous system side effects are rare. Although signs of increased intracranial pressure are observed occasionally, pseudotumor cerebri is extremely infrequent oftentimes occurring in the setting of concomitant use of isotretinoin and tetracyclines.44 Anecdotal reports suggest a causal association between isotretinoin therapy and severe depression with suicide attempts. However, large-scale epidemiologic studies provide no evidence that isotretinoin exposure is associated with any greater risk of psychiatric disorders than is antibiotic use in patients with acne.45 Nevertheless, patients should be counselled on this possible link and followed for the development of depression or suicidal ideation.The association of isotretinoin with inflammatory bowel disease is conflicting. Multiple case-control studies did not observe statistically significant relationship between isotretinoin therapy and inflammatory bowel disease. One recent case control study found a small increase in risk for ulcerative colitis among patients who had received isotretinoin, but no association between isotretinoin and Crohn’s disease. More studies are needed to clarify this association thus patients should be monitored and counselled regarding this possible link.46 Blepharoconjunctivitis occurs with varying severity in about one-third of patients treated with isotretinoin. This is generally alleviated by artificial tears with ophthalmologic consultation infrequently required. Alterations in visual function, mainly poor night vision, excessive glare sensitivity, and changes in color perception, have also been reported.47 Musculoskeletal side effects can also occur. Bone pain without objective evidence of any abnormalities and without sequelae can be seen in patients. Diffuse idiopathic skeletal hyperostosis (DISH) syndrome-like bone changes and calcification of tendons and ligaments are rare.48 Myalgias may occasionally occur in patients taking isotretinoin, particularly in individuals involved in vigorous physical activity.49 Laboratory changes can be associated with isotretinoin therapy. Serum lipid changes are the most frequent abnormalities seen with retinoid treatment. Transient abnormal elevations in serum transaminase can also occur and increase in serum alkaline phosphatase levels have also been infrequently reported. Hematologic abnormalities are uncommon with isotretinoin therapy.50 Most adverse effects associated with isotretinoin are preventable and manageable with judicious patient selection, dosage adjustments, discontinuation of treatment when indicated, and routine monitoring for potential adverse effects. With isotretinoin, women with childbearing potential must have two negative results on a pregnancy test spaced thirty days apart and must practice effective contraception during treatment and for one month after the completion of therapy.51 The iPLEDGE program (http://www. has been put into effect by the Food and Drug Administration and the manufacturer to minimize the risk of isotretinoin-associated teratogenicity. Additional precautions before and during therapy include measurement of serum lipids, complete blood count, and liver enzyme levels. Providers should also assess for any personal and family history of psychiatric conditions, gastrointestinal diseases, and skeletal abnormalities.Retinoids and Acne Scars As discussed previously, one of the major impetus for early and adequate acne treatment is the prevention of scarring. Atrophic acne scarring is one of the most common and difficult to treat sequelae of acne. Loss of dermal matrix is believed to be the main contributing factor, which involves the degradation of collagen that occurs during the inflammatory phase of acne. Activation of transcription factor AP-1 stimulates the production of matrix-degrading metalloproteinases (MMPs), which degrade the extracellular matrix. Studies have shown that MMP-1, MMP-3, and MMP-9 are increased in inflammatory acne lesions.52 Of note, a similar phenomenon is seen in photoaging, which is also characterized by loss of dermal collagen, resulting from the same MMPs shown to play a role in inflammatory acne lesions (Figure 3).53 In photoaging, topical retinoids have been shown to improve fine wrinkles through the partial restoration of reduced levels of collagen seen in sun-exposed skin. It is well established that topical retinoids can stimulate dermal fibroblasts and increase the production of procollagen in photoaged skin. Furthermore, topical tretinoin has a protective effect against ultraviolet radiation-induced loss of procollagen by blocking transcription factor AP-1, thus preventing the increase in MMP synthesis.53 Patients also note an improvement in skin texture, which is partly due to the enhanced deposition of hyaluronic acid brought about by topical retinoids.54 These observations can be applied in the setting of acne scarring in which scarring is improved and potentially prevented with topical retinoid via similar mechanisms. Indeed, a recent study evaluating patients with moderate to severe facial atrophic acne scars found an improvement in skin and scar texture with adapalene 0.3% gel.55 Moreover, a multicenter, randomized, investigator-blinded, vehicle controlled, split-face study found that adapalene 0.1%/benzoyl peroxide 2.5% gel reduced the risk of atrophic acne scars and led to improved scar counts and global severity grading in the retinoid group.56 A separate trial with adapalene 0.3%/benzoyl peroxide 2.5% gel yielded similar results.57 Topical retinoid is an important tool to incorporate in the management and prevention of acne scars. Current treatment options for atrophic acne scars consist of primarily procedure-based modalities.58 However, these invasive procedures may not be suitable or affordable to all patients. They also do not prevent the formation of acne scars