The adverse effect profile of acitretin in a pediatric dermatology population—Longitudinal cohort study and recommendations for monitoring

To the Editor: The clinical benefit of acitretin has been amply shown in the treatment of disorders of keratinization in childhood, particularly in psoriasis and ichthyosis. The adverse effects (AEs) of acitretin are well studied in adults, and monitoring guidelines were issued by the British Association of Dermatologists.1Ormerod A.D. Campalani E. Goodfield M.J. BAD Clinical Standards UnitBritish Association of Dermatologists guidelines on the efficacy and use of acitretin in dermatology.Br J Dermatol. 2010; 162: 952-963Crossref PubMed Scopus (110) Google Scholar However, AEs in childhood are less well studied, particularly in non-psoriasis cohorts. A retrospective case note review was undertaken of all 174 patients prescribed acitretin between 1993 and 2015. Patient variables collected were diagnosis; demographics; age at starting acitretin; length of time monitored while receiving acitretin (as measured by age at stopping treatment or age of transfer to adult services if still receiving the medication); starting, maximal, and final doses; and AEs. Children were usually seen by a dermatologist on a three-monthly basis and none were lost to follow-up in the study period. Clinical AEs were defined as any reported clinical symptom that had arisen since starting and could be attributed to acitretin. Laboratory AEs were defined as hepatic transaminase levels twice the upper limit of the normal range for age, and/or alkaline phosphatase levels at least 1.2-fold the upper limit of normal range for age, and/or triglyceride levels greater than 2.3 mmol/L. Primary outcome measures (clinical and laboratory AEs) were modeled with respect to 5 patient variables (sex, diagnosis, age at starting, dose/kg at starting, and length of time receiving acitretin) by multiple logistic regression (SPSS, version 22; SPSS Inc, Chicago, IL). A Bonferroni correction for multiple testing was applied, reducing the level of significance to P < .005. Response to treatment was not a primary outcome but has been recorded here for comparability with other studies. Cohort data are shown in Table I. There were no fatal or irreversible AEs documented due to acitretin. Clinical AEs were reported in 24%, leading to permanent cessation of treatment in 10% of the total cohort, although this overlapped with lack of adequate response to the medication—in other words, the balance of beneficial and adverse clinical AEs was important and not easily measurable. Laboratory AEs occurred in 22%, leading to permanent cessation in 4% of the total cohort. Importantly, laboratory AEs were very rare after 2 years of uneventful treatment (Supplemental Figure 1; available via Mendeley at https://data.mendeley.com/datasets/x7cp29vtgk/draft?a=11828aec-97a2-46f7-8dd2-49a213c6ddc0). Reduced bone density was seen in 3 patients with ichthyosis, a known risk factor for vitamin D deficiency, but was not routinely screened for. There were no significant associations between clinical or laboratory AEs and the 5 patient variables. Half of those children who had acitretin stopped for any AE subsequently had the drug restarted.Table ICohort demographics and incidence of clinical and laboratory adverse effects potentially due to acitretin therapyDemographics of the total cohort (N = 174)Count∗Where the total cohort number does not equal 174, this is due to missing data.Male/female, n90/84Age at starting acitretin, y, mean ± SEM (range)8.1 ± 0.4 (0.0-18.78)Mean duration of treatment, y, mean ± SEM (range)3.5 ± 0.3 (0.02-17.58)Mean starting dose, mg/kg, mean ± SEM (range)0.42 ± 0.01 (0.15-0.68)Mean maximum dose, mg/kg, mean ± SEM (range)0.45 ± 0.02 (0.14-1.24)Clinical diagnostic groupings, n/total (%) Congenital ichthyosis94/172 (54.7) Psoriasis50/172 (29.1) Other14/172 (8.1) Palmoplantar keratoderma5/172 (2.9) Eczema4/172 (2.3) Immunodeficiency4/172 (2.3) Pityriasis rubra pilaris1/172 (0.6) Missing data on diagnosis2/172 (1.2)Clinical AEs, all reversible, n/total (%) Increased skin irritation, fragility, or rash18/174 (10.3) Dry lips16/174 (9.2) Nausea3/174 (1.7) Tiredness/malaise2/174 (1.1) Mood swings1/174 (0.6) Hair thinning1/174 (0.6) Abdominal pain1/174 (0.6)Clinical AEs of any type, n/total (%)42/174 (24.1) Missing data on clinical AEs0/174Laboratory AEs, all reversible, n/total (%) Abnormal alkaline phosphatase level alone10/170 (5.9) Abnormal alanine transaminase level alone4/170 (2.4) Abnormal alanine transaminase and alkaline phosphatase level1/170 (0.6) Abnormal triglyceride levels alone17/170 (10) Abnormal liver function test results (alanine transaminase or alkaline phosphatase) and triglyceride levels4/170 (2.4) Laboratory AE but missing detail on type2/170 (1.2)Laboratory AEs of any type38/170 (22.4) Missing data on laboratory AEs4/174Reasons for stopping acitretin during study period, temporarily or permanently, n/total (%) Limited or no clinical improvement33/172 (19.2) Clinical AEs (other than worsening of skin disease)21/172 (12.2) Sustained clinical improvement17/172 (9.9) Worsening of skin disease10/172 (5.8) Laboratory AEs7/172 (4.1) Other causes3/172 (1.7)Total stopped acitretin due to any cause, n/total (%)91/172 (52.9) Missing data on stopping2/174AE, Adverse event; SEM, standard error of the mean.∗ Where the total cohort number does not equal 174, this is due to missing data. Open table in a new tab AE, Adverse event; SEM, standard error of the mean. In this cohort, acitretin was therefore a safe drug at the dose used and for the duration of follow-up, subject to clinical and laboratory monitoring. Incidence of AEs was unaffected by sex, diagnosis, age at starting, dose, or duration of therapy; however, laboratory AEs after 2 years of uneventful treatment were uncommon. The overall pattern of AEs is comparable to that in previous studies of acitretin in children,2Dunn L.K. Gaar L.R. Yentzer B.A. O'Neill J.L. Feldman S.R. Acitretin in dermatology: a review.J Drugs Dermatol. 2011; 10: 772-782PubMed Google Scholar, 3Charbit L. Mahe E. Phan A. et al.Systemic treatments in childhood psoriasis: a French multicentre study on 154 children.Br J Dermatol. 2016; 174: 1118-1121Crossref PubMed Scopus (31) Google Scholar, 4Bronckers I.M. Paller A.S. van Geel M.J. van de Kerkhof P.C. Seyger M.M. Psoriasis in children and adolescents: diagnosis, management and comorbidities.Paediatr Drugs. 2015; 17: 373-384Crossref PubMed Scopus (111) Google Scholar, 5Lacour M. Mehta-Nikhar B. Atherton D.J. Harper J.I. An appraisal of acitretin therapy in children with inherited disorders of keratinization.Br J Dermatol. 1996; 134: 1023-1029Crossref PubMed Scopus (119) Google Scholar as is the number of children stopping acitretin due to clinical AEs.4Bronckers I.M. Paller A.S. van Geel M.J. van de Kerkhof P.C. Seyger M.M. Psoriasis in children and adolescents: diagnosis, management and comorbidities.Paediatr Drugs. 2015; 17: 373-384Crossref PubMed Scopus (111) Google Scholar As reported previously, minor changes in blood indices have been associated with acitretin use and do not tend to lead to changes in therapy.5Lacour M. Mehta-Nikhar B. Atherton D.J. Harper J.I. An appraisal of acitretin therapy in children with inherited disorders of keratinization.Br J Dermatol. 1996; 134: 1023-1029Crossref PubMed Scopus (119) Google Scholar In conclusion, our current practice is based on the published adult guidelines1Ormerod A.D. Campalani E. Goodfield M.J. BAD Clinical Standards UnitBritish Association of Dermatologists guidelines on the efficacy and use of acitretin in dermatology.Br J Dermatol. 2010; 162: 952-963Crossref PubMed Scopus (110) Google Scholar and these findings, and is summarized in Fig 1.