Alitretinoin: An Update of Real-World Evidence in The Management of Chronic Hand Dermatitis

Melinda J. Gooderham, MD, MSc, FRCPC

Skin Centre for Dermatology, Peterborough, ON, Canada; Probity Medical Research, Waterloo, ON, Canada; Queen’s University, Kingston, ON, Canada

Conflict of interest:
Melinda Gooderham has been a speaker for Actelion and an investigator, speaker and advisor for Janssen.

Abstract
Chronic hand dermatitis is a debilitating inflammatory dermatosis that has a significant impact on the quality of life of those affected. Alitretinoin is an oral retinoid which has proven efficacy and safety in the treatment of chronic hand dermatitis through randomized controlled trials. Real-world evidence, information gathered in the clinic or community setting, as opposed to a research environment, can complement knowledge gained from clinical trials. Herein, real-world evidence supporting the safety and effectiveness of alitretinoin in the management of chronic hand dermatitis will be reviewed.

Key Words:
alitretinoin, Toctino®, chronic hand dermatitis, chronic hand eczema, retinoid

Chronic hand dermatitis (CHD) has a negative impact on the quality of life of those affected, leading to social and psychological distress and a reduction in productivity.^{1, 2} CHD is common and has a 1-year prevalence of 10% and a lifetime prevalence of up to 15% in the general population.³ Although CHD is notoriously difficult to treat, the endogenous retinoid alitretinoin (9-cisretinoic acid, Toctino®), has proven to be an effective and safe therapeutic option.^4-7 In the pivotal randomized, double-blind, multicenter, placebo-controlled Phase 3 BACH trial, the treatment group receiving alitretinoin 30 mg daily had up to a 75% median reduction in signs and symptoms and 48% were clear or almost clear at the week 24 time point.⁷ Of the patients that achieved remission after 24 weeks, the majority did not require long-term management. However, for those who did relapse and required retreatment, many recaptured their response6 and of those patients who required a second course of therapy, there were no safety concerns.⁵

Real-world evidence is information gathered in clinical care or the community setting, as opposed to a research environment.⁸ It can be derived from electronic health records, claims databases, registries or personal devices and is important because information collected post-marketing can complement knowledge gained from clinical trials.⁸ The realworld effectiveness and safety of alitretinoin has previously been reported and will be reviewed here (see Table 2).^9-14 The TOCCATA non-interventional, observational study reported on the use of alitretinoin in ‘real life’ daily practice in Germany, enrolling 680 adult patients with CHD who were treated with alitretinoin.⁹ Global assessment was performed and reported 56.7% of patients reaching clear or almost clear at week 24.⁹ These real-world results were better than the pivotal trial, likely because participants could continue concomitant therapies, which were not permitted in the BACH trial.⁹ Safety was similar to previous reports and the most common adverse events were headache, hypertriglyceridemia and hypercholesterolemia, as expected with the retinoid class. The FUGETTA study, a second observational study in Germany, explored the effectiveness and impact on quality of life in 658 adults with CHD treated with 10 mg or 30 mg of alitretinoin daily.¹⁵ It reported similar results to the BACH trial, with 48% of participants with severe CHD at baseline reaching clear or almost clear at the final visit for both doses, however, 45% of patients withdrew before the 24 weeks mainly because of hand dermatitis clearing.¹⁵ There was a mean reduction in the Dermatology Life Quality Index (DLQI) score of 58% and 70% for the 30 mg and 10 mg group, respectively.¹⁵ The treatment was well tolerated, with the majority of patients and physicians rating the effectiveness and tolerability of alitretinoin as ‘good’ or ‘very good’.¹⁵ The PASSION study, a third postmarketing observational study performed in Germany, enrolled 631 patients with CHD and, unlike previous trials, 17.7% had already been exposed to alitretinoin within the past 12 months.¹³ The main focus of this trial was to look at the impact of oral alitretinoin on quality of life and work productivity. It was shown that alitretinoin significantly improved quality of life and reduced work incapacity as the number of patients rated as ‘disabled’ reduced from 12.4% at baseline to 2.2% at week 24, and those reporting ‘no work impairment’ increased from 2.7% at baseline to 63.7% at week 24.¹³ The limitation of these observational studies is the short duration of 24 weeks.⁹ Gulliver and Baker (2012) reported on longer-term therapy in 3 patients who took alitretinoin continuously for 36 months with maintained efficacy and no new safety concerns.¹⁰

A recently published chart review includes a follow-up of a previous patient cohort from a 2014 Canadian dermatology practice chart review, which demonstrated that alitretinoin was a safe and well-tolerated treatment in real-world practice.^11,14 The participants in the original chart review were CHD patients who were prescribed alitretinoin from November 2010 until August 2013,¹¹ and their course was further reported until a second cutoff date of January 2017.¹⁴ Participants were prescribed alitretinoin (10 mg or 30 mg daily), and laboratory assessments were conducted approximately every 2 months. As previously reported, the average age was 57.3 ± 12.2 years, and 60% were male (Table 1).¹⁴ The patient cohort included several types of CHD, such as hyperkeratotic, dyshidrotic, fingertip, psoriasiform dermatitis, chronic actinic dermatitis, asteatotic dermatitis, and palmoplantar dermatitis. Of the 80 patients with CHD originally prescribed alitretinoin, 25 (31.3%) did not take the treatment, 53 (96.4%) patients started at 30 mg and 2 (3.6%) patients started at the 10 mg daily (see Figure 1 for patient disposition). Two additional patients from this cohort started alitretinoin therapy since the cutoff in August 2013: 1 patient at 30 mg and the other at 10 mg daily.¹⁴ Of the 55 (68.8%) participants who took alitretinoin, the median time of treatment was 10 months, the average was 12.6 months, and the ongoing maximum was 71 months. Up to January 2017, 44 (55%) patients discontinued treatment for various reasons (see Figure 2). Sixteen (29%) patients who discontinued therapy elected to restart therapy because of recurrence of disease. There were 17 (30.9%) patients who reduced the dose from 30 mg to 10 mg and the main reason was clearance of symptoms. The most common side effects were headaches, nausea and joint pain/stiffness. Less common side effects included depression, elevated triglycerides or cholesterol, blurred vision, hand numbness, and edema. One patient who started at 10 mg increased the dose to 30 mg during the follow-up period to increase effectiveness. During the follow-up period, 4 (7.3%) additional patients from the cohort stopped alitretinoin due to abnormal laboratory values: 1 (1.8%) with elevated triglycerides and 3 (5.5%) with elevated transaminases. Thirteen (23.6%) patients remain on long-term therapy with good control of their disease.¹⁴

Conclusion

Alitretinoin has proven to be a safe and effective treatment option for CHD in both clinical trials and the real-world setting. A quarter of patients in this cohort required ongoing alitretinoin therapy for chronic control of disease, and no increase in safety signals were noted with long-term therapy. Side effects were uncommon and not a frequent cause for discontinuation; the most common reason for dose reduction was clearance of symptoms. These findings, in combination with those of three real-world trials from Germany, support the use of alitretinoin in the management of CHD. Gathering real-world evidence of alitretinoin use in a community setting can complement information gained from the well-controlled pivotal trials of shorter duration.

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