Treatment with alitretinoin in patients taking part in a tertiary individual prevention program for work‐related skin diseases

Patients taking part in a tertiary individual prevention program (TIP) for work‐related skin diseases frequently have chronic hand eczema (HE) for which alitretinoin is a treatment option.

with potent steroids. Alitretinoin is a derivative of vitamin A that binds to both retinoic acid receptors (RARs) and retinoid X receptors (RXRs). 7 The exact mechanism of action is unclear. Studies indicate immunomodulatory and anti-inflammatory effects of alitretinoin, including inhibition of cytokine synthesis, leucocyte recruitment, and T-cell activation by antigen-presenting cells. 7 A dose of 30 mg once daily is recommended as it is associated with a faster and higher response than a daily dose of 10 mg, which is used in patients with pre-existing health concerns or intolerable adverse events related to the higher dose. [7][8][9] The usual treatment duration lasts 12 to 24 weeks depending on tolerability and response. 7 Treatment is ceased if no response is observed until 12 weeks of treatment or if healing occurs prior to a treatment duration of 24 weeks. However, extended treatment beyond 6 months may be beneficial in early non-responders and in patients who experience some, but not sufficient improvements. 10 In case of a good response to a first treatment, re-treatment is an option if the disease worsens or recurs. 11 Due to its teratogenicity, alitretinoin is strictly contraindicated during pregnancy. 7 Treatment of women of child-bearing age should therefore be initiated only after exclusion of pregnancy twice in a 4-week interval. During treatment and until 4 weeks after cessation of treatment, strict adherence to pregnancy-prevention measures and regular pregnancy tests are mandatory.
In Germany, patients with severe work-related skin diseases that are refractory to outpatient treatment and preventive measures are invited to take part in an inpatient/outpatient tertiary prevention program (TIP) financed by the statutory accident insurance. The TIP has been described in detail elsewhere. 12,13 Briefly, it consists of a 3-week inpatient intervention phase in a specialized center including diagnostics, treatment, patient education, and individual selection of adequate personal protective equipment, which is followed by a 3-week outpatient phase of absence from work under the guidance of a local dermatologist at the patient's hometown before returning to work. The majority of TIP patients (>90%) have severe chronic HE 13 and thus are eligible for treatment with alitretinoin. However, not much is known about alitretinoin treatment in patients with chronic workrelated skin diseases in Germany, and if the patient's gender may affect treatment decisions. Therefore, the objective of this retrospective study was to collect data on treatment with alitretinoin prior to or during the TIP, with a special focus on gender-specific differences.

| Patients
Data of patients who took part in the TIP at the Institute for Interdisciplinary Dermatologic Prevention and Rehabilitation (iDerm) at the University of Osnabrück, Germany, between January 2015 and December 2019 were analyzed retrospectively. The patients had given informed consent for use of the routinely obtained data during the TIP for continuous quality management assessments, which also includes scientific analyses of anonymized data. In the case of minors (<18 years of age) informed consent was obtained from their legal representatives. Apart from obtaining a detailed patient history, a thorough diagnostic work-up of the presented skin disease was done during the TIP, including patch testing. A combination of different final diagnoses was possible. At admission and dismissal, a dermatologist used the validated Osnabrueck Hand Eczema Severity Index (OHSI) 14,15 to assess the severity of the disease if the hands were affected. A value >0 in the OHSI subcategory for vesicles was considered an indicator for vesicular HE. Data including age, gender, and treatment with alitretinoin were available for all patients. More detailed data analyses were done of patients who reported treatment with alitretinoin prior to the TIP (group A). Moreover, data from patients in which treatment with alitretinoin was initiated during the TIP (group B) and patients in which treatment was initially considered, but not started during the TIP (group C), were compared. There was an overlap of patients in groups A and B as well as in groups A and C.   Table 1, the 348 patients who reported treatment with alitretinoin prior to the TIP, were significantly older than the other 1266 patients (mean age ± SD: 49.78 ± 10.24 years vs 46.35 ± 12.12 years, P < .001). Particularly, the 146 women reporting treatment with alitretinoin in the past were significantly older than the 680 female patients who did not (mean age ± SD: 50.27 ± 10.45 years vs 45.68 ± 12.60 years, P < .001).

| Self-reported data related to treatment with alitretinoin prior to the TIP in patients with HE
The self-reported data related to treatment with alitretinoin in the past was analyzed in all patients in group A with HE (n = 303). The results are presented in Table S1. The majority  The severity of the disease at admission according to the OHSI was particularly high in female patients with self-reported alitretinoin treatment in the past (7.11), which was significantly higher than the OHSI of men who indicated previous alitretinoin treatment (6.15).
This suggests that men receive treatment with alitretinoin in already less severe cases than women. The related reasons could be similar to the ones discussed for the higher age of female patients reporting treatment with alitretinoin. A significantly higher share of tobacco smokers was found among women than among men with selfreported alitretinoin treatment in the past. Previously, it was shown that HE in TIP patients is more severe and persistent in tobacco smokers than non-smokers. 19 It could be speculated that female tobacco smokers are more likely to be treated with alitretinoin as they may present with more severe and persistent disease than female non-smokers. 46.6%, 9 and 40.9% 20 of patients, respectively. In the study by Dirschka et al,63.9% of patients were classified as at least partial responders, with ratings of "clear", "almost clear," or "mild disease." 9 A lower response rate in our cohort could be related to retrospective self-reporting, which may be partially incorrect and a selection bias as participation in the TIP is specifically offered to patients with severe skin disease refractory to previous outpatient treatments. The majority of patients reported treatment with alitretinoin for 4 to 6 months and received only one treatment cycle. However, rarely treatment for more than 9 months or more than one treatment cycle was reported, which could be beneficial in some patients as published previously. 10,11 A good response to alitretinoin was particularly reported by patients with hyperkeratotic HE, whereas no response or worsening was more commonly reported by patients with vesicular HE. This corresponds well with published data on a higher efficacy of alitretinoin in hyperkeratotic HE than in vesicular HE. 8,22 In addition, patients with atopic HE significantly more often indicated treatment failure, which might be related to the significantly higher prevalence of vesicular HE among these patients as reported previously. 23 13 This might be due to a higher severity and chronicity of atopic HE leading to treatment with alitretinoin. [24][25][26][27][28] Only in 45 patients (2.8%), treatment with alitretinoin was initiated during the TIP. A likely explanation is that a sufficient disease improvement was achieved in most patients during the 3 weeks of inpatient treatment combined with absence from work as shown previously, 13  should be noted that it is difficult to commence treatment with alitretinoin in women of child-bearing age during the TIP as two pregnancy tests in a 4-week interval are necessary to exclude pregnancy, which could hardly be performed given that the usual duration of the TIP is 3 weeks and only rarely 4 weeks. Therefore, the course and response to topical treatment in these female patients are usually awaited until the end of the TIP. In case of a response, treatment with alitretinoin is more likely put on hold, whereas in men the decision to treat with alitretinoin is often already made in earlier phases of the TIP as waiting for 4 weeks is not necessary to commence treatment as in young women.

| LIMITATIONS
This is a retrospective study based on data routinely acquired during the TIP. Very detailed patient's histories had been taken by experienced physicians. However, the data on treatment with alitretinoin prior to the TIP were self-reported, which may decrease the reliability of the results. This may particularly have affected the information on effectiveness and tolerability of the treatment. Moreover, no standardized survey regarding alitretinoin treatment was performed.
Therefore, relevant information was missing for some patients. Nevertheless, despite these limitations, the data correspond well with data from other observational, real-life studies on treatment with alitretinoin.

| CONCLUSIONS
In conclusion, TIP patients with work-related skin diseases are frequently treated with alitretinoin prior to the TIP showing an increase over time, particularly in men. Only rarely, treatment with alitretinoin is initiated during the TIP. As suspected, treatment of female TIP patients with alitretinoin is less frequent than treatment of male patients and depends on age and disease severity.

ACKNOWLEDGEMENT
Open access funding enabled and organized by Projekt DEAL.

CONFLICTS OF INTEREST
There are no conflicts of interest.