Effectiveness of secondary prevention in metalworkers with work‐related skin diseases and comparison with participants of a tertiary prevention program: A prospective cohort study

In Germany, a multistep approach has been established to prevent work‐related skin diseases (WRSDs).


| INTRODUCTION
Work-related skin diseases (WRSDs) are common and comprise mainly contact dermatitis of the hands caused by wet work and occupational exposures to irritants and/or allergens. Due to an often chronic course, they are associated with impaired health-related quality of life and a considerable socioeconomic impact, primarily owing to work absenteeism and lack of productivity. 1 In Germany, a multistep intervention approach funded by the statutory accident insurances has been established to reduce the burden of WRSDs. 1,2 Secondary and tertiary individual prevention measures are provided depending on the severity and stage of the disease. Apart from outpatient treatment and diagnostics, patients with early or mild symptoms of WRSD are offered the opportunity to participate in a secondary individual prevention program (SIP). The set-up and content of the SIP may differ, but it usually involves an outpatient skin protection seminar with emphasis on health education. The short-and long-term effectiveness of these programs has been demonstrated before in occupations at risk. [3][4][5][6][7][8] Patients with severe WRSD refractory to such secondary prevention measures are invited to take part in an interdisciplinary inpatient/outpatient tertiary individual prevention program (TIP). 2,9 The TIP is based on a 3-week inpatient phase in a specialized center providing intensified diagnostics and treatment as well as health education and psychological counseling followed by a 3-week outpatient phase before returning to work. A previous multicenter study revealed that the TIP is associated with sustained improvement in terms of disease severity, ability to work, quality of life, and prognosis. [10][11][12] A high share of participants in the SIP and TIP are metalworkers (MWs), 10,13 who frequently have contact dermatitis, with a reported life-time prevalence of 30% to 63.1%. [14][15][16] The term MWs is ill-defined and summarizes a broad group of professions with varying workplace exposures. Their high risk for WRSDs is due mainly to mechanical strain, wet work, and exposure to hazardous substances, in particular metalworking fluids, with substantial irritant and allergenic potential, 17 while adherence to skin protection regimens is low. 14 The risk of developing WRSD and its course are modified by individual factors, including atopic skin diathesis and atopic dermatitis (AD), which may interfere with preventive efforts. 18 Loss-of-function mutations in the filaggrin gene (FLG) cause skin barrier defects and are associated with increased prevalence and incidence of work-related hand eczema-particularly if it is combined with AD 18-22 -a more unfavorable course of the disease, and a lower probability of remaining in the workforce. 23 Genome-wide association studies (GWAS) may help to discover other genetic variants linked to WRSDs.
They have already been applied in AD and identified susceptibility loci, mostly implicated in immune dysregulation. 24 Furthermore, tobacco smoking may have an impact on work-related hand eczema, which is on average more severe and persistent in smokers than in nonsmokers. [25][26][27] In this prospective cohort study, we evaluated the short-term effectiveness of an SIP in MWs with WRSD. Moreover, a comparison of these patients and MWs with WRSD taking part in the TIP was conducted to reveal factors that may be associated with more severe or persistent disease and lead to participation in tertiary preventive measures.

| Interventions
The provision of SIP and TIP is embedded in a standard multistep procedure for patients with WRSDs applied by the German Statutory Accident Insurance (DGUV). According to this procedure, an SIP should be offered to patients with suspected WRSD shortly after notification of the statutory accident insurance body. The detailed set-up of the outpatient 2-day SIP at the study center in Osnabrück has been described before. 5 Briefly, on one of both days, patients from various occupational fields take part in a skin protection seminar that consists of a structured group training by an experienced health educator on pathogenesis, risk factors, and prevention of WRSDs for about 5 hours (8-13 patients per group). The seminar aims at empowering the patients and improving their self-management skills, disease-specific knowledge, and motivation to perform appropriate skin protection and skin care behavior. On the other day, a dermatologist specializing in WRSDs examines the skin and provides recommendations for diagnostics and treatment. In addition, patients are counseled by a health educator on the correct use of personal protective equipment. There is a special focus on protective gloves, which are individually selected and later provided by the statutory accident insurance. SIP patients are offered an outpatient follow-up visit 8-12 weeks later to refresh their knowledge and, if necessary, to adjust the personal protective equipment. The patients are again examined by the dermatologist who adapts the previous recommendations if necessary.
The TIP is offered to patients with severe skin symptoms that are refractory to outpatient secondary prevention measures and has been described in detail elsewhere. 9,10 Briefly, the TIP 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 in the patient's hometown. After the TIP, the patients ideally return to their workplaces with improved skin condition and optimized skin protection measures under continuous outpatient dermatological supervision. The statutory accident insurance organization ensures that patient receive the selected personal protective equipment and, if necessary, initiates work place visits, for example, to implement technical preventive measures or eliminate relevant allergens based on the information collected during the TIP.

| Study population and design
In an uncontrolled prospective cohort study, MWs with WRSD taking part in either the SIP or the TIP at the Institute for Interdisciplinary Dermatologic Prevention and Rehabilitation (iDerm) at the University of Osnabrück, Germany, between June 2013 and October 2016 were recruited consecutively on a voluntary basis after informed written consent was obtained. TIP patients who had been already enrolled during an SIP were excluded from recruitment during the TIP. Controls were not recruited for ethical and legal reasons. 4 The study protocol was approved by the ethics committee at the University of Osnabrück.
Assessments by dermatologists using standardized questionnaires were carried out in SIP patients at initial consultation (T1) and at follow-up 8-12 weeks later (T2), whereas in TIP patients only at admission to the inpatient program (T1). Basic sociodemographic data and self-reported information on work absenteeism, past treatment, occupational strain (eg, wet work, exposure to skin hazards) and individual skin protection behavior (eg, use of gloves, barrier creams, emollients) were collected.
At T1, body areas other than hands were examined for signs of AD, psoriasis, and foot eczema. An Erlangen atopy score ≥ 10 at baseline was defined as atopic skin diathesis. 28 At T1 and T2, the dermatologist examined the hands and used the validated Osnabrueck Hand Eczema Severity Index (OHSI) 29,30 to assess the severity of the disease. In TIP patients, the second examination of the hands (T2) was performed shortly before discharge, that is, 3-4 weeks after baseline.

| Genotyping
For genetic analyses, 2 mL of saliva per individual was collected with the OG-500 Oragene DNA Self-Collection Kit (DNA Genotek, Ottawa, Canada) following the manufacturer's instructions for sampling and storage. Automated purification of genomic DNA was performed on Autopure LS following the manufacturer's protocol (Qiagen, Hilden, Germany). The four most common FLG variants-R501X, 2282del4, R2447X, and S3247X-were analyzed with the TaqMan allelic discrimination method (Applied Biosystems, Carlsbad, California) as described earlier. 22 For GWAS, all subjects were genotyped on the Infinium Global Screening Array v1.0 BeadChip (Illumina, San Diego, California). Genotype calling was carried out using the Illumina GenomeStudio 2.0.4 Data-Analysis software. Sample and marker quality control (QC) was performed with PLINK (v1.9, https://www.cog-genomics.org/plink/1. 9) 31 as described before. 22 After QC, 478839 variants and 177 individuals were eligible for analysis. For GWAS, allele frequencies were compared between the SIP and TIP patients using logistic regression models with adjustment for sex and population stratification. All analyses were conducted with PLINK (v1.9, https://www.cog-genomics.org/plink/1.9) 31 and R version 3.6.1 (https://www.r-project.org/).

| Basic demographic data
A total of 197 MWs were enrolled in this study. Of these, 114 took part in the SIP and 83 in the TIP. The sociodemographic characteristics of the two groups of MW at baseline are presented in Table 1.
Most (>94%) participants in both groups were male. The TIP patients were significantly older than the SIP patients (P < .001). No significant differences were found regarding atopic skin diathesis. TIP patients reported tobacco smoking significantly more often (P < .05) and had a significantly higher daily cigarette consumption (P < .05).
About half of all TIP patients (49.4%) reported to have attended a SIP in the past.

| Work-related and other skin diseases
Most patients in both groups had hand eczema (>90%) ( Table 1). The most common cause was irritant contact dermatitis, which was diagnosed significantly more often in SIP patients (P < .05). Allergic contact dermatitis of the hands (n.s.) and atopic hand eczema (P < .05) were more common in TIP patients. Moreover, AD on body areas other than the hands was diagnosed more often in TIP patients than in SIP patients (P < .001). The duration of skin symptoms related to WRSDs prior to recruitment had been significantly longer in TIP patients than in SIP patients (P < .001), and the disease severity according to OHSI was significantly higher in TIP patients than in SIP patients at baseline (P < .001). In the year before T1, TIP patients had a significantly higher number of days of absence from work due to WRSDs (P < .001) and had been treated systemically with corticosteroids significantly more often (P < .001) or alitretinoin (P < .05), or had received psoralene plus ultraviolet A irradiation (PUVA) phototherapy (P < .001). A logistic regression analysis adjusting for age, AD, and T A B L E 1 Sociodemographic data and data on work-related and other skin diseases of metalworkers taking part in the secondary individual prevention program (SIP) or in the tertiary individual prevention program (TIP) at baseline (T1) SIP n total = 114 TIP n total = 83 tobacco smoking revealed that only age (P < .001) and AD (P < .01) were independently associated with participation in the TIP (data not shown).

| FLG mutation status
DNA was available from 182 MWs (93.0% and 91.6% of all SIP and TIP patients, respectively) and all of them were successfully genotyped for FLG mutations. The call rates for all four mutations were > 99% and genotype distributions were within the Hardy-Weinberg equilibrium.
Fifteen SIP patients (14.2%) and nine TIP patients (11.8%) were heterozygous carriers of one of the four analyzed mutations (

| Workplace exposures and skin protection behavior
Most of the patients worked in professions with similar occupational exposures, primarily involving in metal processing such as cutting machine operators, industrial mechanics, toolmakers, and construction mechanics/model builders (Table S1). Data on self-reported exposure to skin hazards and skin protection behavior in the SIP and TIP patients are shown in Table 2. No significant differences were found regarding prevalence of wet work or soiling >2 hours/day. About twothirds of MWs in both groups reported exposure to water-based metalworking fluids. In addition, other exposures and work tasks were similar in SIP and TIP patients. Only milling was reported significantly more often in SIP patients (P < .05). The self-reported use of protective gloves, skin barrier creams and emollients was high in both groups. However, MWs taking part in the TIP reported that they wore protective gloves for a significantly longer period each day than MWs in the SIP at baseline (P < .05). Notably, TIP patients who had not taken part in a SIP before, showed a significantly lower extent of glove use than the other TIP patients (data not shown). Moreover, significantly more SIP patients reported not wearing protective gloves when exposed to water-based metalworking fluids, oil-based metalworking fluids, other oils, or detergents. The frequency of handwashing was similar in both groups. The use of abrasive detergents was slightly higher in SIP patients.

| Follow-up
The disease severity was assessed again in all 83 TIP patients at discharge, revealing a significantly lower mean OHSI than at admission (5.99 ± 3.26 vs 3.00 ± 2.22, P < .001). Ninety-three SIP patients (81.6%) attended the follow-up (T2). On average, they had worked 9.71 ± 5.46 weeks between T1 and T2. No statistically significant differences in baseline characteristics between drop-outs and the remaining participants were detected, except for grinding, which was significantly less frequently reported at baseline by drop-outs (P < .05, data not shown). The data of the remaining 93 SIP patients at T1 and T2 is presented in Table 3. The severity of symptoms was significantly lower and the knowledge score significantly higher at T2 than at T1 (both P < .001). There was a significant decrease of self-reported wet work >2 hours/day (P < .01) and soiling >2 hours/day (P < .01), whereas self-reported use of protective gloves (P < .05) and amount of time wearing gloves per day (P < .001) significantly increased. Moreover, a significant decrease of handwashing frequency was noted. The use of abrasive detergents was significantly lower at T2 (P < .001).

| Factors associated with severity of hand eczema or tobacco smoking
To assess factors associated with hand eczema severity or tobacco smoking, subgroups were analyzed, excluding patients without hand eczema and those who had stopped smoking in the past. In the remaining 89 SIP patients and 73 TIP patients, no significant associations were found between tobacco smoking and days of absence from work in the previous year or the different etiological subtypes of hand eczema (Table S2). When assessing the individual morphological variables of the OHSI separately, compared to nonsmokers, tobacco smokers among TIP patients significantly more often had values >0 for vesicles indicating presence of vesicular hand eczema, both at T1 (48.7% vs 23.5%, P < .05) and T2 (51.3% vs 11.8%, P < .001). As presented in Table 4, the OHSI at T1 was higher in smokers than in nonsmokers both in SIP and TIP patients; however, reaching no statistical significance. No correlation was found between the number of cigarettes smoked and the OHSI (data not shown). The OHSI at T1 was significantly higher in SIP patients with an atopic skin diathesis (P < .05). In TIP patients, the OHSI at T1 and T2 was significantly higher in patients with an atopic skin diathesis or AD on body areas other than hands. Moreover, the duration of the disease correlated with the OHSI at T1 (Pearson 0.271, P < .05) and T2 (Pearson 0.286, P < .05) in SIP patients. In TIP patients, the OHSI at T1 correlated with days of absence from work prior to the TIP (Pearson 0.261, P < .05), whereas the OHSI at T2 correlated with duration of the disease (Pearson 0.271, P < .05). No significant associations or correlations were found between the OHSI and other variables, including age, gender, FLG mutation status, handwashing frequency, and protective behavior (data not shown).

| DISCUSSION
The SIP was effective in improving disease-specific knowledge and protective behavior in MWs with WRSDs while reducing the severity of the disease. To the best of our knowledge, this is the first direct comparison of SIP and TIP patients from the same occupational field.
The study confirms clearly that MWs with WRSDs participating in the TIP had more severe and longstanding disease than those taking part in the SIP. AD and tobacco smoking were significantly more frequent in the TIP patients.
An increase of disease-specific knowledge after participation in an SIP was already reported by Wilke et al. 13 The mean OSD-KQ scores of their study cohort of 105 SIP patients (21.   The TIP is offered to patients with severe symptoms refractory to secondary prevention measures, whereas the SIP targets patients with early and/or mild symptoms of the disease, shortly after notification of the statutory accident insurances. Accordingly, the disease severity was significantly lower and its prior duration significantly shorter in SIP patients than in TIP patients. In a previous multicenter study comprising 1788 TIP patients, the mean OHSI value at admission was 6.30, 10    In accordance with other studies, irritant contact dermatitis was the most common diagnosis in both groups. 6,10 Atopic skin diathesis and AD, which are associated with impaired skin barrier function, are well-recognized risk factors for developing WRSDs, particularly irritant contact dermatitis. 18,34,35 In the present study, an atopic hand eczema component and AD observed at body areas other than the hands were significantly more common in TIP patients than in SIP patients. Notably, atopic skin diathesis and AD were associated with severity of hand eczema in TIP patients, and atopic skin diathesis also in SIP patients. AD may not only worsen the severity and course of work-related hand eczema, but may itself cause chronic and relapsing skin symptoms. It is therefore a challenge in these patients to differentiate if symptoms leading to participation in the TIP were caused primarily by WRSD or AD. Moreover, extensive body involvement of AD may increase willingness in taking part in the TIP. The high prevalence of FLG mutations in SIP patients (14.2%) and TIP patients (11.8%) is in accordance with other studies reporting an increased risk of developing work-related hand eczema in FLG mutation carriers, 18,19,21 which subsequently leads to participation in the SIP and TIP. Recently, we demonstrated in 303 metal work apprentices that FLG mutations are significantly associated with incident hand eczema during apprenticeship. 22 The rate of FLG mutation carriers in apprentices with incident hand eczema was 13.0% and thus corresponds well with the current results. In contrast to AD, FLG mutations were not associated with severity of hand eczema and not more common in TIP than in SIP patients in the present study. This suggests that severity of hand eczema and need for the TIP were rather linked to factors related to AD other than FLG mutations. Similarly, no significant differences between SIP and TIP patients were found by the explorative GWAS. Possible explanations were the small study size and a healthy worker effect. The duration of the disease correlated with the severity of hand eczema at baseline in SIP patients and at follow-up both in SIP and TIP patients. A longstanding disease may impair the skin regeneration capacity, thereby resulting in a more severe and persistent disease stressing the need for early interventions.
Tobacco smoking is thought to induce proinflammatory mechanisms and tissue damage in the skin. 36 Accordingly, we recently found a significant association between tobacco smoking and incident hand eczema in metalwork apprentices. 22 However, data on associations between tobacco smoking and hand eczema are contradictory. 37 Previously we revealed that work-related hand eczema was more severe and persistent in smokers than in nonsmokers among TIP patients and that tobacco smoking was associated with work absenteeism and leaving the workforce. 25 Others also showed that tobacco smoking is T A B L E 4 Severity of hand eczema at baseline (T1) and follow-up (T2) in subgroups of patients taking part in the secondary prevention program (SIP) or in the tertiary prevention program (TIP) excluding those who stopped tobacco smoking in the past associated with severity and impaired healing of work-related hand eczema. 26,27 In the present study, self-reported tobacco smoking was significantly more common among TIP patients than SIP patients. This may indicate that tobacco smoking contributed to severity and persistence of the disease leading to the TIP. However, when adjusting for age and AD, tobacco smoking was not independently associated with the TIP. The severity of hand eczema at baseline and work absenteeism in the previous year were higher in smokers than in nonsmokers among both TIP and SIP patients. However, these differences did not reach significance, which may be related to the small study size. Of interest, tobacco smoking was significantly associated with vesicular hand eczema in TIP patients. In addition, in a previous study focusing on the different morphological subtypes of hand eczema in TIP patients, vesicular hand eczema was the only clinical subtype associated with selfreported tobacco smoking. 38 In line with our current findings, Kütting et al demonstrated in metalworkers with irritant hand dermatitis that smokers had significantly higher hand eczema score values than nonsmokers for both erythema and vesicles. 39 Thus tobacco smoking may, in particular, have an influence on the occurrence and course of vesicular hand eczema.
Regarding limitations of our study, as mentioned earlier, a controlled study design was not possible. 4 Another limitation is that no long-term results were available, including information on how many of the SIP patients participated in the TIP afterwards. Some of the data were self-reported, which may have compromised accuracy. Furthermore, the small study size hampered the genetic analyses, particularly the GWAS. Because the study was done in MWs only, it is difficult to draw any conclusions regarding patients working in other occupations, even though it is likely that some of the results would be similar.
In conclusion, the SIP was effective in improving disease-specific knowledge and protective behavior in MWs with WRSD, while reducing the severity of the disease. Individual factors, including particularly AD, may confer a higher severity and persistence of the disease leading to participation in the TIP.