The Effect of Four Approaches to Treat Actinic Keratosis on the Health-Related QOL, as Assessed by the Skindex-29 and Actinic Keratosis QOL
2021; Elsevier BV; Volume: 141; Issue: 7 Linguagem: Inglês
10.1016/j.jid.2020.12.023
ISSN1523-1747
AutoresShima Ahmady, Maud H.E. Jansen, Patty J. Nelemans, Brigitte A.B. Essers, J.P.H.M. Kessels, Nicole W.J. Kelleners-Smeets, Klara Mosterd,
Tópico(s)Cutaneous Melanoma Detection and Management
ResumoTo evaluate the impact of actinic keratosis (AK) and the effect of four AK treatments on the health-related QOL (HRQOL), the Skindex-29 and AK QOL (AKQOL) questionnaires were completed by 624 patients with AK participating in a randomized controlled trial comparing 5% fluorouracil cream (Efudix, Meda Pharma B.V., Amstelveen, the Netherlands), 5% imiquimod cream (Aldara, Meda Pharma B.V., Solna, Sweden), methyl aminolevulinate (Metvix, Galderma SA, Penn Pharmaceutical Services, Gwent, UK) photodynamic therapy (MAL-PDT), and 0.015% ingenol mebutate gel (Picato, LEO Pharma A/S, Bellerup, Denmark) (Jansen et al., 2019Jansen M.H.E. Kessels J.P.H.M. Nelemans P.J. Kouloubis N. Arits A.H.M.M. van Pelt H.P.A. et al.Randomized trial of four treatment approaches for actinic keratosis.N Engl J Med. 2019; 380: 935-946Crossref PubMed Scopus (103) Google Scholar). In this trial, the probability of treatment success at 12 months was 74.7% for fluorouracil, 53.9% for imiquimod, 37.7% for MAL-PDT, and 28.9% for ingenol mebutate. Patients completed the questionnaires at baseline and at 12 months after treatment.The Skindex-29 consists of 29 items covering three domains: symptoms, emotions, and functioning (Chren et al., 1997Chren M.M. Lasek R.J. Flocke S.A. Zyzanski S.J. Improved discriminative and evaluative capability of a refined version of Skindex, a quality-of-life instrument for patients with skin diseases.Arch Dermatol. 1997; 133: 1433-1440Crossref PubMed Google Scholar). The overall and domain scores range from 0 to 100, with higher scores indicating more impairment of HRQOL. For interpretation of the Skindex-29 scores in clinical practice, the cutoff scores defined by Prinsen et al., 2011Prinsen C.A. Lindeboom R. de Korte J. Interpretation of Skindex-29 scores: cutoffs for mild, moderate, and severe impairment of health-related quality of life.J Invest Dermatol. 2011; 131: 1945-1947Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar were used to classify patients as having mild (25–32), moderate (32–44), and severe (≥44) impairment of HRQOL.The AKQOL is the only validated AK-specific questionnaire, consisting of nine questions covering three domains: emotion (three items), function (three items), and control of life (two items) and one single global item ("my quality of life is decreased because of my sun damaged skin") (Esmann et al., 2013Esmann S. Vinding G.R. Christensen K.B. Jemec G.B. Assessing the influence of actinic keratosis on patients' quality of life: the AKQoL questionnaire.Br J Dermatol. 2013; 168: 277-283Crossref PubMed Scopus (42) Google Scholar). The sum of all questions leads to the total score (0–27), with higher scores indicating more impairment of HRQOL.For analysis, the mean change in Skindex-29 and AKQOL scores from baseline was compared between treatment groups, and independent samples t-test was used to test for significance.Of all the 624 patients, 89% were male, and the mean age was 72.64 (SD = 7.49) years. Skindex-29 and AKQOL scores at 12 months after treatment were available for 575 and 576 patients, respectively.The mean baseline Skindex-29 score was 12.65 (SD = 9.45). A total of 557 patients (89.3%) reported less than mild impairment, 36 patients (5.8%) reported mild impairment, 24 patients (3.8%) reported moderate impairment, and 7 patients (1.1%) reported severe impairment of their HRQOL. Patients scored highest on the symptoms domain (mean = 27.28, SD = 17.05) and lower on the emotions (mean = 13.10, SD = 12.23) and functioning (mean = 3.70, SD = 7.16) domains.The mean AKQOL baseline score (scale 0–27) was 4.22 (SD = 3.54), and the mean domain scores were 0.94 (SD = 1.07) for control of life domain (scale 0–6), 1.56 (SD = 1.69) for emotion domain (scale 0–9), 1.54 (SD = 1.34) for functioning domain (scale 0–9), and 0.17 (SD = 0.44) for the global item (scale 0–3).Table 1 and Figure 1 show small improvements in HRQOL after treatment. The largest impact on HRQOL as measured by the Skindex-29 was observed in the symptoms domain. The improvement in the symptoms domain after treatment with fluorouracil—the treatment that was most effective in terms of lesion reduction—was significantly larger than after treatment with MAL-PDT (P = 0.001), but the differences with the other less effective topical treatments were not significant. Treatment of AK also led to some improvement in the emotions domain, whereas improvement in the functioning domain was very small.Table 1The Mean Changes (±SD) in the Skindex-29 and AKQOL Scores after Treatment in Patients with Less Than Mild, Mild, and Moderate to Severe Impairment at BaselineQuestionnaireTreatmentsAll Patients (N = 575)Less Than Mild Impairment at Baseline (n = 515)Mild Impairment at Baseline (n = 34)Moderate to Severe Impairment at Baseline (n = 26)Skindex-29Fluorouracil–4.89 (6.88)–4.15 (6.10)–12.45 (8.73)–20.26 (14.02)Imiquimod–4.80 (9.54)–3.14 (7.59)–17.61 (7.50)–21.43 (16.43)MAL-PDT–2.93 (7.55)–1.56 (5.70)–13.28 (11.74)–13.79 (11.33)Ingenol mebutate–4.30 (8.29)–2.72 (6.35)–13.47 (8.69)–16.90 (13.71)Overall–4.22 (8.12)–2.90 (6.51)–14.00 (9.27)–17.54 (13.42)AKQOLFluorouracil–0.90 (3.08)–0.81 (3.04)–1.67 (3.67)–4.00 (1.41)Imiquimod–0.99 (2.66)–0.60 (2.42)–4.29 (2.69)–4.57 (1.99)MAL-PDT–0.18 (2.86)–0.02 (2.73)–1.40 (3.10)–2.14 (4.14)Ingenol mebutate–1.14 (3.47)–0.70 (2.69)–1.88 (4.52)–6.10 (6.61)Overall–0.80 (3.05)–0.52 (2.75)–2.18 (3.57)–4.46 (4.84)Abbreviations: AKQOL, actinic keratosis QOL; HRQOL, health-related QOL; MAL-PDT, methyl aminolevulinate photodynamic therapy.Negative values reflect improved scores. Larger changes indicate more improvement in HRQOL.Interpretation of the Skindex-29 scores is based on Prinsen et al., 2011Prinsen C.A. Lindeboom R. de Korte J. Interpretation of Skindex-29 scores: cutoffs for mild, moderate, and severe impairment of health-related quality of life.J Invest Dermatol. 2011; 131: 1945-1947Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar. Open table in a new tab As seen in Table 1, patients who reported mild or moderate and/or severe impairment at baseline had more benefit from the treatment than patients with less than mild impairment, but the differences in the magnitude of HRQOL improvement between the four treatments remained small.The results of this study showed generally low impairment of HRQOL in patients with AK before the start of their therapy. The score changes from baseline reflect small improvements in HRQOL in all the four treatment groups, although HRQOL score changes were more substantial in patients who reported mild to severe impairment at baseline. There is no obvious trend toward more improvement with increasing treatment effectiveness in terms of lesion reduction. All the three home-applied creams and gel (even with the least effective ingenol mebutate) were associated with similar improvements in HRQOL scores. An explanation for this finding may be that the HRQOL score also reflects the degree of discomfort associated with a treatment. Ingenol mebutate had to be applied for only 3 days, whereas fluorouracil had to be used for 4 weeks. MAL-PDT treatment is more effective than ingenol mebutate but can be painful and requires a visit to the hospital.The largest improvement was seen in the symptoms domain of the Skindex-29 questionnaire. Patients scored very low on the functioning domain, and changes in scores after treatment were very small. Because the majority of items of the Skindex-29 questionnaire (12 of the total 29 items) relate to functioning, they have a large influence on the overall score. This might explain the limited impact of AK treatment on the total HRQOL score changes.It has been hypothesized that the disease-specific AKQOL questionnaire is more suitable to capture changes in HRQOL after treatment than the Skindex-29 questionnaire, which was designed for all kinds of skin diseases (Tennvall et al., 2015Tennvall G.R. Norlin J.M. Malmberg I. Erlendsson A.M. Hædersdal M. Health related quality of life in patients with actinic keratosis--an observational study of patients treated in dermatology specialist care in Denmark.Health Qual Life Outcomes. 2015; 13: 111Crossref PubMed Scopus (28) Google Scholar; Vis et al., 2018Vis K. Waalboer-Spuij R. Snels D.G.C.T.M. Hollestein L.M. Validity and reliability of the Dutch adaptation of the actinic keratosis quality of life questionnaire (AKQoL).Dermatology. 2018; 234: 60-65Crossref PubMed Scopus (3) Google Scholar). The nine-item AKQOL questionnaire also covers emotions and functioning, each with three items. However, the mean changes in the total AKQOL score of about 1 point on a scale from 0 to 27 were not larger than the mean changes in the total Skindex-29 score of about 4 points on a scale of 0–100. Therefore, the findings in this study do not indicate that the AKQOL questionnaire is more responsive than the Skindex-29 questionnaire.The results of other studies that reported the impact of AK treatment on HRQOL scores varied from no impact with imiquimod treatment to a temporary impact with PDT and fluorouracil (Gholam et al., 2013Gholam P. Kroehl V. Enk A.H. Dermatology life quality index and side effects after topical photodynamic therapy of actinic keratosis.Dermatology. 2013; 226: 253-259Crossref PubMed Scopus (21) Google Scholar; Pomerantz et al., 2017Pomerantz H. Chren M.M. Lew R. Weinstock M.A. VA Keratinocyte Carcinoma Chemoprevention (VAKCC) Trial Group∗. Validation and comparison of quality-of-life measures for topical 5-fluorouracil treatment: results from a randomized controlled trial.Clin Exp Dermatol. 2017; 42: 488-495Crossref PubMed Scopus (4) Google Scholar; Waalboer-Spuij et al., 2015Waalboer-Spuij R. Holterhues C. van Hattem S. Schuttelaar M.L. Gaastra M.T. Kuijpers D.I. et al.Patient perception of imiquimod treatment for actinic keratosis and superficial basal cell carcinoma in 202 patients.Dermatology. 2015; 231: 56-62Crossref PubMed Scopus (10) Google Scholar). These studies had a short follow-up period (4–8 weeks) and did not compare multiple treatment modalities. The strength of our study is that data were collected in a large multicenter randomized controlled trial with 1-year follow-up and allow for HRQOL comparison between different treatment groups. To the best of our knowledge, treatment impact on HRQOL with the AKQOL has not been previously reported.In conclusion, in the majority of patients, AK and its treatments have a limited impact on HRQOL scores, although substantial improvement can be achieved in patients who report moderate to severe impairment at baseline. Most patients with AK experience few skin-related emotional and functional problems. Because items in these two domains are the main components of the HRQOL questionnaires, clinical effectiveness in terms of lesion reduction is not well-reflected by total HRQOL scores.Ethics StatementThis study was reviewed and approved by Maastricht University Medical Center and Ethics Committee (#142052).Data availability statementDatasets related to this article can be found at https://doi.org/10.34894/SGKIMW, hosted at DataVerseNL (https://dataverse.nl/dataverse/MUMC).ORCIDsShima Ahmady: http://orcid.org/0000-0002-9551-1721Maud H.E. Jansen: http://orcid.org/0000-0002-0175-4790Patty J. Nelemans: http://orcid.org/0000-0002-9669-7353Brigitte A.B. Essers: http://orcid.org/0000-0002-7703-7114Janneke P.H.M. Kessels: http://orcid.org/0000-0002-1213-5469Nicole W.J. Kelleners-Smeets: http://orcid.org/0000-0001-6542-7740Klara Mosterd: http://orcid.org/0000-0002-9065-3050Conflict of InterestMHEJ reports receiving grants from the Dutch Organization for Scientific Research ZonMW (80-83600-98-3054) during the conduct of the study and nonfinancial support (receiving conference costs) from Galderma outside the submitted work. NWJKS reports receiving institutional research grants (clinical trials) from Galderma and Will Pharma and advisory board and speakers' honoraria from Janssen-Cilag, Galderma, AbbVie, and Leo Pharma outside the submitted work. The remaining authors state no conflict of interest. To evaluate the impact of actinic keratosis (AK) and the effect of four AK treatments on the health-related QOL (HRQOL), the Skindex-29 and AK QOL (AKQOL) questionnaires were completed by 624 patients with AK participating in a randomized controlled trial comparing 5% fluorouracil cream (Efudix, Meda Pharma B.V., Amstelveen, the Netherlands), 5% imiquimod cream (Aldara, Meda Pharma B.V., Solna, Sweden), methyl aminolevulinate (Metvix, Galderma SA, Penn Pharmaceutical Services, Gwent, UK) photodynamic therapy (MAL-PDT), and 0.015% ingenol mebutate gel (Picato, LEO Pharma A/S, Bellerup, Denmark) (Jansen et al., 2019Jansen M.H.E. Kessels J.P.H.M. Nelemans P.J. Kouloubis N. Arits A.H.M.M. van Pelt H.P.A. et al.Randomized trial of four treatment approaches for actinic keratosis.N Engl J Med. 2019; 380: 935-946Crossref PubMed Scopus (103) Google Scholar). In this trial, the probability of treatment success at 12 months was 74.7% for fluorouracil, 53.9% for imiquimod, 37.7% for MAL-PDT, and 28.9% for ingenol mebutate. Patients completed the questionnaires at baseline and at 12 months after treatment. The Skindex-29 consists of 29 items covering three domains: symptoms, emotions, and functioning (Chren et al., 1997Chren M.M. Lasek R.J. Flocke S.A. Zyzanski S.J. Improved discriminative and evaluative capability of a refined version of Skindex, a quality-of-life instrument for patients with skin diseases.Arch Dermatol. 1997; 133: 1433-1440Crossref PubMed Google Scholar). The overall and domain scores range from 0 to 100, with higher scores indicating more impairment of HRQOL. For interpretation of the Skindex-29 scores in clinical practice, the cutoff scores defined by Prinsen et al., 2011Prinsen C.A. Lindeboom R. de Korte J. Interpretation of Skindex-29 scores: cutoffs for mild, moderate, and severe impairment of health-related quality of life.J Invest Dermatol. 2011; 131: 1945-1947Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar were used to classify patients as having mild (25–32), moderate (32–44), and severe (≥44) impairment of HRQOL. The AKQOL is the only validated AK-specific questionnaire, consisting of nine questions covering three domains: emotion (three items), function (three items), and control of life (two items) and one single global item ("my quality of life is decreased because of my sun damaged skin") (Esmann et al., 2013Esmann S. Vinding G.R. Christensen K.B. Jemec G.B. Assessing the influence of actinic keratosis on patients' quality of life: the AKQoL questionnaire.Br J Dermatol. 2013; 168: 277-283Crossref PubMed Scopus (42) Google Scholar). The sum of all questions leads to the total score (0–27), with higher scores indicating more impairment of HRQOL. For analysis, the mean change in Skindex-29 and AKQOL scores from baseline was compared between treatment groups, and independent samples t-test was used to test for significance. Of all the 624 patients, 89% were male, and the mean age was 72.64 (SD = 7.49) years. Skindex-29 and AKQOL scores at 12 months after treatment were available for 575 and 576 patients, respectively. The mean baseline Skindex-29 score was 12.65 (SD = 9.45). A total of 557 patients (89.3%) reported less than mild impairment, 36 patients (5.8%) reported mild impairment, 24 patients (3.8%) reported moderate impairment, and 7 patients (1.1%) reported severe impairment of their HRQOL. Patients scored highest on the symptoms domain (mean = 27.28, SD = 17.05) and lower on the emotions (mean = 13.10, SD = 12.23) and functioning (mean = 3.70, SD = 7.16) domains. The mean AKQOL baseline score (scale 0–27) was 4.22 (SD = 3.54), and the mean domain scores were 0.94 (SD = 1.07) for control of life domain (scale 0–6), 1.56 (SD = 1.69) for emotion domain (scale 0–9), 1.54 (SD = 1.34) for functioning domain (scale 0–9), and 0.17 (SD = 0.44) for the global item (scale 0–3). Table 1 and Figure 1 show small improvements in HRQOL after treatment. The largest impact on HRQOL as measured by the Skindex-29 was observed in the symptoms domain. The improvement in the symptoms domain after treatment with fluorouracil—the treatment that was most effective in terms of lesion reduction—was significantly larger than after treatment with MAL-PDT (P = 0.001), but the differences with the other less effective topical treatments were not significant. Treatment of AK also led to some improvement in the emotions domain, whereas improvement in the functioning domain was very small. Abbreviations: AKQOL, actinic keratosis QOL; HRQOL, health-related QOL; MAL-PDT, methyl aminolevulinate photodynamic therapy. Negative values reflect improved scores. Larger changes indicate more improvement in HRQOL. Interpretation of the Skindex-29 scores is based on Prinsen et al., 2011Prinsen C.A. Lindeboom R. de Korte J. Interpretation of Skindex-29 scores: cutoffs for mild, moderate, and severe impairment of health-related quality of life.J Invest Dermatol. 2011; 131: 1945-1947Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar. As seen in Table 1, patients who reported mild or moderate and/or severe impairment at baseline had more benefit from the treatment than patients with less than mild impairment, but the differences in the magnitude of HRQOL improvement between the four treatments remained small. The results of this study showed generally low impairment of HRQOL in patients with AK before the start of their therapy. The score changes from baseline reflect small improvements in HRQOL in all the four treatment groups, although HRQOL score changes were more substantial in patients who reported mild to severe impairment at baseline. There is no obvious trend toward more improvement with increasing treatment effectiveness in terms of lesion reduction. All the three home-applied creams and gel (even with the least effective ingenol mebutate) were associated with similar improvements in HRQOL scores. An explanation for this finding may be that the HRQOL score also reflects the degree of discomfort associated with a treatment. Ingenol mebutate had to be applied for only 3 days, whereas fluorouracil had to be used for 4 weeks. MAL-PDT treatment is more effective than ingenol mebutate but can be painful and requires a visit to the hospital. The largest improvement was seen in the symptoms domain of the Skindex-29 questionnaire. Patients scored very low on the functioning domain, and changes in scores after treatment were very small. Because the majority of items of the Skindex-29 questionnaire (12 of the total 29 items) relate to functioning, they have a large influence on the overall score. This might explain the limited impact of AK treatment on the total HRQOL score changes. It has been hypothesized that the disease-specific AKQOL questionnaire is more suitable to capture changes in HRQOL after treatment than the Skindex-29 questionnaire, which was designed for all kinds of skin diseases (Tennvall et al., 2015Tennvall G.R. Norlin J.M. Malmberg I. Erlendsson A.M. Hædersdal M. Health related quality of life in patients with actinic keratosis--an observational study of patients treated in dermatology specialist care in Denmark.Health Qual Life Outcomes. 2015; 13: 111Crossref PubMed Scopus (28) Google Scholar; Vis et al., 2018Vis K. Waalboer-Spuij R. Snels D.G.C.T.M. Hollestein L.M. Validity and reliability of the Dutch adaptation of the actinic keratosis quality of life questionnaire (AKQoL).Dermatology. 2018; 234: 60-65Crossref PubMed Scopus (3) Google Scholar). The nine-item AKQOL questionnaire also covers emotions and functioning, each with three items. However, the mean changes in the total AKQOL score of about 1 point on a scale from 0 to 27 were not larger than the mean changes in the total Skindex-29 score of about 4 points on a scale of 0–100. Therefore, the findings in this study do not indicate that the AKQOL questionnaire is more responsive than the Skindex-29 questionnaire. The results of other studies that reported the impact of AK treatment on HRQOL scores varied from no impact with imiquimod treatment to a temporary impact with PDT and fluorouracil (Gholam et al., 2013Gholam P. Kroehl V. Enk A.H. Dermatology life quality index and side effects after topical photodynamic therapy of actinic keratosis.Dermatology. 2013; 226: 253-259Crossref PubMed Scopus (21) Google Scholar; Pomerantz et al., 2017Pomerantz H. Chren M.M. Lew R. Weinstock M.A. VA Keratinocyte Carcinoma Chemoprevention (VAKCC) Trial Group∗. Validation and comparison of quality-of-life measures for topical 5-fluorouracil treatment: results from a randomized controlled trial.Clin Exp Dermatol. 2017; 42: 488-495Crossref PubMed Scopus (4) Google Scholar; Waalboer-Spuij et al., 2015Waalboer-Spuij R. Holterhues C. van Hattem S. Schuttelaar M.L. Gaastra M.T. Kuijpers D.I. et al.Patient perception of imiquimod treatment for actinic keratosis and superficial basal cell carcinoma in 202 patients.Dermatology. 2015; 231: 56-62Crossref PubMed Scopus (10) Google Scholar). These studies had a short follow-up period (4–8 weeks) and did not compare multiple treatment modalities. The strength of our study is that data were collected in a large multicenter randomized controlled trial with 1-year follow-up and allow for HRQOL comparison between different treatment groups. To the best of our knowledge, treatment impact on HRQOL with the AKQOL has not been previously reported. In conclusion, in the majority of patients, AK and its treatments have a limited impact on HRQOL scores, although substantial improvement can be achieved in patients who report moderate to severe impairment at baseline. Most patients with AK experience few skin-related emotional and functional problems. Because items in these two domains are the main components of the HRQOL questionnaires, clinical effectiveness in terms of lesion reduction is not well-reflected by total HRQOL scores. Ethics StatementThis study was reviewed and approved by Maastricht University Medical Center and Ethics Committee (#142052). This study was reviewed and approved by Maastricht University Medical Center and Ethics Committee (#142052). Data availability statementDatasets related to this article can be found at https://doi.org/10.34894/SGKIMW, hosted at DataVerseNL (https://dataverse.nl/dataverse/MUMC). Data availability statementDatasets related to this article can be found at https://doi.org/10.34894/SGKIMW, hosted at DataVerseNL (https://dataverse.nl/dataverse/MUMC). Datasets related to this article can be found at https://doi.org/10.34894/SGKIMW, hosted at DataVerseNL (https://dataverse.nl/dataverse/MUMC). ORCIDsShima Ahmady: http://orcid.org/0000-0002-9551-1721Maud H.E. Jansen: http://orcid.org/0000-0002-0175-4790Patty J. Nelemans: http://orcid.org/0000-0002-9669-7353Brigitte A.B. Essers: http://orcid.org/0000-0002-7703-7114Janneke P.H.M. Kessels: http://orcid.org/0000-0002-1213-5469Nicole W.J. Kelleners-Smeets: http://orcid.org/0000-0001-6542-7740Klara Mosterd: http://orcid.org/0000-0002-9065-3050 Shima Ahmady: http://orcid.org/0000-0002-9551-1721 Maud H.E. Jansen: http://orcid.org/0000-0002-0175-4790 Patty J. Nelemans: http://orcid.org/0000-0002-9669-7353 Brigitte A.B. Essers: http://orcid.org/0000-0002-7703-7114 Janneke P.H.M. Kessels: http://orcid.org/0000-0002-1213-5469 Nicole W.J. Kelleners-Smeets: http://orcid.org/0000-0001-6542-7740 Klara Mosterd: http://orcid.org/0000-0002-9065-3050 Conflict of InterestMHEJ reports receiving grants from the Dutch Organization for Scientific Research ZonMW (80-83600-98-3054) during the conduct of the study and nonfinancial support (receiving conference costs) from Galderma outside the submitted work. NWJKS reports receiving institutional research grants (clinical trials) from Galderma and Will Pharma and advisory board and speakers' honoraria from Janssen-Cilag, Galderma, AbbVie, and Leo Pharma outside the submitted work. The remaining authors state no conflict of interest. MHEJ reports receiving grants from the Dutch Organization for Scientific Research ZonMW (80-83600-98-3054) during the conduct of the study and nonfinancial support (receiving conference costs) from Galderma outside the submitted work. NWJKS reports receiving institutional research grants (clinical trials) from Galderma and Will Pharma and advisory board and speakers' honoraria from Janssen-Cilag, Galderma, AbbVie, and Leo Pharma outside the submitted work. The remaining authors state no conflict of interest. This work was funded by The Netherlands Organization for Health Research and Development (ZonMW): grant 80-83600-98-3054 , ClinicalTrials.gov number NCT02281682. This work was reviewed and approved by Maastricht University Medical Center+ Ethics Committee (#142052) (Maastricht, The Netherlands). We thank the patients who participated in this study and all the employees of the dermatology departments of the participating hospitals. Conceptualization: SA, KM, MHEJ, PJN, BABE; Formal Analysis: SA; Investigation: SA, MHEJ, JPHMK; Methodology: SA, PJN, BABE; Project Administration: SA; Supervision: KM, PJN, NWJKS; Writing - Original Draft Preparation: SA, KM, PJN, MHEJ, NWJKS, BABE, JPHMK
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