1/7 INVESTIGATIVE REPORT Chronic Nodular Prurigo: A European Cross-sectional Study of ActaDV Patient Perspectives on Therapeutic Goals and Satisfaction Manuel P. PEREIRA1#, Claudia ZEIDLER1#, Joanna WALLENGREN2, Jon A. HALVORSEN3, Elke WEISSHAAR4, Simone GARCOVICH5, Laurent MISERY6, Emilie BRENAUT6, Ekin SAVK7, Nikolay POTEKAEV8, Andrey LVOV8, Svetlana BOBKO8, Jacek C. SZEPIETOWSKI9, Adam REICH10, Agnieszka BOZEK11, Franz J. LEGAT12, Martin METZ13, Markus STREIT14, Esther SERRA-BALDRICH15, Margarida GONÇALO16, Michael STORCK17, Teresa NAU1, Vincent HOFFMANN1, Sabine STEINKE1, Ina GREIWE1, Martin DUGAS17, Matthias AUGUSTIN18 and Sonja STÄNDER1; on behalf of the European Prurigo Project (EPP) Consensus Conference Participants 2017* 1 Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Münster, Germany, 2Department of Clinical Acta Dermato-Venereologica Sciences Lund, Dermatology and Venereology, Lund University, Lund Sweden and Skåne University Hospital, Lund, Sweden, 3Department of Dermatology, Oslo University Hospital, University of Oslo, Oslo, Norway, 4Department of Social Medicine, Occupational and Environmental Dermatology, University of Heidelberg, Germany, 5Fondazione Policlinico Universitario A. Gemelli IRCCS, Dipartimento di Scienze Mediche e Chirurgiche, UOC Dermatologia, Università Cattolica del Sacro Cuore, Rome, Italy, 6Department of Dermatology, University Hospital of Brest, Brest, France, 7Department of Dermatology, Aydın Adnan Menderes University, Aydın, Turkey, 8Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology, Moscow, Russia, 9Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, 10Department of Dermatology, University of Rzeszów, 11Department of Dermatology, School of Medicine, University of Information Technology and Management, Rzeszów, Poland, 12Department of Dermatology, Medical University of Graz, Graz, Austria,13Department of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Berlin, Germany, 14Department of Dermatology, Kantonsspital Aarau, Aarau, Switzerland, 15Department of Dermatology, Sant Pau Hospital, Barcelona, Spain, 16Department of Dermatology, University Hospital and Faculty of Medicine, University of Coimbra, Coimbra, Portugal, 17Institute of Medical Informatics, University of Münster, Münster, and 18Competence Center for Healthcare Research in Dermatology (CVderm), Institute for Healthcare Research in Dermatology and Nursing (IVDP), University Hospital of Hamburg-Eppendorf, Hamburg, Germany # Shared first-authorship. *EPP Consensus Conference Participants 2017: Florence Dalgard, Malmö, Sweden; Jesper Elberling, Copenhagen, Denmark; Caroline Forner, Münster, Germany; Uwe Gieler, Giessen, Germany; Tabi A. Leslie, London, UK; Claudia Riepe, Münster, Germany; Gudrun Schneider, Münster, Germany; Hartmut Ständer, Bad Bentheim and Dortmund, Germany Chronic nodular prurigo is characterized by recalci- trant itch. Patient perspectives on therapeutic goals, SIGNIFICANCE satisfaction with therapy and efficacy of therapeutic Chronic prurigo is a highly impairing itchy skin disease, which ActaDV regimens for this condition are unknown. This ques- is difficult to treat. This questionnaire study of 406 patients tionnaire study examined these issues in 406 patients with active disease at 15 centres across 12 European with chronic nodular prurigo from 15 European derma- countries revealed that improvements in itch, skin lesions tological centres. Improvements in itch, skin lesions and sleep are the most important goals for patients. Most and sleep were the most important goals. Emollients, patients were not satisfied with their therapy. Almost 10% topical corticosteroids and antihistamines were the of patients surveyed did not receive any treatment despite most frequently used treatments, while a minority of having active disease, while only a minority received potent patients were prescribed potent medications, such as medication to treat their chronic prurigo. In general, patients systemic immunosuppressants and gabapentinoids. with chronic prurigo considered that they were not ade­ quate­ly treated and experienced high levels of dissatisfac­ Advances in dermatology and venereology Most patients were not satisfied with their previous therapy (56.8%), while 9.8% did not receive any tion with their therapy. ther­apy despite having active disease. A substantial C number of respondents (28.7%) considered none of the hronic nodular prurigo (CNPG; also known as therapeutic options effective. Although chronic nodu- prurigo nodularis) is the most prevalent subtype of lar prurigo is a severe disease, most patients were not treat­ed with potent systemic drugs, which may contri- chronic prurigo and is characterized by the development bute to the high levels of dissatisfaction and disbelief in of severely pruritic hyperkeratotic nodules, a consequence available therapies. Specific guidelines for chronic no- of chronic itch and prolonged scratching (1). Treatment of dular prurigo and the development of novel therapies CNPG is complex, and the disease is often refractory to are necessary to improve care. available drugs (2). Recommendations for management of CNPG are discussed in national and international gui- Key words: nodular prurigo; chronic nodular prurigo; patient- delines for pruritus and in a newly deve­loped guideline reported outcome; itch; pruritus; therapy. specific for CNPG (3, 4). A stepwise approach should Accepted Dec 14, 2020; Epub ahead of print Dec 15, 2020 be adopted in the treatment of CNPG. If possible, the Acta Derm Venereol 2021; 101: adv00403. underlying diseases leading to chronic itch should be treated, although in most cases this does not lead to an Corr: Manuel P. Pereira, Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Von-Esmarch-Str. 58, DE- improvement in CNPG (5). Topical corticosteroids and 48149 Münster, Germany. E-mail: manuelpedro.pereira@ukmuenster.de calcineurin-inhibitors, as well as ultraviolet (UV) therapy, This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta doi: 10.2340/00015555-3726 Society for Publication of Acta Dermato-Venereologica Acta Derm Venereol 2021; 101: adv00403 2/7 M. P. Pereira et al. have shown antipruritic efficacy in clinical studies (6–8). variables (number of drugs taken by patients between different Recommended systemic options include gabapentinoids, European regions), the Mann–Whitney U test was applied. The χ2 ActaDV test was used for group comparisons of categorical variables (e.g. antidepressants, immunosuppressants (cyclosporine A, frequency of therapies used between very satisfied patients and the methotrexate) and opioid modulators; however, clinical remaining cohort). Two-sided significance was set at p < 0.05. As trials on these substances are lacking (3, 4). Monoclonal there were missing values, the number of observations is given for antibodies are promising novel agents (9–11), which each item for transparency. For comparisons between European may constitute a therapeutic option for CNPG in the regions, the countries were divided by regions according to a historical classification, as previously performed (13). Germany near future. In a recent survey, European itch specialists was regarded as a region on its own, due to its larger sample size revealed that the drugs they most often prescribe for and because 3 recruiting centres were located in Germany. All CNPG include antihistamines, antidepressants, gaba- analyses were performed with SPSS v. 25.0 for Windows (IBM Acta Dermato-Venereologica pentinoids and immunosuppressants, while there is a Corporation, Armonk, NY, USA). need for development of novel targeted therapies (12). Data on patient perspectives on available therapeutic RESULTS options and their efficacy are lacking. Therefore, a pro- spective multicentre patient-oriented questionnaire-based Study population study was performed, aiming to assess the perception of A total of 509 patients were invited to participate in the patients with CNPG on therapeutic goals, previously used study, between March 2017 and June 2019. Of these, therapies, overall satisfaction with therapy, efficacy of 406 (251 females (61.8%), 155 males (38.2%); median available therapeutic regimens and out-of-pocket costs. age 63 years (interquartile range (IQR) 51–71 years)) reported having itch and pruriginous lesions in the pre- MATERIALS AND METHODS vious 7 days and were therefore qualified to complete The methods and population of this prospective, cross-sectional, the whole questionnaire (Germany n = 137; Northern cohort study are described in our initial publication related to the Europe n = 69; Central Europe n = 57; Eastern Europe European Prurigo Project (EPP) (13). In brief, after signing the n = 76; Southern Europe n = 67). Detailed information informed consent, patients with CNPG aged 18 years or older on the study population, including demographics and reporting having itch and nodular prurigo lesions in the previous comorbidities, is given in the previous publication on week were asked to complete a questionnaire, either on paper or electronically. Patients were recruited at dermatological tertiary the European cross-sectional study (13). ActaDV centres across Europe. Data were pseudonymized and collected centrally at a database in Münster (14). Therapeutic goals In this study, 15 European centres from 5 regions, i.e. Germany (Münster, Berlin, Heidelberg), Northern Europe (Norway – Oslo, Asked for the 3 most important therapeutic goals, impro- Sweden – Lund), Central Europe (Austria – Graz, France – vement in itch was mentioned most frequently (79.5%, Brest, Switzerland – Aarau), Eastern Europe (Poland – Rzeszow, 271/341), followed by improvement in skin lesions Poland – Wroclaw, Russia – Moscow), and Southern Europe (57.2%, 195/341) and improvement in sleep (30.5%, (Italy – Rome, Portugal – Coimbra, Spain – Barcelona, Turkey – Aydın) participated. The ethics committees corresponding to the 104/341). All reported therapeutic goals are shown in participating centres approved the study (main ethics committee: Fig. 1. Advances in dermatology and venereology Medical Faculty of the University of Münster, 2017-168-f-S), which was performed according to the Declaration of Helsinki. The study is registered at the German registry of clinical trials Previous therapies (DRKS00012876, registration date: 09.08.2017). Emollients, topical corticosteroids and antihistamines were the therapeutic regimens applied most often. All Assessments other therapies were used to a lower extent (Table I). This part of the study analysed the answers to question numbers The median total number [IQR] of drugs used by patients 27–37 of the patient questionnaire (Appendix S11). The questions was 4 [2; 6], n = 379, while 1 of 4 drugs taken by the pa- related to the most important therapeutic goals (questions 35–37) tients was used to treat CNPG (1 [0; 2], n = 375). Patients (15), the overall number of drugs used, and the number of drugs used specifically for treatment of CNPG (questions 27 and 28), from Central Europe took a lower amount of drugs for previous therapies for CNPG (questions 29 and 30), overall satis- CNPG compared with patients from Northern Europe faction with therapy (question 31), best and worst therapeutic regi- (p = 0.012), Eastern Europe (p = 0.007) and Southern mens (questions 32 and 33), and out-of-pocket costs (question 34). Europe (p = 0.005). Statistical analysis Satisfaction with therapy All data were analysed descriptively (shown as absolute and per- centage values for categorical data; median (interquartile range; Overall, more than half of the patients were not satis- IQR) for continuous data). For group comparisons of continuous fied with the therapy they had received in the previous 6 months (not satisfied or rather not satisfied: 56.8%, 225/396), while 9.8% (39/396) did not receive any https://doi.org/10.2340/00015555-3726 1 therapy in the previous 6 months, despite having active www.medicaljournals.se/acta Chronic nodular prurigo: patient perspectives on therapy 3/7 ActaDV Acta Dermato-Venereologica Fig. 1. Most important therapeutic goals. First, second and third most important therapeutic goals from the patients’ point-of view. In total, 341 out of 406 patients indicated at least one therapeutic goal. For each goal, the percentage of patients considering it as a top 3 goal is shown. disease. Only 33.3% of patients were satisfied or very (13.6% and 10.5%, respectively) and least effective satisfied with the therapy. The highest proportion of pa- (10.0% and 28.1%, respectively) therapy. Systemic im- tients who were not satisfied or rather not satisfied with munosuppressants were frequently considered as the the therapy was recorded in Southern Europe (73.1%) most effective therapy (12.5%). When considering only and the lowest in Northern Europe (46.2%; Fig. 2). the patients who previously used them, 46.3% (44/95) When asked about the most effective therapies reported this drug class as the most effective. All other (n = 352), a substantial proportion of patients considered options were chosen by less than 10% of respondents. ActaDV that none of the options were effective (28.7%). Topical Antihistamines (11.7%) next to UV therapy (11.1%) were steroids and emollients were regarded both as the most often reported as the least effective therapy (Table II). Table I. Previous treatment regimens All Germany Northern Europe Central Europe Eastern Europe Southern Europe n = 406 n = 137 n = 69 n = 57 n = 76 n = 67 Previous therapies n (%) n (%) n (%) n (%) n (%) n (%) Ever Emollients 344 (84.7) 126 (92.0) 60 (87.0) 51 (89.5) 50 (65.8) 57 (85.1) Topical steroids 237 (58.4) 40 (29.2) 51 (73.9) 30 (52.6) 63 (82.9) 53 (79.1) Advances in dermatology and venereology Antihistamines 224 (55.2) 74 (54.0) 25 (36.2) 32 (56.1) 47 (61.8) 46 (68.7) Ultraviolet therapy 171 (42.1) 60 (43.8) 47 (68.1) 26 (45.6) 19 (25.0) 19 (28.4) Systemic immunosuppressants 95 (23.4) 28 (20.4) 22 (31.9) 7 (12.3) 24 (31.6) 14 (20.9) Antidepressants 89 (21.9) 31 (22.6) 11 (15.9) 14 (24.6) 10 (13.2) 23 (34.3) Gabapentin/pregabalin 70 (17.2) 39 (28.5) 4 (5.8) 15 (26.3) 7 (9.2) 5 (7.5) Topical immunomodulators 37 (9.1) 12 (8.8) 7 (10.1) 3 (5.3) 7 (9.2) 8 (11.9) Psychotherapy 35 (8.6) 23 (16.8) 6 (8.7) 2 (3.5) 4 (5.3) 0 (0) Othera 43 (10.6) 15 (10.9) 13 (18.8) 5 (8.8) 4 (5.3) 6 (9.0) None 9 (2.2) 3 (2.2) 1 (1.4) 0 (0) 2 (2.6) 3 (4.5) Past 6 months Emollients 341 (84.0) 126 (92.0) 61 (88.4) 46 (80.7) 49 (64.5) 59 (88.1) Topical steroids 210 (51.7) 35 (25.5) 42 (60.9) 27 (47.4) 53 (69.7) 53 (79.1) Antihistamines 176 (43.3) 60 (43.8) 14 (20.3) 19 (33.3) 37 (48.7) 46 (68.7) Ultraviolet therapy 83 (20.4) 39 (35.8) 11 (15.9) 10 (17.5) 12 (15.8) 11 (16.4) Antidepressants 82 (20.2) 30 (21.9) 9 (13.0) 10 (17.5) 11 (14.5) 22 (32.8) Systemic immunosuppressants 70 (17.2) 24 (17.5) 11 (15.9) 4 (7.0) 18 (23.7) 13 (19.4) Gabapentin/pregabalin 55 (13.5) 32 (23.4) 2 (2.9) 13 (22.8) 4 (5.3) 4 (6.0) Psychotherapy 27 (6.7) 20 (14.6) 1 (1.4) 4 (7.0) 2 (2.6) 0 (0) Topical immunomodulators 23 (5.7) 13 (9.5) 2 (2.9) 1 (1.8) 3 (3.9) 4 (6.0) Otherb 29 (7.1) 14 (10.2) 3 (4.3) 5 (8.8) 4 (5.3) 3 (4.5) None 10 (2.5) 2 (1.5) 2 (2.9) 3 (5.3) 3 (3.9) 0 (0) Data are shown for all patients and for each region i.e. Germany (Münster, Berlin, Heidelberg), Northern Europe (Norway – Oslo, Sweden – Lund), Central Europe (Austria – Graz, France – Brest, Switzerland – Aarau), Eastern Europe (Poland – Rzeszow, Poland – Wroclaw, Russia – Moscow), and Southern Europe (Italy – Rome, Portugal – Coimbra, Spain – Barcelona, Turkey – Aydın). a Including sole/therapeutic baths, topical tar derivatives, potassium permanganate, wet dressings, zinc, intralesional steroids, systemic steroids, alitretinoin, opioid receptor modulators (nalbuphine, naltrexone), thalidomide, serlopitant, apremilast, biologics (nemolizumab, omalizumab, ustekinumab), antibiotics, benzodiazepines, compression therapy, occupational therapy, homeopathy, diet, stress reduction, yoga, walks outside. bIncluding sole/therapeutic baths, systemic steroids, alitretinoin, opioid receptor modulators (naloxone, naltrexone), apremilast, biologics (nemolizumab, omalizumab, ustekinumab), antibiotics, acupuncture, homeopathy, diet, stress reduction. Acta Derm Venereol 2021 4/7 M. P. Pereira et al. ActaDV Acta Dermato-Venereologica Fig. 2. Patient satisfaction with therapy in the previous 6 months (n = 396). Out-of-pocket costs the presence of skin lesions (13). As a result of the itch and skin lesions, patients with CNPG are burdened with Overall, the majority of patients (59%, 236/400) esti- substantial impairment in their quality of life, sleep loss mated up to €500 or more out-of-pocket costs owing to (13), high incidence of depression and other psychiatric CNPG treatments in the previous 6 months (including comorbidities (16), and potentially higher risk of suicide personal purchases, prescribed drugs and travel costs to (17). Owing to the severity of the disease, effective the physician). The distribution of out-of-pocket costs treatment is of great importance for those affected. The overall and across regions is shown in Fig. 3. current study showed, as expected, that treatment of itch is by far the most important priority for patients with DISCUSSION CNPG, followed by improvement in skin lesions and sleep quality, which is in line with the clinical profile CNPG is a severe condition, in which itch plays a central of the disease (13). A homogenous profile regarding role. Patients experience itch of high intensity, often ac- therapeutic goals was observed across European regions. companied by painful sensory symptoms, such as burning Interestingly, understanding the origin of CNPG was also ActaDV and stinging. Affected individuals consider itch to be mentioned by a substantial number of patients. Itch as- the most burdensome aspect of the disease, followed by sociated with CNPG can be of dermatological, systemic, Table II. Most and least effective treatments All Germany Northern Europe Central Europe Eastern Europe Southern Europe n (%) n (%) n (%) n (%) n (%) n (%) Most effective treatment n = 352 n = 111 n = 55 n= 56 n = 65 n = 65 Topical steroids 48 (13.6) 7 (6.3) 12 (21.8) 5 (8.9) 12 (18.5) 12 (18.5) Advances in dermatology and venereology Systemic immunosuppressants 44 (12.5) 13 (11.7) 6 (10.9) 4 (7.1) 14 (21.5) 7 (10.8) Emollients 37 (10.5) 14 (12.6) 12 (21.8) 7 (12.5) 2 (3.1) 2 (3.1) Ultraviolet therapy 35 (9.9) 8 (7.2) 7 (12.7) 8 (14.3) 5 (7.7) 7 (10.8) Antihistamines 19 (5.4) 6 (5.4) 0 (0) 3 (5.4) 5 (7.7) 5 (7.7) Gabapentin/pregabalin 12 (3.4) 6 (5.4) 0 (0) 4 (7.1) 1 (1.5) 1 (1.5) Antidepressants 8 (2.3) 1 (0.9) 1 (1.8) 2 (3.6) 1 (1.5) 3 (4.6) Topical immunomodulators 4 (1.1) 2 (1.8) 1 (1.8) 0 (0) 0 (0) 1 (1.5) Psychotherapy 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Othera 44 (12.5) 22 (19.8) 10 (18.2) 4 (7.1) 6 (9.2) 2 (3.1) None 101 (28.7) 32 (28.8) 6 (10.9) 19 (33.9) 19 (29.2) 25 (38.5) Least effective treatment n = 360 n = 119 n = 54 n = 55 n = 69 n = 63 Emollients 101 (28.1) 31 (26.1) 14 (25.9) 10 (18.2) 24 (34.8) 22 (34.9) Antihistamines 42 (11.7) 8 (6.7) 0 (0) 8 (14.5) 12 (17.4) 14 (22.2) Ultraviolet therapy 40 (11.1) 18 (15.1) 10 (18.5) 4 (7.3) 5 (7.2) 3 (4.8) Topical steroids 36 (10.0) 2 (1.7) 4 (7.4) 7 (12.7) 13 (18.8) 10 (15.9) Gabapentin/pregabalin 12 (3.3) 9 (7.6) 1 (1.9) 1 (1.8) 1 (1.4) 0 (0) Systemic immunosuppressants 9 (2.5) 4 (3.4) 3 (5.6) 1 (1.8) 1 (1.4) 0 (0) Antidepressants 6 (1.7) 3 (2.5) 2 (3.7) 0 (0) 0 (0) 1 (1.6) Psychotherapy 4 (1.1) 1 (0.8) 0 (0) 1 (1.8) 2 (2.9) 0 (0) Topical immunomodulators 2 (0.6) 2 (1.7) 0 (0) 0 (0) 0 (0) 0 (0) Otherb 21 (5.8) 6 (5.0) 10 (18.5) 0 (0) 3 (4.3) 2 (3.2) None 87 (24.2) 35 (29.4) 10 (18.5) 23 (41.8) 8 (11.6) 11 (17.5) Data are shown for all patients and for each region, i.e. Germany (Münster, Berlin, Heidelberg), Northern Europe (Norway – Oslo, Sweden – Lund), Central Europe (Austria – Graz, France – Brest, Switzerland – Aarau), Eastern Europe (Poland – Rzeszow, Poland – Wroclaw, Russia – Moscow), and Southern Europe (Italy – Rome, Portugal – Coimbra, Spain – Barcelona, Turkey – Aydın). a Including therapeutic baths, climate therapy, salt water, antiseptics, topical tar derivatives, systemic steroids, alitretinoin, opioid receptor modulators (nalbuphine, naloxone, naltrexone), thalidomide, fosaprepitant, apremilast, biologics (dupilumab, nemolizumab), antibiotics, benzodiazepines, change of medication, diet, lactose and sorbitol-free diet, acupuncture, homeopathy. bIncluding therapeutic baths, salt water, sunbathing, sorbitol-free diet, antibiotics. www.medicaljournals.se/acta Chronic nodular prurigo: patient perspectives on therapy 5/7 ActaDV Acta Dermato-Venereologica Fig. 3. Patients’ estimate of out- of-pocket costs (in Euro) related to chronic nodular prurigo in the previous 6 months (n = 400). neurological, psychiatric/psychosomatic, multifactorial high costs of emollients for the patients limit their use or unknown origin (1, 18). However, once established, in some countries. CNPG is a distinct disease, and diagnosis and therapy of The low awareness and experience with CNPG among the triggering condition does not lead to improvement in physicians, the lack of approved therapies and shortage in the majority of patients. The treatment goals of patients recommending off-label therapies in CNPG are relevant with CNPG should be taken into account by attending factors contributing to the use of less effective therapies physicians in the management of these patients. and, consequently, the subpar care of CNPG patients. Owing to the lack of approved therapies, only a minor­ Other factors influencing patient satisfaction, such as ity of patients across all regions in Europe reported the patient-doctor relationship and attention to quality treatment with potent medications. Systemic drugs with of life (26), were not analysed in this study and should anti-inflammatory effects or those with a central anti- be addressed in the near future. pruritic action were seldom used. Only a few patients High levels of disbelief were detected in patients with ActaDV had been prescribed biologics (nemolizumab (n = 1), CNPG regarding the efficacy of available treatment omalizumab (n = 1), ustekinumab (n = 1); Table I). Even options. When asked about the most effective treatment though randomized controlled trials are still lacking, regimen, almost one-third of patients considered none of case series have shown beneficial effects of systemic the options to be effective (Table I). Of the total patient immunosuppressive drugs (cyclosporine (19, 20), met- population, 12.5% regarded systemic immunosuppres- hotrexate (21, 22)), gabapentinoids (23) and μ-opioid sive drugs as the most effective agents. Considering receptor antagonists (24, 25). In a recently consented that only 23.4% of the current patient cohort had ever guideline on the treatment of chronic prurigo, systemic received immunosuppressive agents to treat CNPG, this Advances in dermatology and venereology medications are recommended to patients with CNPG represents a relatively large proportion of patients. In refractory to commonly used treatments, such as emol- contrast, antihistamines (5.4%) and emollients (10.5%) lients, topical steroids, antihistamines and phototherapy were only seldom indicated as the most effective therapy, (26) (Table I), provided contraindications are excluded. especially when taking into account that these are often- These findings suggest that a substantial proportion of used therapies (55.2% and 84.7%, respectively). Inte- patients were not offered potent systemic medication, and restingly, emollients were considered both as the most this omission results in low levels of satisfaction with and least effective therapy by a substantial number of therapy and documents the high unmet need (Fig. 2). patients (10.5% and 28.1%, respectively). While emol- In line with this, 9.8% of patients from the current co- lients may provide relief when applied to itchy skin, the hort did not receive any therapy in the 6 months prior effect is usually of short duration, which would explain to completing the survey, despite having active disease, the conflicting observations in this study. pointing to insufficient care. The proportion of patients Novel agents, such as biologics (dupilumab and nemo- not receiving any treatment was highest in Northern lizumab), as well as opioid receptor modulators (nalbu­ Europe (20.0%) and lowest in Southern (1.5%) and phine) and neurokinin-1 receptor antagonists (aprepitant) Eastern Europe (4.1%), suggesting possible disparities were reported as the most effective therapies by a few across Europe regarding the healthcare systems. The patients. To date, these drugs are only available in clinical current study also observed discrepancies in the use of trials or at expert centres in off-label regimens, but may emollients across Europe, with the highest percentage constitute effective therapies for resistant CNPG cases of patients using emollients in Germany (92.0%) and in the future. A recent 12-week randomized placebo- lowest in Eastern Europe (65.8%). It is possible that the controlled, double-blind, phase 2 trial investigating the Acta Derm Venereol 2021 6/7 M. P. Pereira et al. efficacy of nemolizumab in CNPG showed promising may impact the current findings, since these tertiary results (9), while case series suggest a good anti-pruritic units probably treat the most severe cases of CNPG. On ActaDV effect of dupilumab (11, 27, 28). Clinical trials investiga- the other hand, patients being treated in dermatological ting these substances in patients with CNPG are needed offices or by primary care physicians may less often be in order to confirm their efficacy and safety. prescribed more potent medications, such as systemic Thalidomide was also referred to by one patient as the immunosuppressants or biologics, and have less access most effective therapy. Although case series indicate a to novel substances being tested in clinical trials. Another beneficial effect of thalidomide in CNPG (29–31), its limitation is that the patient questionnaire used was not use should be considered only in exceptional cases by validated. Moreover, data was obtained by self-report physicians with experience with this drug, due to the and was not validated through medical records. Acta Dermato-Venereologica high risk of developing irreversible adverse reactions, such as peripheral neuropathy. Conclusion Some patients with CNPG mentioned a vast array of non-pharmacological treatments (e.g. homeopathy, This large multicentre study, performed in 12 European acupuncture, diet, therapeutic baths, climate therapy, salt countries, documents the low use of potent systemic water; Table II) as the most effective therapy, reflecting drugs and high level of dissatisfaction and disbelief in their disbelief in conventional medical therapeutic options. available treatments in CNPG. A greater awareness of Twenty-one patients reported being very satisfied with CNPG and the development of guidelines specifically for the therapy they had received in the previous 6 months. CNPG are essential in order to improve its management, Very satisfied patients showed, as expected, lower itch while novel therapies, such as biologics and opioid mo- intensities (NRS: p < 0.001; verbal rating scale: p = 0.001, dulators, may be decisive to improve care in the future. (13)) and impairment in quality of life (5 pruritus life quality: p < 0.001, (13)) compared with the remaining ACKNOWLEDGEMENTS patients receiving a therapy in the previous 6 months. The authors thank B. Pfleiderer, MD, for assistance in the study Of note, very satisfied patients were treated more often preparation. with “other therapies” in the previous 6 months compar­ This study was supported by the European Academy of Derma- ed with the remaining cohort (p = 0.021). Nemolizumab tology and Venereology (EADV, No. 2016-012 to MP). Galderma (n = 2), fosaprepitant (n = 1) and apremilast (n = 1) were S.A, Kiniksa Pharmaceuticals and Menlo Therapeutics provided ActaDV mentioned as the most effective drugs by very satisfied support for the study. patients, suggesting that novel innovative drugs may Conflicts of interest. MPP is an investigator for Trevi Therapeutics; a consultant for Galderma; and has received speaker honoraria/ improve care in CNPG. In addition, very satisfied patients travel fees from Galderma, Menlo Therapeutics, Novartis and more frequently reported having had psychotherapy in Trevi Therapeutics. CZ has received speaker honoraria/travel fees the past (p = 0.005), indicating the importance of psycho­ from Beiersdorf and Dermasence. EW is an investigator for Menlo logical care in this condition. Other factors, such as age, Therapeutics, Trevi Therapeutics, Kiniksa Pharmaceuticals and sex, geographical distribution or presence of atopic a member of the advisory board meetings for Menlo and Trevi. SG has received consulting support from companies, including conditions, did not differ when comparing very satisfied Menlo Therapeutics. LM is a consultant for Galderma, Menlo, patients with the remaining cohort receiving a therapy. Advances in dermatology and venereology Trevi, Sanofi, and was investigator for Galderma, Trevi, Sanofi. An additional burden for patients is the relatively high EB is an investigator for Biogen, Galderma, and is a consultant out-of-pocket costs related to CNPG. The vast majority and/or member of the advisory board for Janssen, Lilly, Celgene, of patients reported out-of-pocket costs below 500€ Novartis, Pfizer, and received financial support from Sanofi, Abbvie. AL is a consultant for Galderma and Novartis; and has across the European regions in the previous 6 months received speaker honoraria/travel fees from Galderma, Bayer, (82.5–89.3%), while a larger percentage of patients from LEO, Pierre Fabre. SB has received speaker honoraria/travel fees Eastern Europe (65.3%) and Northern Europe (46.2%) from LEO. JCS is an investigator for AbbVie, Amgen, Janssen, reported costs below 100€. Across Europe, only a small Menlo Therapeutics, Merck, Novartis, Regeneron, Trevi, UCB, minority of patients mentioned spending over 500€ in Galapagos, Pfizer, Helm, InflaRX, Incyte; advisor for AbbVie, Leo Pharma, Novartis, Pierre-Fabre, Menlo Therapeutics, Trevi the previous 6 months. However, these results should and speaker for AbbVie, Novartis, Sanofi-Genzyme, Janssen, Leo be interpreted with caution, since the current study did Pharma, Novartis, SunFarm, Eli Lilly. AR is a consultant or spea- not control for disease severity, general cost of living, ker for AbbVie, Bioderma, Celgene, Chema Elektromet, Eli Lilly, discrepancies in health insurance systems or other costs Galderma, Janssen, Leo Pharma, Medac, Menlo Therapeutics, (e.g. absenteeism), socioeconomic status and divergent Novartis, Pierre-Fabre, Sandoz and Trevi; Principal Investigator currencies across European countries. or Subinvestigator in clinical trials sponsored by AbbVie, Drug Delivery Solutions Ltd, Galderma, Genentech, Janssen, Kymab Limited, Leo Pharma, Menlo Therapeutics, MetrioPharm, MSD, Study limitations Novartis, Pfizer and Trevi. FJL is an investigator for DS Biop- harma, Eli Lilly, Galderma, Pfizer, Menlo Therapeutics, Trevi One limitation of this study is that patients with CNPG Therapeutics. He is a member of the advisory boards and/or has were recruited at specialized tertiary units, such as received speaker honoraria/travel fees from AbbVie, Almirall, university hospitals or large community hospitals. This Celgene, Eli Lilly, Janssen, Leo Pharma, Menlo Therapeutics, www.medicaljournals.se/acta Chronic nodular prurigo: patient perspectives on therapy 7/7 Novartis, Pfizer, Trevi Therapeutics. MM has received honoraria 11. Almustafa ZZ, Weller K, Autenrieth J, Maurer M, Metz M. as a speaker and/or consultant for Amgen, Aralez, argenx, Bayer, Dupilumab in treatment of chronic prurigo: a case series and ActaDV Beiersdorf, Celgene, Galderma, Menlo, Moxie, Novartis, Roche, literature review. Acta Derm Venereol 2019; 99: 905–906. 12. Pereira MP, Basta S, Moore J, Ständer S. Prurigo nodularis: a Sanofi, Shire, Uriach. MS is a consultant and member of advisory physician survey to evaluate current perceptions of its clas­ boards of AbbVie, Almirall, Celgene, Eli Lilly, Janssen-Cilag, sification, clinical experience and unmet need. J Eur Acad Menlo, Novartis and Pfizer. He has received speaker honoraria/ Dermatol Venereol 2018; 32: 2224–2229. travel fees from AbbVie and Novartis. ES-B is an investigator, a 13. Pereira MP, Hoffmann V, Weisshaar E, Wallengren J, Halvor­ consultant or gave presentations for Regeneron, Sanofi, Stiefel/ sen JA, Garcovich S, et al. Chronic nodular prurigo: clinical GSK, Pierre Fabre, La Roche Posay, Leo Pharma, Novartis, Al- profile and burden. A European cross-sectional study. J Eur mirall, Pfizer, Galderma, Lilly, Abbvie. MG has been a consultant Acad Dermatol Venereol 2020; 34: 2373–2383. and received speaker honoraria for Novartis and Sanofi. MA re- 14. Storck M, Zeidler C, Rehr M, Riepe C, Dugas M, Ständer S, et al. Validation of pruritus measures gathered with the ports receiving speakers honoraria or grants from, or participated electronic patient-reported outcome system MoPat. Acta Acta Dermato-Venereologica in clinical trials or health services research projects for Abbott/ Derm Venereol 2018; 98: 38–43. AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, 15. Blome C, Augustin M, Siepmann D, Phan NQ, Rustenbach SJ, Celgene, Centocor, Eli Lilly, Forward Pharma, Galderma, GSK, Ständer S. Measuring patient-relevant benefits in pruritus Hexal, Janssen, LEO Pharma, Medac, MSD, Novartis, Pfizer, treatment: development and validation of a specific outcomes Sandoz, Teva, TK, Trevi, and Xenoport. MD is co-founder of tool. Br J Dermatol 2009; 161: 1143–1148. Hippokrates IT. SS is an investigator for Dermasence, Galderma, 16. Brenaut E, Halvorsen JA, Dalgard FJ, Lien L, Balieva F, Sam­ Kiniksa Pharmaceuticals, Menlo Therapeutics, Trevi Therapeu- pogna F, et al. The self-assessed psychological comorbidities tics, Novartis, Sanofi, and Vanda Pharmaceuticals Inc.; and is a of prurigo in European patients: a multicentre study in 13 countries. J Eur Acad Dermatol Venereol 2019; 33: 157–162. consultant and/or member of the advisory board for Almirall, 17. Jorgensen KM, Egeberg A, Gislason GH, Skov L, Thyssen JP. Bayer, Beiersdorf, Bellus Health, Bionorica, Cara Therapeutics, Anxiety, depression and suicide in patients with prurigo no­ Celgene, Clexio Biosciences, DS Biopharma, Galderma, Menlo dularis. J Eur Acad Dermatol Venereol 2017; 31: e106–e107. Therapeutics, Novartis, Perrigo, and Trevi Therapeutics. TAL has 18. Ständer S, Weisshaar E, Mettang T, Szepietowski JC, Carstens been a consultant for Menlo and Novartis. HFS is an advisor and/ E, Ikoma A, et al. Clinical classification of itch: a position or investigator for Menlo Therapeutics, Abbvie and Novartis. JW, paper of the International Forum for the Study of Itch. 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