Dupilumab for Chronic Prurigo: Case Series on Effectiveness, Safety, and Quality of Life Open Access

Chronic prurigo (CPG) is defined by presence of chronic pruritus for at least 6 weeks and pruritic, scratched, and encrusted papules, nodules, and plaques, usually in a symmetrical distribution. Persistent scratching maintains the pruritus and the formation of nodules, papules or plaques, resulting in an itch-scratch cycle with subsequent scarring [1]. CPG encompasses all subtypes: nodular, papular, plaque, and ulcerated. Potential triggers include other dermatoses, systemic diseases, neurologic, and mental illnesses. Estimates show that approximately half of all patients with prurigo have an atopic disposition [2]. The association of CPG and atopic dermatitis (AD) is termed pruriginous atopic eczema [3]. Chronic itch results in reduced quality of life (QoL) [4]. Treatment for CPG consists of topical agents, UV therapy and systemic medication [5]. New systemic therapies, such as dupilumab, nemolizumab or opioid receptor modulation, are currently being investigated [6, 7]. Treatment of CPG is challenging and patients report low levels of satisfaction with therapy [8].

Dupilumab is a monoclonal human IgG antibody that inhibits signaling of the interleukin 4 (IL-4) and IL-13 pathways. It occupies the shared alpha subunit of the IL-4 receptor (IL-4R), which occurs in IL-4R complex type 1 and 2 [9]. Neuronal signaling in chronic itch involves the IL-4R on sensory neurons in the dorsal root ganglia [10, 11]. Side effects are generally mild and include local reaction at the injection site, conjunctivitis, upper respiratory tract infection, headache, and oral herpes [12]. The effectiveness of dupilumab in patients with CPG has previously been reported showing beneficial effects on both skin manifestations and QoL [13‒23].

Patients with CPG receiving dupilumab often report great improvement in itch and overall QoL. The aim was to assess QoL, safety, and treatment response in patients with CPG who received dupilumab.

Patients with CPG at the Department of Dermatology at the University Hospital Zurich, Switzerland, were studied. Subjects with concomitant diseases that are potential triggers of CPG were excluded. Exclusion criteria were dermatoses such as pemphigoid, systemic diseases such as poorly controlled diabetes mellitus (HbA1c > 7.2%), advanced-stage kidney disease (GFR <30 mL/min), liver cirrhosis (CHILD A–C), lymphomas, and other hemato-proliferative diseases. Demographic data were taken from the hospital information system. Data on disease activity, QoL and itch at specific, predefined points in time were retrieved from the patient files (photographs) and by interview, either by phone or in person, using validated questionnaires. These assessments were routinely made at approximately 2 weeks prior to treatment as well as up to 2 years after starting treatment with dupilumab (−2 weeks, +2, +4, +8, +12, +24 weeks and +1, +1.5 and +2 years). All patients had at least two measurements for each response variable. The Prurigo activity and severity score (PAS) and concomitant treatments were collected prospectively; the patient reported outcomes (DLQI, ItchyQoL, and NRS) were collected a-posteriori. PAS is used to objectively establish the type, number, distribution, size, represented body area, and activity in terms of percentage of lesions with excoriations/crusts in patients with CPG. It can be filled out by experienced clinicians [24]. Patient reported outcomes used.

The Dermatology Life Quality Index (DLQI) is a self-administered questionnaire, which assesses QoL over the last 7 days for patients with skin disease. The higher the score, the greater the impairment of QoL. It has good reliability [25].

The Itchy Quality of Life Questionnaire (ItchyQoL) tests QoL in patients with chronic pruritus. It assesses symptoms, ability to work, and emotional lability. The maximum score is 110 [26].

The Numerical Rating Scale (NRS) is easy to use, reliable, and capable of detecting change in symptoms. A 3.8-point (or 40%) improvement on the 0–10 scale was used as a responder threshold for meaningful improvement [27].

All analyses were run with R version 4.2.2 [28]. All response variables were analyzed with a robust mixed-effects model where the robustlmm add-on package was used [29]. Patients were taken as random effect. Time was taken as fixed effect. The effect of time was assumed to be linear and all time points were assumed to be equidistant regardless of the actual time elapsed between them. The assumption of linearity and the model assumptions were formally proofed. Formal inference on the effect of time was carried out by estimating 95% confidence intervals of the slope and by computing p values. Confidence intervals were estimated based on the asymptotic normality assumption as well as via bootstrap. p values were computed based on t values.

The study was conducted in accordance with the WMA Declaration of Helsinki (2013). It was reviewed and approved by the Local Ethics Committee (BASEC ID: 2022-00928).

Among the 15 eligible participants, 4 patients refused to participate because they did not wish to recall the course of their CPG. One eligible participant could not be reached. Ten patients were included in this study. The median age was 71 years (range 45–83), 6 patients were female (60%). Six (60%) had pruriginous atopic eczema (defined as coexistence of CPG and AD), 2 (20%) were active smokers, and 3 (30%) were former smokers. Comorbidities are shown in Table 1. All of the patients received dupilumab injections every 2–5 weeks. The median dosage was 300 mg (200–300), with a starting dose of 600 mg. At the time of the interviews, the mean duration of treatment was 59.9 weeks (21.9–116.7). The mean time from first diagnosis of CPG to beginning of treatment with dupilumab was 2.5 years, shown in Table 1. Before treatment with dupilumab, all patients had used emollients, topical corticosteroids, and UV therapy. The use of concomitant treatments decreased during treatment with dupilumab (shown in Table 2). Side effects, namely headache and vertigo, were reported by 4 patients (40%). Transient eosinophilia was observed in 1 patient (shown in Table 2). Vertigo was self-limited. No serious side effects were reported.

Missing data were removed in order to include the fitted values in the same data frame as the original observations. The response variables for DLQI, ItchyQoL, NRS, and PAS analyses showed a statistically significant decrease over time. The percent decrease after 1 year of treatment (this estimate is based on model estimates) ranges from −42% to −82%. DLQI score after long-term treatment with dupilumab showed significant reduction (p ≤ 0.0001; slope −1.06 [−0.84; −1.27]). The model-based percent decrease after 1 year is −42% (shown in Table 3; Fig. 1). ItchyQoL score after long-term treatment with dupilumab showed significant reduction as well (p ≤ 0.0001; slope −14.29 [−9.89; −18.69]). The model-based percent decrease after 1 year is −45%. Likewise, the NRS score for average and maximum pruritus showed significant reduction after long-term treatment with dupilumab (p ≤ 0.0001; slope −0.69 [−0.52; −0.86] and resp. ≤ 0.0001; slope −0.75 [−0.55; −0.94]). Both NRS scores showed a −54% decrease after 1 year of treatment (shown in Table 3; Fig. 1). The number of lesions assessed with the PAS showed a significant improvement over time (p = 0.0005; slope −3.49 [−1.70; −5.28]). The model-based percent reduction after 1 year of treatment is −82%. A clinical example of long-term treatment with dupilumab is shown in Figure 2.

CPG can be challenging to treat and the impact on QoL of those affected is substantial [4], as reflected in a mean DLQI score of 15.8 points prior to treatment with dupilumab. Patients treated with dupilumab for up to 2 years had a significant improvement in QoL and itch. Table 3 shows that the decreasing trend is statistically highly significant for the response variables PAS, ItchyQoL, DLQI, and NRS implying a decreasing trend. This trend is consistent with other studies, which have reported a treatment response after 20 weeks [30]. As the range of the response variable can vary, the decrease was expressed in percent decrease after 1 year of treatment (this estimate is based on model estimates). The decreases range from −42% to −82%. This implies that these results are also practically relevant. Side effects were reported by 40% but were mild. This favorable safety profile is also reported in current literature, with conjunctivitis and keratitis being common side effects [23]. Those side effects were not reported in this study, possibly due to small sample size. Concomitant treatment in patients with CPG receiving dupilumab is frequent [21]. Concomitant treatments decreased over time reflecting the significant improvement in prurigo lesions. The improvement in NRS was more than 50%, which can be considered meaningful [27]. Current literature shows similar rates of improvement in NRS score with dupilumab [31]. Pölking et al. [24] showed that the PAS correlates to the DLQI further supporting an improvement in QoL in the studied cohort. Due to comorbidities like CKD or diabetes, systemic medication can be contraindicated in patients with CPG. Dupilumab, among other novel substances [7], can be a safe and effective treatment option in these patients.

CPG can be associated with inflammatory dermatoses, most frequently with AD [2]. AD is highly pruritic and the itch-scratch cycle might promote CPG [32]. CPG may continue after cessation of AD. The coexistence of CPG and AD is termed pruriginous atopic eczema. In this study, 60% had pruriginous atopic eczema, a similar prevalence is described in a review by Zeidler et al. [3]. Patients with CPG frequently are atopic without any history of active dermatosis [30]. It is estimated that approximately half of all patients with prurigo have an atopic disposition [2]. The prevalence was slightly higher in this study (60%), possibly due to less stringent definition of atopy. However, dupilumab was effective in all patients, suggesting efficacy partly independent of atopic disposition.

Since this study is a retrospective trial, recall bias can occur. However, some variables (PAS number of lesions and concomitant medication) were truly recorded over time and thus do not suffer from recall bias. There were no nonresponders in the small sample. This may be explained by a possible sampling bias in the recruitment of patients. To minimize bias, QoL, itch, and effectiveness of dupilumab were analyzed using standardized questionnaires and scores recommended for CPG [5]. In these analyses, all consecutive time points are assumed to be equidistant regardless of the actual time elapsed between them. This reflects clinical practice. In addition, considering the actual time lag elapsed between time points is not advisable as this would imply that the latest time points (e.g., “+2 years”) have a disproportionate importance when estimating the regression lines (i.e., influential observations). The same methodology (i.e., a robust mixed-effects model) was used to model all response variables despite their different nature (e.g., some are counts other are scores). The rationale behind this choice is consistency and comparability across analyses. The robust methods used here do not rely on strong distributional assumptions (see also analyses of all variables in the online suppl. material; for all online suppl. material, see https://doi.org/10.1159/000531708). Additionally, the residuals were inspected, and no clear violations of the model were found. Due to the small sample size and being a single-center study, the results may not be generalizable.

QoL and number of lesions improve over time with dupilumab both in patients with pruriginous atopic eczema and in nonatopic patients. Dupilumab could be a promising treatment option for patients with CPG. However, this study is small and more extensive prospective studies are needed to investigate its efficacy and safety.

Dupilumab is effective and safe for treatment of chronic prurigo.

The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Oral consent was obtained from all participants. Written consent was not required. This study protocol was reviewed and approved by the Local Ethics Committee (Kantonale Ethikkommission Zurich), approval number 2022-00928.

The authors have no conflicts of interest to declare.

This study was funded by the JH Rahn Foundation, Zurich, which is dedicated to research and teaching in dermatology.

C.R., C.G., M.T., N.T., and J.H. contributed substantially to the conception, acquisition and interpretation of data for the work, drafting the work, to revising it critically for important intellectual content, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. M.S., P.S.-G., T.K., M.N., and M.-C.B. contributed substantially to conception and interpretation of data, revising it critically for important intellectual content, final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

All data generated or analyzed during this study are included in this article and its supplementary material files. Further inquiries can be directed to the corresponding authors (C.R. or J.H.).