# Introduction

Until recently, the concept of prurigo was rather vague and variable among different countries. As defined in 2018 in the consensus conference of the European Academy of Dermatology and Venereology (EADV) pruritus task force, chronic prurigo (CP) is a distinct skin condition characterised by the appearance of multiple localized to generalized papules, nodules and/or plaques due to chronic intense pruritus (≥ 6 weeks) [1,2]. In France, its estimated prevalence is in the range of 8.4–46.7 per 100,000 [3]. CP is often associated with an underlying dermatological, systemic, neurological, psychiatric, mixed or undetermined condition and is frequently multifactorial [4,5]. Nevertheless, there is no evidence that the initial underlying aetiology has an influence on the clinical symptoms, severity, or course of CP, supported by its autonomous persistence after treatment of the underlying cause [1].

The pathophysiological mechanisms involved are increasingly well understood and consist of peripheral and central sensitization to pruritus [6]. Indeed, itch perception and the appearance of prurigo lesions are related to specific interactions between keratinocytes, sensory nerve endings and pruriceptors via synaptic-like contacts [7]. As in atopic dermatitis (AD) and other itchy dermatoses, recent studies have characterized the implication of the T-helper (Th) 2 cytokine proinflammatory pathway [interleukin (IL) −4, IL-13, IL-31], which induces neuronal sensitization, leading to an itch-scratch cycle [8,9]. Cutaneous and systemic Th17 and Th22 polarization has also been identified [10,11]. The International Forum for the Study of Itch (IFSI) guidelines provided clear recommendations about the use of off-label multimodal treatments and proposed a treatment ladder including topical and intralesional corticosteroids, topical calcineurin inhibitors, capsaicin, phototherapy, and systemic agents (i.e., antihistamines, gabapentinoids, cyclosporine, methotrexate, thalidomide, antidepressants, µ opioid receptor antagonists, azathioprine, cyclophosphamide), notwithstanding inconsistent clinical benefits and some serious adverse effects [2,12,13]. This lack of effective therapy was associated with markedly impaired quality of life [14,15,16].

Dupilumab is a fully human monoclonal immunoglobulin (Ig) G antibody that occupies the shared alpha subunit receptor site for IL-4, which blocks the effects of the IL-4 and IL-13 signalling pathways. Until recently, the indications of this drug in dermatology were limited to moderate-to-severeatopic dermatitisinadequately controlled with topical prescription therapies in patients aged 6 months or older. Dupilumab demonstrated a marked reduction in chronic pruritus that is the hallmark of AD [17,18]. Underscoring relevant similarities in pathogenesis emerging from AD and CP, several authors have suggested a beneficial role of dupilumab in this condition [19,20]. Since 2019, multiple papers have reported successful treatment of patients with CP using dupilumab [21].

Thanks to two pivotal Phase 3 trials, dupilumab is now the first and only treatment with marketing authorization for the treatment of adults with moderate-to-severe prurigo nodularis requiring systemic therapy.

In the present study, we analysed a retrospective multicentre cohort of patients with CP to obtain real-life data on the efficacy and safety of dupilumab in this indication.

# Materials and methods

Patients were selected retrospectively via collection of data from the Nancy University Hospital and the Metz-Thionville Hospital Centre covering the period from November 2018 to May 2022. A keyword search was also performed on the hospital data management software but did not enable further inclusions. The inclusion criteria were a clinical diagnosis of CP (of duration ≥ 6 weeks) by the clinician, and off-label treatment with dupilumab for at least 2 months. Patients lost to follow-up and for whom final data were missing were excluded.

At each visit, each patient’s disease activity was routinely evaluated by means of the reported worst numerical rating scale of itch (NRSI) score (ranging from 0 to 10) over the previous 7 days, [22], the number of lesions using the investigator global assessment (IGA) score [2], the patient’s reported quality of life measured on the dermatology life quality index (DLQI), and their quality of sleep measured using the numerical rating scale of sleep (NRSS ranging from 0 to 10, where 10 indicates a perfect undisturbed night’s sleep). We collected data on NRSI before dupilumab therapy (NRSI baseline) and at the end of follow-up (NRSI final), and, where available, at 4, 8 and 16 weeks of treatment. Additionally, we designed categorical variables to assess efficacy: complete response with NRSI final = 0, partial response with improvement ≥ 4 but NRSI final > 0, and no response with improvement < 4 and NRSI final > 0. We defined our primary outcome as the proportion of patients with NRSI reduction ≥ 4 or NRSI final = 0 and final IGA = 0–1.

Other secondary outcomes included reduction in the number of lesions, and improvement in sleep and quality of life. Furthermore, we collected the following data: gender, age, medical history, disease duration, previous treatment, concomitant treatment while on dupilumab, personal history of atopy (i.e. AD, asthma, allergic conjunctivitis, allergic rhinitis), eosinophilia, high serum IgE (> 150 kU/l). Safety was evaluated in terms of treatment-emergent adverse events.

The demographic and clinical characteristics are presented as percentages for categorical variables and as mean standard deviation (SD) or median interquartile range (IQR) for continuous variables. Univariate logistic regression analyses were conducted to explore the association between response to dupilumab and the following potential predictive factors: gender, age, presence of atopy or AD, eosinophilia, high serum IgE, Time-First and previous systemic treatments. Fisher’s exact test was used as appropriate for categorical variables. A Mann-Whitney U test was used where appropriate for continuous variables. Spearman correlation-coefficient tests were used to explore the direction of associations. In all cases, p < 0.05 was considered statistically significant. To perform the analysis, we used Medistica., pvalue.io, a graphic user interface to the R statistical analysis software, 2021 version. The missing values of key variables were imputed using the Multiple Imputation by Chained Equation (MICE) where a parameter had more than 5% missing data, and medians or modes where a parameter had less than 5% missing data.

# Results

We identified 16 patients from our data collections. Two patients were excluded because of unavailable NRSI final results. Thus, 14 patients were included in the analysis.

Patient characteristics are summarized in Table 1
                     . Twelve patients had prurigo nodularis and 2 had excoriated plaque prurigo. We noted that 36% of patients (5/14) had a history of AD, whereas 64% (9/14) had a history of atopic manifestation, similar to the rate of high serum IgE patients (64%). CP had been present for an average of 3 years [IQR 2; 3]: all patients had failed on topical steroids, 50% (7/14) had already been treated with methotrexate and phototherapy, 79% (11/14) with antihistamines, 36% (5/14) with pregabalin, and 7% (1/14) with cyclosporine and thalidomide.

All patients were initially treated with subcutaneous injections of dupilumab at the approved dosage for AD, i.e. 600 mg at baseline followed by 300 mg every 2 weeks. The only systemic concomitant treatment was an antihistamine in one patient and 5 patients continued the use of topical steroids. The median duration of follow-up was 14.5 months; IQR [10; 26.8], min–max (2–37). No patients discontinued treatment at the end of follow-up. The mean NRSI baseline was 7.93 ± 2.02 and NRSI final was 0.64 ± 0.74, i.e. a mean reduction of 7.29 ± 2.27 (p < 0.01). Half of the patients had a partial response, and the other half had complete remission of their pruritus (i.e. 7 patients with complete response, 7 patients with partial response, and 0 patient swith no response) (Fig. 1
                     a,b). It should be noted that for one patient the NRSI baseline was 3 (beneficial effect of previous methotrexate treatment) and that this patient improved rapidly, with complete remission of pruritus in 4 weeks,and the patient was thus categorized as a complete responder. At the end of follow-up, 13 (93%) out of 14 patients reached the primary outcome, i.e. NRSI reduction ≥ 4 or NRSI final = 0 and IGA final = 0–1. The only patient who did not meet this outcome had a complete reduction in pruritus, but persistence of ≥ 5 for nodular lesions (IGA = 2).

After 16 weeks of treatment, 1 (13%) out of 8 patients with available data had complete remission of pruritus and 7 (87%) out of 8 patients had a partial response with a reduction in NRSI ≥ 4. An overall reduction in the number of lesions over baseline was seen in 13 of 14 patients who achieved an IGA score of 0–1, as well as a significant improvement in sleep and quality of life (Table 2
                     , Fig. 2
                     a,b).

Interestingly, the frequency of administration was spaced every 3 weeks for patients 7 and 9, and every 4 weeks for patient 5 (after 10, 14 and 22 months of treatment respectively). All 3 patients had completely responded to the treatment at the standard dosage, with maintenance of a complete response after spacing (at 31, 17 and 28 months of follow-up).

No difference in NRSI reduction was observed with respect to atopy history, existence of eosinophilia or high serum IgE, use of previous systemic treatments, or time to initial improvement. The results of the exploratory univariate analysis are presented in Tables S1-4, supplementary material available online.

Treatment-emergent adverse events included two cases of conjunctivitis, one case of xerophthalmia, and one case of face and neck eczema with cheilitis. None of these events resulted in treatment discontinuation. Patients who achieved a complete response following dupilumab treatment appeared to experience a higher incidence of adverse effects (p = 0.021). However, the limited sample size precludes any further statistical analysis.

# Discussion

The present study, conducted in a real-world clinical setting, demonstrates a statistically significant mean reduction in pruritus of 92%. Furthermore, 50% of patients achieved complete resolution of pruritus, while 100% exhibited marked improvement of this burdensome symptom. Furthermore, a 78% reduction in IGA scores was observed, with 93% of patients achieving a score of 0–1. The rate of improvement in pruritus observed in this study is greater than that reported in our recent systematic review (73.6% mean reduction in pruritus in a cohort of 132 patients) and in the PRIME phase 3 trial (60% of dupilumab patients experienced a reduction in itch ≥ 4; 48% achieved clear skin vs. 18% of placebo patients) [21,23]. Furthermore, dupilumab is rapidly effective in reducing pruritus in our cohort with a mean time to first improvement of around 4 weeks and a mean time to freedom from pruritus of 14 weeks, which is consistent with our systematic review [21]. In contrast with the findings of our review, no difference in final efficacy was observed depending on whether the time to initial improvement was ≤ 4 weeks or longer.

It is also worth noting that there may be a gain in efficacy when treatment is maintained for more than 4 months in patients who have already experienced an improvement in pruritus (here, 13% complete responders at 16 weeks vs. 50% at the end, with most of these gains being seen among those responding partially at 16 weeks).

These results collectively indicate the potential efficacy of targeting IL-4 and IL-13, central drivers of Th2 inflammation, in reducing itch and skin lesions in CP. In addition to dupilumab, the efficacy of nemolizumab, an anti-IL31 R α, in improving these symptoms lends further support to this potential benefit [24].

Associations between AD and CP have been suggested for more than twenty years, with CP being subcategorized into early-onset atopic and late-onset non-atopic forms [25]. Thus, cases of patients with AD can be considered of the prurigo-like AD phenotype [26]. The proportion of CP patients with a history of AD (36%) observed in our study is consistent with that reported in previous studies [5], but no correlation was identified between the efficacy of dupilumab and the presence of atopic diathesis, as evidenced by either clinical or laboratory findings. Based on previously published data, the reduction in pruritus seemed less marked in patients with a history of AD, although the proportion of patients having a partial response (NRSI reduction ≥ 4) was equivalent regardless of whether they had a history of AD [21].

To the best of our knowledge, this study is the first to describe in real clinical practice a spacing of dupilumab dosing of 300 mg every 3 or 4 weeks with maintained complete response after long follow-up periods in CP patients. These regimens were studied in AD patients and resulted in dose-dependent worsening of EASI with a similar rate of NRSI final [27]. Further randomized studies are necessary to determine the appropriate regimen for CP patients.

Our safety results were generally consistent with the known safety profile of dupilumab [18]. Indeed, 2 out of 13 patients (15%) with available data developed conjunctivitis of unspecified cause that resolved without interrupting dupilumab treatment. Both had an atopic diathesis: one with a history of rhinitis and conjunctivitis, the other with a history of asthma and atopic dermatitis. This rate is higher than that encountered in the phase 3 “LIBERTY-PN-PRIME” trial which detected conjunctivitis in up to 6.5% of dupilumab-treated patients [28]. It would be interesting to know the proportion of atopic patients in this trial, as we previously reported a significant association between the occurrence of conjunctivitis as an adverse event and the presence or history of atopic manifestations [21]. No such associations were found in our cohort. However, we observed a significant difference in the occurrence of adverse effects that appeared to be greater in the case of a complete response; these results were not consistent with our other findings and the limited sample size did not allow any further statistical analysis [21]. One patient with known eosinophilia but without a history of AD developed face and neck eczema. Topical steroid withdrawal may have played a role in the mechanisms of this adverse event [29].

While this study reports real-world data with, for the most part, long follow-up periods allowing for the necessary hindsight on the maintenance of efficacy and long-term safety, it has several limitations. Our findings are based on retrospective cases with heterogeneous follow-up periods, assessments of final efficacy made at different times, and the absence of a control group. The limited sample size precluded the possibility of undertaking a multivariate analysis or achieving statistically significant results.

# Conclusion

This study provides further data on the efficacy and safety profile of dupilumab in chronic prurigo, here mainly prurigo nodularis, with 50% of patients achieving complete resolution of pruritus, while all patients experienced marked improvement with a sustained response over time. There may be a gain in efficacy when dupilumab is maintained for more than 4 months in partial responders. In complete responders, spacing the injections may be possible without any loss of efficacy, but it must be determined on a case-by-case basis. Further real-world studies are required to refine these results.

# Funding sources

None.

# Ethical approval and informed consent

The study protocol was approved by the local ethics committee.