Abstract
Background: Prurigo nodularis (PN) is a chronic pruritic skin disease which is difficult to treat. Current treatment options often lead to limited clinical benefit or severe side effects. Objective: The objective of this study was to evaluate the efficacy and safety of dupilumab in the treatment of PN in adults. Method: This study is a retrospective cohort study. Twenty-four adult patients with PN were included and treated with dupilumab. The primary outcomes were the mean reduction in the Investigator’s Global Assessment (IGA) score and pruritus numeric rating scale (p-NRS) score. Outcomes were assessed at baseline, week 4, week 16, and week 36. Results: The study included 24 patients, of whom 9 (37.5%) were male, and the mean (SD) age of the enrolled patients was 49.88 ± 16.71 years. At the end of the 16-week treatment, the mean p-NRS score decreased from 7.50 ± 2.21 to 1.41 ± 0.91 (p < 0.001), sleeplessness numeric rating scale (s-NRS) score declined from 5.33 ± 3.29 to 0.18 ± 0.59 (p < 0.001), and Dermatology Life Quality Index (DLQI) score decreased from 13.32 ± 4.88 to 0.91 ± 0.81 (p < 0.001). Fourteen (63.6%) of 22 patients achieved IGA 0/1 and 21 (95.5%) patients achieved IGA activity 0/1. Among 14 patients who achieved IGA 0/1, 10 had an elevated serum IgE level, and patients with a high serum IgE level showed a more remarkable reduction in IGA (r = 0.52, p = 0.03). Patients with AD responded faster than those without AD (3.76 ± 1.71 weeks vs. 6.40 ± 1.67 weeks, p = 0.01). Adverse events were recorded in 4/24 (16.6%) patients, with conjunctivitis being the most frequent. Conclusion: This study demonstrated that dupilumab is effective and safe for PN and could be a potential therapeutic option.
Introduction
Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by isolated, hard papules, nodules, and even plaques with severe itching [1]. The lesions often involve the extensor of extremities and trunk, causing sleep disorders and even psychiatric disturbance [1, 2]. All age groups are affected by PN, although it occurs in adults more frequently [3]. The mechanism of PN is linked to T-helper (Th)2 inflammation and increasing sensitization of neurons and the development of the itch-scratch cycle also plays an important role [4]. Current treatments for PN have limited response or severe side effects [2], which highlights the need for novel therapy.
Dupilumab is a human monoclonal antibody that inhibits the signaling of both interleukin 4 (IL-4) and interleukin 13 (IL-13). Dupilumab has been successfully used in the treatment of moderate to severe atopic dermatitis (AD) [5, 6] and even found to lead to a significant improvement of AD in the elderly [6] and neglected body sites such as genitals [7]. It has been reported that dupilumab was also effective for Caucasian patients with PN [6, 8, 9, 10]. However, data about Asian subjects and response details were limited. This study aimed to assess the efficacy and safety of dupilumab in adult patients.
Materials and Methods
Twenty-four adult patients with PN were treated with dupilumab from February 1, 2021, to January 1, 2022, at Peking University People’s Hospital. Inclusion criteria: patients with PN aged >18 years; agreed to use dupilumab; and gave their informed consensus. Exclusion criteria: patients with severe comorbidities or who have a recent plan for pregnancy were excluded.
Before the treatment, demographic and clinical characteristics of all patients were collected and atopic diathesis was recorded to assess if they were consistent with the diagnosis of AD (with Williams’ criteria [11] and Chinese criteria [12]). All patients were treated with subcutaneous injections of dupilumab in the standard dosing regimen (600 mg as the loading dose, followed by 300 mg every 2 weeks). The pruritus numeric rating scale (p-NRS) score, sleeplessness NRS score (s-NRS), Investigator’s Global Assessment (IGA) [13], and Dermatology Life Quality Index (DLQI) were assessed at baseline, week 4, week 16, and week 36. Adverse events were monitored during the treatment.
Paired t-test was used to analyze the statistical significance of the scores before and after treatment. The Mann-Whitney U test was applied in continuous variables and Fisher’s exact test was used in categorical variables. Spearman rank-order correlation was used to evaluate the monotonic relationship between continuous or ordinal variables. p < 0.05 was considered to be significant. All statistical procedures were performed using SPSS statistics version 20.0 (IBM, Armonk, NY, USA).
Results
Baseline Demographic and Clinical Characteristics
Twenty-four patients who were diagnosed with PN were included, with the mean age of 49.88 ± 16.71 years (range 25–79 years), and 9 (37.5%) were male. The baseline demographic and clinical characteristics of 24 patients are summarized (shown in Table 1). The mean age of PN onset was 44.73 ± 16.16 years, and the average disease duration was 5.15 ± 4.38 years. Nine (37.5%) of them met Williams’ criteria for AD and 18 (75.0%) patients met Chinese criteria for AD. Seventeen (70.83%) of 24 patients have a history of other atopic diseases, and the most frequent atopic comorbidity was allergic rhinitis (8/24; 33.3%), followed by urticarial (5/24; 20.8%), asthma (3/24; 12.5%), and allergic conjunctivitis (1/24; 4.2%). Other comorbidities are reported in Table 1. Fourteen (58.3%) patients have been found with a family history of atopic diseases. Sixteen (66.7%) were found an elevated IgE level, and all patients showed normal blood eosinophils count. All patients have accepted systemic treatment before dupilumab treatment. Systemic corticosteroids and immunosuppressants were the most commonly used therapies. All patients claimed that they had not used any biologics before. Of 24 patients, 20 (83.3%) showed diffused lesions (>2 areas involved) and 3 patients had localized distribution (1–2 areas involved). Baseline disease severity was assessed by IGA score and classified as IGA score 3 (12/24; 50.0%) and IGA score 4 (12/24; 50.0%). Baseline disease activity was assessed by IGA activity score, classified as IGA activity 1 (3/24; 12.5%), IGA activity 2 (3/24; 12.5%), IGA activity 3 (17/24; 70.8%), and IGA activity 4 (1/24; 4.2%).
Characteristic . | . |
---|---|
Age, mean±SD, years | 49.88±16.71 |
Sex, n (%) | |
Male | 9 (37.5) |
Female | 15 (62.5) |
BMI, mean±SD | 23.52±3.61 |
Onset age of PN, mean±SD, years | 44.73±16.16 |
Duration of PN, mean±SD, years | 5.15±4.38 |
Distribution | |
Diffuse (more than 2 areas affected), n (%) | 21 (87.5) |
Localized (only 1 or 2 areas affected), n (%) | 3 (12.5) |
p-NRSa, mean±SD | 7.50±2.21 |
s-NRSb, mean±SD | 5.33±3.29 |
DLQIc, mean±SD | 13.32±4.88 |
Baseline IGAd, n (%) | |
IGA 3 | 12 (50.0) |
IGA 4 | 12 (50.0) |
Baseline IGA activitye, n (%) | |
IGA activity 1 | 3 (12.5) |
IGA activity 2 | 3 (12.5) |
IGA activity 3 | 17 (70.8) |
IGA activity 4 | 1 (4.2) |
Increase of total serum IgE, n (%) | 16 (66.7) |
Increase of peripheral blood eosinophils, n (%) | 0 (0) |
History of other atopic diseases, n (%) | 17 (70.8) |
Over-reaction of insect bite response, n (%) | 15 (62.5) |
Allergic rhinitis, n (%) | 8 (33.3) |
Urticaria, n(%) | 5 (20.8) |
Asthma, n (%) | 3 (12.5) |
Allergic conjunctivitis, n (%) | 1 (4.2) |
Other comorbidities, n (%) | |
Hypertension and cardiovascular disorders | 8 (33.3) |
Diabetes | 2 (8.3) |
Chronic viral hepatitis | 1 (4.2) |
Pulmonary fibrosis | 1 (4.2) |
IgA nephropathy | 1 (4.2) |
Family history of atopic diseases, n (%) | 14 (58.3) |
Systemic treatment received before dupilumab, n (%) | |
Corticosteroids | 6 (25.0) |
Immunosuppressant | 6 (25.0) |
Total | 9 (37.5) |
Characteristic . | . |
---|---|
Age, mean±SD, years | 49.88±16.71 |
Sex, n (%) | |
Male | 9 (37.5) |
Female | 15 (62.5) |
BMI, mean±SD | 23.52±3.61 |
Onset age of PN, mean±SD, years | 44.73±16.16 |
Duration of PN, mean±SD, years | 5.15±4.38 |
Distribution | |
Diffuse (more than 2 areas affected), n (%) | 21 (87.5) |
Localized (only 1 or 2 areas affected), n (%) | 3 (12.5) |
p-NRSa, mean±SD | 7.50±2.21 |
s-NRSb, mean±SD | 5.33±3.29 |
DLQIc, mean±SD | 13.32±4.88 |
Baseline IGAd, n (%) | |
IGA 3 | 12 (50.0) |
IGA 4 | 12 (50.0) |
Baseline IGA activitye, n (%) | |
IGA activity 1 | 3 (12.5) |
IGA activity 2 | 3 (12.5) |
IGA activity 3 | 17 (70.8) |
IGA activity 4 | 1 (4.2) |
Increase of total serum IgE, n (%) | 16 (66.7) |
Increase of peripheral blood eosinophils, n (%) | 0 (0) |
History of other atopic diseases, n (%) | 17 (70.8) |
Over-reaction of insect bite response, n (%) | 15 (62.5) |
Allergic rhinitis, n (%) | 8 (33.3) |
Urticaria, n(%) | 5 (20.8) |
Asthma, n (%) | 3 (12.5) |
Allergic conjunctivitis, n (%) | 1 (4.2) |
Other comorbidities, n (%) | |
Hypertension and cardiovascular disorders | 8 (33.3) |
Diabetes | 2 (8.3) |
Chronic viral hepatitis | 1 (4.2) |
Pulmonary fibrosis | 1 (4.2) |
IgA nephropathy | 1 (4.2) |
Family history of atopic diseases, n (%) | 14 (58.3) |
Systemic treatment received before dupilumab, n (%) | |
Corticosteroids | 6 (25.0) |
Immunosuppressant | 6 (25.0) |
Total | 9 (37.5) |
BMI, body mass index; PN, Prurigo nodularis; p-NRS, pruritus numeric rating scale; s-NRS, sleeplessness numeric rating scale; IGA, Investigator’s Global Assessment; DLQI, Dermatology Life Quality Index; Ig, immunoglobulin.
aNumeric rating scale scores ranged from 0 to 10, with higher scores reflecting worse itch.
bNumeric rating scale scores ranged from 0 to 10, with higher scores reflecting worse sleeplessness.
cDLQI scores ranged from 0 to 30, with higher scores reflecting worse influence on the quality of life.
dIGA scores classified the stage as clear (0), almost clear (1), mild (2), moderate (3), severe (4) according to the numbers of lesions.
eIGA activity scores classified the activity as clear (0), almost clear (1), mild (2), moderate (3), severe (4) according to the rate of lesions with excoriations or crusts.
Improvement of NRS, DLQI, and IGA after the Therapy of Dupilumab
All 24 patients completed 4 weeks of treatment. The mean p-NRS score decreased from 7.50 ± 2.21 to 4.67 ± 1.79 (p < 0.001), and the s-NRS score dropped from 5.33 ± 3.29 to 2.13 ± 1.99 (p < 0.001). Two patients discontinued treatment after 4 weeks and the remaining 22 patients continued the treatment for 16 weeks. At the end of the 16-week treatment, the p-NRS score continued to decline to 1.41 ± 0.91 and the s-NRS score decreased to 0.18 ± 0.59. The DLQI score decreased from 13.32 ± 4.88 to 0.91 ± 0.81 (p < 0.001) (shown in Fig. 1). IGA score dropped from 3.50 ± 0.51 to 1.09 ± 0.81 (p < 0.001). IGA 0–2 was attained by all patients and 14 (63.6%) patients achieved IGA 0/1. IGA 0 was achieved in 6 (27.3%) patients and they all met the Chinese criteria for AD. In addition, for the activity of PN, all 22 patients achieved IGA activity 0–2 and 16 (72.7%) achieved IGA activity 0 (no lesions have excoriations or crusts) (shown in Fig. 2). Eight patients were followed up at week 36 and most of them reported maintaining the efficacy. Of 8 patients, 3 patients who tried to discontinue the injection at week 20 still held their pruritus score and IGA reduction, but 2 patients experienced a recurrence and similar remission was reached again after they restarted the injection. One patient who sustained standard injection complained of a moderate relapse of lesions and itchy symptoms at week 30.
Differences in Response between Patients with AD and without AD
To investigate the differences in response between patients with AD and patients without AD, we divided the patients into 2 groups according to the Chinese criteria for AD. Between the 2 groups, no significant difference in the scores was observed at baseline, week 4, and week 16. However, patients with AD showed earlier responses than those without AD (3.76 ± 1.71 weeks vs. 6.40 ± 1.67 weeks, p = 0.01). Patients with higher serum IgE levels showed a greater IGA reduction (r = 0.52, p = 0.03).
Safety and Adverse Events
Three patients developed mild conjunctivitis in the first 2–4 weeks and none of them had a history of conjunctivitis but all had a history of AD. One patient reported a local injection reaction. None of them led to the discontinuation of the treatment.
Discussion
It has been described that PN often overlaps with AD. In our series, 18 (75.0%) patients met the Chinese AD criteria, and according to Williams’ criteria, 9 (37.5%) were diagnosed with AD, which supports the view that chronic PN could be regarded as a clinical subtype of adult AD [14]. However, several differences need to be pointed out. Compared with the normal clinical phenotype of AD, PN often involves the extensor of extremities and trunk [1, 2], while flexural dermatitis is more common among adult AD. Considering that Williams’ criteria place more emphasis on flexural dermatitis, we tend to use Chinese criteria to assess atopic diathesis of PN patients for better sensitivity. Besides, in our study, most patients (16/24, 66.6%) are found with an elevated level of serum IgE but a normal level of the total number of blood eosinophils, and this result is similar to another research [15]. Pathological mechanisms of AD still remain unclear, but immune dysregulation, barrier defects, and cutaneous dysbiosis are demonstrated to be involved and the importance of Th2 cells has been focused [16‒18]. Several studies have proved the overexpression of some Th2 cytokines (such as IL-4, IL-31) [19, 20] in prurigo, suggesting that dupilumab may benefit patients with PN by blocking type 2 inflammation.
A significant improvement of p-NRS and s-NRS was observed at week 4, which is similar to the results in an Italian study [9]. All patients achieved complete response or partial response after 16 weeks, whether overlapping with AD or not. Given that dupilumab was usually used in generalized PN, 3(12.5%) patients who presented with a local prurigo also proved to respond well in our study. Two patients discontinued the treatment at week 4. Both of them had lower baseline p-NRS (2.3, respectively) and s-NRS (2.0, respectively), indicating that there may be a correlation between severe pruritus and treatment compliance.
We found that dupilumab actually functioned much faster (4.32 ± 2.01 weeks) than the previous report (10.15 ± 10.56 weeks) [21]. The delayed response was uncommon [10, 21]; thus, if the early response is not attained, additional therapy should be considered. Long-term data are limited, a few cases demonstrated the efficacy of dupilumab in the long-term observation [9, 10], and the recurrence of 2 cases (2/5; 40.0%) in our study showed that the withdrawal of the treatment needs to be deliberated by lengthening the interval of dosage regimen gradually. Besides, patients with a higher serum IgE level showed a greater reduction in the number of lesions. A faster response was found in patients with atopic diathesis which means patients with AD could benefit more from dupilumab.
In accordance with our study, mild conjunctivitis is the most common side effect of dupilumab therapy [9, 21]. Occasional psoriatic dermatitis has been reported in a few cases [22] and this may be associated with the fact that IL-4/IL-13 blockers are dynamically skewing immune responses toward some IL-23/IL-17 cytokine pathway-related diseases [23]. In our series, patients with a history of chronic viral hepatitis, pulmonary interstitial fibrosis, and IgA nephropathy were also included, suggesting that dupilumab is safe in patients with these diseases.
Conclusion
PN is a chronic and refractory disease that affects all age groups. Severe itching could impair the quality of life and even contribute to psychic disturbance. Although patients with AD and higher serum IgE level showed better responses, this study demonstrated that dupilumab is effective and safe in adult patients with PN whether it overlaps with AD or not. Other perspectives and postulates being studied for the treatment of AD such as JAK inhibitors, anti-IL-31R antibody, neurokinin 1 receptor (NK1R) antagonist, skin microbiome modulator, and nanoparticles [24‒28] may also benefit patients with PN potentially.
Limitations
We have to point out that our patients’ number was limited and bias may exist. Further larger scale study is needed to provide stronger evidence, and there is a need for a widely used tool to evaluate the severity of PN in order to assess the efficacy among different studies.
Key Message
Dupilumab is effective and safe for PN.
Statement of Ethics
The study protocol was reviewed and approved by the Institutional Ethics Committee (Ethics Committee of Peking University People’s Hospital, approved number 2021PHB072-01), and the written informed consent was obtained from each patient. During their individual treatment, all patients provided their approval for using their anonymized data for research purposes. None of the patients had been treated with an intensified dupilumab dose in order to be included in the present work. The collection of anonymized data was performed retrospectively from the patients’ records.
Conflict of Interest Statement
No conflict of interest relevant to this article could be reported.
Funding Sources
No funding or sponsorship was received for the conduct of this study or the preparation of this article.
Author Contributions
Zhang and Gao designed the study; all authors contributed to implementation of the research; Gao and Dou contributed to the analysis of the results; and Zirui Gao and Jianzhong Zhang wrote the manuscript in consultation with Yuanqing Dou, Pei Zhao, and Caroline J. Wang.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.