Introduction:
Prurigo nodularis (PN) is a chronic, intensely itchy skin condition linked to immune and nerve dysfunction, often affecting individuals with darker skin. It severely impacts quality of life. While traditional treatments are limited, nemolizumab shows promise. However, more diverse and long-term studies are needed to confirm its effectiveness.
Methods:
This systematic review followed PRISMA 2020 guidelines, analyzing studies on nemolizumab for PN. Data from multiple databases were assessed for efficacy, safety, and bias. Statistical analysis used Review Manager 5.4 with random-effects modeling and heterogeneity evaluation.
Results:
This meta-analysis included four randomized controlled trials (RCTs) involving 859 participants. Nemolizumab significantly improved Peak Pruritus Numerical Rating Scale (PP-NRS; ≥4 points) in weeks 4 and 16 [risk ratio (RR): 5.87 and 3.52], and PP-NRS <2 (RR: 11.87 and 5.63). It also improved the Sleep Disturbance and Numerical Rationg Scale (SD-NRS) and Investigator’s Global Assessment responses. Adverse events were slightly higher (RR: 1.13), though injection reactions, infections, headaches, and gastrointestinal events showed no significant differences. The risk of neurodermatitis was significantly lower with nemolizumab. Trial Sequential Analysis suggests that further large RCTs should be carried out to validate our results.
Conclusion:
This review confirms nemolizumab as an effective, well-tolerated treatment for PN, providing rapid relief from itching, skin lesions, and sleep issues. With a favorable safety profile, it marks a major advancement in managing this challenging, underserved condition.
Introduction
Prurigo nodularis (PN) is a chronic, intensely pruritic skin disorder marked by multiple firm, hyperkeratotic nodules predominantly on the extensor surfaces of the limbs and trunk. Its pathogenesis is driven by a self-perpetuating itch–scratch cycle in which continuous scratching promotes cutaneous inflammation, enhances peripheral nerve sensitivity, and ultimately leads to scarring, and post-inflammatory hyperpigmentation[1,2]. Beyond these physical manifestations, PN has a substantial psychosocial burden, impairing sleep, daily functioning, and overall quality of life, and is associated with higher rates of anxiety, depression, and suicidal ideation[1–3]. Epidemiologically, PN) primarily affects middle-aged to elderly adults, with higher prevalence in individuals of African descent and darker skin phototypes[1,3,4]. Global prevalence varies widely (8–200 cases per 100,000 population), influenced by case ascertainment, diagnostic criteria, and geographic factors[3,4]. Misdiagnosis and under recognition, often confusing PN with conditions like nodular scabies and chronic eczema, complicate accurate disease burden assessment.
HIGHLIGHTS
- Rapid and Sustained Itch Relief: Nemolizumab significantly reduced pruritus in patients with prurigo nodularis, with noticeable improvement by week 4 and sustained effects through week 16.
- Improved Skin Lesions and Quality of Life: The treatment led to marked improvement in skin lesion clearance and sleep quality, addressing both physical and psychosocial aspects of the disease.
- Safe and Well-Tolerated: Nemolizumab had a favorable safety profile, with mostly mild adverse events and no increase in serious complications, making it a promising option for long-term management.
The pathophysiology of PN involves complex neuroimmune interactions. Key risk factors include personal or family history of atopic diathesis (e.g., atopic dermatitis, asthma, allergic rhinitis) and comorbid systemic conditions such as diabetes mellitus, chronic kidney disease, and HIV infection[1,3,4]. Central to the itch signaling cascade is interleukin-31 (IL-31), a pruritogenic cytokine produced by activated T cells, which binds to the IL-31 receptor A (IL-31RA) on cutaneous nerves and keratinocytes to promote neural sensitization and inflammation[1,3,4]. Nonetheless, the precise molecular mechanisms driving nodular formation, epidermal hyperplasia, and aberrant nerve remodeling in PN remain incompletely elucidated.
Historically, treatment options such as high-potency topical corticosteroids, systemic immunosuppressants (e.g., methotrexate, cyclosporine), phototherapy, and various neuromodulatory or psychotropic agents have provided only partial relief and are often limited by adverse effects[3,4]. Advances in understanding PN’s molecular pathways have led to the development of targeted biologic therapies. Nemolizumab, a humanized monoclonal antibody targeting IL-31RA, has shown significant reductions in pruritus, improved lesion severity, better sleep, and enhanced quality of life in the OLYMPIA-1 and OLYMPIA-2 phase III trials, with a favorable safety profile[1–4].
Despite these promising findings, important gaps persist. Long-term efficacy and safety data for nemolizumab beyond 24 weeks are still emerging[4], and most trials have underrepresented patients with darker skin tones, who bear a disproportionate share of PN’s burden[1,3,4]. Moreover, further investigation is needed to unravel the downstream signaling pathways and cutaneous neuroimmune crosstalk that drive nodule development and chronicity. PN lacks effective treatments evidence on IL-31RA targeting with nemolizumab is limited, requiring further clinical investigation.
This article provides a comprehensive overview of PN, encompassing its epidemiology, clinical presentation, and pathophysiology, with a focus on IL-31–mediated mechanisms. We critically appraise existing and emerging therapies, highlight current limitations, and propose directions for future research aimed at improving outcomes for all patients affected by this debilitating condition.
Methods
This systematic review and meta-analysis were made and reported in line with the guidelines of Preferred Reporting Items for Systematic Review and Meta-Analysis Statement (PRISMA 2020).
Search strategy
A comprehensive search was performed in various databases, including Medline (via PubMed), Embase, the Cochrane Library, and Scopus, covering the period from their inception to March 2025. The search employed a combination of keywords related to nemolizumab and PN: (“Nemolizumab” OR “nemolizumab-ilto” OR “CIM331” OR “nemluvio”) AND (“Prurigo Nodularis” OR “Nodular prurigo” OR “Picker’s nodules” OR “Chronic prurigo” OR “Lichen simplex chronicus”). The search strategy was adapted according to the demands of specific databases.
Study selection and eligibility criteria
The selection of studies for this review was based on these inclusion criteria: (1) evaluation of the efficacy and safety of nemolizumab in PN, (2) randomized controlled trials, (3) patients (18 years or older) diagnosed with PN. Studies with inaccessible full texts, abstracts, reviews, letters to the editor, case reports, non-randomized studies, observational studies, and case reports, studies where nemolizumab is not the primary treatment, and case series were excluded. Two reviewers independently assessed the titles and abstracts of the initial studies, with a third reviewer involved in resolving any discrepancies.
Data extraction and quality assessment
Data from eligible studies, including the first author, publication year, country, number of patients in each group, mean age, for clinical outcomes PP-NRS improvement from baseline of ≥4 points, PP-NRS <2, the Sleep Disturbance and Numerical Rationg Scale (SD-NRS) improvement from baseline of ≥4 points, and for Adverse events: Injection-related reaction, neurodermatitis or atopic dermatitis, infection, headache, nasopharyngitis and gastrointestinal events were extracted into a validated Excel sheet by two independent inspectors. To eliminate mistakes and ensure accuracy, the extracted data was double-checked verified by both inspectors. The Risk of Bias 2 (ROB2) tool was used to assess bias in all randomized controlled trials (RCTs) based on various domains. Each study was rated as 1: high risk of bias, 2: some concerns of bias, or 3: low risk of bias. The quality assessment was performed by two reviewers, with a third inspector consulted in cases of disagreement.
The Grading of Recommendations Assessment, Development and Evaluation assessment
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was applied to determine the certainty and strength of evidence for all evaluated outcomes. GRADE classifies evidence into four levels: high quality, indicating that further research is unlikely to alter confidence in the estimated effects; moderate quality, where additional studies may influence confidence; low quality, meaning further research is likely to have an important impact on effect estimates; and very low quality, indicating substantial uncertainty and limited confidence in the available evidence.
Statistical analysis
Statistical analyses were conducted using Review Manager software 5.4 (Cochrane Collaboration, Denmark) and the DerSimonian–Laird random-effects model. For dichotomous outcomes, risk ratios (RRs) along with their 95% confidence intervals (CIs) were combined using the Mantel–Haenszel method and the random-effects model. A P-value of less than 0.05 was considered significant. Heterogeneity among the studies was assessed using the Higgins I2 statistic, with values exceeding 50% indicating considerable heterogeneity. An I2 value of 0% suggests no heterogeneity among studies, but this should be interpreted cautiously due to the small number of studies included. Limited statistical power may not detect heterogeneity, and further research with larger samples is needed. Due to the limited amount of data reported and the cumulative pooling of trials, there is an increased risk of type 1 and type 2 errors. To minimize this risk, we used Trial Sequential Analysis (TSA) to determine if the evidence from the pooled trials is conclusive and reliable. The intervention’s confidence level is considered conclusive and sufficient when the z-line on the curve crosses both the conventional boundary and the boundary of sequence monitoring, indicating that no further studies are necessary. Conversely, if the z-line on the curve does not cross any boundary, the evidence is insufficient, and further studies are necessary. In this meta-analysis, we used an alpha error of 0.05 and a beta error of 80% power.
Results
Search results
A comprehensive search across Medline (via PubMed), Web of Science, Scopus, Embase, and Cochrane databases identified 169 studies. After removing duplicates, 94 studies remained for title and abstract screening, leading to the exclusion of 90 studies. The remaining four full-text articles were independently assessed, all of which met the eligibility criteria for inclusion. The search and selection process is depicted in Figure 1.
Figure 1.
Flowchart of the selection process.
Characteristics of the included studies
This review included four RCTs, published from 2020 to 2025[1–4]. The RCTs reported data for 560 patients in the intervention group and 299 patients in the comparison group. One study was conducted in Switzerland, one in France, one in Japan, and one in a multicenter (nine countries). The mean age in the intervention group was 53–57 years, and the comparison group was 50–57 years. The number of males and females in the intervention group was 235 and 327, respectively, and the number of males and females in the comparison group was 127 and 172, respectively (Table 1).
Table 1
The baseline characteristics of the included studies.
Sample sizeMean ageMales and femalesStudyCountryStudy designDosesInterventionComparisonInterventionComparisonInterventionComparisonNCTAimConclusionStänder et al.,2025SwitzerlandRCTs0.5 mg per kilogram of body weightNemolizumab (n = 190)Placebo (n = 96)57.5 (12.8)57.6 (13.4)80, 11040, 56NCT03181503To assess the efficacy and occurrence of adverse events in adults with moderateto severe PN treated with nemolizumab vs those receiving placeboIn this randomized clinical trial, nemolizumab monotherapy led to clinically meaningful and statistically significant improvements in core signs andsymptoms of PN.Ständer et al.,2020FranceRCTs30 mg, 60 mgNemolizumab(N = 34)Placebo(N = 36)59.7 ± 13.252.4 ± 17.514, 2215,21NCT04501666To assess the efficacy and safety of nemolizumabas compared with placebo in the treatment ofPNNemolizumab resulted in a greater reduction in pruritus and severity of skin lesions than placebo in patients with PN but was associated withadverse events. Larger and longer trials are needed to determine the durability and safety of nemolizumab for the treatment of PN.Kwatra et al., 2023Multicenter (nine countries)RCTs30 mg, 60 mgNemolizumab (N = 183)Placebo (N = 91)53.7 ± 14.450.8 ± 15.070, 11336, 55NCT4501679To assess the efficacy and safety of nemolizumabas compared with placebo in the treatment ofPNNemolizumab monotherapy significantly reduced the signs and symptoms of PN.Yokozeki et al., 2024JapanRCTs30 mg, 60 mgNemolizumab (N = 153)7630 mg (50.0 [15–84]); 60 mg (61.7 [36.0–109.6])54.0 (15–78)30 mg (37, 40); 60 mg (34, 42)36, 40jRCT number 2011200017To evaluate the optimal dose, efficacy and safety of long-term treatment with nemolizumab in patients with PN in JapanImprovements in PN were greater following nemolizumab treatment, despite continuation of topical corticosteroids in both groups.
PN, prurigo nodularis; RCT, randomized controlled trial.
Quality assessment
ROB-2 tool was used to assess the quality of the included studies. All the included studies were considered to have a low risk of bias, indicating high quality. Full details are available on Supplemental Digital Content Figure S1, available at: http://links.lww.com/MS9/B121. The GRADE rating results are shown in Supplemental Digital Content Table S1, available at: http://links.lww.com/MS9/B122 According to the GRADE system, the strength of evidence was high for all reported outcomes including PP-NRS improvement from baseline by ≥ 4 points at week 16, PP-NRS < 2 at week 16, SD-NRS improvement from baseline by ≥ 4 points at week 16, Investigator’s Global Assessment (IGA) response at weeks 12–16, any adverse events and neurodermatitis or atopic dermatitis.
Meta-analysis
Peak Pruritus Numerical Rating Scale (PP-NRS)
PP-NRS improvement from baseline of ≥4 points
Two studies reported the outcome. Our analysis revealed that patients treated with nemolizumab had a significantly higher PP-NRS improvement from baseline of ≥4 points at week 4 (RR: 5.87, 95%CI [3.42, 10.05], P <0.00001) and week 16 (RR: 3.52, 95%CI [1.91, 6.5], P <0.0001), with zero heterogeneity (I2 = 0%) (Fig. 2).
Figure 2.
Pooled meta-analysis for PP-NRS improvement from baseline of ≥4 points.
PP-NRS<2
Two studies reported the outcome. Our analysis revealed that patients treated with nemolizumab had a significantly higher PP-NRS <2 points at week 4 (RR: 11.87, 95%CI [3.79, 37.18], P <0.0001) and week 16 (RR: 5.63, 95%CI [3.12, 10.16], P <0.00001), with zero heterogeneity (I2 = 0%) (Fig. 3).
Figure 3.
Pooled meta-analysis for PP-NRS <2.
SD-NRS improvement from baseline of ≥4 points
Three studies reported the outcome. Our analysis revealed that patients treated with nemolizumab had a significantly higher SD-NRS improvement from baseline of ≥4 points at week 4 (RR: 4.42, 95%CI [2.62, 7.45], P <0.00001) and week 16 (RR: 3.04, 95%CI [2.23, 4.15], P <0.00001), with low heterogeneity (Fig. 4a).
Figure 4.
(a) Pooled meta-analysis for SD-NRS improvement from baseline of ≥4 points. (b) TSA for SD-NRS improvement.
The manuscript reports that the TSA Z-line “crossed the benefit boundary but did not reach the required information size,” yet the interpretation remains superficial and incomplete. Crossing a benefit boundary without achieving the required sample size does not confirm robustness of the effect and should not be presented as supportive evidence. Instead, this pattern indicates potential overestimation of the treatment effect, insufficient accumulated evidence, and the need for cautious interpretation. The authors should clarify this and avoid drawing affirmative conclusions based solely on partial TSA signals. A more rigorous explanation of the TSA parameters, assumptions, and implications is required (Fig. 4b).
IGA response at weeks 12–16
Two studies reported the outcome. Our analysis revealed that patients treated with nemolizumab had a significantly higher response (RR: 4.06, 95%CI [2.42, 6.8], P <0.00001) than placebo group, with zero heterogeneity (I2 = 0%) (Fig. 5).
Figure 5.
Pooled meta-analysis for the Investigator’s Global Assessment response at weeks 12–16.
Adverse events
Four studies reported the outcome of any adverse events. Our analysis revealed that patients treated with nemolizumab had a higher risk of adverse events (RR: 1.13, 95%CI [1.01, 1.26], P = 0.04) than placebo, with zero heterogeneity (I2 = 0%) (Fig. 6a).
Figure 6.
(a) Pooled meta-analysis for any adverse events, Injection-related reaction, and infection. (b) TSA for adverse events.
The TSA results for adverse events are described in a purely mechanical manner without appropriate methodological interpretation. The cumulative Z-line remaining within the zone of non-statistical significance and failing to cross any monitoring boundary indicates insufficient evidence and high uncertainty, not merely the need for larger trials. The authors should emphasize that the current data are underpowered and cannot reliably exclude either harm or benefit. Furthermore, TSA conclusions should be integrated into the broader risk-of-bias assessment and certainty of evidence rather than reported as isolated statistical outputs (Fig. 6b).
Four studies reported the outcome of injection-related reaction. Our analysis revealed no significant difference between nemolizumab and placebo groups (RR: 3.35, 95%CI [0.58, 19.24], P = 0.18), with zero heterogeneity (I2 = 0%). Three studies reported the outcome of infection. Our analysis revealed no significant difference between nemolizumab and placebo groups (RR: 0.86, 95%CI [0.61, 1.20], P = 0.36), with zero heterogeneity (I2 = 0%) (Fig. 7).
Figure 7.
Pooled meta-analysis for secondary adverse events.
Four studies reported the outcome of neurodermatitis or atopic dermatitis. Our analysis revealed that patients treated with nemolizumab had a lower risk of neurodermatitis or atopic dermatitis (RR: 0.66, 95%CI [0.46, 0.95], P = 0.02) than placebo, with zero heterogeneity (I2 = 0%). Two studies reported the risk of nasopharyngitis and gastrointestinal events. Our analysis revealed no significant difference between nemolizumab and placebo groups in both outcomes (RR: 0.87, 95%CI [0.42, 1.77], P = 0.69), and (RR: 1.27, 95%CI [0.61, 2.64], P = 0.52), respectively (Fig. 7).
Headache outcome was reported by three studies. Our analysis revealed no significant difference between nemolizumab and placebo groups (RR: 1.75, 95%CI [0.75, 4.10], P = 0.19), with zero heterogeneity (I2 = 0%) (Fig. 7).
Discussion
This systematic review and meta-analysis provides robust evidence supporting the efficacy and safety of nemolizumab for the treatment of PN, a chronic and debilitating dermatologic condition characterized by intensely pruritic hyperkeratotic nodules. Our findings, derived from four high-quality randomized controlled trials, demonstrate that nemolizumab offers rapid and sustained improvements in pruritus, skin lesions, and sleep disturbance, with a favorable safety profile.
The most notable finding of our analysis was the significant and rapid reduction in pruritus with nemolizumab treatment. Patients achieved a clinically meaningful ≥4-point improvement in PP-NRS as early as week 4 (RR: 5.87, 95% CI [3.42, 10.05], P < 0.00001). This benefit continued through week 16 (RR: 3.52, 95% CI [1.91, 6.5], P < 0.0001). The low heterogeneity (I2 = 0%) shows the consistency of nemolizumab’s anti-pruritic effect across studies. These results are important because pruritus greatly affects quality of life in PN, disrupting sleep, mental health, and daily functioning.
Our findings match PN’s known pathophysiology, where IL-31 plays a central role in itch signaling[5]. By targeting the IL-31 receptor alpha subunit, nemolizumab directly blocks this pathway[6]. The rapid onset of improvement seen within the first month suggests that nemolizumab may offer faster relief than many other systemic therapies, which is especially valuable for patients with severe, refractory pruritus who need prompt symptom control. Publication bias may overestimate the efficacy and safety of nemolizumab for PN, as positive results are more likely to be published. Additionally, the predominance of White populations in clinical trials limits generalizability, particularly given the higher prevalence of PN in individuals with darker skin. More diverse studies are needed.
Beyond pruritus reduction, our analysis demonstrated meaningful improvements in several secondary outcomes. Patients receiving nemolizumab were significantly more likely to achieve complete or near-complete itch resolution (PP-NRS <2), with relative risks of 11.87 at week 4 and 5.63 at week 16 compared with placebo. Nemolizumab also produced notable improvements in skin lesion severity, as reflected by IGA responses (RR: 4.06, 95% CI [2.42, 6.8], P < 0.00001). Collectively, these findings indicate that nemolizumab may influence not only symptomatic relief but also the underlying disease mechanisms in PN, potentially by disrupting the itch–scratch cycle and associated inflammatory pathways[7].
The improvement in sleep disturbance observed with nemolizumab treatment is another clinically important finding. Sleep disruption is a major contributor to the disease burden in PN, and its amelioration may have far-reaching benefits for patients’ overall well-being and quality of life. The rapid improvement in sleep parameters, which paralleled the reduction in pruritus, further supports the central role of itch in PN-related sleep disturbances. When comparing nemolizumab to other available treatments for PN, particularly dupilumab, several distinctions emerge[8]. While both biologics have demonstrated efficacy in PN, nemolizumab appears to offer a more rapid onset of pruritus relief, with significant improvements observed[9]. This difference may reflect their distinct mechanisms of action – nemolizumab directly targets the IL-31 pathway implicated in itch signaling, while dupilumab’s effects on pruritus may be mediated through its broader anti-inflammatory actions on the IL-4/IL-13 pathway[10]. The choice between these agents in clinical practice may therefore depend on the urgency of symptom control required and individual patient characteristics. Nemolizumab provides faster antipruritic effects than dupilumab, likely due to its direct IL-31RA blockade, whereas dupilumab acts through broader IL-4/IL-13 pathway modulation. While both improve PN, nemolizumab’s earlier itch reduction may offer clinical advantages[10]. Nemolizumab may face high pricing similar to other dermatologic biologics, potentially limiting affordability and widening access disparities. Biologic therapies often impose substantial financial burden and restricted insurance coverage, challenging equitable treatment availability[11].
The safety profile of nemolizumab emerging from our analysis is generally favorable. While we observed a slightly increased risk of overall adverse events (RR: 1.13, 95% CI [1.01, 1.26]), most were mild to moderate in severity. The most notable adverse effects included eczematous reactions and headache, which were more frequent in the nemolizumab group compared to placebo. The eczematous reactions, while generally manageable, warrant further investigation as they may represent a paradoxical inflammatory response to IL-31 blockade. Importantly, no significant differences were observed in severe adverse events, infections, or injection-site reactions, supporting the overall tolerability of nemolizumab in the PN population.
Several limitations of our analysis should be acknowledged. First, the included studies had relatively short follow-up periods (maximum 24 weeks), limiting our ability to assess long-term efficacy and safety. Ongoing extension studies, such as the OLYMPIA LTE trial, will provide valuable data on the durability of response and long-term safety profile of nemolizumab. Second, the study populations in the included trials were predominantly White, which may affect the generalizability of our findings to more diverse populations. Future studies should aim to include more representative patient samples to ensure the applicability of these results across different ethnic groups. Future research directions should include head-to-head comparisons between nemolizumab and other PN treatments, particularly dupilumab, to better define their relative efficacy, safety, and optimal positioning in the treatment algorithm. Investigation of combination therapies and biomarkers predictive of treatment response would also be valuable.
Conclusion
This review demonstrates consistent and clinically meaningful benefits of nemolizumab across trials, particularly rapid reductions in pruritus and improvements in lesion severity and sleep quality. Strengths include the use of standardized outcome measures and low heterogeneity across studies. However, limitations remain, such as the short duration of follow-up, limited real-world data, and a need for comparisons with other systemic treatments. Overall, nemolizumab represents a promising targeted therapy for PN, offering rapid and durable symptom relief for patients with severe disease.
Ethical approval
Not applicable.
Consent
Not applicable.
Sources of funding
None.
Author contributions
A.O.A.: Validation, Visualization, Writing – original draft, Writing – review and editing. Re.A.: Conceptualization, Data curation, Formal analysis. Ra.A.: Supervision, Validation, Visualization, Writing – original draft. Z.M.A.: Data curation, Formal analysis, Methodology, Project administration. L.H.A.: Conceptualization, Software, Supervision, Resources. A.S.A.: Validation, Visualization, Writing – original draft. Ah.A.: Conceptualization, Writing – review and editing. I.A.: Software, Visualization, Writing – original draft. R.Y.: Validation, Writing – review and editing. Ab.A.: Validation, Visualization, Writing – review and editing.
Conflicts of interest disclosure
The authors declare no competing interests. No AI tools were used in the research design, data collection, data analysis, statistical evaluation, image creation, or manuscript writing.
Research registration unique identifying number (UIN)
Not applicable.
Guarantor
Ali O. Aldamen.