Efficacy and Safety of Conventional and Biologic Therapies in Prurigo Nodularis: A Systematic Review and Meta‐Analysis

ABSTRACT

Prurigo nodularis (PN) is a chronic, intensely pruritic skin disorder characterized by hyperkeratotic nodules and a debilitating itch–scratch cycle. Conventional therapies have limited efficacy and safety issues, while biologics have recently emerged as a promising alternative. A systematic search of PubMed, Embase, and CENTRAL databases was conducted on November 20, 2023, to identify studies assessing treatments for PN. Primary outcomes were changes in pruritus and quality of life. Safety was evaluated by adverse event incidence. Random‐effects meta‐analyses were conducted when sufficient data were available. Of 4914 records screened, 128 studies met the inclusion criteria, of which 25 were included in the meta‐analysis. In studies of dupilumab, treatment was associated with marked reductions in pruritus (mean difference [MD], −5.76; 95% confidence interval [CI], −6.86 to −4.67) and significant improvement in quality of life (MD, −11.84; 95% CI, −22.76 to −0.92), with adverse events reported in 13% of patients (95% CI, 0.02–0.52). Phototherapy achieved complete responses in 23% (95% CI, 9%–48%), partial responses in 60% (95% CI, 39%–78%), and no response in 7% (95% CI, 1%–40%). Thalidomide was associated with complete, partial, and no response rates of 15% (95% CI, 1%–71%), 49% (95% CI, 23%–75%), and 12% (95% CI, 6%–23%), respectively. Dupilumab offers consistent, clinically meaningful improvements in PN with a favorable safety profile, supporting its use as the preferred first‐line treatment. Phototherapy and thalidomide remain alternatives for selected patients but achieve complete clearance in few cases and carry greater safety concerns.

1. Introduction

Prurigo nodularis (PN) is a chronic inflammatory skin disease that usually presents with pruritic nodules on the extensor surfaces of the extremities and trunk and is characterized by a vicious itch‐scratch cycle [1, 2]. The estimated prevalence is 72 per 100.000, but the actual number of patients may be higher [3]. Patients have a significantly reduced quality of life, with subsequent depression, anxiety, sleep disturbances, and even suicidal tendencies [4, 5, 6, 7].

The pathogenesis of PN is not fully elucidated. It is related to immune and neural dysregulation, often associated with peripheral neuropathies that may result from chronic scratching. The condition is mediated by inflammatory cytokines (interleukin (IL)‐4, IL‐13, IL‐17, IL‐22, and IL‐31) and neuropeptides such as substance P and calcitonin gene‐related peptide. Additionally, type 2 inflammation, along with immune responses driven by T‐helper 17 (Th17) and Th22 cells, plays a significant role in PN [8, 9].

The therapeutic challenge of PN is demonstrated by the wide range of treatment modalities that have been explored, from topical corticosteroids and calcineurin inhibitors to phototherapy with UVB or UVA. Systemic options have included immunosuppressants such as methotrexate and cyclosporine, immunomodulators such as thalidomide, neurokinin‐1 receptor antagonists (serlopitant, aprepitant), opioid modulators (naloxone, nalbuphine), as well as certain antidepressants and gabapentinoids [10, 11]. Many of the previously used treatments demonstrated limited efficacy and were associated with significant adverse events [1, 10]. In contrast, recently introduced biologic therapies offer the potential for greater efficacy and an improved safety profile, as they specifically target key pathogenic pathways involved in PN [11]. The U.S. Food and Drug Administration (FDA) has approved two biologics for PN: dupilumab, an IL‐4/IL‐13 inhibitor approved in 2022, and nemolizumab, an IL‐31 inhibitor approved in 2024. Dupilumab, however, had been used off‐label for PN since 2019 [12, 13, 14].

The efficacy of PN treatments is primarily assessed by reductions in itch intensity (Numerical Rating Scale (NRS) or Visual Analog Score (VAS)) and nodule count (IGA). Complementary patient‐reported outcomes, such as the Dermatology Life Quality Index (DLQI), Itch‐Related Quality of Life (ItchyQoL), sleep disturbance indices, and depression scales, are used to capture broader effects on quality of life [15, 16, 17, 18, 19, 20].

Here, we aimed to conduct a systematic review and meta‐analysis to evaluate the efficacy and safety of available therapies for PN, including both conventional and biologic therapies.

2. Methods

This systematic review and meta‐analysis was conducted in accordance with the PRISMA 2020 guidelines, [21, 22] and followed the recommendations of the Cochrane Handbook [23]. The protocol of the study was registered on PROSPERO (registration number CRD42023484730). We deviated from the protocol by including letters, originally listed as exclusion criteria, when they contained detailed case reports or study descriptions.

2.1. Eligibility Criteria

We included studies of patients diagnosed with PN who received therapeutic interventions specifically targeting the condition. No restrictions were applied on geographic location or comorbidities; however, studies exclusively involving pediatric populations were excluded. The population–intervention–control–outcome (PICO) framework was as follows: P—adults with PN; I—biologic treatment; C—conventional treatment, placebo, or no treatment; O—improvement in pruritus, reduction in nodules, changes in quality of life, and safety.

2.2. Search and Selection

On November 20, 2023, we conducted a systematic search of PubMed, Embase, and CENTRAL. Detailed search strategies and the number of retrieved records are provided in the Supporting Information S1.

EndNote 21 (Clarivate Analytics, Philadelphia, PA, USA) was used for the selection of articles [24]. Citation screening at title/abstract and full‐text levels was performed by two reviewers (AL, RÁ) who worked independently using the software tool of Rayyan Systems (Cambridge, MA, USA) [25]. Any discrepancies were resolved by consensus or by a third reviewer (FAM). The flowchart was generated using the PRISMA 2020 Flow Diagram online tool [26].

2.3. Data Collection and Data Items

Two reviewers (AL, RÁ) independently extracted data from the included studies into an Excel spreadsheet (Office 365, Microsoft, Redmond, WA, USA), with discrepancies resolved by a third reviewer (FAM). Extracted information included first author, publication year, journal, study population characteristics, total and per‐arm sample size, type and duration of therapy, and treatment outcomes.

Itch reduction was assessed on a scale of 0–10, where 0 indicates no itch and 10 indicates severe itch. Nodule reduction was measured with the Investigator Global Assessment (IGA) score, ranging from 0 (no nodules) to 4 (> 100 nodules). Quality‐of‐life outcomes were evaluated using the Dermatology Life Quality Index (DLQI), ItchyQoL, Hospital Anxiety and Depression Scale (HADS), and various sleep scores, with higher values indicating greater impairment. Safety was assessed by the reported incidence of adverse events.

In studies that did not use standardized outcomes, such as the Investigator Global Assessment (IGA) or Visual Analog Scale (VAS), we created a single aggregated outcome encompassing both itch and nodule reduction. To enable comparison, we applied unified response categories: No Response: no measurable therapeutic effect; Partial Response: moderate improvement, between the criteria for complete and no response; Complete Response: meeting the definition of complete therapeutic response as specified in the respective study.

2.4. Synthesis Methods

We conducted a meta‐analysis using mean differences and proportional changes from baseline as effect sizes, which were visualized using forest plots. For continuous outcomes, pooled estimates were calculated as mean or median differences with 95% confidence intervals, and standardized mean differences (Hedges' g) were applied where appropriate. Binary outcomes were analyzed using a random‐intercept logistic regression model. Heterogeneity was quantified using the I ² and τ ² statistics estimated via the REML method, and confidence intervals were adjusted with the Hartung–Knapp approach where more conservative estimates were warranted. Pre‐specified subgroup analyses were performed according to intervention type and underlying patient condition, assuming separate τ ² values for subgroups; when subgroup sizes were small, a common τ ² was used. All analyses were conducted using R software (version 4.2.3; R Core Team, 2023) [27]. Detailed statistical analysis methods are described in the Supporting Information S1.

2.5. Study Risk of Bias Assessment and Certainty of Evidence

For the risk of bias assessment, we used the Rob2 tool for randomized controlled trials (RCTs) [28], the ROBINS‐I tool for comparative cohort studies [29], the MINORS tool for non‐randomized single‐arm studies [30], and the JBI tool for case reports and case series [31]. Two independent reviewers (AL, RÁ) performed the assessments, and an independent third investigator (FAM) resolved disagreements.

The certainty of evidence was assessed using the GRADE pro, as recommended by the Cochrane Collaboration [32].

3. Results

3.1. Search and Selection

The database search yielded 4914 citations; after duplicate removal, 3715 unique records remained. After screening and full‐text review, 128 articles met the eligibility criteria for further evaluation [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160], of which 25 were included in the meta‐analysis [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57], and 103 in the systematic review [58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160].

The study selection process is illustrated in Figure 1.

FIGURE 1.

PRISMA 2020 flow diagram of the search and screening process.

Included studies were conducted in multiple countries and enrolled participants aged 18 years or older with moderate to severe PN.

3.2. Baseline Characteristics of Included Studies

Baseline characteristics of enrolled studies are detailed in the (Table S2).

3.3. Meta‐Analysis

3.3.1. Efficacy

3.3.1.1. Improvement in Itch

3.3.1.1.1. Dupilumab

Eight observational studies were analyzed at different time points. The mean difference (MD) in itch score reduction was −5.28 (95% confidence interval [CI], −10.55 to −0.01; I ² = 96%) at Week 4, −6.46 (95% CI, −11.35 to −1.56; I ² = 92%) at Week 12, and −5.64 (95% CI, −7.30 to −3.98; I ² = 82%) at Week 16. The pooled overall reduction, irrespective of follow‐up time, was −5.76 (95% CI, −6.86 to −4.67; I ² = 91%) (Figure 2).

FIGURE 2.

Forest plots showing mean changes in itch scores at different time points in patients with prurigo nodularis treated with dupilumab (CI, Confidence interval; MD, Mean difference, SD, Standard deviation).

3.3.1.2. Overall Response

3.3.1.2.1. Phototherapies

Eight observational studies of phototherapy (PUVA, excimer light, UVA1, UVB, and UVB + UVA) including 92 patients were analyzed. Pooled proportions for no response, partial response, and complete response were 0.07 (95% CI, 0.01–0.40; I ² = 0%), 0.60 (95% CI, 0.39–0.78; I ² = 56%), and 0.23 (95% CI, 0.09–0.48; I ² = 15%), respectively (Figure 3A).

FIGURE 3.

Forest plots showing the incidence of overall response in patients with prurigo nodularis treated with conventional therapies: (A) phototherapy and (B) thalidomide (CI, Confidence interval).

3.3.1.2.2. Thalidomide

Six observational studies including 99 patients were analyzed. Pooled proportions for no response, partial response, and complete response were 0.12 (95% CI, 0.06–0.23; I ² = 0%), 0.49 (95% CI, 0.23–0.75; I ² = 75%), and 0.15 (95% CI, 0.01–0.71; I ² = 63%), respectively (Figure 3B).

3.3.2. Safety

3.3.2.1. Dupilumab

Five observational studies, including 101 patients, were analyzed. The overall incidence of adverse events (AEs) in the dupilumab group was 0.13 (95% CI, 0.02–0.52; I ² = 0%) (Figure 4). The most frequent AEs were conjunctivitis, dry eyes, and local injection site reactions (See Tables S3 and S4).

FIGURE 4.

Forest plot showing the incidence of adverse events in patients with prurigo nodularis treated with dupilumab (AE, Adverse events; CI: Confidence interval).

3.3.3. Quality of Life

3.3.3.1. Dupilumab

Three observational studies assessing changes in DLQI were analyzed, involving 44 patients treated with dupilumab. The summary MD was −11.84 (95% CI, −22.76 to −0.92; I ² = 73%) (Figure 5).

FIGURE 5.

Change in Dermatology Life Quality Index (DLQI) from baseline in patients with prurigo nodularis treated with dupilumab after 16 weeks (CI, Confidence interval, MD, Mean difference, SD, Standard deviation).

3.4. Systematic Review

Detailed results of studies included only in the systematic review are provided in the (Tables S3 and S4). Table S3 summarizes findings from case reports and case series, and Table S4 summarizes results from observational studies and RCTs.

3.5. Risk of Bias Assessment

Risk of bias assessment results are detailed in Tables S5–S14. Among the studies included in the meta‐analysis, one of the two‐arm observational studies assessed with the ROBINS‐I tool was rated as high risk and one as moderate risk. Of single‐arm observational studies evaluated with the MINORS tool, 16 were high risk and 7 were moderate risk.

3.6. Certainty of Evidence

Detailed results on the certainty of evidence for dupilumab treatment are presented in the Summary of Findings table in the Supporting Information S1. Certainty was rated very low for observational studies due to inconsistent results, indirect effects, imprecise measurement methods, and risk of bias.

4. Discussion

Management of PN remains complex and challenging. Although numerous studies have evaluated conventional therapies and emerging biologic agents in recent years, no clear consensus has been reached on their optimal use [9].

In our quantitative analysis, dupilumab was associated with a rapid and substantial reduction in pruritus, with a mean decrease of 5.76 points on itch scores. A reduction exceeding 4 points is generally considered clinically meaningful [158], underscoring the robustness of this effect. Improvement was evident within the first 4 weeks of treatment. Thalidomide achieved complete response in 15% of cases, whereas phototherapy modalities, including UVB, PUVA, and excimer laser, achieved complete response in 23%. Adverse events with dupilumab were uncommon and predominantly mild, including conjunctivitis, dry eyes, and localized injection site reactions, supporting its favorable safety profile. In contrast, the use of thalidomide is limited by modest efficacy and well‐documented toxicities, including thromboembolic events and irreversible peripheral neuropathy, which substantially restrict long‐term use [161]. Moreover, based on our quantitative analysis, findings indicate that dupilumab not only alleviates pruritus but also produces clinically meaningful improvements in quality of life, as evidenced by substantial reductions in DLQI scores, where mean improvements exceeding the 10‐point threshold are considered highly significant.

The qualitative analysis identified a wide range of therapeutic approaches, including biologic and non‐biologic agents. Emerging biologics such as nemolizumab and vixarelimab consistently showed meaningful improvements in pruritus and nodule severity in individual studies [99, 134, 142, 143]. Other systemic agents, including JAK inhibitors [55, 58, 81, 104, 112, 119, 121, 157], aprepitant [92, 140, 148], duloxetine [87], alitretinoin [68, 77, 80, 106] and naloxone [113], demonstrated antipruritic activity, and thalidomide [59, 62, 67, 100, 117, 128, 153, 159] induced remission in selected patients despite safety concerns.

Other systemic agents such as methotrexate [68, 70, 136], cyclosporine [69, 88, 131, 150, 155], and gabapentinoids [65, 91, 107, 116] showed clinical benefit in selected patients. However, complete or sustained remission was uncommon, and relapse after treatment discontinuation was frequently reported, particularly with gabapentinoids [65].

Phototherapy modalities, particularly narrowband UVB [75, 83, 145] and excimer laser [72, 110, 114], were associated with clinical improvement after relatively few treatment sessions. Biologics were generally well tolerated, as were phototherapy and topical therapies, whereas the safety profile of conventional systemic immunosuppressants differed considerably across therapies. Thalidomide's long‐term use remains restricted by well‐documented toxicities, particularly the risk of peripheral neuropathy and sedation [33, 34, 38, 44, 49, 51, 62, 67, 100, 128]. Despite these limitations, thalidomide received more detailed consideration owing to the greater availability of published studies. Cyclosporine demonstrated high efficacy in several reports; however, its use was limited by a substantial adverse‐event burden, affecting up to half of treated patients and including hypertension, renal dysfunction, and rare but serious complications such as thromboembolic events [69, 131, 155]. Methotrexate was most commonly associated with gastrointestinal adverse events and laboratory abnormalities, including nausea, elevated liver enzymes, and dyslipidemia [68, 70, 136].

Gabapentinoids were generally better tolerated but provided only moderate and often transient antipruritic effects. The most commonly reported adverse event was fatigue [65, 107].

We quantitatively assessed and underlined the limited efficacy of conventional systemic therapies, which had previously been summarized only in systematic reviews [162]. Although recent systematic reviews have noted the potential of dupilumab, most were based on case series or small cohorts and did not include quantitative synthesis [163, 164]. In the meta‐analysis by Metko et al., dupilumab was associated with improvements in pruritus, quality of life, and sleep quality in PN [165]. In contrast, our analysis evaluated RCTs and observational studies separately and could not quantitatively assess sleep outcomes due to the limited number of RCTs. Two recent meta‐analyses of nemolizumab (Raja et al. and Sinha et al.) reported significant benefits compared with placebo in terms of pruritus, sleep, and IGA scores, with predominantly mild to moderate adverse events; however, several relevant trials were unavailable at the time of our analysis, precluding pooled comparisons with dupilumab [166, 167]. A network meta‐analysis by Wang et al. ranked dupilumab as the most effective therapy for pruritus, skin clearance, quality of life, and safety, ahead of vixarelimab and nemolizumab. Nalbuphine reduced itch but was associated with mood deterioration at higher doses, whereas serlopitant provided only moderate symptomatic relief without significant improvement in emotional well‐being [168].

4.1. Strengths and Limitations

This systematic review and meta‐analysis has several strengths and limitations.

The analysis used a comprehensive search strategy, allowing inclusion of all relevant literature regardless of study design or publication format. To our knowledge, this is the first meta‐analysis to quantitatively synthesize treatment responses for PN, including phototherapy and thalidomide. Although few controlled studies were available, we were able to extract and pool data on treatment response proportions from studies with predefined, therapy‐specific outcome categories. The use of proportion‐based forest plots for therapies lacking comparative data offers additional insight into their real‐world effectiveness in the context of a rare disease. In addition, we also extracted data from case reports and case series for a more comprehensive evaluation of all available therapies.

This meta‐analysis has several limitations. Most included studies were observational, single‐arm, and involved small sample sizes. The absence of control groups and the retrospective design of many studies introduce potential bias and limit the ability to infer causality. Inconsistencies in outcome definitions and reporting contributed to heterogeneity and may have affected the validity of pooled estimates. In addition, a quantitative synthesis of adverse events, particularly for thalidomide, was not feasible owing to substantial heterogeneity in safety reporting across studies, including inconsistent definitions, variable reporting formats, and the absence of patient‐level denominator data. The lack of preregistration in most studies raises the possibility of reporting and publication bias. Finally, at the time of analysis, data on emerging biologics such as nemolizumab, vixarelimab, and targeted agents such as tofacitinib and upadacitinib were insufficient to permit direct comparisons among these agents, dupilumab, and conventional treatments.

4.2. Implications for Practice

Translating research findings into clinical practice is essential for developing evidence‐based guidelines for the use of the most effective and safest agents for the treatment of PN [169, 170]. Our findings demonstrate that dupilumab is an effective treatment for PN and highlight that, beyond efficacy, safety remains a critical factor in therapeutic decision‐making. Dupilumab appears to offer a particularly favorable balance between both. The only international guideline currently available, issued by the International Forum for the Study of Itch (IFSI) in 2020, recommends biologic agents solely as fourth‐line therapy [171]. Therefore, our findings support the consideration of dupilumab as a first‐line systemic treatment option for PN when available.

4.3. Implications for Research

More randomized clinical trials are needed to evaluate emerging therapies, including biologics and Janus kinase (JAK) inhibitors. Comparative studies between biologics and JAK inhibitors are essential to clarify relative efficacy and safety profiles and to guide treatment selection. Further research should also address the long‐term efficacy of novel therapies, relapse rates, and the establishment of uniform outcome measures to reduce variability across studies.

5. Conclusion

Dupilumab provides consistent, clinically meaningful improvements in PN with a favorable safety profile, supporting its use as the preferred first‐line treatment option when available. Phototherapy and thalidomide remain alternatives for selected patients, but achieve complete clearance only in a few cases and have harbored significant safety concerns.

Funding

The authors have nothing to report.

Disclosure

Medical writing, editorial, and other assistance: Language editing assistance was provided by Judit Császár, Vice‐Director for Operative Management, Institute of Languages for Specific Purposes, Semmelweis University, Budapest, Hungary.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1: Supporting Information.

Data Availability Statement

The datasets used in this study can be found in the full‐text articles included in the systematic review and meta‐analysis.