INTRODUCTION
Prurigo nodularis (PN) is a chronic, intensely pruritic skin condition marked by the presence of multiple nodular lesions, which lead to persistent itching and scratching, significantly impairing the quality of life of affected individuals [1]. Nodules usually appear on extensor surfaces of the arms, legs, and trunk. Clinically distinctive, pruriginous lesions are characterized by a hyperkeratotic epidermis with irregular epidermal hyperplasia, focal parakeratosis, papillary dermal fibrosis, and increased number of fibroblasts, capillaries, and inflammatory cells [2]. While the exact pathogenesis of PN remains unclear, emerging evidence points to the involvement of immune and neural dysregulation in its development [3, 4]. This review aims to describe novel therapies for the treatment of PN.
PATHOGENESIS
Prurigo nodularis lesions exhibit increased infiltration of T lymphocytes, mast cells, and eosinophils, driving inflammation and intense pruritus through mediators such as IL-31, tryptase, eosinophil cationic protein, histamine, prostaglandins, and neuropeptides [5]. Among these, eosinophil cationic protein and eosinophil-derived neurotoxin are particularly significant due to their neurotoxic effects and elevated levels in PN-affected skin [6]. By releasing these neurotoxins along with neurotrophins, chemokines, and cytokines, eosinophils may contribute to nerve damage and perpetuate pruritus [7]. IL-31 exacerbates itch by binding to the heterodimeric IL-31A and oncostatin M (OSM) receptors. IL-31 and OSM play central roles in the pathophysiology of PN; IL-31 is a key mediator of skin pruritus [8] and OSM is a mediator of skin inflammation, hyperkeratosis, and fibrosis [9]. Moreover, cytokines released by T lymphocytes initiate signalling through the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway, leading to the upregulation of genes involved in inflammatory responses [10].
Dysregulation of several neuropeptides, particularly calcitonin gene-related peptide (CGRP) and substance P (SP), has been also implicated in the pathogenesis of PN [11]. SP, a neurotransmitter released by neurons, binds to the neurokinin-1 receptor in both the skin and the central nervous system. Studies have shown an increased presence of SP+ nerve fibres and elevated SP expression in the dermis of PN-affected skin. Similarly, CGRP is another neuropeptide with mechanisms akin to SP, also upregulated in PN, contributing to disease pathogenesis [12]. CGRP can be released into cutaneous tissue via nerve fibres, promoting neurogenic inflammation by regulating eosinophils and mast cells. Further, CGRP affects endorphin levels and disrupts mu and kappa opioid receptors, potentially exacerbating pruritus [13]. PN, however, rarely responds to antihistamines, which suggests that histamine is not the main cause of pruritus [14]. Despite the wide range of treatment methods available (summarized in table 1), PN remains challenging. Therefore, there is a need for new emerging therapies for this entity that target these pruritogens and their receptors.
Table 1
Summary of current therapies
CURRENT TREATMENT
Topical therapy
The treatment of PN begins with diligent skin care and an initial course of topical steroid therapy, typically administered for two months. Long-term use of topical steroids is discouraged due to potential side effects, especially in treatment-resistant cases. In such scenarios, alternative therapies, such as moisturizers, may be employed. In patients with mild PN, topical anesthetics can provide modest relief from itch in patients with chronic pruritus. It is possible to use over-the-counter lotions, sprays, and creams that contain 1% pramoxine, lidocaine and compounded topical anesthetics. In a previous study of 30 patients with PN treated with either 1% pimecrolimus or 1% hydrocortisone cream, both groups showed a significant reduction in pruritus intensity (p = 0.001), with no significant differences between them (p = 0.394) [15]. Topically applied activated vitamin D3 analogues are an alternative in cases where topical steroids are minimally effective or when their use is limited by associated side effects. This treatment is, however, based on limited evidence. Topical capsaicin has shown promise in suppressing neurogenic inflammation and itch transmission by binding to vanilloid receptors (TRPV1) on nerve endings [16]. It induces the release and depletion of neuropeptides like substance P and CGRP, thereby disrupting nerve signal transmission and reducing symptoms.
Phototherapy
For PN symptoms, ultraviolet (UV) light therapy is an option, particularly for patients with limited treatment options due to comorbidities or drug interactions. Treatments like excimer light, bath PUVA, narrowband UVB, and UVA1 have proven effective in reducing symptoms [17]. Among these, narrow-band UVB (NB-UVB) therapy, administered 2–3 times weekly, is considered a first-line treatment for PN patients. However, phototherapy combined with topical treatments is only sufficient for a small number of PN patients, with most requiring additional systemic therapy.
Systemic therapy
Systemic options include immunosuppressants, gabapentinoids, antidepressants, and mu-opioid receptor antagonists. Methotrexate and cyclosporine are immunosuppressants that have been shown to be effective in treating PN in retrospective studies. Methotrexate for treating PN demonstrated significant relief from itching and effective healing of lesions in affected patients. It is commonly prescribed as a first-line immunosuppressive treatment, typically starting at doses of 15–20 mg per week, in combination with topical therapies [18]. If the condition is more severe, cyclosporine may be an option to consider. Several reports have indicated that cyclosporine, at doses of 2–5 mg/kg/day, can improve PN symptoms and even lead to the resolution of nodules [19]. However, a key drawback of cyclosporine is its notable side effect profile, which necessitates regular monitoring of blood pressure, renal function, liver function, and complete blood counts. Thalidomide, at low doses, may be considered for PN cases resistant to other treatments and significantly impacting daily life. Its use should be carefully evaluated due to potential neurotoxic and teratogenic side effects. Antidepressants such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (amitriptyline, doxepin) or mirtazapine may also be prescribed for treatment-resistant PN and provide mild to moderate relief of pruritus [20]. Additionally, gabapentin and pregabalin, which act on voltage-gated calcium channels, are beneficial in managing itch by reducing the secretion of excitatory neurotransmitters [21]. These medications increase the itch threshold, providing relief for some patients. As higher doses are often required to reduce itch intensity, sedation often becomes an important side effect and is the leading reason for treatment discontinuation.
EMERGING THERAPEUTICS
Monoclonal antibodies
Dupilumab
Dupilumab is a human monoclonal IgG4 antibody, which acts as a dual inhibitor of interleukin (IL)-4 and IL-13 signalling by selectively binding to the IL-4 receptor α (IL-4Rα) subunit, which is shared by the receptor complexes for both IL-4 and IL-13. It has shown significant efficacy and safety in treating various type 2 inflammation-driven diseases, such as atopic dermatitis and asthma [22]. Research has established that the cytokines IL-4 and IL-13, associated with the Th2 axis, play a role in the pathogenesis of PN. Dupilumab, administered with a loading dose of 600 mg, subcutaneously (SC) on day 1 followed by dupilumab 300 mg once every 2 weeks for 24 weeks, showed significant improvements in various symptom measures – including itch, skin pain, and sleep disturbances, as well as health-related quality of life (QoL) over a 24-week treatment period. These findings were demonstrated in two phase 3 clinical trials, LIBERTY PN-PRIME (NCT04183335) and PRIME2 (NCT04202679), involving adult patients with ≥ 20 nodules and severe itch uncontrolled with topical therapies [23] as well as in series with 16 and 24 patients [24, 25]. The administration of dupilumab has been shown to be safe, with no severe adverse events (SAEs) reported. The most commonly documented side effects in the literature are injection site reactions, herpes viral infection and episodes of conjunctivitis [23, 26]. The Food and Drug Administration (FDA) has approved dupilumab for the treatment of PN in adults (table 2).
Table 2
Summary of monoclonal antibodies
Nemolizumab
As a neuroimmunological cytokine, IL-31 is produced mainly by type 2 immune cells, including type 2 helper T (Th2) cells, type 2 innate lymphoid cells, mast cells, eosinophils, basophils, and monocytes. As compared to healthy controls, patients with lesional PN have higher levels of IL-31, and dermal levels are positively correlated with itch intensity [27]. Nemolizumab is an IL-31 receptor alpha antagonist that inhibits the signalling of IL-31 and suppresses the Th2 (IL-13) and Th17 (IL-17) immune axes, which contributes to improving clinical responses in terms of itch severity and lesion healing [28]. In the OLYMPIA 2 phase 3 clinical trial (NCT04501679) nemolizumab patients weighing less than 90 kg received an injection of 60 mg initial dose, followed by 30 mg every 4 weeks, and those weighing 90 kg or more received 60 mg every 4 weeks for 16 weeks. In week 16, 56.3% of nemolizumab-treated patients compared to 20.9% of placebo-treated patients, had clinically meaningful improvement in their itch intensity (defined as a reduction of ≥ 4 points on the Peak Pruritus Numerical Rating Scale) [29]. In addition to itch response, nemolizumab also improved sleep disturbances and lesion healing. Furthermore, results suggest rapid reductions in itch intensity and sleep disturbances, which began as early as week 4 [29]. In each group, one patient experienced a serious adverse event linked to the trial regimen: bullous pemphigoid in the nemolizumab group and generalized exfoliative dermatitis in the placebo group. The most frequently reported adverse events (occurring in ≥ 5% of patients) that were more common in the nemolizumab group compared to the placebo group included atopic dermatitis and headache. Adverse events of particular interest, such as peripheral or facial oedema and asthma, were also observed more often in the nemolizumab group. Conversely, infections were more prevalent in the placebo group [29]. In the ongoing 192-week OLYMPIA LTE trial (NCT04204616), long-term safety and efficacy data for nemolizumab are being collected. Studies on nemolizumab have been also enrolling patients aged 13 to 18 years, as well as those currently using topical corticosteroids [30]. In a phase 2/3 clinical trial, participants were randomized to receive nemolizumab at a dose of 30 mg following a 60-mg loading dose (77 patients), 60 mg (76 patients), or a placebo. The combination of nemolizumab with topical corticosteroids demonstrated a more significant reduction in both pruritus and PN lesions compared to placebo with topical corticosteroids alone [30]. Adverse skin events, including eczema, erythema, dermatitis, and folliculitis, were reported in ≥ 5% of patients in the nemolizumab group and occurred more frequently than in the placebo group [30].
Vixarelimab
Vixarelimab (KPL-716) is a first-in-class fully human monoclonal antibody that is being evaluated for the treatment of PN. Vixarelimab targets oncostatin M receptor beta (OSMRβ), a receptor that pairs with IL-31Rα to mediate IL-31 signalling or with the glycoprotein 130 (gp130) chain from the OSM type II receptor, to mediate OSM signalling [31]. This dual mechanism enables vixarelimab to simultaneously inhibit the signalling pathways of IL-31 and OSM, both of which are associated with pruritus, inflammation, hyperkeratosis, and fibrosis [9]. Importantly, vixarelimab does not bind to or inhibit the leukemia inhibitory factor (LIF) receptor complex (gp130/LIFR or OSM receptor type I), which mediates haematopoiesis through OSM and LIF [9]. In the phase 2a clinical trial (NCT03816891) patients with moderate-to-severe pruritus received weekly subcutaneous vixarelimab 360 mg (720 mg loading dose) or placebo for 8 weeks. Vixarelimab demonstrated a rapid reduction in pruritus and achieved clear or almost clear skin in one-third of patients by week 8, compared to significantly fewer patients in the placebo group achieving this level of lesion improvement. The relief of itching and resolution of skin nodules highlight two significant therapeutic advancements for managing PN. In addition, the treatment was well tolerated. No deaths, serious treatment-emergent adverse events (TEAEs), or TEAEs requiring dose interruption were observed. There was an increase in upper respiratory tract infections, nasopharyngitis, headaches, nummular eczema, urticaria (acute onset, short-lived), and procedural headaches (> 5%) in the vixarelimab group. In the placebo group, these were reported with generally similar frequency. Overall, 91.3% (21/23) of vixarelimab recipients reported at least one TEAE, compared to 76.9% (20/26) of those receiving placebo. Drug-related TEAEs were comparable between the groups, occurring in 43.5% (10/23) of vixarelimab-treated patients and 38.5% (10/26) of placebo recipients. For a longer-term efficacy observation, the ongoing phase 2b study (NCT03816891) includes a 16-week treatment period followed by an open-label extension.
Barzolvolimab
Barzolvolimab (CDX-0159) is a humanized antibody designed to inhibit KIT activation by stem cell factor (SCF), resulting in dose-dependent suppression of plasma tryptase, indicative of systemic mast cell ablation. It has already been evaluated in a phase 1b study (NCT04548869) involving patients with chronic inducible urticaria, where it was well tolerated and demonstrated rapid, marked and durable depletion of skin mast cells (MC), reduced circulating tryptase levels, and significant clinical improvements [32]. These findings suggest enhanced disease control and quality of life (QoL), highlighting its potential as a therapeutic option for MC-mediated disorders. Currently, barzolvolimab is undergoing evaluation in a double-blind, placebo-controlled phase 2 clinical study (NCT06366750) for PN.
Janus kinase inhibitors
The Janus kinase (JAK) family includes JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). The JAK pathway has been implicated in PN pathogenesis by promoting the upregulation of genes involved in inflammatory responses, triggered by cytokines released from T lymphocytes [3, 10]. Therefore, blocking the pathway can suppress multiple inflammatory pathways involved in PN. However evidence regarding the therapeutic potential of JAK inhibitors is limited. JAK inhibitors currently being tested for the treatment of PN are shown in table 3. The oral JAK1 inhibitor abrocitinib has completed phase 2 studies, while povorcitinib is currently in ongoing phase 3 trials. Meanwhile, the topical JAK1/2 inhibitor ruxolitinib is also undergoing phase 3 studies. Tofacitinib, which primarily targets JAK1 and JAK3, is set to undergo a prospective observational pilot study. Additionally, the JAK1 inhibitor upadacitinib is being considered in an observational study focused on prurigo-type atopic dermatitis.
Table 3
Summary of JAK-inhibitors
Ruxolitinib
Ruxolitinib, a JAK1 and JAK2 inhibitor, suppresses activation of the JAK-STAT pathway triggered by inflammatory cytokines, thereby modulating multiple inflammatory pathways implicated in PN. Topical ruxolitinib has already been approved for treating atopic dermatitis, where it demonstrated significant improvement in pruritus [33]. Currently, several phase III clinical trials are underway to assess its safety and efficacy in PN (NCT05764161; NCT06213831; NCT05755438).
Abrocitinib
Abrocitinib is an oral JAK1 inhibitor that interferes with the JAK–STAT pathway by specifically targeting JAK1. This pathway plays a key role in signalling for cytokines and molecules such as IL-2, IL-4, IL-6, IL-13, IL-15, IL-22, IL-31, thymic stromal lymphopoietin, interferon (IFN)-γ, and IFN-α [34]. Given its success in treating atopic dermatitis: rapid antipruritic effects, often providing relief within a few days [35], a phase II clinical trial is currently underway to evaluate the efficacy of abrocitinib in 10 patients with PN and 10 patients with chronic pruritus of unknown origin (NCT05038982). Additionally, there is a case report documenting the successful use of abrocitinib in a patient with chronic nodular prurigo, who had not responded to dupilumab [36]. Reported treatment-emergent adverse events (TEAEs) of abrocitinib include nasopharyngitis, atopic dermatitis, nausea, and headache [35].
Povorcitinib
Povorcitinib, another oral JAK1 inhibitor, has successfully completed phase II clinical trials for PN. The phase II study evaluated three doses of the drug (15 mg, 45 mg, and 75 mg) with a total enrolment of 140 patients (NCT05061693). Currently, patient recruitment is ongoing for a phase III clinical trial (NCT06516952; NCT06516965).
Tofacitinib
A novel small-molecule drug, tofacitinib, has been shown to have favourable benefit-risk balances in treating rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis in adults [37] and is also being tested to treat other autoimmune, dermatologic, and rheumatoid diseases. It targets JAK signalling, in particular JAK1 and JAK3 and, to some extent, JAK2 and TYK2 [38]. Tofacitinib’s efficacy and safety will be evaluated in a prospective, observational pilot study for refractory PN (NCT06201715).
Upadacitinib
Upadacitinib is a small-molecule drug designed to selectively inhibit the JAK1 protein. Traditionally, it has been used to treat moderate to severe rheumatoid arthritis. Recently, the FDA approved its use for several additional conditions, including severe atopic dermatitis, psoriatic arthritis, nonradiographic axial spondyloarthritis, ankylosing spondylitis, and ulcerative colitis. Two case reports have documented the successful use of upadacitinib in treating PN, both demonstrating rapid therapeutic responses. In the first case [39], an Asian patient achieved complete remission of PN following treatment with upadacitinib at a daily dose of 15 mg, combined with once-daily topical desoximetasone, which was gradually tapered over 2 months. At the 2-month follow-up, complete remission of nodular lesions was observed, with only residual post-inflammatory pigmentation remaining. The patient also reported a marked absence of pruritus. The second case involved a 53-year-old man who had not responded to standard treatments or previous therapy with dupilumab (300 mg) and methotrexate. He was administered off-label upadacitinib 15 mg twice a day [40]. After 1 month, the patient demonstrated a positive response, with marked improvement in both lesions and pruritus, as reflected by an Investigator’s Global Assessment (IGA) score of 1. The response was further evaluated using the Worst Itch Numeric Rating Scale and the Dermatology Life Quality Index, both of which yielded scores of 2. He reported no adverse effects and his blood test results remained unremarkable. By week 16, the patient exhibited only one nodular lesion on the upper limb, with residual hypopigmentation elsewhere, and reported no pruritus (body surface area: 0%; Worst Itch Numeric Rating Scale: 0; IGA: 0).
Currently, an observational study (NCT05451316) is underway to evaluate the effectiveness of upadacitinib in participants with prurigo-type atopic dermatitis. The potential of upadacitinib to inhibit the JAK-STAT pathway and interrupt the scratch-itch cycle makes it a promising emerging therapy for PN.
Opioid receptor antagonist/agonist
Opioids are often associated with itch, particularly when they are administered epidurally or intrathecally. The mechanisms underlying opioid-induced itch, however, remain unclear, although mu-opioid receptors (MOR) and gastrin-releasing peptide receptors (GRPR) have been implicated. Activation of MOR located on inhibitory interneurons in the spinal cord are primarily involved in a disinhibition of the itch signalling pathway [41]. Consequently, excitatory neurons, particularly GRPR, become more active, transmitting itch signals to higher brain centres [41]. This mechanism explains why opioid-induced itch is particularly pronounced following intrathecal or epidural administration. In contrast, kappa-opioid receptor (KOR) activation alleviates it, suggesting that these receptors hold potential as therapeutic targets [42].
Nalbuphine
Nalbuphine, a partial MOR antagonist and KOR agonist, is approved for pain management and is also effective in suppressing itch caused by endogenous opioids [43]. Results of the phase II clinical trial (NCT02174419) have already been published [44]. In this trial, nalbuphine extended-release (NAL-ER) tablets demonstrated a numerical but not statistically significant reduction in pruritus severity compared to placebo over 10 weeks of treatment. Specifically, 44.4% of patients in the 162 mg NAL-ER group and 27.3% in the 81 mg NAL-ER group achieved a ≥ 30% reduction in pruritus compared to 36.4% in the placebo group (p = 0.32 and p = 0.78, respectively). Reported TEAEs included gastrointestinal issues such as nausea, along with general symptoms like headache, fatigue, and dizziness. These findings suggest that while there may be a potential for dose-dependent efficacy of NAL-ER, further studies with larger sample sizes and optimized trial designs are needed to confirm its clinical benefits in reducing pruritus. Phase II/III clinical trials examining the safety and effectiveness of nalbuphine, for PN have now been completed (NCT02174432, NCT02174419, NCT03497975).
Studies have shown nalbuphine’s low effectiveness and potential for addiction, indicating caution and a need to thoroughly evaluate its risks and benefits for long-term treatment of PN.
Nalfurafine hydrochloride
Nalfurafine hydrochloride is not generally recommended for PN due to insufficient epidemiological data. However, it has been effective in managing pruritus associated with haemodialysis or chronic liver disease. As a KOR agonist, it suppresses central nervous system itch and shows potential for antihistamine-resistant cases [45].
Difelikefalin
Difelikefalin is an FDA-approved selective kappa-opioid receptor agonist for the management of chronic kidney disease-associated pruritus (CKD-aP) in haemodialysis patients [46]. Through selective binding to peripheral KORs, it reduces pruritus without affecting the central nervous system, thus minimizing central opioid-related side effects such as sedation and respiratory depression [47]. Based on the results of five randomized controlled trials (RCTs) involving 896 participants, difelikefalin significantly reduced pruritus symptoms when compared to placebo [47]. The primary efficacy outcomes included a reduction in the weekly mean Worst Itch Numerical Rating Scale (WI-NRS) score, the 5-D itch scale total score, and the Skindex-10 total score. However, difelikefalin was associated with some adverse events, including dizziness, diarrhoea, nausea, and constipation. Even though the incidence of adverse events was higher than in placebo, there was no significant difference in the incidence of severe adverse events or mortality. For patients with CKD-aP, particularly those on haemodialysis, difelikefalin offers a promising therapeutic option. Due to its peripheral mechanism, it has minimal central side effects, making it an optimal choice for long-term treatment. Further studies are needed to assess its efficacy in other pruritic conditions besides CKD-aP.
Naloxone
Naloxone is an opioid receptor antagonist primarily used to counteract opioid overdose by competitively binding to μ, κ, and δ opioid receptors. Aside from this role, naloxone has also shown potential as a treatment for pruritus, especially caused by dermatological and systemic conditions [48]. High-dose naloxone (50 mg/day) has shown efficacy in reducing pruritus in several studies, including randomized controlled trials involving patients with chronic kidney disease-associated pruritus. Low-dose naloxone (1.5 to 4.5 mg/day) has also been explored for chronic inflammatory skin conditions such as Hailey-Hailey disease and lichen planopilaris [48]. Studies have reported marked improvements in symptoms, including reductions in itch severity and lesion resolution. When compared with high-dose naloxone regimens, low-dose naloxone generally has minimal side effects. Dizziness and mild gastrointestinal symptoms are the most common side effects [48]. Although naloxone shows potential as an anti-pruritic agent, its efficacy can vary significantly depending on the underlying cause of pruritus and the dosage administered. More extensive clinical trials are needed to establish standard dosages and long-term safety profiles.
NK1R antagonists
Aprepitant and serlopitant
Aprepitant and serlopitant are neurokinin-1 receptor (NK1R) antagonists that target the neural mechanisms of itch by blocking substance P (SP), which is implicated in inflammation, vasodilation, and nerve-related itch signalling [49, 50]. SP is thought to play a significant role in chronic pruritus, as patients with certain conditions, such as PN, often exhibit elevated serum levels of SP, increased NK1R expression, and a greater density of SP-positive nerve fibres in the dermis [51, 52]. Aprepitant, an FDA-approved medication for chemotherapy-induced nausea and vomiting [53], has been used off-label to manage chronic pruritus [54]. While the dosage varies depending on the underlying condition, it has been prescribed at 80 mg daily for this purpose. A randomized phase 2 study, however, failed to demonstrate a significant reduction in itch severity in PN when aprepitant 80 mg/day was taken for 4 weeks [55]. Serlopitant, on the other hand, showed a significantly greater reduction in pruritus when compared with placebo in phase II clinical trials [49]. Unfortunately, it failed to meet its primary endpoints in phase III studies (NCT02196324).
PROMISING THERAPEUTICS
Stapokibart
Stapokibart, a humanised monoclonal antibody targeting IL-4Rα to inhibit IL-4 and IL-13 signalling, is under investigation for the treatment of atopic dermatitis [56], severe eosinophilic chronic rhinosinusitis with nasal polyps [57], and seasonal allergic rhinitis [58] (table 4).
Table 4
Summary of promising therapeutics
SHR-1819
SHR-1819 is an innovative monoclonal antibody engineered to target human IL-4Rα effectively inhibiting signalling pathways of both IL-4 and IL-13. Preclinical studies in mouse models of asthma, atopic dermatitis, and allergic rhinitis demonstrated that SHR-1819 fulfils the criteria for a promising clinical candidate in treating IL-4/IL-13-related inflammatory conditions [59]. Currently, SHR-1819 is under clinical development for asthma (NCT04772365), severe atopic dermatitis (NCT06012812), and PN (NCT06554509).
Rocatinlimab
The OX40-OX40L pathway drives acute and chronic inflammation in atopic dermatitis by enhancing T-cell responses (Th2, Th1, Th17, Th22) [60]. Rocatinlimab, an anti-OX40 monoclonal antibody, inhibits and reduces activated OX40-expressing T cells [61]. It has shown promising results in treating moderate-to-severe atopic dermatitis [61], prompting further clinical trials to evaluate its efficacy, including in conditions like PN in phase 3 clinical trial (NCT06527404).
Apremilast
Apremilast is an orally administered small molecule that selectively inhibits the phosphodiesterase-4 (PDE4) enzyme. By increasing intracellular cyclic adenosine monophosphate (cAMP) levels, it modulates the immune system, reducing the production of IL-2, IL-8, interferon-γ, and tumor necrosis factor (TNF) [62]. It has received FDA approval for the treatment of psoriasis, psoriatic arthritis, and oral ulcers associated with Behçet disease [62]. However, a study involving 10 patients with PN found that 12 weeks of 30 mg twice daily apremilast treatment did not significantly alleviate pruritus in most participants (70%) and showed no improvement in quality of life or sleep [63]. Additionally, apremilast failed to clinically reduce the severity of PN, which was consistent with the absence of significant changes in cytokine or chemokine concentrations [63].
CONCLUSIONS
The field of PN treatment is undergoing significant progress, marked by the emergence of targeted therapies that bring renewed hope to patients. Nonetheless, more research is essential to comprehensively evaluate their long-term impact and potential side effects. As our understanding and approach to managing PN continue to improve, these innovative therapies hold the promise of becoming more widely available, providing much-needed relief for those affected by this challenging condition. Ultimately, the outlook for effective PN management is increasingly optimistic.
