Maria Leis, BA1; Patrick Fleming, MD, FRCPC2,3; Charles W. Lynde, MD, FRCPC2,3
1Faculty of Medicine, University of Toronto, Toronto, ON, Canada
2Division of Dermatology, University of Toronto, Toronto, ON, Canada
3The Lynde Institute of Dermatology, Markham, ON, Canada
Conflict of interest:
All of the authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Abstract:
Prurigo nodularis (PN) is a chronic, recalcitrant inflammatory skin condition characterized by the presence of pruritic nodules. The exact pathogenesis of the disease is unknown, although immune and neural dysregulation are indicated in driving the itch-scratch cycle. Specifically, interleukin-4 and interleukin-31 pathways have been recently implicated in transmission of the pruritic sensation. There are currently no US FDA-approved targeted therapies for the treatment of PN. This article aims to review our present understanding of the disease pathogenesis and treatments, with a focus on emerging therapeutics. Specifically, this article explores the developing use of monoclonal antibodies nemolizumab and dupilumab, opioid receptor modulation and cannabinoids as potential treatments for PN.
Key Words:
prurigo nodularis, nemolizumab, dupilumab, chronic pruritus
Clinical Presentation
Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by the presence of pruritic nodules. Lesions vary in size from a few millimeters to 2-3 cm in diameter, and range in number from a few to hundreds.1 Nodules may be flesh-colored, erythematous, or hyperpigmented (depending on skin type), and are typically located in symmetric linear arrangements along extensor surfaces.1 PN has some predilection for elderly patients and individuals with dark skin, particularly persons of African ancestry.2,3 Although the disease affects patients of either sex, some research suggests women may be disproportionately affected in terms of frequency, age of onset, and severity.4 Numerous risk factors have been elucidated prior to development of PN, including eczemas, psychiatric diagnoses, and chronic medical diseases such as malignancy, liver failure, chronic renal failure, diabetes and human immunodeficiency virus (HIV) infection.3,5-7
Pathophysiology
The pathogenesis of PN is thought to be characterized by a cutaneous reaction pattern due to chronic itching and repeated scratching, otherwise termed the “itch-scratch cycle.” Although the exact pathogenesis of PN is unknown, immune and neural dysregulation drive the pruritic cycle.8
Histopathologic studies investigating the immune response of PN have demonstrated increased infiltrate in the dermis of PN lesions consisting of increased T lymphocytes, mast cells and eosinophilic granulocytes.8,9 The intense itch is created by an inflammatory response in the skin through mediators such as interleukin (IL)-31, tryptase, eosinophil cationic protein, histamine, prostaglandins and neuropeptides.8,9 Specifically, eosinophils and IL-31 are particularly implicated in the pathogenesis of the disease through their increased expression and pathologic mechanisms in the dermis of PN lesioned skin.8-13
Neuronal dysregulation has also been demonstrated in PN; studies have shown differences in nerve fiber density between the dermis and epidermis in individuals with PN.11 Further, dysregulation of neuropeptides has been implicated in the pathogenesis, with particular increases in calcitonin gene-related peptide and substance P in dermal PN skin.8-11,14 Although these changes may be secondary to repeated mechanical scratching, they still contribute to the pruritic cycle through regulation of eosinophils, mast cells, effects on endorphins and mu- and kappa-opioid receptors.8,9,11
Regardless of the aforementioned potential triggering pathologies, central nervous system functioning is essential for transmitting the itch signal from the periphery. Recent seminal findings by Oetjen and colleagues have demonstrated that the IL-4 receptor is directly expressed on sensory neurons in the dorsal root ganglia of both humans and mice. This receptor is directly activated by expression of type 2 cytokines, such as IL-4, IL-13 and IL-31.15 Most importantly, the authors demonstrated that ablating the IL-4 receptor in a mouse model significantly diminished chronic pruritus, and treating human patients with recalcitrant chronic itch that failed other immunosuppressive therapies with inhibitors of the type 2 cytokine pathway (Janus kinase – JAK – inhibitors) markedly improved their symptoms.15 Taken together, therapeutics targeting the inhibition of this central nervous system pathway may potentially be groundbreaking in the treatment of PN.
Current Treatments
Currently, there are no US Food and Drug Administration (FDA) approved targeted treatments for PN. Although the treatment goal is to break the itch-scratch cycle to allow the nodules to heal, there is a high degree of variability between providers and treatment regimens in the use of off-label therapies.8,16 A recent systematic review assigned level of evidence ratings to the current treatment options for PN (Table 1). The review found that many current therapies have low efficacy or a high frequency of side effects, limiting their effectiveness. Further, there was a paucity of randomized control trials (8 RCTs, with only 3/8 having >22 participants with PN) and quality studies looking at treatment of PN. Overall, topical agents, including corticosteroids, calcineurin inhibitors, calcipotriol, and capsaicin, had the highest evidence ratings, with some beneficial effects.17 The majority of studies investigating phototherapy and photochemotherapy reported mild side effects and demonstrated good partial response rates, as did thalidomide, although it had poorer quality studies and a large side effect profile. Antiepileptics and antidepressants, such as pregabalin, amitriptyline, paroxetine, fluvoxamine, and neurokinin-1 receptor antagonists had strong evidence ratings with promising treatment results and low risks of side effects. Lastly, systemic immunomodulatory therapies, such as cyclosporine and methotrexate, demonstrated some benefit in a limited number of low evidence level studies. However, these systemic treatments had poor safety profiles.17
The lack of success with current treatments is likely due to the heterogeneity of disease and dearth of regimens addressing the immunologic and neural pathophysiologic components of PN.8,17
| Treatment | Level of Evidence | Side Effects |
| Topical agents: corticosteroids, calcineurin inhibitors, calcipotriol, and capsaicin |
5/5 studies level 2b or higher | Mild; skin irritation |
| Phototherapy and photochemotherapy | 6/8 studies level 2b or higher | Mild; erythema, hyperpigmentation, vesicles, edema |
| Thalidomide | 2/6 studies level 2b or higher | Severe; poor safety profile, including peripheral neuropathy, sedation, dizziness, rash, depression, nausea, thromboembolism, teratogenicity |
| Systemic immunomodulatory drugs: methotrexate and cyclosporine | 4/4 studies level 4 | Mild; nausea, transaminitis, gastrointestinal symptoms, hypertension, hypercholesterolemia, elevated creatinine, gingival hyperplasia |
| Antiepileptics and antidepressants | 3/3 studies level 2b | Moderate; central nervous system effects, gastrointestinal effects, cardiovascular effects |
| Table 1: Current treatments of prurigo nodularis.Note: Level of evidence (LOE) ratings were assigned according to an adaptation of the Oxford University Centre for Evidence-Based Medicine LOE by a recent systematic review by Qureshi and colleagues.17
1a: Systematic review of randomized controlled trials |
||
Emerging Treatments
Currently, several new treatments are being explored for itch pathogenesis in PN (Table 2).
| Treatment | Level of Evidence | Side Effects |
| Nemolizumab | 1b (ongoing RCT) | Mild; abdominal pain and diarrhea, nonspecific musculoskeletal symptoms |
| Dupilumab | 2b | Mild; dry eyes |
| Opioid receptor modulation: nalbuphine, butorphanol, naloxone, and naltrexone | 1b | Moderate; insomnia, constipation, somnolence, dizziness, vomiting, sensation of heat, nasal congestion |
| Cannabinoids | 3a | Unknown |
| Table 2: Emerging treatments of prurigo nodularis.Note: LOE ratings were assigned according to an adaptation of the Oxford University Centre for Evidence-Based Medicine LOE. | ||
Nemolizumab
Nemolizumab is a new drug designed to interrupt the itch-scratch cycle in PN. Considering that up-regulation of IL-31 messenger RNA has been reported in PN lesions compared to healthy skin biopsies, a drug interrupting this increase could be beneficial.13 Nemolizumab was designed as a humanized anti-human IL-31 receptor A monocloncal antibody. This monoclonal antibody disrupts the binding of IL-31 to its receptor, and in doing so inhibits part of the cascade of inflammatory events causing the itch sensation.18,19
Results of a phase 2 trial of nemolizumab on adults with moderate-to-severe PN were recently published. Moderate-to-severe PN was defined as 20 or more nodules, while severe PN was characterized as a mean score of at least 7 (range 0-10) for the worst daily intensity of pruritus. PN patients were randomly equally assigned to receive subcutaneous injections of nemolizumab 0.5 mg/kg (n=34), or matching placebo (n=36).20 Three total injections were administered at baseline, week 4 and week 8, with three more visits at weeks 12, 16 and 18. At week 4 there was a 53% reduction from baseline in peak pruritus score (4.5 points) in the nemoluzimab group, compared to a 20% reduction in the placebo group (1.7 points). Reductions were maintained throughout the trial period.20 The mean number of prurigo lesions decreased by a greater proportion in the nemolizumab group compared to the placebo group at week 12. Other secondary outcome measures such as assessments investigators’ global assessments, sleep quality and Dermatology Life Quality Index also demonstrated greater improvements in the nemolizumab group compared to placebo.20 Nemolizumab was associated with more side effects than placebo, namely abdominal symptoms such as abdominal pain and diarrhea, as well as nonspecific musculoskeletal symptoms.20
Based on these strong and promising results for treatment of PN, the FDA recently approved nemolizumab for Breakthrough Therapy status, thus expediting its development and approval process.21 Phase 3 trials are currently underway (NCT03989206).
Dupilumab
Similar to nemolizumab, dupilumab is a monoclonal antibody antagonist of the IL-4 receptor, another integral component of the neural pathway for pruritus.15 Further, it has already been approved by the FDA for three indications including treatment of moderate-to-severe atopic dermatitis.22
The largest recently published case series has demonstrated the benefit of dupilumab in the treatment of chronic pruritus. Twenty recalcitrant pruritus patients at a tertiary care center were treated with off-label dupilumab at standard atopic dermatitis dosing. Promising results were observed, with complete resolution obtained in 12/20 patients and an overall mean reduction of 7.55 points on the numeric rating scale for itch intensity (range 0-10). Specifically, 9 patients in this series had PN, and reported a mean reduction in itch ratings of 7.89. Further, the drug was well tolerated in all patients and no significant adverse events were reported.22 The same authors have also reported success in its specific use for PN in a previously published case series.23 Several other case series and reports all published within the last year have also described the benefit of dupilumab for treatment of PN.24-28
Further, a recent retrospective cohort study examined the effectiveness of dupilumab in treating adults affected by persistent atopic dermatitis with clinical features of generalized PN. A total of 90 atopic dermatitis patients were treated, of which 9 patients demonstrated generalized PN. Significant improvements in Eczema Area and Severity Index, Dermatology Quality of Life Index, and pruritus visual analogue scale score were observed after treatment.29 Another recent retrospective cohort study of 16 adult patients with chronic PN refractory to multimodal treatment regimens reported similar results.30 Taken together with the evidence from the case series, the use of dupilumab in treatment of PN shows promise, and warrants further research with randomized control trials.
Opioid Receptor Modulation: Nalbuphine, Butorphanol, Naloxone and Naltrexone
Other research has examined the efficacy of opioid receptor modulating drugs in the treatment of pruritus. Considering that imbalances between mu- and kappa-opioid signalling have been indicated in generalized itch pathogenesis, mixed kappa-opioid agonist/mu-opioid antagonists may interrupt this cycle.31 The mechanisms of nalbuphine and butorphanol both act as such, and each have been demonstrated to have some beneficial effects on reducing pruritus. Specifically, one study examined the effects of nalbuphine in hemodialysis patients on treating uremic pruritus, and found discernable reductions in measures of itch severity with increasing dosage.32 Further, case investigations examining the effects of butorphanol on intractable pruritus have also demonstrated its benefit.31 Importantly, a recent multicenter, double-blind randomized control trial examined the effects of nalbuphine on itch severity in PN, as well as evaluated the safety and tolerability of the drug in this population. Phase 2 results have been released, but not yet published, and demonstrated promising beneficial effects of nalbuphine in reducing pruritus (NCT02174419).
Intravenous naloxone and oral naltrexone, both mu-opioid receptor antagonists, have also demonstrated antipruritic effects in select PN patients.33,34 A double-blind, randomized control trial investigating the use of naloxone infusions in patients with pruritus of cholestasis (n=29) found that it was associated with reduced pruritic perception and actual reduction of scratching.35 Further, another trial of 65 patients examined the effects of naltrexone on pruritus, and found significant benefits including lesion healing and symptom reduction.36 Further studies examining the efficacy of opioid receptor modulation in pruritic pathways are warranted given these promising combined results.
Cannabinoids
Cannabinoid receptor (CB)1 and CB2 are expressed on cutaneous nerve fibers, with agonists of these receptors diminishing histamine-induced excitation and leading to reduction of itch.37,38 As such, these cannabinoid receptors are thought to contribute to the pruritic sensation. A recent systematic review examined the efficacy of cannabinoids for the treatment of chronic refractory pruritus. Only 5 studies were included in the analysis, but all reported a reduction in itch intensity following cannabinoid therapy.39 Considering the recent growth in acceptance of use and favorable legislation of medical marijuana, further research is warranted to explore its potential use in PN.40
Conclusion
Novel therapeutics are currently being explored for the treatment of PN. It is important for treatments to consider targeting both the neural and immunologic components of the itch-scratch cycle. Nemolizumab and dupilumab both demonstrate promise in inhibiting specific central nervous system pathways responsible for transmission of the pruritic sensation. Moving forward it is important for clinicians to better understand the pathogenesis of PN, and apply an integrated approach to treatment of this chronic, recalcitrant condition.
References
