Prurigo Nodularis: Review and Emerging Treatments

Maria Leis, BA; Patrick Fleming, MD, FRCPC; Charles W. Lynde, MD, FRCPC

Disclosures

Skin Therapy Letter. 2021;26(3):5-8. 

In This Article

Emerging Treatments

Currently, several new treatments are being explored for itch pathogenesis in PN (Table 2).

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]

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