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

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

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.

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¹Northern Ontario School of Medicine, Thunder Bay, ON, Canada
²Faculty of Medicine, University of Toronto, Toronto, ON, Canada
³Department of Family & Community Medicine, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
⁴Division of Dermatology, University of Toronto, Toronto, ON, Canada

Conflict of interest:
Jeremy Strain has no conflicts of interest to disclose. Maria Leis has no conflicts of interest to disclose. Kyle O. Lee has received honoraria and/or consulting fees and/or advisory board fees for Bausch Health, Eli Lilly, Eisai, Elvium, and Pfizer for work unrelated to this manuscript. Patrick Fleming has received honoraria and/or consulting fees and/or advisory board fees for AbbVie, Altius, Aralez, Bausch Health, Cipher, Galderma, Eli Lilly, UCB, Novartis, Pfizer, and Sanofi-Genzyme for work unrelated to this manuscript.

Abstract:
Psoriasis is a chronic, immune-mediated skin condition which commonly affects women of childbearing age. Certolizumab pegol (CZP) is an anti-tumor necrosis factor-alpha (anti-TNFα) agent that has demonstrated long-term safety and efficacy in treating moderate-to-severe plaque psoriasis. Previously, there has been limited safety data surrounding its use in pregnancy. The objective of this article is to review pivotal clinical trial data for CZP and explore safety considerations for this agent in pregnancy. This review demonstrates that CZP offers a safe and effective treatment option for women during childbearing years based on pharmacokinetics and available safety data. The observed occurrence of major congenital malformations and miscarriages appears to be no greater than the background occurrence of those in the general population, and risks to the mother are minimal based on its known safety profile. The use of CZP for treatment of plaque psoriasis should be considered and discussed with patients considering childbearing or whom are currently pregnant or breastfeeding.

Key Words:
psoriasis, certolizumab, Cimzia, biologics, anti-TNF agents, pregnancy, obstetrics

Introduction

Plaque psoriasis is a chronic inflammatory immune-mediated skin disorder associated with genetic and environmental factors. The global prevalence of psoriasis is approximately 2% with some regional variation.^1,2 Although psoriasis primarily affects the skin, it also has widespread systemic effects including psoriatic arthritis, depression, and cardiovascular disease.²

Over the past two decades our understanding of the pathogenesis of psoriasis has been largely elucidated. Research has demonstrated that the disease is primarily driven through a mediated pathogenic T-cell pathway. Specifically, high levels of interleukin (IL)-23/T-helper type 17 T-cell are thought to stimulate release of IL-17.³ IL-17 upregulation in turn leads to a “feed forward” cycle, including inflammatory responses in keratinocytes which further drive the development of psoriatic plaques by inducing characteristic changes such as epidermal hyperplasia and cell proliferation and leukocyte recruitment.³

TNFα is a pro-inflammatory cytokine further implicated in the immunopathogenesis of psoriasis.³ The upregulation of TNFα leads to increased production of IL-23, further stimulating the psoriatic pathway. Additionally, TNFα works synergistically with IL-17 to upregulate transcription of many pro-inflammatory genes. Increased understanding of these inflammatory pathways has led to the advent of biologic therapies, including TNFα inhibitors, which have revolutionized the treatment of psoriasis.³

Although advances in our understanding of the disease pathogenesis have spawned the development of targeted biologic therapies, research is limited on the use of these medications in specific subpopulations. Considering that psoriasis often affects women of childbearing age, effective and safe treatment options during pregnancy are an important consideration.⁴ The objective of this article is to review pivotal clinical trial data for certolizumab pegol (CZP), a PEGylated anti-TNFα biologic agent, and explore safety considerations for this treatment option in pregnancy.

Certolizumab Pegol and Early Clinical Trials

CZP (Cimzia®) is a recombinant humanized monoclonal anti- TNFα antibody approved to treat plaque psoriasis, psoriatic arthritis, Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis, and axial spondyloarthritis. CZP contains the antigen-binding fragment (Fab) of an immunoglobulin G (IgG) antibody and lacks the fragment crystallizable (Fc) region.⁵ A single cysteine residue allows the Fab portion to be conjugated with polyethylene glycol (PEG) to form CZP, increasing its halflife to 14 days while maintaining its ability to avidly bind TNFα.⁵

Two phase III double-blind randomized placebo-controlled studies (CIMPASI-1 and CIMPASI-2) using CZP for moderate-severe plaque psoriasis found biweekly doses of either 200 mg or 400 mg led to significantly improved responses of the Psoriasis Area and Severity Index (PASI) PASI-75, PASI-90, and Physician’s Global Assessment (PGA) 0/1, when compared to placebo.⁶ The pooled data from CIMPASI-1 and CIMPASI-2 show that after 16 weeks, CZP 200 mg q2w resulted in PASI-75 of 76.7% (P<0.0001), PGA 0/1 of 56.8% (P<0.0001), and PASI-90 of 45.9% (P<0.0001), while CZP 400 mg q2w showed PASI-75 of 82% (P<0.0001), PGA 0/1 of 65.3% (P<0.0001), and PASI-90 of 52.2% (P<0.0001) (supplemental Table 1).⁶ A similar study (CIMPACT) compared its use to etanercept, also a TNFα inhibitor, with CZP 200 mg q2w showing a PASI-75 of 61.3%, with 8% higher when compared to etanercept (P<0.1523).7 Similarly, CZP 400 mg q2w showed a PASI-75 responder rate of 66.7%, with 13.4% higher responder rate when compared to etanercept (P<0.0152) (supplemental Table 2), with efficacy either comparable or superior to etanercept in psoriasis.⁷ However, pregnant and breastfeeding patients were excluded in these initial studies.^6,7

Certolizumab Pegol in Pregnancy

Psoriasis commonly affects women during childbearing years, making safe and effective treatment in this population important.^4,8,9 Up to 32% of women may have worsening or ongoing high disease activity during pregnancy,¹⁰ with increased psoriatic disease linked to adverse outcomes such as low birth weight, preterm delivery, preeclampsia, small for gestational age and fetal loss.⁴ Following, control of psoriatic disease during pregnancy leads to improved pregnancy outcomes, such as reducing preterm delivery, fetal loss, and low birth rates.⁴ Disease control prior to pregnancy and into the postpartum period are also important to maternal and fetal outcomes.¹⁰

Most anti-TNF agents (infliximab, adalimumab, golimumab, etanercept) have a classical IgG structure with an Fc region which can attach to the neonatal Fc receptor for IgG (FcRn) and cross the placenta.¹¹ In particular, circulating maternal IgG antibodies are actively transported across the placenta in the second half of pregnancy, facilitated by FcRn¹¹ Importantly, IgG levels at term in the newborn are higher than maternal levels, with a half-life approximately twice as long as that in the mother.^11-13 Unlike other anti-TNF agents, CZP lacks the Fc-binding property. Results from CZP nonclinical and human placental perfusion data demonstrate that in fact CZP does not bind to FcRn, and consequently suggest that there is no active FcRn-mediated placental transport.^5,14

Several studies have specifically examined the use of CZP during pregnancy. The CRIB study (n=16 mother-infant pairs) measured any potential placental transfer of CZP from mothers to infants at birth, along with concentrations of CZP in the plasma of mothers at delivery and umbilical cords at birth.¹⁵ Maternal CZP plasma levels at delivery were within the expected range (median = 24.4 μg/mL), and infant levels were below the lower limit of quantitation (0.032 μg/mL). Further, the investigators found that gestational age and weight at birth of all infants were within the expected range for healthy infants.¹⁵ Safety data was consistent with the known safety profile of CZP for mothers, and clinical events by infants did not show any patterns of clusters of events suggesting a specific adverse safety signal.¹⁵ The CRIB study provides evidence that levels of CZP are not present in sufficient amounts in infants to cause treatment emergent adverse effects.

Similarly, a recent pooled analysis of n=11,317 patients in clinical trials examined the long-term safety of CZP in rheumatoid arthritis, psoriatic arthritis, psoriasis and Crohn’s disease.¹⁶ With regards to its use during pregnancy, the study concluded there is no to minimal placental transfer from mothers to infants (suggesting a lack of in utero exposure during the third trimester), with the median Relative Infant Dose of CZP in breastmilk (0.125%) considered to be in the safe range for breastfeeding (<10%). The authors concluded that the safety profile of CZP is in line with that of other anti-TNF agents in all indications¹⁶

The CRADLE study (n=18 mothers, n=17 infants) examined the concentration of CZP in mature human breast milk, and assessed safety profiles in both mothers and infants.¹⁷ The study demonstrated almost all breast milk concentrations were less than two times the lower limit of quantification. Further, adverse events in mothers and infants were mostly mild to moderate in intensity (mothers: 3 mild, 6 moderate; infants: 6 mild, 2 moderate). No serious adverse events were reported in infants, and no hospitalizations or deaths in mothers or infants occurred.¹⁷ Overall, this study suggests very low to undetectable levels of CZP in breast milk, which corresponded with no increased risk for breastfeeding infants of mothers using CZP.

A recent review by Clowse and colleagues examined pregnancy outcomes, including major congenital malformations, in women receiving CZP, with a specific focus on the timing of exposure. This analysis represents the largest published cohort (n=538) of pregnant women with known outcomes exposed to CZP for the management of chronic inflammatory diseases.¹⁸ Results demonstrated that most maternally CZP-exposed pregnancies resulted in live births (Figure 1), with miscarriage, induced abortion and stillbirth representing trends similar to the general population (Figure 2). Timing-wise, maternal exposure to CZP occurred during at least the first trimester for 367 of the 452 prospective pregnancies (81.2%) and almost half of the pregnant women (44.5%) were exposed to CZP during all three trimesters. Eight major congenital malformations were observed (Table 1).¹⁸ Further, serious maternal infections occurred in 22 (4.2%) pregnancies, and among those which resulted in a live birth, maternal comorbidities were due to preeclampsia (5 patients, 1.1%) and gestational diabetes (6 patients, 1.3%).¹⁸ Overall, the results suggest there is no increased teratogenic effect of CZP compared to the general population, nor a greater incidence of fetal death. Maternal complications are similar to the general population. Important limitations include a lack of an untreated control group for comparison, lack of follow up for a third of cases, and numbers of pregnancy outcomes in patients receiving an anti-TNF therapy are relatively small for less common birth characteristics.

The above studies provide evidence that CZP use during the third trimester of pregnancy has low or undetectable levels of CZP in infants’ blood, low to undetectable levels of CZP are present in breastmilk, and observed occurrence of major congenital malformations and miscarriages is no greater than that of the general population in mothers using CZP. Considering these findings and the increasingly emergent use of anti-TNF biologics in pregnancy, a Canadian consensus paper on management of plaque psoriasis in women of child-bearing potential was recently published.¹⁹ A panel of nine Canadian dermatologists managing psoriasis reviewed the relevant literature, focusing on TNF-α inhibitors, IL-23 inhibitors, IL-12/23 inhibitors, and IL-17 inhibitors. With respect to CZP, three main conclusions were drawn. First, CZP is the only biologic demonstrating no active placental transport throughout pregnancy due to the lack of the Fc portion, and as such can be used throughout all three trimesters. Second, CZP is the only biologic for psoriasis for which infants exposed have no detectable drug levels. Third, CZP has the most evidence of all biologics reviewed suggesting no to minimal exposure for the fetus and infant.¹⁹ Taken together, these results provide evidence for the safety of CZP throughout all three trimesters of pregnancy and during the breastfeeding period.

Conclusion

Psoriasis is a common condition affecting women during childbearing years, with untreated disease contributing to adverse events for both the mother and infant. CZP appears to offer a safe and effective treatment for patients who are considering pregnancy, pregnant, or lactating based on its pharmacokinetics and available safety data. Importantly, the observed occurrence of major congenital malformations and miscarriages appears to be no greater than the background occurrence of those in the general population, and risks to the mother are minimal based on its known safety profile. The use of CZP for treatment of plaque psoriasis should be considered and discussed with patients considering childbearing or whom are currently pregnant or breastfeeding.

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