STL Volume 28 Number 6 – Skin Therapy Letter https://www.skintherapyletter.com Written by Dermatologists for Dermatologists Tue, 06 Feb 2024 22:41:49 +0000 en-US hourly 1 https://wordpress.org/?v=6.8.1 Risankizumab in Adults with Psoriatic Arthritis https://www.skintherapyletter.com/psoriatic-arthritis/risankizumab/ Tue, 12 Dec 2023 23:15:11 +0000 https://www.skintherapyletter.com/?p=14913 Karla Machlab, MD1; Jensen Yeung, MD, FRCPC2,3; Melinda Gooderham, MSc, MD, FRCPC4-6

1Department of Medicine, University of Toronto, ON, Canada
2Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
3Department of Dermatology, Women’s College Hospital, Toronto, ON, Canada
4Probity Medical Research, Peterborough, ON, Canada
5SKiN Center for Dermatology, Peterborough, ON, Canada
6Queen’s University, Kingston, ON, Canada

Conflict of interest: Karla Machlab has no conflicts of interest. Jensen Yeung has served as an investigator, speaker, and/or advisory board member for, and/or received grants/honoraria from: AbbVie, Amgen, Anacor, Astellas, Arcutis, Bausch Health, Baxalta, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, Incyte, Janssen, Leo Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, and Xenon. Melinda Gooderham serves as the Vice President of the Dermatology Association of Ontario and has served as an investigator, speaker, advisor and/or consultant for, and/or received grants/honoraria from: AbbVie, Akros, Amgen, Arcutis, Aslan, Aristea, AnaptysBio, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Janssen, Kyowa Kirin, Leo Pharma, MedImmune, Meiji, Merck, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, and UCB. Funding sources: None.

Abstract: Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease associated with psoriasis. Its major clinical domains include peripheral and axial arthritis, enthesitis, dactylitis and skin and nail involvement. Approximately 30% of patients with psoriasis develop psoriatic arthritis. The pathophysiology of PsA is complex and involves a dysregulated immune response. In particular, interleukin (IL)-23 is a major regulatory cytokine that has been implicated in PsA, including bone remodeling, enthesitis, synovitis and psoriatic lesions. Risankizumab is a humanized immunoglobulin G1 monoclonal antibody that targets the p19 subunit of IL-23. It has been approved for the treatment of moderate-to-severe plaque psoriasis and, more recently, PsA. The efficacy and safety of risankizumab for the treatment of PsA has been demonstrated in phase 2 and phase 3 clinical trials. Risankizumab showed efficacy in decreasing the number of swollen and tender joints, clearing psoriatic plaque and improving quality of life. Treatment with risankizumab was well-tolerated, with the most common adverse event being upper respiratory tract infection. Overall, the current literature demonstrates that risankizumab is both a safe and effective therapeutic option for the treatment of PsA. Herein, week 24 and 52 results are reviewed.

Keywords: risankizumab, Skyrizi®, IL-23, psoriatic arthritis

Introduction

Psoriatic arthritis (PsA) is an inflammatory musculoskeletal disease characterized by a range of clinical features including arthritic inflammation, dactylitis, enthesitis, and skin and nail changes. PsA may also be associated with multiple comorbidities including type 2 diabetes, hypertension, metabolic syndrome and cardiovascular disease.1,2 Accordingly, PsA can greatly impair one’s quality of life (QoL) and therefore prompt intervention is crucial.3,4

PsA affects males and females equally with an estimated prevalence of 1-2 in 1000.5 Approximately 30% of patients with psoriasis will develop PsA.6-8sup> Given the high prevalence of PsA, it is important to continue to find effective and safe therapeutic options. This review focuses on the current literature regarding the efficacy and safety of risankizumab for the treatment of PsA up to 52 weeks of treatment.

Pathophysiology

The pathophysiology of PsA is complex and multifactorial. Although the exact mechanism is not completely understood, genetic and environmental factors interact to trigger immune pathways. PsA is associated with class II major histocompatibility complex (MHC) alleles, including HA-B*27, B*0801, B*3801 and B*3901.9 Risk factors include severe psoriasis, scalp, inverse or nail psoriasis, obesity and trauma (Koebner phenomenon).10 T-cells are major effectors in PsA and the role of CD8+ T-cells is supported by a strong association with HLA-1 alleles.11 Type 17 T-cells, which include CD4+ type 17 helper T (Th17) cells, and type 3 innate lymphocytes, which produce interleukin (IL)-17 and IL-22, are increased in synovial fluid in patients with PsA.12

IL-23/IL-17 and tumor necrosis factor (TNF) pathways also play a central role and contribute to most domains of PsA, including synovitis, enthesitis, axial inflammation and psoriatic plaques. Dendritic cells produce IL-23, which triggers the differentiation and proliferation of Th17 cells, and activates other cytokine pathways including IL-17, IL-22 and TNF-α.13 These subsequently activate downstream effector cells, including keratinocytes, fibroblasts, osteoclast precursors, B-cells and macrophages. An inflammatory immune response is initiated resulting in keratinocyte proliferation, bone erosion and pathologic bone formation. Murine models have shown that administration of IL-23 leads to entheseal inflammation, inflammatory arthritis, bone erosion, periosteal bone formation, and increased production of IL-17.14,15

Overview of Therapy

Treatment of PsA is initially guided by severity of disease and, importantly, the degree of activity in each of the domains. Mild PsA can be managed with non-steroidal anti-inflammatory drugs (NSAIDs) or intra-articular steroids. However, in moderateto- severe PsA, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, leflunomide or sulfasalazine are typically used first line. Newer novel agents, such as phosphodiesterase-4 (PDE4) inhibitors, Janus kinase (JAK) inhibitors, and biologic DMARDs (bDMARDs) are also approved efficacious agents. Biologics include TNF, IL-17, and IL-12/23 or IL-23 inhibitors.

TNF inhibitors were previously considered gold standard and are effective at improving clinical signs and symptoms of PsA and reducing radiographic progression of disease.16 Currently, five TNF inhibitors (etanercept, adalimumab, golimumab, certolizumab and infliximab) are approved for the treatment of PsA. The efficacy and safety of these agents are comparable;17,18 ultimately, the choice of agent depends on factors such as patient preference for route and frequency of administration, physician experience, availability, and cost. Patients must be screened for latent tuberculosis and hepatitis B virus (HBV) infections and treated prophylactically if there is evidence of current or prior infection.19 Moreover, TNF inhibitors are contraindicated in patients with significant heart failure, recent malignancy or a family history of multiple sclerosis.20,21 Newer classes of biologics have also been approved for the treatment of PsA and these include cytokine inhibitors anti-IL-17 (secukinumab and ixekizumab), anti-IL-12/23 (ustekinumab), and anti-IL-23 (guselkumab and risankizumab). These cytokine inhibitors have proven to be effective in treating PsA and are especially useful in patients who have contraindications to TNF inhibitors, but caution should be exercised with IL-17 inhibitors in patients with a history of inflammatory bowel disease.

Risankizumab for the Treatment of Psoriasis

Risankizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that targets the p19 subunit of IL-23. In 2019, it was approved for the treatment of moderate-to-severe plaque psoriasis. Administration follows a dosing schedule of 150 mg at week 0, week 4, and then every 12 weeks thereafter. Several clinical trials have established its ability to treat psoriasis with high efficacy and safety compared to biologics from each of the other classes. Two randomized, double-blinded phase 3 trials, UltIMMA-1 (n = 506) and UltIMMa-2 (n = 491), showed that risankizumab has significantly greater efficacy than ustekinumab and placebo.22 Skin clearance was seen as early as 4 weeks of treatment. Treatmentrelated adverse events (TEAEs) were comparable across all groups. Risankizumab was also proven superior to adalimumab in the phase 3 trial IMMvent (n = 605) where subjects were randomly assigned to a standard dosing regimen of risankizumab or adalimumab.23 Efficacy was measured by the Psoriasis Area and Severity Index (PASI) and after 16 weeks of treatment 70% of patients on risankizumab achieved a 90% decrease in their PASI score from baseline (PASI90), compared to 44% those on adalimumab. In the phase 3b trial IMMerge, risankizumab was found to be superior to secukinumab at week 52 with PASI90 rates of 86.6% for risankizumab versus 57.1% for secukinumab.24 These head-to-head studies have demonstrated risankizumab’s superior efficacy for plaque psoriasis when compared to adalimumab, ustekinumab and secukinumab.

Risankizumab for the Treatment of PsA

Given the critical role that IL-23 plays in the pathogenesis, risankizumab is an important therapeutic option for PsA. In a phase 2 trial, 185 subjects with active PsA were randomized into five groups: risankizumab 150 mg at week 0, 4, 8, 12 and 16 (arm 1); risankizumab 150 mg at week 0, 4 and 16 (arm 2); risankizumab at week 0 and 12 (arm 3); risankizumab 75 mg at week 0 (arm 4), or placebo.25 The primary endpoint at week 16 was American College of Rheumatology 20 (ACR20) response. ACR20 is a composite measure defined as a 20% improvement from baseline in the number of tender and swollen joints, and a 20% improvement in three or more of five variables: patient-assessed global activity, evaluator-assessed global activity, patient pain activity, functional disability, and acute phase response (ESR or CRP). Secondary endpoints included ACR50/70, dactylitis count, Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index, and health assessment questionnaire and disability index (HAQDI), a questionnaire designed to evaluate functional status and QoL in patients with arthritis. After 16 weeks of treatment, ACR20 was significantly higher across all treatment arms (57.1- 65.0%) compared to placebo (35.7%). ACR50 was higher across all treatment arms, and significant in arm 3 (39%) compared to placebo (12%). ACR70 was also higher across all treatment arms, and significant in arms 1, 1+2, 3 and 4 (14.3-25.6%) compared to placebo (0.0%). PASI75/90/100 responses were also significantly greater in all treatment groups (PASI75: 67-75%, PASI90: 52- 67%; PASI100: 33-56%) compared to placebo (10%; 10%; 7%, respectively). Dactylitis counts were similar across all groups, and improvements in enthesitis and HAQ-DI were greater in treatment groups compared to placebo but not statistically significant. Of the 185 subjects enrolled in the study, 145 continued in a 52-week single arm open-label extension (OLE). Subjects received 150 mg of risankizumab every 12 weeks for 36 weeks and continued to respond positively over all efficacy measures during this period. TEAEs were comparable in all arms and were similar in the 24- week study and OLE. Approximately 60% of subjects experienced a TEAE, with the most common being viral upper respiratory tract infection (11%). There was one serious adverse event (SAE) reported, but no malignancies, deaths or active cases of tuberculosis. Overall, risankizumab was well-tolerated and only 3.4% of patients discontinued due to side effects.

Notably, risankizumab was not found to be effective in the treatment of ankylosing spondylitis (AS)26 in a double-blinded phase 2 study. In this trial, 159 subjects were randomized to four treatment groups (risankizumab 18 mg one dose at week 0; risankizumab 90 or 180 mg at week 0, 8, 16 and 24; and placebo) over a 24-week period. The primary endpoint was Ankylosing Spondylitis Disease Activity Score (ASDAS) 40, a composite measure defined as a 40% improvement from baseline in three or more out of four variables: back pain, peripheral pain and swelling, duration of morning stiffness and patient global assessment. After 12 weeks of treatment, risankizumab failed to meet the primary endpoint as ASDAS40 responses were comparable and non-significant in treatment groups (15.0-25.0%) and placebo (17.5%). Similarly, in three multicentered, randomized, placebo-controlled studies, patients with AS were treated with ustekinumab.22 However, ustekinumab also did not demonstrate clinical efficacy in treating AS, as it failed to meet both primary and secondary endpoints including Assessment in Ankylosing Spondylitis (ASAS)20/40. These studies support the hypothesis that axial disease is driven by different mechanisms that are less reliant on IL-23.27,28

Development Program for PsA

Pivotal phase 3 studies of risankizumab in PsA are currently ongoing. Two randomized, double-blinded studies compare risankizumab to placebo in subjects with active PsA who have failed to respond to at least one csDMARD (KEEPsAKE-1, NCT03675308) or bDMARD (KEEPsAKE-2, NCT03671148).29,30 Subjects were randomized 1:1 to the treatment group (risankizumab at week 0, 4, 16 or 24) or placebo for a 24-week period. The study design for these trials is shown in Figure 1.

Risankizumab in Adults with Psoriatic Arthritis - image
Figure 1. KEEPsAKE-1 and KEEPsAKE-2 study design. Patients were randomized into a treatment group (risankizumab [RZB] 150 mg at week 0, 4, 16 or 24) or placebo for a 24-week period. At week 16, patients were classified as non-responders if they did not achieve a 20% or more improvement in their tender joint count and/or swollen joint count at weeks 12 and 16. Non-responders were given the option to change or add concomitant therapy, and were discontinued from the study drug at 36 weeks. Patients were given the choice to enroll in an open label extension for a total of a 208-week period. csDMARD-IR, conventional systemic disease-modifying antirheumatic drug inadequate responder.
The primary endpoint of ACR20 was assessed after 24 weeks, and key secondary endpoints included ACR50/70, HAQ-DI, PASI90, and minimal disease activity (MDA) index as well as resolution of enthesitis and dactylitis (Table 1a). In KEEPsAKE-1, ACR20/50/70 response rates were significantly higher in subjects on risankizumab (57/33/15%) compared to those in the placebo group (34/11/5%) (Figure 2). Subjects receiving risankizumab achieved greater resolution of enthesitis at week 24 (risankizumab: 51%, placebo: 37%) and dactylitis (risankizumab: 67%, placebo: 54%) as well as a greater change from baseline in HAQ-DI compared to placebo (risankizumab: -0.31, placebo: -0.11). Significantly higher response rates were also observed with PASI90 and MDA for subjects on risankizumab (PASI90: 52%; MDA: 25%) compared to placebo (10%; 10%).

Risankizumab in Adults with Psoriatic Arthritis - image
Figure 2. Proportion of patients (%) on risankizumab or placebo achieving ACR20/50/70 response at week 24 (Period 1) and week 52 (Period 1 and 2); *p<0.001.

Similarly in KEEPsAKE-2, ACR20/50/70 response rates at week 24 were significantly higher with risankizumab (risankizumab: 51/26/12%; placebo:27/9/6%) (Figure 3). Subjects in the treatment group achieved greater resolution of enthesitis at week 24 (risankizumab: 43%, placebo: 30%) and dactylitis (risankizumab: 73%, placebo: 42%) and a greater change from baseline in HAQ-DI (risankizumab: -0.22; placebo: -0.05). In addition, PASI90 and MDA response rates were significantly higher with treatment (PASI90: 55%; MDA: 26%) compared to placebo (10%; 11%). Overall, in both trials, risankizumab produced more favorable outcomes in reducing disease activity, the number of affected joints, as well as improving psoriasis clearance and QoL.

Risankizumab in Adults with Psoriatic Arthritis - image
Figure 3. Proportion of patients (%) on risankizumab or placebo achieving ACR20/50/70 response at week 24 (Period 1) and week 52 (Period 1 and 2); *p<0.001, †p<0.05.

After week 24, patients continued in an open label extension (OLE, Period 2) and received risankizumab 150 mg every 12 weeks until week 208. ACR 20/50/70 rates continued to improve to week 52 in KEEPsAKE-1 (risankizumab: 70/43/26% and placebo to risankizumab: 63/37/20%) and KEEPsAKE-2 (risankizumab: 59/32/17% and placebo to risankizumab: 56/32/21%) (Table 1b). Pooled data from both studies showed resolution of enthesitis in 55% of patients receiving risankizumab from baseline and in 57% of patients who transitioned from placebo to risankizumab in Period 2. Similarly, pooled data for resolution of dactylitis was reported in 76% of risankizumab patients and 73% of placebo to risankizumab patients in Period 2. The mean change in HAQ-DI at week 52 was -0.41 and -0.32 in risankizumab and placebo to risankizumab, respectively, in KEEPSaKE-1 and -0.26 and -0.34 in risankizumab and placebo to risankizumab, respectively, in KEEPSaKE-2. PASI90 responses were stable (risankizumab: 68% and placebo to risankizumab: 60%) in KEEPSaKE-1 and (risankizumab: 64% and placebo to risankizumab: 60%) in KEEPSaKE-2. The proportion of patients achieving MDA improved through week 52 (risankizumab: 38% and placebo to risankizumab: 27%) in KEEPSaKE-1 and (risankizumab: 27% and placebo to risankizumab: 34%) in KEEPSaKE-2 (Table 1b).

Adverse events were similar across all groups as of the data cut-off for week 52 analysis. By week 24, serious infection was reported in 2.7-2.9 events per 100 patient years (E/100PYs) of patients on risankizumab and did not increase in the long-term 52-week analysis (2.8 and 2.0E/100PY in KEEPsAKE-1 and -2, respectively). Serious TEAEs also did not increase from week 24 with 7.4E/100PY in KEEPsAKE-1 and 9.4E/100PY in KEEPSaKE-2 in the long-term. There were no reports of active tuberculosis or anaphylaxis in either study, but there was one case of oropharyngeal candidiasis in each study. There were no deaths in KEEPsAKE-2 but there were two deaths in KEEPsAKE-1; an 81-year-old male with dementia who was hospitalized with pneumonia and died of urosepsis and a 41-year-old male experienced sudden death on day 502. There were no reports of major cardiovascular events in KEEPsAKE-1 and three events in KEEPsAKE-2 which were reported as a non-fatal stroke in a patient with a history of hypertension and two non-fatal myocardial infarctions in patients with risk factors. Once again, risankizumab proved to be well-tolerated and discontinuation due to adverse events was low and occurred in 2.3E/100PY in KEEPSaKE-1 and 1.6E/100PY in KEEPSaKE-2.

Future Outlook

PsA is a multi-faceted, complex disease affecting multiple domains including skin, entheses, peripheral and axial joints. Although there are currently many options for treatment, there remains an unmet need for more efficacious and safer options. The addition of IL-23 inhibitors to the therapeutic landscape is welcomed given their tolerability, safety, and convenience of use. Conventional treatments for PsA including methotrexate, sulfasalazine, and leflunomide are burdened with tolerability issues, adverse effects, and end-organ toxicity. Newer oral agents also present challenges. Apremilast provides modest benefit but has issues with gastrointestinal intolerance and headaches. The JAK inhibitors are efficacious but have a boxed warning for serious infection and venous thromboembolism; more recent warnings for tofacitinib of cardiovascular events and malignancy, based on results from the ORAL Surveillance study,31 may make their use unsuitable in high-risk patients. The strength of IL-23 inhibition is the proven safety of this class in the psoriatic population. There is no signal for tuberculosis or other serious infections and can safely be used in patients with other comorbidities such as cardiac, renal, or hepatic disease. The convenient dosing schedule of injections as frequent as every 8 weeks to as infrequent as every 12 weeks will contribute favorably to QoL for patients by reducing the treatment burden and improving adherence. The current agents approved for use in PsA to target IL-23 are guselkumab, risankizumab and ustekinumab.

Risankizumab provides efficacy similar to that of other biologic agents for PsA, however the effect may take longer as we have not observed the early responses seen with other agents such as JAK inhibitors or IL-17 blocking agents. Guselkumab has shown in a network meta-analysis to have efficacy similar to IL-17 and TNF-α inhibiting biologic therapies supporting the important role of blocking IL-23 in the management of PsA.32 For patients with a prominent skin domain, targeting IL-23 may be preferred as it is very effective at clearing the skin in the majority of patients. Limiting its use will be the lack of efficacy in AS and further research will be required to understand the impact of risankizumab on axial PsA.

Conclusion

When choosing a treatment for PsA, ACR scores only tell part of the story, and we need to consider other disease measures such as enthesitis, dactylitis and QoL scores such as HAQ-DI, which were all shown to be significantly improved with risankizumab compared to baseline. Risankizumab has the potential to offer a treatment with a combination of efficacy, safety, convenience and overall improvement in QoL. However, more data is required and the complete long-term 208-week results from clinical studies for the management of PsA are eagerly anticipated.

References



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]]> Dupilumab for the Treatment of Prurigo Nodularis https://www.skintherapyletter.com/dermatology/dupilumab-prurigo-nodularis/ Tue, 12 Dec 2023 20:22:23 +0000 https://www.skintherapyletter.com/?p=14919 Ayaa Alkhaleefa, BHSc; Taylor Evart Woo, MD, MSc; Laurie Parsons, MD, FRCPC

Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

Conflict of interest: Ayaa Alkhaleefa, Taylor Evart Woo, and Laurie Parsons have no relevant disclosures. Funding sources: None.

Abstract: Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by the presence of pruritic nodules. Dupilumab was approved by the US Food and Drug Administration in September 2022 and Health Canada in July 2023 for the treatment of PN. Dupilumab is a human monoclonal immunoglobulin G4 antibody that binds the interleukin (IL)-4 receptor alpha subunit, blocking intercellular signalling of IL-4 and IL-13. Inhibition of these cytokines downregulates the inflammatory response and improves disease severity and pruritus. Two randomized controlled trials have shown dupilumab to be effective in reducing pruritus and lesion count in patients with PN. The approval of dupilumab for PN represents the first approved therapy for PN and may indicate a paradigm shift in the way this condition is treated.

Keywords: dupilumab, Dupixent®, immunomodulator, biologic, prurigo nodularis, nodular prurigo, clinical trial

Introduction

Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by prurigo nodules, a cutaneous reaction pattern in which pruritus is a central component.1,2 It presents with papulonodules distributing along the trunk and extensor surfaces and ranges from few to hundreds of lesions.2,3 It is among the dermatoses that demonstrate the “butterfly sign”, where skin on the upper back is spared.4 The mean age of patients with PN is 50.9 years, and it is slightly more common in females who have darker skin phototypes.4 PN may be associated with underlying systemic diseases, including chronic obstructive pulmonary disease, congestive heart failure, chronic nephritis, type 2 diabetes mellitus, or the human immunodeficiency virus (HIV) infection. Clinical features of PN include intense pruritus that is present constantly, intermittently, or paroxysmally for ≥6 weeks. The diagnostic workup for PN includes a complete blood cell count with differential, liver and renal function tests, diabetes screening, thyroid function testing, infectious etiologies including viral hepatidies, and excluding other systemic etiologies.3

The pathogenesis of PN involves immune and neural dysregulation.3-5 Biopsy of prurigo lesions show dense dermal, interstitial, and perivascular infiltrates in the dermis.3 These infiltrates primarily consist of increased numbers of T-lymphocytes, mast cells, and eosinophilic granulocytes. These collections of immune cells generate a robust inflammatory response releasing interleukin (IL)-31, tryptase, eosinophil cationic protein, histamine, prostaglandins, and neuropeptides causing an intractable itch. In addition, there is upregulation of several neuropeptides such as calcitonin gene-related peptide and substance-P. Upregulation of neuropeptides promotes their secretion into cutaneous tissue via nerve fibers, ultimately causing neurogenic inflammation.

Treatment options for PN involve addressing potential underlying causes, providing symptomatic relief, and breaking the itchscratch cycle.3,6 The first-line topical therapy for PN is high potency topical corticosteroids, such as betamethasone valerate 0.1% tape.3 Other treatment options include topical calcineurin inhibitors, topical capsaicin, neuromodulators (gabapentinoids, cannabinoids, or anesthetics), antidepressants, phototherapy, and immunosuppressants. However, many treatments for PN are commonly used off-label and there exists variability in dosing regimens, leading to varying degrees of efficacy and clearance rates.7

Dupilumab represents the first and only US FDA and Health Canada approved medication for the treatment of PN.8 Dupilumab is a human monoclonal immunoglobulin G4 antibody that works by binding the IL-4 receptor alpha subunit shared by the IL-4 and IL-13 receptor complexes (Figure 1). Binding to this subunit inhibits both the inflammatory and pruritic processes, which are integral components in managing the itch-scratch cycle. IL-31 is a cytokine that is associated with the immune cascade and is believed to contribute towards symptoms of intense pruritus in PN.4,6

Dupilumab for the Treatment of Prurigo Nodularis - image
Figure 1. The mechanism of action of dupilumab in prurigo nodularis (PN). PN induces a type-2 inflammatory response, which involves Th2 cells. Th2 cells secrete interleukins 4, 5, and 13 and stimulate type 2 immunity, which is characterized by high immunoglobulin E antibody titers and eosinophilia. Cessation of the inflammatory response triggered by Th2 cells inhibits the ability of eosinophils and mast cells to produce neuroinflammatory peptides and begin the allergic inflammatory response, respectively. Figure created using BioRender.com.

Supporting Evidence for Dupilumab Monotherapy

The clinical trials involved in the regulatory approvals of dupilumab for PN, PRIME and PRIME2, showed significant improvement in the treatment of extreme pruritus and reduction in lesion count. The clinical investigations included two 24-week randomized, double-blind, placebo controlled, multicenter, parallel-group trials.9,10 Adults aged 18-80 years (n=311) with ≥20 nodules and pruritus were included. Pruritus was graded using the Worst-Itch Numeric Rating Scale (WI-NRS), where 0 indicated no itch and 10 indicated insupportable itch. Only patients with WI-NRS score of ≥7 prior to commencement of dupilumab were investigated. Additional inclusion criteria included a history of failing a 2-week course of medium-to-superpotent topical corticosteroid or when topical corticosteroids were not medically advisable. Both clinical trials assessed the effect of dupilumab in reducing the number of lesions along with pruritus improvement. Efficacy was assessed by a reduction in WI-NRS by ≥4 points and Investigator’s Global Assessment PN-Score (IGA PN-S) of 0-1, which is equivalent to a reduction in the number of nodules down to 0-5. Patients received either dupilumab 600 mg subcutaneously on day 1 followed by 300 mg once every other week for 24 weeks on a background therapy of topical corticosteroids/topical calcineurin inhibitors at a stable dose, or a matching placebo drug. The mean age of patients was 49.5 years, and 65% of subjects were female. At baseline, the WI-NRS score was 8.5, and 66% of patients had 20-100 nodules while 34% had more than 100 nodules. In addition, 43% of patients had a history of atopy.

The first clinical trial (PRIME) showed that 38.7% of patients had an improvement in both their WI-NRS score (≥4 points) and reduction in the number of nodules down to 0-5 (IGA PN-S of 0-1) versus 9.2% of patients who received placebo (Table 1).9 The second clinical trial (PRIME2) showed that 32.1% of patients had an improvement in both their WI-NRS score (≥4 points) and reduction in the number of nodules down to 0-5 (IGA PN-S of 0-1) versus 8.5% of patients who received placebo (Table 2).10 Overall, dupilumab demonstrated efficacy in treating both the extreme pruritus and for reducing the number of PN nodules over a 24- week period.

PRIME Dupilumab (n=75) Placebo (n=76)
Reduction in both WI-NRS scores by ≥4 points and an IGA PN-S scores of 0 or 1 from baseline at week 24 38.7% 9.2%
Improvement in WI-NRS score by ≥4 points 60% 18.4%
Reduction in the number of nodules down to 0-5 (IGA PN-S of 0-1) 48% 18.4%

Table 1. Outcomes assessing efficacy of dupilumab for the treatment of PN (PRIME).
PRIME2 Dupilumab (n=78) Placebo (n=82)
Reduction in both WI-NRS scores by ≥4 points and an IGA PN-S scores of 0 or 1 from baseline at week 24 32.1% 8.5%
Improvement in WI-NRS score by ≥4 points 57.7% 19.5%
Reduction in the number of nodules down to 0-5 (IGA PN-S of 0-1) 44.9% 15.9%

Table 2. Outcomes assessing efficacy of dupilumab for the treatment of PN (PRIME2).

Safety

Dupilumab appears to be safe for the treatment of PN. The most common side effects include 1-2% of patients who developed injection site reactions, which was more likely to occur with the initial loading dose. In addition, 8.6% of patients (n=152) had headache, 5.3% of patients (n=152) had nasopharyngitis, 4% (n=152) of patients developed conjunctivitis, and 3% (n=152) of patients developed herpes infection, dizziness, myalgias, and diarrhea.9,10 Serious adverse events, including neurodermatitis occurred in 1.3% of patients (n=152). The following serious adverse events occurred in <1% of the patient sample: coronavirus disease of 2019 pneumonia, musculoskeletal chest pain, papillary thyroid cancer, asthma, interstitial lung disease, pelvic inflammatory disease, acute pyelonephritis, lipoma, and uterine leiomyoma. The aforementioned adverse effects were not considered related to the study intervention, except for sepsis and mesenteritis which occurred in one patient in the placebo group.11

Combination Therapy Studies

Studies exploring combination therapies with dupilumab are limited. Kabbani et al. shared a case study of a 49-year-old woman who had psoriasis and PN and was successfully treated with a combination of dupilumab and ustekinumab.12 Ustekinumab is a human monoclonal antibody that is used to treat plaque psoriasis, psoriatic arthritis, and inflammatory bowel disease.13 It specifically inhibits the inflammatory response caused by IL-12 and IL-23. After 3 months of ustekinumab 45 mg every 12 weeks and dupilumab 600 mg loading dose followed by 300 mg every 2 weeks, the patient had complete resolution in her pruritus. After 10 months on this combination therapy, she achieved complete clearance of her nodules. The patient has been on this combined therapy for 4 years, and has maintained her clinical response in remission. The combination therapy has been well tolerated, and there have been no safety concerns reported.

Special Populations

Safety and efficacy of dupilumab for pediatric patients younger than 18 years of age with PN have not been established.9,10 PN has an incidence of 21.6 per 100,000 children and is commonly associated with atopic dermatitis.14 Few case reports have highlighted the use of dupilumab in pediatric patients. For example, a 7-year-old boy who had PN was treated with dupilumab 400 mg followed by 200 mg every 2 weeks. He was also using topical corticosteroids at the time. After 4 weeks of dupilumab therapy, the patient noted improvement in his prurigo lesions and no new lesions developed. By 12 weeks, the patient reported resolution of pruritus, and at the 1 year follow-up there were only a minimal number of active skin lesions and almost no excoriations. Overall, further clinical trials are required to determine the efficacy and safety of using dupilumab for PN in the pediatric population.

Conclusion

Dupilumab is an effective treatment for adult patients who have PN. Most notably, therapy improves the severe pruritus associated with this condition. Dupilumab has been shown to have a promising safety-profile and represents a paradigm shift in the way patients with PN are treated. However, further research is also required to determine the efficacy and safety of dupilumab for PN in the pediatric population.

References



  1. Cao P, Xu W, Jiang S, etal. Dupilumab for the treatment of prurigo nodularis: A systematic review. Front Immunol. 2023 Jan 20;14:1092685.

  2. Pereira MP, Steinke S, Zeidler C, et al.; EADV Task Force Pruritus group members. European academy of dermatology and venereology European prurigo project: expert consensus on the definition, classification and terminology of chronic prurigo. J Eur Acad Dermatol Venereol. 2018 Jul;32(7):1059-65.

  3. Williams KA, Huang AH, Belzberg M, et al. Prurigo nodularis: pathogenesis and management. J Am Acad Dermatol. 2020 Dec;83(6):1567-75.

  4. Huang AH, Williams KA, Kwatra SG. Prurigo nodularis: epidemiology and clinical features. J Am Acad Dermatol. 2020 Dec;83(6):1559-65.

  5. Hughes JM, Woo TE, Belzberg M, et al. Association between prurigo nodularis and etiologies of peripheral neuropathy: suggesting a role for neural dysregulation in pathogenesis. Medicines (Basel). 2020 Jan 8;7(1):4.

  6. Bewley A, Homey B, Pink A. Prurigo nodularis: a review of il-31ra blockade and other potential treatments. Dermatol Ther (Heidelb). 2022 Sep;12(9):2039-48.

  7. Elmariah S, Kim B, Berger T, et al. Practical approaches for diagnosis and management of prurigo nodularis: United States expert panel consensus. J Am Acad Dermatol. 2021 Mar;84(3):747-60.

  8. Center for Drug Evaluation and Research. FDA approves first treatment for prurigo nodularis [Internet]. U.S. Food & Drug Administration. Content current as of: September 29, 2022 [cited February 28, 2023]. Available from: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-firsttreatment-prurigo-nodularis

  9. Study of dupilumab for the treatment of patients with prurigo nodularis, inadequately controlled on topical prescription therapies or when those therapies are not advisable (LIBERTY-PN PRIME) [Internet]. CTG Labs – NCBI. [cited April 20, 2023]. Available from: https://beta.clinicaltrials.gov/study/NCT04183335

  10. Study of dupilumab for the treatment of patients with prurigo nodularis, inadequately controlled on topical prescription therapies or when those therapies are not advisable (PRIME2) [Internet]. CTG Labs – NCBI. [cited April 20, 2023]. Available from: https://beta.clinicaltrials.gov/study/NCT04202679

  11. Yosipovitch G, Mollanazar N, Ständer S, et al. Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials. Nat Med. 2023 May;29(5):1180-90.

  12. Kabbani M, Mboyo Mpita G, Benhadou F. Ustekinumab plus dupilumab in the treatment of concomitant psoriasis and prurigo nodularis. J Eur Acad Dermatol Venereol. 2022 Dec;36(12):e1050-1.

  13. Colquhoun M, Kemp AK. Ustekinumab. [Updated 2023 Mar 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK570645/

  14. Oliveira J, Nogueira M, Pinto D, et al. Role of dupilumab in pediatric prurigo nodularis: Beyond the skin. Pediatr Allergy Immunol. 2023 Jan;34(1):e13912.


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