¹Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, USA
²Division of Dermatology, University of Calgary, Calgary, AB, Canada
³Beacon Dermatology, Calgary, AB, Canada

Conflict of interest: Leah Johnston does not have any conflicts of interest to disclose. Andrei Metelitsa has been an advisor and speaker for AbbVie, Eli Lilly, Galderma, Leo, Pfizer, Sanofi. Susan Poelman has been an advisor and speaker for AbbVie, Eli Lilly, Galderma, Leo, Pfizer, Sanofi.
Funding sources: None.

Abstract:
Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that impacts approximately 10-15% of the population in the United States and Canada. Lebrikizumab is a novel systemic human monoclonal immunoglobulin G4 antibody that inhibits the activity of interleukin-13. In June 2024, lebrikizumab was approved by Health Canada for the treatment of moderate-to-severe AD in adults and adolescents who are 12 years of age and older, followed by US Food and Drug Administration approval in September 2024. This review provides an overview of data from clinical trials on the efficacy and safety of lebrikizumab in adult patients.

Keywords:atopic dermatitis, lebrikizumab, interleukin-13, IL-13, biologics, eczema, dermatitis

Introduction

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that presents with pruritic, erythematous, eczematous patches and plaques that has a predilection for flexural sites. The estimated prevalence of AD in Canada and the United States is 8-16% in adolescents aged 12-17 years and 2-11% in adults.^1-7 Approximately 40% of AD patients have moderate-to-severe disease.⁷ AD has a significant negative impact on quality of life in individuals with the condition and is associated with increased rates of anxiety, depression, and sleep disturbances.⁸ Additionally, AD can be costly to manage for both patients and the healthcare system at large, and previous studies have found that AD has a major adverse impact on workplace productivity and absenteeism.⁸

First-line treatments for AD include emollients with use of wet wraps and topical agents including corticosteroids, calcineurin inhibitors, phosphodiesterase-4 inhibitors, and Janus kinase (JAK) inhibitors.⁹ Patients who do not achieve an adequate improvement with topical therapies alone or have severe, widespread AD at baseline may require narrowband phototherapy or systemic therapies to improve disease control.¹⁰ Currently, three monoclonal antibodies and two small molecule inhibitors have received Health Canada approval for the treatment of moderate-to-severe AD (Table 1).¹⁰ This review presents efficacy and safety data from clinical trials of lebrikizumab, the most recently approved treatment for AD in patients ≥12 years of age.

Table 1

Mechanism of Action

AD has numerous predisposing genetic and environmental factors that lead to a predominantly T‐helper type 2 (Th2) cell and type 2 innate lymphoid cell (ILC2)‐driven inflammatory response. Activation of Th2 and ILC2 cells leads to an increase in type 2 inflammatory cytokines, including interleukin (IL)‐4, IL‐5, IL‐13, and IL‐31.¹¹ IL‐4 is thought to primarily exert central effects by regulating the development of immune cells, such as Th2 cells, and promoting production of immunoglobulin E (IgE) by B cells. Conversely, IL‐13 primarily acts in the periphery and both cytokines are implicated in the pathogenesis of AD.¹² IL‐13 is overexpressed in AD lesions and non‐lesional skin compared to healthy controls and levels of IL‐13 in lesional skin correlate with AD severity.¹² IL‐4 and IL‐13 also contribute to cutaneous microbial dysbiosis and disruption of the skin barrier, with IL‐13 predominantly stimulating decreases in antimicrobial peptide and filaggrin protein levels and increasing local expression of IgE and migration of eosinophils.^11,13 Both IL‐4 and IL‐13 can bind to IL‐13 receptor α1 (IL‐13Rα1), inducing the formation of a heterodimeric receptor with the IL‐4 receptor α (IL‐4Rα) subunit and subsequently activating downstream JAK1 and tyrosine kinase 2 (TYK2)‐mediated pro‐inflammatory pathways.¹¹ IL‐13 also binds to IL‐13Rα2, which plays a negative regulatory role by stimulating IL‐13 degradation.^12‐14 Different IL‐13Rα2 receptor epitopes affect IL‐13 clearance rates, which has been observed in asthma studies.¹² Dupilumab binds to IL‐4Rα in IL‐4Rα/IL‐13Rα1 receptor complexes and decreases receptor signaling.^11,15 Although both lebrikizumab and tralokinumab are monoclonal antibodies that bind to IL‐13, lebrikizumab is known to have the highest binding affinity for IL‐13.¹² Lebrikizumab‐bound IL‐13 can still bind to IL‐13Rα1, but formation of IL‐4Rα/IL‐13Rα1 receptor complexes is blocked by lebrikizumab (Figure 1). Tralokinumab prevents IL‐13 from binding to IL‐13Rα1, which also subsequently inhibits IL‐4Rα/IL‐ 13Rα1 heterodimerization.^11,12,16 Tralokinumab also inhibits binding of IL‐13 to IL‐13Rα2, which does not occur with lebrikizumab.¹² In contrast, lebrikizumab‐bound IL‐13 is transported intracellularly after binding to Il‐13Rα2, where it co‐localizes and is subsequently degraded by lysosomes.¹² This mechanism promotes for clearance of IL‐13, while the underlying mechanism of tralokinumab inhibits this process and may lead to persistence of elevated IL‐13 levels.¹²

Figure 1

Production, Administration, Ingredients, Storage and Dosing

Lebrikizumab is a humanized IgG4 monoclonal antibody that consists of two identical heavy gamma chains and two identical light chains.¹⁷ Recombinant DNA technology is used to produce lebrikizumab in Chinese Hamster Ovary cells.¹⁷

Lebrikizumab is administered via subcutaneous (SC) 125 mg/mL (250 mg in 2 mL sterile solution) injections using either pre‐filled syringes or pre‐filled pens.¹⁷ The sterile solution in lebrikizumab is comprised of acetic acid, histidine, polysorbate 20, sucrose, and water. The medication should be stored in a refrigerator with a temperature between 2 and 8 degrees Celsius.

The initial loading dose of lebrikizumab is 500 mg (two injections) at baseline and 2 weeks,¹⁷ followed by administration every 2 weeks in 250 mg SC doses until 16 weeks. After 16 weeks, the dosing frequency can be decreased to every 4 weeks.¹⁷ In some cases, patients who achieved partial responses may be recommended to continue 250 mg every 2 weeks until 24 weeks.¹⁸

Pharmacokinetics

Serum levels of lebrikizumab peak at 7-8 days after SC injections and the estimated bioavailability is 86%.^17,19 Metabolism of lebrikizumab is theorized to occur through the same protein catabolism pathways that typically degrade endogenous antibodies.^19,20 No dose adjustments are required for patients with hepatic or renal insufficiency, or geriatric patients (≥65 years of age).¹⁷

Contraindications to Lebrikizumab

Lebrikizumab is contraindicated in patients with known allergies or hypersensitivity to any ingredients in its formulation.¹⁷ Clinical trials for lebrikizumab have not been conducted in pediatric patients <12 years of age or >12 years who weigh less than 40 kg, and therefore, it is not currently approved by Health Canada for use in these individuals.¹⁷ Lebrikizumab is not currently recommended in pregnant individuals due to a lack of safety data in humans.¹⁷ As lebrikizumab is an IgG4 antibody, it is able to cross the placenta. However, studies in pregnant monkeys that tested lebrikizumab at exposure levels that were 18 to 22‐fold higher than the dosages used in humans, no adverse fetal effects were observed.¹⁷ Fetal serum levels of lebrikizumab were approximately 30% of maternal serum levels.¹⁷ Recent clinical practice guidelines suggest that dupilumab is likely to be safe during pregnancy and other biologics targeting similar pathways are expected to have similar pregnancy safety profiles, though this conclusion cannot be drawn due to the current lack of safety data.²¹

Clinician-Reported Efficacy Data from Phase 2 and 3 Clinical Trials in AD

Three phase 2 clinical trials have been conducted to evaluate the efficacy of lebrikizumab in adults with moderate-to-severe AD (Table 2).^16,22,23 Following completion of phase 2 trials, which demonstrated efficacy for improving AD as well as high safety and tolerability, six phase 3 clinical trials of lebrikizumab have been completed.^24-31 Additional long-term phase 3 efficacy and safety trials are currently being conducted.^32,33

Table 2

The ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) monotherapy, randomized, phase 3 placebo-controlled trials further demonstrated the efficacy of lebrikizumab as a treatment for AD.^24-26 The ADvocate trials enrolled both adolescents ≥12 years of age and adults.^24-26 The primary outcome in both trials was the proportion of participants who achieved an Investigator Global Assessment score (IGA) of 0 or 1 at 16 weeks, representing complete or near complete clearance of AD.²⁴ The secondary efficacy outcome was the proportion of participants who achieved Eczema Area and Severity Index (EASI)-75, indicating ≥75% improvement from baseline, at 16 weeks. In ADvocate1, 43.1% of the lebrikizumab group and 12.7% of the placebo group achieved an IGA score of 0 or 1 at 16 weeks (P < 0.001).²⁴ EASI-75 was achieved by 58.8% and 16.2%, respectively (P < 0.001).²⁴ In ADvocate2, 33.2% of the lebrikizumab group and 10.8% of the placebo group had IGA 0/1 scores at 16 weeks (P < 0.001), and EASI-75 was achieved in 52.1% and 18.1%, respectively (P < 0.001).²⁴ After 16 weeks, patients in the ADvocate1 and ADvocate2 trials who received treatment with lebrikizumab were randomized to either continue 250 mg every 2 weeks, switch to lebrikizumab 250 mg every 4 weeks, or discontinue treatment with lebrikizumab.²⁵ The primary efficacy endpoint, IGA 0/1, was maintained in 71.2% of the lebrikizumab every 2 weeks group, 76.9% of the lebrikizumab every 4 weeks group, and 47.9% of the group that was switched to placebo after week 16.²⁶ The group that received lebrikizumab 250 mg every 4 weeks had the highest proportion of participants who maintained EASI-75 at the end of 52 weeks of treatment (81.7%), compared to 78.4% of patients in the lebrikizumab 250 mg every 2 weeks group and 66.4% of the lebrikizumab discontinuation group.²⁵ No fluctuations in maintenance of EASI-75 occurred in 70.8% of the lebrikizumab every 2 weeks group, 71.2% of the lebrikizumab every 4 weeks group, and 60.0% of the lebrikizumab withdrawal group.²⁶ During the maintenance treatment period (weeks 16 to 52) in the ADvocate1 and ADvocate2 trials, 12.4% of the lebrikizumab every 2 weeks group, 16.1% of the lebrikizumab every 4 weeks group, and 18.3% of the lebrikizumab withdrawal group required treatment with topical therapies to optimize control of their AD.²⁵

The ADhere trial (NCT04250337) was a 16‐week, phase 3 randomized, placebo‐controlled trial of lebrikizumab, combined with low to mid‐potency topical corticosteroids and/or topical calcineurin inhibitors, which participants were instructed to use on an as‐needed basis.²⁷ The primary endpoint, attainment of IGA 0/1 at 16 weeks, occurred in 41.2% of patients in the lebrikizumab 250 mg every 2 weeks group and 22.1% of the placebo injection group (P = 0.01).²⁷ EASI‐75 was achieved in 69.5% of lebrikizumab and 42.2% of placebo group patients (P < 0.001).²⁷ The mean proportion of topical therapy‐free days at 16 weeks was numerically greater in the lebrikizumab group, but this difference was not statistically significant.²⁷

The ADjoin (NCT04392154) trial is a phase 3, long-term, efficacy and safety trial that is pending completion. Preliminary data from this trial demonstrated that 76% of the ADvocate1 and ADvocate2 trial participants and 79% of the ADhere trial participants maintained IGA 0/1 after 2 years of treatment with lebrikizumab at 250 mg every 4 weeks maintenance dosing.²⁸ This data suggests that lebrikizumab is an effective long-term therapy for maintaining complete or near-complete clearance of AD in patients who have optimal responses at 16 weeks.²⁸

Clinician-Reported Efficacy Data from Phase 3 Trials in Pediatric Patients with AD

The ADore trial (NCT04250350) analyzed the effects of lebrikizumab exclusively in adolescent patients between 12 and 17 years of age with moderate‐to‐severe AD.²⁹ Patients received 500 mg loading doses of lebrikizumab at baseline and week 2, followed by 250 mg every 2 weeks throughout the 52‐week trial.²⁹ The primary endpoint was safety and the proportion of participants who discontinued lebrikizumab due to adverse events. At 4 weeks, 28.6% of patients achieved EASI‐75, which rose to 73.2% at week 16 and continued to steadily increase to 81.9% at the end of the 52‐week trial.²⁹ IGA 0/1 was achieved in 14.4% at week 4, 46.3% at week 16, and 62.6% at week 52.²⁹ Rescue therapies were needed in 27.2% of participants.²⁹ The ADorabale‐1 (NCT05559359) and ADorable‐2 (NCT05735483) trials, two phase 3 placebo‐controlled randomized controlled trials (RCTs) in children aged ≥6 months, are currently in progress.^32,33

Subset efficacy analyses from the ADvocate1, ADvocate2, and ADhere trials found that data collected from adolescent patients were consistent with overall population outcomes.³⁰

Effects of Lebrikizumab on Vaccine-Induced Immune Responses

The ADOPT-VA trial (NCT04626297) was a phase 3 placebo-controlled RCT that was conducted to analyze responses to non-live vaccines in patients receiving treatment for AD with lebrikizumab.³¹ No differences in response rates between the lebrikizumab and placebo groups were observed following the meningococcal conjugate vaccine and the tetanus toxoid booster vaccine.³¹ Improvements in AD severity and symptoms were similar to results from other lebrikizumab trials.³¹

It is recommended that patients receive age-appropriate live vaccinations prior to starting lebrikizumab, as they are contraindicated during treatment.¹⁷

Patient‐Reported Outcomes

Across published phase 2 and 3 trials, patients who received lebrikizumab 250 mg every 2 weeks had significantly higher rates of achieving a ≥4‐point decrease in Pruritus Numerical Rating Scale severity scores compared to the placebo groups.^16,24,27,31 At 52 weeks, more than 60% of participants in the ADvocate1 and ADvocate2 trials maintained this improvement.²⁶ Additionally, sleep loss and the interference of pruritus with sleep were significantly better with lebrikizumab compared to placebo,³⁴ Furthermore, these improvements were associated with higher Dermatology Life Quality Index ratings.³⁵ Patients in the ADvocate1 and ADvocate2 trials who received treatment with lebrikizumab also experienced significant improvements in depression and anxiety ratings compared to placebo.³⁶

Safety Data

A pooled safety analysis of the eight clinical trials of lebrikizumab for AD found that the rates of adverse events (AEs) were 49.2% in participants who were treated with lebrikizumab 250 mg every 2 weeks and 53.1% in participants who received treatment with a placebo, of which 2.3% and 4.4% were classified as severe AEs, respectively.³⁷ AEs leading to treatment discontinuation occurred in 2.3% of lebrikizumab 250 mg every 2 weeks and 1.4% of placebo group participants.³⁷

Conjunctivitis was the most common treatment-emergent adverse event (TEAE) in the lebrikizumab groups (6.5%).³⁷ Allergic conjunctivitis was reported in 1.8% of the lebrikizumab 250 mg every 2 weeks groups and in the TREBLE RCT, more than half (53%, n=8/15) of all instances of conjunctivitis were allergy-related.^22,37 Approximately 20% of patients in both the lebrikizumab and placebo groups had a past history of conjunctivitis at baseline, but only 1.8% of the placebo groups developed the condition during the trials.³⁷ Targeting IL-13 signaling is theorized to interfere with maintenance of the conjunctival mucosa by decreasing levels of conjunctival goblet cells, thereby increasing the risk of conjunctivitis.³⁷ Other TEAEs that were more common in participants who received lebrikizumab included nasopharyngitis (4.4%), headache (4.4%), dry eye (1.4%), allergic rhinitis (1.0%), and injection site reactions (2.5%).³⁷ No participants developed anaphylaxis or hypersensitivity reactions.³⁷ Eosinophilia occurred more frequently in the placebo groups (0.8%) than the lebrikizumab every 2 weeks groups (0.6%).³⁷

The lebrikizumab every 2 weeks groups developed herpes zoster (0.6%) and herpes simplex (0.3%) infections at higher rates compared to the placebo groups, in which no cases were reported.³⁷ Eczema herpeticum was not reported in patients receiving lebrikizumab every 2 weeks, while the incidence was 0.7% in the placebo groups.³⁷ Lebrikizumab could theoretically increase the risk of helminth infections, though this was not observed in the lebrikizumab every 2 weeks trial groups.^17,37 No confirmed opportunistic infections occurred in any of the lebrikizumab or placebo groups.

Non‐melanoma skin cancers (NMSC) occurred in 0.3% of the lebrikizumab 250 mg every 2 week groups and 0.5% of the placebo groups.³⁷ No other malignancies were observed during the 16‐week trial period in the lebrikizumab 250 mg every 2 weeks and placebo groups.³⁷ In a pooled analysis of all participants who received lebrikizumab with any dosing protocol (including a single dose at baseline), 0.3% of participants developed NMSC and 0.4% developed other malignancies, including prostate cancer (n=1), cutaneous T‐cell lymphoma (n=2), endometrial adenocarcinoma (n=1), invasive breast cancer (n=1), a neuroendocrine tumor (n=1), and metastatic pancreatic carcinoma (n=1).³⁷ All malignancies were classified as unrelated to lebrikizumab by the study investigators and were similar to expected malignancy rates.³⁷

Data from Clinical Trials for Asthma

Asthma is a common comorbidity of AD and in patients with both moderate‐to‐severe asthma and AD, consideration should be given to systemic therapies that can optimize management of both conditions. Some phase 2 and 3 trials of lebrikizumab found reductions in rates of asthma exacerbations and hospitalizations in adolescents and adults with poorly controlled asthma, though other studies have failed to demonstrate consistently significant results.^38‐40

Efficacy Comparison of Lebrikizumab to Other Biologics and Small Molecule Inhibitors for AD

A 2024 network meta‐analysis of RCTs that investigated biologics and small molecule inhibitors for moderate‐to‐severe AD found that lebrikizumab, along with dupilumab and tralokinumab, had intermediate efficacy and the most favorable safety profiles.⁴¹ While JAK inhibitors, including upadacitinib and abrocitinib, have demonstrated the highest efficacy in improving AD, they were associated with significantly higher rates of AEs. Compared to dupilumab, lebrikizumab has shown a slightly reduced but non‐significant difference in reducing EASI scores from baseline, though dupilumab was associated with a higher chance of achieving EASI‐50 and IGA 0/1 at 16 weeks.^42,43 Lebrikizumab showed comparable or superior performance to tralokinumab for clinician and patient‐reported efficacy measures.^41,42

A comparative study that analyzed propensity‐matched participant cohorts based on week 16 EASI and % BSA scores from the ADvocate trials and the SOLO‐CONTINUE dupilumab phase 3 RCT found that lebrikizumab every 4 weeks showed comparable or superior maintenance of efficacy outcomes between week 16 and week 52.⁴³ Lebrikizumab may be advantageous due to the less frequent dosing schedule during the maintenance phase, as the FDA‐approved maintenance frequency of dupilumab is every 2 weeks.⁴³

Conclusion

Lebrikizumab is a novel monoclonal IgG4 antibody that targets IL‐13 and prevents IL‐4Rα/IL‐13Rα1 receptor signaling and is approved by Health Canada for the treatment of moderate‐to‐severe AD in adolescents 12 years or older and adults. Lebrikizumab has comparable efficacy to other monoclonal antibody treatments for AD, including dupilumab and tralokinumab, requires less frequent monthly maintenance doses than dupilumab after 16 weeks, and is associated with a lower rate of adverse events compared to JAK inhibitors. Lebrikizumab is a promising option for the treatment of moderate‐to‐severe AD given its favorable safety profile, durable efficacy in long‐term follow‐up studies, and major improvements in pruritus, sleep, and overall quality of life in patients with AD.

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¹Center for Clinical Studies, Webster, TX, USA
²Department of Dermatology, University of Texas Health and Sciences Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there is no conflict of interest.
Funding sources: None.

Abstract:
Nanodermatology has been an emerging area of research and drug development in the last two decades. Nanodermatology lies at the intersection of nanotechnology, chemical engineering, biophysics, and pharmacology. Increasing research has yielded potential benefits of nanotechnology in the treatment of various skin conditions via enhanced transdermal drug delivery. Nanoparticles, defined as particles ranging from 1 to 1000 nanometers, have been more frequently explored for their potential role in targeted drug delivery systems. Nanocarriers, which include liposomes, ethosomes, and vesicle carriers, have been increasingly investigated to improve efficacy of various drugs via enhanced delivery to the target site. Many dermatologic conditions are preferentially treated with topical formulations to locally target the affected area and reduce systemic absorption, but these formulations are limited in their penetration. The ability of topical formulations to effectively deliver active ingredients to the target site is uncertain, therefore nanoparticles have been increasingly investigated as an approach to boost drug delivery to the deeper layers of the skin, improve absorption, and decrease adverse effects. Enhanced drug delivery utilizing nanoparticles has been successfully trialed for treatment of psoriasis, vitiligo, acne vulgaris, and atopic dermatitis in many research studies, however more investigation is needed prior to utilization in humans.

Keywords:nanodermatology, nanoparticles, enhanced drug delivery, nanocarriers

Introduction

Nanodermatology has been an emerging area of research and drug development in the last decades. Nanodermatology lies at the intersection of nanotechnology, chemical engineering, biophysics, and pharmacology. Increasing research has exhibited potential benefits of nanotechnology in the treatment of various skin conditions via enhanced transdermal drug delivery.¹

Nanoparticles, defined as particles ranging from 1 to 1000 nanometers, have been increasingly investigated for their potential role in targeted drug delivery systems. Nanocarriers, which include liposomes, ethosomes, and vesicle carriers, have been more frequently explored in order to improve the efficacy of various drugs via enhance delivery to the target site.

Many dermatologic conditions are preferentially treated with topical formulations to locally target the affected area and reduce systemic absorption, but topical formulations are limited in their penetration. The ability of topical formulations to effectively deliver active ingredients to the target site is uncertain, therefore nanoparticles have been increasingly investigated as an approach to increase drug delivery to the deeper layers of the skin, improve absorption, and decrease adverse effects.²

This article will discuss the promising application of nanotechnology as a route of increased transdermal drug delivery in order to treat various common dermatological conditions, including psoriasis, vitiligo, acne vulgaris and atopic dermatitis, as well as nanoparticle utilization in sun protection.

Psoriasis

Psoriasis is a common inflammatory skin disorder, affecting over 125 million people worldwide, that can range in presentation from erythematous plaques to pustules. Traditionally, mild psoriasis can be treated with topical medications, including corticosteroids, betamethasone/calcipotriol, calcineurin inhibitors, and retinoids.³ However, moderate to severe disease often requires systemic treatments such as methotrexate, cyclosporine, and biologic agents. These systemic treatments often come with the risk of significant adverse effects.

Multiple drug‐loaded nanoparticles and nanocarriers have been found to have promising potential in the treatment of psoriasis, while minimizing the risk for adverse effects and maximizing transdermal drug delivery.⁴ Tazarotene (TZ), a topical antipsoriatic retinoid with significant irritation potential, was loaded into fluidized spanlastic nanovesicles that measured about 260 nanometers. When compared to commercially available topical tazarotene, researchers found that the nanovesicles not only showed higher antipsoriatic activity in human subjects but also demonstrated deeper penetration during ex vivo testing.⁵ Tacrolimus, an immunosuppressive agent that has often been used topically to treat psoriasis, exhibits poor cutaneous bioavailability, particularly in hyperkeratotic plaques. Therefore, topical tacrolimus ointment was compared to a micelle nanocarrier tacrolimus formula. The micelle formula showed increased tacrolimus delivery into the stratum corneum and epidermis when compared to the traditional topical tacrolimus ointment.⁶

In addition to improved delivery of classic topical treatments, researchers have been utilizing nanotechnology to investigate the transdermal delivery potential of drugs traditionally used as systemic therapy, such as methotrexate and cyclosporine. Both methotrexate and cyclosporine are typically reserved for severe psoriasis due to the significant risks of toxicity and adverse effects. However, when combined with nanotechnology, these drugs can be applied topically, therefore greatly minimizing the risk for systemic adverse effects.⁴

Cyclosporine, a calcineurin inhibitor, is incredibly effective as a systemic therapy for psoriasis, but unfortunately, its use comes with risks of nephrotoxicity, neurotoxicity, metabolic disruptions, and immunosuppression.⁷ In an imiquimod induced psoriatic plaque on mice, cyclosporine‐loaded liposomes were more effective at reducing psoriatic features than cyclosporine gel.⁸

Like cyclosporine, systemic methotrexate has shown great utility in the treatment of psoriasis, however there is risk of significant side effects. In an in vivo skin deposition study, methotrexate niosomes, or non‐ionic surfactant vesicles, resulted in a greater percentage of drug deposition in the skin when compared to a simple methotrexate topical solution.⁹ Similarly, gold nanoparticles loaded with methotrexate led to improvement of scaling, erythema, epidermal thickness, and parakeratosis in mice models with imiquimod induced psoriasis. The methotrexate‐gold nanoparticles also showed deeper penetration when compared to topical methotrexate. Additionally, after treatment there was no significant difference in the blood count, AST, and ALT of the treatment group when compared to the control.¹⁰

Nanoparticles have not only allowed for greater skin penetration and drug delivery than classical topical treatments, but they have also allowed researchers to create topical formulations of systemic medications that come with risk of significant adverse effects. More research is needed to compare the efficacy of systemic therapy with nanoparticle formulations.

Vitiligo

Vitiligo, an acquired disorder characterized by the development of depigmented macules, is thought to be caused by autoimmune destruction of melanocytes. Treatment is typically focused on preventing progression and inducing some degree of repigmentation. Recent investigation into the utility of nanodermatology has led to exciting treatment potential.

Berberine, an isoquinoline alkaloid, despite exhibiting potential benefit as a topical vitiligo treatment, has limited utility due to its poor skin permeability. In order to improve delivery, berberine was loaded into hyalurosomes, which are modified nanovesicles that have enhanced skin penetration abilities and are non‐irritating. In human skin studies, berberine hyalurosomes showed greater permeability and greater drug retention when compared to a conventional berberine gel. In a vitiligo‐induced mouse model, the berberine loaded hyalurosomes showed a significant return of normal pigmentation that was greater than the conventional berberine gel.¹¹

Psoralen in combination with ultraviolet light (PUVA) is a common treatment for vitiligo. However, psoralen has weak percutaneous permeability. Resveratrol, a sirtuin activator, has the potential to manage vitiligo by reducing oxidative stress, therefore psoralen and resveratrol were loaded into ultra deformable liposomes and used as combination antioxidants in PUVA therapy for vitiligo. This combination not only demonstrated greater skin penetration but also showed significant melanin stimulation and tyrosinase activity. Administration of a nanocarrier loaded with resveratrol and psoralen in combination with UV light therapy stimulated pigment and reduced oxidative stress, making it a promising potential therapy for vitiligo.¹²

While the mechanism of vitiligo is not completely understood, oxidative stress is believed to play a significant role in the disease. Platinum and palladium have been investigated for their strong antioxidant properties as they are inducers of superoxide dismutase.¹³ PAPLAL, a topical cream consisting of platinum and palladium nanoparticles, has been shown to be an effective treatment for vitiligo that was refractory to first‐line therapies including narrow band UVB and topical corticosteroids.¹⁴

Acne Vulgaris

Acne vulgaris is one of the most common skin conditions, affecting up to 90 percent of adolescents with presentation ranging from mild to severe. The pathophysiology is multifactorial, making treatment complicated. Therapeutic options for mild to moderate acne typically consists of topical agents, including retinoids, antibiotics, benzoyl peroxide, and salicylic acid, whereas treatment for severe acne consists of oral therapy with isotretinoin, antibiotics, or hormonal agents.¹⁵

While topical tretinoin is an effective treatment, its use is limited by low water solubility and high instability in air and heat. Its use also comes with the risk of significant skin irritation and dryness. Therefore, nanocarriers have been investigated to achieve greater photostability and lower irritation potential. Tretinoin was encapsulated into solid lipid nanoparticles which improved its photostability and showed significantly less irritation when compared to the gel formula in an animal model.¹⁶

Similar to tretinoin, adapalene has been widely used in the treatment of acne vulgaris since gaining US FDA approval in 2016, however it has limited bioavailability in the hair follicle and its use also comes with the risk of irritation and dryness. Adapalene was successfully encapsulated into tyrosine derived nanospheres (TyroSphere™). In ex vivo follicular penetration studies, the tyrospheres significantly enhanced adapalene delivery to the pilosebaceous unit, when compared with commercially available adapalene. In vitro irritation studies also demonstrated decreased irritation potential of the tyrosphere formula.¹⁷

Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic inflammatory skin condition that presents with dry, eczematous, erythematous patches, and pruritus. AD is likely mediated by a combination of epidermal changes, increased immunoglobulin E levels, and T-helper 1 and 2 proliferation which leads to elevated levels of inflammatory cytokines. Traditionally, topical corticosteroids have been the treatment of choice for acute flares, however long-term use of topical corticosteroids can cause skin atrophy.

Liposomes, composed of phospholipids, have a strong affinity for the stratum corneum, allowing for increased skin permeability and uptake. Both betamethasone 17‐valerate (BMV), a moderate potency corticosteroid, and diflucortolone valerate (DFV), a high potency corticosteroid, were loaded into liposomes. The liposomes showed 2.68 to 3.22 times greater retention in the stratum corneum and epidermis when compared to the commercially available BMV and DFV creams. In pharmacodynamic evaluation, the liposome formula showed greater anti‐inflammatory activity when compared to the commercial creams, despite the liposome gel having 10 percent less active drug than the commercial cream. This result was thought to be due to enhanced delivery and decreased systemic absorption. Finally, in rat models, AD was induced by dinitrofluorobenzene, and the liposomes formulas not only showed lower erythema, edema, and scratching behaviors, but also to the commercial creams.¹⁸

In a similar study, chitosan nanoparticles were loaded with hydrocortisone (HC) and hydroxytyrosol (HT). These nanoparticles exhibited deeper penetration and a higher concentration of drug in the epidermal layer. This could reduce the dose and frequency of drug application needed for effective treatment, which could decrease the risk of adverse effects. Systemic adverse effects of glucocorticoids include hypocalcemia and hyperglycemia. When commercially available hydrocortisone was repeatedly applied to rat models, they showed a significant decrease in serum calcium concentration and an increase in serum glucose concentration, while the HC‐HT nanoparticle solution did not cause any biochemical derangements. This demonstrates that utilizing a nanoparticle drug delivery system could potentially reduce systemic adverse effects of glucocorticoids, while also increasing skin penetration.¹⁹

While corticosteroids have been considered the first‐line for AD, other topical calcineurin inhibitors, like tacrolimus and pimecrolimus, are being increasingly utilized in AD. Calcineurin inhibitors are often considered safer for long‐term use and use on sensitive areas like the face, but they often cause an uncomfortable burning sensation at the site of application. Tacrolimus has a high molecular weight and poor water solubility which limits its permeability. To reach therapeutic dosing, larger quantities of topical tacrolimus must be applied, which increases the risk of irritation. Chitosan nanoparticles were used as the carrier for tacrolimus. The nanoparticle solution led to greater drug retention in the stratum corneum, epidermis, and dermis than the commercially available cream. In AD induced rat models, AD was successfully managed with the nanoparticle solution containing one‐third the dose in the commercially available cream.²⁰

Sunscreen

Sunscreen commonly contains minerals like zinc oxide and titanium dioxide as the primary active sun protection agents. However, sunscreens with these ingredients are typically opaque and white, which lends cosmetic concerns to many users. Many cosmeceutical companies have begun incorporating nanoparticles into their sunscreens in an attempt to create a more desirable and better tolerated formula.

Sunscreens with zinc oxide and titanium dioxide nanoparticles have been shown, in an in vitro study, to provide enhanced sun protection. Additionally, sunscreen containing nanoparticles demonstrated improved texture with no residual white cast when compared to creams with zinc oxide and titanium dioxide particles.²¹

However, some studies have shown that zinc oxide and titanium dioxide nanoparticles lead to an alteration in the recommended UVA/UVB ratio. Currently, the FDA recommends that at least one‐third of the overall sun protection factor should be against UVA. Reducing the size of the zinc oxide and titanium dioxide particles confers an increased UVB protection at the expense of UVA protection. In order to mitigate this, some researchers have recommended that using various sizes of particles in one formulation, for example using micro and nano zinc oxide (20‐ 200 nanometers) particles and nano titanium dioxide (20‐35 nanometers) particles may remedy this discrepancy. However, more research is needed to determine the ideal size of particles to adhere to the recommended 3 to 1 UVB/UVA ratio.²²

Concerns

As nanoparticle use increases both in treatment of skin disease and in cosmetics, there are concerns regarding the long-term health effects and potential toxicities. The potential for nanoparticles to accumulate in the skin and contain harmful impurities are important considerations regarding toxicity.²³

Due to rising concerns that nanoparticles are depositing into deeper layers of the skin and causing cellular damage, multiple studies have sought to determine the long-term effects of utilizing nanoparticles in various formulations. One study found that both coated and uncoated zinc oxide nanoparticles localized primarily in the stratum corneum with limited penetration into viable epidermis. This study also found that the nanoparticles did not alter the skin barrier function or the redox state of the viable epidermis.²⁴ There are also concerns regarding the ability of titanium dioxide to induce DNA damage and potentially act as a carcinogen.²⁵ However, the carcinogenic effects of titanium dioxide are typically seen after subcutaneous injection or inhalation of nanoparticles.²⁶

There is conflicting data regarding the penetration of zinc and titanium nanoparticles, and thus the ability for these nanoparticles to cause damage. However, despite the conflicting data, the consensus appears to be that nanoparticles in sunscreens and skin care do not pose a health risk, however more research and collaboration is needed between the scientific and cosmetic communities as many cosmetic companies do not advertise their products as containing nanoparticles.^25,27

Conclusion

Nanoparticles, defined as a particle ranging from 1 to 1000 nanometers, have shown extremely encouraging potential in targeted drug delivery systems in the treatment of various dermatologic diseases and conditions. Not only do nanoparticles or nanocarriers exhibit increased penetration and retention of existing topical drugs, but they also have been employed to create topical formulations of drugs that are primarily given as systemic therapy. This allows drugs like methotrexate and cyclosporine to be used topically and without the risk of severe adverse effects. Overall, the utilization of nanoparticles as an enhanced drug delivery system is an incredibly promising area of research with exciting implications in the treatment of many common dermatologic conditions. Nanocarriers appear to be safe, however more research and development is needed as the majority of current research is being done in animal models. It is also important for cosmeceutical and scientific communities to collaborate on research, particularly when it comes to utilization of nanoparticles in sunscreens. Cosmetic companies should also be encouraged to publish or advertise the use of nanoparticles in their products.

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¹School of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, University of Texas Health and Sciences Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there are no conflicts of interest. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abstract:
Prurigo nodularis and atopic dermatitis are chronic, inflammatory skin conditions characterized by significant pruritus that disrupts daily life. They also involve dysfunction of the T-helper 2 immune response, leading to the over secretion of interleukin-31 (IL-13) in the dermis and serum. Nemolizumab is a new IL-31 receptor antagonist that has shown high efficacy in the treatment of prurigo nodularis (PN) and atopic dermatitis (AD) in multiple phase 3 trials, with a good safety profile. A brief overview of PN and AD including highlights of the findings from three trials of nemolizumab in treating these disorders will be presented herein.

Keywords: atopic dermatitis, interleukin-31, nemolizumab-ilto, prurigo nodularis, pruritus

Introduction

Prurigo nodularis (PN) is a chronic, inflammatory skin condition characterized mainly by pruritus, leading to a disruption of sleep and daily activities.^1,2 The pruritus is often intense, lasting over 6 weeks, and may also present with a burning or stinging sensation.^3,4 Diagnosis is primarily made by clinical examination of the lesions and through the patient’s history, revealing clusters of nodules commonly located on the extremities or trunk.³ Biopsy can also help to confirm the diagnosis in unusual cases, which typically reveals hyperkeratosis, hypergranulosis and increased fibroblasts.³

PN disproportionally impacts individuals of African ancestry and the elderly, although it can affect patients of any age.⁴ Men and women are equally susceptible.⁵ A significant number of patients also suffer from anxiety, depression, and suicidal ideation due to the severity of the condition.^2,4,5 In 2022, dupilumab became the first US Food and Drug Administration approved treatment for PN.⁶ Other conventional treatments have typically been less effective, involve off-label uses of medications and mainly aim to reduce itching by targeting the neural and immunologic aspects of the condition.³

Similarly, atopic dermatitis (AD) is also an inflammatory cutaneous disease commonly manifesting with erythema, papules, edema, and crusting.^7,8 AD most commonly affects the pediatric population, with 90% of cases first presenting with symptoms under the age of 5 years, persisting with episodical outbreaks in adulthood.⁸ AD is highly variable in presentation and current management of the condition depends on its severity.^7,9 First-line therapy involves the use of topical corticosteroids, along with emollients and regular bathing.⁹ Systemic therapies are also commonly used, including ciclosporin, methotrexate, azathioprine, and mycophenolate mofetil.¹⁰ Other treatments include calcineurin inhibitors, crisaborole, rofumilast, ruxolitinib, ultraviolet B phototherapy, and, more recently, dupilumab, tralokinumab, abrocitinib, and upadacitinib, which may be used in more severe or treatmentresistant AD.⁹

IL-31 Pathway and Mechanism of Nemolizumab

T-helper 2 (Th2) cells are primarily responsible for the release of interleukin-31 (IL-31), with CD4+, CD8+, and mast cells also producing IL-31 in the presence of allergens of pathogens.^4,11-13 This leads to the stimulation of eosinophils and contributes to the itching in AD, as well as other inflammatory skin disorders.¹¹ There are multiple proposed mechanisms as to how IL-31 leads to the pruritus in AD and PN, such as the abundance of IL-31 receptors in the dorsal root ganglia (DRG) of cutaneous sensory nerves.¹¹ IL-31 may also activate receptors present in keratinocytes, which subsequently activate unmyelinated C fibers, leading to pruritus.¹¹ Transient receptor potential cation channels in the DRG and chemokine release by keratinocytes due to IL-31 are possible additional mechanisms.¹¹

Both PN and AD are inflammatory cutaneous conditions that involve impaired IL-31 signaling.⁴ PN skin lesions form as a result of the chronic scratching induced by immunologic and neural dysfunction.⁴ Skin biopsy reveals the presence of T lymphocytes, mast cells, and eosinophils that release IL-31, tryptase, and histamine.⁴ There is also increased nerve fiber density, along with neuropeptides such as substance P and calcitonin gene-related peptide in the dermis, which contribute to the pathogenesis of pruritus in PN.^3,4 Similarly, IL-31 serum levels increase with higher severity of AD, and gene polymorphisms have been linked with the development of the disease.^4,11-13 Nemolizumab is an IL-31 receptor alpha antagonist that has shown potential in treating both PN and AD in multiple phase 3 clinical trials.⁴ These investigations demonstrated that treatment with nemolizumab reduced itch intensity, improved lesion healing and inhibited Th2 (IL-13) and Th17 (IL-17) cells.⁴

Phase 3 Clinical Trials for Prurigo Nodularis

A phase 3 clinical trial of nemolizumab in PN enrolled 274 patients, aged 18 years and older, from 68 sites and 9 different countries, for a 16-week treatment period and subsequent 8-week follow-up.⁵ Patients were selected based on a history of PN for ≥6 months and pruritus classified as severe by the Peak Pruritus Numerical Rating Scale (PP-NRS).⁵ This scale ranges from a score of 0 (no itch) to 10 (worst itch), where a score of 7 or greater is severe and qualified patients for enrollment in the trial.⁵ Patients were also selected for the presence of 20 or more nodules, and a score of 3 or 4 on the Investigator’s Global Assessment (IGA), which assesses the severity of the disease on a scale of 0-4 by the type, size and quantity of lesions.^5,14 Patients with active AD, neuropathic or psychogenic pruritus, or pruritus due to causes other than PN were excluded from the study.⁵

183 patients were randomly chosen to receive nemolizumab and another 91 patients were given a placebo.⁵ Participants were administered an initial dose of 60 mg of nemolizumab, followed by 30 mg or 60 mg based on their starting weight, every 4 weeks over a period of 16 weeks.⁵ Overall, both groups were similar and balanced prior to treatment; only 4.4% of participants were Black.⁵

19.7% and 35% of the nemolizumab group achieved almost complete itch relief at 4 weeks and 16 weeks, respectively.⁵ In the placebo group, 2.2% and 7.7% reported similar itch relief after 4 weeks and 16 weeks, respectively.⁵ 37.2% and 51.9% of patients receiving nemolizumab achieved a decrease in sleep disturbance by 4 and 16 weeks, respectively.⁵ In contrast, only 9.9% and 20.9% of the placebo group reported a clinically significant decrease in sleep disturbance.⁵ 16 week after treatment, 56.3% of the nemolizumab group and 20.9% of the control group achieved a significant decrease in itch intensity, defined as a 4 or greater point decrease on the PP-NRS.⁵ Patients who received nemolizumab demonstrated significant improvements in skin lesions, pruritus, sleep disturbance, pain, global disease assessment, quality of life, and anxiety and depression symptoms compared to the control group.⁵ Improvements in itch, skin lesions, sleep disturbance, and quality of life continued through week 52, with more than two-thirds of patients becoming itch-free or nearly itch-free and 90% reporting clinically meaningful improvement in quality of life.¹⁵ Quality of life was assessed using the Dermatology Life Quality Index (DLQI), which is composed of 10 questions designed to evaluate how patients perceive the impact of their skin condition on different areas of their life, including symptoms/feelings, daily activities, leisure, work/school, personal relationships, and treatment.⁵

61.2% of participants that received nemolizumab and 52.7% of placebo experienced at least one adverse event (AE) (Table 1).⁵ In the treatment group, most AEs were common side effects and included mild AD and headache.⁵ Peripheral or facial edema and asthma were more common in patients receiving nemolizumab, while infections were more prevalent in the control group.⁵ One case of bullous pemphigoid was reported in the nemolizumab group, and a case of generalized exfoliative dermatitis was recorded in the placebo group.⁵ In addition, a higher number of placebo patients required rescue therapy (15.4%) compared to those receiving nemolizumab (4.9%).⁵ 2.2% of patients in each group withdrew from the trial due to adverse reactions.⁵ Long-term data over a 52- week extended study remained consistent with the safety profiles in phase 3 trials.¹⁵

In patients with no history of asthma, 6 of 156 in the nemolizumab group and 2 of 77 in the placebo group had decreased expiratory flow below 80% during the treatment period.⁵ In those with a history of asthma, 5 of 22 patients receiving nemolizumab showed peak expiratory flow under 80% of the predicted value during the treatment period, however, only 2 of these were confirmed as worsening asthma.⁵ In comparison, 1 of 13 patients with a history of asthma in the placebo group experienced a peak expiratory flow under 80% of the expected value during the treatment period.⁵ An increased eosinophil count was reported in 7.7% of the nemolizumab group and 4.4% of the placebo group.⁵ Moreover, 5.8% of nemolizumab patients developed antidrug antibodies.⁵

Table 1.

Phase 3 Clinical Trials for Atopic Dermatitis

In two identical phase 3 trials of nemolizumab for the management of AD, ARCADIA 1 and ARCADIA 2, 1142 patients over the age of 12 years received 30 mg of nemolizumab (after a loading dose of 60 mg), while 586 participants were given a placebo every 4 weeks over a period of 16 weeks.¹⁶ The Eczema Area and Severity Index (EASI), which assesses the surface area of the skin affected by AD and the severity of lesions, as well as the IGA, were used to characterize the severity of AD.^16,17 Primary endpoints were defined as an IGA score of 0 or 1 with a ≥2-point improvement from baseline and at least 75% improvement in EASI.¹⁶ Patients in the nemolizumab group who successfully achieved these endpoints were then randomly reassigned in a 1:1:1 ratio.¹⁶ They were to receive either 30 mg of nemolizumab every 4 weeks, 30 mg of nemolizumab every 8 weeks, or a placebo every 4 weeks in a maintenance period.¹⁶

In the nemolizumab group, 36% of patients in ARCADIA 1 and 38% in ARCADIA 2 achieved IGA success, compared to 25% (ARCADIA 1) and 26% (ARCADIA 2) of patients in the control group.¹⁶ 75% improvement in EASI was observed in 44% (ARCADIA 1) and 42% (ARCADIA 2) of patients in the nemolizumab group, compared to 29% (ARCADIA 1) and 30% (ARCADIA 2) of those receiving placebo.¹⁶ Improvements in pruritus were observed from week 1 in the nemolizumab group, with additional improvements reported in quality of life, sleep, and a decrease in pain by 16 weeks.¹⁶ Additionally, clinically meaningful improvements in itch, skin lesions, and sleep disturbance persisted through week 56 of an extended study.¹⁸ Overall, the study showed that a statistically significant proportion of patients with moderate to severe AD achieved clinically meaningful improvements in symptoms of pruritus and inflammation with nemolizumab (Table 2).¹⁶

Table 2.

In terms of safety, 50% of patients in ARCADIA 1 and 41% in ARCADIA 2 receiving nemolizumab reported an AE, with serious effects occurring in 1% and 3% of patients in each respective trial.¹⁶ Worsening of AD was the most commonly reported adverse effect, occurring in a total of 112 patients receiving nemolizumab from both trials, compared to 49 patients in the control group. Worsening of asthma was reported in 1% of patients in ARCADIA 1 and 5% of patients in ARCADIA 2 in the nemolizumab group; however, there was no significant difference compared to those receiving placebo.¹⁶ Serious drug-related AEs were rare, reported in 5 patients in ARCADIA 2, and included infection, peripheral edema, eosinophilic colitis, and small intestinal obstruction.¹⁶ Additionally, AEs resulting in treatment discontinuation occurred in a total of 24 patients in the nemolizumab group, compared to 6 patients in the control group across both trials.¹⁶ Safety results of nemolizumab after 56 weeks aligned with previous findings, supporting its use in adolescents and adults with moderate-to-severe AD.¹⁸

Conclusion

Nemolizumab demonstrated high efficacy in the treatment of PN and AD in phase 3 trials, yielding marked improvements in symptom control with an overall favorable safety profile.^5,16 In the PN trial, a significant number of patients receiving nemolizumab exhibited improvements in pruritus, sleep disturbances, and quality of life based on the DLQI compared to the control group.⁵ The most common side effects were nasopharyngitis, AD, and headaches.⁵ In the AD trials, similar improvements in pruritus, sleep quality, and a decrease in pain levels were observed with the most common side effect being worsening of AD.¹⁶ Overall, nemolizumab has shown promising results in reducing pruritus and is particularly useful in treating severe or therapy-resistant PN and AD.^4,5,16

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¹Schulich School of Medicine and Dentistry, Western University, Windsor, ON, Canada
²Department of Health Sciences, Brock University, St. Catharines, ON, Canada
³Windsor Clinical Research Inc, Windsor, ON, Canada

Conflict of interest: Karen Michael, Jaefer Mohaad and Nuha Nasir have no conflicts. Jerry Tan is an advisor, consultant, speaker and/or trialist for Bausch, Cipher, Cutera, Galderma and Sun Pharma.

Funding sources: None.

Abstract: Clindamycin phosphate 1.2%/benzoyl peroxide 3.1%/adapalene 0.15% (IDP-126) is a novel fixed-dose triad gel combination approved by the US FDA October 2023 and by Health Canada August 2024 for the treatment of acne vulgaris in patients aged 12 years and older. IDP-126 was efficacious in moderate to severe acne compared to vehicle and component topical dyads in phase 2 and to vehicle in phase 3 randomized controlled studies. Efficacy outcomes were inflammatory and noninflammatory lesion counts and Evaluator’s Global Severity Score. IDP-126 also had a favorable tolerability and safety profile.

Keywords: acne, topical, triple combination, fixed-dose, clindamycin, adapalene, benzoyl peroxide, treatment, Cabtreo™

Introduction

The pathogenesis of acne involves different mechanisms including follicular proliferation of Cutibacterium acnes (C. acnes), follicular hyperkeratinization, inflammation, and increased sebum production.¹ Current topical medications include retinoids, benzoyl peroxide, antibiotics, azelaic acid, and dapsone – either as monads or dyads. Recently, a novel topical fixed-dose triad, combining clindamycin phosphate 1.2%/benzoyl peroxide (BPO) 3.1%/adapalene 0.15% (IDP-126) has been developed. Herein, we summarize pivotal trials leading to regulatory approval in the US and Canada.

Phase 2 Studies

The phase 2 study, conducted in the US and Canada, was randomized, controlled and double-blinded involving participants 9 years or older with moderate [Evaluator’s Global Severity Score (EGSS) of 3] to severe (EGSS 4) facial acne.² Participants were randomized to one of five different treatment groups for 12 weeks: vehicle, IDP-126 (triple combination), and the following dyad formulations: benzoyl peroxide 3.1%/adapalene 0.15% gel (BPO/ ADAP), clindamycin phosphate 1.2%/benzoyl peroxide 3.1% (CLIN/BPO), or clindamycin phosphate 1.2%/adapalene 0.15% gel (CLIN/ADAP).

Treatment success, defined by achievement of ≥2-grade reduction in EGSS and clear/almost clear (EGSS 0 or 1), was achieved by 52.5% of participants at week 12 with IDP-126. This was significantly greater than the three dyad gels (range 27.8-30.5%; P ≤ 0.001, all) and vehicle (8.1%; P < 0.001). IDP-126 resulted in significant mean reductions in inflammatory (29.9) and noninflammatory lesions (35.5) from baseline to week 12 (P < 0.05, all) compared to all dyad treatments and vehicle (Figure 1). Overall, IDP-126 demonstrated over 70% reductions in both inflammatory and noninflammatory lesions.

Phase 3 Studies

Two identical randomized, double-blind, vehicle-controlled 12-week trials were conducted in subjects aged 9 years and older in moderate to severe acne.³ Participants were randomized to IDP-126 or vehicle gel, at a 2:1 ratio. Co-primary outcomes were ≥2-grade reduction from baseline and achievement of clear/almost clear on EGSS, and changes in inflammatory and noninflammatory lesion counts.

All coprimary efficacy endpoints were achieved in both trials with IDP-126 gel outperforming vehicle at week 12. Significantly greater percentages of participants achieved a 2-grade reduction in EGSS and clear/almost clear at week 12 with IDP-126 vs. vehicle (Study 1: 49.6% vs. 24.9%, P ≤ 0.01; Study 2: 50.5% vs. 20.5%; P ≤ 0.001).

When comparing IDP-126 vs. vehicle at week 12, greater reductions were also observed in inflammatory (Study 1: 27.7% vs. 21.7%, P ≤ 0.01; Study 2: 30.1% vs. 20.8%; P ≤ 0.001) and noninflammatory (Study 1: 35.4% vs. 23.5%, P ≤ 0.01; Study 2: 35.2% vs. 22.0%; P ≤ 0.001) lesion counts (Figure 2). Significant differences in inflammatory and noninflammatory lesion counts with IDP-126 vs. vehicle were noted by week 4 (P < 0.05).

Treatment-emergent adverse events (TEAEs) were observed with greater frequency in the IDP-126 group (Study 1: 24.6% vs. 8.2%; Study 2: 30.0% vs. 8.3%) and considered related in a smaller proportion (Study 1: 18.0% vs. 0%; Study 2: 21.7% vs. 3.3%). These were primarily mild-moderate in severity and attributed to application site pain (Study 1: 10%; Study 2: 15.0%), erythema (Study 1: 4.9%; Study 2: 2.5%), dryness (Study 1: 1.6%; Study 2: 4.2%), irritation (Study 1: 0.8%; Study 2: 3.3%), exfoliation (Study 1: 3.3%; Study 2: 0%) and xerosis (Study 1: 0%; Study 2: 2.5%). Three severe adverse events were reported, all in the IDP-126 cohorts (Study 1: application site burn, n = 1, led to study withdrawal; Study 2: application site pain and dryness, n =1; application site pain, n = 1; related). No serious adverse events were reported.

Network Meta-Analysis

A network meta-analysis compared the relative efficacy of commercially available acne treatments for moderate to severe acne.⁴ Inclusion criteria were randomized controlled trials (RCTs) with minimum duration of 4 weeks involving subjects aged 9 years and older. Notably, isotretinoin studies were excluded from this analysis due to either absence of global assessments in current use for regulatory approval, or non-randomized designs. Primary outcomes evaluated were percentage of patients achieving a ≥2-grade reduction in acne severity, almost clear/clear for global severity score, and changes in inflammatory lesion (IL) counts, and noninflammatory (NIL) counts. Treatments were ranked using surface under cumulative ranking (SUCRA) values. SUCRA scores rank treatments based on their effectiveness across studies, simplifying comparison by assigning higher scores to more consistently effective treatments. The top treatments across these outcomes were: (1) IDP-126, a combination of topical antibiotics/ BPO/retinoids (SUCRA 0.96 for Global Assessment, 0.90 for inflammatory lesions, and 0.91 for noninflammatory lesions), (2) fixed-dose dyad topical treatments with oral antibiotics (SUCRA 0.88, 0.98, and 0.99, respectively), and (3) topical retinoid/ BPO combinations (SUCRA 0.74, 0.79, and 0.79, respectively). These rankings highlight the strong overall performance of these treatment combinations across different acne efficacy outcome measures. In addition to efficacy, IDP-126 showed a favorable safety and tolerability profile with lower discontinuation rates (2.8%). It also had fewer patients with TEAEs than dyads.

Conclusion

The topical fixed-dose triad of clindamycin phosphate 1.2%/BPO 3.1%/adapalene 0.15% gel (IDP-126) represents an effective and well-tolerated novel topical treatment option for moderate to severe acne. In comparison to currently available topical and systemic treatments (except for oral isotretinoin), it ranks within the top three of the most effective treatments for moderate to severe acne.

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¹University of Central Florida/HCA Healthcare Consortium, Tallahassee, FL, USA
²Dermatology Associates of Tallahassee, Tallahassee, FL, USA
³Florida State University College of Medicine, Tallahassee, FL, USA
^* Co-first authors

Conflict of interest: None.
Funding sources: None.
Disclaimer: This research was supported in whole or in part by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the authors and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.

Abstract:
Seborrheic dermatitis (SD) is a chronic inflammatory skin disorder most commonly affecting areas rich in sebaceous glands, such as the scalp, face, axilla, and groin. Several factors can precipitate SD development, such as colonization of Malassezia, sebocyte activity, impaired immunity, and environmental influences. Topical antifungals, corticosteroids, and calcineurin inhibitors are the current mainstay treatment of SD. Recent clinical trials have validated the efficacy of non-steroidal roflumilast 0.3% foam for the treatment of SD. In this review, we analyze the safety and efficacy profile of roflumilast 0.3% foam.

Keywords: seborrheic dermatitis, treatment, roflumilast, PDE-4 inhibitor

Introduction

Seborrheic dermatitis (SD) is a chronic inflammatory skin disorder most commonly affecting areas rich in sebaceous glands, such as the scalp, face, axilla, and groin.¹ While clinical presentations may differ, typical findings include erythematous, pruritic plaques and patches with a yellow, greasy appearance.^1,2 This condition can significantly impact quality of life due to activity limiting symptoms and emotional distress exacerbated by cosmetic ramifications.³ SD affects approximately 5% of the global population, whereas its non-inflammatory counterpart, dandruff, likely impacts closer to 50%.⁴ Despite such high prevalence, the pathogenesis and exact mechanisms via which these yeasts cause inflammation have yet to be fully elucidated.

Malassezia is a part of the human microbiome, interacting with the innate and acquired skin immune system. Innate immunity plays a critical role in initiating the initial immune response against Malassezia.⁵ Sensitization to Malassezia can cause a type I hypersensitivity reaction leading to redness, itching, and scaling.⁶ Further studies point towards Malassezia causing an irritant, non-immunogenic stimulation of the immune system, leading to complement activation and a localized increase in NK1+ and CD16+ cells.^7,8

Currently, there are many mainstay treatments for SD. Due to the underlying mechanism of Malassezia proliferation, most commonly topical antifungals are used for long-term treatment and topical corticosteroids and calcineurin inhibitors for short-term treatment (Table 1).¹ Due to the chronicity of SD, ongoing maintenance therapy is often necessary to achieve low recurrence rates of visible signs of the condition, as well as alleviate associating symptoms, such as pruritus.

Table 1

Phosphodiesterase-4 (PDE-4) inhibitors, including roflumilast, represent a significant advancement in the treatment of SD and other inflammatory conditions. These drugs work by inhibiting the PDE-4 enzyme, which plays a role in modulating inflammatory responses by breaking down cyclic adenosine monophosphate (cAMP).^9,10 Elevated levels of cAMP result in reduced inflammation, making PDE-4 inhibitors effective in managing various ongoing inflammatory disorders such as chronic obstructive pulmonary disease (COPD) and asthma.¹⁰ In dermatology, PDE-4 inhibitors have received regulatory approval in the US and Canada for plaque psoriasis, psoriatic arthritis, atopic dermatitis and, most recently, SD. They have shown promise in off-label treatment of a myriad of other inflammatory skin conditions. Apremilast is an oral PDE-4 inhibitor FDA-approved for psoriasis and psoriatic arthritis in patients ≥6 years of age. Crisaborole is a topical PDE-4 inhibitor, currently FDA-approved for atopic dermatitis in patients ≥3 months of age. Roflumilast has also demonstrated safety and efficacy in managing chronic inflammatory skin conditions, with the regulatory approval status in the US and Canada summarized in Table 2. Compared to currently available PDE-4 inhibitors, apremilast and crisaborole, used to treat skin disease, roflumilast has demonstrated greater selectivity and potency.^9,10

Table 2

Herein, the review will focus on the treatment of SD with a particular emphasis on roflumilast 0.3% foam.

Mechanism of Action

Roflumilast and its active metabolite (roflumilast N-oxide) are inhibitors of PDE-4.⁹ Inhibition of PDE-4 leads to an increase in cAMP and subsequent decrease in pro-inflammatory mediators such as interleukin (IL)-17, IL-23, tumor necrosis factor alpha, and interferon gamma.¹⁰

Clinical Trials

Phase 2¹¹

The Phase 2a study design was a parallel-group, double-blind, vehicle-controlled randomized clinical trial of once-daily roflumilast 0.3% foam. A total of 226 participants aged 18 or older were enrolled in the 8-week trial conducted at 24 sites in the US and Canada with a clinical diagnosis of SD for a 3-month long duration and affecting less than 20% body surface area, including the scalp, face, trunk, and/or intertriginous areas. Roflumilast 0.3% foam demonstrated a statistically significant increase in treatment success, with 104 participants (73.8%) achieving an Investigator Global Assessment (IGA) score of 0 or 1, compared to its vehicle. At week 8, 50 individuals (35.5%) attained an IGA score indicating clearance, while 54 patients (38.3%) achieved an IGA score signifying almost clear skin. In comparison, the vehicle group exhibited lower rates of improvement, with only 10 patients (15.2%) reaching clearance and 17 patients (25.8%) achieving almost clear status. Roflumilast patients exhibited significantly higher rates of erythema success, defined as an overall erythema score of 0 (clear) or 1 (almost clear) plus a 2-grade improvement from baseline, compared to those treated with the vehicle. At weeks 2, 4, and 8, respective absolute differences were 16.6% (95% Confidence Interval (CI): 6.4%-24.8%), 25.2% (95% CI: 13.1%-34.9%), and 23.5% (95% CI: 9.6%-35.0%). Similar results were noted for scaling success, defined as overall scaling score of 0 (clear) or 1 (almost clear) plus a 2-grade improvement from baseline. Statistically significant differences at weeks 2, 4, and 8: absolute differences were 11.8% (95% CI: -0.3% to 21.8%), 20.4% (95% CI: 6.8%-31.8%), and 28.8% (95% CI: 14.4%-41.0%), respectively. Overall, roflumilast 0.3% foam exhibited good tolerability, with a low occurrence of adverse events.

Phase 3¹²

The Phase 3 trial design was a parallel-group, double-blinded, vehicle-controlled, multicenter (50 centers) study with participants aged ≥9 years who were clinically diagnosed with SD affecting up to 20% body surface area, including the scalp, face, trunk, and/or intertriginous areas. 457 patients were randomly assigned in a 2:1 ratio to roflumilast (n = 304) or vehicle (n = 153). The primary endpoint was an IGA score of 0 (clear) or 1 (almost clear) and a ≥2-point improvement from baseline by week 8. The secondary endpoints included IGA success by weeks 2 and 4 and a ≥4-point improvement on the Worst Itch Numeric Rating Scale score (WI-NRS).

During this 8-week trial, a statistically significant amount of roflumilast treated patients (79.5%) achieved IGA success compared with vehicle (58.0%; P < 0.001). Roflumilast also demonstrated success at weeks 2 and 4, with percentages of IGA success of 43.0% versus 25.7% (P < 0.001) and 73.1% versus 47.1% (P < 0.001). At week 8, a higher percentage of patients treated with roflumilast (62.8%) achieved WI-NRS success compared to those treated with the vehicle (40.6%: P < 0.001), with improvement observed within 48 hours after the first application, respectively (Table 3).

Table 3

Safety and Tolerability

Overall, roflumilast 0.3% foam was well tolerated, and had similar rates of adverse events (AE) as the vehicle. During all phases of the study, there were no treatment emergent adverse events (TEAEs) reported as a direct result of roflumilast 0.3% foam treatment.^11,12 The most prevalent adverse reactions, observed in ≥1% of subjects across both Phase 2 and Phase 3 study groups included nasopharyngitis (1.5%), nausea (1.3%), and headache (1.1%).^11,12 Less frequent AEs included application site pruritus, application site pain, and diarrhea.^11,12 There were no significant differences between groups noted in clinical laboratory assessments. Vital signs, body weight, and body mass index indicated no clinically meaningful variations.¹² Moreover, evaluations for depression, suicidal ideation, and behavior revealed no safety concerns.¹²

Contraindications

Contraindications include individuals with a known hypersensitivity to roflumilast or any of the components in the formulation, as this can lead to severe allergic reactions. Additionally, patients with moderate to severe liver impairment (Child-Pugh B or C) should not use roflumilast, as it may exacerbate liver dysfunction.¹³ The coadministration of roflumilast with systemic CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 may increase roflumilast systemic exposure and result in increased adverse reactions.¹³ It should be noted that no formal drug-drug interaction studies were done with topical roflumilast and these recommendations are based on oral roflumilast, which has a much greater bioavailability.

Regulatory Approval

The roflumilast 0.3% foam formulation was approved by the US FDA in December of 2023 and Health Canada in October 2024 for the treatment of SD in individuals aged ≥9 years.¹⁴ The medication is to be applied once daily to the affected areas, with the duration determined by the healthcare provider. One pressurized can of roflumilast 0.3% foam (60 g) contains 3 mg roflumilast per 1 g.

Discussion

Current first-line therapies for SD typically include topical antifungals and topical steroids (Table 1). These treatments are often readily available and affordable, leading to their widespread use. While these are effective in many cases, some individuals require a combination of multiple topicals for control which contributes to patient non-compliance due to complex treatment regimens.⁴ Moreover, these treatments may be ineffective in some individuals and can be associated with poor tolerability due to various AEs such as local skin reactions, burning, pruritus, and blistering.⁴

Roflumilast 0.3% foam provides an additional non-steroidal anti-inflammatory treatment option in those who have failed first-line therapies or prefer a once daily treatment regimen. It marks the first regulatory approved medication for SD with a novel mechanism of action in over two decades. This foam is uniquely formulated in a water-based emollient formula without skin irritating fragrances or alcohols such as, propylene glycol, polyethylene glycol, isopropyl alcohol, or ethanol.¹⁴ It is reported to be the first-in-class drug formulated with a novel emulsifier that lacks ceramide stripping properties. The hydrating features of the vehicle itself may add to its therapeutic effect. Moreover, the non-irritating, non-steroidal formula enables use anywhere on the body, including the eyelids and genitalia. The non-greasy foam formulation lends itself to use on hairy scalps.

Roflumilast may improve adherence and tolerance due to its once daily application, potent formulation, and minimal AEs. Its greater selectivity for PDE-4 than apremilast and crisaborole, likely contributes to its low side effect profile. Few patients reported stinging, burning, application site reactions, or application site pain with roflumilast.¹² Data from key trials reported IGA success, defined as IGA of 0 (clear) or 1 (almost clear) plus ≥2-point improvement from baseline in 80% of participants, with some reaching IGA success as early as weeks 2 and 4.¹² Pruritus, measured via the WI-NRS, improved as early as 48 hours after application. These results are in-line with other first-line therapies (Table 3).

With the continual push for more effective and safer therapies, roflumilast appears to be a useful agent added to the SD armamentarium.

Conclusion

Due to its minimal AEs and favorable tolerability, the novel roflumilast 0.3% foam offers a safe treatment for the erythema, scaling, and pruritus caused by SD. Its once daily application and potent formulation provides a convenient and effective treatment for SD. This treatment highlights the importance of continued advancement in the development of innovative therapies for SD as it is essential to improve outcomes and enhance the quality of life for individuals affected by this condition.

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¹John P. and Kathrine G. McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, The University of Texas Health Science Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there are no conflicts of interest.
Funding sources: None.

Abstract: Psoriatic arthritis (PsA) is a chronic, inflammatory disease with heterogeneous clinical features. The pathogenesis of PsA involves a complex interplay of genetic, immunologic, and environmental factors, leading to the activation of the immune system and subsequent inflammation. Over the past decade, the understanding of the immune mechanisms underlying PsA has advanced significantly, particularly regarding the role of the interleukin-23/T helper 17 pathway in the disease process. Guselkumab, a novel IL-23 inhibitor, has emerged as a promising therapeutic option for PsA, offering an alternative to conventional therapies and other biologics. This review aims to summarize the current evidence on the efficacy, safety, and clinical utility of guselkumab in the treatment of PsA.

Keywords: psoriatic arthritis, guselkumab, treatment, efficacy, psoriasis, arthritis

Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory disease that will develop in about 30% of individuals with psoriasis. The condition is characterized by a wide range of clinical features, making it complex and diverse in its presentation. The pathogenesis of PsA involves a multifaceted interaction between genetic, immunologic, and environmental factors, which leads to immune system activation and subsequent inflammation.¹

Currently, there are no specific diagnostic criteria or tests for PsA. Diagnosis is typically based on the presence of inflammatory musculoskeletal symptoms in joints, entheses, or the spine, alongside skin and/or nail psoriasis, and the usual absence of rheumatoid factor and anti-cyclic citrullinated peptide. The progression from psoriasis to PsA may occur in stages, although the underlying mechanisms remain unclear. Interestingly, the severity of musculoskeletal inflammation does not always correlate with the severity of skin or nail psoriasis, a phenomenon likely influenced by genetic variability, particularly in the human leukocyte antigen (HLA) region.¹

Over the past decade, the understanding of the immune mechanisms underlying PsA has advanced significantly, particularly regarding the role of the interleukin-23 (IL-23)/T helper 17 (Th17) pathway in the disease process. Guselkumab is a human monoclonal antibody that selectively binds to the p19 subunit of IL-23, thereby inhibiting its interaction with the IL-23 receptor. By blocking IL-23 signaling, guselkumab prevents the activation and proliferation of Th17 cells, which are pivotal in the pathogenesis of PsA. Th17 cells produce several pro-inflammatory cytokines, including IL-17A, IL-17F, and IL-22, which contribute to the inflammation and joint damage observed in PsA. By targeting IL-23, guselkumab effectively reduces the levels of these downstream cytokines, thereby attenuating the inflammatory response and improving clinical outcomes in patients with PsA.²

Guselkumab has been approved by the United States Food and Drug Administration (FDA), Health Canada, and the European Medicines Agency (EMA) for the treatment of adult patients with active psoriatic arthritis and moderate-to-severe psoriasis (PSO) who are candidates for systemic therapy. Additionally, the EMA has approved guselkumab for the treatment of active psoriatic arthritis in adults who have had an inadequate response to, or are intolerant of, previous disease-modifying antirheumatic drug (DMARD) therapy.²

This review aims to summarize the current evidence on the efficacy, safety, and clinical utility of guselkumab in the treatment of PsA.

Methods

Our search focused on English-language literature concerning clinical trials of guselkumab in adults with psoriatic arthritis. We conducted a search in the Medline database via PubMed up until September 1, 2024, using the MeSH terms “guselkumab” AND “psoriatic arthritis.” This search yielded 177 results. We excluded books, meta-analyses, reviews, and systematic reviews, narrowing our focus to clinical trials and randomized controlled trials, resulting in 30 trials. Out of these, we included 9 trials and excluded 10 due to integrated analysis of multiple trials, 7 due to duplication, and 4 due to a focus on topics other than PsA.

Results

The included studies primarily consisted of double-blind, randomized, placebo-controlled Phase 3 trials that evaluated the efficacy of guselkumab in patients with PsA (Table 1). Across these trials, guselkumab demonstrated significant efficacy in achieving American College of Rheumatology (ACR) response criteria at various time points:

Table 1

ACR20 Response

Guselkumab consistently showed superior results compared to placebo. For instance, Deodhar et al. reported that 59% of patients treated with guselkumab every 4 weeks and 52% treated every 8 weeks achieved ACR20, compared to 22% in the placebo group.³ Similar trends were observed in other studies, with response rates ranging from 44% to 76% for guselkumab, significantly higher than the placebo groups, which ranged from 20% to 33%.^4-7

ACR50 and ACR70 Responses

Some trials also assessed higher response thresholds. McInnes et al. observed ACR50 and ACR70 responses in 48-56% and 30-36% of patients, respectively, in the guselkumab-treated groups.⁸ Ritchlin et al. noted that 33% and 31% of patients achieved ACR50 at week 24 in the every-4-weeks and every-8-weeks groups, respectively, compared to 14% in the placebo group. ACR70 responses were achieved by 13-19% of guselkumab-treated patients, compared to 4% in the placebo group.⁹

Additional Outcomes

Beyond ACR responses, trials such as Curtis et al. and Orbai et al. assessed work productivity and patient-reported outcomes, showing significant improvements in these domains among patients treated with guselkumab. Improvements in presenteeism, work productivity, non-work activity, and Patient-Reported Outcomes Measurement Information System® (PROMIS)-29 scores were all more substantial in guselkumab groups compared to placebo, with improvements continuing through week 52 after placebo patients were switched to guselkumab.^10,11

These results highlight the efficacy of guselkumab in improving clinical outcomes in PsA patients, particularly in achieving ACR response criteria and enhancing patient-reported outcomes.

Discussion

In the management of PsA, the primary objective of pharmacological treatment is to enhance patients’ health-related quality of life. This is achieved by alleviating symptoms, preventing structural joint damage, and restoring normal function and daily activities. A significant reduction in inflammation is crucial to reaching these goals. Within this therapeutic landscape, guselkumab offers several distinct advantages over other biologics, particularly tumor necrosis factor (TNF) inhibitors and IL-17 inhibitors.

TNF inhibitors are commonly used in PsA treatment, but their efficacy in managing skin symptoms can be variable, and they are associated with a higher risk of certain adverse events (AEs), such as infections and demyelinating diseases. IL-17 inhibitors, including secukinumab and ixekizumab, are effective for both skin and joint manifestations but may increase the risk of inflammatory bowel disease. In contrast, guselkumab specifically targets the IL-23 pathway, offering a more focused modulation of the immune response in PsA. This targeted inhibition may lead to fewer offtarget effects and a more favorable safety profile, particularly concerning infections and autoimmune-related AEs. Additionally, guselkumab has shown efficacy in patients who have not responded adequately to TNF inhibitors, making it an invaluable option for this challenging subset of patients.¹²

The safety profile of guselkumab has been thoroughly evaluated in both clinical trials and post-marketing surveillance. Across these studies, the incidence of AEs was comparable between guselkumab and placebo groups, with the most common being nasopharyngitis, upper respiratory tract infections, and headaches. Serious adverse events were infrequent and occurred at similar rates across treatment groups. Importantly, guselkumab did not increase the risk of serious infections, malignancies, or major cardiovascular events, which supports its suitability for long-term use.

Overall, guselkumab emerges as a promising therapeutic option for PsA, particularly for patients who require an alternative to TNF inhibitors or those concerned with the safety profiles of currently available biologics. Its focused mechanism of action, combined with a robust safety profile, positions guselkumab as an effective and well-tolerated treatment in the ongoing effort to improve patient outcomes in PsA.

Conclusion

Guselkumab represents a significant advancement in the treatment of PsA, providing a novel mechanism of action with robust clinical efficacy and a favorable safety profile. The evidence from RCTs and real-world studies supports its use in a broad range of patients, including those who are biologic-naïve and those with previous biologic exposure. As the understanding of the IL-23/Th17 pathway continues to evolve, guselkumab and other IL-23 inhibitors are likely to play an increasingly important role in the management of PsA, offering patients new hope for improved disease control and quality of life. Future research should focus on long-term outcomes, comparative effectiveness with other biologics, and the identification of biomarkers to personalize treatment strategies for patients with PsA.

References

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Ustekinumab-stba SC/IV injection

Nivolumab + hyaluronidase-nvhy for SC injection

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¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
²Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
³Division of Dermatology, BC Children’s Hospital, Vancouver, BC, Canada

Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding sources: None.

Abstract:
Hidradenitis suppurativa (HS) is a chronic, recurring inflammatory skin disease that significantly impacts the quality of life of patients.¹ HS is more common in adults and adolescents, although true incidence rates may be underestimated due to a lack of earlier recognition of HS in children.² Pediatric HS is a challenging clinical entity to diagnose and manage. Although considered uncommon, treatment of pediatric HS can drastically improve psychosocial well-being and should be considered in children presenting with recurring painful skin nodules, abscesses, scarring and sinus tracts. Multiple comorbidities are associated with pediatric HS, including depression, anxiety, inflammatory bowel disease, metabolic syndrome, and obesity.³ Medical management of pediatric HS poses a unique challenge given the paucity of literature surrounding efficacy and long-term treatment outcomes in pediatric patients. The purpose of this article is to discuss the epidemiology, pathogenesis, comorbidities, and management of pediatric HS.

Keywords: childhood hidradenitis, early onset hidradenitis suppurativa, hidradenitis suppurativa in children, inflammatory disorders, pediatric dermatology

Introduction

Hidradenitis suppurativa (HS) is a chronic disease involving the follicular unit that typically presents with inflammatory intertriginous lesions.⁴ Depending on severity, cutaneous involvement can manifest as painful nodules, abscesses, sinus tracts, and/or hypertrophic scarring.⁵ HS usually presents in adolescents and adults, and is considered uncommon in children, with an estimated prevalence of less than 2% in prepubescent children.⁶ A recent cross-sectional analysis reported 96.8% of pediatric patients with HS were ≥10 years old, with the highest prevalence reported in patients aged 15-17 years old.⁷ Some have noted that delays in care for pediatric patients may reflect an under-recognition of pediatric HS.⁴ In the adult population, women are more commonly affected by HS in comparison to men. Similarly, pediatric HS is more commonly reported in girls, although the exact prevalence is unknown.⁸ Unfortunately, most literature on pediatric HS is limited to small case series, case studies, or extrapolation from adult studies.⁹ More pediatric focused research is needed to better understand disease burden, prevalence, and treatment.

Pathogenesis

The pathogenesis of HS specific to pediatric patients is not well understood and primarily relies on extrapolation from basic sciences and adults with HS. HS pathophysiology is complex and involves environmental, immunologic, and genetic factors. HS is considered a disorder of follicular occlusion, in which hair follicle dysregulation and inflammation play key roles.¹⁰ As affected hair follicles become occluded and eventually rupture, bacteria and keratin enter the surrounding dermis, promoting an inflammatory state and subsequent lesion formation. Many patients with HS have a positive family history, which has prompted genetic studies.¹¹ Gene mutations that alter antimicrobial peptides and cytokines have been demonstrated in patients with HS.¹² Heterozygous mutations in gamma‐secretase (γ‐S), a protease involved in follicular keratinization regulation have been identified in autosomal dominant forms, supporting a genetic link.^12,13 Gamma-secretase deficiencies have also been associated with impaired sebaceous gland formation and follicle disintegration in mice studies.¹⁴ Some research suggests that patients with early-onset HS appear more likely to have a positive family history.¹⁵ From an immunologic standpoint, both the innate and adaptive immune system play important roles. Decreased expression of antimicrobial peptides may facilitate superficial colonization by bacteria and promote ongoing inflammation through pro-inflammatory cytokines.¹⁶ Pro-inflammatory cytokines involved in HS include but are not limited to interleukin (IL)-1, IL-10, IL-17, IL-22, IL-23, and tumor necrosis factor (TNF)-alpha.^9,16 Other factors that can promote HS pathogenesis and impact disease severity include microbial dysbiosis, microbial colonization, mechanical friction, and hormones.¹⁷ In addition, sinus tracts develop a psoriasiform lining, which tries to recapitulate the epidermis, shedding keratin and causing further inflammation. Hence, persistent lesions still exist despite systemic therapy and deroofing is often curative and essential to include in full-spectrum care.

Clinical Features and Diagnosis

Pediatric HS is a clinical diagnosis based on its typical morphology of deep nodules, cysts, sinus tracts, and fibrotic scars in intertriginous areas. A cross-sectional study assessing the clinical features of children <18 years old (mean age of 15.3 years) with HS reported a similar presenting clinical spectrum to adult-onset disease.¹⁸ Typical sites include those abundant with apocrine glands, such as the axillae, inframammary area, groin, and perianal region. Drainage from involved sites is a commonly reported symptom.¹⁹ There are currently no guidelines regarding investigations for HS in pediatric patients or adults. Laboratory investigations or skin biopsy are unnecessary for diagnosis, but imaging may be considered for operative planning when assessing sinus tracts.¹⁸ Ultimately, given the lack of research and consensus, there are currently no screening guidelines for investigating potential comorbidities in pediatric patients with HS. The Hurley staging system is often used to categorize patients into three disease groups based on their level of severity.²⁰ Stage I includes abscess formation (single or multiple), without sinus tract(s) or scarring, Stage II includes those with recurrent abscesses with sinus tracts and scarring present, and Stage III encompasses diffuse involvement, with multiple abscesses and interconnected sinus tracts.²⁰ The Sartorius scoring system is typically reserved for clinical trials and is not commonly used in clinical practice.8 Another useful scoring system is the International Hidradenitis Suppurativa Severity Score System (IHS4) which is a validated, dynamic assessment of HS severity that encompasses counting nodules, abscesses, and draining sinus tracts/fistulas.²¹ The Hidradenitis Suppurativa Quality Of Life (HiSQOL) scoring system may also be useful for capturing impactful areas of HS such as pain, odor, and drainage, which are not measured by the Dermatology Life Quality Index (DLQI) and should be considered by treatment providers.

Associated Comorbidities

Multiple comorbidities have been associated with pediatric HS, including more hormonal imbalances in comparison to adult populations, with manifestations including acne, premature adrenarche, adrenal hyperplasia, metabolic syndrome, and obesity.⁶ Although the overall association between early-onset HS and premature adrenarche and hormonal imbalance remains unclear, assessing for precocious puberty in children presenting with HS may be an important consideration depending on the clinical presentation. From a database of 870 pediatric patients, an elevated body mass index (BMI) and obesity were higher in comparison to reference population standards, as was the prevalence of smoking.¹⁸ Aside from metabolic syndrome, inflammatory bowel disease (IBD) and spondyloarthropathy have also been shown to be associated with HS.⁹ Patients with Down syndrome have been shown in multiple studies to have an earlier onset of HS although the mechanism behind this remains unknown.⁹ A detailed history, including inquiring about a family history of HS and associated comorbid symptoms and a physical examination should be completed. From a psychosocial perspective, HS can drastically impact quality of life and is associated with significant psychological distress.⁸ Painful, inflammatory lesions can limit children’s ability to play, exercise, or attend school which can contribute to obesity and further worsening of disease.⁶ Furthermore, social stigma surrounding HS can negatively affect psychosocial well-being, especially during the adolescent period. Overall, higher rates of anxiety and depression have been reported in pediatric-aged HS patients compared to those without HS.⁹ A cross-sectional study recently examined the quality of life impacts of HS in 25 pediatric patients aged 12-17 years of age.²² They found that 32% of patients had positive screening results for depression on the Patient Health Questionnaire-2, a depression screening tool.²² The Skindex-Teen questionnaire, an adolescent quality of life questionnaire for skin disease was also used, which demonstrated a higher average score in patients with more moderate-severe HS.²² Overall, clinicians should have a high level of suspicion for psychological comorbidities when treating pediatric patients with HS.

Treatment

Management of HS in the pediatric population is limited given the lack of information surrounding long-term outcomes. Determining the appropriate treatment involves weighing the biopsychosocial impact on the child, disease severity, and side effects of medications or procedures. In general, treatment of HS includes topical or systemic medications and surgical modalities depending on the severity. Lifestyle modifications are typically encouraged for all patients and include smoking cessation, weight management, and avoidance of triggers. Patient and family education should emphasize that HS is a chronic disease without a cure, with treatment focusing on disease and symptom management.

For Hurley Stage I disease, conservative management with topical treatment, such as clindamycin 1% solution, azelaic acid 15%, resorcinol 15%, or combination treatment with clindamycin/ benzoyl peroxide is recommended.⁶ Of note, resorcinol is the only topical treatment with studies completed for HS in adults and is a medication that must be compounded. Topical antiseptics and clindamycin are considered safe for use but may be ineffective for more moderate or severe HS.²³ For non-prescription treatments, laser hair removal has been effective via the Hidradenitis Suppurativa Clinical Response (HiSCR) response in patients with mild-to-moderate disease.²⁴ Supplementation with 100 mg of oral zinc has also been shown to improve HS.²⁵ Concurrent supplementation with 4 mg of copper should be considered to prevent copper deficiency.²⁵ For those where topical treatments fail or children with Hurley Stage II disease, systemic medications can be explored. Systemic antibiotics such as doxycycline, clindamycin with rifampicin, metronidazole, and erythromycin are appropriate for use in children with more severe disease.⁶ Counselling regarding potential tooth discoloration and enamel hypoplasia should be done for patients under 8 years old receiving tetracycline antibiotics.²³ However, antibiotics are not a feasible long-term solution. If there is recurrence after treatment, adalimumab or secukinumab should be considered. Oral finasteride demonstrated improvement in resistant cases from a small pediatric case series, however potential side effects include transient sexual dysfunction in males, and pediatric safety data is lacking, particularly for prepubertal males.²⁶ Systemic retinoids used for the treatment of HS include acitretin and isotretinoin, although these have considerable risks and isotretinoin tends to be more effective in milder, folliculocentric subtypes. The long-lasting teratogenic effects of acitretin make it unsuitable for patients with childbearing potential and isotretinoin in children under 12 years of age has been reported to cause premature epiphyseal closure.²⁷ Importantly, all patients of childbearing potential should be counselled surrounding teratogenic effects where applicable.

In terms of biologics, adalimumab is currently the only approved choice in North America for pediatric patients older than 12 years of age who weigh at least 30 kg.²⁸ Safety data surrounding the use of adalimumab in pediatric patients for HS is limited, although adalimumab has been used effectively in pediatric patients for other inflammatory diseases including Crohn’s disease, psoriasis, and juvenile idiopathic arthritis.²⁹ Secukinumab, an IL-17 inhibitor, is both Health Canada and US FDA approved for treatment of adults with moderate-to-severe HS. Based on clinical studies in adults, it may be a therapeutic option for first- or second-line off-label treatment of pediatric HS patients.^30,31 Overall, dermatologists should have a low threshold to treat systemically and preventatively, as HS is typically a progressive disease that can become less responsive to biologic therapy as time passes and severity increases. Surgical modalities may be another option for older children. Depending on the extent of disease, wide excision and/or minimally invasive deroofing can be considered. A recent cross-sectional study found that surgical excision and deroofing were reported as useful for all 23 pediatric patients assessed, while those treated with simple excision had zero responders in 7 cases treated with simple excision.³² However, a surgical approach is more invasive and carries the risk of infection, scarring, and recurrence.⁹ A retrospective review of 11 patients under 18 years old with a total of 23 operative sites reported an overall complication rate of 87% and a 7% reoperation rate.³³ Remission after a single procedure was reported in 57% of included sites.³³ However, it is crucial to combine both medical preventative treatments with surgical therapy, as success rates are much higher with a combination approach.

Conclusion

Pediatric HS is an understudied and underrecognized disease with significant biopsychosocial impacts. Unfortunately, diagnosis is often delayed given the wide variety of presentations in early disease. Clinicians should consider associated comorbidities such as metabolic syndrome, inflammatory bowel disease, and anxiety and depression. Early recognition, diagnosis, and management are essential in improving quality of life and managing symptoms for children and adolescents with HS. Further research focused on long-term outcomes, associated comorbidities, and medical management is needed to improve our understanding and treatment of pediatric hidradenitis suppurativa.

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