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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¹Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
²Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
³Division of Dermatology, University of Calgary, Calgary, AB, Canada
⁴Beacon Dermatology, Calgary, AB, Canada
⁵Toronto Dermatology Centre, Toronto, ON, Canada
⁶Division of Dermatology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
⁷Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, AB, Canada

Conflict of interest: Leah Johnston does not have any conflicts of interest to disclose. Benjamin Barankin has been an advisor and speaker for Paladin Labs.
Jaggi Rao has been an advisor and speaker for Paladin Labs. Andrei Metelitsa has been an advisor and speaker for Abbvie, Clarion, Galderma, Merz Pharma, Paladin Labs.
Susan Poelman has been an advisor and speaker for Abbvie, Galderma, Merz Pharma and Paladin Labs. Geeta Yadav has been an advisor and speaker for Paladin Labs.
Funding sources: None.

Abstract:
Pain management is an important aspect of dermatologic procedures, which are typically performed on awake patients in outpatient settings. The first-line modalities for procedural analgesia during most dermatologic procedures are topical and injectable local anesthetics, such as lidocaine. However, in some medical and cosmetic dermatologic procedures, pain cannot be effectively managed with local anesthetics due to procedure-specific lack of efficacy, large treatment surface areas, high dosage requirements, allergies, or other contraindications. In these circumstances, methoxyflurane inhalers may be highly beneficial. Methoxyflurane (Penthrox^®) has demonstrated efficacy for providing pain relief in randomized controlled trials in patients who presented to emergency departments with acute trauma-related pain, as well as in patients undergoing painful procedures for other medical indications. The limited side effect profile, ease of patient self-administration, rapid onset and quick resolution of central nervous system effects following cessation makes methoxyflurane an ideal choice for analgesia during outpatient dermatologic procedures. This review provides an overview of the supporting evidence for methoxyflurane inhalers and clinical commentary on potential indications for methoxyflurane use in dermatology.

Keywords: methoxyflurane, Penthrox, inhaled analgesia, pain control, dermatology

Introduction

Methoxyflurane is a volatile, halogenated hydrocarbon that can be vaporized and subsequently inhaled for analgesia at low doses and can also be used as an anesthetic agent at high concentrations.¹ Methoxyflurane was widely used as an inhaled anesthetic agent in the 1960s and in 1968, Abbott Laboratories developed the first low-dose methoxyflurane inhaler (Analgizer^®) for self-administration by patients.² However, in the 1970s, use of methoxyflurane as an anesthetic declined due to emerging reports of nephrotoxicity and hepatotoxicity and in 1999, Abbott Laboratories discontinued production and distribution of methoxyflurane inhalers in the United States and Canada.^1,3,4 In 2005, the United States Food and Drug Administration (FDA) responded to reports of methoxyflurane toxicity by formally withdrawing the license for methoxyflurane anesthetic agents, preventing future new drug applications in the United States.^3,4

Medical Developments International re-branded low dose methoxyflurane through the development of the Penthrox^® inhaler for analgesia in 2003. Since then, Penthrox^® has received health regulatory approval in Europe and Canada in 2015 and 2018, respectively. In 2018, the FDA lifted its previous clinical hold on methoxyflurane, allowing Penthrox^® to receive regulatory approval as a new investigational drug.³ This review provides an overview of the evidence on methoxyflurane for analgesia and clinical commentary on applications for its use in dermatology.

Mechanism of Action and Pharmacodynamics of Inhaled Methoxyflurane

Once inhaled into the lungs, methoxyflurane undergoes rapid absorption into the blood, allowing for a quick onset of action that starts after 30 seconds and can be detected by changes in pain scores within the first 2-5 minutes of inhalation.⁵ The exact mechanism of action of methoxyflurane in pain relief has not been fully delineated, but it is theorized to exert its analgesic effects by potentiating activation of gamma-aminobutyric acid (GABA) and glycine receptors in the central nervous system (CNS) and altering the immunoreactivity of substance P and beta-endorphin in the brain.^6-9 Methoxyflurane’s ability to provide analgesia at lower doses (3-6 mL), in addition to its use as an anesthetic at higher doses (40-60 mL), is unique among fluorinated anesthetic agents.^10-13

Based on estimates from disappearance curves, the apparent half-life of methoxyflurane is approximately 15-20 minutes.⁴ Methoxyflurane is highly lipid soluble and diffuses slowly from adipose tissue into the bloodstream, and approximately 50% is metabolized by multiple different cytochrome P450 (CYP450) enzymes in the liver.^4,14 Methoxyflurane undergoes the biochemical processes of oxidative demethylation and defluorination to form the following metabolites: fluoride, oxalic acid, dichloroacetic acid, and 2,2-difluoro-2-methoxyacetic acid.⁴ Methoxyflurane and its metabolites are renally excreted and methoxyflurane may also be metabolized by kidney microsomes, leading to intrarenal fluoride formation.¹⁵

The Penthrox^® Inhaler

In Canada, Penthrox^® is inhaled via an inhalation device (Figure 1).^4,16 Each inhaler device comes with a 3 mL bottle of methoxyflurane, which is poured into the base of the inhaler, as well as an activated carbon (AC) chamber that is attached to the top of the inhaler at the dilutor hole.¹⁶ Once the device is assembled, the patient can then inhale methoxyflurane from the mouthpiece.¹⁶ To minimize exposure of individuals in the surrounding environment to methoxyflurane, patients are instructed to exhale into the inhaler.¹⁶ The exhaled vapor passes through the AC chamber, allowing for adsorption of exhaled methoxyflurane.¹⁶ To provide a stronger dose of methoxyflurane with each inhalation, patients can cover the dilutor hole on the top of the AC chamber with their fingers.¹⁶ The estimated concentration of methoxyflurane provided with each inhalation is 0.2-0.4% with the dilutor hole uncovered and 0.5-0.7% when the dilutor hole is covered.¹² Approximately 6-10 initial breaths are needed to initiate adequate analgesia.¹⁶ The Penthrox^® inhaler can be used continuously for up to 25-30 minutes and, if needed, a second 3 mL inhaler can be utilized to provide ongoing analgesia for up to 54 minutes.^12,17 If used intermittently, a single inhaler may provide up to 1 hour of analgesia.¹⁷ The maximum recommended daily and weekly doses of methoxyflurane are 6 mL and 15 mL, respectively.⁴

Clinical Trials

A summary of randomized controlled trials (RCTs) that have been conducted in human participants using the Penthrox^® brand of methoxyflurane inhalers is provided in Table 1.

Initial studies on Penthrox^® focused on evaluating its use as a potential alternative treatment for procedures requiring sedation. A 2011 randomized, cross-over study conducted by Abdullah et al. investigated the use of methoxyflurane inhalation for conscious sedation and analgesia during third molar surgical extraction, in comparison to treatment with nitrous oxide.¹⁸ The study found that sedation was comparable between the two groups, though patient satisfaction scores demonstrated that methoxyflurane was preferred by patients over nitrous oxide (p<0.05) and had a more favorable side effect profile. In a 2013 study by Nguyen et al. in patients undergoing colonoscopies, methoxyflurane was compared to the standard of care, intravenous (IV) midazolam and fentanyl, for procedural sedation and analgesia.¹⁹ The study found that 92% of patients (n=115/125) in the methoxyflurane group received adequate procedural analgesia and sedation with methoxyflurane alone, and only 10 patients required additional IV sedation.¹⁹ Patients in the methoxyflurane group awoke sooner following the procedure and were also able to be discharged more quickly.¹⁹ In patients undergoing dressing changes following severe burns, a 2016 randomized, pilot cross-over study found that 63% (n=5/8) of patients preferred methoxyflurane inhalation over patient-controlled analgesia with IV 10 mg/mL ketamine and 0.5 mg/mL midazolam for pain control.²⁰

The ‘STOP!’ trial in the United Kingdom was a 2014 placebo-controlled, double-blind, RCT on methoxyflurane use in patients aged 12 years or older who presented to the emergency department with minor traumatic injuries.² A total of 300 patients, including 90 patients between the ages of 12 to 17 years, were enrolled in the study.^2,17,21 Methoxyflurane reduced Visual Analog Scale (VAS) pain severity ratings significantly more than placebo (p<0.0001) at 5, 10, 15 and 20 minutes, with the greatest improvement in pain (-18.5 mean change in VAS rating from baseline) observed at 15 minutes.² The median time to initial pain relief was 4 minutes, which occurred after 1-5 inhalations in 49.7% (n=74) and after 6-10 inhalations in 34.9% of participants (n=52).² Another 2014 placebo-controlled, double-blind, RCT demonstrated the efficacy of methoxyflurane in reducing pain in patients undergoing routine bone marrow biopsies.²²

Safety Profile and Precautions for Use

Cardiorespiratory Depression

Methoxyflurane is contraindicated in individuals with hemodynamic instability and/or respiratory compromise.¹⁶ However, methoxyflurane use may be safe in the context of stable chronic respiratory conditions and it has been safely used in patients with obesity, obstructive sleep apnea, and asthma.^33-36

Nephrotoxicity

Nephrotoxicity has occurred in patients treated with anesthetic doses of methoxyflurane when plasma fluoride ion concentrations exceeded 50 μmol/L.¹⁵ However, nephrotoxicity is not commonly observed in patients treated with sevoflurane, another halogenated inhalational anesthetic, when plasma fluoride ion concentrations surpass a similar threshold.¹⁵ Sevoflurane defluorination by kidney microsomes occurs at a lower rate compared to methoxyflurane, suggesting that the renal toxicity observed with high doses of methoxyflurane may be attributable to increased intrarenal fluoride production during methoxyflurane elimination.¹⁵ In clinical studies that used the Penthrox^® inhaler, participants’ serum fluoride levels remained under 10 μmol/L after inhalation of 3 mL of methoxyflurane and no studies have reported nephrotoxicity from Penthrox^® use.¹⁶ A large retrospective post-authorization study found that Penthrox^® provided a reduced risk of nephrotoxicity compared to other commonly used analgesic agents.³⁴ These studies suggest that with the lower methoxyflurane dose used in the Penthrox^® inhaler, serum methoxyflurane levels and subsequent intrarenal fluoride production remain well below the nephrotoxicity threshold.

Hepatotoxicity

Hepatotoxicity is an established risk that occurs with anesthetic doses of methoxyflurane and previous reports include some fatal cases of methoxyflurane-induced hepatic dysfunction.¹⁶ Penthrox^® has not been associated with an increased risk of hepatotoxicity compared to other analgesic agents in post-authorization studies, however, there have been some cases published in the last 40 years on methoxyflurane-associated hepatitis that occurred following treatment with analgesic doses of methoxyflurane.^16,34 Methoxyflurane should be avoided in patients with evidence of underlying hepatic dysfunction and patients who have had previous hepatic damage following the use of methoxyflurane or other halogenated hydrocarbon anesthesics.¹⁶

Malignant Hyperthermia

A previous personal or family history of malignant hyperthermia in response to methoxyflurane or other halogenated anesthetics is a contraindication to methoxyflurane use.¹⁶

Central Nervous System, Psychomotor and Cognitive Effects

Methoxyflurane may cause transient dizziness, headache, muscle relaxation and sometimes drowsiness following inhalation.¹⁶ Methoxyflurane is contraindicated in individuals with an altered level of consciousness.¹⁶ A 2016 placebo-controlled RCT investigated the psychomotor and cognitive effects following 15 minutes of inhalation of a 3 mL methoxyflurane inhaler.³³ This study found that impairments in psychomotor and cognitive performance, including cognition, hand-eye coordination, and auditory reaction time resolved within 30 minutes of cessation of methoxyflurane inhalation.³³ This finding supports the claim that most patients should be able to safely drive and can return to work on the same day following procedures that use methoxyflurane inhalation for analgesia.³³ However, it is recommended that patients wait for up to 30 minutes after discontinuing methoxyflurane inhalation before driving.³³

Abuse Potential

The CNS side effect of euphoria with methoxyflurane use can be a risk factor for potential misuse and there have been very rare post-marketing reports of abuse related to anesthetic use.¹⁶ However, in comparison to many other analgesics, such as opioids, methoxyflurane has a significantly lower potential for abuse when treating acute pain.²⁵

Pregnancy and Breastfeeding

The potential for long-term effects of fluoride exposure during pregnancy and breastfeeding on offspring development has not been fully delineated.¹⁶ In studies that investigated the use of methoxyflurane during labor, elevated fetal serum and urine fluoride levels were measured post-delivery, though these levels were sub-nephrotoxic and no clinical signs of nephrotoxicity were observed.^37-39 Additionally, a retrospective study in females who received methoxyflurane during pregnancy found that there were no significant differences in maternal and fetal outcomes and rates of congenital abnormalities compared to patients who received fentanyl or no analgesia.⁴⁰ In the perinatal period, methoxyflurane use during labor was associated with reduced perinatal mortality rates and a reduced incidence of fetal distress, compared to cases where no analgesia was administered.⁴⁰

A study in Sprague-Dawley rats also did not demonstrate a teratogenic effect of methoxyflurane when used in pregnancy.⁴¹ However, daily 8-hour methoxyflurane exposure at a concentration of 0.08% for the full 21-day gestational period was associated with a 9% reduction in birth weight compared to the control group, while in the 50% nitrous oxide group, a 21% reduction in birth weight was observed.⁴¹ In Swiss/ICR mice, 4-hour daily exposure to methoxyflurane at trace (2 parts per million [ppm]) and subanesthetic (60 ppm) concentrations for 10 days was not associated with adverse effects but at anesthetic concentrations of 2000 ppm, reductions in birth weight, skeletal ossification, and renal maturation, as well as an increased incidence of minor skeletal abnormalities, were observed.⁴²

Based on the current literature, limited methoxyflurane use at analgesic doses during pregnancy does not appear to be associated with an increased risk of maternal or fetal adverse outcomes. However, the long-term effects on offspring development are unknown and therefore methoxyflurane is currently classified as a Pregnancy Category C drug by the FDA, indicating that it is not recommended for use during pregnancy and breastfeeding unless benefits are expected to outweigh potential risks.^16,40

Combination Analgesia and Potential Drug Interactions

Methoxyflurane has been used safely in combination with other analgesic agents, including topical and injectable local anesthetics, acetaminophen, IV morphine and IV fentanyl.^29,43-45 However, methoxyflurane should be used with caution in patients undergoing concomitant treatment with other CNS depressants, such as opioids, sedatives, muscle relaxants, and sedating antihistamines, due to the potential for transient drowsiness and alterations in psychomotor function.¹⁶

Methoxyflurane use should be avoided in individuals who are taking other medications with a potential risk of nephrotoxicity, including contrast dyes, gentamicin, tetracycline, colistin, polymyxin B and amphotericin B, and should be used with caution in patients who are concurrently taking non-steroidal anti-inflammatory drugs.¹⁶ Drugs that induce the activity of CYP2E1 and/or CYP2A6, which are the CYP450 enzyme subtypes that predominantly metabolize methoxyflurane, can also increase the risk of methoxyfluraneinduced nephrotoxicity.¹⁶ These drugs include alcohol, isoniazid, phenobarbital, and rifampicin.¹⁶

Vital Signs

Clinically significant changes in vital sign parameters, including blood pressure, pulse rate, respiratory rate, and peripheral capillary oxygen saturation, have not been observed with Penthrox^® use in clinical trials.^2,19,36 Continuous monitoring of vital signs during and after Penthrox^® use is not required in healthy patients who do not have major comorbidities.^16,23,28,44 However, some healthcare providers may recommend that patients remain in clinic for observation for 10-15 minutes after finishing methoxyflurane inhalation.

Storage, Handling and Preparation

Penthrox^® inhalers have a shelf-life of approximately 36 months, should be stored at temperatures between 5° and 30° Celsius and can be discarded with normal waste disposal.¹⁶ Contact precautions are not required when handling the inhalers. Penthrox^® inhalers may be stored in a clinic setting or patients may obtain their inhalers from a pharmacy prior to appointments. A major advantage of the Penthrox^® inhaler over other methods of analgesia is that minimal preparation of the inhaler device is needed before use. The first step for setting up the inhaler is to insert the AC chamber into the dilutor hole on the top of the inhaler.¹⁶ Administration of Penthrox^® without the AC chamber should be avoided, as this can significantly increase occupational exposure to methoxyflurane.¹⁶ Once the inhaler is assembled, liquid from the Penthrox^® bottle can be poured into the inhaler base, and it is recommended that subsequent use of the inhaler occur shortly after this step.¹⁶ If the inhaler is not used immediately and is stored under open conditions, approximately 50% of methoxyflurane will be lost after 5 hours.⁴⁶ Placement of an assembled inhaler into a low-density polyethylene bag within the inhaler’s original packaging can limit major losses of methoxyflurane for up to 3 days.⁴⁶

Occupational Exposure

The maximum exposure level for methoxyflurane is approximately 15 ppm.^45,47 In Canada, provincial legal limits for methoxyflurane exposure range from 2 ppm per day to 2 ppm over the course of 1 week.³⁷ While occupational exposure to methoxyflurane from patients’ exhalations is a theoretical health risk for healthcare providers, the real-world observed exposure level following 8-hour shifts is much lower than the legal exposure limits, ranging between 0.008 and 0.736 ppm in nurses who supervised methoxyflurane use.⁴⁸ Additionally, serum fluoride levels measured in ambulance paramedics were not significantly elevated above healthy reference ranges.⁴⁹ Typical exposure to methoxyflurane results in serum fluoride level increases that are nearly 50-fold lower than the thresholds that have been associated with nephrotoxicity, suggesting that methoxyflurane exposure has a low risk of negative health effects for healthcare providers when used in well-ventilated environments.^16,47,48 In a study that monitored ambient air in emergency department triage rooms, methoxyflurane concentrations ranged from 0.002 to 0.024 ppm, suggesting that exposure is very low for healthcare providers who work in adjacent rooms.⁴⁸

The long-term risks of methoxyflurane exposure in pregnant healthcare workers who supervise methoxyflurane use have not been studied.³⁷ Currently, it is recommended that pregnant or breastfeeding healthcare workers limit their exposure to methoxyflurane by avoiding direct supervision of Penthrox^® use.³⁷

Environmental Impact and Cost-Effectiveness

In a study that compared the climate change impact of Penthrox^® inhalers to nitrous oxide in terms of all materials and processes involved in manufacturing, clinical use, and disposal, Penthrox^® was found to have a lower environmental impact than nitrous oxide.⁵⁰ The current market cost of Penthrox^® in Canada is $55 per 3 mL inhaler, making it more expensive than the estimated costs per treatment session of IV acetaminophen, opioid analgesics, and nitrous oxide.^51-53 However, although the estimated cost during dermatologic procedures for nitrous oxide use is $20 per session, this estimate does not account for the expensive initial cost of purchasing a nitrous oxide delivery system, which can cost approximately $8,000-$12,000.^52,54,55 Nitrous oxide machines can also take up a significant amount of space in clinic rooms, which is not an issue with methoxyflurane given the small size of the inhaler device. Overall, the favorable efficacy, safety profile, and lower environmental impact of Penthrox^®, in addition to the lack of requirement for an expensive initial purchase of space-occuping equipment to administer Penthrox^®, makes it worth the slightly higher material cost per treatment session (Table 2).^50-53

Applications in Dermatology and Real-World Commentary

Pre-procedural evaluation for pain control is essential prior to the start of dermatologic procedures.⁵⁶ While injections of local anesthetic agents can effectively manage pain during many dermatologic procedures, such as simple punch or shave biopsies, some procedures may require additional interventions to optimize patient comfort. It is important to take into consideration both patient and procedure-specific factors. Pediatric patients, patients with chronic pain, and patients with procedural anxiety are more likely to experience higher levels of pain during and after dermatologic procedures.^57,58 Additionally, procedures where pain cannot be effectively managed with local anesthetic infiltration due to demonstrated lack of efficacy, large treatment surface areas, high dosage requirements or other contraindications, including allergies to local anesthetics, may warrant consideration of alternative analgesic methods. Given the demonstrated efficacy, limited side effect profile, rapid onset, and complete resolution of CNS effects within 30 minutes of cessation, methoxyflurane is an ideal choice for analgesia during many procedures that are performed in outpatient dermatology settings. Presently, no studies have been published on methoxyflurane use during dermatologic procedures. Based on the real-world clinical experience of the authors of this article, we propose that methoxyflurane inhalers are a useful tool to consider for pain relief during a variety of dermatologic procedures.

Potential Indications for Methoxyflurane in Medical Dermatology

Platelet-Rich Plasma and Intralesional Corticosteroid Injections for Hair Loss Disorders

Intradermal injections into the scalp with either intralesional corticosteroids and/or platelet-rich plasma (PRP) are a mainstay of treatment for many hair loss disorders, including alopecia areata, androgenetic alopecia and scarring alopecias. However, the abundance of pain sensory receptors in the scalp contributes to high levels of pain that many patients experience during scalp injections.⁵⁹ Pain, as well as interference of local anesthetics with platelet functionality, limits their use during PRP sessions.⁵⁹ Methoxyflurane may be useful in reducing pain during scalp injections and it does not carry the same risk of local interactions with intradermally-injected therapies.

Botulinum Toxin Injections

Methoxyflurane may also be beneficial for analgesia during botulinum toxin (BTX) injections. Common medical indications for BTX include axillary and palmoplantar hyperhidrosis as well as chronic migraines, which can be treated with a series of standardized injections into sites on the head and neck. BTX treatment sites, especially the palms and soles, can be highly sensitive during BTX injections.⁶⁰ Methoxyflurane inhalation may help to minimize discomfort during BTX injection sessions.

Photodynamic Therapy

Photodynamic therapy (PDT) is commonly used to treat patients with field cancerization and superficial non-melanoma skin cancers, which often occur in sun-exposed areas on the face and scalp. PDT can be painful and previous studies have demonstrated a lack of efficacy of topical anesthetic agents in controlling pain during PDT sessions.⁶¹ One study that used inhaled nitrous oxide during PDT sessions found that it provided a statistically significant reduction in pain levels compared to the control group.⁶² Methoxyflurane inhalation may be similarly beneficial in reducing pain during PDT treatments.

Deroofing Surgery for Hidradenitis Suppurativa

While intraoperative pain during deroofing procedures for hidradenitis suppurativa (HS) can be effectively managed with infiltration of local anesthetic agents, the process of injecting local anesthetics can be very painful given the relatively high levels of pain that HS patients experience from inflamed HS lesions, in addition to the skin sensitivity in the intertriginous areas where HS lesions typically arise.⁶³ Methoxyflurane inhalers may help to provide pain relief during this first step of deroofing surgeries if inhalation is initiated a few minutes prior to and during injections of local anesthetic agents.

Other Minor Surgical Procedures

Depending on provider and patient preferences, methoxyflurane inhalation may be beneficial as an adjuvant to local injectable anesthesia or may be used alone during minor surgical procedures of short duration, including removal of syringomas, skin tags, extensive dermatosis papulosa nigra, and surgical subcision of acne scars. In the pediatric population, methoxyflurane inhalation may be useful during wart removal with liquid nitrogen cryotherapy and laser treatment sessions, as well as prior to local anesthetic injections in individuals with needle phobias.

Potential Indications for Methoxyflurane in Cosmetic Dermatology

Anxiety about pain is a major barrier to patients choosing to undergo cosmetic dermatologic procedures.⁶⁴ Thus, it is important to be able to provide patients with effective options to alleviate procedural pain and discomfort. While pre-treatment application of ice, topical anesthetic creams and injections of local anesthetics can be used for pain management, these modalities often have limited efficacy, and in the case of local anesthetic injections, may require higher than the maximum safe doses to provide adequate analgesia to an entire area.

Methoxyflurane may be useful in many cosmetic procedures, as it can effectively provide widespread analgesia during procedures involving large body surface areas, such as the full face and/or neck. The hand-held inhaler design of Penthrox^® makes it preferable to other delivery methods for inhaled analgesia due to the lack of bulky tubing and masks, which can block treatment sites on the face. Another benefit is that methoxyflurane is relatively less cumbersome for patients to use compared to holding ice packs at treatment sites for several minutes or applying topical anesthetic creams, which often require occlusion to achieve maximal efficacy.⁶⁵ Additionally, methoxyflurane is non-flammable, making it a safe choice for use during cosmetic dermatologic procedures that involve the use of lasers and energy-based devices.¹⁶ Potential procedural indications for methoxyflurane in cosmetic dermatology may include full-face ablative and non-ablative fractional laser resurfacing, laser tattoo removal, laser hair removal, radiofrequency microneedling, radiofrequency and ultrasound skin tightening procedures, sclerotherapy, and dermal filler injections.

Conclusion

In summary, methoxyflurane is an inhaled fluorinated analgesic agent that has demonstrated efficacy in managing pain in RCTs for a variety of different painful medical procedures. It is a compelling choice for analgesia in outpatient dermatology settings given its high efficacy, limited side effect profile, ease of patient self-administration, rapid onset, quick resolution of CNS effects following discontinuation, cost-effectiveness, and lower environmental impact compared to other inhaled analgesics.

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¹Beacon Dermatology, Calgary, AB, Canada
²Division of Dermatology, University of Calgary, Calgary, AB, Canada
³Dermatologie Clinic, Drummondville, QC, Canada
⁴Bausch Health Canada Inc, Laval, QC, Canada
⁵SKiN Centre for Dermatology, Peterborough, ON, Canada
⁶Queen’s University, Kingston, ON, Canada

Conflict of interest: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article:
Isabelle Delorme has been a member of advisory boards for AbbVie, Bausch Health, Eli-Lilly, Janssen, Novartis, Sanofi-Genzyme. She has been a part of clinical trials for AbbVie, Amgen, Anaptys Bio, Arcutis, Bausch Health, BMS, Celgene, Dermira, Devonian, Eli-Lilly, Galderma, Glenmark Pharmaceutical, Innovaderm Research, Janssen, Leo Pharma, Novartis, Regeneron. She has recieved honoraria from AbbVie, Amgen, Avene, Celgene, Eli-Lilly, Janssen, Novartis, UCB Pharma. She has been part of speaker’s bureaus for AbbVie, Celgene, Bausch Health, Eli-Lilly, Janssen, Medexus Inc., Novartis, Sanofi Genzyme. Melinda Gooderham has been an investigator, speaker and/or advisor for – AbbVie, Amgen, Akros, Arcutis, Aslan, Bausch Health, BMS, Boehringer Ingelheim, Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, Kyowa Kirin, Leo Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, and UCB. Andrei Metelitsa has been a consultant for Bausch Health, Galderma, Leo Pharma and Pfizer.
Daniel O’Sullivan, Rami Zeinab and Mark Legault are employees of Bausch Health Canada.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abstract:
Dermatological diseases such as atopic dermatitis, acne, and psoriasis result in significant morbidity and decreased quality of life. The first line of treatment for such diseases is often topical medications. While topical delivery allows active drug to be delivered directly to the target site, the skin is a virtually impermeable barrier that impedes delivery of large molecules. Thus, the formulation and delivery system are integral elements of topical medications. Patients also have preferences for the properties of topical formulations and these preferences can positively or negatively impact adherence. Therefore, the choice of topical formulation is a key consideration. Recent developments in drug delivery systems have produced enhanced topical treatments that improve efficacy, safety, and patient acceptability. Awareness of the delivery system in which drugs are formulated is critical as this can have profound implications on treatment success. This paper provides an overview and clinical commentary on advances in topical delivery systems and their impact on dermatological practice.

Keywords: acne, corticosteroid, dermatitis, dermatology, halobetasol, psoriasis, retinoid, tazarotene, topical, vehicle, Duobrii, Arazlo, Bryhali

Introduction

Topical therapies are often the first line of treatment for common skin diseases such as atopic dermatitis (AD), acne vulgaris (AV), and psoriasis (PsO).¹ Prescribing effective therapy is crucial for optimal treatment outcomes.² However, the composition of topical treatments is complex and should be taken into consideration when choosing a topical treatment in terms of both “formulation” and “drug delivery system” wherein the formulation includes the active drug and vehicle while the delivery system refers to technologies affecting the therapeutic action of the drug (including potency, stability, dispersion, and penetration). Both formulation and delivery system should be considered for each patient on the basis of the potency of the active molecule, patient preference, skin type, skin condition, and affected site.³ Several recent reviews have discussed topical vehicles, ingredients, and their effects on the skin,^4-10 however, there is a gap in reviewing advanced delivery systems currently in clinical use. This paper provides an up-to-date review of advances in topical delivery systems with a focus on those in clinical use for the treatment of AD, AV, and PsO.

Atopic Dermatitis, Acne Vulgaris and Psoriasis

Skin conditions are a common cause of disease globally,¹¹ with AD, AV, and PsO amongst those with the highest disease burden on patients¹². These conditions disrupt the normal skin function,¹³ trigger abnormal inflammatory responses, alter skin microbiome, and increase susceptibility to irritants/allergens.^5-7 AD is a chronic, relapsing disease, presenting as inflamed skin with intense itching.^14,15 AV is due to inflammation of the sebaceous follicles, resulting in increased sebum production and a favorable environment for bacterial growth.¹⁶ PsO is a chronic disease that presents with characteristic scaling, redness, and thickening of the skin. All of these skin diseases can have important detrimental effects on short and long-term psychosocial and physical health, with substantial morbidity and reduced quality of life.^15,17,18 As such, early treatment with the most efficacious therapies available is critical.

Factors to Consider with Topical Drug Delivery Systems

Applying treatment topically provides several advantages for managing skin diseases. It enables delivery of drug directly to the target site, minimizing systemic exposure.¹⁹ The skin provides for a regulated, constant delivery rate and circumvents first-pass metabolism.²⁰ However, delivering drugs to targets beneath the epidermis can be challenging.²¹ The skin is a multi-layered defense barrier constructed to withstand the penetration of external compounds.²² The stratum corneum is very effective in performing this role and minimizes the ingress and egress of molecules/ chemicals.²³ As a result, the skin is impermeable to almost all compounds with a molecular weight greater than 500 Daltons.^22,23 As diffusion is the principal mechanism by which a drug penetrates the skin,²² formulations must be optimized to maintain solubility, stability, dispersion, and penetration of the active ingredient(s) while ensuring they are sustained at the target site for sufficient time, as well as limit systemic exposure³.

The effectiveness of a topical medication depends not only on pharmacodynamic factors but also on patient preferences, adherence, and the location of disease.^2,24 Patient preferences are related to the formulation and drug delivery system whose attributes include moisturization, absorption, greasiness, stickiness, as well as ease and frequency of use.²⁵ These attributes influence adherence to the therapeutic regimen which is a major determinant of treatment success.²⁵ Teixeira et al.²⁶ reported that adherence was impacted not only by patient preferences, but also the body area affected. For example, adherence was higher for patients using gel/cream vs. ointment formulations when the body area affected was large. However, this was reversed with smaller areas. As such, delivery systems are no longer only considered ‘carriers’ of active ingredients, but also integral to the formulation. Hence, drug delivery system research and development have been the main drivers of recent advancements in topical formulations.

Advanced Topical Drug Delivery Systems

Over the years, advanced drug delivery systems have been developed to enhance effectiveness, tolerability, safety, and patient acceptability of topical formulations. Some of these advanced delivery systems are integrated into approved products utilized in clinical practice in Canada (Figures 1 & 2). As such, it is important for healthcare providers to be aware of these systems and their profound implications on treatment outcomes. The following summary provides an overview of some recent advances in drug delivery systems and their clinical application (Table 1).

Table 1. Advanced topical drug delivery systems in clinical use

Microencapsulation

Description of Delivery System

Microencapsulation is a technique that involves entrapping active ingredient(s) in a microcapsule, creating a barrier between the ingredients and the skin.²⁷ Once applied, microcapsules allow controlled release of active ingredients over time.²⁸ This offers advantages for topical delivery of agents (Table 1) where active ingredients are protected against degradation and maintained at the target site for an extended time while limiting local adverse reactions.^28,29

Clinical Application Highlights

Encapsulation is the technology behind two topical treatments approved for treatment of moderate to severe AV in the US. The first formulation is a foam-based delivery system that optimizes the topical delivery of minocycline (minocycline topical foam 4%, Amzeeq®).³⁰ Minocycline was previously not available topically due to its instability and systemic side effects.³¹ Such limitations were mitigated with microencapsulation. In phase 2^32,33 and 3³⁴ clinical trials, microencapsulated minocycline significantly reduced AV lesions and severity compared to placebo; with minimal adverse effects. The second is a cream-based formulation combining tretinoin 0.1% and benzoyl peroxide (BPO) 3% (Twyneo®).³⁵ Tretinoin and BPO are individually entrapped within silica-based microcapsules preventing the degradation of tretinoin by BPO.²⁸ The active ingredients are released over time, providing a consistent drug concentration at the affected site.³⁶ Results from clinical trials show that patients who received this encapsulated combination therapy had improved treatment outcomes compared with patients who received vehicle only. The treatment was well tolerated.³⁶

Microsponges

Description of Delivery System

Microsponges are microscopic, uniform, spherical, porous delivery systems.³⁷ Some features of micropsonges are summarized in Table 1. Their large surface area allows a range of substances to be incorporated into gels, creams, liquids, or powders.³⁸ They can absorb skin secretions, therefore reducing the oiliness of the skin.^38,39 When applied, the release of drug is controlled through diffusion, rubbing, moisture, pH, friction, or ambient skin temperature, producing a controlled release and reducing side effects.⁴⁰ Microsponge polymers possess the ability to load a spectrum of active ingredients and provide the benefits of enhanced effectiveness, mildness, and tolerability to a wide range of skin therapies.⁴¹ The microsponge system is stable over a range of pH and temperatures, compatible with most vehicles and ingredients, self-sterilizing as average pore size prevents bacterial penetration, and has a higher payload⁴² (50-60%) vs. conventional topical drugs and microencapsulation. However, due to their size (5-300 μm), passage through the stratum corneum is limited.³⁹

Clinical Application Highlights

Early topical formulations of tretinoin had high concentrations of active ingredients in alcohol-based solutions leading to skin dryness and irritation.^43,44 The innovation of microsponges led to the first alcohol-free, topical retinoid delivery system (tretinoin gel, Retin-A Micro^®).⁴⁵ This microsponge gel contains tretinoin in concentrations of 0.04%, 0.06%, 0.08%, and 0.1%. Tretinoin is entrapped in patented methyl methacrylate/glycol dimethacrylate copolymer porous microspheres (Microsponges^® system), within a carbomer-based gel. In the vehicle-controlled clinical trials, tretinoin gel was significantly more effective than vehicle in reducing the severity of acne lesions; and significantly superior to vehicle in the investigator’s global evaluation of the clinical response.^46-48 Microsponge delivery of tretinoin has also been associated with decreased irritation compared to earlier alcoholbased cream (Retin-A® cream, 0.1%).⁴⁹

Polymeric Emulsion Technology

Description of Delivery System

In polymeric emulsion technology (PET), active ingredients are encapsulated within oil droplets, together with moisturizing/ hydrating ingredients (light mineral oil, diethyl sebacate).⁵⁰ The oil droplets are uniformly dispersed within an oil-in-water emulsion and separated by a three-dimensional mesh matrix.⁵¹ Recently, PET has been combined with optimized selection of excipients and emollients to produce a patented delivery system called Prismatrex™. This novel technology allows simultaneous and uniform dispersion of active ingredients onto the skin at lower doses than conventional formulations to achieve comparable therapeutic effect, while providing enhanced hydration and moisturization.⁵² Also, the technology allows many attributes of patient preferences to be met. By combining water-soluble moisturizing components within the matrix, a lotion can have a pleasant feel; the use of moisturizers over alcohol-based components creates a lowirritancy/ low-drying formulation; and the mesh network breaking down upon contact with the salts on the skin surface results in quick release and absorption, leaving behind minimal greasy or sticky residue.^50,51

Clinical Application Highlights

Prismatrex™ is used in recent formulations containing retinoids, corticosteroids, or combination of both. Topical corticosteroids are a mainstay in the treatment of AD and PsO. Due to the defective skin barrier in AD and PsO, formulations with moisturizing effects in a patient-preferred format offer additional therapeutic advantages over previous formulations.⁵³ Halobetasol propionate (HP) 0.01% lotion (Bryhali^®), formulated with Prismatrex™, provides several improvements compared to the older 0.05% cream formulation. For example, a reduced concentration of drug while maintaining comparable efficacy to the cream formulation, and a safety profile that allows extended use up to 8 weeks.⁵⁴ Furthermore, the formulation is non-greasy and aesthetically pleasing, providing a patient preferred treatment option.⁵⁵

Topical retinoids are a cornerstone in the treatment of AV. However, dryness, erythema, and peeling are important side effects that can impact treatment adherence.⁵⁶ Prismatrex™ has been used to formulate the third-generation retinoid, tazarotene (TAZ) 0.045% lotion (Arazlo®). The small particle size with this formulation allows better access to the pilosebaceous unit.⁵⁷ Also, this novel technology allows for uniform distribution of TAZ on the skin along with moisturizing ingredients and emollients, therefore, TAZ may be delivered at a lower and potentially less irritating concentration than the previous 0.1% cream formulation.⁵⁸ Two identical phase 3, vehicle-controlled studies demonstrated statistically superior efficacy for TAZ 0.045% lotion vs. placebo in once-daily treatment of moderate to severe AV.⁵⁹

A fixed-combination lotion containing both HP 0.01% and TAZ 0.045% (Duobrii®, HP/TAZ) is formulated using Prismatrex™ technology and indicated for PsO treatment. Higher tissue permeation efficiency of both HP (vs. HP 0.05% cream) and TAZ (vs. TAZ 0.1% cream, Tazorac®) has been achieved with the combination using Prismatrex™ technology.⁵⁰ The delivery of both active ingredients with anti-inflammatory and anti-proliferative properties into a lotion confers a synergistic effect.^50,52 Also, it has demonstrated improved efficacy, tolerability, and maintenance of therapeutic effect compared with monotherapy with either of the active ingredients.^50,52,60-62 HP/TAZ’s acute and long-term efficacy (including maintenance of efficacy after cessation of treatment), tolerability, and safety have been demonstrated in phase 2 and 3 vehicle-controlled trials and an open-label extension study.⁶³ Importantly, HP/TAZ is associated with low incidences of adverse events that may be of concern with corticosteroid and retinoid monotherapy.⁶⁴ Skin atrophy occurs in up to 5% of patients treated with topical corticosteroids.⁶⁴ In HP/TAZ clinical trials, incidences of skin atrophy were rare and generally resolved by the end of the study despite 8 weeks of daily application.^63-64 This may be because TAZ increases the number and activity of dermal fibroblasts and stimulates collagen and elastin production.⁶⁵ Irritation, pain, and retinoid dermatitis may be a challenge with retinoid monotherapy. Incidences of these AEs were lower with HP/TAZ, than with TAZ monotherapy, potentially due to the anti-inflammatory properties of HP.⁶⁴ Clinical trials have also shown that the majority of participants who achieve clear skin with HP/TAZ, experience prolonged maintenance of therapeutic effect after treatment cessation.⁶⁰ Taken together, HP/TAZ provides a treatment option for PsO that is efficacious, safe, combines the beneficial effects of corticosteroids and retinoids, delivers moisturizing and hydrating ingredients, yields longer remission, and is acceptable to patients.

Real World Clinical Commentary

A challenge frequently encountered by dermatologists when managing AD, AV, and PsO is balancing sustained disease suppression with the avoidance of local/systemic side effects. To address this concern, advanced drug delivery systems, such as Primsmatrex™, allow for more efficient delivery of lower doses of active ingredients without compromising efficacy. However, this must also be balanced with overall patient acceptance. Patients consistently cite the following preferences for treatment options: non-greasy applications, reduced skin irritation, spreadable and easily absorbed,³⁶ easily applied in certain body sites (e.g., scalp); easy to wash off with minimal residue, and fast skin responses.⁶⁶ Novel delivery systems often enhance utilization of existing ingredients making them more acceptable to patients, resulting in therapeutic advances. For example, in acne, the innovative drug delivery systems used in Retin-A Micro®, Arazlo® and Twyneo® have significantly improved tolerability of existing topical retinoid ingredients without sacrificing the overall efficacy of these molecules. While patients are advised to maintain a dosing schedule of every second day during the initial phases of treatment to avoid potential irritation, these agents are well tolerated given the nature of the formulations.

The microencapsulation of minocycline foam allows delivery in a topical formulation as opposed to an oral format, which significantly enhances the safety profile. In psoriasis, where availability of topical agents is quite limited, the Prismatrex™ technology in HP/TAZ provides an excellent new treatment option which combines two effective drugs and is a welcome addition to our therapeutic algorithm. In clinical practice, this formulation is effective, can be less irritating to the skin than TAZ alone and is less likely to induce steroid-induced atrophy as compared to HP alone. Another advantage to these advanced topicals is that they result in improved adherence and therefore better treatment outcomes in the long run. Overall, when choosing the optimal therapeutic agent for treatment of AD, AV, or PsO the dermatologist now has the option to select a formulation that uses an advanced drug delivery system to maximize the chances of achieving successful treatment outcomes. Research in advanced delivery systems is vast, with a wide range of technologies showing promise for future clinical use, such as nanoparticles⁶⁷, ethosomes⁶⁸, niosomes⁶⁹, and liposomes⁷⁰.

Conclusion

Topical treatment is a cornerstone in managing AD, AV, and PsO;¹⁹ however, the delivery of active drugs through the dermal barrier remains a challenge. Furthermore, patient acceptability is a major contributing factor to the effectiveness and adherence to topical treatments. Advances in topical drug formulations and delivery systems address many limitations seen with older formulations. These advances allow for efficient and uniform delivery of active ingredients to target sites, greater patient acceptability, and enhanced treatment outcomes.

Acknowledgements

Medical writing assistance for this manuscript was provided by KTP (Knowledge Translation Partners), Montreal, Canada, funded by Bausch Health Canada.

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¹Skin Centre for Dermatology, Peterborough, ON and Queen’s University, Kingston, ON, Canada
²Associate Professor, University of Toronto, ON, Canada
³Lynde Institute for Dermatology, Markham, ON, Canada
⁴Clinical Instructor, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁵Assistant Professor in Clinical Teaching faculty of medicine, Sherbrooke University, Sherbrooke, QC, Canada
⁶Assistant Professor, Division of Dermatology, University of Ottawa, Ottawa, ON, Canada
⁷Dermatology, CHU de Québec-Université Laval, Quebéc, QC, Canada
⁸Centre hospitalier universitaire Dr-Georges-L.-Dumont, Moncton, NB, Canada
⁹Assistant Professor, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
¹⁰Queen’s University, Kingston, ON, Canada
¹¹Clinical Associate Professor, Memorial University of Newfoundland, St. John’s, NL, Canada
¹²Clinical Assistant Professor, Discipline of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
¹³Associate Clinical Professor Dermatology, University of Calgary, AB, Canada
¹⁴Associate Professor, Dalhousie University, Halifax, NS, Canada
¹⁵Université de Montréal, Montréal and Dermatologie Sima Recherches, Verdun, QC, Canada
¹⁶Dermatology, CHU de Québec-Université Laval, Québec, QC, Canada
¹⁷Ottawa, ON, Canada
¹⁸Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada
¹⁹Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

Introduction

Chronic hand dermatitis (CHD) can affect up to 10% of the population and have a significant impact on quality of life (QoL).^1-3 It presents as a chronic, recurrent, inflammatory condition with erythema, scaling, fissuring, pruritus and lichenification of the hands. The etiology is multi-factorial and includes both genetic and environmental factors.¹Treatment is notoriously difficult as symptoms frequently recur despite standard therapy. Undertreated CHD can lead to a substantial burden on patients as well as an economic burden on society due to reduced work productivity and many work-related compensation claims.^2-5

Recently, practical guidelines for the management of CHD were published in the Skin Therapy Letter, Family Practice Edition (October 2016).⁶ This series of cases using alitretinoin (Toctino®, GlaxoSmithKline and distributed by Actelion, Laval, QC) is a follow on to that publication to put the guidelines into context.

Abbreviations: AEs – adverse events, CHD – chronic hand dermatitis, ENT – ear, nose, and throat, HD – hand dermatitis, QoL – quality of life

Diagnosing HD – Important points to cover

• Determine if the patient has eczema, or a childhood history of eczema (erythematous, scaling patches with some fissuring in typical locations).
• Ask about a personal or family history of atopy, including asthma, seasonal ENT allergies, nasal polyps.
• Ask about a history of psoriasis and comorbidities such as psoriatic arthritis.
• Does the patient have occupational exposures that could lead to allergic or irritant contact dermatitis?
• Has the patient had any recent exposures to irritants? Frequent handwashing?
• Do a skin scraping for fungal KOH and culture to rule out tinea manuum, as needed.

Case

Case 1:

A 39-year old dairy farmer presented with a 15-year history of redness, scaling and painful fissuring of the hands. He has used multiple potent topical steroids over the years with only temporary benefit. Despite the continued use of topical steroids he reported that his symptoms always return. After a skin scraping for fungal culture was taken and reported negative, he was referred to a dermatologist for assessment.

A diagnosis of CHD was confirmed. Given the failure of potent topical steroids for >8 weeks and inability to attend regular phototherapy sessions, his dermatologist started him on alitretinoin 30 mg PO QD for a 6-month course. By week 12, his hands were almost clear and by week 24, his hands were clear. He stopped the medication after a 6-month course of alitretinoin and entered into remission. At follow up appointments at year 5 and year 11, his hands remained clear. (Figure 1 and 2)

• Alitretinoin (9-cis retinoic acid) is an endogenous retinoid (physiological vitamin A derivative) and is the only systemic agent approved for CHD. It has proven to be safe and effective for the treatment of CHD in controlled clinical trials7-10 and in real-world experience.^11-15
• In the pivotal BACH trial, 1032 patients with CHD were treated with alitretinoin (10 mg, 30 mg) or placebo for up to 24 weeks. The group that received alitretinoin 30 mg QD had up to a 75% median reduction in signs and symptoms and 48% were clear or almost clear at the week 24 time point.⁸
• In patients who were clear/almost clear, 67% did not relapse within 24 weeks off therapy. In those patients who did relapse, 80% of those re-treated with 30 mg QD recaptured their response.⁹
• Approximately half of those patients receiving 10 mg QD and 40% of those receiving 30 mg QD who did not initially respond to alitretinoin, did respond to retreatment with the 30 mg QD dose for an additional 24 weeks.¹⁰
• The majority of patients do not require long-term management with alitretinoin as some patients enter a remission period with 24 weeks of therapy. For those who relapse and require re-treatment, the majority recapture their response⁹ and in those patients who require ongoing therapy, there are no safety concerns with continuous dosing.^10,12,13

Figure 2. No further prescribed systemic or topical treatments since 2005. (2A) Year 5, (2B) Year 11.Photos courtesy of Dr. Yves Poulin

Case 2:

A 52-year old female teacher presented with a 15-year history of recurrent CHD. She had tried numerous moisturizers and mild to superpotent topical steroids over the years without relief. She tried 6 months of narrowband UVB phototherapy with only partial resolution. She was frustrated and looking for a better solution. Her past medical history is significant for obesity and hypothyroidism. Her dermatologist started her on alitretinoin 30 mg PO QD with excellent response. However, her baseline liver enzymes were 1.5 times the upper limit of normal and 2 months after initiating therapy, increased to 3 times the upper limit so the alitretinoin was discontinued.

Ultrasound demonstrated fatty liver and further work up revealed diabetes. After initiation of metformin and 10 kg of weight loss, the patient’s transaminases returned to within the normal range but her CHD flared. A repeat course of phototherapy and superpotent topical steroids failed again. Slow re-introduction of alitretinoin at 10 mg, followed by 20 mg and then 30 mg led to recapture of response and her transaminases have remained within normal range throughout a continued 3-year course of therapy with alitretinoin.

• In clinical trials, alitretinoin was well tolerated by the majority of patients, although a dose dependent effect was noted with the AE of headache (up to 21.6% with 30 mg dose, 11.6% with 10 mg dose) and with mucocutaneous side effects.^8-10
• Laboratory abnormalities consistent with a retinoid class effect were noted in the trials, with dose dependent elevations in serum cholesterol and triglycerides most commonly noted; reduced thyroid stimulating hormone was reported, but there were no cases of clinical hypothyroidism.^8-10
• A hepatic effect of alitretinoin was not identified in the clinical trials^8-10 or in real-world studies,^11,14 however transient and reversible increases in transaminases have been noted in the product monograph.¹⁶ In the case presented, her transaminitis was likely related to her underlying fatty liver; she had no further issues with ongoing alitretinoin use, once she had proper management of her comorbid conditions (obesity, diabetes). If persistent elevations in transaminases are noted, reduction of the dose or discontinuation should be considered.¹⁶
• Post-marketing surveillance of the use of alitretinoin has identified AEs of special interest in the retinoid class that were not identified in clinical trials. Depression has been reported as well as very rare cases of inflammatory bowel disease and benign intracranial hypertension.¹⁴
• Work-up and monitoring for patients taking alitretinoin is similar to other commonly used retinoids (isotretinoin, acitretin) and should include: baseline hepatic transaminases and lipid profiles, repeated at one month, and then every 2-3 months during therapy. Beta-HCG should be done in women of child-bearing potential prior to initiation of therapy and repeated monthly during therapy and one month after discontinuation.¹⁶
• Retinoids are potent teratogens so practitioners should follow the Pregnancy Prevention Program,¹⁶ and women of child-bearing potential should be counselled on strict pregnancy prevention, use of two highly effective forms of birth control simultaneously and be monitored monthly with a serum pregnancy test.¹⁶
• Of 2 pregnancies reported in the clinical trials and 12 in post-marketing reports, 13 pregnancies were terminated early (elective or spontaneous abortion) and one healthy baby was born. No congenital abnormalities have been reported to date.¹⁴

Case 3:

A 68-year old retired woman had been suffering from hand dermatitis for the past 3 years since she had been at home caring for her elderly husband. She had been applying emollients throughout the day and trying to avoid frequent hand washing. Neither the potent topical corticosteroid nor the topical calcineurin inhibitor prescribed for her have helped. She was finding chores at home difficult with fissured finger tips and could not enjoy her hobbies of knitting or gardening because of the painful fissures. She was started on alitretinoin at 30 mg PO QD and noted good response, however she suffered from frequent headaches. Her dose was reduced to 10 mg PO QD with partial return of her CHD symptoms. Addition of a potent topical steroid and a course of narrowband UVB phototherapy to the alitretinoin 10 mg QD provided an effective combination regimen to control her CHD.

• Although clinical trials excluded concomitant therapy with topical medications or phototherapy, these concomitant treatments are often continued or added in real-world practice.^11,13
• Narrowband UVB phototherapy has been shown to be effective in CHD.¹⁷
• We know from vast experience in treating psoriasis, the combination of retinoids and UVB phototherapy is a very safe and effective way to optimize treatment outcomes and can reduce the cumulative dose of UVB exposure.^18,19
• According to expert opinion based on the experiences of the authors, combination of alitretinoin with topical corticosteroids or phototherapy is safe, can improve responses and may be a good option for patients who can only tolerate the 10 mg QD dose or who have not reached clear/almost clear status with the 30 mg QD dose.¹³
• Regardless of the combination of treatments selected, always remember to assess adherence and counsel each patient on appropriate prevention and avoidance strategies, regular moisturization and proper use of medications.⁶ (see Figure 3)

Case 4:

A 34-year-old mechanic presented with a 3.5-year history of CHD. His job is dependent on the use of his hands and he has a young family to support. He responded poorly to multiple courses of mid to superpotent topical steroids and a topical calcineurin inhibitor. Contact dermatitis was suspected and he was referred to a dermatologist for patch testing.

Patch testing with the North American Contact Dermatitis Group standard series revealed a positive reaction to methylisothiazolinone, which happened to be an ingredient in the citrus hand scrub he used at work and in the wet wipes he used when changing his child’s diaper. Modification of his home and work place environment to avoid this allergen has improved his CHD somewhat but it is not clear and is still causing problems at work. He was fearful of jeopardizing his employment and requested further treatment. A course of alitretinoin at 30 mg QD was initiated with good response and he continued to avoid methylisothiazolinone at work and home.

• CHD may be related to a contact dermatitis, which can be either irritant contact dermatitis or in some cases allergic contact dermatitis.²⁰ Many times patients also have an underlying atopic diathesis putting them at increased risk of developing hand dermatitis.²¹
• Contact dermatitis should be suspected when patients are not responding to treatment or worsening despite therapy; these patients should be referred for patch testing.^20,21
• Many different allergens can be responsible for the onset or exacerbation of CHD. In this particular patient’s case, methylisothizolinene, a common preservative in personal care products,^21-23 was a factor. This outlines the importance of patch testing, and considering contact dermatitis in the differential diagnosis.
• Whether the patient has CHD of unknown etiology or due to irritant contact dermatitis, allergic contact dermatitis or underlying atopic dermatitis, alitretinoin is still an option for management as second line therapy after failure of potent or superpotent topical steroids. Patch testing can help determine if an allergen should be avoided as part of the management plan, although lengthy wait times for this test in some jurisdictions should not delay therapy. In some cases, once identified, allergen avoidance may be all that is necessary for symptom resolution.
• In the real-world observational study, PASSION, it was shown that treating CHD with alitretinoin resulted in significant and rapid improvement in symptoms, increased QoL and reduced work impairment. The number of patients rated as ‘disabled’ was reduced from 12.4% at baseline to 2.2% at week 24, and those reporting no work impairment increased from 2.7% at baseline to 63.7% at week 24, showing that alitretinoin can significantly reduce work incapacity.¹⁵

Conclusions

CHD is a common condition causing a significant impact on quality of life and an economic burden due to reduced productivity and cause for disability. Many patients do not respond to standard treatments, making it a challenging condition to manage. This case series is a follow on to a recent publication of practical guidelines for the general practitioner on the management of CHD, to put the use of alitretinoin in context. The addition of alitretinoin to our therapeutic armamentarium has changed the way we are able to manage patients who suffer from this condition, providing a safe and effective treatment option to improve QoL and reduce work impairment. When managing patients with CHD, we must always remember to confirm the diagnosis, assess adherence, counsel our patients on prevention and avoidance strategies, encourage moisturization and proper use of medications and refer patients for patch testing if a contact allergy is suspected.

Patient Resources:
https://eczemahelp.ca/
http://www.eczemacanada.ca/

Acknowledgement

The authors wish to acknowledge Evert Tuyp, MD, FRCPC for his editorial assistance in the preparation of this manuscript.

References

1. Thyssen JP, et al. Contact Dermatitis. 2010 Feb;62(2):75-87.
2. Lynde C, et al. J Cutan Med Surg. 2010 Nov-Dec;14(6):267-84.
3. Kouris A, et al. Contact Dermatitis. 2015 Jun;72(6):367-70.
4. Augustin M, et al. Br J Dermatol. 2011 Oct;165(4):845-51.
5. Cvetkovski R, et al. Br J Dermatol. 2005;152(1):93-8.
6. Gooderham M, et al. Skin Therapy Letter, Family Practice Edition. 2016 Oct;11(1):1-5.
7. Ruzicka T, et al. Arch Dermatol. 2004 Dec;140(12):1453-9.
8. Ruzicka T, et al. Br J Dermatol. 2008 Apr;158(4):808-17.
9. Bissonnette R, et al. Br J Dermatol. 2009 Feb;162(2) :420-6.
10. Lynde C, et al. Clin Exp Dermatol. 2012 Oct;37(7):712-7.
11. Diepgen TL, et al. Acta Derm Venereol. 2012 May;92(3)251-5.
12. Gulliver WP, et al. J Cutan Med Surg. 2012 May;92(3):251-5.
13. Ham K, et al. J Cutan Med Surg. 2014 Oct;18(5):332-6.
14. Morris M, et al. J Dermatolog Treat. 2016;27(1):54-8
15. Thaçi D, et al. J Dermatolog Treat. 2016 Nov;27(6):577-83.
16. Toctino® (alitretinoin) soft capsules (product monograph on the Internet). Mississauga (ON): GlaxoSmithKline Inc, Distributed by Actelion Pharmaceuticals Canada, 2016 [revised 04 APR 2016].
17. Sezer E, Etikan I. Photodermatol Photoimmunol Photomed. 2007 Feb;23(1):10-4.
18. Green C, et al. Br J Dermatol. 1992 Jul;127(1):5-9.
19. Ruzicka T, et al. Arch Dermatol. 1990 Apr;126(4):482-6.
20. Diepgen TL, et al. JDDG. 2015 Jan;13(1):77-85.
21. Mowad C, et al. J Am Acad Dermatol. 2016 Jun;74(6):1029-40.
22. Ham K, et al. Dermatitis. 2015 Jul-Aug;26(4):166-9.
23. Cahill JL, et al. Med J Australia. 2014 Mar;200(4):208

Introduction

Hand dermatitis (HD) can have a significant impact on quality of life of those affected. It may interfere with activities both at work and in the home and can be associated with social and psychological distress.^1,2 The chronic form, chronic hand dermatitis (CHD) affects up to 10% of the population, which can have a considerable societal impact.² Canadian Guidelines for the management of chronic hand dermatitis have been published to help guide management of this burdensome condition.³ This article provides helpful practical guidance for the general practitioner in the management of patients with HD.

Abbreviations: CHD – chronic hand dermatitis; ENT – ear, nose, and throat; HD – hand dermatitis; KOH – potassium hydroxide; QoL – quality of life; TCI – topical calcineurin inhibitors; TCS – topical corticosteroid(s)

Diagnosing HD – Important points to cover:

• Determine if the patient has eczema, or a childhood history of eczema (erythematous, scaling patches with some fissuring in typical locations).
• Ask about a personal or family history of atopy, including asthma, seasonal ENT allergies, nasal polyps.
• Ask about a history of psoriasis and comorbidities such as psoriatic arthritis.
• Does the patient have occupational exposures that could lead to allergic or irritant contact dermatitis?
• Has the patient had any recent exposure to irritants? Frequent handwashing?
• Do a skin scraping for fungal KOH and culture to rule out tinea manuum as needed.

Figure 1.
Examples of hand dermatitis(HD)

Determining if HD is Acute or Chronic

Figure 2.
Establish diagnosis of acute hand dermatitis and chronic hand dermatitis (CHD). HD – hand dermatitis

• It is important to first differentiate between acute and chronic forms of HD, as the treatment options may vary.
• Acute HD lasts less than 3 months or occurs only once in a calendar year.
• CHD lasts for at least 3 months and/or patients experience at least 2 relapses in a calendar year.

TIP: Could This Be Tinea?

• Check the feet for signs of tinea pedis and onychomycosis.
• Look for an active border suggestive of tinea.
• Take a skin scraping for KOH microscopy and culture.

TIP: Could This Be Psoriasis?

• Check the feet, scalp, elbows, knees, gluteal cleft and umbilicus for signs of psoriasis.
• Check the nails for signs of psoriasis: pitting, onycholysis, subungual hyperkeratosis, splinter hemorrhages, salmon patches (oil drops).

Prevention, Avoidance and Patient Education

• Every patient with HD, whether acute or chronic, should protect their hands and avoid irritants and exacerbating factors.
• Avoid wet work, frequent hand washing and alcohol-based hand sanitizers.
• Gloves should be worn to protect the hands: cotton gloves at home, or during the night; gel padded gloves for friction and protective gloves for wet work and irritant exposure.
• The following tips are provided for patients on what to use, what to avoid and helpful common practices.

Assessing and Encouraging Patient Adherence

• Ask patients to bring products and prescriptions to follow up appointments to assess usage.
• More frequent patient follow up visits improve adherence.
• Provide education on the disease, treatment options and potential side effects of therapy.
• Choose treatment in agreement with the patient.
• Suggest joining a support group or organization, such as the Eczema society of Canada ( https://eczemahelp.ca/).

Emollient Therapy

• All patients with HD should use a bland, rich emollient to help restore the skin barrier, and apply frequently throughout the day.
• Regular application may prevent itching and reduce the number of flares.
• For hyperkeratotic eczema, patients should use an emollient with keratolytic agent (salicylic acid 10-20% or urea 5-10%).
• Unscented petroleum jelly is inexpensive and helpful for many patients.

Management of Acute HD

• It is important to make a diagnosis of acute HD so that treatment can be started as quickly as possible to maximize the outcome and prevent chronic involvement.
• Patients with HD should be adequately counselled on prevention and avoidance strategies.
• Avoidance of irritants, potential allergens and regular use of emollients is essential.
• Early treatment includes control of flares with a potent or super-potent topical corticosteroid (TCS) applied twice daily. For example, clobetasol propionate 0.05% ointment applied twice daily is generally effective in acute flares.
• For less severe flares, consider betamethasone valerate 0.1% ointment applied twice daily until controlled.
• In more severe cases, systemic steroids (prednisone, intramuscular triamcinolone) should be considered. Prednisone starting at 40-50 mg orally once a day and tapering over three weeks is an effective treatment course.
• Avoid short courses of prednisone as the condition may flare again, so a tapering dose is advised.
• Look for signs of infection and treat concomitantly.
• Try to identify any allergen exposures and recommend avoidance. If allergy is suspected, the patient should be referred for patch testing.
• Once controlled, consider maintenance therapy with topical calcineurin inhibitors (TCIs), such as tacrolimus 0.1% ointment twice daily when necessary, or twice weekly as maintenance therapy.

Figure 3.
Severity-based treatment algorithm for the management of hand dermatitis (HD). CS – corticosteroid; TCS – topical corticosteroid

QoL Consideration

• Patients with mild or moderate CHD who have a significant impact on QoL should be managed as severe CHD.

Did You Know?

• Hydrocortisone topical agents should not be recommended for most cases of HD because it is rarely effective and patients may become sensitized.
• Hydrocortisone is responsible for the majority of allergies to topical steroid products.

Management of Chronic HD

• The treatment plan for CHD depends on whether it is mild, moderate or severe.

Management of Mild CHD

• Patients with mild CHD should be educated on proper prevention and avoidance strategies as outlined earlier.
• Regular emollient therapy should be used to restore and maintain the skin barrier.
• TCS therapy should be initiated with betamethasone valerate 0.1% ointment twice daily for 4-8 weeks.
• If not responding, adherence to the treatment plan should be assessed. Ask the patient to bring medication to follow up appointment to assess amount of product actually used.
• The patient can then be counselled on proper use of the product and provide support for ongoing management.
• If not responding with an adequate trial, a higher potency TCS, such as clobetasol priopionate 0.05% ointment should be prescribed as next line therapy. Reassess after 2 weeks. If not responding to an adequate trial of a potent or super potent TCS, the patient should be considered to have moderate CHD.

Figure 4.
Treatment algorithm for the management of mild chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

TIP: Always assess adherence, reconsider the diagnosis and rule out contact allergens, concomitant infection or colonization when patients do not respond to therapy.

Management of Moderate CHD

• In addition to regular use of emollients, patients with a diagnosis of moderate CHD should be given a 4-8 week trial of a moderate TCS, such as betamethasone valerate 0.1% ointment, or a super potent TCS, clobetasol propionate 0.05% ointment for a 2-week trial. If improved, the patient can continue this as necessary, for control of the condition.
• Another option is maintenance with a TCI, such as tacrolimus 0.1% ointment twice a day as needed, or twice weekly for maintenance. If not improved, reconsider the diagnosis and assess the patient for adherence.
• If a diagnosis of moderate CHD is confirmed, consider treating the patient with a course of phototherapy, if accessible. If unavailable or the patient does not respond, consider treating as severe CHD.

*Ensure patient education and check compliance. Consider reassessment to rule out infection and infestation, or consider differential diagnosis.

Figure 5.
Treatment algorithm for the management of moderate chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

Safety Tip

When patients show signs of adverse effects to TCS, including
atrophy or telangiectasias or they cannot tolerate topical steroid
use, consider TCI (tacrolimus ointment 0.1%) as a non-steroid
topical therapy option for treatment and maintenance.

When to Refer

• Patients with CHD should be referred to a dermatologist when:
  • They may require patch testing
  • They are not responding to therapy
  • Condition is worsening instead of improving
  • Require phototherapy

Management of Severe CHD

• Patients who are diagnosed with severe CHD, patients with mild to moderate CHD who have failed an adequate trial on therapy, or patients who have a significant impact on the QoL, should be treated as having severe CHD.
• Treatment should be initiated with a potent or super-potent TCS, such as clobetasol propionate 0.05% ointment twice a day for 4-8 weeks (2 weeks on dorsal hands if super potent). If improved, patients may continue to use on an as needed basis, or switch to a TCI for ongoing maintenance therapy.
• Patients should be reassessed at 4-8 weeks. If they are not responding to therapy, consider adherence and review proper care.
• A course of phototherapy may also be considered if available.
• Treatment with oral alitretinoin (30 mg orally, once a day) is the next line of therapy based on best available evidence.⁴ Alitretinoin should be prescribed by those who are comfortable with prescribing retinoids.
• As with all retinoids, caution should be used in females of child bearing potential due to teratogenic potential. Monitoring of therapy with regular blood tests for hepatotoxicity and alterations in lipid profile is also recommended.
• If the patient responds to therapy, it should be continued for 3-6 months and reassessed at that time. Patients may discontinue therapy at this point, and continue with ongoing maintenance with topical therapy. If, in the future, they experience a flare, they can be retreated with alitretinoin.⁵
• If a patient does not respond to 12 weeks of alitretinoin, they should be referred for confirmation of diagnosis and other treatment options, which would include treatment with immunosuppressive therapy such as cyclosporine, methotrexate, mycophenolate mofetil or azathioprine.

*Ensure patient education and check compliance. Consider reassessment to rule out infection and infestation, or consider differential diagnosis.

Figure 6.
Treatment algorithm for the management of severe chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

Conclusion

HD can have a significant burden on the patient with an impact on
QoL. Early diagnosis of acute or chronic HD is important for optimal
management. Other conditions such as tinea manuum and psoriasis
need to be ruled out and managed appropriately. Once a diagnosis of
HD is confirmed, treatment depends on the severity of the disease.
A treatment algorithm has been developed to assist the general
practitioner to make a diagnosis and either refer or treat accordingly.
Whichever treatment option is prescribed, all patients should be
educated on emollient therapy, hand protection and avoidance of
irritants or allergens, which may be contributing to their disease.

References

1. Diepgen TL, Agner T, Aberer W, et al. Management of chronic hand eczema. Contact Dermatitis 2007;57:203-10, doi:10.1111/j.1600- 0536.2007.01179.x.
2. Agner T. Hand eczema. In: Johansen JD, Frosch PJ, Lepoittevin J-P, editors. Contact dermatitis. 5th ed. Berlin: Springer-Verlag; 2011. p. 395-406
3. Lynde C, Guenther L, Diepgen TL, Sasseville D, Poulin Y, Gulliver W, Agner T, Barber K, Bissonnette R, Ho V, Shear NH, and Toole J. Canadian Hand Dermatitis Management Guidelines. J Cut Med Surg 2010; 14(6): 267-284
4. Ruzicka T, Lynde CW, Jemec GB, et al. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebocontrolled, multicentre trial. Br J Dermatol 2008;158:808-17, doi:10.1111/j.1365- 2133.2008.08487.x.
5. Bissonnette R, Worm M, Gerlach B, et al. Successful retreatment with alitretinoin in patients with relapsed chronic hand eczema. Br J Dermatol 2009;162:420-6, doi:10.1111/j.1365-2133.2009.09572.x.
6. Veien NK, Larsen P, Thestrup-Pedersen K, and Schou G. Long-term, intermittent treatment of chronic hand eczema with mometasone furoate British Journal of Dermatology Volume 140( 5): 882-886, May 1999
7. Krejci-Manwaring J, McCarty MA, Camacho F, Manuel J, Hartle J, Fleischer A Jr and Feldman SR: Topical tacrolimus 0.1% improves symptoms of hand dermatitis in patients treated with a prednisone taper. J Drugs Dermatol. 7:643-646. 2008. PubMed/NCBI
8. Thestrup-Pedersen K, Andersen KE, Menne T, and Veien NK. Treatment of hyperkeratotic dermatitis of the palms (eczema keratoticum) with oral acitretin. A single blind placebo controlled study. Acta Derm Venereol 2001; 81: 353-355
9. Granlund H, Erkko P , Eriksson E , and Reitamo S. Comparison of cyclosporine and topical betamethasone-17,21-dipropionate in the treatment of severe chronic hand eczema. Acta Dermato-venereologica [1996, 76(5):371-376]

Key Words:
Q-switched, quality-switched, tattoo, tattoo removal, ablative fractional, nonablative fractional, laser, review

The first evidence of efforts to remove body art exists in the writings of Scribonius Largus (54 A.D.), physician for the Roman Emperor Claudius. He described the use of a preparation of cantharides to induce blistering and eschar formation.¹ In the early 20th century chemical methods of tattoo removal continued to predominate. A 1928 Journal of the American Medical Association (JAMA) review of tattoos highlighted removal methods including surgical excision and electrolysis, but concluded that 50% tannic acid yielded the best results.² Quality-switched (QS) lasers for tattoo removal (694 nm ruby) was first reported in 1965 by Goldman.³ However, it was not until the theory of selective photothermolysis was introduced in 1983 that QS lasers became the gold standard for modern day tattoo
removal.⁴

In order to optimize the outcomes of laser tattoo removal, it is imperative at the initial consultation to thoroughly educate patients regarding the treatment process. It is costly, often far exceeding the expense of obtaining the body art. Amateur tattoos generally require four to six treatments and professional tattoos may need eight or more sessions. Tattoos in acral locations prove more challenging to remove than those placed on truncal sites and older tattoos respond more readily than newer ones.⁵ The procedures can be painful and may not result in complete removal. A recent retrospective review of 238 paying patients who underwent an average of 3.57 treatments (ranging between 1-18 sessions) found that 1.26% achieved total clearance of the tattoo, defined as complete absence of pigment.⁶ The authors attributed the suboptimal results to their patients being inadequately informed of the process and subsequently underwent fewer treatments. To set reasonable expectations for our prospective patients presenting with professional tattoos, the authors suggest that 75% of pigment can be diminished, however, complete removal is difficult to achieve. Prior to initiating treatment, it is important to examine the skin and query the patient regarding whether they have a history of hypertrophic scars/keloids or infectious diseases. Q-switched laser treatments are absolutely contraindicated in patients who have received gold therapy as they induce chrysiasis. Baseline photographs are highly recommended.

Appropriate Device Selection

When approaching a patient for tattoo removal, the laser practitioner must choose an appropriate device. A QS laser is necessary to achieve selective photothermolysis, as the exposure time in the nanosecond (10^-9) domain is less than half the thermal relaxation time of the target pigment. This ensures that the thermal damage is spatially confined to the target chromophore, resulting in photoacoustic destruction and minimizing damage to the surrounding tissue from thermal diffusion. The four available QS laser wavelengths are in the visible and infrared domain and include the 694 nm ruby, 755 nm alexandrite, the 1064 nm neodymium:yttrium-aluminumgarnet (Nd:YAG), which when passed through a potassium titanyl phosphate (KTP) crystal will double the frequency (halve the wavelength) to 532 nm. It is essential to utilize a wavelength that will be selectively absorbed by the tattoo particle (see Table 1). Additionally, dye laser handpieces can convert 532 nm to 585 nm (sky blue) and 650 nm (green). Despite these guidelines, it is important to remember that tattoo composition can be highly variable and the pigment may not respond predictably to QS laser treatment.⁷ The QS Nd:YAG is the device of choice when treating tattoos on Fitzpatrick type IV to VI patients, as the 1064 nm wavelength penetrates deepest and is minimally absorbed by epidermal melanin.

Treatment and Technical Considerations

Adequate pain control is necessary to deliver a pleasant treatment experience. Depending on the size of the tattoo, its location, and the pain tolerance of the patient, the authors utilize topical anesthesia with a forced air-cooling device or intralesional anesthesia. When QS laser energy is directed at the tattoo, the desired endpoint is usually immediate tissue whitening, though this may not occur once the tattoo has faded significantly. The whitening, which lasts approximately 20 to 30 minutes, is a result of rapid heating of the chromophore leading to gas formation.⁸The optimal fluence is the lowest possible setting that elicits this endpoint in order to minimize the risk of thermal injury, such as blister formation and scarring. Failure to choose the proper wavelength will result in no visible laser-tissue interaction. It is beneficial for practitioners to have multiple wavelengths of light in their laser armamentarium to treat the spectrum of colors in modern-day professional tattoos.

An additional consideration is to utilize the largest spot size possible when treating tattoos. Because the smaller the spot size the greater the beam scatter, an increased amount of laser energy scattering at the edge of the field results in decreased depth of penetration.⁹ There is a tendency among practitioners to reduce the spot size in order to increase the fluence in non-responding tattoos, however, this results in a more superficial delivery of energy and potentially increases epidermal damage. Treatment spots are applied with approximately 10-20% overlap and fluence is chosen to minimize pinpoint bleeding. Laser treatments are ideally spaced 4 to 6 weeks apart, however, it takes approximately 3 months for the full effect of the treatment to be realized. The authors apply a cooled hydrogel dressing (2nd Skin® Moist Burn Pads) immediately following treatment. It is important to apply emollients and an occlusive dressing to the treated area until reepithelialization is complete.

Potential Adverse Effects

The most common side-effects of QS laser tattoo removal include scarring and dyspigmentation. When therapy is done properly, the estimated incidence of these effects is approximately 5%.¹⁰ Hypopigmentation is more common with the 694 nm ruby laser as it is well absorbed by melanin, but can also occur with other wavelengths.^11,12 As well, all QS wavelengths can produce hyperpigmentation in darker skin types.^11,12 Moreover, because epidermal melanin serves as a competing chromophore, increasing the chance of hypopigmentation or hyperpigmentation, it is imperative that patients avoid all sun exposure at the tattoo site prior to laser treatment.

The aforementioned 1928 JAMA review cautioned, “Bad results follow attempts at removal by professional tattooers and advertising charlatans.”² In fact, there are recent European reports of the increasing frequency of laser tattoo removal performed by laypeople.^13,14 Furthermore, the literature is replete with cases of scarring and disfigurement associated with the use of intense pulsed light, long-pulsed lasers, and even radiofrequency devices to remove body art.^2,15-17 The light devices violate the principle of selective photothermolysis by delivering energy over a longer duration than necessary, exceeding the thermal relaxation time of the pigment, thereby causing excess heat conduction to the surrounding dermis and subsequent scarring.

Caution must also be undertaken when attempting to remove pink, tan, white, yellow or other light-colored tattoos with QS lasers. These colors are often utilized in cosmetic tattoos for permanent makeup. Paradoxical darkening can occur as the titanium dioxide or iron oxide pigment is reduced by the QS laser treatment.^18,19 It is therefore prudent to perform a test spot prior to treating the entire tattoo. When paradoxical darkening occurs, clearing can at times be achieved with additional QS laser treatment.²⁰ Another option for cosmetic tattoos is to avoid QS lasers and treat primarily with fractional carbon dioxide (CO2) or erbium:YAG (Er:YAG) devices. Arndt and colleagues remind practitioners to question patients whether the tattoo is a “double tattoo,” with one covering the original.²¹ In such cases, failure to reduce the fluence accordingly could result in hypertrophic scarring.

There are reports in the literature of successful treatment of tattoo pigment-induced local allergic reaction with QS lasers, and the authors have performed treatments after pre-medication with oral antihistamines. However, extreme prudence is recommended as there are reports of laser tattoo removal resulting in systemization of the allergic response and anaphylaxis.^15,22 In two recently reported cases, fractional Er:YAG with or without adjunctive QS laser therapy proved successful in treating tattoo pigment-induced allergy.²³

Advances and Future Perspectives

Research is underway to improve both the techniques and devices used for laser tattoo removal. The recently presented “R20” method suggests repeating QS laser treatment four times in a single session spaced 20 minutes apart to allow whitening to fade.²⁴ The investigators found more rapid clearing with the R20 technique versus areas of the same tattoo that received a single treatment per session. Weiss et al. found that adding nonablative fractional 1550 nm laser treatment after QS laser reduced the amount of treatment-induced hypopigmentation.²⁵ The investigators also found that fractional CO2 laser therapy immediately after QS laser treatment enhanced the rate of pigment clearance versus QS laser alone. The theoretical mechanisms described include the fractional CO2 laser ablation of superficial tattoo pigment and the induction of an immune response that potentiates removal of the treated pigment.

Lasers in the picosecond (10^-12) domain are currently under development.²⁶ Theoretically, delivering a sub-nanosecond pulse could more effectively confine the energy to the tattoo particle, resulting in increased photoacoustic breakup of the target. This would allow for effective treatment utilizing lower fluences, thereby decreasing thermal energy transfer to surrounding tissues and minimizing the risk of scarring.

Conclusion

Quality-switched lasers remain the gold standard for tattoo removal, but employing the appropriate device and technique does not guarantee a successful outcome. Practitioners must educate their patients in detail regarding the process of laser tattoo removal and reasonable post-treatment expectations in order to create a therapeutic alliance. Exciting new technologies and techniques promise to augment our ability to effectively rid patients of their unwanted body art.

References

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