Division of Dermatology, Department of Medicine, Western University, London, ON, Canada
Guenther Research Inc., London, ON, Canada

Conflict of interest: Dr. Guenther has been a speaker for AbbVie, Actelion, Amgen, Altana, Aralez, Bausch, Cipher, Eli Lilly, Galderma, GSK, Janssen, Johnson and Johnson, La Roche Posay, Leo Pharma, Merck, Novartis, Pfizer, Sanofi Aventis and UCB. She has been a consultant for AbbVie, Actelion, Amgen, Aslan, Altana, Aralez, Bausch, BMS, Celgene, Eli Lilly, Galderma, Incyte, Johnson and Johnson, La Roche Posay, Leo Pharma, Merck, Pfizer, Regeneron, and UCB. She has been a principal investigator for AbbVie, Actelion, Amgen, Bausch, BMS, Boehringer Ingelheim, Celgene, Cipher, Eli Lilly, Galderma, Isotechnika, Innovaderm, Janssen, La Roche Posay, Leo Pharma, Merck, Novartis, Pfizer and UCB. She has been a member of the PSOLAR Janssen registry since its inception.

Abstract:
The lifetime risk for herpes zoster (HZ) of approximately 1 in 3 is increased with advancing age, a family history of HZ, diseases with altered immune function, immunosuppression, physical trauma and psychological stress. In dermatology, monotherapy with current biologics does not increase risk, however systemic steroids, Janus kinase inhibitors and combination biologic/conventional disease-modifying antirheumatics do. The recombinant zoster vaccine (RZV, Shingrix^®), an adjuvanted non-live subunit vaccine against the glycoprotein E subunit of varicella zoster virus, is approved for prevention of HZ in adults ≥50 years of age, and adults ≥18 years of age who are or will be at increased risk of HZ due to immunodeficiency or immunosuppression due to disease or treatment. It is administered as two 0.5 ml intramuscular injections 2-6 months apart. In immunocompromised individuals, the spacing between injections may be reduced to 1-2 months. Where possible, the first dose should be administered at least 14 days before onset of immunosuppressive treatment. Studies in immunocompetent individuals have shown high efficacy including prevention of HZ, postherpetic neuralgia and other complications, with persistence of effect 10 years after vaccination. The acceptable safety profile and efficacy in five different immunocompromised populations support its use in at-risk adult dermatologic patients.

Keywords: Shingrix, recombinant zoster vaccine, vaccination, herpes zoster, immunocompromised, atopic dermatitis, psoriasis, systemic, biologic, JAK inhibitors

Introduction

New oral and biologic treatments are being developed to treat common conditions such as atopic dermatitis and psoriasis. Some of these treatments may increase HZ, the recurrent infection caused by reactivation of the varicella-zoster virus (VZV). The lifetime risk is approximately 1 in 3¹ and increases with advancing age,² immunosuppression,² a family history of HZ,³ systemic lupus erythematosus^4,5 rheumatoid arthritis,^4,5 inflammatory bowel disease,^4,5 chronic renal disease,⁵ cancer,⁵ multiple sclerosis,⁴ psoriasis,⁴ asthma,⁵ chronic obstructive pulmonary disorder (COPD),⁵ diabetes mellitus,⁵ depression,⁵ physical trauma⁵ and psychological stress (Table 1).^5,6

Table 1. Factors which increase the risk of developing HZ.

Typical clinical features include a prodrome with pruritus, tingling and/or pain followed by painful erythematous macules, papules and vesicles on an erythematous base over a single dermatome.² The eruption crusts over and usually heals within 4 weeks,² however, complications such as postherpetic neuralgia (PHN) may persist for >1 year particularly in those over age 70 years.⁷ Recurrent HZ occurs in up to 6.41% of individuals.⁸ In immunocompromised patients, the eruption can be multi-dermatomal,⁹ bilateral,¹⁰ disseminated11 or necrotic,¹² and there is a higher rate of HZ related complications.¹³

In 2006 in the US and 2011 in Canada, the first HZ vaccine, a single dose, subcutaneous, live attenuated vaccine, Zostavax™ was approved. This vaccine was discontinued in 2020 in the US and 2022 in Canada. Shingrix^®, an adjuvanted non-live subunit vaccine against the glycoprotein E subunit of VZV (recombinant zoster vaccine, RZV), received approval in 2017 for immunocompetent individuals 50 years of age and older, and in 2021 for individuals 18 years of age or older who are or will be at increased risk of HZ due to immunodeficiency or immunosuppression due to disease or treatment.¹⁴ It has to be first reconstituted before administration and used within 6 hours after reconstitution. It is administered as two 0.5 ml intramuscular injections 2-6 months apart.¹⁴ In immunocompromised individuals the spacing between injections may be reduced to 1-2 months.¹⁴ Health Canada recommends that the first dose be administered at least 14 days before onset of immunosuppressive treatment.¹⁵ If this is not possible, it should be administered during periods with less immunosuppression when the immune response is expected to be stronger.¹³ For patients treated with rituximab, it is recommended that RZV be administered at least 5 months after the last dose and at least 4 weeks before the next dose of rituximab.^16,17

Background

Some immunomodulatory medications can increase the risk of HZ and zoster-related complications. A systematic review of 35 rheumatoid arthritis studies,¹⁶ and study of psoriasis patients in the Israeli Clalit Health Services database¹⁸ showed that methotrexate was not associated with an increase in HZ. Tumor necrosis factor (TNF) antagonists do not appear to increase HZ in patients with psoriasis.^18-20 A network meta-analysis showed no effect of monotherapy with anti-TNFs, ustekinumab or rituximab.²¹ Another systematic review in psoriasis and psoriatic arthritis (PsA) also showed no effect with biologic monotherapy, but an increased risk was associated with systemic steroids, tofacitinib and combination biologic/conventional disease-modifying antirheumatics.¹⁷ Interleukin (IL)-17 and IL-23 inhibitors do not appear to increase the risk of HZ.^22,23

Janus kinase (JAK) inhibitors may increase HZ risk. In the tofacitinib psoriasis trials, HZ events per 100 patient years (PY) were 2.55 vs. 0 for placebo.²⁴ Asian descent (HR 2.92), 10 mg vs. 5 mg twice daily dosing (HR 1.72), prior use of biologics (HR 1.72) and older age (HR 1.30) were risk factors.²⁴ Tofacitinib has approval for PsA, rheumatoid arthritis (RA), and ulcerative colitis (UC), but not psoriasis, or alopecia areata (AA) for which there are case reports of successful hair regrowth.²⁵ Baricitinib is a JAK inhibitor which has approval for AA as well RA, and in some countries, atopic dermatitis (AD). In AA and AD trials, the HZ events per 100 PY (1.4 and 2.3 respectively) were lower than the RA rate (3.0/100 PY).²⁶ Psoriasis studies with 6 mg deucravacitinib, a once daily Tyk2 inhibitor, showed a rate of 0.9/100 PY during the first year and 0.7/100 PY during year 2.²⁷ However, in a phase II PsA trial involving 203 patients randomized 1:1:1 to placebo, deucravacitinib 6 mg or 12 mg once a day, there were no cases of HZ after 16 weeks of treatment.²⁸

During the first 16 weeks of treatment in upadacitinib AD studies, HZ rates were 0.6% for placebo, 1.6% for 15 mg and 1.5% for 30 mg.²⁹ In adolescents, the 30 mg rate was comparable to the adult rate.²⁹ Upadacitinib was initially approved for RA. In a pooled safety analysis of 5306 RA patients, HZ rates were also higher with the 30 mg dose than the 15 mg dose (5.3 vs. 3.0/100 PY)³⁰ and higher than the comparators methotrexate (0.8/100 PY) and adalimumab + methotrexate (1.1/100 PY). Asian patients were at higher risk.³⁰ In abrocitinib AD studies, the rates of HZ in patients aged 18-65 years was 3.44/100 PY and for those ≥age 65 years, 7.40/100 PY. Nine patients on 200 mg and one on 100 mg developed mild/moderate multidermatomal zoster.³¹

Supporting RZV Efficacy Evidence from Clinical Trials

Two randomized, placebo-controlled studies in >30,000 immunocompetent individuals (ZOE-50 for those 50 years of age and older³² and ZOE-70 for those 70 years and older³³) had initial 3.1 and 3.9 year respective follow-ups.¹⁴ Assessment of efficacy was restricted to individuals who received the two vaccine doses and did not have a confirmed episode of HZ before 1 month after the second dose. In ZOE-50, vaccine efficacy in individuals ≥50 years was 97.2% (p<0.001). In individuals 70 years and older, vaccine efficacy was 91.3% and prevention of PHN 88.8%.¹⁴ There was only 1 case of other zoster complications in the ZOE-50/70 RZV group vs. 16 in the placebo group. At 5 years, participants were offered participation in a long-term follow-up study; 7277 subjects were included in efficacy assessments.³⁴ An interim analysis of vaccine efficacy over the period from 1 month post-initial vaccination to a mean of 9.6 +/-0.3 years follow-up, showed 89% (95% CI 85.6%- 91.3%) efficacy in preventing HZ.³⁵ Immune responses remained >5 fold higher than pre-vaccination levels.³⁵

RZV has been studied in 1587 patients with 5 different immunocompromising (IC) situations – autologous hematopoietic stem cell transplant (auHSCT), hematologic malignancies (HM) vaccinated during or following cancer therapy course, solid tumors (ST) undergoing chemotherapy, renal transplant patients on chronic immunosuppressive therapy at the time of vaccination, and patients with human immunodeficiency virus.¹⁴ In all of these populations, RZV induced humoral and cell-mediated immune responses persisting for at least 1 year of follow-up.³⁶ In auHSCT, vaccine efficacy was 68.2% overall with a median follow-up of 21 months.³⁷ PHN (1 vs. 9 cases, p=0.02), other zoster-related complications (3 vs. 13 cases, p=0.02) and hospitalizations (2 vs. 13 cases, p=0.01) were also significantly reduced in vaccine vs. placebo groups, respectively.³⁷ In the hematologic malignancies study, zoster incidence was reduced from 6.62 (placebo group) to 0.85 per 100 PY (p=0·0021) giving an 87.2% efficacy rate in a post hoc analysis.³⁸

Safety

In immunocompetent studies, local (pain and swelling at the injection site) and general adverse events (fatigue, myalgia, headache, shivering, fever, nausea, vomiting diarrhea, and/or abdominal pain) were more common in the 50-69 year age group vs. the ≥70 year group, and generally mild to moderate with a median duration of 3 days.¹⁴ New onset or exacerbation of existing potential immune-mediated diseases (pIMDs) were noted in 1.2% who received RZV vs. 1.4% treated with placebo (median 4.4 year follow-up).¹⁴ In each group, psoriasis and autoimmune thyroiditis were each reported in 0.1%, and polymyalgia rheumatica in 0.2%. RA was reported in 0.1% treated with RZV vs. 0.2% with placebo.¹⁴ In a ≥ 65 year old post-marketing observational study, an estimated 3 excess cases per million doses administered of Guillain-Barre syndrome was noted during the 42 day follow-up period after vaccination.¹⁴ Safety in IC individuals was similar to that in immunocompetent older individuals.³⁸

Conclusion

RZV is highly efficacious (>90%) in immunocompetent individuals with a modest decline in clinical efficacy as well as humoral and cellular immunity over 10 years. It prevents PHN and other zoster complications. The acceptable safety profile and efficacy in a broad population of IC adults including demonstration of immune responses in 5/5 different IC populations and efficacy in two different IC populations, including auHSCT at a time of greatest risk, support its use in our IC adult dermatologic patients. Dermatologists should be proactive in recommending RZV to all patients over age 50 years, particularly those with a family history of zoster and diseases with altered immune function. Adult patients who are immunocompromised because of their diseases or treatment (e.g., systemic steroids, JAK inhibitors, combination biologic/conventional disease-modifying antirheumatics), should also be encouraged.

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Disclosures: The authors disclosed receipt of the following financial support for the research, authorship, and publication of this manuscript. This work was supported by an unrestricted educational grant from La Roche-Posay Canada. All authors contributed to the study and the manuscript, reviewed it, and agreed with its content. LG: AbbVie, Amgen, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Janssen, La Roche Posay, LEO Pharma, Merck Frosst, Novartis, Pfizer, Sun Pharmaceuticals, and UCB – consultant, investigator, and speaker; BMS Consultant and investigator.

Abstract

Introduction: Over the years, the number of surgical excisions, cryosurgery, electrodesiccation, curettage, and facial laser treatment has increased. Presently pre- and post-procedural care and minor wound management remain highly variable, and standards are lacking. This review addresses peri-procedural treatment requirements to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing.

Methods: A panel of eight Canadian dermatologists (panel) who perform dermato-surgery convened to discuss the findings of a structured literature search on peri-procedural measures for surgical excision, cryosurgery, electrodesiccation, curettage, and facial laser treatment. The information from the literature searches, together with the panels’ expert opinions and experience, was applied in this review.

Results: Peri-procedural measures depend on individual patient factors and the type of treatment. Post-procedure moisturizer application may be beneficial for promoting wound healing. Studies have shown no differences in infection rates between post-procedural sites treated with topical antibiotics and petrolatum-based products. Moreover, topical antibiotics are among the top ten allergic contact dermatitis-causing agents.

Conclusions: Cutaneous healing should occur with minimal discomfort and an esthetic scar. Applying a moisturizer without an antibiotic was shown to be beneficial in promoting cutaneous healing. Standards for peri-procedural care and minor wound management may support healthcare providers in improving patient outcomes.

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Introduction

Over the years, the number of skin surgery procedures (surgical shave and elliptical excision, Mohs surgery, cryosurgery, electrodesiccation, curettage, electrodesiccation and curettage (ED&C), laser, and other facial rejuvenation treatments) has increased. The American Society for Dermatologic Surgery reported over 15.6 million cosmetic treatments performed in 2020 in the United States (U.S.) alone.¹ About 13.3 million of these were minimally invasive cosmetic procedures, including neuromodulator injections, soft tissue filler injections, microdermabrasion and chemical peels).¹ The top minimally invasive cosmetic procedures comprised neurotoxins 3.65 million (33%), dermal fillers 1.85 million (32%), skin treatment (chemical peels, hydro-facials) 1.39 million (6%), hair removal 0.45 million (2%), skin treatment (combination Lasers) 0.43 million (4%) and skin tightening 0.39 million (7%).²

While many guidance and consensus documents exist that describe best practices for performing skin surgery procedures, few discuss specific pre- and post-procedure measures. Surveys of aesthetic medicine providers confirmed a lack of consistency in the types and duration of peri-procedural measures for dermatosurgery, laser, and minimally invasive cosmetic procedures.^3,4 Presently, skin surgery pre and post clinical care and minor wound management remain highly variable and there are no standards,^3,4 however, cutaneous healing should occur with minimal discomfort and an esthetic scar. This review addresses peri-procedural treatment requirements to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing.

Methods

The project aims to provide insights into skin conditions and lesions created when performing dermatosurgery, minimally invasive cosmetic procedures, and facial laser treatment, followed by developing standards for these measures.

A panel of eight Canadian dermatologists (panel) who perform skin surgery was convened to discuss the findings of a structured literature search on peri-procedural measures for surgical excision, cryosurgery, electrodesiccation, curettage, and facial laser treatment.

We searched PubMed and Google Scholar (secondary source) databases for studies published from 2010 until September 2022. We divided the search terms into four groups to allow optimal results and avoid duplications.

Group 1: Pre-/post-procedure measures AND surgical excision OR curettage OR ED & C) OR cryotherapy OR facial laser treatment; AND Guidelines OR Algorithms OR consensus papers; AND Adverse events OR Complications OR Pain OR Bruising OR Swelling OR Discoloration OR Infection OR Reactivation of herpes simplex virus OR Antiviral medication OR Scarring OR Comfort OR Sun exposure; AND antimicrobial stewardship OR topical antimicrobials OR systemic antimicrobials

Group 2: Surgical excision, curettage, ED & C, cryotherapy AND healing by primary intent; AND post-procedure measures OR skincare OR topical wound treatment OR wound dressings

Group 3: Surgical excision healing by secondary intent; AND post-procedure measures OR skincare OR topical wound treatment OR wound dressings

Group 4: Peri-procedure measures for laser treatment; AND Guidelines OR Algorithms OR Consensus papers; AND Adverse events OR Complications OR Pain OR Bruising OR Swelling OR Discoloration OR Infection OR Reactivation of herpes simplex virus OR Antiviral medication OR Scarring OR Comfort OR Sun exposure OR Skincare OR wound healing regimen

Exclusion criteria were no original data, information not specific to peri-procedure measures for skin surgery, minimally invasive procedures, and facial laser treatment, and publication in a language other than English. The results of the searches were evaluated independently by two reviewers (AA, TE) and yielded 98 papers. After reviewing abstracts and removing duplicates and papers that did not contribute to this review (n = 43), fifty-five remained. Guidance and consensus documents are available on dermatosurgery, minimally invasive procedures, and facial laser treatment; however, few discussed peri-procedural measures and wound treatment which did not allow for grading.

Results

Procedures Included in the Review

The review addresses the following procedures: surgical excision, cryotherapy, electrodesiccation, curettage, ED&C, and facial laser treatment.

Surgical Excision

A Canadian national survey amongst dermatologists showed that epileptiform excisions, shave excisions, punch biopsies, curettage, and ED&C was most frequently performed, whereas Mohs micrographic surgery (MMS) was the least frequent procedure.⁵ These procedures are used to remove benign and malignant lesions.⁵

Adverse events are usually minor and include bleeding, hematoma, wound dehiscence, infection, discoloration (post-inflammatory hyper (PIH) or hypopigmentation), and atrophic, hypertrophic, or keloid scar formation.⁵

Curettage and Electrodesiccation

Curettage or electrodesiccation can be used to remove benign (e.g. condyloma acuminatum, seborrheic keratosis, pyogenic granuloma, excess granulation tissue) and malignant lesions. With malignant lesions, curettage is often combined with electrodesiccation (ED&C) or cryotherapy. For many indications, ED&C has been replaced by curettage alone, as it yields similar cure rates and a better cosmetic outcome.^12-16 Dermatologists routinely perform these procedures in their offices.

The disadvantage of curettage with or without electrodesiccation or cryotherapy is the absence of histopathologic margin evaluation.^13-15 Studies on low-risk non-melanoma skin cancers show 5-year ED&C cure rates from 91 to 97%.^15,16

Cryosurgery

Cryosurgery has several indications for both benign and malignant lesions. Benign lesions that can be treated with cryosurgery include seborrheic keratosis, verruca, skin tags, molluscum contagiosum, solar or senile lentigo, and actinic keratosis.^16-20 In the case of exophytic lesions, curettage should be considered prior to cryotherapy. This procedure can be delivered quickly and cost-effectively in an outpatient setting.^16-20

Recurrence rates of actinic keratoses treated with cryotherapy vary significantly (1–39%) in prospective studies likely due to a lack of homogeneity in patient and tumor selection, follow-up period, and inter-operator performance approach.^19,20 Malignant lesions can be treated with this modality, but the depth and extent of freezing may not be known without the use of a cryoprobe. Light cryotherapy often leaves no mark but may not remove the desired lesions. A deeper freeze may be associated with permanent white marks due to the destruction of melanocytes, postinflammatory hyperpigmentation, pseudoepitheliomatous hyperplasia, and depressed scars, which may resolve spontaneously, alopecia which may be permanent due to the destruction of hair bulge cells, and tissue distortion (e.g. nail dystrophy or notching of cartilage) due to damage to the nail matrix/cartilage.¹⁶ Cryosurgery should not be used for conditions that can be exacerbated by cold exposure (cryoglobulinemia, multiple myeloma, Raynaud disease, cold urticaria) and a previous history of cold-induced injury or poor circulation at the site or in that body part.¹⁷ Vasoconstriction induced by cryosurgery in poorly perfused areas may lead to tissue necrosis.¹⁷

Facial Laser treatment

Many different types of lasers are available, and laser treatment has many indications.³ Pulsed dye lasers (PDL) may be used for the treatment of port wine stains in adults and children. A further indication for PDL may be the treatment of telangiectatic rosacea.³ Other indications include radiodermatitis, ulcerated hemangioma, and erythrose of the neck.

For hair removal, various types of lasers, such as pulsed diode lasers, Nd: YAG lasers, or intense pulsed light (IPL) lasers, can be used.³ With the proper preparation and an experienced provider, patients with richly pigmented skin can also safely undergo laser and light-based treatments for hair removal, pigment abnormalities, skin resurfacing, and skin tightening.²¹ Facial rejuvenation aims to correct rhytides, telangiectasias, lentigines, and skin texture.³ Laser and energy devices may be used for facial resurfacing, depending on clinical indication, individual subject characteristics, and the operator’s expertise.^3,4 Lasers, such as CO2 or erbium laser, can be used to remove tattoos, Ota’s nevus, and, to a lesser degree, liver spots and Becker’s nevus.^3,21-24 These lasers permit dermabrasion in treating verrucous hematoma, extensive benign superficial dermo-epidermal lesions, and the esthetic treatment of non-muscular wrinkles, i.e., excepting wrinkles of the forehead and nasal sulcus.^21-24 Laser-assisted administration of photodynamic therapy (PDT) photosensitizers has demonstrated efficacy for superficial BCC.^25-27 The recurrence rates of BCC were markedly reduced in two randomized controlled trials using aminolaevulinic acid PDT with erbium compared to PDT and erbium.^25-27

Cutaneous adverse events with all types of laser treatment, such as reactive hyperemia, edema, scarring, and discomfort, may occur.^3,21-24

Pre-procedural Measures

All Discussed Procedures

Skin conditions and infections can exacerbate and cause complications following skin surgery.^3,4,28,29 For all patients considering having a procedure done, medical history including current and previous treatments, including procedures for the lesion under question, what the patient and treating physician hope to accomplish with the proposed procedure, current medications, and allergies, history of systemic disease, history of abnormal wound healing such as post-inflammatory dyspigmentations, abnormal scarring.^3,4,28,29 In patients that have had previous surgical treatments anywhere on their body, it is often good to assess the resultant scars prior to agreeing to perform a procedure on the individual.

Before the procedure, patients should attend the clinic with clean skin without makeup or cosmetics in the area to be treated.^30-34 Hair should be secured away from the treatment area. Patients should not shave since shaving can cause micro-wounds and increase the risk of infection.

Curettage, Electrodesiccation, ED&C, and Cryotherapy

Typically, additional pre-procedural measures are not required.

Laser Treatment

Laser devices are frequently used for facial rejuvenation. Device and treatment choice depends on individual patient characteristics, expectations, and physician expertise.^22-24 For optimal treatment outcomes, patients should be appropriately selected and screened, followed by a physical exam before treatment, depending on the type of procedure.^23,24 Outcomes of previous skin or surgical treatments are obtained, especially dermabrasion (if previously performed) responses.^28,29 People with hypertrophic scars, keloids, or changes in pigmentation will need peri-procedural cosmetic practices to reduce the risk of these complications or should be advised against the procedure.^28,29 Previously published surveys and algorithms confirmed more than 90% of clinicians recommended sun avoidance before, during, and after facial cosmetic treatments.^3,28,29

Peri-procedural measures are based on individual patient factors and the type of laser procedure.^21-24 For patients receiving ablative laser therapy, pre-treatment of underlying conditions, such as rosacea, dermatitis, and prevention of recurrences in patients with recurrent Herpes simplex, may reduce complications and enable adequate healing time to restore the skin’s barrier function.^3,28 Check patients for remote infections. Caution should be applied when considering extensive laser procedures in patients with compromised immune systems, such as HIV, cancer treatment, immunotherapy, or poorly controlled diabetes.^3-28

Measures During the Procedure

Surgical Excision

Prior to the procedure, the surgical site may be prepared with chlorhexidine (2%), isopropyl alcohol (70%), or hypochlorous acid (HOCL).^30-34 Povidone iodine is less commonly used since it is messy and permanently stains clothing. Chlorhexidine is an effective cleanser but may induce allergic contact dermatitis and can be toxic to the eyes and ears, whereas isopropyl alcohol is flammable and can irritate the skin.^31,32 Stabilized HOCL is highly active against bacteria, viruses, and fungal organisms without chlorhexidine’s oto or ocular toxicity; it has been proposed as a future gold standard for wound care.³³ HOCL has been shown to have dose-dependent favorable effects on fibroblast and keratinocyte migration compared to povidone-iodine and media alone.^33,34 It also increases skin oxygenation at treatment sites which may aid healing. There is evidence that HOCL may reduce the risk of hypertrophic scars and keloids as it reduces inflammation and the risk of infection. ^33,34

Local anesthesia and pain management can be customized depending need based on the procedure and patient factors and added at the treating physician’s discretion.

Cryosurgery, Electrodesiccation, Curettage, ED&C

Minimal skin preparation is needed for cryosurgery, ED or curettage if the procedure does not result in bleeding. Therefore, antiseptics are not typically indicated in the majority of procedures.¹⁶ However, topical antiseptics should be applied to lesions that are to be curetted or treated with ED&C.¹⁶

Pain management can be customized depending on the procedure and added at the treating physician’s discretion. Pre-procedure anesthesia should be considered for lesions to be curetted or treated with ED&C and large or extensive lesions. Topical anesthetics applied several hours before the procedure or intralesional anesthesia can help reduce surgical pain. For small lesions, injection of local anesthetic may be more painful than the procedure itself and is therefore not indicated.

Laser Treatment

Before the procedure, makeup removal and skin cleansing using a gentle cleanser is required.^30-34 The treatment site is prepared with chlorhexidine (2%), isopropyl alcohol (70%), or hypochlorous acid (HOCL).^30-34 Local anesthesia and pain management can be customized depending on the procedure and added at the discretion of the treating physician.^28,29

Post-procedural and Wound Healing Measures

Surgical Excision Healing by Primary Intent

A local anesthetic given before the procedure takes about 1-2 hours to wear off. For further pain management post-surgery, oral acetaminophen is preferred over aspirin, naproxen, or ibuprofen, as the latter encourages bleeding.

Topical postoperative wound care involves maintaining a protected wound and a clean, moisturized surface.^35,36 Wound care includes cleansing with either a gentle cleanser or water, applying a topical, and covering the wound with a dressing.^35,36 While previous investigators have evaluated methods for reducing risks of adverse events due to the treatment procedure, robust studies on post-procedural wound management for primarily closed wounds are lacking.^35-38

Physicians typically cover sutured wounds using either a dressing, adhesive tape strips, or both.^35-38 Wound dressings can be classified according to their function, material, and physical form of the dressing (Table 1).³⁵ Wound dressings for sutured wounds are typically left in place for 24-48 hours after surgery.^35-37 If there is a lot of tension on the wound or bleeding during the procedure, the dressing is typically left on for 2 or more days. The dressing can act as a physical barrier to protect the wound until skin continuity is restored and to absorb exudate from the wound, and prevent bacterial contamination from the external environment.^35-37 Some studies have found that the moist environment created by some dressings accelerates wound healing, although excessive exudate can cause maceration of the suture line and peri-wound skin.^35-37 A dressing should absorb wound exudate, minimize maceration and prevent bacterial contamination.³⁶

Table 1: Types of wound dressings and moisturizers

The utility of dressing surgical wounds beyond 48 hours of surgery is controversial, although^35-37 in addition to the above, dressings can prevent irritation from rubbing from clothing.

A systematic review on early versus delayed dressing removal after primary closure of clean superficial wounds found no detrimental effect on the patient when removing the dressing after 24 hours.³⁵ However, the point estimate supporting the conclusion is based on very low-quality evidence.³⁵

Cleansing the suture line after dressing removal post-procedure using an antimicrobial solution or applying an antimicrobial ointment is equally controversial.^35,36

The incidence of surgical site infections (SSI) varies between 1% and 80% depending upon the types of surgery, the hospital setting (community hospital, tertiary‐care hospital, etc.), the classification of surgical wounds, and the method of skin closure.³⁵ In addition, many skin surgeries are performed in the community in physician offices where infection rates range from 0.2% to 2.5%.⁴¹ Antimicrobial resistance is a growing concern, especially when antimicrobial products are used routinely and inappropriately.^39-44 Moisturizers are frequently used to keep the wound moist; however, evidence for beneficial effects on sutured wounds is inconclusive and mainly from small studies.^45-50

After suture removal, the topical application of a moisturizer containing madecassoside, panthenol, and copper-zinc-manganese has been shown to be beneficial.^45-48 The product is available as a cream, emollient, drops, gel, lotion, oil, ointment, solution, and spray in a concentration of 2-5%.^45-48 Petrolatum jelly and water-free petrolatum-containing ointments or products containing HOCL may also be used postoperatively to keep the wound moist, however, since they are occlusive, they may induce maceration.^49,50

In a study on postoperative wound care after MMS procedures (N = 76) patients were randomized to wound care with an ointment containing petrolatum, humectants, and natural barrier lipids (group 1: n = 27), white petrolatum (group 2: n = 32) or no ointment (group 3: n = 17).⁵⁰ Group 1 demonstrated an incidence of swelling and erythema of 52% (14/27); in group 2 erythema occurred in 12% (4/32) and swelling and erythema in 9% (3/27); and in group 3 erythema was noted in 12% (2/17) and swelling and erythema in 6% (1/17) patients.⁵⁰ The use of antibiotic-containing ointments is best avoided as they may cause allergic reactions and contribute to antimicrobial resistance.^39-44 Moreover, the rate of surgical site infections in minor surgical wounds is low and preventive use of topical antibiotics is not indicated.^35,44-52

If a hypertrophic scar develops, treatment with a silicone gel sheet or gel may improve the scar appearance and pain. Another option is self-adhesive propylene glycol and hydroxyethyl cellulose sheeting; however, evidence of the efficacy of these products in improving scar appearance and reduction of pain is inconclusive.⁵³

Surgical Excision, Curettage, ED&C, and Cryosurgery Healing by Secondary Intent

In a simplified model, wound healing processes occur in four phases 1) vascular response, 2) coagulation, 3) inflammation, and 4) new tissue formation.^54-57 During the initial inflammatory phase, the adaptive immune system is activated to prevent infection at the wound site.^54-57 Macrophages remove neutrophils, bacteria, and debris from the wound site. They then change phenotype to M2 macrophages, starting the proliferative and epithelialization phase, producing anti-inflammatory mediators and extracellular matrices.^54-57 If this phase is hindered, wound healing may be disturbed. The proliferative or epithelialization phase overlaps with the inflammatory phase and usually takes two to three weeks post-procedure.⁵⁴ During this phase, the dermal matrix matures, and inflammatory processes continue in the reticular dermis. The reticular dermis is sensitive to wound stress and infection and is affected by patient-related conditions such as age, sun exposure, or genetic profile.^54-57 Persistent inflammation plays a role in the development of hypertrophic or keloid scars, although it may not be the entire cause.^54-57 During the remodeling phase the wound contracts, and collagen remodeling occurs, which can last for up to a year post-procedure.

Pain management is similar to that previously discussed for primary healing wounds. Patients should be instructed to avoid sun exposure to the treated area, along with sun protection measures such as sunscreen with SPF 50 plus UVA block to prevent discoloration.^3,4,28,29

When a dressing is used post-procedure, the patient should be instructed to keep it dry and leave it in place for 24-48 hours. After dressing removal, a gentle, non-irritating cleanser can be used twice daily to cleanse the treated area.^3,4,28,29 The wound site must be handled with care, particularly during the initial healing phase of 7-10 days when newly formed epithelium can be early inadvertly removed.^3,4,28,29

Moisturizers or products containing HOCL may be applied to keep the wound moist and to promote wound healing (Table 2).^49,50 Similar to what was discussed for sutured wounds, moisturizers containing antibiotics should not be used on wounds not showing signs of infection to avoid allergic reactions and antimicrobial resistance.^39-44,49-52

Table 2: Complications from laser treatment

A moisturizer containing madecassoside, panthenol, and copper-zinc-manganese may be beneficial.^45-48 It is available as a cream, emollient, drops, gel, lotion, oil, ointment, solution, and spray in a concentration of 2-5%.^45-48,59 In an unpublished international observation study, 11,464 adults, children, and infants with a mean age of 31 years (1 week to 97 years) with superficial wounds applied the ointment for 14 days. Clinical (desquamation, cracks, erosion, erythema) and subjective symptoms (tightness, pain, burning sensation, pruritus) showed a significant improvement at 14 days, while tolerance and esthetic aspects of the ointment were rated good.

Wound Healing After Laser Procedures

For patients undergoing ablative procedures, prophylactic oral antivirals such as acyclovir (400 mg orally three times daily) or valacyclovir (500 mg orally two times daily), starting typically one day before resurfacing and continuing for 6–10 days post-procedure may be indicated.^3,28 Patients undergoing ablative laser treatment with baseline melasma or post-inflammatory hyperpigmentation may require pre-procedure lightening agents such as hydroquinone 2-4% cream twice per day in the morning and evening.^3,28

Gold and colleagues developed an algorithm for pre-/post-procedure measures for facial laser and energy device treatment and listed complications from laser treatment and actions that can be taken (Table 2).²⁸

Post-laser management is similar to that discussed for secondary healing wounds.

Limitation

Although few studies on peri-procedural measures for dermato-surgery care and minor wound management are available, the advisors recommend applying a moisturizer without antibiotics for antimicrobial stewardship and contact allergy avoidance.

Conclusion

Peri-procedural measures depend on individual patient factors and the type of dermato-surgery. Standards are required to support healthcare providers to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing. Applying a moisturizer without an antibiotic was shown to be beneficial in promoting cutaneous healing. Studies are required to evaluate purpose-designed moisturizers for dermato-surgery post-procedural application improving patient outcomes.

Charles W Lynde MD, FRCPC¹, James Bergman MD, FRCPC², Loretta Fiorillo MD³, Lyn Guenther MD, FRCPC⁴, Marissa Joseph MD, FRCPC, FAAD⁵, Jill Keddy-Grant MD⁶, Ian Landells MD, FRCPC⁷, Danielle Marcoux MD, FRCPC⁸, Catherine McCuaig MD, FRCPC⁹, Michele Ramien MD¹⁰, Wingfield Rehmus MD MPH FAAD¹¹

Introduction

Atopic dermatitis (AD) is a lifelong pruritic, inflammatory skin disease associated with altered immune function and epidermal barrier dysfunction.^1-3 The chronic and recurring cyclic waxing and waning nature of AD leads the patient to treatment fatigue and imposes a significant burden on both the patients’ and caregivers’ quality of life (QoL).¹ AD frequently appears early in childhood and affects over 20% of children and up to 3.5% of adults.^2,3 Measurements of the prevalence of AD can differ, and this variability can be impacted by geographic location, population studied, and definition of AD used. A Canadian study showed that the adult prevalence of AD is up to 3.5% and that AD may be more prevalent among First Nations populations.² This research further revealed that men were less affected than women and that AD decreases with age. Additionally, the study noted that the severity of AD varies per region.² In many countries, the prevalence of AD is on the rise, especially in young children from developing lower-income countries in South East Asia and Latin America.⁴ Although the role of race and ethnicity in the pathophysiology of AD remains unclear, a higher incidence of AD was observed in Black American children (17.3%) compared to White children (10.4%).⁴

The pathophysiology includes skin barrier defects, inflammatory cytokines, and immune abnormalities. ADs’ etiology is multifactorial and involves an incompletely understood interaction between genetic factors, immune system dysfunction, skin barrier disorders, genetic and environmental stressors.^5,6 Most of the patients with AD have mild disease; however, 10% – 20% of children with AD are categorized as severe, and these rates are slightly higher in adults.²

There is a need for a variety of therapeutics targeted to different levels of severity.^6,7 A treatment paradigm that recognizes that patients may oscillate between degrees of severity and integrates topical and systemic therapies may align more closely with clinical reality.^8,9 AD treatment is often challenging due to the disease itself, treatment fatigue, and patient/caregiver concerns. Patients and caregivers frequently have concerns about medication safety and adverse events (AEs) as well as the long-term use of topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI).⁹ Crisaborole ointment is an effective and safe alternative to TCS and TCI.⁹ Sharing best clinical practice standards, addressing challenges in treatment application, and methods to improve patient adherence to therapy may improve treatment results.⁹

This paper aims to review best clinical practices in treating AD patients, explore optimal use of crisaborole in mild to moderate disease, and provide expert guidance for the real-world use of crisaborole ointment to improve patient outcomes. This papers’ target audience is general practitioners, pediatricians, pediatric dermatologists, and dermatologists who treat patients with AD.

Methods

The project used a modified Delphi communication technique for interactive decision-making for medical projects, adapted from face-to-face meetings to suit a virtual platform.^10-12 The meeting was virtually convened on May 8, 2021, and the expert panel consisted of eleven dermatologists, including nine pediatric dermatologists from diverse geographical regions within Canada, who commonly treat patients with AD. In preparation for the meeting, a literature review surrounding crisaborole for the treatment of mild-moderate AD was conducted, and the panel members were surveyed regarding the use of crisaborole ointment for the treatment of AD.

The literature review and the pre-meeting survey results were presented at the virtual meeting. During the meeting, the experts were divided into three breakout groups to discuss and adopt draft recommendations for the real-world use of crisaborole ointment that were prepared from the literature searches by CWL and AA. The three groups presented their adapted versions of the recommendations to the larger group following the breakout session. The adapted recommendations were then collated and edited if necessary. The panel then voted and adopted the recommendations using evidence coupled with expert opinion based on the clinical experience of the advisors. The meeting summary and subsequent review of the manuscript were performed online (Figure 1).

Literature Review

Searches for English-language literature [2015– 2020] took place on April 14, 2021, on PubMed and Google Scholar as a secondary source. The data gathered by the literature review prioritized clinical studies published on the use of crisaborole, articles describing the current best practice in AD, and the most recent clinical guidelines, consensus papers and, algorithms. Excluded were duplications, articles of insufficient quality [small sample size, flawed methodology], and the most recent reviews were used in the case of review articles.

The searches yielded sixty-two papers deemed clinically relevant to current best practices of crisaborole use in AD. After removing duplicates and articles of insufficient quality, thirty publications remained: Four on epidemiology, ten reviews, three consensus papers and algorithms, four guidelines, five clinical studies, and four systematic reviews, meta-analyses, or posthoc analyses.

Results

The literature review indicated that the guidelines, algorithms, and consensus papers for topical AD treatment had not changed significantly over the past decade apart from adding crisaborole ointment and removing the black box for topical calcineurin inhibitor (TCI) treatment.^{7-9, 13-21}

A consensus paper and algorithm that explored the need for practical solutions to improve AD care was developed and published by the authors’ panel.⁸ The consensus statements and algorithm for topical treatment and maintenance of AD were integrated into the panels’ recommendations presented in this publication.

The DERMA (D: Diagnosis/Distribution; E: Education/Emollients; R: Red/Itchy; M: Medication/Maintenance; A: Assessment /Adherence) AD Algorithm targets a broad base of health care professionals treating patients with AD. The consensus statements and DERMA AD algorithm for topical treatment and maintenance of AD reflected current practice and were integrated into the panels’ recommendations (Figure 2).

Clinical Evidence of Crisaborole

Crisaborole is a small molecule, anti-inflammatory nonsteroidal PDE4-I inhibitor for the treatment of AD, which has demonstrated safety and efficacy in patients with mild-to-moderate AD.^22-30 Two percent crisaborole ointment was first approved by the American Food and Drug Administration (FDA) in December 2016 and then in 2018 by Health Canada for mild-to-moderate AD patients aged 2 years and over and in March 2020 (USA) and May 2021 (Canada) for patients aged 3 months and over.²⁵

The efficacy and safety studies on crisaborole used various clinical assessment scales such as Investigator Static Global Assessment (ISGA), Atopic Dermatitis Severity Index (ADSI), Eczema Area, and Severity Index (EASI) score, and Patient-Oriented Eczema Measure (POEM).

A randomized, double-blind, intra-patient controlled study (for the first 14 days) was continued as an open-label study applying crisaborole to all lesions. The study, including 40 patients of 18 years-old and older, demonstrated significant changes from baseline in crisaborole-treated lesions, ISGA, and pruritus NRS improvement from day fifteen assessment onwards.²³ The study also showed normalization of the genomic skin profile (approximated normal skin), inhibition of inflammatory genes known to be induced through degradation of cAMP by PDE4, and reduction in epidermal hyperplasia and TEWL.²³

The safety and efficacy of crisaborole treatment over 28 days were shown in two identical randomized, double-blind, vehicle-controlled studies including 1,522 patients with mild-to-moderate AD of 2 years and over.²² Significantly more patients treated with crisaborole than vehicle reached the primary endpoint (ISGA: clear, almost clear) than those treated with the vehicle at day 29 assessment.²² A long-term, open-label, single-arm 48 weeks safety study that included 517 patients of 2 years and over showed similar safety results as in a previous study that included adult AD patients.^22,24 In the long-term open-label study, nine patients (1.7%) withdrew due to AEs such as a stinging sensation after applying the ointment.²⁴ Another phase four open-label, single-arm study on 137 infants aged 3 months to less than 24 months of age demonstrated that crisaborole is safe and effective. ISGA of clear or almost clear was achieved at day 29 assessment by 30.2% of patients.²⁵ The study further indicated that improvements exceeded the minimal clinically significant difference in total POEM score at day eight and day twenty-nine.²⁵ The POEM subscale data further revealed improved sleep and pruritus, markedly improving patients’ and their caregivers’ quality of life.²⁵ Crisaborole yielded a rapid and statistically significant reduction in pruritus within four days.^26-28 Notably, in two vehicle-controlled studies, the vehicle effect on pruritus was considerable.^26,28

A pooled analysis of four studies of mild-to-moderate AD patients demonstrated efficacy and local tolerability of crisaborole treatment. After crisaborole use, most patients had mild to no pruritus from the first assessment through the remainder of treatment.²⁷

In a further study, treatment with crisaborole resulted in a marked improvement in QoL for patients and their parents, caregivers, and families.²⁸

A post hoc analysis of 2 phase 3 studies showed the effectiveness of crisaborole compared to the vehicle in significantly alleviating mild-to-moderate AD severity (per ADSI), and percentage of body surface area (%BSA) affected.²⁹

Finally, a systematic literature review and network meta-analysis comparing efficacy and safety profiles of crisaborole ointment, 2%, versus other topical treatments for mild-to-moderate AD showed crisaborole was superior to vehicle and pimecrolimus 1% cream, and comparable to tacrolimus, 0.1% or 0.03% ointments, concerning ISGA 0/1 at 28-42 days.³⁰ Additionally, the systematic review showed that the AEs rates for application site burning/stinging were much higher for TCIs than for crisaborole.³⁰ The studies included different patients, and endpoints varied, so comparative assessment of medications from this meta-analysis is difficult. Head to head comparative studies are needed to see objective scientifically-grounded efficacy comparison.

Crisaborole works better for mild than moderate disease, where it provides a faster reduction of pruritus and other AD symptoms relieve.^9,25-30 Crisaborole is not typically used with TCI due to potential irritation, but the combination may be suitable for steroid-phobic patients and those at high risk of sequelae.⁹

It is advisable to avoid crisaborole application on significantly flared skin due to possible irritation. Crisaborole ointment can be beneficial for dermatitis of the hands and feet due to the potential for deeper penetration into inflamed, thicker lichenified skin as a result of the smaller molecular size of crisaborole. There appears to be less irritation of the hands and feet, and the good safety profile of crisaborole justifies application in infants and children.^9,25-30

Statements and Recommendations

Statement 1: Atopic dermatitis (AD) is a lifelong inflammatory skin condition associated with epidermal barrier dysfunction and altered immune function. When AD is not controlled by behavioral measures such as skincare and avoidance of triggers, treatments such as TCS, TCI, and more recently, PDE4-I should be considered. It is important to use topical agents in conjunction with moisturizers and gentle cleansers.

The complex multifactorial pathogenesis of AD includes genetic and environmental factors.⁵ The skin barrier in AD is dysfunctional, and this defective skin barrier leads to water loss from the skin and the ingress of irritants, pathogens and allergens resulting in further inflammation.⁷ As the dysfunctional barrier at baseline is further disrupted, an inflammatory immune response is upregulated, which further disrupts the barrier leading to a feedback loop.^6,31,5,6

AD presents clinically as recurrent scaly erythematous and pruritic papules and plaques of skin with varying severity. This morphology, in addition to pruritus and family history of atopy, are important diagnostic criteria.^7,32 Specific signs of AD include oozing, scaling, crusting, erythema, edema, and lichenification, which, together with the body surface area involved and the impairment of daily activities, help determine AD severity (Figure 3-5).
Most patients with AD present with mild disease and can be adequately treated with frequent moisturization and topical therapy such as TCS, TCI, or crisaborole.^{3,5,7,8,12-21}

Educating patients and caregivers about the condition, avoiding triggers, and daily skincare regime, including gentle cleansers and moisturizers, is a vital part of the approach.^{7-9, 13-21}

AD is a chronic disease, and as a result, adherence to therapy is a major obstacle. Education and patient support and can improve adherence and, in turn, outcomes. It is important to remember that AD education is not a one-and-done phenomenon. Ongoing reinforcement of the treatment plan and goals is needed. Clinicians need to explain the condition, the rationale for treatment, optimal treatment use, and demonstrate the application process in their office.^8,9 During the detailed conversation, solicit the patients’ or caregivers’ input and questions to enable their active role in the process.⁹ This will help manage expectations, adherence to treatment, and maintenance of the lifelong chronic disease.⁹ Actions to improve patient adherence with treatment include detailed but easy to follow information and options to revisit the information by reading materials or trusted websites (Box 1).^8,9,15,19

Box 1: Patient and caregivers information and education about crisaborole

Statement 2: Crisaborole, 1% ointment, is a nonsteroidal anti-inflammatory PDE4-I with demonstrated efficacy in patients aged three months and older with mild to moderate AD. It is a well-tolerated alternative to TCS or TCI and can be used on any body site. It may be especially beneficial for:

• Sensitive areas prone to thinning from TCS such as the face, intertriginous areas, and genitals
• Hand, feet, palms, and soles, where the small molecular size may allow potential deeper penetration

A previous publication by the panel reviewed various cases that reflect real-world clinical use of crisaborole aimed to clarify its optimal use as monotherapy, combination therapy, sequential therapy, and maintenance therapy.⁹ Crisaborole can provide a good and safe alternative to TCS and TCI, such as in cases of steroid or TCI avoidance, and can be used in mild-to-moderate AD patients from 3 months of age upwards.²⁵

The case studies discussed in the article suggested that crisaborole treatment was effective and well-tolerated for pediatric AD of the face, hands, and feet of infants, toddlers, young children, and adults where therapy with TCS or TCI had failed.⁹ One of the cases was a 5-year-old boy with moderate-to-severe AD of his hands that was painful and severely impacting daily activities, such as playing and interacting with other children. After eight weeks of crisaborole use, his hand palms and wrists involvement had almost entirely cleared.⁹

The advisors recommend that the smaller molecular size of crisaborole may allow better penetration into the skin to the site of inflammation.⁹ The advisors also indicated that there might be a cumulative effect of adding crisaborole for hands and feet that can benefit from its optimal penetration as part of a combination regimen with TCS and TCI in moderate-to-severe AD cases.⁹

Statement 3: Crisaborole may be used as a first-line topical agent and is also a good choice when previous treatment has yielded suboptimal results when TCS side effects constitute a significant concern, and in the case of TCS/TCI phobia.

TCS and TCI hesitancy exists among all cultures and likely contribute to AD treatment failure.³³ Widely available biased unreliable, and inaccurate sources of information about eczema and topical therapies such as TCS and TCI are not helpful for AD patients and hinder physicians ability to educate and treat appropriately.³³ Clinicians must inquire about and if present must thoroughly discuss the patients and caregivers’ concerns about TCS and TCI and emphasize that these treatments are vital and, if used appropriately, safe and effective.^{5,7,8,9,12-21} Providing the patient with trusted websites can give balanced information, thus addressing the issues that are adding to patients concerns, especially in those with TCS and TCI phobia.^15,19

If patients or caregivers continue to have safety concerns surrounding TCS/TCI treatment, then crisaborole can offer a safe alternative even in infants as young as three months of age.²⁵ In this situation, offering a safe and effective alternative to TCS or TCI may improve treatment adherence and patient outcomes.⁹

Statement 4: When starting topical therapies such as crisaborole, consider the following:

• Test the patients’ tolerability with a sample before a prescription to determine the degree of stinging
• Avoid its initial use on severely inflamed or open areas of skin
• Limit its use to areas less likely to sting/burn
• Use the product in combination with a refrigerated moisturizer

The recommendations are supported by the advisors’ clinical experience⁹, a post hoc analysis of 2 phase 3 studies²⁹, and a systematic literature review comparing efficacy and safety profiles of crisaborole and other topical treatments in mild-to-moderate AD.³⁰ Crisaborole is used in mild-to-moderate AD, but it is best to avoid application on severely inflamed and open areas if possible to minimize stinging.^29,30

Testing the patients’ tolerability in-office before prescribing crisaborole provides an opportunity to teach the patient about the appropriate application of the medication and identifies the uncommon patient who has more prominent stinging and thus may not tolerate the medication. The application also helps to identify the patient who has mild discomfort. Proper education and guidance can minimize the symptoms and allow then to get past the short-term symptom. Application in the office and identifying these subgroups will instill greater confidence in the medication and make it more likely that the prescription will be filled and utilized rather than abandoned after one application.

Improved knowledge about the central roles a defective skin barrier and dry skin may play in AD increasingly recognizes the benefits of daily and ongoing use of mild cleansers and moisturizers.³⁴ The use of a gentle cleanser that employs advanced vehicles with a near-physiologic pH (4.0–6.0) may help maintain skin barrier function by optimizing skin surface pH levels.³⁴ Utilizing moisturizers to optimize the barrier decreases water loss, decreases inflammation, and improves the skin’s barrier and natural moisturizing factors. Moisturizers that contain skin lipids such as ceramides have shown benefits over standard emollients when used for AD patients.³⁵

In an algorithm for South and East Asian AD patients, moisturizers were included as a standard measure when using topical treatments for AD, such as pimecrolimus.³⁶ A refrigerated moisturizer used in combination with crisaborole ointment may prevent irritation, burning, or stinging.⁹

Statement 5: TCS, TCIs, and PDE4-I may induce application site pain such as burning and stinging. Information and education on measures to prevent or treat these side-effects, such as testing/limiting application sites and concomitant use of a refrigerated moisturizer, can help optimize results and decrease skin irritation.

Few AEs such as irritation, burning, and stinging were reported in clinical studies using crisaborole but seem to be occurring more frequently in clinical practice.^16,9

Clinical trials report stinging or burning occurring in up to 8%, but the symptoms are usually transient, and 1.7% of patients withdrew due to these symptoms. In practice, clinicians have anecdotally noted that the rate of stinging seems to be greater than that reported in clinical trials, but generally, the stinging is mild and transient.^16,9 Topical medications can sting due to the stabilizers and preservatives in the vehicle cream or due to the medication itself. TCIs can sting, and this stinging is often correlated to the degree of inflammation in the area. Clinicians often apply TCS initially to calm down the AD, after which the TCI is better tolerated. Whether this technique applies to crisaborole is not clear but should be answered by future reports/ studies.^8,9

Before starting crisaborole therapy, inform and educate the patient and caregiver on measures that may prevent or quickly resolve irritation, burning, or stinging if it occurs.⁹ Best practice tips of the panel include the use of crisaborole with daily skincare, such as a gentle cleanser and a refrigerated moisturizer.⁹ Apply a patient age-appropriate regimen and patient education.⁹ Identifying patients prone to skin irritation may benefit from an in-office trial with a sample before prescribing the ointment.

Survey Results

A pre-meeting survey was conducted among the panel to share best practice standards and clinical pearls they use in prescribing crisaborole to mild-to-moderate AD patients. All eleven advisors completed the survey. Demographics, number of visits of AD patients, the severity of AD, and treatment are shown in Table 1. When asked: If Crisaborole is not your first choice, indicate why not? stinging (63% [7]), burning (40% [4]) and costs (91% [10]) were frequently mentioned. Six physicians also answered crisaborole was not used for other reasons, which included: Lack of payer coverage, Need to be off-flare to initiate the treatment to get a good response, It is not as effective and does not work as quickly as TCS or TCI, Other medications are effective and more readily available and with which there is more clinical experience. The advisors noted to specifically use crisaborole for various body locations such as the face (72% [8]), hands (91% [10]), eyelids (55% [6]), intertriginous areas (63% [7]), genitals (63% [7]), and feet (81% [9]). According to the advisors, they hypothesize that the small molecular size of crisaborole appears to allow better penetration on areas with thicker skin.

Table 1: Pre-meeting survey results
N=11
Topical corticosteroid (TCS), atopic dermatitis (AD)

When asked the main reasons to prescribe crisaborole, all (100% [11]) answered that there is a need for a nonsteroidal alternative. Other answers included TCS phobia (91% [10]) and TCI phobia (63% [7]) and suboptimal results with previous therapy (63% [7]).

When stinging or burning occurred with crisaborole use, the advisors discontinued the treatment more frequently in children than adults. For preventing and managing AEs, the advisors provided education before starting crisaborole treatment. Some tested patients’ tolerability to the treatment in the office prior to a prescription to determine the degree of stinging. Further, they recommended measures to reduce stinging, such as concomitant use of a gentle cleanser and refrigerated moisturizer, cooling the ointment in the fridge, and concomitant TCS or TCI use (Figure 6). Finally, the advisors agreed to avoid the application of crisaborole on severely flaring skin.

When asked about the patients’ response to crisaborole treatment within four weeks, forty percent of responders noted that on average, 20-50% of patients had improved, and 50% of the panel noted an improvement in over 50% of their patients (Figure 7 and 8).

Limitations

Measures to reduce burning and stinging that may occur when using crisaborole were developed using the authors’ expert opinion and clinical experience, and further studies are needed to support the possible benefits of these measures.

Conclusions

The review explored best clinical practices of crisaborole for mild to moderate AD patients and provided expert guidance for the real-world use of crisaborole ointment.

Atopic dermatitis is a common chronic inflammatory disorder in which patients experience a waxing and waning disease state that is punctuated by episodes of flares. If their disease is quiescent, then the patient continues good skincare by utilizing moisturizers and avoiding irritants. Patients will escalate and add topical medications at the first sign of a flare. Since every patient has a distinct disease course, some patients may never be fully clear while others clear between episodes. Recognition that patients with AD have a disease that often varies in severity and location on their body allows physicians to choose the appropriate treatments based on their clinical experience. The physician needs to educate their patient to escalate therapy accordingly at the first sign of disease in order to prevent severe flares. An eczema treatment plan is a necessity to ensure a smooth transition of therapy from baseline to flare. For mild to moderate AD patients, three topical options can be prescribed to control inflammation. Traditionally these medications have been divided into first and second-line therapy. However, the expert panel believes that the choice of a specific agent should be decided by the clinician based on factors such as disease severity, location, physician experience with the product, cost, and patient preference.

Crisaborole is a nonsteroidal PDE4-I with demonstrated safety and efficacy in patients aged three months and older with mild to moderate AD. It is a well-tolerated alternative to TCS or TCI and can be used on any cutaneous non-mucosal body site. It may be especially beneficial for areas with thicker skin, such as hands and feet, possibly due to improved penetration to the site of inflammation as a result of its small molecular size. There are no concerning serious safety signals associated with crisaborole. Crisaborole does cause a burning sensation in 8% of patients, but this is usually transient and may be minimized by the concomitant application of cool moisturizers. Consideration of in-clinic test site application of crisaborole to high-risk individuals may help identify those at risk and allow patient education, which may decrease the side effect and in turn improve adherence and outcome.

¹Associate Professor, Department of Medicine, University of Toronto, Toronto, ON, Canada
²Clinical Assistant Professor, Department of Dermatology, University of British Columbia, Vancouver, BC, Canada
³Clinical Professor, Director of Pediatric Dermatology, University of Alberta, Edmonton, AB, Canada
⁴Professor, Western University, London, ON, Canada
⁵Assistant Professor, Department of Medicine, Department of Pediatrics, University of Toronto, Toronto, ON, Canada
⁶Assistant Professor, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada
⁷Division of Dermatology, Sainte-Justine University Medical Center; Clinical Professor in Pediatrics, University of Montreal, Montreal, QC, Canada
⁸Division of Dermatology, Sainte-Justine University Medical Center; Clinical Professor in Pediatrics, University of Montreal, Montreal, QC, Canada
⁹Clinical Associate Professor, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

Funding:
This Supplement was developed using the Authors’ Expert Opinion, supported by an unrestricted Educational Grant from Pfizer Canada.
Use crisaborole ointment in off-label settings is left up to the discretion of the treating health care professional after careful clinical evaluation.

Abstract:
Background: Atopic dermatitis (AD) is associated with epidermal barrier dysfunction. The chronic skin condition presents clinically with pruritus and recurrent skin lesions. The psychosocial impact of the condition is severe for most patients and their families.
Crisaborole, a topical PDE4 inhibitor, has demonstrated efficacy in patients with mild-to-moderate AD.

Objectives: A diversity of cases are presented that reflect real-world clinical use of topical crisaborole ointment, as a mechanism to help optimize patient care.

Methods: Evidence from the literature coupled with the panels’ expert opinion, experiences and, key insights reflect the panels’ clinical use of topical crisaborole ointment for AD and irritant dermatitis (off-label use) and how patients can benefit from its use, i.e., “what experienced specialists are doing across Canada.”

Results: The panel treated and presented cases that report on crisaborole ointment used as monotherapy, combination therapy, sequential therapy, and maintenance therapy. The presented cases aim to illustrate the diversity of crisaborole use concerning age range, skin type/ethnicity, and body location. Each case presents a summary of the learning points.

Conclusions: The presented cases reflect the panels’ real-world clinical experience with crisaborole for the treated patients. The panel suggested that crisaborole ointment provides a good safe alternative to TCS and TCI. Treatment with the ointment should be avoided on severely flaring skin and for those that experience irritation, burning, or stinging while testing it on unaffected skin areas.

Key Words:
Atopic dermatitis, Real-world cases, Topical PDE-4 inhibitor

Introduction

Atopic dermatitis (AD) is a lifelong inflammatory skin condition associated with epidermal barrier dysfunction and altered immune function, presents clinically with recurrent episodes of pruritic erythematous papules and plaques.¹ AD usually starts in infancy, where it affects up to 20% of children in North America, and is also highly prevalent in adults.² Two-thirds of AD patients are reported to have mild disease, 26% moderate, and 7% severe AD disease.³ The majority of patients are treated by primary care physicians who primarily use topical anti-inflammatory therapy for their mild-to-moderate AD cases.^4-13

The psychosocial burden of AD on patients and their families is enormous.¹⁵ The inflammatory skin disease increases the risk of other immune-mediated inflammatory atopic disorders, such as asthma, allergic rhinitis and food allergies, as well as mental health disorders in some.^15,16

Patients with AD should use gentle cleansers and moisturizers that are balanced to the skin pH in addition to behavioural measures such as avoidance of irritants and triggers.

AD is a chronic relapsing disorder with periods of quiescence punctuated by intermittent flares. When AD flares then treatments such as topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), and more recently, phosphodiesterase-4 (PDE4) inhibitors should be considered, while continuing skincare and measures to avoiding triggers of AD. TCS and TCI treatments are widely used as monotherapy in cases of mild-to-moderate AD or in combination with systemic treatments for more severe AD involvement. These treatment regimens are supported by clinical guidelines and clinical pathways worldwide and have an established safety record.^4-13 Crisaborole ointment (Eucrisa, Pfizer), a unique topical prescription option for AD, is a PDE4 inhibitor with demonstrated efficacy in patients aged two and older with mild to moderate AD.¹⁶

The presented real-world case-based approach explores the role topical crisaborole can play in the prevention, treatment and maintenance of AD and other inflammatory skin conditions, in clinical practice. The selected patient cases aim to outline a diversity of cases that reflect real-world use of topical crisaborole ointment for patients with AD and other skin conditions, either as monotherapy or in combination with other treatments. Any discussion concerning off-label use is considered an expert opinion only.

Methods

Aim of the Project

This current real-world case project was conceived as a mechanism to help optimize patient care by recognizing the role crisaborole ointment can play in the prevention, treatment and maintenance of AD. Additionally, the project explores where this therapeutic agent could be used in managing AD in patients who require a combination of therapies. The cases intend to illustrate the authors’ real-world clinical experience rather than reflect controlled clinical trial data. Evidence coupled with the expert opinion, experiences, key insights and recommendations is presented and discussed. Recommendations given by the panel reflect the use of topical crisaborole ointment for AD and how patients can potentially benefit from its use, i.e. “what experienced specialists are doing across Canada”. Any discussion concerning off-label use is considered an expert opinion only.

The target audience for this publication is physicians and other health-care professionals who treat patients with AD.

Steps in the Process

The five-step procedure included a) project definition and panel selection, b) collection of information and preparation of cases, c) meeting to select cases for the publication, d) literature review to support the cases, and e) creation, review, and finalization of the manuscript.¹⁷

Role of the Panel

An expert panel of eight dermatologists and pediatric dermatologists, selected to represent the diverse geographical regions within Canada, who commonly treat patients with AD, was convened on November 9, 2019, in Toronto, as part of the semiannual Dermatology Update conference. The panel members reported clinical cases of pediatric and adult patients who were suitable candidates for crisaborole ointment treatment.

The panel members discussed the cases in the light of the supporting literature, then decided which cases would be included in the publication. The publication was prepared and reviewed by the panel members.

Topical Treatment for Mild-To-Moderate AD

Avoidance of triggers of AD flares and education are the first steps in the prevention, treatment, and maintenance of AD.6

Skincare Using Gentle Cleansers and Moisturizers

Skincare using gentle cleansers and moisturizers remains the cornerstone of treatment for all severities of AD. Daily use of this skincare regimen is supported by established guidelines and clinical pathways.^4-13 Moisturizers play an important role in combating and controlling xerosis, decreasing epidermal water loss, and restoring epidermal barrier function.^6,10 Moisturizers should be liberally and frequently applied and can be used alone for mild disease or in combination with other therapies regardless of the severity of their AD. ^6,10

TCS and TCI

If avoidance of triggers and the use of a daily skincare regimen with gentle cleansers and moisturizers are not effective, topical anti-inflammatory agents, such as corticosteroids (TCSs) or calcineurin inhibitors (TCIs) are used twice a day until the lesions have cleared.^3-13 TCS is the first-line anti-inflammatory option, available in a variety of strengths from mild to potent and very potent.^6,11 Side effects such as skin atrophy, purpura, telangiectasia, striae, focal hypertrichosis, impaired wound healing, allergic contact dermatitis, and acneiform or rosacea-like eruptions on the face are very uncommon when TCS is used appropriately.⁶ Both patients’ and parents’ fear of TCS and steroid phobia should be discussed to improve adherence and avoid under-treatment.⁶

TCI’s are another safe and effective treatment option, however short-term side effects such as skin burning, and pruritus, especially when applied to acutely inflamed skin and cutaneous viral infections, may occur.⁶ Patients and parents should be informed about these potential side effects to avoid premature discontinuation of treatment.⁶ TCIs are therapeutic agents often used for mild AD on the face, neck, and folds, and used in prevention and TCS reduction elsewhere on the body.

Systemic Therapy

For patients affected by more severe AD, agents that target immune responses and inhibit T cells by targeting Th1, Th2, Th22, phosphodiesterase-4 (PDE4), IL-4, and IL-31 are available.¹⁸ Phototherapy and traditional systemic therapies, including methotrexate, cyclosporine, and mycophenolate mofetil, can also be used off-label in severe AD.

Crisaborole Ointment

Crisaborole (Eucrisa, Pfizer), a topical prescription option for AD, is a PDE4 inhibitor with demonstrated efficacy in patients aged two and older with mild to moderate AD.16 Two, multicenter phase III trials, demonstrated early sustained control of mild-to-moderate AD in patients aged over two years with crisaborole ointment use over twenty-eight days.¹⁶ When compared to the vehicle, treatment with the 2% crisaborole ointment showed reduced pruritus, AD severity, and other signs of AD (erythema, exudation, excoriation, induration/papulation, and lichenification), although clinicians have expressed concerns about stinging and burning on at application sites.^16,19

A multicenter extension study indicated that crisaborole ointment for up to fifty-two weeks is safe.¹⁷ The extension study reported an overall 10.2% rate of crisaborole treatment-related adverse events such as dermatitis (3.1%), application site pain, stinging, burning (2.3%), and application site infection (1.2%).³ These events were considered mild, and no one withdrew from the study due to these adverse events.

Less common potential side effects included skin irritation and hives or welts, which may be due to underlying atopy. Given the good tolerability and safety profile, crisaborole ointment makes for an alternative steroid-sparing topical option to TCS and TCI.¹⁶

Data Gathering of Real-World Cases on Crisaborole Ointment Use

The panel members used a template for their case studies, which asked the following questions:

• What are the cases and the impact of the condition?
• What are the treatment options, and what treatment(s) were previously used for this case
• Why might crisaborole ointment work in this case, where does it fit and what were the results of the treatment?
• Did any adverse events occur? If yes, describe.
• What (if any) are the special circumstances related to this particular case, and which lessons are learned?

Patient evaluations were at baseline (start) and at eight weeks (+/- 5 days) using physician reported skin condition (SCORing Atopic Dermatitis Clinical assessment [SCORAD] score.²¹ SCORAD recorded AD location and percentage area (A), Intensity (B): Redness, swelling, oozing/crusting, scratch marks, skin thickening, dryness [the intensity of each of the following signs is scored as none (0), mild (1), moderate (2) or severe (3)] and subjective symptoms (C) [Sleeplessness: 0 = no sleeplessness and 10 = the worst imaginable sleeplessness, Itch: 0 = no itch and 10 = the worst imaginable itch]). Total SCORAD is the sum of A, B, and C, minimum score = 0, maximum score = 103.21 The impact of the skin condition after treatment regime use and adverse events were recorded at baseline (start) and week 8 (+/- 5 days) (end).

Some of the physicians used quality of life for the participants 15 years or younger as assessed by Children’s Dermatology Life Quality Index (CDLQI). The minimum score is 0, and the maximum score is 30, the latter corresponds with the most severe impairment of quality of life. Other scores used were severity of itching as assessed by the Pruritus score determined using the Numerical Rating Scale (Minimum score is 0. The maximum score is 10, the latter corresponding to the most severe itching imaginable by the patient).

Selected Real-World Cases

The panel selected a total of eleven cases that reported on realworld use of crisaborole ointment as monotherapy, combination therapy, sequential therapy, maintenance therapy, preventive therapy, and its application in dermatitis beyond AD. (Table 1). The presented cases aim to illustrate the diversity of crisaborole use concerning age range, skin type/ethnicity, body location, the severity of AD, and reports of off-label use.

Case 1: A 4½-year old girl with AD since the first months of life, which had recently increased in severity. The moderate-tosevere condition involved multiple sites, including hands and feet. Previous treatment with various TCS formulations was unsuccessful. When crisaborole started, mometasone ointment was continued as needed on the lesions on her body. The rationale for starting topical 2% crisaborole ointment was the failure of previous treatments and a specific interest in improving the skin condition of her hands and feet. Her skin condition markedly improved over the eight week treatment period (Figure 1A-1J). No adverse events occurred, and the ointment was well tolerated even on the face.

Learning point: Crisaborole is a well-tolerated (even on the face) alternative for TCS and is effective on hands and feet.

Figure 1A – 1D

Figure 1E and 1F

Figure 1G and 1H

Figure 1I and 1G

Case 2: For four months, a 4-year-old boy had suffered from AD, primarily on the face, antecubital, and popliteal fossa. He had almost constant pruritus and open, erythematous skin. His interaction with other children was poor, and both the patient and parents had difficulty sleeping. Previous long-term TCS treatments lacked success. Moreover, his mother was concerned about prolonged steroid use and requested trying crisaborole ointment. After eight weeks of crisaborole ointment application, his skin condition had greatly improved (Figure 2A and 2B). Although at first, the ointment caused skin irritation, this was easily alleviated with the use of a moisturizer.

Learning point: Crisaborole seems to induce irritation, burning, and stinging more frequently in clinical practice than reported in clinical trials. The patient experienced irritation, burning, and stinging in the areas where crisaborole was used. Information and education on measures to prevent or to treat these side-effects were effective. The advice given included the use of a refrigerated moisturizer, frequently applied before and after application of the ointment to optimize crisaborole results and decrease irritation. The mother was encouraged to continue treatment after the physician discussed the expected outcomes of the therapy. The irritation was alleviated with the use of a moisturizer as instructed.

Figure 2A and 2B

Case 3: A 29-year-old neonatal intensive care unit (NICU) nurse developed hand dermatitis one year ago. During work, she frequently used a hand sanitizer causing pruritus and painful fissures. She had a negative history for AD, and other atopic disorders and Patch tests were negative. The eruptions cleared when she was on holiday. After consultation with the occupational health department for help and guidance, she received a special hand sanitizer. She refused TCS as she was concerned about developing skin thinning. Within eight weeks of starting crisaborole ointment, the condition had resolved. The ointment was well tolerated, and she resumed her work as a NICU nurse (Figure 3A and 3B).

Learning point: The patient with occupational irritant hand dermatitis did not want to use TCS. The alternative treatment with crisaborole ointment was successful for this patient. Use of crisaborole in the treatment of irritant contact hand dermatitis is off-label.

Figure 3A and 3B

Case 4: A 68-year-old woman with a history of rosacea also had recurrent facial eruptions. Patch testing was positive to Kathon CG, which was found in her laundry product which she had since avoided. Since TCS were unsuccessful, treatment with crisaborole ointment was started, used in combination with ceramides containing cream as needed. Her skin condition markedly improved within two weeks (Figure 4A – 4D).

Learning point: The ointment may be a useful alternative for TCS for facial areas in patients with concomitant facial inflammatory skin conditions. Although crisaborole may induce irritation, burning, and stinging, in this patient with underlying rosacea, the product was well tolerated. Topical steroids can induce a rosacealike eruption. Crisaborole did not aggravate this patient’s rosacea. Patch testing was useful in identifying the causative allergen. The use of crisaborole in allergic contact dermatitis is off-label.

Figure 4A and 4D

Case 5: An 11-month-old baby-boy had facial AD from the age of nine months. He had coincident acute myelogenous leukemia (AML) and was recovering from chemotherapy. His parents were concerned about TCS and TCI being immunosuppressive agents and due to his ongoing AML treatment refused them. Crisaborole ointment seemed a good alternative option. His skin condition improved within an eight week observation period, and no adverse events occurred (Figure 5A – 5D).

Learning point: In immunosuppressed or otherwise vulnerable patients, crisaborole ointment is an effective alternative to TCS to treat AD even on the face. Parental wishes to not use TCS or TCI were granted because crisaborole’s mechanism is not immunosuppressive. Although crisaborole is approved for use in individuals 2 years of age and older, it was safely and effectively used in this infant.

Figure 5A and 5D

Case 6: A 2-month-old baby boy presented with diffuse xerosis and AD present since three days of age. His condition impacted the entire family. His mother had applied Vaseline six times a day and TCS twice a day. He had not responded to treatment with several different types of TCS. The physician was concerned about absorption and possible adrenal axis suppression. After eight weeks of crisaborole ointment use, pruritus had subsided and both the baby and his family were able to sleep through the night (Figure 6A and 6B). Before starting treatment with crisaborole ointment, he had regularly had skin infections with MRSA, which did not reoccur since the start of the crisaborole ointment.

Learning point: Crisaborole proved to be a useful alternative for TCS where absorption and possible adrenal axis suppression were a major concern. Of interest is the resolved recurrent infection since the use of crisaborole, which may be attributed to the improved skin condition. Crisaborole is approved for use in individuals with AD two years of age and older.

Figure 6A and 6B

Case 7: A 15-year-old male had recurrent resistant atopic dermatitis and dyspigmentation from chronic TCS use. Treatment of the generalized flares and superinfection consisted of intravenous antibiotics and oral cyclosporine, to which he had a good initial response. To address his concern about TCS use and the desire for a simpler regimen, twice daily application with crisaborole ointment was started while continuing the cyclosporine. After eight weeks of use, he had an excellent response, with marked improvement in his quality of life. Whenever the patient stops topical crisaborole, some AD returns (Figure 7A and 7B).

Learning point: The use of crisaborole ointment in combination with systemic therapy was effective for this patient. The ointment is to be applied at the first sign of a flare before lesions develop and avoided the need to increase systemic therapy. As a result, he gained confidence in controlling his skin condition and improving his outlook on his situation.

Figure 7A and 7B

Case 8: A 5½-year-old boy had mild-to-moderate AD since the age of three and recently developed symptomatic hand and feet involvement. The rationale for crisaborole use on his hands and feet was the suboptimal response to previous TCS/TCI therapy. Concomitant use of TCS and TCI was continued together with crisaborole. His skin had almost cleared after eight weeks of crisaborole ointment use (Figure 8A – 8D).

Learning point: An incremental benefit of adding crisaborole as part of a combination regimen with TCS and TCI TCI introduces new possibilities for patients with AD on their hands and feet.

Figure 8A and 8D

Case 9: Since the first months of life, a 5-year-old male has had moderate-to-severe AD with symptomatic painful involvement of his hands, impacting daily activities. He had difficulty handling toys and interacting with other children and their parents. TCS and TCI treatments were not successful. With crisaborale, his hand palms and wrists’ involvement almost completely cleared. (Figure 9A – 9E).

Learning point: Effective penetration of crisaborole on thicker skin such as hand-palms and foot-soles may facilitate improvement in these special sites.

Figure 9A and 9B

Figure 9C and 9E

Case 10: A 4-year-old girl had AD. TCS therapy was started for her flaring disease. Her mother was concerned about vaccines and TCS use. Crisaborole ointment treatment was started to address the mother’s concerns. At eight weeks of ointment application, there was an 80% clinical improvement; however, some moderate AD persisted at some sites which required strong TCS.

Learning point: Although the crisaborole ointment did not completely resolve the disease, the mother preferred it to TCS for milder lesions and wished to reserve TCS for more resistant lesions.

Figure 10A and 10G

Case 11: A 12-year-old male with AD since infancy had involvement of the hands and limbs. His condition failed to show improvement from intermittent TCS. The rationale for starting crisaborole ointment was the family’s frustration with the lack of results and a possible penetration advantage of the ointment on the hands. A left/right assessment of clobetasol versus crisaborole ointment was conducted. His mothers’ perceptions were that his hands both improved, but the crisaborole ointment was more effective than clobetasol. On the arms and legs, both treatments were successful, but clobetasol outperformed crisaborole ointment. The therapy was continued after the eight weeks study period as the family was happy with the treatment response. No adverse events occurred. Subsequently, mom used crisaborole alone on his hands and had ongoing good maintenance and prevention of flares. (Figure 10A – 10G). Follow up results are shown in Figure 11A – 11E.

Learning point: The crisaborole ointment performed better on the hands than clobetasol, however when used on the arms and legs, the reverse was the case, indicating that the ointment may be particularly useful on thicker skin areas.

Figure 11A and 11E

Discussion

For each case, the age, skin type, underlying skin condition, rationale for using crisaborole, and in some cases, treatment duration were highlighted as well as its role as part of a maintenance/prevention and treatment regimen. The cases presented a spectrum of clinical responses to crisaborole, including instances of poor response, such as in case 10, where AD persisted, and TCS was further needed. The panel discussed challenges of recognizing and managing AD in darker skin which may be addressed using crisaborole ointment, although studies are needed to confirm possible benefits. Most of the cases were atopic dermatitis, the approved indication. Two other types of dermatitis (hand dermatitis, allergic contact dermatitis) were included although they have not approved indications since these conditions are often difficult to treat and do not always respond to topical steroids. In addition, on the face, topical steroids may be associated with a greater potential for adverse events.

Steroid Phobia

Steroid phobia refers to the negative feelings and beliefs related to TCSs experienced by patients and patients’ caregivers. The panel expressed concerns that this phenomenon may be a contributing factor in treatment failure in AD patients. A systematic review²² found that TCS phobia is present across all cultures and that adequate information for patients and parents is lacking. The authors of the systematic review propose that the sources from which patients are receiving information about TCS may be targetable for intervention to increase adherence to TCS treatment regimens.²²

Crisaborole can be an effective alternative for TCS and TCI, especially in patients with conditions requiring long-term TCS or TCI use.

In case of safety concerns (even when subjective) with TCS and TCI use in young patients or concerns about steroid absorption in all groups, patients can safely use crisaborole ointment. Moreover, preservatives in crisaborole pose no safety issues. The panel agreed that crisaborole ointment provides a good safe alternative to TCS and TCI in such cases, enhancing treatment adherence and thus outcomes.

Irritation, Burning and Stinging

Crisaborole seems to induce irritation, burning, and stinging more frequently in clinical practice than reported in clinical trials.^3,6,19 This side effect was also reported for two of the presented cases (case 2 and 4). The panel suggested that in their experience, irritation, burning, and stinging are more quickly resolved than in the case of TCI use, where similar side effects are also observed. If TCI related stinging occurs most clinicians will apply steroids temporarily and then subsequently TCIs are usually tolerated.

The panel recommended providing information on this issue and education on measures to prevent or to treat it before the start of the treatment with crisaborole. The panel recommended frequent use of a refrigerated moisturizer before and after application of the ointment, and the use of an anti-itch lotion as needed throughout the day. The panel further suggested that it may be helpful to have patients testing crisaborole on healthy skin. Modify or discontinue the treatment if the formulation triggers burning or stinging even on healthy skin with concomitant use of a refrigerated moisturizer. The panel discussed avoiding crisaborole ointment use on severely flaring skin and starting with TCS until the flare is controlled, followed by crisaborole ointment.

Antibiotic Resistance

Antibiotics are commonly used as part of the management of AD. However, only a minority of patients with AD have clinically significant S. aureus infection. Moreover, data is lacking for highly beneficial outcomes with exclusive use of antibiotics in the management of AD.²³ Case 6 shows an example of the possible use of crisaborole as a steroid-sparing and antibiotic-sparing agent. Because of antibiotic resistance, the use of the crisaborole ointment may be of interest and aligns with current emphasis on antibiotic stewardship in AD. Anti-inflammatory agents control eczema, which leads to less frequent infections and less antibiotic use.

Combination Treatment

Combining or alternating crisaborole with TCS or TCI may be successful for more severe disease. The ointment was safely used in time-intervals between the application of a moisturizer, TCS, or in combination with systemic therapy. Several cases showed a marked improvement in the skin condition of the treated patients and no adverse events.

Specific Body Locations

Case 4 shows an example of the safety and tolerability of crisaborole when used on specific sites (e.g., face and lips). An incremental benefit of crisaborole use as part of a combination regimen was shown in a patient (case 8) who recently had AD involvement of his feet, with hyperkeratosis and desquamation.

The rationale for crisaborole use, in this case, was good absorption of the ointment due to the relatively small size of the molecule allowing better penetration.

Case 11 showed beneficial crisaborole use on the hands, which did not improve with intermittent TCS application. This patient conducted a real-time comparative test using clobetasol on one side of the body and crisaborole on the other. Crisaborole worked better on the hands while clobetasol showed better results on his arms and legs.

The use of crisaborole for non-AD (case 3) was shown in a patient with occupational HD, which resulted in complete response. Advisors recommended further studies of crisaborole on the hands and feet (e.g., the study of occupational hand dermatitis and penetration study) to support the use of the ointment for these complex areas.

Table 1: Summary of the eleven cases studies
Case 1: TCS^a: Betametasone dipropionate 0.1% ointment, Mometasone ointment, TCI^b. Tacrolimus 0.1% ointment, Skincarec: Hydratation-Eucerin, Aquaphor, Aderma cleanser and hydrating agent.
Case 2: TCS^d: Desonide cream BID x 1 year, Hydrocortisone 17 valerate UNG BID x 1 year.
Case 3: TCS^e: Hydrocortisone cream
Case 4: TCS^f: 1% hydrocortisone cream
Case 6: TCS^g: Hydrocortisone 2.5%g then switched to desonide for body, Dermasmoothe FS for scalp and face. Then switched to hydroval 0.2% ointment to entire body.
Case 8: TCS^h: 0.1% betametasone valerate ointment (body), 0.1% protopic ointment (face).
Case 9: TCSⁱ and TCI: Betametasone dipropionate 0.1% ointment, Mometasone ointment, Tacrolimus 0.1% ointment.
Case 10: TCS^j: Begin with strong corticosteroids, Desonide ointment for the face, Betamethasone valerate 0,1% ointment for the hands and feet.
Case 11 : TCS^k : Clobetasol.

Atopic dermatitis (AD), Twice daily (BID), Crisaborole ointment (CO), Adverse events (AEs), Neonatal intensive care unit (NICU), Hand Dermatitis (HD), Medical history (Hx), Acute Myelogenous Leukemia (AML), Intravenous (IV) Oral (PO).

Maintenance Therapy

The panel discussed the spectrum of clinical response of crisaborole used in adjunction to a moisturizer as maintenance therapy and suggested that crisaborole ointment should start at the first sign of a new flare before the development of lesions. TCS should be added if it is not successful. Currently, data on the use of crisaborole ointment for long term maintenance therapy is lacking; however, the panel suggested further studies of crisaborole as maintenance therapy.

Conclusion

The discussed cases reflect the panels’ real-world clinical experience with crisaborole for the treatment of patients with AD and the off-label treatment of irritant dermatitis. The panel suggested that crisaborole ointment provides a good safe alternative to TCS and TCI. Use of crisaborole should be avoided on severely flaring skin and for those that experience irritation while testing it on unaffected skin areas.

Acknowledgement

The authors acknowledge and thank Anneke Andriessen, PhD, for her invaluable assistance with preparing this manuscript.

Limitations

The cases are intended to illustrate the real-world experience rather than reflect a controlled clinical trial data environment, nor do they presented cases mirror statistical outcomes. Use crisaborole ointment in off-label settings is left up to the discretion of the treating health care professional after careful clinical evaluation.

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Conflict of interest: No funding was received to write this paper.

Introduction

Medical algorithms are created, yet there is a paucity of information about how such algorithms should be created and the optimal way to develop an excellent algorithm. An algorithm is a logical sequence of steps to solve a problem.¹ It is a precise, unambiguous set of steps to solve a problem using a finite amount of data in a finite amount of time.²

Background

• Algorithms are commonly used for data processing and calculation in computer and mathematical operations.³
• They are used in everyday life. Examples of algorithms include how to wash clothing in your washing machine and dryer, how to operate a home security system and cookie recipes. An excellent cookie recipe gives the necessary ingredients, preparation and cooking procedures to produce reproducible cookies every time you bake them.
• Computational algorithms are used for addition, subtraction, multiplication and division.
• More than 1 algorithm can be used to solve the same problem. For example, mathematical problems can often be solved in many ways.

Medical Algorithms

• Medical algorithms are used to make medical decisions such as test selection, diagnoses, treatment including drug allergies and drug-drug interactions, and prognosis.⁴
• Examples include calculators to determine body mass index using weight and height as inputs.
• Decision trees are used to decide the cause of a symptom and nomograms such as a moving circular slide to calculate body surface area or drug dosage.
• The purpose of medical algorithms is to improve and standardize medical decisions even when there is a variety of health care providers.
• They are used to standardize the selection and use of treatment regimens, thereby improving adherence to evidence-based guidelines. They can also predict outcome (e.g. critical care scoring system).

Features of Great Algorithms

• Great algorithms have inputs and outputs, are simple and precise with steps uniquely defined, with the results depending on the input and results of the preceding step(s).
• There should be only one way to interpret the instructions and the exact circumstances in which an action is to be carried out should be specified.
• The terms “occasionally”, “sometimes” and “maybe” should not be used.⁵
• They must proceed through steps and end with a conclusion (output).
• The results must be correct and complete with all sets of input.
• Algorithms should be complete and account for all inputs and stop after a finite number of instructions.⁶
• There should be no unnecessary steps or complexity.
• Each step should carry out one logical step of the process.
• Steps should not be defined as “Do this after you have done that.”⁵
• Abstraction (i.e. grouping steps) may be used but should be appropriate.⁶
• Abstraction considers an item independently of its associations, or an attribute independently of the item to which it belongs. It allows us to view algorithms as a series of major aggregate steps, with details hidden in a lower level (top down design). After determining major steps, the details for how to accomplish them is determined and additional levels are filled in as required.
• A great algorithm should follow the pneumonic “RECUR”—

Reliable
Efficient
Clear
Understandable
Remember easily

• Taking the example of a cookie recipe, it is reliable if you follow the recipe exactly and the cookies come out the same every time. It is efficient if no extra ingredients or steps are used in the recipe. The instructions are clear if they are not confusing, ambiguous, or vague. The recipe is understandable if it makes sense. Good recipes should also be easy to remember.
• The best algorithm depends on the situation. For example, who are the cookies for—children or adults? What are they paired with? Does the recipe work at all altitudes? A variation in the recipe or another recipe may meet the different needs. In addition, not all experts will agree on the best recipe. Analyzing a number of different recipes may enable chefs to adapt their baking for a variety of situations.

Great Medical Algorithms

• An example of a great medical algorithm is the International algorithm for the management of chronic spontaneous/idiopathic urticaria.^7,8
• It is a simple algorithm that is easy to remember.

There are 4 steps:

1. 1. 1. Second-generation antihistamines at standard doses.
      2. Increased dosage up to 4-fold of second-generation antihistamines if the symptoms persist after 2-4 weeks.
      3. Omalizumab if there is inadequate control after 2-4 weeks.
      4. Cyclosporin A if there is inadequate control after 6 months.

• This is a reliable, efficient (only 4 steps), clear, understandable algorithm that is easy to remember. The solution is always the same under all circumstances.
• It is much simpler and a better algorithm than the US algorithm which is much more complicated without clear guidance as to what should be used in the next step. For example, in the US chronic urticaria treatment algorithm, step 2 is not binary and includes multiple choices (increased dosage of second-generation antihistamine, addition of another second-generation antihistamine, addition of a H₂-antagonist, addition of leukotriene-modifying agents and addition of a first-generation antihistamine at bedtime.⁸ This algorithm is complex and would not result in reproducible results.

How to Create a Great Algorithm

• The problem should be first determined (e.g. directions, recipe, solving a problem, medication treatment plan).
• The input variables should then be determined (e.g. width and length to determine area) and output stated.
• A simple complete precise plan with or without abstraction should then be developed after determining the audience.
• There is often no reason to reinvent the wheel and a search should be made for algorithms that are already in existence to treat a given problem.
• Necessary steps should also be determined, and
•  The plan tried out to determine if:
  • The plan works
  • Each step is right/correct
  • Each step is necessary (efficiency)
  • The solution is reproducible and accurate under all circumstances.
• In medical treatment algorithms, it is often difficult to have a single treatment option for a particular step since different classes of medications could potentially be used.
• Where possible, using classes of medications rather than specific medication names may help simplify the algorithm and make it easier to remember and implement.

Conclusion

Adherence to the “RECUR”—Reliable, Efficient, Clear, Understandable and Remember easily pneumonic should increase the quality of medical algorithms being created. Well constructed medical algorithms have the potential to improve and standardize medical decisions, enhance adherence to better guidelines and improve patient care.

Professor of Dermatology, Western University, London ON, Canada

Conflict of interest:
Dr. Guenther has been a consultant, speaker and clinical researcher for Leo Pharma Inc. Dr. Guenther received an unrestricted educational grant from Leo Pharma to write the paper.

Introduction

In 2018, Fucibet^® was launched in Canada by Leo Pharma Inc. for the topical treatment of confirmed or suspected secondarily infected Staphylococcus aureus eczematous dermatoses, such as atopic dermatitis (AD), discoid eczema, stasis dermatitis, and seborrheic dermatitis.¹ It is intended to be used for a maximum of 2 weeks. Safety in individuals greater than age 6 years has been established.¹

It was first launched in 1992 in Europe in a different vehicle under the name of “Fucicort^® cream”, then in 2007 in a lipid cream base as “Fucicort Lipid cream” in an effort to ameliorate dryness. Fucibets^® has the same base as “Fucicort Lipid cream.” It contains 2% fusidic acid and 0.1% betamethasone 17-valerate, and the non-medicinal ingredients all-rac-α-tocopherol, cetostearyl alcohol, citric acid monohydrate, hypromellose, liquid paraffin, methyl parahydroxybenzoate, potassium sorbate, propyl parahydroxybenzoate, purified water, steareth-21 and white soft paraffin.

Background

• Up to ¼ of children² and 10% of adults³ are affected by AD.
• In contrast to the 3% colonization rate of S. aureus in healthy individuals, 70% of AD patients are colonized, with higher rates in severe disease.³
• Disruption of the epidermal barrier, filaggrin mutations, lower antimicrobial peptide production and activation of the Th2 pathway in AD increase susceptibility to S. aureus infection. AD flares are preceded by microbial dysbiosis dominated by S. aureus.³
• Secondary skin infection may present clinically as impetigo, pustulosis, folliculitis, abscesses and cellulitis.³

Treatment Management Options for Infected Eczematous Dermatoses

• Mild localized skin infections are usually treated with a topical antibiotic, while more severe and widespread infections are treated with a course of systemic antibiotics such as an early-generation cephalosporin or amoxicillin-clavulanate.³
• Antibiotics should only be given when there is clinical evidence of an infection; indiscriminate use may increase bacterial resistance.
• It is important to realize that skin cultures in colonized patients may grow S. aureus even when patients are not clinically infected and that a culture may not be able to distinguish colonization from infection.

Treatment Rationale for Combination Fusidic Acid/Betamethasone Lipid Cream

• The combination of the topical antibiotic fusidic acid, and topical steroid betamethasone valerate, allows for eradication of the secondary infection and improvement of dermatitis at the same time.
• Fusidic acid cream and ointment have been marketed in Canada since 1985. Fusidic acid has high activity against methicillin-sensitive and methicillin-resistant S. aureus [minimum inhibitory concentration of 50% (MIC₅₀) of Canadian isolates of 0.12 and MIC₉₀ of 0.25], and low (<3%) resistance in Canadian hospitals.⁴
• Up to 2.5% of topical fusidic acid can cross intact human skin within 30 minutes, with up to 10% penetrating into the stratum corneum.¹ Fusidic acid also has high activity against Clostridium and Corynebacteria spp., and moderate in vitro activity against streptococci.⁵
• Its unique structure limits cross-resistance to other antibiotics.⁴
• It is associated with a very low incidence of hypersensitivity in contrast to other antibiotics such as neomycin.⁶
• Topical steroids are standard anti-inflammatory therapy for AD.² Steroids stimulate the production of a glycoprotein called lipocortin which results in inhibition of phospholipase A2 and inhibition of release of arachidonic acid and biosynthesis of prostaglandins and leukotrienes.⁷ They also cause direct repression of the NF-κB transcription factor, inhibit mRNA for proinflammatory genes including those for interleukin-1 (Il-1), Il-2, Il-6, TNF-α, Il-4 and inducible nitric oxide (iNOS), and promote transcription of anti-inflammatory genes such as Il-10.⁷
• There is no evidence that treatment of infected dermatoses with topical steroids in addition to topical antibiotics allows for overgrowth of pathogens and masks clinical infection.

Supporting Evidence from Clinical Trials

• In a study of 629 patients with clinically infected AD, two weeks treatment with twice daily Fucidin/betamethasone in the lipid base and original base resulted in comparable reduction in the total severity of score (TSS) of the eczematous lesions (82.9% and 82.7% respectively vs. 33.0% for vehicle) and successful bacteriological response (89.7% and 89.6% vs. 25.0% for vehicle). In 94.1% of patients with fusidic acid susceptible isolates, active treatment was successful in eradicating the organisms.⁸ There were fewer perilesional adverse drug reactions (primarily pruritus and skin burning) with the active agents vs. placebo. The onset of action was rapid with a ⅔ reduction in TSS after the first week of treatment.
• In a double-blind, 1 week left/right infected or potentially infected AD and contact dermatitis study involving 81 patients (55 adults and 26 children), 2% fusidic acid/0.1% betamethasone was marginally superior to 0.1% betamethasone, although the combination eliminated 67% of bacteria vs. 51% with steroid.⁹ In addition, there was a significant patient preference for the combination (32 vs. 14 vs. 35 with no preference p<0.05).
• In two published studies^6,10 the clinical and bacteriological efficacy of fusidic acid/betamethasone valerate cream and neomycin/betamethasone cream were similar.
• In an open parallel, randomized comparison study involving 46 patients, fusidic acid/betamethasone produced similar clinical improvement to mupirocin ointment followed by betamethasone valerate cream twice daily for 2 weeks.¹¹ In this study, there was no evidence that the fusidic acid/steroid combination increased resistance of S.aureus to fusidic acid.
• A randomized, open study involving 99 adult and pediatric patients, showed that treatment with twice daily 2% fusidic acid/0.1% betamethasone was superior clinically to the fixed combination product containing 0.1% gentamicin/0.1% betamethasone [54% vs. 38% respectively “excellent” at day 2-4, and 74% vs. 55% respectively “excellent” after 7-12 days of treatment, p=0.03].¹² In addition, there was a statistically significant greater reduction in the mean severity scores for individual symptoms with fusidic acid/betamethasone. Seventy-four percent on fusidic acid/betamethasone rated the treatment as excellent vs. 55% on gentamicin/betamethasone (p=0.08 not significant). Although there was greater clinical improvement with fusidic acid/betamethasone, there was no difference between the two treatments in eradication of pathogens and no tendency for selection of resistant skin bacteria.
• It is therefore difficult to explain the superior efficacy of fusidic acid/betamethasone since they both contain the same steroid. Furthermore, in another study, there was no difference in the release of betamethasone from fusidic acid/betamethasone valerate lipid cream (Fucibet^®) and gentamicin/betamethasone valerate cream (Valisone-G^®), however, at day 7, fusidic acid/betamethasone lipid cream showed significantly higher skin hydration compared to gentamicin/betamethasone valerate cream (p<0.05).¹³ The fusidic acid/betamethasone lipid base was found to be more adhesive and less spreadable than that of gentamicin/betamethasone cream suggesting that the former may function as a film-forming product, retaining active ingredients in place for a longer time in contact with the skin surface.
• The difference in efficacy in the study by Strategos may also be related to the bacteriological method which was only semi-quantitative.¹² At the start of the study, there was a lower rate of resistance of isolated Staph aureus to fusidic acid (9%) vs. gentamicin (21%).¹²

Conclusion

Fusidic acid/betamethasone 17-valerate cream (Fucibet^®) is a cosmetically acceptable, well tolerated cream which is hydrating and improves the TSS dermatitis score in secondarily infected dermatitis. In addition, it clears bacteria in infected dermatitis better than vehicle suggesting that improving the dermatitis with a steroid might be synergistic, perhaps through a reduction in bacterial load.

Division of Dermatology, University of Western Ontario, London, ON, Canada
The Guenther Dermatology Research Centre (GDRC), London, ON, Canada

Conflict of interest:
Dr. Guenther has been a speaker, consultant and involved in clinical research for: Abbvie, Allergan, Amgen, Celgene, Eli Lilly, Galderma, GlaxoSmithKline, Janssen, Leo Pharma, Merck Frosst, Novartis, Pfizer, and Stiefel.

ABSTRACT
The scalp is involved in up to 80% of individuals with psoriasis. Eighty percent of those with scalp psoriasis experience a negative impact on quality of life. Topical treatment with corticosteroids with or without vitamin D3 analogues is the mainstay of treatment. Topical therapy most suitable for the scalp is formulated as a solution, lotion, gel, foam, spray, oil, or shampoo. Twice weekly maintenance in frequent relapsers may decrease the time to first relapse. Intralesional steroids, phototherapy and the excimer laser are occasionally used for resistant cases. In patients with moderate-to-severe psoriasis, apremilast, adalimumab and etanercept have been shown to significantly improve scalp psoriasis. They should be considered in patients who have failed topical therapy.

Key Words:
biologics, laser and light therapies, scalp dermatoses, scalp psoriasis, steroids, vitamin D derivatives

Introduction

Up to 80% of individuals with psoriasis have scalp involvement, and 80% of those with scalp psoriasis experience a negative impact on quality of life.¹ Topical therapy is first-line treatment, with both the active ingredient(s) as well as the vehicle affecting efficacy, tolerability and treatment adherence.² In 2009, the US National Psoriasis Foundation recommended intralesional corticosteroids as second-line treatment, and phototherapy, conventional systemics and biologics as third-line treatments.³

Topical Therapy

Topical Steroids

Topical steroids are the most commonly prescribed scalp treatments.⁴ They are more efficacious than calcipotriol, coal tar and tazarotene.³ The scalp is relatively resistant to atrophy induced by topical steroids.³

Clobetasol propionate (CP) in various formulations appears to be highly efficacious for scalp psoriasis. In a vehicle-controlled, randomized, double-blind study, after 4 weeks of twice daily application, 85% of patients on CP spray were clear/almost clear compared to 13% on vehicle (p<0.001).⁵ Another study showed that CP 0.05% solution was superior to 0.05% betamethasone dipropionate solution.⁶ In another study involving 142 individuals with scalp psoriasis, after 4 weeks, CP 0.05% shampoo was more effective than vehicle in reducing total severity score (p<0.001) and 42.1% treated with CP were clear/almost clear compared to 2.1% in the vehicle arm.⁷ After an initial daily treatment for 4 weeks, twice weekly maintenance use of this shampoo over 6 months decreased the median time to first relapse (141 days vs. 30.5 days for vehicle, p<0.0001).⁸

The formulation of the topical steroid can make a difference. Foams have the following cosmetic advantages including drying quickly, easy application, and minimal residue after application.⁹ In addition, the human cadaver skin model showed greater absorption of CP foam than solution, with a more than double peak rate.¹⁰ In a 14-day study of 26 patients with moderateto- severe psoriasis involving >20% body surface area (BSA), both the CP foam and CP ointment caused similar reversible hypothalamic-pituitary-adrenal (HPA) axis suppression (3 in each group) as has been noted with other class I topical corticosteroids.¹⁰ In a double-blind study involving 188 adults with moderate-to-severe scalp psoriasis, greater reduction in scaling was noted at day 15 with CP (Olux®) foam than with CP solution (p=0.0142); the difference was maintained over the next 14 days despite no additional treatment.¹⁰ Seventy-four percent on CP foam, 63% on CP solution, and 4% and 10% in the placebo groups were clear/almost clear after 14 days of treatment.¹⁰

Similarly, in the human cadaver skin study, after 12 hours, the bioavailability of betamethasone valerate (BMV) was 300% greater with the foam than the lotion.¹¹ However, a study in atopic dermatitis in which the foam was applied to 30% or more of BSA showed that BMV foam had little propensity to induce hypothalamic-pituitary axis suppression.¹¹ In a twice daily 4 week study comparing BMV 0.12% (Luxiq®) foam to BMV lotion, placebo foam and placebo lotion, 72% on BMV foam were clear/almost clear compared to 47% on BMV lotion, and 21% on placebo foam (p<0.05).¹¹ In a cross-over study involving 210 patients, 88% on BMV foam were clear/almost clear compared to 66% on standard therapy [other topical steroids in 55% of cases [mometasone (70%), betamethasone dipropionate (25%), BMV (3%), and hydrocortisone butyrate (2%)], or calcipotriol lotion in 45% of cases; p<.001].¹² Feldman et al found similar efficacy between once and twice daily BMV foam in the treatment of scalp psoriasis, suggesting that once daily application should be sufficient.¹³

Vitamin D Derivatives

Vitamin D derivatives may cause irritation, but do not cause atrophy.³ It takes longer to see optimal improvement with vitamin D derivatives (8 weeks) than with steroids (2-3 weeks).¹⁴ In a large (n=3396) observational study of scalp psoriasis, 80% of individuals treated with calcipotriol solution had ‘good’ or ‘very good’ improvement after 8 weeks.¹⁵ One study showed similar efficacy between calcipotriol solution and BMV 1% lotion,¹⁶ although in another study involving 474 patients with scalp psoriasis, more patients (75%) were clear or markedly improved with BMV 0.1% solution than with calcipotriol 50 mcg/ml solution (58%, p<0.001) and there was a greater reduction in the total sign score (61% and 45% respectively, p<0.001).¹⁷ An additional study showed that calcipotriol solution was also inferior to clobetasol propionate shampoo.¹⁸

Vitamin D/steroid combination: Dovobet® gel (formerly Xamiol®; also called Daivobet® and Taclonex®) contains calcipotriol 0.005% and betamethasone dipropionate 0.05%.⁴ It has a fast onset of action and is superior to its individual ingredients,⁴ and calcipotriol scalp solution.¹⁹ More than twice as many patients treated with Dovobet® gel (68.6% vs. 31.4% on calcipotriol scalp solution) had absent/very mild disease after 8 weeks of use.19 Absent or very mild disease is achieved by approximately 60% of patients after just 2 weeks of therapy and 70% after 8 weeks.⁴ Dovobet® gel is efficacious for very severe scalp psoriasis. After 8 weeks, 36.4% who had very severe disease at baseline, demonstrated absent/very mild disease compared to none treated with calcipotriol solution.¹⁹

Two long-term 52-week studies showed that Dovobet® gel is efficacious and well tolerated.^20,21 Absent/very mild/mild disease was noted in 92.3% of visits with Dovobet® gel vs. 80% with calcipotriol in the first study, while in the second study, the median number of visits with clear/minimal/mild disease was 100%.

Dovobet® gel is well tolerated with no reports of atrophy, striae, purpura, or significant changes in serum calcium in trials.⁴ Some patients, however, have had difficulty removing Dovobet® gel from their hair. Application of shampoo, particularly a clarifying shampoo, to dry hair where Dovobet® gel was applied, prior to entering the shower and wetting the hair, aids significantly in the removal of gel.

Other Topical Treatments

Due to its keratolytic effect, salicylic acid may enhance penetration of topical corticosteroids.³ The National Psoriasis Foundation recommends tazarotene as first-line therapy based on its efficacy off the scalp.³ Scalp studies are lacking, but the author has successfully used the gel formulation in resistant cases.

Topical Shampoos Other Than Steroid Shampoos

Tar and imidazole antifungal shampoos have modest, at best, efficacy in scalp psoriasis.²² In an 8-week randomized, open-label study involving 475 patients, a 1% coal tar/1% coconut oil/0.5% salicylic acid shampoo was found to be inferior to calcipotriol (p<0.001). Tar’s malodor, hair staining and drying, poor efficacy and carcinogenicity limit its use.^3,22 Imidazole antifungals have been tried since pityrosporon overgrowth has been associated with psoriasis, however, not all studies have shown efficacy.²²

Systemic, Light and Laser Therapies

Intralesional Corticosteroids

There are no studies of intralesional corticosteroids in scalp psoriasis, although anecdotal reports support their use for localized disease.³

Phototherapy and Excimer Laser Treatment

Treatment of scalp psoriasis with phototherapy or laser is difficult since hair shields the scalp from ultraviolet (UV) radiation. UV combs have been developed for scalp use, and blow dryers may help expose the scalp for excimer laser (308 nm) treatment, but large controlled trials are lacking and treatment may be cumbersome.^2,3

Systemic/Biologic Treatment

Although the traditional systemic agents methotrexate, cyclosporine and acitretin have been used in patients with moderate-to-severe psoriasis with scalp involvement,²² studies in scalp psoriasis are lacking.

Apremilast, an oral phosphodiesterase 4 inhibitor, which has recently received approval for treatment of moderate-to-severe plaque psoriasis, improves scalp psoriasis. In the ESTEEM I phase 3 trial, at week 16 [n=374 on apremilast and n=189 on placebo, who had a baseline Scalp Physician’s Global Assessment (ScPGA) score of at least 3; 66.7% of total patients], 46.5% on apremilast achieved an ScPGA of 0 or 1 compared to 17.5% on placebo (p<0.0001).²³ At week 52, ScPGA response was achieved by 73% of apremilast patients.²³

A subanalysis of the phase 3 adalimumab BELIEVE trial showed that by week 8, 76.5% of patients with scalp psoriasis at baseline had achieved a Psoriasis Scalp Severity Index (PSSI) response (PSSI 4 or less). At week 16, the median and mean decreases in PSSI were 100% and 77.2% respectively.²⁴ Patients with scalp involvement had a lower Psoriasis Area and Severity Index (PASI) 75 response early in treatment, but differences declined with time and at week 16, PSSI scores correlated with PASI 75.²⁴

A double-blind, placebo-controlled study of etanercept in 124 adults with moderate-to-severe psoriasis involving 10% or more body surface area, a PASI score of at least 10, and 30% or more scalp involvement with a PSSI of at least 15, showed 86.8% improvement in PSSI after 12 weeks of etanercept 50 mg twice weekly compared to 20.4% for the placebo arm.²⁵ From week 12 to 24, the etanercept arm was stepped down to 50 mg once a week, while the placebo arm was treated with etanercept 50 mg twice weekly. At week 24, the mean PSSI improvements were 90.6% for the etanercept/etanercept arm and 79.1% for the placebo/ etanercept arm.

Conclusion

Topical steroids with or without calcipotriol are the mainstay of therapy for scalp psoriasis. There are a number of newer formulations including foams, shampoos, gels and sprays which enhance cosmetic acceptability and adherence. Twice weekly treatment should be considered as maintenance therapy for patients who relapse quickly.²⁶ Systemic treatment should be considered for recalcitrant cases. Studies have shown excellent efficacy with apremilast, adalimumab and etanercept.

References

1. Krueger G, Koo J, Lebwohl M, et al. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-membership survey. Arch Dermatol. 2001 Mar;137(3):280-4.
2. Papp K, Berth-Jones J, Kragballe K, et al. Scalp psoriasis: a review of current topical treatment options. J Eur Acad Dermatol Venereol. 2007 Oct; 21(9):1151-60.
3. Chan CS, Van Voorhees AS, Lebwohl MG, et al. Treatment of severe scalp psoriasis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2009 Jun;60(6):962-71.
4. Guenther LC. Treatments for scalp psoriasis with emphasis on calcipotriol plus betamethasone dipropionate gel (Xamiol). Skin Therapy Lett. 2009 May;14(4):1-4.
5. Sofen H, Hudson CP, Cook-Bolden FE, et al. Clobetasol propionate 0.05% spray for the management of moderate-to-severe plaque psoriasis of the scalp: results from a randomized controlled trial. J Drugs Dermatol. 2011 Aug;10(8):885-92.
6. Lassus A. Local treatment of psoriasis of the scalp with clobetasol propionate and betamethasone-17,21-dipropionate: a double-blind comparison. Curr Med Res Opin. 1976 4(5):365-7.
7. Jarratt M, Breneman D, Gottlieb AB, et al. Clobetasol propionate shampoo 0.05%: a new option to treat patients with moderate to severe scalp psoriasis. J Drugs Dermatol. 2004 Jul-Aug;3(4):367-73.
8. Poulin Y, Papp K, Bissonnette R, et al. Clobetasol propionate shampoo 0.05% is efficacious and safe for long-term control of scalp psoriasis. Cutis. 2010 Jan;85(1):43-50.
9. Stein L. Clinical studies of a new vehicle formulation for topical corticosteroids in the treatment of psoriasis. J Am Acad Dermatol. 2005 Jul;53(1 Suppl 1):S39-49.
10. Franz TJ, Parsell DA, Myers JA, et al. Clobetasol propionate foam 0.05%: a novel vehicle with enhanced delivery. Int J Dermatol. 2000 Jul;39(7):535-8.
11. Franz TJ, Parsell DA, Halualani RM, et al. Betamethasone valerate foam 0.12%: a novel vehicle with enhanced delivery and efficacy. Int J Dermatol. 1999 Aug;38(8):628-32.
12. Andreassi L, Giannetti A, Milani M, Scale Investigators Group. Efficacy of betamethasone valerate mousse in comparison with standard therapies on scalp psoriasis: an open, multicentre, randomized, controlled, crossover study on 241 patients. Br J Dermatol. 2003 Jan;148(1):134-8.
13. Feldman SR, Ravis SM, Fleischer AB, Jr, et al. Betamethasone valerate in foam vehicle is effective with both daily and twice a day dosing: a singleblind, open-label study in the treatment of scalp psoriasis. J Cutan Med Surg. 2001 Sep-Oct;5(5):386-9.
14. van der Vleuten CJ, van de Kerkhof PC. Management of scalp psoriasis: guidelines for corticosteroid use in combination treatment. Drugs. 2001 61(11):1593-8.
15. Thaci D, Daiber W, Boehncke WH, et al. Calcipotriol solution for the treatment of scalp psoriasis: evaluation of efficacy, safety and acceptance in 3,396 patients. Dermatology. 2001 203(2):153-6.
16. Duweb GA, Abuzariba O, Rahim M, et al. Scalp psoriasis: topical calcipotriol 50 micrograms/g/ml solution vs. betamethasone valerate 1% lotion. Int J Clin Pharmacol Res. 2000 20(3-4):65-8.
17. Klaber MR, Hutchinson PE, Pedvis-Leftick A, et al. Comparative effects of calcipotriol solution (50 micrograms/ml) and betamethasone 17-valerate solution (1 mg/ml) in the treatment of scalp psoriasis. Br J Dermatol. 1994 Nov;131(5):678-83.
18. Reygagne P, Mrowietz U, Decroix J, et al. Clobetasol propionate shampoo 0.05% and calcipotriol solution 0.005%: a randomized comparison of efficacy and safety in subjects with scalp psoriasis. J Dermatolog Treat. 2005 Feb;16(1):31-6.
19. Kragballe K, Hoffmann V, Tan J, et al. Calcipotriene plus betamethasone dipropionate gel compared to calcipotriene solution in patients with scalp psoriasis. J Am Acad Dermatol. 2008 Feb;58(2 Suppl 2):AB131.
20. Luger TA, Cambazard F, Larsen FG, et al. A study of the safety and efficacy of calcipotriol and betamethasone dipropionate scalp formulation in the long-term management of scalp psoriasis. Dermatology. 2008 217(4):321-8.
21. Tyring S, Mendoza N, Appell M, et al. A calcipotriene/betamethasone dipropionate two-compound scalp formulation in the treatment of scalp psoriasis in Hispanic/Latino and Black/African American patients: results of the randomized, 8-week, double-blind phase of a clinical trial. Int J Dermatol. 2010 Nov;49(11):1328-33.
22. van de Kerkhof PC, Franssen ME. Psoriasis of the scalp. Diagnosis and management. Am J Clin Dermatol. 2001;2(3):159-65.
23. Papp K, Reich K, Leonardi C, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in nail and scalp psoriasis: 52-week results from the ESTEEM 1 study. [e-poster IST13-2033]. 22nd Annual Meeting of the European Academy of Dermatology and Venereology, October 2-6, 2013, Istanbul, Turkey.
24. Thaci D, Unnebrink K, Sundaram M, et al. Adalimumab for the treatment of moderate to severe psoriasis: subanalysis of effects on scalp and nails in the BELIEVE study. J Eur Acad Dermatol Venereol. 2015 Feb;29(2):353-60.
25. Bagel J, Lynde C, Tyring S, et al. Moderate to severe plaque psoriasis with scalp involvement: a randomized, double-blind, placebo-controlled study of etanercept. J Am Acad Dermatol. 2012 Jul;67(1):86-92.
26. Ortonne J, Chimenti S, Luger T, et al. Scalp psoriasis: European consensus on grading and treatment algorithm. J Eur Acad Dermatol Venereol. 2009 Dec;23(12):1435-44.

¹Dermatrials Research Inc.
²Department of Medicine, McMaster University, Hamilton, ON, Canada

Introduction

External genital warts (EGW) is a common sexually transmitted infection (STI) affecting millions of individuals worldwide. It is likely the most frequent STI in both Canada and the US and is caused by infection with human papilloma virus (HPV) 6 and 11: importantly, these are non-oncogenic strains.¹ The lesions can be caused by HPV 6 (most commonly) or 11, both subtypes are rarely found together.² Patient and provider-applied therapies can be utilized concomitantly to effectively treat EGW. Recently, prophylactic strategies using HPV vaccines have been introduced with success, as has the introduction of a topical immunomodulator in a new formulation, all of which improve the therapeutic armamentarium, and ultimately, patient care.

Background

• The term EGW relates to the anatomic location of these lesions. The areas commonly involved include the penis, vulva, groin, perineum, perianal, suprapubic and even upper thighs and buttocks.³
• Most often EGW is painless and not bothersome. However, in certain individuals it can be quite symptomatic causing itching, pain during intercourse, stinging and burning. Larger lesions can cause obstruction of the meatus and the anus leading to restriction or complete blockage of normal excretionary functions.
• Women are more frequently affected than men, with the most common age groups being 20-24 years and 25-29 years in men.⁴
• Reports indicate that lesions are only noticed in 65% of cases. Males notice the lesions 79% of the time likely due to the anatomic visibility.⁵ Conversely, women only notice the lesions 52% of the time.⁵
• EGW are diagnosed by physicians in 16% of cases, more often in females and very infrequently in males.⁵ Likely, the clinician visit may have been regarding complaints of genital symptoms which lead to an unexpected diagnosis of EGW.⁵
• EGW carries a significant psychosocial impact. Often patients are embarrassed, angry and disgusted.^5,6 Anxiety not only results in sexual tension but also raises concerns regarding recurrence, cancer, and the effectiveness of treatment.^{7, 8}
• EGW diagnosis can often result in a change in lifestyle.⁵ Therefore, patients may have higher expectations from their physician to properly diagnose, counsel, manage and treat these lesions.

Treatment Options

• Patients should expect a treatment that provides favourable efficacy, safety, tolerability, low recurrence rates, minimal scaring and that can be self-applied in the privacy of their own home.
• According to Canadian STI Guidelines, therapies are broadly grouped as patient-applied or office-based treatments.⁹ Often, combinations of treatments are used.
  • Office-based cytodestructive therapies for EGW involve either chemical eradication or physical removal, specifically:
    • Cryotherapy (liquid nitrogen)
    • Surgical/ablative techniques (surgical excision, carbon dioxide laser, electocautery)
    • Trichloroacetic or bichloroacetic acid
    • Podophyllin resin
    • Podophyllotoxin (0.5%) – standardized concentration of purified podophyllin
• Patient-applied treatments are usually preferred and include podophylotoxin and imiquimod.
  • Immunomodulatory therapy with topical imiquimod:
    • Classified as an immune response modifier, imiquimod has antiviral effects functioning through TLR-7 agonism.¹⁰
    • It induces TH-1 type immune responses resulting in the expression of cytokines such as interferon-alpha and tumour necrosis factor-alpha.¹⁰
    • Due to its favourable efficacy, safety and tolerability profiles, as well as lowest recurrence rate, Canadian Consensus Guidelines on HPV 14 recommends the use of imiquimod prior to initiating more invasive strategies, such as destructive/ excision or laser therapies.⁹
• Imiquimod 5% cream (Aldara™):
  • Approved by Health Canada in 1999.
  • Officially indicated for the treatment of external genital and perianal warts in immunocompetent adults.
  • Applied 3 times weekly for up to 16 weeks to a specific treatment area.
  • In a Phase 3 clinical trial, 72% of women and 33% of men had complete clearance of baseline target warts (analyses did not include non-target or new warts).¹¹
  • Side effects include erythema (67%), erosion (32%), excoriation/flaking (25%), edema (16%).¹¹
• Imiquimod 3.75% cream (Vyloma™):
  • Approved by Health Canada in March 2011 for the topical treatment of EGW and perianal warts (whether present at the start of therapy or emerging during therapy) in immunocompetent adults.
  • Developed from its predecessor, imiquimod 5%, with the goal of encouraging treatment adherence by shortening treatment length, simplifying the dosing regimen, and improving tolerability.
  • Applied once-a-day for up to 8 weeks to the external genital/perianal warts, but should not exceed 8 weeks even in the event of missed doses or rest periods.¹²
  • Treatment is generally well tolerated and common side effects included pain, irritation and pruritus at the treatment site.¹³
  • Two randomized, placebo-controlled, double-blind studies of imiquimod 3.75% in 534 women (mean age 33.4 years) with 2-30 lesions (mean 7.9) in the vulvar (including mons), inguinal, perineum, and/or perianal areas, and with a minimum total wart area of 10 mm2 demonstrated good efficacy and safety.¹³
  • Imiquimod 3.75%, applied once daily for 8 weeks, achieved complete clearance in 36.6% of women versus 14.2% who applied placebo (p<0.001). A 63.5% decrease in wart count was seen in the imiquimod 3.75% group compared to a 10.7% decrease in the placebo arm (p<0.001). Discontinuation rates were 2.3% for the imiquimod 3.75% group versus 0.9% for placebo.
  • Of the patients who completely cleared, 70% (71/102) remained clear of recurred EGW at the end of the 12-week follow-up.¹²
  • Imiquimod 3.75% is pregnancy class C.
  • It is available in 250 mcg single dose sachets and in a pump containing 7.5 g of cream.¹²

Vaccines for EGW

Currently, 2 vaccines are available for the prevention of HPV infection:

• Quadrivalent (HPV types 6, 11, 16, 18) vaccine (Gardasil®):14
  • Prevents EGW caused by HPV 6, 11 and cervical cancer and other cancers caused by HPV 16, 18 including vulva and vaginal cancers, cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, and vaginal intraepithelial neoplasia.
  • Indicated in females aged 9-45 years.
  • Indicated in males aged 9-26 years.
• Bivalent (HPV types 16, 18) vaccine (Cervarix®):15,16
  • Prevents cervical cancer and other cancers caused by HPV 16, 18.
  • Adjuvant results in very high serum antibody levels against HPV, excellent subtype cross-protection.
  • Does not protect against EGW acquisition.
  • Indicated in females aged 10-25 years.

Conclusion

EGW is a global problem. In addition to its physical symptoms, patients also suffer associated psychosocial sequelae. Therefore, the effective and safe treatment of this STI is important for a host of reasons. Therapeutic strategies for EGW include officebased cytodestructive therapies and patient administered topical therapy with imiquimod. Further, effective vaccines have been developed and are now widely available. All of these approaches are associated with good outcomes, and aid the clinician in helping their patients effectively manage EGW.

References

1. Hsueh PR. J Microbiol Immunol Infect. 2009;42(2):101-6.
2. Garland SM, et al. Cancer Epidemiol, Biomarkers, Prev. 2009;18(6):1777-84.
3. Wiley D, et al. Obstet Gynecol Surv. 2006;61(6 Suppl 1):S3-14.
4. Marra F, et al. Sex Transm Infect. 2009;85(2):111-5.
5. Maw RD, et al. Int J STD AIDS;1998;9(10):571-8.
6. Voog E, et al. Acta Derm Venereol. 1992;72(3):185-6.
7. Sheppard S, et al. Genitourin Med. 1995;71(3):194-5.
8. Persson G, et al. Sex Transm Dis. 1993;20(1):10-3.
9. Genital human papillomavirus (HPV) infections. Canadian guidelines on sexually transmitted infections. Public Health Agency of Canada (January 2008).
10. Zyclara® cream, 3.75% [prescribing information]. Medicis Pharmaceutical Corp. 2013.
11. Edwards L, et al. Arch Dermatol. 1998;134(1):25-30.
12. Vyloma product monograph
13. Baker DA, et al. et al. Infect Dis Obstet Gynecol.;2011:806105. [Epub 2011 Aug 24].
14. Gardasil product monograph. Kirkland, QC: Merck Canada Inc.; August 26, 2011.
15. Cervarix product monograph. Mississauga, ON: GlaxoSmithKline Inc.; July 12, 2010.
16. Hsueh PR. J Microbiol Immunol Infect. 2009;42(2):101-6.

Division of Dermatology, University of Western Ontario, London, ON, Canada

Introduction

Oatmeal has been used for centuries in skin care as a soothing agent to relieve itch and irritation associated with various skin conditions, such as xerotic and inflammatory dermatoses. It contains a number of compounds with moisturizing, cleansing, buffering, anti-inflammatory, anti-pruritic and anti-oxidant properties. Products containing colloidal oatmeal are well tolerated with only rare reports of allergic contact dermatitis. Clinical studies support the adjunctive use of these products in the treatment of atopic dermatitis.

Background

• The oldest oat grains were found in Egypt about 2000 BC.¹
• The nutritional value of oatmeal and its benefits when used as a topical have been recognized since Roman times as shown in texts by Pliny, Columella and Theophrastus.^1,2
• Oats were introduced to North America at the beginning of the 17th century.¹
• Of the cultivated oats today, more than 75% belong to the Avena sativa (A. sativa) type.²
• In the 1930s, oatmeal started to be used for its cosmetic benefits in facial masks and bath oils and for cleansing, moisturizing and relieving itching.²
• In 1945, a ready to use colloidal oatmeal for skin care became available.
• The colloidal oatmeal, which was made by finely milling dehulled oats to a powder, contained a concentrated starch-protein fraction of the oat grain.^2,3
• In 2003, the US FDA approved colloidal oatmeal as a skin monograph ingredient which can temporarily protect and help relieve minor skin irritation and itching.^2,3
• Today there are many formulations of colloidal oatmeal including cleansers, washes, bath products, creams, lotions, shampoos and shaving gels.^2,3

Components of Colloidal Oatmeal and Their Therapeutic Effects

• Colloidal oatmeal contains starch (65-85%), proteins (15-20%), lipids (3-11%), fiber (5%), and beta-glucans (5%).³
• The lipid content is much higher than in other cereal grains, with unsaturated triglycerides rich in unsaturated fatty acids, being the most abundant lipids.²
• The phenolic compounds avenanthramides, ferulic and caffeic acids, glyceryl esters of hydroxycinnamic, and p-Coumaric in oat flour have antioxidant activity and protect the lipids from oxidation.^2,3
• Avenanthramides also have anti-inflammatory and anti-pruritic properties. They have been shown to decrease activation of nuclear factor-kappa B (NF-κB) and production of proinflammatory cytokines, and reduce oxazolone-induced contact hypersensitivity, histamine-mediated itch and resiniferatoxin-induced neurogenic inflammation.³
• Flavonoids in oat absorb in the 320-370nm UVA range, while saponins with their large lipophilic region and short chain of sugar residues have a soap-like action.²
• Beta-D-glucan is a hydrocolloid which binds water, forming a colloidal film holding moisture in the stratum corneum.²
• Colloidal oatmeal can also act as a skin buffer, restoring the normal pH of the skin.²
• Alpha-tocopherol, also present in oatmeal, has antiinflammatory and anti-photodamage effects and can inhibit the synthesis of prostaglandin E2.²

Safety and Colloidal Oatmeal Skin Care

• Although more than 8 million oat-based cosmetics are sold yearly, there are very few reports of allergic contact dermatitis or contact urticaria.⁴ In the few patients with cutaneous adverse events to topical oat, the reactions were generally very mild and often did not recur with repeat applications.⁵
• In a double-blind, randomized, controlled study, colloidal oatmeal was applied for 15 minutes as an open patch test, and under a patch for 24-48 hours. No urticarial or contact allergic reactions occurred.⁶
• Transient low-level reactions have been reported in 1% of 2,291 men and women treated in 12 independent repeat insult patch test studies of 12 oatmeal-containing skin care products.⁵ No reactions occurred in 2 safety-in-use studies involving 80 adults and 30 children, of which one-third had atopic dermatitis.⁵
• In 302 children who underwent atopy patch tests, a 15% positive result was reported as was a 19% positive skin prick test.⁷

Efficacy of Topical Colloidal Oatmeal

• Colloidal oatmeal skin care can alleviate dry skin. In a 2-week, single-blinded study of subjects with Fitzpatrick skin types IV-VI, a significant improvement in moisturization and skin brightness was seen within the first day (p<0.05) and was maintained throughout the study period, when using the moisturizer containing colloidal oatmeal twice daily.⁸
• Moisturizers that soothe pruritus, hydrate, protect and restore the skin barrier are an essential part of the management of atopic dermatitis (AD).^9,10 They may be first-line in mild AD or with more severe disease, or complementary to prescription medications for enhancement of treatment efficacy and for their steroid-sparing effects.^3,5,9,11
• In a 6-week randomized, controlled study involving 173 infants with moderate to severe AD, the group treated with oat moisturizer demonstrated significant improvements in the Scoring Atopic Dermatitis Index (SCORAD) and quality of life scores (p<0.0001).¹² Further, the quantity of moderate- and high-potency corticosteroids that were used decreased by 7.5% and 42% (p<0.05), respectively.¹²
• In an open-label, 12-week, multicenter study involving 99 patients aged 6 months to adulthood with mild-to-moderate AD, the efficacy and tolerability of an A. sativa extract based moisturizing cream used twice daily showed that by week 12, the SCORAD index improved by 48%.¹³ Skin hydration assessed in selected patients showed a 90% increase at week 8 and an increase of 100% at week 12. The results reported by patients indicated similar trends. The quality of life questionnaires showed significant improvement by week 4. Moreover the steroid sparing effect shown by Grimalt et al, was confirmed in this study.^12,13
• A study conducted in Brazil, that evaluated colloidal oatmeal cream in an open trial in 75 AD patients aged 3-50 years showed significant improvements in SCORAD from baseline as early as week 4.¹⁴ At the end of the study, the SCORAD improvement was very similar to data reported by Nollent (2012).¹⁴
• Patients on chemotherapy with epidermal growth factor receptor inhibitors and tyrosine kinase inhibitors more often than not develop cutaneous adverse effects including acneiform eruptions which can preclude continuation of the treatment. In a study of 10 evaluable patients, treatment with an oatmeal-based lotion resulted in a complete clearing of the cutaneous adverse effects in 6 patients and a partial response in the remainder. ³

Conclusion

There are many different formulations of colloidal oatmeal including cleansers, washes, bath products, creams, lotions, shampoos and shaving gels. Colloidal oatmeal contains a number of components which contribute to its moisturizing, cleansing, buffering, anti-inflammatory, anti-pruritic and antioxidant properties.

Products containing colloidal oatmeal are well tolerated with only rare reports of allergic contact dermatitis. Studies have shown that A. sativa based products significantly decrease skin dryness, itch and irritation, improving quality of life in patients with mild to severe AD. Colloidal oatmeal use in patients with AD has been shown to significantly reduce topical corticosteroid consumption.

References

1. Gibson L, et al. Origin, history, and uses of oat (Avena sativa) and wheat (Triticum aestivum).
2. Kurtz ES, et al. J Drugs Dermatol. 2007;6(2):167-70.
3. Cerio R, et al. J Drugs Dermatol. 2010;9(9):1116-20.
4. Goujon-Henry, C et al. Allergy. 2008;63:781-2.
5. Criquet M, et al. Clin Cosmetic Invest Dermatol. 2012;5:183-93.
6. Pigatto et al: Am J Contact Dermatitis. 1997;8:207.
7. Boussault P, et al. Allergy. 2007;62(11):1251-6.
8. Nebus J, et al. J Am Acad Dermatol. 2004;50:P77.
9. Lebwohl M, et al. Cutis. 2005;76(suppl 6):7-12.
10. Eichenfield LF, et al. J Am Acad Dermatol. 2003;49(6):1088-95.
11. Fowler JF, et al. J Drugs Dermatol. 2012;11(7):804-7.
12. Grimalt R, et al. Dermatology. 2007;214(1):61-7.
13. Nollent V, et al. Multi-centric clinical study on infants, children and adults with atopic dermatitis. Poster EADV Congress, 27-30 September 2012, Prague, Czech Republic.
14. Nebus J, et al. The Dermatologist. 2012;20(10)(suppl):1-4.

Division of Dermatology, University of Western Ontario, London, ON, Canada
The Guenther Dermatology Research Centre, London, ON, Canada

ABSTRACT

Although biologics are very efficacious as monotherapy in patients with psoriasis, combination treatment with traditional systemic and topical therapies may increase the speed of onset and enhance efficacy without significant additional toxicity. In contrast, in psoriatic arthritis, the addition of methotrexate to anti-tumour necrosis factor-alpha therapy does not enhance efficacy in either the skin or joints.

Key Words:
acitretin, adalimumab, alefacept, biologics, calcipotriol, combination therapy, cyclosporine, etanercept, infliximab, methotrexate, phototherapy, psoriasis

Introduction

Psoriasis is a chronic inflammatory disorder that is associated with a number of comorbidities including arthritis, cardiovascular risk factors, and inflammatory bowel disease.¹ Patients with moderate to severe disease usually require phototherapy, traditional systemic medications (e.g. methotrexate, acitretin, and cyclosporine), or biologic agents (e.g., adalimumab, alefacept, etanercept, infliximab, and ustekinumab) for adequate control.² Alefacept binds to CD2 on CD45RO+ effector T lymphocytes, inhibiting their activation and inducing apoptosis of these T cells, while adalimumab, etanercept, and infliximab inhibit tumour necrosis alpha, a cytokine that is elevated in patients with psoriasis, and ustekinumab inhibits interleukins 12 and 23, which are also elevated in psoriasis.³ Although biologics are generally used as monotherapy, in Europe the concurrent use of traditional systemic agents can be found in up to 30% of cases.⁴ Addition of a biologic to traditional systemic therapy can enhance efficacy, or permit discontinuation or dose reduction of the traditional systemic agent without compromising disease control. On the other hand, addition of a systemic agent, phototherapy, or topical therapy to a biologic can enhance efficacy, including speed of onset, degree of clearing, and in some cases duration of remission or improve safety. Since acitretin can suppress the development of skin cancers, such as squamous cell carcinoma in high risk patients,⁵ addition to at-risk individuals receiving biologic treatment might enhance safety.

In rheumatoid arthritis (RA) and psoriatic arthritis patients, methotrexate is routinely used with tumour necrosis factor-alpha (TNF-alpha) inhibitors without additional toxicity.^6,7 In contrast to the psoriasis and RA investigations, studies in patients with psoriatic arthritis have shown that concurrent methotrexate and anti-TNF agents (adalimumab,⁸ etanercept,⁹ infliximab¹⁰) does not enhance efficacy in either the skin or joints. Some efficacy and safety data in psoriasis are available for combination therapy with adalimumab, alefacept, etanercept, and infliximab, but not for ustekinumab.

Combination Therapy with Adalimumab (Humira®)

Calcipotriol + Betamethasone Dipropionate

Adalimumab used in combination with calcipotriol + betamethasone dipropionate (Dovobet®) showed a more rapid and higher PASI 75 response at week 4 (40.7% vs. 32.4%, p=0.021) compared with adalimumab monotherapy.¹¹ However, at week 16, there was no significant difference in PASI 75 response (64.8% with combination therapy vs. 70.9% with adalimumab monotherapy, p=0.086).

Methotrexate

Adalimumab in combination with methotrexate results in down regulation of more inflammatory markers in psoriatic plaques than monotherapy with either agent.¹² In the ADEPT psoriatic arthritis trial, at week 48, PASI 50, 75, 90, and 100 response rates were greater in the with-methotrexate subgroups (n=29) compared to the adalimumab without methotrexate subgroup (n=40), but only the PASI 50 results were statistically significant (PASI 50 in 83% vs. 55 %, p<0.05).¹³

Combination Therapy with Alefacept (Amevive®)

Alefacept has Health Canada approval for use in combination with mid- to high-potency topical agents, ultraviolet B (UVB) phototherapy, methotrexate, cyclosporine, and systemic retinoids.¹⁴ The Canadian AWARE study showed that alefacept allowed for a reduction in dosage or discontinuation of concomitant systemic agents or phototherapy.¹⁵

In an open-label study of 1-3 courses of alefacept (n=449), combination therapy with topical agents occurred in approximately one-third and combination treatment with phototherapy or traditional systemic agents was also used in approximately one-third of patients [UVB (n=24), methotrexate (n=63), cyclosporine (n=42), systemic retinoids (n=23), and prednisone (n=7)].¹⁶ When alefacept was added to existing treatment regimens, ≥30% achieved a response of mild or better. Concurrent therapy with methotrexate or cyclosporine resulted in lower response rates than with other agents. A physician global improvement (PGA) of at least two categories was achieved by 20-21% on methotrexate, 31-43% on cyclosporine, 50-64% on systemic retinoids, 43-62% on mid- to high-potency topical agents, and 55-77% on UVB. There was no increased risk of infection or malignancy when alefacept was used in combination with methotrexate or cyclosporine. The lower response rates with methotrexate combination therapy may be secondary to the study requirement for discontinuation of methotrexate within 4 weeks of initiation of alefacept and the fact that many patients experienced flares as soon as it was discontinued. Cyclosporine was also initially suspended within the first 4 weeks of alefacept therapy; however, due to flares, the protocol was amended so that cyclosporine could be discontinued within 6 weeks after the 12-week alefacept dosing period. Other therapies could be continued throughout the treatment courses.

UVB Phototherapy

In an open label study of 60 patients, greater efficacy and a more rapid onset of action were noted with a combination of alefacept and narrowband (nb) or broadband (bb) UVB compared with alefacept monotherapy.¹⁷ Four weeks after treatment was started, PASI 50 was achieved at the US site in 0% on monotherapy vs. 22% on bb UVB + alefacept, and at the French site 44% on monotherapy vs. 82-90% on nb UVB + alefacept. Similarly in a half-side comparison alefacept/nb UVB study (n=14), the side treated with nb UVB had accelerated and improved clearance.¹⁸

Acitretin

A case series of two patients who had previously been unresponsive to ultraviolet phototherapy, methotrexate, and acitretin showed that combination therapy of alefacept with low dose (10 mg, 25 mg) acitretin shortened the onset of improvement to 4-5 weeks (compared with the usual 8 weeks) and improved inverse and palmoplantar psoriasis.¹⁹ In one patient with a history of squamous cell carcinoma (SCC) who developed three SCCs every 2 weeks while on etanercept monotherapy, after acitretin 25 mg every other day was added only actinic keratoses developed during the 18 month follow-up.²⁰

Combination Therapy with Etanercept (Enbrel®)

Calcipotriol

The addition of calcipotriol cream twice daily for 4 weeks, then once daily for 8 weeks, in patients with psoriasis and psoriatic arthritis who had not achieved PASI 50 at week 12 (n=45 patients) with etanercept 50 mg twice weekly, allowed 31.1% (14 patients) to become PASI 75 responders and 51.1% (23 patients) to become PASI 50 responders at week 24 despite a dose reduction in etanercept to 25 mg twice weekly at week 12.²¹

Phototherapy

Narrowband UVB enhances efficacy irrespective of whether it is used from the start (12 week PASI 75 in 90% vs. 40% on etanercept 25 mg twice weekly monotherapy)²² or added after 6 weeks to patients who had not attained PASI 75 response with etanercept 50 mg twice weekly (after 6 weeks of combination therapy: mean PASI=1.6 vs. 4.7 for non-UVB treated body half, p=0.0192).

Methotrexate

In the EASE trial, the odds ratio of a ‘clear’/’almost clear’ PGA was 2.246 (95% confidence interval (CI) 1.25, 4.0; p=0.0069) for concomitant methotrexate/etanercept when compared with etanercept monotherapy.²³ In this study, 30% of patients could reduce their weekly dose of methotrexate and 16% could stop it altogether. In the EDUCATE study, 29% could discontinue methotrexate and 7% could lower their dose.²⁴ In cases of inadequate response to methotrexate, in one study continuation of the methotrexate when etanercept was initiated resulted in greater efficacy with a similar safety profile than when the methotrexate was tapered and discontinued during the first 4 weeks (PGA ‘clear’ or ‘almost clear’ at 24 weeks in 66.7% vs. 37.0% respectively, p=0.025).²⁵

Acitretin

A small study (n=60) showed that etanercept 25 mg twice weekly and etanercept 25 mg once weekly + acitretin 0.4 mg/kg/day had similar efficacy at week 24 (PASI 75: 45% and 44% respectively; mean BSA reduction: 80% and 78.2% respectively), suggesting that concomitant use of acitretin can lower the required dose of etanercept.²⁶

Cyclosporine

Small case series suggest that etanercept can maintain control when cyclosporine discontinuation is needed.^23,27 In a small psoriatic arthritis study, addition of cyclosporine 3.0 mg/kg/day to 11 patients whose arthritis was in remission, but who had an insufficient skin response, resulted in 9/11 achieving PASI 75 at week 24.²⁸

Combination with Infliximab (Remicade®)

Warren et al. used methotrexate in one patient and cyclosporine in two patients at transition to infliximab therapy in order to prevent a flare.²⁹ Dalaker and Bonesrønning treated 17 patients with infliximab 3 mg/kg + methotrexate 7.5-15 mg/wk, one with infliximab 5 mg/kg + methotrexate, and five patients with infliximab 5 mg/kg + azathioprine 50 mg/day.³⁰ At week 14, 69.6% achieved PASI 75 and 39.1% PASI 90. Two patients on methotrexate + infliximab stopped treatment because of loss of response, one after 14 months and one after 3 years.

Methotrexate

The National Institute for Health and Clinical Excellence (NICE) guidelines recommend concurrent use of methotrexate with infliximab to enhance efficacy, reduce the development of antibodies to infliximab, and in cases where it is need, to associated arthritis.31 Co-administration of methotrexate with infliximab may result in higher infliximab serum levels.³¹

Conclusion

Combination therapy of biologics with topicals, phototherapy, and/or traditional systemics is commonplace and may enhance efficacy including speed of onset and maintenance of response. Moreover, biologics can permit discontinuation or dose reduction of traditional systemic agents. Conversely, traditional systemic agents may permit lowering of the biologic dose. Rather than changing biologic agents, combination therapy should be considered in circumstances of inadequate efficacy or relapses/ flares with monotherapy.

References

1. Guenther L, Gulliver W. Psoriasis comorbidities. J Cutan Med Surg 13(Suppl 2):S77-87 (2009 Sep-Oct).
2. Guenther L, Langley RG, Shear NH, et al. Integrating biologic agents into management of moderate-to-severe psoriasis: a consensus of the Canadian Psoriasis Expert Panel. February 27, 2004. J Cutan Med Surg 8(5):321-37 (2004 Sep-Oct).
3. Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 58(5):826-50 (2008 May).
4. Driessen RJ, Boezeman JB, van de Kerkhof PC, et al. Three-year registry data on biological treatment for psoriasis: the influence of patient characteristics on treatment outcome. Br J Dermatol 160(3):670-5 (2009 Mar).
5. Marquez C, Bair SM, Smithberger E, et al. Systemic retinoids for chemoprevention of non-melanoma skin cancer in high-risk patients. J Drugs Dermatol 9(7):753-8 (2010 Jul).
6. Greenberg JD, Reed G, Kremer JM, et al. Association of methotrexate and tumour necrosis factor antagonists with risk of infectious outcomes including opportunistic infections in the CORRONA registry. Ann Rheum Dis 69(2):380-6 (2010 Feb).
7. Kristensen LE, Gulfe A, Saxne T, et al. Efficacy and tolerability of anti-tumour necrosis factor therapy in psoriatic arthritis patients: results from the South Swedish Arthritis Treatment Group register. Ann Rheum Dis 67(3):364-9 (2008 Mar).
8. Mease PJ, Gladman DD, Ritchlin CT, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a doubleblind, randomized, placebo-controlled trial. Arthritis Rheum 52(10):3279-89 (2005 Oct).
9. Mease PJ, Kivitz AJ, Burch FX, et al. Continued inhibition of radiographic progression in patients with psoriatic arthritis following 2 years of treatment with etanercept. J Rheumatol 33(4):712-21 (2006 Apr).
10. Kavanaugh A, Krueger GG, Beutler A, et al. Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial. Ann Rheum Dis 66(4):498-505 (2007 Apr).
11. Thaci D, Ortonne JP, Chimenti S, et al. A phase IIIb, multicentre, randomized, double-blind, vehicle-controlled study of the efficacy and safety of adalimumab with and without calcipotriol/betamethasone topical treatment in patients with moderate to severe psoriasis: the BELIEVE study. Br J Dermatol 163(2):402-11 (2010 Aug).
12. De Groot M, Teunissen MBM, Picavet DI, et al. Adalimumab in combination with methotrexate more effectively reduces the numbers of different inflammatory cell types in lesional psoriatic skin than does single treatment with adalimumab or methotrexate. Br J Dermatol 158(6):1401 (2008 Dec).
13. Gladman DD, Mease PJ, Ritchlin CT, et al. Adalimumab for long-term treatment of psoriatic arthritis: forty-eight week data from the adalimumab effectiveness in psoriatic arthritis trial. Arthritis Rheum 56(2):476-88 (2007 Feb).
14. Searles G, Bissonnette R, Landells I, et al. Patterns of combination therapy with alefacept for the treatment of psoriasis in Canada in the AWARE study. J Cutan Med Surg 13(Suppl 3):S131-8 (2009 Dec).
15. Alefacept (Amevive®) product monograph. June 1, 2006. Astellas Pharma Canada, Inc., Markham, ON, Canada.
16. Krueger GG, Gottlieb AB, Sterry W, et al. A multicenter, open-label study of repeat courses of intramuscular alefacept in combination with other psoriasis therapies in patients with chronic plaque psoriasis. J Dermatolog Treat 19(3):146-55 (2008).
17. Ortonne JP, Khemis A, Koo JY, et al. An open-label study of alefacept plus ultraviolet B light as combination therapy for chronic plaque psoriasis. J Eur Acad Dermatol Venereol 19(5):556-63 (2005 Sep).
18. Legat FJ, Hofer A, Wackernagel A, et al. Narrowband UV-B phototherapy, alefacept, and clearance of psoriasis. Arch Dermatol 143(8):1016-22 (2007 Aug).
19. Moore A, Wright E, Slay D, et al. Alefacept and low-dose acitretin therapy for inverse psoriasis and palmar/plantar psoriasis shortens the onset of action. Poster 5288 at: 21st World Congress of Dermatology (September 30-October 5, 2007), Buenos Aires, Argentina.
20. Smith EC, Riddle C, Menter MA, et al. Combining systemic retinoids with biologic agents for moderate to severe psoriasis. Int J Dermatol 47(5):514-8 (2008 May).
21. Campione E, Mazzotta A, Paterno EJ, et al. Effect of calcipotriol on etanercept partial responder psoriasis vulgaris and psoriatic arthritis patients. Acta Derm Venereol 89(3):288-91 (2009).
22. De Simone C, D’Agostino M, Capponi A, et al. Combined treatment with etanercept and narrow band UVB phototherapy for chronic plaque psoriasis. Poster 5259 at: 21st World Congress of Dermatology (September 30-October 5, 2007), Buenos Aires, Argentina.
23. Foley PA, Quirk C, Sullivan JR, et al. Combining etanercept with traditional agents in the treatment of psoriasis: a review of the clinical evidence. J Eur Acad Dermatol Venereol 24(10):1135-43 (2010 Oct).
24. Gottlieb AB, Kircik L, Eisen D, et al. Use of etanercept for psoriatic arthritis in the dermatology clinic: the Experience Diagnosing, Understanding Care, and Treatment with Etanercept (EDUCATE) study. J Dermatolog Treat 17(6):343-52 (2006).
25. Zachariae C, Mork NJ, Reunala T, et al. The combination of etanercept and methotrexate increases the effectiveness of treatment in active psoriasis despite inadequate effect of methotrexate therapy. Acta Derm Venereol 88(5):495-501 (2008).
26. Gisondi P, Del Giglio M, Cotena C, et al. Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: a 24-week, randomized, controlled, investigator-blinded pilot trial. Br J Dermatol 158(6):1345-9 (2008 Jun).
27. Yamauchi PS, Lowe NJ. Cessation of cyclosporine therapy by treatment with etanercept in patients with severe psoriasis. J Am Acad Dermatol 54(3 Suppl 2):S135-8 (2006 Mar).
28. D’Angelo S, Cutro MS, Lubrano E, et al. Combination therapy with ciclosporin and etanercept in patients with psoriatic arthritis. Ann Rheum Dis 69(5):934-5 (2010 May).
29. Warren RB, Brown BC, Lavery D, et al. Biologic therapies for psoriasis: practical experience in a U.K. tertiary referral centre. Br J Dermatol 160(1):162-9 (2009 Jan).
30. Dalaker M, Bonesronning JH. Long-term maintenance treatment of moderateto- severe plaque psoriasis with infliximab in combination with methotrexate or azathioprine in a retrospective cohort. J Eur Acad Dermatol Venereol 23(3):277-82 (2009 Mar).
31. Smith CH, Anstey AV, Barker JN, et al. British Association of Dermatologists’ guidelines for biologic interventions for psoriasis 2009. Br J Dermatol 161(5):987- 1019 (2009 Nov).