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.

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

Introduction

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

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

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

Diagnosing HD – Important points to cover

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

Case

Case 1:

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

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

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

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

Case 2:

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

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

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

Case 3:

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

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

Case 4:

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

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

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

Conclusions

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

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

Acknowledgement

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

References

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

Introduction

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

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

Diagnosing HD – Important points to cover:

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

Figure 1.
Examples of hand dermatitis(HD)

Determining if HD is Acute or Chronic

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

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

TIP: Could This Be Tinea?

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

TIP: Could This Be Psoriasis?

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

Prevention, Avoidance and Patient Education

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

Assessing and Encouraging Patient Adherence

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

Emollient Therapy

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

Management of Acute HD

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

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

QoL Consideration

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

Did You Know?

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

Management of Chronic HD

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

Management of Mild CHD

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

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

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

Management of Moderate CHD

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

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

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

Safety Tip

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

When to Refer

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

Management of Severe CHD

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

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

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

Conclusion

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

References

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

¹Memorial University of Newfoundland Faculty of Medicine, St. John’s, NL, Canada
²Nexus Clinical Research, St. John’s, NL, Canada

ABSTRACT

Early diagnosis of psoriatic arthritis (PsA) is essential for preventing disease progression and joint destruction. The majority of patients develop PsA years after the onset of their skin disease. Therefore, dermatologists are in a strategic position to make the diagnosis of PsA, and either manage it or refer the patient to a rheumatologist in order to prevent the potentially irreversible destruction of the affected joints. We will review the presentation and temporal relationship of psoriasis and PsA, the diagnosis, classification, and management, in addition to the role of the dermatologist in the early detection of PsA.

Key Words:
Distal interphalangeal joint (DIP), metatarsophalangeal joint (MTP), psoriasis, psoriatic arthritis, PsA

Psoriatic arthritis (PsA) is often described as a chronic, inflammatory arthropathy affecting the distal interphalangeal joints (DIP) of the hands, metatarsophalangeal joints (MTP)
of the feet, and spine in association with psoriasis.1 One to three percent of the world population has been diagnosed with psoriasis.²

Estimates of the prevalence of PsA within the psoriasis population range from 6%-39%.3 The Psoriasis Foundation 2001 Benchmark Survey estimated the prevalence of PsA in patients with psoriasis to be as high as 23%.⁴ PsA is often under diagnosed or misdiagnosed, and therefore, statistics may be misrepresented.

Clinical Presentation

There appears to be great variability in the case definition for PsA. One such definition, proposed by Moll and Wright, defines PsA as “an inflammatory arthritis associated with
psoriasis and usually with a negative serological test for rheumatoid arthritis.”⁵ Due to the broad spectrum of PsA there has been a need to create subgroups (Table 1).

Characteristic features of psoriatic arthritis include: swelling, erythema, warmth, and inflammation of the affected joint. PsA can present with asymmetrical joint distribution,
involving more joints over time and progressing as an oligoarticular/polyarticular disease. Almost any joint can be involved including peripheral (e.g., the DIPs) and/ or axial joints (e.g., spine and sacroiliac joints). PsA can also manifest with involvement of periarticular structures such as tenosynovitis (inflammation of the tendon sheath), dactylitis or “sausage digit” (inflammation of entire digit), and enthesitis (insertion of the tendon).⁴

As with other sero-negative spondylarthropathies, there can also be extra-articular manifestations of PsA. These features may include inflammation of the eye, mucous
membranes, urinary system, and cardiovascular system (i.e., iritis, conjunctivitis, aortic dilation, and urethritis).⁶

There does not appear to be a difference in the prevalence of psoriasis between the sexes,⁷ however, the onset of disease seems to be earlier in women.⁸ The onset of psoriasis is bimodal with a median age of onset at 29.1 years.⁹ Those with early disease can have a greater body surface area involved, unstable psoriasis, frequent relapses, and a higher incidence of guttate psoriasis and nail involvement.^9,10

Patients with later onset tend to have a more stable course and less severe disease, but more frequent palmoplantar pustulosis.^9,10

The temporal sequence of disease onset can vary, making the diagnosis of PsA difficult. As high as 75%-80% of psoriasis patients will present with cutaneous manifestation 5-10 years prior to the onset of joint complaints.4,11 There can exist a flare in arthritis with or without a coinciding flare of psoriasis.4

The majority of patients with PsA have mild or moderate cutaneous manifestation,12 and 80%-90% of this population have nail lesions.^12,13 However, 46% of patients with psoriasis (no affected joints) have nail involvement.¹³ The extent and severity of both skin and joint disease correlate closely with the severity of psoriatic nail involvement, however this association is more commonly found in the DIP arthritis form of PsA.¹⁴

Differential Diagnosis

Distinguishing PsA from other inflammatory conditions can be challenging since the clinical features may overlap. The differential diagnosis may include: rheumatoid arthritis (RA), reactive arthritis, inflammatory bowel disease (IBD) and ankylosing spondylitis, to name a few. (See Table 2.)

To further complicate matters, other rheumatologic conditions such as osteoarthritis, soft tissue rheumatism, septic arthritis, and true RA can coexist with psoriasis. In addition, psoriasis has been found to occur with higher frequency in patients with IBD and ankylosing spondylitis.^15,16,17

The presence of such confounding variables stresses the importance of a full history and physical examination that includes serological, radiological, and perhaps genetic investigations to aid in the diagnosis.

Making the Diagnosis

There exist several PsA classification criteria in the literature. The Classification criteria for Psoriatic Arthritis (CASPAR) are newly developed criteria for the diagnosis of PsA. They are simple to use, have a high specificity of 98.7%, and a sensitivity of 91.4% for the diagnosis of PsA.18

CASPAR Criteria

A patient must have inflammatory articular disease (joint, spine, or entheseal) with 3 or more of the following 5 criteria:

1. Current OR personal history of psoriasis, OR family history of psoriasis (1st or 2nd degree relative). Psoriasis is defined as skin or scalp disease.
2. Psoriatic nail disease including: onycholysis, pitting, hyperkeratosis on current physical exam
3. Negative for rheumatoid factor (by any method except latex)
4. History of or current dactylitis recorded by a rheumatologist
5. Radiographic evidence of juxta-articular new bone formation, appearing as ill defined ossification near joint margins (but excluding osteophyte formation) on plain radiographs of the hand or foot.

Based on these criteria and established clinical features of PsA, a basic workup for a new patient in your office with psoriasis should include a history, physical examination, laboratory investigations, and review of treatment options as summarized below.

History

• Current OR personal history of psoriasis, OR family history of psoriasis
• Swelling of joints
• Pain or tenderness in joints
• Morning stiffness >30 minutes
• Functional capacity in activities of daily living (changes in ability to function at home and at work and impact on quality of life), etc.

Physical Examination

• Nails: evidence of onycholysis, pitting, hyperkeratosis, oil-drop sign, and nail crumbling
• Skin: see Table 1.

Musculoskeletal

• Signs of joint inflammation such as swelling, effusion, synovial thickening, erythema, decrease in range of movement
• Other manifestations: DIP joint involvement, enthesis, dactylitis, spondylitis and sacroiliitis, eye symptoms (i.e., iritis), etc.
• See Table 1 for other characteristic findings for PsA.

Diagnostic Investigations

• Laboratory tests should include: complete blood count, erythrocyte sedimentation rate, C-reactive protein, Rh factor, and routine renal and liver function tests.
• Plain radiographs: these can be normal in the early stages of disease. However, juxta-articular new bone formation, periarticular osteopenia, and later stages may demonstrate “pencil in cup” erosive disease in the hands or feet.

Treatment

When treating the cutaneous and joint manifestations, as in PsA, each aspect of the disease must be considered. The 2 may be treated independently, although a number of
systemic therapies may benefit both. Treatment options that can improve both PsA and psoriasis include:

1. Traditional systemic agents

• Cyclosporine (3-5mg/kg PO daily)
• Methotrexate (doses ranging from 15-25mg PO/IM weekly)

2. Biologic agents (with indication for PsA)

• Etanercept (50mg SC bi-weekly)
• Infliximab (5mg/kg IV at week 0, 2, 6 and then every8 weeks)
• Adalimumab (40mg SC every 2 weeks)

However, some may help one while adversely affecting the
other. Drugs that can induce disease exacerbation include:²⁰

1. Drugs that treat arthritis, but may worsen psoriasis

• Gold
• Systemic corticosteroids
• Hydroxychloroquine

2. Drugs that treat psoriasis, but may worsen arthritis

• Acitretin
• Efalizumab

The Role of the Dermatologist

The recognition and early treatment of PsA is analogous to that of acne. We are aware of the importance of early recognition of acne and the urgency in treating it aggressively in order to induce remission and prevent further damage. The destruction of the joints in PsA follows the same principle: treat early to prevent the damage. The dermatologist who monitors a psoriatic patient can detect PsA at its earliest stage.

A study by Zanolli and Wikle concluded that a large portion of patients with psoriasis presenting to a dermatologist for treatment were recognized to have coexisting joint complaints; and the prevalence of PsA is greater than that identified by a nondermatologist.²¹

The prevalence of psoriasis is greater than PsA, and psoriasis typically precedes the joint complaints.^4,11,22 Therefore, the dermatologist is in a unique position to screen patients with
psoriasis for PsA by maintaining a high index of suspicion and close follow-up. In limited cases, consultation with a rheumatologist may be necessary to make the diagnosis of PsA.

A screening questionnaire could be designed for patients presenting to the dermatologist for the first time with psoriasis. The Psoriasis and Arthritis Screening Questionnaire (PASQ)²³ that was developed by our group was created using the CASPAR criteria as its framework. This questionnaire does not replace a proper history, but reminds us to consider the diagnosis of PsA in any patient with symptoms of psoriasis, regardless of the severity of the cutaneous
manifestations.

Conclusion

The dermatologist is in a strategic position for early diagnosis, intervention, and appropriate management of the patient with PsA at its onset. The skin and joint involvement
in PsA can significantly affect a patient’s function and quality of life, and may increase cardiovascular morbidity and mortality.²⁴ These effects, in turn, may have significant impact on the family and society in general. Early diagnosis and effective therapy for PsA can prevent the progression of joint damage, and possibly induce a remission of the disease.

References

1. Stern RS. The epidemiology of joint complaints in patients with psoriasis. J Rheumatol 12(2):315-20 (1985 Apr).
2. Myers WA, Gottlieb AB, Mease P. Psoriasis and psoriatic arthritis: clinical features and disease mechanisms. Clin Dermatol 24(5):438-47 (2006 Sep-Oct).
3. Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol 53(4):573 (2005 Oct).
4. Qureshi AA, Husni ME, Mody E. Psoriatic arthritis and psoriasis: need for a multidisciplinary approach. Semin Cutan Med Surg 24(1):46-51 (2005 Mar).
5. Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 3(1):55-78 (1973).
6. Weinstein GD, Gottlieb AB, editors: Therapy of Moderate to Severe Psoriasis, 2nd ed. New York: Marcel Dekker, (2003).
7. Lebwohl M. Psoriasis. Lancet 361(9364):1197-204 (2003 Apr 5).
8. Myers W, Opeola M, Gottlieb AB. Common clinical features and disease mechanisms of psoriasis and psoriatic arthritis. Curr Rheumatol Rep 6(4):306-13 (2004 Aug).
9. Ferrandiz C, Pujol RM, Garcia-Patos V, et al. Psoriasis of early and late onset: a clinical and epidemiologic study from Spain. J Am Acad Dermatol 46(6):867-73 (2002 Jun).
10. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol 13(3):450-6 (1985 Sep).
11. Alenius GM. Psoriatic arthritis-new insights give new options for treatment. Curr Med Chem 14(3):359-66 (2007).
12. Cohen MR, Reda DJ, Clegg DO. Baseline relationships between psoriasis and psoriatic arthritis: analysis of 221 patients with active psoriatic arthritis. Department of Veterans Affairs Cooperative Study Group on Seronegative Spondyloarthropathies. J Rheumatol 26(8):1752-6 (1999 Aug).
13. Gladman DD, Anhorn KA, Schachter RK, et al. HLA antigens in psoriatic arthritis. J Rheumatol 13(3):586-92 (1986 Jun).
14. Williamson L, Dalbeth N, Dockerty JL, et al. Extended report: nail disease in psoriatic arthritis–clinically important, potentially treatable and often overlooked. Rheumatology (Oxford) 43(6):790-4 (2004 Jun).
15. Yates VM, Watkinson G, Kelman A. Further evidence for an association between psoriasis, Crohn’s disease and ulcerative colitis. Br J Dermatol 106(3):323-30 (1982 Mar).
16. Hellgren L. Association between rheumatoid arthritis and psoriasis in total populations. Acta Rheum Scand 15:316-26 (1969).
17. Brockbank J, Gladman D. Diagnosis and management of psoriatic arthritis. Drugs 62(17):2447-57 (2002).
18. Taylor W, Gladman D, Helliwell P, et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 54(8):2665-73 (2006 Aug).
19. Gladman DD. Clinical Manifestations and diagnosis of psoriatic arthritis. In: UpToDate online 2007 version 15.3.
20. Soriano ER, McHugh NJ. Therapies for peripheral joint disease in psoriatic arthritis. A systematic review. J Rheumatol 33(7):1422-30 (2006 Jul).
21. Zanolli MD, Wikle JS. Joint complaints in psoriasis patients. Int J Dermatol 31(7):488-91 (1992 Jul).
22. Thumboo J, Uramoto K, Shbeeb MI, et al. Risk factors for the development of psoriatic arthritis: a population based nested case control study. J Rheumatol 29(4):757-62 (2002 Apr).
23. Kraishi M, Heale C, Landells I, et al. The Psoriasis and Arthritis Screening Questionnaire (PASQ): a sensitive and specific tool to diagnose psoriatic arthritis patients with high correlation to the CASPAR criteria. Accepted for presentation at the 83rd Annual Conference of the Canadian Dermatology Association, June 27-July 2, 2008, Montréal, QC.
24. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA 296(14):1735-41 (2006 Oct 11).

ABSTRACT

Psoriasis is a common dermatosis, affecting children in North America. Many papers have stressed the treatments available for adult psoriasis, but few have dealt with this disorder in children. Topical treatment modalities continue to be the first line therapy for childhood psoriasis. This paper summarizes the general topical treatments available including their clinical use, benefits, cost, and side-effects.

Key Words:
childhood psoriasis, topical treatments

Psoriasis is a common dermatosis affecting 1-3% of the North American population.^1,2 In children it is also very common, representing 4.1% of all childhood skin conditions, and usually occurring after 10 years of age; but 10% occur before age 10, and 2% before 2 years.^3-5 This disorder causes significant morbidity, social embarrassment, and financial burden.²

Childhood Psoriasis

In infants, psoriasis often starts in the diaper area, but a confident diagnosis at this stage is often difficult. Childhood psoriasis tends to be more extensive and severe than that seen in adults.⁶ However, systemic antipsoriatic modalities may have devastating and potentially irreversible side-effects that limit their use in children.⁷ Thus topical therapies are generally preferred in the pediatric population.

It is important to keep in mind that children are not simply small adults. There is a need for child and parental education, compliance, and cooperation. This is why, while being treated, children with psoriasis should be followed closely. Successful psoriasis treatment is a life-long task requiring major contributions from the family and physician, and failure to treat has been shown to have an adverse effect on quality of life in children.⁷

There are five forms of psoriasis: plaque psoriasis, guttate psoriasis, pustular psoriasis, inverse psoriasis and erythrodermic psoriasis. In children, the most common types of psoriasis are the guttate and chronic plaque types. Psoriatic arthritis is seen in approximately 6% of children and adults.^7,8

Signs and symptoms of psoriasis include erythema, scaling, skin thickening, and pruritus. Athorough physical examination should include assessment of joints, scalp, elbows, knees, nails, palms, and soles of the feet.^1,3,9

Triggers

Triggers of psoriasis include comorbid inflammatory diseases (e.g., Crohn’s disease, HIV); emotional stress; withdrawal of systemic corticosteroids; preceding streptococcal infections in the case of guttate psoriasis; climate (northern regions); drugs (e.g., lithium, antimalarials, systemic interferon, and betablockers); and physical trauma (e.g., pressure, friction, rubbing and scratching).^1,10,11 Exacerbating triggers are different in children and adults, with infections and trauma being the most common triggers in children.⁷

Pathogenesis

Psoriasis is a complex disorder that may undergo periods of waxing and waning, recurrence and regression, and involves variable body surface areas. Genetic studies have linked it to several chromosomal loci (HLA-Cw6, 17q25, 4q), and psoriasis is an immunologic disorder leading to secondary hyperproliferation of keratinocytes.¹² The normal turnover rate of keratinocytes from the basal cell layer to the stratum corneum is 28-44 days, but in psoriasis it is reduced to 4 days.² Abnormal keratinocyte differentiation and infiltration of inflammatory cells are also typical features.^11,13 Treatments available are designed to counteract one or more of these features.¹⁴

Treatment Options

Available treatment modalities target keratinocyte hyperproliferation, abnormal keratinocyte differentiation, and infiltration of inflammatory cells. Treatment options for children include:

• Topical treatments, e.g., corticosteroids (mild, mid and high potency agents), keratolytics, anthralins, coal tars, vitamin D analogs, retinoids, ureas, and emollients.^1,9,11,15 Many of these are available as ointments (cutaneous plaques), creams (intertriginous areas) and lotions (scalp) (see Table 1).
• Phototherapy (e.g., UVB with topical adjuvant therapy, topical or systemic PUVA in teenagers). Sunlight and phototherapy can be beneficial if multiple areas are affected, but care must be taken to apply sunscreen to all unaffected areas.
• Systemic therapies for severe, or resistant conditions (e.g., methotrexate, cyclosporine, retinoids, dapsone, hydroxyurea).^1,3,8,9,11

Topical Treatments

Therapy should start with a combination of emollients, topical corticosteroids and calcipotriol, with or without the addition of tar, salicylic acid, and other topical agents.^1,3 For severe or resistant forms systemic modalities should be implemented. The choice of therapeutic agent should be based upon the location and extent of the plaques, the resistance to previous modalities, the various side-effects (see Table 2), and the cost of treatment (see Table 3).¹ As a rule of thumb, ointments are more effective than creams, which are in turn, better than lotions. Other factors influencing the decision include the age of the patient, type of psoriasis, and associated medical disorders.

Topical Corticosteroids

Corticosteroid efficacy is related to potency and absorption into the skin. There are four potency levels: low, mid-, high and ultra. A mild potency corticosteroid should be used for delicate skin, e.g., on the face and genitals. Mid-potency corticosteroids should be used on the torso and extremities, and high potency corticosteroids should be used to treat recalcitrant plaques, as well as the palms and soles. In children, the least potent topical steroid that is effective should be used, and the strength tapered as the condition improves. When used chronically, or at high doses, they can cause skin atrophy, tachyphylaxis, acne, localized hypertrichosis, striae, telangiectasia, and purpura. The may also suppress the Hypothalamic-Pituitary-Adrenal axis.^{1,3,8,11,18,19}

Keratolytics

These preparations act by decreasing the cell-to-cell cohesion as measured by the ease by which layers of cells can be stripped from the surface of treated skin. Excessive use of salicylic acid in children can result in salicylates toxicity. The effect of these ointments in removing scales and relieving the symptoms of dryness is enhanced when used under an occlusive plastic dressing (i.e., saran wrap). Children are sensitive to alphahydroxy acid, and small areas of the skin should be tested before applying it over wide areas. Salicylic acid is commonly used in combination with other topical preparations (e.g., corticosteroids, tars, anthralins, emollients).^{1,3,8,11,18,19}

Anthralins

Anthralins are effective in inhibiting the hyperproliferative growth observed in psoriasis. Although it is an effective agent, it is not an ideal drug because of irritating and staining properties. Regardless of these shortcomings, it is the treatment of choice (in the US) for plaque psoriasis. These agents also have the benefit of synergistic effects when used in combination with UVB therapy, and salicylic acids. Emollients or suitable corticosteroid may be applied after the anthralin treatment has been washed off to potentiate the desired clinical outcome. Common side-effects include brownish staining of the skin, erythema, irritancy, and contact dermatitis.^{1,3,8,11,18,19}

Coal Tar

Tar products have both anti-inflammatory as well as antiproliferative effects. Their benefits are synergistic in combination with steroids, emollients, and especially UVB treatment. Coal tar can also be used effectively as a shampoo for psoriatic scalp lesions. Side-effects include folliculitis, contact allergic dermatitis, aggravation of acne, and photosensitization of the skin. Patients dislike it because it is messy, stains skin, clothing, and bathtubs, and has an unpleasant odor.^{1,3,8,11,18,19}

Table 2: Adverse Effects of Topical Psoriasis Medications ^{1, 3, 8, 11}

Calcipotriol

Calcipotriol, or Vitamin D analogues, act to inhibit proliferation, and promote differentiation of keratinocytes. They are slow acting, however, and results may not be noted for 6-8 weeks. Adverse effects include irritant dermatitis and hypercalcemia with high doses or extensive use. In view of the risk of hypercalcemia and high cost, this preparation is not recommended for patients with extensive psoriasis. However, the vitamin D analogue does not suppress the Hypothalamic-pituitary-adrenal axis, making its use in pediatric patients a good alternative to topical steroids. Calcipotriol has been commercially combined with topical steroids with success, but is not stable if compounded by an independent pharmacy. Pulse topical steroids with maintenance calcipotriol is becoming the standard therapy for mild-moderate plaque psoriasis.^{1,3,8,11,18,19}

Retinoids

Tazorotene and Retin-A® are actively involved in mediating cell differentiation, and decreasing cell proliferation. They are nonsensitizing, nonphototoxic, and nonphotoallergenic. Application is once daily to affected areas only, with clearing occuring in 12 weeks. The most common side-effect is local skin irritation, although pruritis, and photosensitivity may be observed. These agents used orally are teratogenic, and potentially have similar effects at high doses topically.^{1,3,8,11,18,19}

Ureas

Urea is aproteolytic at high concentrations. It is most useful when applied to thickened nails secondary to psoriasis. It has also been added to some topical glucocorticoid preparations and is useful in treating psoriatic plaques and ichthyosis. The most common side-effect experienced by some patients is local irritation.^3,8,18,19

Table 3: Cost (in USD) of topical psoriasis treatments.^20,23
* Cost of 15g of topical steroids (includes drug cost only)
** Cost of 50g or 50ml or 30-day supply — includes drug cost only (excluding topical steroids)

Emollients

Emollients are occlusive agents that make the skin soft and pliable by increasing hydration of the stratum corneum. They act to soften dry skin and relieve itching. Petrolatum is probably the most occlusive and therefore the best emollient available. In terms of efficacy, the more occlusive a preparation is, the more effective it is. In order to be most effective, emollients should be applied to damp skin. There are no reported side-effects, but they may be greasy and sticky, and patients may find it difficult to maintain compliance.^18,19

Cost of Psoriasis Topical Treatment

Competing therapies for the treatment of psoriasis have substantially different cost implications. Clearly, assessment of the cost and benefits of a treatment needs to consider all costs (direct and indirect) as well as objective measurement of benefit (decrease in morbidity) from the patient’s perspective. Topical corticosteroids vary in price from <$7 to >$34USD per month based on potency (cheaper for low potency) and vehicle (lotions more expensive than creams and ointment). The newest topical treatments (retinoids and Vitamin D analogues) can be extremely expensive with monthly costs exceeding $100. Other topical treatment options are comparable in price to the low potency steroids, although combination therapy is commonly used in resistant plaques and costs may become very high.^18,20,21

Conclusion

The treatment of psoriasis in children differs from that in adults. It is important to emphasize educating the family, dealing with emotional aspects of the disease, and eliminating triggering factors. Since psoriasis is a common dermatosis that can adversely affect the lives of children, these patients’ treatment should be active and effective. It is important to point out to patients that psoriasis is not contagious, that the disease can disappear in some cases, and that the doctor is there to help manage the problem. There is no cure, and this disease bears an enormous emotional and financial cost upon children and their families.

References

1. Fitzpatrick TB, Johnson RA, Wolff K. Color Atlas and Synopsis of Clinical Dermatology, Common and Serious Diseases. New York:McGraw-Hill (1997) pp. 76-92.
2. Federman DG, Froelich CW, Kirsner RS. Topical Psoriasis Therapy. Am Fam Physician 59(4):957-62, 64 (1999 Feb).
3. Buxton PK. ABC of Dermatology, 3rd ed. London:BMJ publishing group (1998) pp. 12-15.
4. Oranje AP, Marcoux D, Svensson A. Topical calcipotriol in childhood psoriasis. J Am Acad Dermatol 36(2 Pt 1):203-8 (1997 Feb).
5. Darley CR, Cunliffe WJ, Green CM, Hutchinson PE, Laber MR, Down N. Safety and efficacy of calcipotriol ointment (Dovonex) in treating children with psoriasis vulgaris. Br J Dermatol 135(3):390-3 (1996 Sep).
6. Salleras M, Sanchez-Regana M, Umbert P. Congenital Erythrodermic Psoriasis: Case Report and Literature Review. Pediatr Dermatol 12(3):231-4 (1995 Sep).
7. Burden AD. Management of psoriasis in childhood. Clin Exp Dermatol 24(5):341-5 (1999 Sep).
8. Sauer GC, Hall JC. Manual of Skin Diseases, 7th ed. Philadephia (PA):Lipincott-Raven Publishers (1996) pp.138-143.
9. Bork K, Brauninger W. Diagnosis and Treatment of Common Skin Diseases. Philadephia (PA):W.B. Saunders Company (1988) pp.120-121.
10. Seyger MM, van de Kerkhof PC, van Vlijmen-Willems IM, de Bakker E, Zwiers F, de Jong EM. The efficacy of a new topical treatment for psoriasis: Mirak. J Eur Acad Dermatol Venerol 11(1):13-8 (1998 Jul).
11. Pardasani AG, Feldman SR, Clark AR. Treatment of Psoriasis: An Algorithm Based Approach for Primary Care Physicians. Am Fam Physician 61(3):725-33 (2000 Feb).
12. Bhalerao J, Bowcock AM. The genetics of psoriasis: A complex disorder of the skin and immune system. Hum Mol Genet 7(10):1537-45 (1998 Apr).
13. Weinstein GD, Keueger GG, Lowe NJ, et al. Tazarotene gel, a new retinoid, for topical thrapy of psoriasis: Vehicle-controlled study of safety, efficacy, and duration of therapeutic effect. J Am Acad Dermatol 37(1):85-92 (1997 Jul).
14. Hagemann I, Proksch E. Topical treatment by urea reduces epidermal hyperproliferation and induces differentiation in psoriasis. Acta Derm Venerol 76(5):353-6 (1996 Sep).
15. Bondi EE, Jegasothy BV, Lazarus GS. Dermatology: Diagnosis and Therapy. Norwalk (CN):Appleton and Lange (1991) pp. 14-20.
16. Baker H, Pegum JS. Clinical Dermatology, 4th ed. London: Bailliere-Tindall Publishers (1989) pp.104-106.
17. Dezfoulian, B., et al., A new generation of hydrocolloid dressings in combination with topical corticosteroids in the treatment of psoriasis vulgaris. J Eur Acad Dermatol Venerol (1997).
18. Freedberg IM, Fitzpatrick TB. Fitzpatrick’s Dermatology in General Medicine, 5th Edition. NY:McGraw-Hill (1999).
19. Roenigk HH, Maibach, HI. Psoriasis, 3rd Edition, Revised and Expanded. NY:Marcel Decker, Inc. (1998).
20. Marchetti A, LaPensee K, An P. A Pharmacoeconomic analysis of topical therapies for patients with mild-to-moderate plaque psoriasis: A U.S. study. Clin Ther 20(4):851-69 (1998 Jul-Aug).
21. Gray J, Gillis AM, editors. Therapeutic Choices, 3rd edition. Ottawa: Canadian Pharmacists Association (2000).

ABSTRACT

Although hemangiomas are frequently encountered in pediatric practice, their management has been controversial because they are notoriously unpredictable, especially in early infancy. In the past, clinicians believed that infant and childhood hemangiomas were best left untreated, due to spontaneous involution and the adverse effects of treatments such as radiotherapy and surgery.¹ However, today there is an increased awareness of both the physical and psychological sequelae associated with hemangiomas, a small percentage of which can be life threatening and this has resulted in a renewed push to treat them. Furthermore, therapeutic advances have been made, and new therapies are on the horizon.

Key Words:
active non-intervention, hemangiomas, PHACES Syndrome

Hemangiomas, benign tumors of infancy, occur in 1-2% of newborns and up to 10% of children aged ≥ 1 year.² Fifty five percent present at birth, while the rest develop within the first few weeks of life. They are more commonly found in premature infants weighing less than 1500gm,² and a female’s chance of being affected is three times greater than a male’s.³

Typically, hemangiomas begin as pale blue-red macules with superficial telangiectases. Over the next 8-14 months they proliferate rapidly into bright red elevated plaques if they are superficial. If they lie deeper within the skin they appear as a bluish nodule. They are most commonly a combination of both.^3,4 The proliferative phase is followed by slow involution, and almost all hemangiomas resolve spontaneously over time. By 5 years of age, 50% of hemangiomas involute, 70% by age 7, and 90% by age 9.^2,3 Approximately 20-40% leave residual changes in the skin, which can have a lasting psychological effect. Approximately 10% require treatment, and less than 1% are life threatening. Hemangiomas are usually solitary, but up to 20% of affected children have multiple lesions.³

Past and Current Therapies

Historically, the treatment of hemangiomas usually involved surgical excision or radiation. Today, while it is recognized that most hemangiomas do not need treatment, ‘active nonintervention’, rather than ‘benign neglect’ is advised.¹ Before and after photographs are extremely helpful in reassuring parents of the natural involution of this phenomenon.³

Hemangiomas that threaten life or an important bodily function, such as vision or the airway, do require intervention. Recognizing high risk hemangiomas and being aware of all possible associated malformations, e.g., PHACES syndrome (Posterior fossa malformations, Hemangiomas of the cervicofacial region, Arterial anomalies, Cardiac anomalies, Eye anomalies and Sternal or abdominal clefting or ectopia cordis), is essential to ensure the patient receives the most appropriate treatment and to reduce sequelae. For example, midline hemangiomas can be markers for occult spinal malformations, and anomalies of the anorectal and urogenital regions. Consequently, spinal imaging should be done.³

For management, a multidisciplinary approach is best, including dermatology, pediatrics, plastics and radiology.² In the more severe cases, psychological and social support services can also be helpful. Essentially, the type and location of hemangioma, the associated complications, as well as the patient’s age should guide the treatment.

Hemangiomas That Require Treatment

Lesions that require treatment include:

• life and function threatening hemangiomas, e.g., those causing impairment of vision, Kasabach-Merritt coagulopathy, respiratory compromise, congestive heart failure, hepatic involvemen
• hemangiomas in certain anatomic locations that often leave permanent scars or deformity, especially the nose, lip, ear, and glabellar area
• large facial hemangiomas, especially those with a prominent dermal component (more likely to leave permanent scarring)
• smaller visible hemangiomas, (e.g., the face and hands) may be considered for treatment with modalities unlikely to cause scarring or significant side effects
• ulcerated hemangiomas
• pedunculated hemangiomas (likely to leave significant fibrofatty tissue after involution)
• hemangiomas that are psychologically disturbing, such as lesions on the face, hands and feet.²

Treatment

Corticosteroids

While the mechanism of action for corticosteroids is unknown, there are data to suggest that vasoconstriction of arterioles and precapillaries may be responsible, and it has been suggested that steroid therapy works by increasing the sensitivity of arterioles and precapillaries to other, physiologically occurring vasoconstrictive agents.⁵ Certain steroids inhibit angiogenesis in the presence of a fragment of heparin. Triamcinolone reduced the transcription of the growth factors, PDGF-A and -B, IL-6, TGF- β1 and – β3. Furthermore, there was up-regulation of the mitochondrial cytochrome b gene expression.⁶

Superficial hemangiomas requiring treatment, with the exception of those affecting vision or causing respiratory distress, are generally treated with either localized use of corticosteroids (potent topical or intralesional) or with pulsed dye laser.¹

The use of triamcinolone, 20mg/ml, can be used as intralesional corticosteroid therapy for any small, bossed, facial hemangioma. The drug should be injected at low pressure, using a 3ml syringe and 25-gauge needle.⁷ The dose should not exceed 3-5mg/kg per procedure. Treatment in the periocular region is contraindicated except by an experienced ophthalmologist, as there is a risk of embolic occlusion of the retinal artery or oculomotor nerve palsy.³

During the injection of any facial lesion, the surrounding tissue should be compressed, either digitally or with the finger ring of an instrument. Usually three to five injections are needed, given at 6-8 week intervals. The response rate is similar to that for systemic corticosteroids. If there is necrotic tissue and/or secondary infection, the injections should not be undertaken.⁷

Resulting complications have been few, although serious consequences may result. Shorr and Seiff⁸ reported a case of central retinal artery occlusion due to retrograde blood flow. This resulted from the force of injection or digital pressure, which in turn propelled steroid suspension particles into the central retinal artery. Full thickness eyelid necrosis may be related to spontaneous thrombosis within the lesion. Linear subcutaneous fat atrophy following lymphatic channels has been reported, but remits spontaneously.⁹

As a mainstay of treatment for serious cases, the most common choice is oral prednisone, at a dosage of 2-4mg/kg/day given either in a single morning dose or divided doses in emergent cases. Within days approximately 1/3 of affected infants exhibit dramatic shrinkage of the hemangioma. Stabilization of growth without measurable shrinkage can be seen in another third, and minimal or no effect in the final third. Increasing the dosage does not enhance results in situations where there is poor response. If effective, corticosteroids must be continued for the entire anticipated proliferative phase or regrowth will occur.^1,3,4

Infants treated with systemic corticosteroids need to be observed for adverse effects such as growth retardation, blood pressure elevation, insulin resistance, and immunosuppression. Moon facies have been recorded as a side effect of prednisone. However, they disappear shortly after treatment is completed.⁵

Table 1: Possible complications caused by hemangiomas.³

Interferon Alpha

Although interferon alpha has shown very promising results, there have been reports of neurotoxicity,⁴ and it should be reserved for use only in life threatening cases where high-dose corticosteroid treatment has failed.³ It has a limited role in treating subglottic hemangiomas.

Both interferon alpha-2a and alpha-2b are usually administered as a subcutaneous (SC) injection of 3 million U/m² of body-surface area per day.³ Regular neurological monitoring before and during treatment is mandatory.⁴ For high-risk hemangiomas SC interferon alpha-2a should be given, at an initial dose of 1 million U/m²/day, which is then increased to 3 million U/m²/day if tolerated.²

Common side effects, including irritability, neutropenia, liver enzyme abnormalities, and spastic diplegia, were recently reported in 20% of patients.³

Pulsed Dyed Laser

Flash-lamp-pumped pulsed dye laser works well for small, superficial lesions and for some large, plaque-like lesions. However, there is only a brief window of opportunity during infancy when hemangiomas are thin enough to be effectively treated with this laser, because its penetration is limited to approximately 1.2mm. It can improve residual telangiectases after involution. Though it has not been proven reliable in eliminating ulcerated hemangiomas, this treatment can result in reduced pain and prompt reepithelialization.¹

Rarely, laser treatments can induce ulceration, and shallow scars may develop, even at relatively low fluences. For unknown reasons, this type of scarring seems to occur more commonly in infants with hemangiomas than in infants with port wine stains.¹

Intralesional Laser Therapy

In one study the ND:YAG laser was reported to be useful for treating large capillary/cavernous hemangiomas, often rendering an inoperable lesion safely resectable, or markedly decreasing the size and functional impact of the lesion.¹⁰

Surgical Excision

The benefits and risks of surgery must be weighed carefully, since the scar may be worse than the results of spontaneous regression.³ Generally, it is recommended that a re-evaluation be done when the child is 4 years old, in order to assess the potential benefit of excision. Factors such as the extent of residual hemangiomas must be considered if:

• the involution is slow
• there is post ulcerative scarring, unalterably expanded skin, or a high probability of fibrofatty residuum
• surgery is likely to have a good result.¹

Surgery is especially good for small, pedunculated hemangiomas and occasionally, in cases where there may be functional impairment. It is usually used to repair residual cosmetic deformities.³ Nasal and labial hemangiomas seem to involute more slowly. In the case of nasal tip hemangioma, the tumor can be debulked using unilateral/bilateral rim incisions, which allow the skin to contract by whatever elasticity remains.⁷ General anesthesia is usually required for children younger than 10 years of age, but older patients can sometimes be managed with local anesthesia.⁷

Other treatment modalities

In exceptional cases, when earlier therapies have failed cyclophosphamide, embolization, radiotherapy, and sclerotherapy may be considered. A recent study evaluated the use of sclerotherapy for treating hemangiomas over a period of 20 years (1975-1995). A total of 157 patients found it to be a relatively simple, inexpensive, and effective form of therapy. In the study, sclerotherapy with polidocanol was carried out on monstrous or rapidly growing cavernous hemangiomas that were mainly localized on the face. The results showed that one to three injections were sufficient to maintain the sclerosis effect and long-term aesthetic results were encouraging. No severe complications were observed.¹¹ Evolving therapies include leuprolide acetate, a GnRH agonist with antiproliferative effects, ketotifen (Zaditor®, Zaditen®, Ciba Visions/Novartis), new selective lasers, and new angiogenesis inhibitors. ²

Major goals of treatment

When treating a hemangioma, the major goals should include:

• prevention or reversal of any life-threatening or functionthreatening complications
• prevention of permanent disfigurement left by residual skin changes after involution
• minimization of psychosocial distress from the presence of hemangiomas for the patient and his/her family
• avoidance of aggressive, potentially scarring procedures for treatment of those hemangiomas likely to have an excellent prognosis without therapy
• prevention or adequate treatment of ulcerated hemangiomas to minimize scarring, infection, and pain.²

Conclusion

Most hemangiomas require no treatment. However, active nonintervention is recommended in order to recognize those that may require treatment quickly. When treatment is undertaken, it is important that it be customized to the individual patient, and that the possible physical, and psychological complications be discussed in advance. Often, a multidisciplinary approach is recommended. In cases where treatment must be undertaken, it is important that it not be delayed. Rapid tapering or discontinuation of treatment in the proliferative phase should be avoided.

References

1. Frieden IJ. Which hemangiomas to treat – and how? Arch Dermatol 133:1593-5 (1997 Dec).
2. Frieden IJ, Eichenfield LF, Esterly NB, Geronemus R, Mallory SB. Guidelines of care for hemangiomas in infancy. AAD Guidelines/Outcomes Committee. J Am Acad Dermatol 37(4):631-7 (1997 Oct).
3. Drolet BA, Esterly NB, Frieden IJ. Hemangiomas in children. N Engl J Med 341(3):173-81 (1999 Jul).
4. Drolet BA, Esterly NB, Frieden IJ. Hemangiomas in children. N Engl J Med 341(3):173-81 (1999 Jul).
5. Sadan N, Wolach B. Treatment of hemangiomas of infants with high doses of prednisone. J Pediatr 128(1):141-6 (1996 Jan).
6. Hasan Q, Tan ST, Gush J, Peters SG, Davis PF. Steroid therapy of a proliferating hemangioma: histochemical and molecular changes. Pediatrics 105(1 Pt 1):117-20 (2000 Jan).
7. Roberts LJ. Management of hemangiomas. Pediatr Dermatol 14(1):57-83 (1997).
8. Shorr N, Seiff SR. Central retinal artery occlusion associated with periocular corticosteroid injection for juvenile hemangioma. Ophthalmic Surg 17(4):229-31 (1986 Apr).
9. Reyes BA, Vazquez-Botet M, Capo H. Intralesional steroids in cutaneous hemangioma. J Dermatol Surg Oncol 15(8):828-32 (1989 Aug).
10. Burstein FD, Simms C, Cohen SR, Williams JK, Paschal M. Intralesional laser therapy of extensive hemangiomas in 100 consecutive pediatric patients. Ann Plast Surg 44(2):188-94 (2000 Feb).
11. Winter H, Drager E, Wolfram S. Sclerotherapy for treatment of hemangiomas. Dermatol Surg 26(2):105-8 (2000 Feb).