¹Scientific Insights Consulting Group Inc., Mississauga, ON, Canada
²Sunnybrook Health Sciences Centre, Toronto, ON, Canada
³University of Toronto, Toronto, ON, Canada

Conflict of interest:
Bonnie Kuehl has consulted for and accepted consulting fees from Aralez Pharmaceuticals and LEO Pharma Canada; Neil Shear has been a consultant/speaker for AbbVie, Celgene, Valeant, Lilly, Novartis, Janssen, LEO Pharma, and Sanofi Genzyme.

Abstract
Most people with mild-to-moderate psoriasis manage their disease with topical therapies. However, adherence to topical treatment remains a challenge, as the daily application creates a significant treatment burden. New topical therapeutic options need to offer higher efficacy and better patient acceptability, including easier application, to reduce treatment burden and enhance patient adherence. Topical foam vehicles are innovative alternatives to creams and ointments, addressing many patient challenges with traditional vehicles. Well-designed foam vehicles are easily spread over large areas of the skin, while importantly not leaving a greasy or oily film on the skin after application. Calcipotriol/betamethasone dipropionate aerosol foam is a new psoriasis treatment option that is rapidly effective, offers greater efficacy versus ointment and gel formulations, and has been shown to increase patient treatment satisfaction. Hence, by addressing the several crucial unmet clinical needs in patients with mild-to-moderate psoriasis, this optimized foam formulation is poised to improve treatment follow-through.

Key Words:
calcipotriol/betamethasone dipropionate, drug delivery, vehicle, aerosol, foam, psoriasis, topical

Introduction

Psoriasis is an immune disorder that most commonly manifests itself with visible plaques on the skin, resulting in considerable morbidity for those affected. The World Health Organization characterizes psoriasis as “a chronic, non-communicable, painful, disfiguring and disabling disease for which there is no cure.”¹ The majority of patients are classified as having mild-moderate disease with an estimated 20% having moderate-severe disease.² In a multinational survey (US, Canada, France, Germany, Italy, Spain, UK), dermatologists acknowledged that psoriasis is undertreated with an ongoing unmet treatment need for patients.³ In the survey, dermatologists reported not initiating or maintaining treatment due to concerns regarding the long-term safety, tolerability and efficacy of currently available therapies.³ The MAPP survey (population-based survey of psoriasis and/or psoriatic arthritis patients in North America and Europe) revealed that the majority of psoriasis patients are undertreated; >80% of patients with ≥4 palms body surface area (BSA) were receiving no treatment or topical treatment only. Further, 57% who received oral therapy and 45% who received biologic therapy discontinued treatment, citing safety/tolerability concerns and a lack/loss of efficacy.⁴

As with any chronic disease, patient adherence to topical psoriasis therapy is low. The high burden of treatment and the substantial effort required to maintain ongoing therapy leads to treatment fatigue. According to published data, approximately 75% of patients³ with psoriasis vulgaris (plaque psoriasis), regardless of severity, manage their disease with topical therapies, which may lead to quicker treatment fatigue as the daily treatment regimen can be cumbersome and time consuming.² Studies in medication adherence in psoriasis have shown that 39-73% of patients do not use their medication as prescribed.^5-7 Factors influencing adherence include patient specific characteristics, disease-related characteristics, treatment satisfaction, cosmetic acceptability and complexity of treatment protocols.⁸ Studies also report that cosmetic acceptability is a key contributor to adherence, with adherence being reduced if treatments are perceived as messy to apply and sticky on the skin.⁹ There is evidence that low adherence to psoriasis therapies may be related to insufficient instruction on how to use the drug, misperceptions regarding possible adverse events (AEs) and mistaken expectations about the speed and degree of improvement.¹

A challenge to the use of currently available topical therapies is that many patients fail to achieve complete or almost complete clearance of their psoriasis.¹⁰ Increasing awareness of the burden of psoriasis and the psychosocial impact of the disease have underscored the clinical need for a topical therapy that is easy to use, cosmetically appealing, rapidly efficacious with short-term use, as well as be able to induce sustained efficacy for long-term maintenance.^8,10

Rationale for New Topicals in Psoriasis

Topical treatment of skin conditions is an ancient technique meant to soothe and cool the skin. This practice transitioned into a scientific technique in the 19th century with evidence demonstrating that topically applied agents could impact the skin and offer systemic benefits. A growth in the understanding of skin architecture, topical drug formulation and drug delivery resulted in the ongoing development of topical therapies to address visible skin injury and dermal delivery, ideally optimizing directed delivery of an applied drug. Traditionally, topical therapy carrier vehicles were developed empirically by combining favorite and known ingredients affecting the percutaneous absorption of the drug/active ingredient. There was little consideration of cosmetic acceptability and limited knowledge of the skin penetration/ permeation of the drug at the target site. New materials and a greater understanding of product formulation and consumer acceptability have led to the identification of criteria that constitute the “ideal” vehicle, which include properties such as easy application and removal, nonirritating/nonallergenic, chemically stable, homogenous, bacteriostatic, cosmetically acceptable, pharmacologically inert, and ability to rapidly release the drug for enhanced, controlled or targeted absorption.^11,12

With the knowledge that the topical carrier vehicle can influence the performance of the drug, as well as have a direct effect on the appearance and condition of the skin barrier, new vehicle compositions have been developed. These new vehicles offer improved control of application, increased skin absorption, and the maintenance or improvement to the skin barrier.¹³ Beyond this, compounds of active ingredients with new agents need to offer a combination of higher efficacy and better patient acceptability compared with currently available therapies in order to enhance patient adherence.¹⁰ A simplified dosing schedule, such as once per day, and rapid onset of observed effect are key factors that can improve adherence to topical therapies.^14,15

More important than the carrier or the delivery vehicle, the primary consideration is the active drug and its impact on the inflammatory process responsible for psoriasis. The immune pathogenesis of psoriasis involves dendritic cells, T-cells, keratinocytes and a diverse group of inflammatory mediators (chemokines, cytokines, antimicrobial peptides) that further amplify the inflammatory response and trigger the hyperproliferation of keratinocytes. Once activated, this inflammatory process results in the development of painful, itchy, erythematous plaques covered in silvery scales.¹⁶

Vitamin D receptor agonists (e.g., calcipotriol) and glucocorticoids (e.g., betamethasone dipropionate) have shown benefit in treating psoriasis. Glucocorticoids are known potent anti-inflammatory agents that block multiple anti-inflammatory pathways. Vitamin D receptor agonists appear to enhance the immunosuppressive activity of regulatory T-cells, driving T-cells toward a T helper 2 (Th2) profile while inhibiting Th1/Th17 cells. Calcipotriol has been shown to normalize the pro-inflammatory cytokine cascade in psoriasis, ultimately interrupting the pro-inflammatory feedback loop that drives disease pathogenesis.^17,18 Recent data further supports the benefit of combining betamethasone with calcipotriol. The combination of the two agents showed additive effects, inhibiting the secretion of interleukin (IL)-17A and tumor necrosis factor (TNF)-α by dendritic cells and CD4+ and CD8+ T-cells, as well as reducing the inflammatory response of stimulated keratinocytes. This cellular data supports the enhanced clinical efficacy observed with the combination product, compared to the respective monotreatments in psoriasis patients.¹⁷

Vehicle – Getting it Right

When considering topical dermatological treatment, formulators, clinicians and consumers place extraordinary importance on the type of formulation (i.e., principle of the structural matrix – cream, ointment, solution, foam) and the individual excipients of the topical preparations. This importance has been driven by the visibility of the application site, texture and feel of the applied product on the skin, as well as ease of use. The excipients are responsible for enhancing penetration/permeation of the active ingredients, skin hydration, occlusiveness and stability of the topical preparation. The formulation type is equally important as it impacts several aspects of the topical preparation including: cosmetic acceptability (greasiness, messiness, stickiness, visibility on skin and tactile sensation); ease of use/convenience (spreadability, time required for application and drying, staining of clothes/bedding); and potency of the topical preparation. Clinically, the key question is which formulation types (creams, gels, ointments, foams or liposomes) are better at delivering a drug to the skin, promoting cutaneous absorption and potentially leading to enhanced clinical efficacy. Drug delivery is controlled by the vehicle excipients as these impact partitioning of the active ingredients into, and diffusion through, the stratum corneum (absorption and penetration).^12,19 Traditionally, the choice of vehicle for a particular disease was governed by a classification of preparations and disease/patient factors (e.g., location of disease, skin type, type of disease). The evolution and development of new chemical combinations and entities have driven the need for advancements in vehicle delivery. Thus, modern formulations should be able to facilitate enhanced drug delivery to different layers of the skin as well as extend the release time/activity of delivered drugs.¹²

Foam vehicles were developed to address several needs beyond the effective delivery of active ingredients. The formulation also needs to spread easily on large areas of the skin; not require excessive rubbing into already damaged sensitive skin; not leave a greasy or oily film on the skin after application; and not impart a greasy feeling. Foams are an innovative and easy to apply alternative to creams and ointments. Importantly, with any topical vehicle, the excipients should support the stability and delivery of the active ingredients with the additional benefit of helping repair the skin barrier.¹³ Foams are unique delivery vehicles as they are essentially colloids composed of two or three distinct phases: hydrophilic liquid continuous phase with a foaming agent, throughout which a gaseous dispersion phase is distributed, and sometimes a third hydrophobic dispersed phase. Pharmaceutical aerosol foams commonly exhibit three transition states: liquid in the can, propellant/aerosol as it leaves the can and foam on the skin of the patient.²⁰

In the treatment of psoriasis, the fixed combination of calcipotriol and betamethasone as dipropionate (Cal/BD), in either ointment or gel formulations, has shown superior efficacy and improved acceptability compared with the individual active ingredients.^21,22 The rationale behind the development of the fixed dose combination of Cal and BD (as dipropionate) was to allow the delivery of small amounts (0.005% and 0.05%, respectively) of two very potent drugs within a single formulation. Betamethasone dipropionate is available as micronized particles and can be easily suspended homogeneously whereas calcipotriol, present in a much lower concentration, needs to be dissolved in a carefully selected vehicle component to ensure an even distribution.^23,24 While the fixed dose combinations are established first-line therapies for plaque psoriasis, adherence to the ointment formulation remains a significant challenge as the daily treatment regimen can be cumbersome and time consuming.¹⁰

To address patient needs for an easy to apply topical vehicle offering efficacy in psoriasis – an innovative aerosol foam formulation containing calcipotriol and betamethasone in a fixed dose combination was developed. The Cal/BD aerosol foam is a pressurized formulation including an emollient vehicle base, with calcipotriol and betamethasone dissolved in a mixture of volatile propellants, butane and dimethyl ether. Dimethyl ether also acts as a solvent that enhances the solubility of the active ingredients allowing them to completely dissolve, which is in contrast to the ointment and suspension formats.²⁵ Laboratory assays show that the propellants evaporate rapidly after being sprayed on paper, with the calcipotriol and betamethasone remaining completely dissolved in solution (i.e., crystals are absent) creating a stable, supersaturated environment. Further, studies have also demonstrated that the individual components, Cal and BD, in the Cal/BD aerosol foam had significantly greater in vitro skin penetration and increased ex vivo skin permeation (penetration through all skin layers) compared with Cal and BD in the Cal/BD ointment. This is thought to be due to the development of the stable supersaturated solution, leading to greater solubility and skin penetration of the active ingredients, expected to lead to increased skin permeation and increased absorption of actives at the site of action.²⁵

Discussion

The Cal/BD foam has been compared with established topical combination products as well as the individual active ingredients in an extensive clinical trial program. In most studies, the primary efficacy endpoint was “treatment success” as defined by the proportion of patients who were clear or almost clear of psoriasis according to the physician’s global assessment of disease severity (PGA) at week 4, with at least a two-step improvement. Phase II and III studies have demonstrated significantly greater treatment success and at least a 75% reduction in modified psoriasis area and severity index (mPASI75) of the Cal/BD aerosol foam compared to foam vehicle, calcipotriol alone and betamethasone alone, Cal/BD ointment and Cal/BD gel (Table 1) in the treatment of adult patients with psoriasis on the body. The PSO-FAST study demonstrated an early (day 3) significantly greater itch relief and improvement in itch-related sleep loss compared with vehicle in patients receiving the Cal/BD aerosol foam, which was maintained for the remainder of the study.^26,27 These findings are thought provoking as they demonstrate that therapy alleviated common and distressing aspects of psoriasis, including scratching in response to itchiness that can aggravate lesions and sleep loss that can impact daily productivity.³⁰

These studies also showed a significant impact on patient quality of life (QoL) with reductions in Dermatology Life-Quality Index (DLQI) scores. The use of Cal/BD aerosol foam resulted in a significantly greater improvement in DLQI at week 4 versus either the foam vehicle or the Cal/BD gel. DLQI scores of 0/1 achieved by Cal/BD aerosol foam versus Cal/BD gel were, respectively, 46% versus 32% (P=0.013) at week 4 and 61% versus 44% (P=0.03) at week 12.^27,31

Phase II/III studies with the Cal/BD aerosol foam have shown that this new topical agent is efficacious and well accepted in adult patients with psoriasis vulgaris for up to a 4-week treatment period. The safety profile is in alignment with the more established Cal/BD fixed combination ointment. Safety of the Cal/BD aerosol foam versus gel for up to 12 weeks of treatment has been demonstrated in a Phase III trial. Pooled-analysis of the Phase II/III clinical studies showed that the most common AEs with the Cal/BD aerosol foam were nasopharyngitis (n=6, 1.1%) and application-site pain (n=4, 0.7%).^24,26,28 Notably, the Cal/BD aerosol foam has a safety and tolerability profile similar to Cal/BD ointment and the individual active ingredients, demonstrating that the superior efficacy of the aerosol foam does not impact tolerability.¹⁰

The Phase II maximum use systemic exposure (MUSE) study in 35 patients with extensive psoriasis vulgaris (covering 15-30% BSA, with at least 30% scalp involvement), demonstrated that the Cal/BD aerosol foam had no clinically relevant impact on the hypothalamic-pituitary-adrenal (HPA) axis, calcium homeostasis or renal function, demonstrating low systemic absorption of Cal and BD.³²

While long-term data for the Cal/BD aerosol foam is yet to come, 52-week data from the Cal/BD ointment demonstrated that no patients experienced HPA axis suppression and that the fixed dose combination is safe and well tolerated when used longterm.^33-35

Treatment failure, poor clinical outcomes and increased healthcare utilization have been linked to non-adherence to treatment as well as physician recommendations. Adherence to topical agents is related to duration of treatment, complexity of the treatment regimen, as well as patient self-image and QoL.^8,36 Demands associated with disease management can create a significant treatment burden for patients with chronic diseases. This burden combined with general life demands (e.g., job, family) comprises the overall patient workload. Treatment fatigue is common, with disengagement from recommended health behaviors when a person’s workload exceeds their capacity, a primary contributing factor to non-adherence.³⁷ With topical dermatologic products, studies suggest that patients prefer and are more adherent to, certain topical vehicles based on convenience and cosmetic acceptability.³⁸

When considering cost of therapy, it is important to remember both direct (e.g., prescription drug costs, physician visits, treatment in day clinics) and indirect costs (e.g., loss of time from work, loss of income, non-prescription drug costs). These costs are likely exacerbated by non-adherence to medication. In psoriasis particularly, QoL is adversely affected with people coping by avoiding social situations and covering their lesions.⁸ An Ontario study found that greater out-of-pocket expenses was related to a higher rate of cost-related non-adherence.³⁹

Conclusion

The efficacy of a fixed-dose Cal/BD combination is well established in patients with mild-to-moderate psoriasis. With the ongoing clinical challenge of achieving optimal control and adherence to treatment, the Cal/BD aerosol foam was developed to increase the therapeutic options available. The data supports that the Cal/BD aerosol foam offers enhanced efficacy due to improved skin penetration of the active ingredients after the formation of a stable supersaturated solution on the skin. With its further favorable impact on itch and quality of life, this foam formulation has the potential to improve adherence by addressing several unmet needs in patients with psoriasis.

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

Introduction

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

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

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

Diagnosing HD – Important points to cover

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

Case

Case 1:

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

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

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

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

Case 2:

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

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

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

Case 3:

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

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

Case 4:

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

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

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

Conclusions

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

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

Acknowledgement

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

References

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16. Toctino® (alitretinoin) soft capsules (product monograph on the Internet). Mississauga (ON): GlaxoSmithKline Inc, Distributed by Actelion Pharmaceuticals Canada, 2016 [revised 04 APR 2016].
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18. Green C, et al. Br J Dermatol. 1992 Jul;127(1):5-9.
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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]

1. Division of Clinical Pharmacology, 2. Department of Medicine , 3. HOPE Research Centre,
4. Department of Pharmacology, 5. Department of Pharmacy, 6. Division of Dermatology,
University of Toronto, Toronto, ON, Canada

ABSTRACT

Intravenous immunoglobulin (IVIG) has been proposed as a treatment for toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS). A number of retrospective and prospective studies have been conducted, with varying levels of evidence for the efficacy of IVIG. Recent publications provide opposing conclusions. A multi-center, comparative, long-term analysis needs to be conducted to determine the role of IVIG in the management of patients with SJS/TEN.

Key Words:
Intravenous immunoglobulin, IVIG, toxic epidermal necrolysis, TEN, Stevens-Johnson Syndrome, SJS

The terms erythema multiforme (EM), Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have become entangled and confusing over time. Current concepts support EM as a specific disease that is different from the SJS/TEN spectrum. SJS and TEN represent different degrees of a severe, acute mucocutaneous reaction that often can be caused by drugs.¹ TEN or SJS is diagnosed objectively according to a consensus-derived definition.² The differentiation between SJS and TEN is determined based on the percentage of body surface area (BSA) affected: SJS is characterized by mucous membrane erosions and blisters on less than 10% of the total BSA, whereas TEN involves more than 30% of the total BSA.² Important prognostic factors for SJS/TEN include the percentage loss of BSA, age, heart rate, cancer/hematologic malignancy, urea, bicarbonate, and glucose serum levels.³

Clinical Features

SJS/TEN is most commonly characterized by skin changes (scattered 2-ring target-like lesions with a dark red centre and lighter red halo, red macules with central blistering that can coalesce to larger areas of denuded skin), hemorrhagic mucositis (mouth, eyes, genitals, and respiratory tract), and systemic symptoms (fever, malaise, possible internal organ involvement).¹ In severe TEN cases, fingernails and toenails, eyebrows and cilia may be lost as well. There may be extensive involvement of the gastrointestinal tract and respiratory tract. Sepsis and respiratory distress are the most common complications and ultimately the direct causes of death.

Survivors of SJS/TEN may experience numerous long-term sequelae; the most disabling are those involving the eyes. Cicatrization of conjunctival erosions may lead to inverted eyelashes, photophobia, burning sensation in the eyes, watery eyes, a siccalike syndrome, and corneal and conjunctival neovascularization. As many as 40% of survivors of TEN have residual, potentially disabling lesions on the eye and/or surrounding area, that may cause blindness.

Epidemiology

TEN affects between 0.4–1.2 cases per million people every year.^4-7 SJS is seen more frequently, affecting 1–6 cases per million people every year.^5,7 SJS may prove fatal in approximately 5% of patients. Prognosis is worse in TEN, where there is more epidermal sloughing which increases the severity of the condition with mortality rates ranging from 20%–40% for extensive sloughing.

Pathogenesis

The pathogenesis of drug-induced SJS/TEN is unknown, although several theories have been developed. Reactive metabolites of oxidative drug metabolism have been shown to lead to covalent binding that can stimulate an immune response. For some drugs there have been clear associations with HLA-B haplotypes in specific populations.^8,9 Epidermal death is due in part to apoptosis that is triggered by a death signal (Fas-ligand) and in vitro antibodies to Fas-ligand can block the process.

Drug-related SJS/TEN

Many cases of SJS/TEN are related to drug exposure. The drugs most frequently cited as causes of SJS and TEN are anticonvulsants, antibiotics (especially sulfonamides), allopurinol, and NSAIDs (e.g., piroxicam).⁴ Other causes, especially for SJS, include infections, neoplasia, and autoimmune diseases.

Treatment of SJS/TEN

There is currently no specific treatment for TEN and SJS.10 Discontinuation of the suspected drug is the first step in the management of these patients, with supportive care (e.g., wound care, hydration, and nutritional support) forming the basis of treatment. Immunosuppressives (e.g., cyclosporin, cyclophosphamide) are often recommended,¹⁰ although the use of corticosteroids in SJS and TEN remains controversial. Other therapeutic modalities that have been attempted include hyperbaric oxygen,¹¹ granulocyte colony stimulating factor,^12-14 and plasmapheresis.¹⁵
Intravenous immunoglobulin therapy (IVIG) may improve outcomes and reduce mortality and morbidity in this population. Considered by many clinicians as a treatment option, it is produced from the plasma of thousands of healthy blood donors. The pooled plasma is fractionated and purified to produce a final product containing predominantly IgG (90%–98%) as well as traces of IgA, IgM, CD4, CD8, HLA molecules and cytokines.¹⁶ Albumin also appears in IVIG in quantities ranging from trace amounts to 3000ìg/mL.^17-19

A number of retrospective and prospective studies have been conducted to examine the efficacy and safety of IVIG in SJS/TEN patients. A recent review of IVIG use in TEN and SJS examined studies with sample sizes of 10 or more patients.²⁰ Nine studies were included consisting of 134 TEN or SJS/TEN overlap patients and 22 SJS patients. The overall mortality rate of all the studies reviewed was 20.5%, and 22.4% for TEN-specific studies. In a subanalysis of these controlled trials, mortality rate for patients receiving IVIG were 27% compared with 30% for the predicted/control group. Further subanalyses revealed significantly higher average IVIG dose in studies with a positive “effect” conclusion than studies with an “ineffective” conclusion. The authors concluded that there was not strong enough evidence to support IVIG use in TEN or SJS patients. Seven of the nine publications analyzed did not report adverse effects with IVIG treatment. Of the two studies that did report adverse effects, one reported higher complications in the IVIG group. In the other report, there were higher plasma creatinine levels in IVIG patients, especially in elderly patients and in patients with past kidney function impairment.²⁰

An updated review stratified results according to TEN and SJS and examined more studies.²¹ In total, 14 studies in patients with TEN and 3 in patients with SJS were evaluated. The majority of studies reported positive results (11 out of 14),^9,22-31 while three cohort studies did not observe statistically significant improvement with IVIG administration.32-34 For SJS, two of the three studies reported positive results.^23,35 The remaining study showed no significant differences in mortality, progression of detachment or speed of re-epidermalization.³² In the pediatric population there were also positive results for IVIG response and adverse events.^{9,25,28,32,35} Because of the heterogeneity of the studies, a meta-analysis could not be conducted for IVIG in TEN or SJS.

It is important to note that all IVIG studies have examined clinical outcomes based on treatment in adults with doses ranging from 0.2g/kg/day to 2g/kg/day for 1–5 days’ duration. There is no information available on the impact of multiple dosing strategies.

The Toxic Epidermal Necrolysis Website Registry

Recently, a website for TEN and SJS has been launched (www.tenregistry.org) in Canada. At present, this new website is a pilot initiative that was created as an online resource to provide up-to-date information on SJS/TEN to clinicians, patients, and the public. The overall future objective of the website is to create a prospective, longitudinal database or registry of SJS/TEN patients across Canada and globally. At present, cases of suspected TEN or SJS should be reported to the adverse drug reaction monitoring agency. Reports to the adverse drug reaction monitoring centre may provide a signal for drugs that may cause SJS/TEN. Submitted reports of SJS/TEN will aid in determining the epidemiology, prognosis, and the possible causes, and will help plan health policy, especially for newly marketed drugs.

Conclusion

Based on the available data, IVIG may have a positive impact on the treatment of individuals with TEN and SJS. A large, multi-center, long-term analysis needs to be conducted to determine the role of IVIG in the management of these patients.

References

1. Fritsch PO, Ruiz-Maldonado R. Stevens-Johnson syndrome – toxic epidermal necrolysis. In: Freedberg IM, Eisen AZ, Wolff K, et al, Eds. Fitzpatrick’s Dermatology in General Medicine. Fifth Ed. Toronto: McGraw-Hill (1999) p.644-50.
2. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 129(1):92-6 (1993 Jan).
3. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 115(2):149-53 (2000 Aug).
4. Roujeau JC, Guillaume JC, Fabre JP, Penso D, Flechet ML, Girre JP. Toxic epidermal necrolysis (Lyell syndrome). Incidence and drug etiology in France, 1981-1985. Arch Dermatol 126(1):37-42 (1990 Jan).
5. Schopf E, Stuhmer A, Rzany B, Victor N, Zentgraf R, Kapp JF. Toxic epidermal necrolysis and Stevens-Johnson syndrome. An epidemiologic study from West Germany. Arch Dermatol 127(6):839-42 (1991 Jun).
6. Naldi L, Locati F, Marchesi L, Cainelli T. Incidence of toxic epidermal necrolysis in Italy. Arch Dermatol 126(8):1103-4 (1990 Aug).
7. Chan HL, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 126(1):43-7 (1990 Jan).
8. Paquet P, Kaveri S, Jacob E, Pirson J, Quatresooz P, Pierard GE. Skin immunoglobulin deposition following intravenous immunoglobulin therapy in toxic epidermal necrolysis. Exp Dermatol 15(5):381-6 (2006 May).
9. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282(5388):490-3 (1998 Oct).
10. Chave TA, Mortimer NJ, Sladden MJ, Hall AP, Hutchinson PE. Toxic epidermal necrolysis: current evidence, practical management and future directions. Br J Dermatol 153(2):241-53 (2005 Aug).
11. Ruocco V, Bimonte D, Luongo C, Florio M. Hyperbaric oxygen treatment of toxic epidermal necrolysis. Cutis 38(4):267-71 (1986 Oct).
12. Bae RJ, Orgill DP, DeBiasse MA, Demling R. Management of a patient with advanced AIDS and toxic epidermal necrolysis using human growth hormone and G-CSF. AIDS Patient Care STDS 11(3):125-9 (1997 Jun).
13. Jarrett P, Rademaker M, Havill J, Pullon H. Toxic epidermal necrolysis treated with cyclosporin and granulocyte colony stimulating factor. Clin Exp Dermatol 22(3):146-7 (1997 May).
14. Goulden V, Goodfield MJ. Recombinant granulocyte colony-stimulating factor in the management of toxic epidermal necrolysis. Br J Dermatol 135(2):305-6 (1996 Aug).
15. Yamada H, Takamori K, Yaguchi H, Ogawa H. A study of the efficacy of plasmapheresis for the treatment of drug induced toxic epidermal necrolysis. Ther Apher 2(2):153-6 (1998 May).
16. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 345(10):747-55 (2001 Sep).
17. Talecris Biotherapeutics Inc. Gamunex(R) Product Mono-graph. (2006 Feb).
18. Talecris Biotherapeutics Inc. IVIGnexTM Product Mono-graph, (2006 Mar).
19. Baxter International Inc. Gammagard (R) SD Product Monograph. (2004 Jan).
20. Faye O, Roujeau JC. Treatment of epidermal necrolysis with high-dose intravenous immunoglobulins (IV Ig): clinical experience to date. Drugs 65(15):2085-90 (2005).
21. Mittmann N, Chan B, Knowles S, Cosentino L, Shear N. Intravenous immunoglobulin use in patients with toxic epidermal necrolysis and Stevens-Johnson syndrome. Am J Clin Dermatol 7(6):359-68 (2006).
22. Prins C, Kerdel FA, Padilla RS, et al. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol 139(1):26-32 (2003 Jan).
23. Stella M, Cassano P, Bollero D, Clemente A, Giorio G. Toxic epidermal necrolysis treated with intravenous high-dose immunoglobulins: our experience. Dermatology 203(1):45-9 (2001).
24. Tristani-Firouzi P, Petersen MJ, Saffle JR, Morris SE, Zone JJ. Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children. J Am Acad Dermatol 47(4):548-52 (2002 Oct).
25. Lissia M, Figus A, Rubino C. Intravenous immunoglobulins and plasmapheresis combined treatment in patients with severe toxic epidermal necrolysis: preliminary report. Br J Plast Surg 58(4):504-10 (2005 Jun).
26. Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: The University of Miami experience. Arch Dermatol 139(1):39-43 (2003 Jan).
27. Campione E, Marulli GC, Carrozzo AM, Chimenti MS, Costanzo A, Bianchi L. High-dose intravenous immunoglobulin for severe drug reactions: efficacy in toxic epidermal necrolysis. Acta Derm Venereol 83(6):430-2 (2003).
28. Al-Mutairi N, Arun J, Osama NE, et al. Prospective, noncomparative open study from Kuwait of the role of intravenous immunoglobulin in the treatment of toxic epidermal necrolysis. Int J Dermatol 43(11):847-51 (2004 Nov).
29. Tan A, Tan HH, Lee CC, Ng SK. Treatment of toxic epidermal necrolysis in AIDS with intravenous immunoglobulins. Clin Exp Dermatol 28(3):269-71 (2003 May).
30. Mangla K, Rastogi S, Goyal P, Solanki RB, Rawal RC. Efficacy of low dose intravenous immunoglobulins in children with toxic epidermal necrolysis: an open uncontrolled study. Indian J Dermatol Venereol Leprol 71(6):398-400 (2005 Nov-Dec).
31. Nasser M, Bitterman-Deutsch O, Nassar F. Intravenous immunoglobulin for treatment of toxic epidermal necrolysis. Am J Med Sci 329(2):95-8 (2005 Feb).
32. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol 139(1):33-6 (2003 Jan).
33. Brown KM, Silver GM, Halerz M, Walaszek P, Sandroni A, Gamelli RL. Toxic epidermal necrolysis: does immunoglobulin make a difference? J Burn Care Rehabil 25(1):81-8 (2004 Jan-Feb).
34. Shortt R, Gomez M, Mittman N, Cartotto R. Intravenous immunoglobulin does not improve outcome in toxic epidermal necrolysis. J Burn Care Rehabil 25(3):246-55 (2004 May-Jun).
35. Prins C, Vittorio C, Padilla RS, et al. Effect of high-dose intravenous immunoglobulin therapy in Stevens-Johnson syndrome: a retrospective, multicenter study. Dermatology 207(1):96-9 (2003).

Division of Dermatology¹, Department of Medicine² & Department of Pharmacology³,
University of Toronto, Toronto, ON, Canada

ABSTRACT

A manufactured blood product derived from fractionated human plasma, intravenous immunoglobulin (IVIg) contains supra-physiologic levels of IgG. IVIg is currently used in the treatment of immunodeficiency syndromes, inflammatory disorders and infectious diseases. Uncontrolled clinical studies and anecdotal case reports recommend its use in dermatology, but randomized clinical trials are lacking. In selecting the most appropriate IVIg for the patient, convenience, efficacy, safety and tolerability of the different products should be considered. With several measures in place to ensure its safety, IVIg offers new hope for the treatment of many severe dermatologic conditions.

Key Words:
Intravenous immunoglobulin, IVIg, immunodeficiency syndromes, inflammatory disorders, autoimmune disease, infectious disease

Intravenous immunoglobulin (IVIg) is currently used in the treatment of primary and secondary immunodeficiency diseases, autoimmune disorders and certain infectious states. Off-label (non-approved) uses for high-dose IVIg are becoming increasingly common in dermatology.^1,2 As a blood product derivative, IVIg is manufactured from the sterilized, purified human plasma of between 10,000 to 20,000 donors per batch.³ The final IVIg preparation is primarily composed of IgG, with trace amounts of IgA, IgM and albumin.³ For the treatment of autoimmune diseases such as dermatomyositis and pemphigus, the precise mechanism of action is unknown. The immunomodulatory effects may be exerted through one or more of the following: 1) functional blockade of the Fc receptors; 2) inhibition of complement-mediated damage; 3) alteration of cytokine and cytokine antagonist profiles; 4) reduction of circulating antibodies via anti-idiotype antibodies; and 5) neutralization of toxins which trigger autoantibody production.⁴ In toxic epidermal necrolysis, IVIg blocks Fas (CD95) mediated keratinocyte death by inhibiting Fas – Fas ligand interactions.⁵

Use in Dermatology

The efficacy of IVIg is best documented in patients with graft-versus-host disease, Kawasaki’s disease and dermatomyositis; however, its utility in dermatology continues to grow.^6-8 A number of case series have found IVIg effective in the treatment of patients with pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid, herpes gestationis and epidermolysis bullosa acquisita (EBA).^9-16 A consensus statement was recently published on the use of IVIg in patients with autoimmune mucocutaneous blistering diseases.¹⁷ For autoimmune bullous disease the recommended guidelines for IVIg are as follows: 1) failure of conventional therapy; 2) significant adverse effects from conventional therapy; 3) contraindications, relative or absolute, to the use of high-dose long-term systemic therapy; 4) progressive disease despite conventional therapy; 5) uncontrolled, rapid debilitating disease; and 6) rapidly progressive EBA with generalized cutaneous involvement.¹⁷

The evidence for the use of IVIg in toxic epidermal necrolysis has been recently the subject of debate.^5,18-20 No consensus has been reached due to the lack of randomized clinical trials. The anecdotal results differ from one center to another. Yet, IVIg remains commonly used as initial therapy for toxic epidermal necrolysis. Current data are insufficient to recommend the routine administration of IVIg in patients with pyoderma gangrenosum, atopic dermatitis, chronic urticaria and Steven-Johnson syndrome.^21-25 For a review of the major clinical trials and larger case series, refer to Tables 1 and 2.

Table 1. A review of the major clinical trials and case series of IVIg in dermatology.

Table 2. Guidelines for use of IVIg in dermatology. Adapted from Bloody Easy.

Prior to starting IVIg therapy, complete blood cell counts, liver function and renal function studies are preformed. Immunoglobulin levels are measured to exclude IgA deficiency. In the absence IgA, or in the presence of low IgA, anti-IgA titers are ordered to minimize the risk of anaphylaxis. Screening for rheumatoid factor and cryoglobulins is recommended as these patients are at an increased risk of acute renal failure. In patients with compromised cardiac or renal function, IVIg must be carefully administered in order to prevent fluid overload. For medicolegal reasons, baseline testing for hepatitis B, C and the human immunodeficiency virus is advisable. Lastly, a small sample of serum should be stored for future analysis in the event of infectious disease transmission.^17,26

Premedications may be administered to minimize the risk of infusion-related side effects, such as headaches, myalgias and rigors. Analgesics (i.e., acetaminophen), nonsteroidal antiinflammatory agents (i.e., celecoxib), antihistamines (i.e., diphenhydramine) and even low-dose intravenous corticosteroids may be of benefit to a subset of individuals.¹⁷

In Kawasaki’s disease, IVIg is administered as a single 2g/kg infusion over 6-12 hours.⁷ For toxic epidermal necrolysis, a dose of 1g/kg for 3 consecutive days (i.e., total dose 3g/kg) appears most effective.¹⁹ In autoimmune disease, the published experience would suggest that the dose of 2g/kg per cycle is most valuable; however, clinical improvement has been noted with lower doses.¹⁷ A typical cycle consists of the total dose divided equally over 2-5 consecutive days (i.e., 1g/kg daily for 2 days, or 0.4g/kg daily for 5 days). As the half-life of IVIg ranges from 3-5 weeks, the infusions are given monthly until there is effective disease control. While the maintenance schedule for its use has not been adequately established, tapering the frequency of IVIg infusions may be useful in maintaining a disease-free state. Ahmed and Dahl have suggested that the intervals between infusions be increased from 4 to 6, 8, 10, 12, 14 and 16 weeks before discontinuing the IVIg therapy.¹⁷ The rate of IVIg infusion is dependent upon the product recommendations (Table 3).

Table 3. Comparison of the various IVIg preparations available in Canada.

Product Differences

IVIg is distributed by the Canadian Blood Services with the exception of Québec, where Hema Québec is the main distributor. There are four licensed IVIg preparations available in Canada (Table 3). While there are no studies which compare the safety and efficacy of the four products, there are some differences that may be clinically important.

Variability of the manufacturing processes may lead to differences in the marketed IVIg products. The use of additional production steps (i.e., stabilization, purification and/or pathogen safety) has the potential to impact negatively the biological activity and integrity of the IgG molecule, tolerability and yield. As shown in Table 3, IVIg preparations are available in both liquid and lyophilized formulations. While the lyophilized formulations require reconstitution, the liquid formulations are ready-to-use. If the lyophilized form is reconstituted to a higher than recommended concentration, the final osmolarity will be significantly increased above physiologic  levels. Moreover, the higher the concentration of the IVIg product, the less volume required for infusion. For example, a 70-kg individual receiving 1g/kg would require either 700ml of a 10% solution, or 1400ml of a 5% solution. In high-risk patients, such as those with cardiac or renal failure, these factors must be taken into consideration. In selecting the most appropriate IVIg for the patient, convenience, efficacy, safety and tolerability of the different products must be considered.

Safety

Adverse effects with IVIg are usually rare and self-limiting. Infusion-related side effects include: headache, flushing, chills, myalgias, low back pain, nausea, wheezing, chest pain, tachycardia and blood pressure changes.^1,26 These symptoms are generally mild and begin within 30-60 minutes of the infusion. If encountered, the symptoms are easily managed by slowing or temporarily discontinuing the infusion. If symptoms are anticipated, the patient may be premedicated with antihistamines or intravenous steroids.

Anaphylaxis has been reported in IgA-deficient patients with anti-IgA antibodies. As most IVIg preparations contain trace amounts of IgA, administration of IVIg may result in antigen-antibody complex formation.¹⁷ Aseptic meningitis, often presenting with headache and photophobia, occurs in up to 11% of patients treated with IVIg.^29,30 More common in patients with a history of migraines, aseptic meningitis may last several days. Both hematological and dermatological reactions (i.e., eczema, erythema multiforme, urticaria) have also been described.²⁶

Patients with cardiac or kidney disease must be closely followed to prevent fluid overload. Those receiving lyophilized formulations or sucrose containing products (US and Europe only) are at increased risk of renal failure as a result of osmotic injury to the proximal renal tubules.^17,26

An association between IVIg and thromboembolic events has been reported in the literature. Sugar-stabilized and hyperosmolar products may increase serum viscosity.³¹ The risk appears to be greater in the patients receiving high doses or rapid infusion rates. By lowering the dose and slowing the rate of infusion, the risk of thrombotic events may be minimized.³¹

While donors are carefully selected and screened to ensure pathogen safety, a number of viral inactivation methods are used as part of the IVIg manufacturing process. These include: physical inactivation steps (i.e., heat and pasteurization) and chemical inactivation steps (i.e., solvent/detergent, low pH, trypsin, pepsin and caprylate). Pathogens are removed by precipitation, chromatography and filtration techniques. In the Gamunex process, the combination of caprylate precipitation, cloth filtration and chromatography has further been shown to significantly reduce prion transmission.^3,32,33

Pharmacoeconomics

Over the years, there has been an increase in both the cost and utilization of IVIg in Canada. At an average cost of $70 CDN per gram, the pharmacoeconomic impact of IVIg is significant.²⁸ For a 70-kg pemphigus patient receiving IVIg at a dose of 2g/kg, the cost for one cycle amounts to $9,800 CDN. As the average number of cycles required is 18, the total drug bill approaches $176,400 CDN.¹⁵ With an incidence of 1 per 100,000 population, the overall cost for the Canadian health care system exceeds $52 million CDN.

In toxic epidermal necrolysis, a 70-kg patient would receive 1g/kg for three consecutive days, amounting to an overall drug cost of $14,700 CDN. At an estimated annual incidence of 1 per million population, an aggregate cost for Canada is projected at over $400,000 CDN. Laboratory expenses, nursing costs and hospital expenditures must also be considered when determining the economic impact of IVIg. These costs must be balanced against improvement of symptoms and quality of life, reduced costs of conventional therapy, decreased complications, fewer hospital admissions and time off work.

Conclusion

IVIg has become increasingly recognized as a safe, effective therapy for a number of dermatological conditions. The cost impact of this medication is potentially large if the list of indications continues to expand. Formal pharmacoeconomic, burden of illness studies and collaborative clinical trials are required to further explore the role of IVIg in dermatology.

References

1. Jolles S, Hughes J, Whittaker S. Dermatological uses of highdose intravenous immunoglobulin. Arch Dermatol 134:80-6 (1998)
2. Rutter A, Luger TA. Intravenous immunoglobulin: an emerging treatment for immune-mediated skin diseases. Curr Opin Investig Drugs 3:713-9 (2002).
3. Bussel JB, Eldor A, Kelton JG, et al. IGIV-C, a novel intravenous immunoglobulin: evaluation of safety, efficacy, mechanisms of action, and impact on quality of life. Thromb Haemost 91:771-8 (2004).
4. Ibanez C, Montoro-Ronsano JB. Intravenous immunoglobulin preparations and autoimmune disorders: mechanisms of action. Curr Pharm Biotechnol 4:239-47 (2003).
5. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282:490-3 (1998).
6. Winston DJ, Antin JH, Wolff SN, et al. A multicenter, randomized, double-blind comparison of different doses of intravenous immunoglobulin for prevention of graft-versushost disease and infection after allogeneic bone marrow transplantation. Bone Marrow Transplant 28:187-96 (2001).
7. Oates-Whitehead R, Baumer J, Haines L, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev 4:CD004000 (2003).
8. Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatmentfor dermatomyositis. N Engl J Med 329:1993-2000 (1993).
9. Jolles S. High-dose intravenous immunoglobulin (hdIVIg) in the treatment of autoimmune blistering disorders. Clin Exp Immunol 129:385-9 (2002).
10. Gourgiotou K, Exadaktylou D, Aroni K, et al. Epidermolysis bullosa acquisita: treatment with intravenous immunoglobulins. J Eur Acad Dermatol Venereol 16:77-80 (2002).
11. Bystryn JC, Jiao D, Natow S. Treatment of pemphigus with intravenous immunoglobulin. J Am Acad Dermatol 47:358-63 (2002).
12. Ahmed AR, Sami N. Intravenous immunoglobulin therapy for patients with pemphigus foliaceus unresponsive to conventional therapy. J Am Acad Dermatol 46:42-9 (2002).
13. Jolles S. A review of high-dose intravenous immunoglobulin (hdIVIg) in the treatment of the autoimmune blistering disorders. Clin Exp Dermatol 26:127-31 (2001).
14. Ahmed AR. Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 45:825- 35 (2001).
15. Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 45:679-90 (2001).
16. Foster CS, Ahmed AR. Intravenous immunoglobulin therapy for ocular cicatricial pemphigoid: a preliminary study. Ophthalmology 106:2136-43 (1999).
17. Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol 139:1051-9 (2003).
18. Trent JT, Kirsner RS, Romanelli P, et al. Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: The University of Miami Experience. Arch Dermatol 139:39-43 (2003).
19. Prins C, Kerdel FA, Padilla RS, et al. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol 139:26-32 (2003).
20. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol 139:33-6 (2003).
21. Asero R. Are IVIG for chronic unremitting urticaria effective? Allergy 55:1099-101 (2000).
22. Kroiss M, Vogt T, Landthaler M, et al. The effectiveness of low-dose intravenous immunoglobulin in chronic urticaria. Acta Derm Venereol 80:225 (2000).
23. Hagman JH, Carrozzo AM, Campione E, et al. The use of high-dose immunoglobulin in the treatment of pyoderma gangrenosum. J Dermatolog Treat 12:19-22 (2001).
24. Paul C, Lahfa M, Bachelez H, et al. A randomized controlled evaluator-blinded trial of intravenous immunoglobulin in adults with severe atopic dermatitis. Br J Dermatol 147:518- 22 (2002).
25. Dawn G, Urcelay M, Ah-Weng A, et al. Effect of high-dose intravenous immunoglobulin in delayed pressure urticaria. Br J Dermatol 149:836-40 (2003).
26. Wittstock M, Benecke R, Zettl UK. Therapy with intravenous immunoglobulins: complications and side-effects. Eur Neurol 50:172-5 (2003).
27. Callum JL, Pinkerton PH. Bloody Easy: Blood transfusions, blood alternatives and transfusion reactions. A guide to transfusion medicine. Toronto (ON): Sunnybrook and Women’s College Health Sciences Centre (2003).
28. Provincial Blood Coordination Office (Canada), IVIG Utilization Management Handbook. Vancouver (BC): Provincial Blood Coordination Office, Ministry of Health Services (2002).
29. Jolles S, Sewell WA, Leighton C. Drug-induced aseptic meningitis: diagnosis and management. Drug Saf 22:215-26 (2000).
30. Nettis E, Calogiuri G, Colanardi MC, et al. Drug-induced aseptic meningitis. Curr Drug Targets Immune Endocr Metabol Disord 3:143-9 (2003).
31. Katz KA, Hivnor CM, Geist DE, et al. Stroke and deep venous thrombosis complicating intravenous immunoglobulin infusions. Arch Dermatol 139:991-3 (2003).
32. Stenland C, Terry J, Cai K, et al. Evaluation of TSE clearance by the filtration process of a new intravenous immunoglobulin product (GamunexTM, 10%). J Allergy Clin Immunol 111:a611 (2003).
33. Lebing W, Remington KM, Schreiner C, et al. Properties of a new intravenous immunoglobulin (IGIV-C, 10%) produced by virus inactivation with caprylate and column chromatography. Vox Sang 84:193-201 (2003).

¹Scientific Insights Consulting Group, Mississauga, Ontario Canada
²GlaxoSmithKline, Consumer Healthcare, Oakville, Ontario Canada
³Departments of Medicine (Divisions of Dermatology and Clinical Pharmacology), and Pharmacology, University of Toronto Medical School; and Division of Dermatology, Sunnybrook & Women’s College Health Sciences Centre, Toronto, Ontario, Canada

ABSTRACT

Skin cleansers may be an important adjunct to the regimen of those who use cosmetics, have sensitive or compromised skin, or utilize topical therapies. Cleansers emulsify dirt, oil and microorganisms on the skin surface so that they can be easily removed. During cleansing, there is a complex interaction between the cleanser, the moisture skin barrier, and skin pH. Cleansing, with water, soap or a liquid cleanser, will affect the moisture skin barrier. Soap will bring about the greatest changes to the barrier and increase skin pH. Liquid facial cleansers are gentler, effecting less disruption of the barrier, with minimal change to skin pH, and can provide people with a cleanser that is a combination of surfactant classes, moisturizers and acidic pH in order to minimize disruption to the skin barrier.
Key Words: cleansers, emulsifiers, detergents, surfactants, soaps

Skin cleansers are surface-active substances (i.e., mulsifiers/detergents/surfactants/soaps) that lower the surface tension on the skin and remove dirt, sebum, microorganisms and exfoliated corneum cells in an emulsified form. The ideal cleanser should do this without irritating, damaging or disrupting the skin and the moisture skin barrier. Water alone removes approximately 65% of oil and dirt from the skin, but is less effective at removing oils of cosmetic import and some environmental insults. Soaps are the oldest surfactants, and are chemically defined as the alkali salt of fatty acids with a pH of 9.5-10. Synthetic detergents vary in composition and surfactant types (i.e., anionic, amphoteric, cationic, non-ionic, and silicone) and pH. In modern usage, the term “soap” generally refers to any cleansing agent regardless of chemistry.¹

Skin cleansers consist of the following:
• Water
• Surfactants (to emulsify the debris)
• Moisturizers (to hydrate the skin and maintain the skin barrier)
• Binders (to stabilize the formulation)
• Lather enhancers (found in some products)
• Fillers (generally used to harden bar soaps and cleansers)
• Preservatives (to prevent the growth of microorganisms)
• Fragrance (generally used to mask the odour of surfactants)
• Dyes or pigments (found in some products)

Skin cleansing may disrupt or disturb the moisture skin barrier, affect the skin surface pH, and irritate the skin. The moisture skin barrier protects against transepidermal water loss, chemical insult and xenobiotic penetration while preserving water to moisturize and maintain the smoothness and flexibility of the skin. A compromised barrier has been correlated with psoriasis, ichthyoses, and atopic dermatitis.² Moisturizers, both emollients and humectants, within cleansers can maintain skin hydration as well as maintaining and restoring barrier function.³ Emollients impair evaporation of skin moisture by forming a film on the skin surface to impede water loss. Humectants attract and bind water, drawing it up from the dermis into the epidermis. The acid mantle of the skin plays an integral role in skin barrier function as well as regulating bacterial flora.⁴ Studies have shown that skin barrier regeneration/repair proceeds more slowly at neutral pH (7.2) than at physiological pH 5.5.⁵ Cleansers may also cause irritant or allergic contact dermatitis and this effect is enhanced if the skin barrier is compromised.

Table 1: Different forms of cleansers

Types of Cleansers

Surfactants can be utilized quite differently in personal hygiene products. They are selected for their functionality and ability to act as detergents/emulsifiers and foaming agents. Personal hygiene products include soaps, superfatted soaps, beauty bars, dermatological bars or cakes, liquid cleansers including facial liquid cleansers, antiseptic foaming solutions, antibacterial washes, and emulsions. Table 1 outlines different types of cleansers.

Soap, the most commonly used, is a combination of fats and oils (of animal or vegetable origin) and salt.¹ Soap is the simplest anionic surfactant, forming soap salts in water that emulsify whatever is on the skin surface while increasing the pH of the skin. Soap salts also provoke stratum corneum swelling and loss of natural humectants and water leaving the skin dry and the barrier compromised. Enriching soaps (superfatted soaps and beauty bars) with lanolin, sweet almond oil or glycerin helps to alleviate the drying of the skin.⁶

Dermatological bars or cakes are chemically different from soaps, and contain modified detergents to enhance their use. Weak organic acids and emollients need to be added to lower the pH of the product and reduce drying of the skin caused primarily by anionic surfactants. Liquid cleansers are complex formulations that contain a combination of surfactants including anionic, amphoteric, nonionic, and silicone. Liquid cleansers also offer anti-bacterial activity by maintaining the skin at physiological pH and by the activity of the surfactants that emulsify and encapsulate (depending on surfactant and formulation) bacteria for easy removal. One study demonstrated that, following hand cleansing, a liquid cleanser removed 85% of bacteria while a bar soap was able to remove only 65%.⁷ Other studies have shown a relationship between cutaneous surface pH, bacterial microflora and the influence of skin cleanser. Use of an acidic liquid cleanser led to a reduction in inflammatory acne lesions and the number of Propionibacterium acnes (P. acnes) on the skin.^4,8 Generally, liquid cleansers are mild, have an acidic pH, and have a high rinsibility factor.

Antiseptic foaming and antibacterial washes are used as an adjunct to acne treatment, since they contain bacteriostatic agents. When used properly, these washes may effect a reduction in P. acnes and prevent secondary infections in acne skin, but they are drying and irritating to most skin.

Effectiveness/Recent Research Findings

Surfactants cause the majority of adverse skin reactions and disrupt or disturb the moisture skin barrier as surface debris and microorganisms are removed. Anionic/sodium containing surfactants such as sodium lauryl sulphate, sodium tallowate and sodium stearate have been shown to disrupt lipids in the moisture skin barrier, as well as increase the pH of the skin by as much as 2-3 units.^9,10 Disruption and depletion of barrier lipids and an increased skin pH leads to a compromised skin barrier¹¹ leaving the skin in a negative physiologic state with an increased sensitivity to potential irritants.⁸ Other ?”entler” surfactant types, i.e., amphoteric (cocamidopropyl betaine) and nonionic (propylene glycol), have been shown to cause a range of skin and sensory irritations.^12,13

Preservatives are required in all cosmetic, especially liquid, formulations to prevent the growth and infection by microorganisms. Liquid formulations are also protected from microorganisms by being enclosed in a container, so that the bulk of the formulation remains protected from contamination, which can occur with handling. Preservatives, fragrances and dyes used in cleansers also cause irritant or allergic contact dermatitis. Parabens and formaldehyde donors (e.g., diazolidinyl urea, Quaternium-15, DMDM hydantoin) are the major classes of preservatives. Both classes have reported incidents of allergic and contact sensitivity and dermatitis.^14-16 Some compounds are more allergenic than others and cause greater numbers of reactions. One example is Quaternium-15, which is the sixth most common allergen in cosmetic products.¹⁶

Table 2: Comparison of Cosmetic Liquid Cleansers
*Cost in Canadian dollars to consumer as determined from one supplier (Shopper’s Drug Mart, Ontario, Canada)

Liquid facial cleansers are the most effective and beneficial cleansers for sensitive and compromised skin. Their formulations are complex, utilizing a combination of surfactants, moisturizers, binders and preservatives to form a product that will cause the fewest problems and the greatest benefits. Awell-designed liquid facial cleanser will use nonionic and silicone surfactants. Nonionic surfactants (e.g., polysorbate) combine low irritancy with surfactant class and pH compatibility. Silicone surfactants (e.g., dimethicone), provide both a surfactant that can penetrate follicles and crevices thereby bringing debris to the skin surface, and an emollient that softens the skin and creates a film to impede transepidermal water loss.¹⁷ Silicone surfactants also offer properties such as low irritation, and are noncomedogenic and hypoallergenic. Liquid facial cleansers should also contain a mixture of emollients and humectants to help restore the moisture skin barrier and limit the disruption caused by the surfactant. Tolerance is an issue for people with skin conditions such as rosacea, atopic dermatitis, acne vulgaris and sensitive skin. A compromised skin barrier results in their being more susceptible to the effects of topical treatments including cleansing. A liquid facial cleanser with an acidic pH, nonionic/silicone surfactants, moisturizers, and minimal skin residue (high rinsibility) offers the greatest benefits and synergy with topical or systemic therapy. Although liquid facial cleansers are formulated to be less irritating to the skin, some of its components may disrupt the skin barrier or cause contact sensitivities.

Table 2 outlines five cosmetic liquid cleansers that represent a combination of those recommended by dermatologists and those most popular with consumers in Canada. Some of these products are not available outside Canada, and one (Derma Jel®) is the in-store brand for Shopper’s Drug Mart, a nationwide drugstore chain. Most retailers in Canada have a store brand cleanser that is positioned to compete with Spectro Jel®. However, from an ingredients comparison the products are quite different.

Limitations/Adverse Effects

Liquid cleansers are the best choice for whole body cleansing, but cost can be prohibitive. Liquid facial cleansers are more expensive than soap ($2.20 to $7.50/100mL versus $1.00/bar respectively), but prices also vary widely even within the category. The greatest differences between soaps and liquid cleansers are the degree of disruption to the moisture skin barrier and the change to the skin pH. It is difficult, when reading a product label, to determine the function of each ingredient. Many ingredients have more than one function, and the packaging can also be confusing, i.e., phrases such as no preservatives, no surfactants, and fragrance free can be misleading. For example, propylene glycol is a moisturizer but also provides anti-bacterial and emulsifier activity. The term fragrance free can be used in a product if a natural ingredient (not a synthetic ingredient) is used to alter the scent of the product.

Conclusion

The choice of facial cleanser is important for people with normal skin, as well as for those people with sensitive skin and skin diseases such as atopic dermatitis, acne vulgaris. Liquid facial cleansers are the best choice for facial cleansing as they have an acidic pH, moisturizers and high rinsibility. Within the liquid cleanser category, the least irritating cleanser will contain non-ionic/silicone-based surfactants combined with moisturizers, as they will cause the least disruption to the moisture skin barrier and the normal skin flora.

References

1. Friedman M, Wolf R. Chemistry of soaps and detergents: various types of commercial products and their ingredients. Clin Dermatol 14(1):7-13 (1996 Jan-Feb).
2. Marstein S, Jellum E, Eldjarn L. The concentration of pyroglutamic acid (2-pyrrolidone-5-carboxylic acid) in normal and psoriatic epidermis, determined on a microgram scale by gas chromatography. Clin Chim Acta 49(3):389-95 (1973 Dec).
3. Elias PM. Lipids and the epidermal permeability barrier. Arch Dermatol Res 270(1):95-117 (1981).
4. Korting HC, Hubner K, Greiner K, Hamm G. Chanages in skin pH and resident flora by washing with synthetic detergent preparations at pH 5.5 and 8.5. J Soc Cosmet Chem 42:147-58 (1991).
5. Schreiner V, Maerker H, Hoppe U. Dependence of barrier repair in human skin on intra- and extracellular pH (abstract). J Invest Dermatol 106:917 (1996).
6. Solomon BA, Shalita AR. Effects of detergents on acne. Clin Dermatol 14(1):95-9 (1996 Jan-Feb).
7. Osborne RC, Grube J. Hand disinfection in dental practice. J Clin Prev Dent 4(6):11-5 (1982 Nov-Dec).
8. Korting HC, Braun-Falco O. The effect of detergents on skin pH and its consequences. Clin Dermatol 14(1):23-7 (1996 Jan-Feb).
9. Lee CH, Maibach HI. The sodium lauryl sulfate model: an overview. Contact Dermatitis 33(1):1-7 (1995 Jul).
10. Rippke F, Schreiner V, Schwanitz HJ. The acidic milieu of the horny layer: new findings on the physiology and pathophysiology of skin pH. Am J Clin Dermatol 3(4):261-72 (2002).
11. Imokawa G, Akasaki S, Minematsu Y, Kawai M. Importance of intercellular lipids in water-retention properties of the stratum corneum: induction and recovery study of surfactant dry skin. Arch Dermatol Res 281(1):45-51 (1989).
12. Pigatto PD, Bigardi AS, Cusano F. Contact dermatitis to cocamidopropylbetaine is caused by residual amines: relavance, clinical characterisics and review of the literature. Am J Contact Dermatitis 6:13-6 (1995).
13. Funk JO, Maibach HI. Propylene glycol dermatitis: re-evaluation of an old problem. Contact Dermatitis 31(4):236-41 (1994 Oct).
14. Soni MG, Burdock GA, Taylor SL, Greenberg NA. Safety assessment of propyl paraben: a review of the published literature. Food Chem Toxicol 39(6):513-32 (2001 Jun).
15. Fransway AF, Schmitz NA. A problem of preservation in the 1990s: (II). Formaldehyde and formaldehyde-releasing biocides: incidences of crossreactivity and the significance of the positive response to formaldehyde. Am J Contact Dermatitis 2:78-88 (1991).
16. Marks JG, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis Group patch test results for the detection of delayed-type hypersensitivity to topical allergens. J Am Acad Dermatol 38(6 Pt 1):911-8 (1998 Jun).
17. Gordon ML. The role of clobetasol propionate emollient 0.05% in the treatment of patients with dry, scaly, corticosteroid-responsive dermatoses. Clin Ther 20(1):26-39 (1998 Jan-Feb).