Clinical Instructor, Department of Dermatology and Skin Science University of British Columbia, Vancouver, BC, Canada

Introduction

According to the Canadian Dermatology Association¹, acne affects approximately 20% of the Canadian population, somewhere between five and six million individuals. For most people, acne appears at puberty and may last until adulthood. In adolescence, acne is nearly ubiquitous, with approximately 90% of individuals experiencing it to some degree. However, adult acne is increasingly common with women making up about three-quarters of adult cases.^1,2 In a large study, acne peaked in the teenage years, but 45% of women aged 21-30, 26% aged 31-40, and 12% aged 41-50 had acne.³ Acne can have a negative impact on the quality of life of patients, leading to a decrease in self-esteem, embarrassment, and frustration, as well as discrimination in the workplace and in other social situations.² It is important to recognize and treat these patients early to prevent scarring, and to help improve quality of life as there is a high psychosocial impact of the disease. For the purposes of this article, the focus will be on the topical treatment of post-adolescent mild to moderate acne. A selection of over-the-counter and prescription based topical treatments are discussed below.

Background

• Acne is a multifactorial inflammatory disease centered on the pilosebaceous gland of the skin.
• Key pathogenic features in the development of acne are abnormal follicular keratinization, colonization with Propionibacterium acnes, sebum production, and complex inflammatory mechanisms. In addition, studies have suggested that hormones, diet, genetic and other factors may contribute to the multifactorial process of acne pathogenesis.^4,5
• To improve and prevent acne, treatment should target as many factors as possible.
• Acne is usually classified by the number, type and distribution of acne lesions.
  • Mild acne tends to consist of comedones (whiteheads and blackheads), few papules and pustules.
  • Moderate acne has several papules, pustules, and may contain nodules.
  • Severe acne has numerous papules, pustules, multiple nodules, cysts and scarring. The distribution is commonly on the face, but may also involve the back, chest and upper arms.⁶

Therapy for acne can be broadly divided into four categories:

1. Topical
2. Systemic
3. Light-based
4. Physical therapies

• The goals of treatment are to clear existing lesions, prevent new lesions, minimize scarring and dyspigmentation, and reduce the psychological impact.
• For most patients with mild acne, and many with moderate, topical therapy will be sufficient to clear the skin lesions. If this proves insufficient, clinicians should not hesitate to change the regimen, either trying an alternative topical treatment or adding a systemic therapy.
• The type of acne should be a primary consideration when evaluating treatment options.

Topical Treatments

Benzoyl Peroxide

• This is antibacterial and mildly comedolytic (inhibits formation or treats comedones).
• It does not cause bacterial resistance.
• Benzoyl peroxide may cause mild skin irritation or dryness. It can also cause bleaching of hair, clothes, bed linens, etc.⁷
• It is reasonable to initiate therapy with 2.5% products since limited evidence shows efficacy similar to 5% and 10% formulations but with less irritation.⁸
• It is available as a monotherapy in several over-the-counter products (e.g., creams, lotions, gels, cleansers) and is also a component of prescription combinations with a topical antimicrobial.

Glycolic Acid

• Glycolic acid (an alpha-hydroxy acid) is mildly comedolytic and is commonly used when other topicals are not tolerated.
• It may also be used at higher concentrations in chemical peels to help clear comedones.⁴

Salicylic Acid

• Salicylic acid is comedolytic.
• Concentrations of 1-2% are tolerated but not as effective as topical retinoids. Higher concentrations are usually too irritating.
• It is most commonly found in nonprescription products.⁴

Topical Retinoids

• These are strong comedolytic agents and are the recommended first line treatment for mild comedonal acne in adult women.^{9, 10}
• Retinoids promote the reversal of comedogenesis, leading to a reduction of microcomedones, a precursor of both inflammatory and non-inflammatory lesions.
• Several forms of retinoids are available on the market including tretinoin, adapalene, and tazarotene.
• Tretinoin is the most cost effective but also the most photosensitizing. Adapalene is the least irritating and tazarotene the most potent.¹¹
• Tretinoin reverses thickening of the stratum corneum and the abnormal desquamation of keratinocytes and has been a mainstay of acne treatment for 30 years.¹²
• Newer retinoid formulations, such as tretinoin microsphere gel, have been shown to retain photostability (i.e. protect against photodegradation).¹³
• Tretinoin microsphere technology introduces small amounts of tretinoin to the skin over time, leading to higher efficacy and better tolerability versus tretinoin.¹⁴

Topical Antibiotics

• Topical antibiotics are used to decrease skin colonization with P. acnes and can be anti-inflammatory.
• Clindamycin is typically the preferred topical antibiotic therapy for acne.⁴
• Monotherapy with topical antibiotics should not be used routinely, because of the risk of bacterial resistance.⁶
• Combination with benzoyl peroxide reduces the risk of bacterial resistance.⁶

Azelaic Acid

• This is comedolytic and antibacterial but does not lead to resistant organisms.
• It can be irritating.
• It also has a role in reducing hyperpigmentation.⁴

Topical Dapsone

• This treatment comes as a topical gel formulation and is effective for inflammatory acne.
• The benefit in women seems to exceed the benefit in male and adolescent patients.⁴

Topical fixed-dose combination therapies available include:

• • Clindamycin plus benzoyl peroxide
  • Clindamycin plus tretinoin
  • Benzoyl peroxide plus adapalene
• The benefit of using topical combination therapies include targeting different pathogenic factors, faster resolution of lesions, and minimizing antibiotic resistance. They may also lead to improved adherence and efficacy.^5,15
• Both the fixed-dose combination of clindamycin 1.2% and tretinoin 0.025% gel (Biacna®) and benzoyl peroxide 2.5% and adapalene 0.1% gel (Tactuo®) were shown to be superior to the individual components and vehicle.¹⁵
• Recent Canadian Practice Guidelines suggest treatment with benzoyl peroxide, topical retinoids or fixed dose combinations as first-line therapy for comedonal or mild to moderate papulopustular acne.¹⁵
• Addition of systemic treatments such as oral contraceptive pills, oral antibiotics or isotretinoin can be considered particularly in the case of moderate to severe papulopustular acne.¹⁵
• Adverse events related to topical acne therapies most commonly involve dryness, redness, burning, irritation and peeling.⁴ It is important to have strategies to manage these side effects (Box 1).

Tips for Acne Treatment

1. To prevent development of new acne lesions, topical therapies should be applied to the affected areas (all over) rather than to the lesions alone.
2. As many acne treatments are irritating, use a gentle skin-care regimen; avoid astringents and abrasive skin care products.
3. Topical retinoids, benzoyl peroxide and topical combination therapies are effective and recommended as first-line therapy for many patients but are often underutilized due to patients having difficulty with irritation. It is important to review strategies to improve adherence (Box 1).
4. Each time a topical medication is added or changed, allow several weeks of treatment before assessing effectiveness.
5. Acne is a disease that commonly lasts years. Once control has been achieved, the treatment regimen may be simplified but maintenance therapy may be required.

Special Considerations

• Adult acne may be seen in women of child bearing potential and may be seen after discontinuation of oral contraceptive pills, so it is important to understand treatments that are safe in pregnancy
• Benzoyl peroxide and topical antibiotics such as clindamycin and erythromycin have been used extensively and both are generally considered safe in pregnancy.¹⁶
• Glycolic acid and azelaic acid have low systemic absorption and are unlikely to pose a risk to the fetus.¹⁷
• Although systemic absorption of topical dapsone appears low, safety in pregnancy has not been established.¹⁶
• Safety of topical retinoids has not been sufficiently studied and their use remains contraindicated,¹⁷ however, one meta-analysis showing no major congenital malformations may be reassuring to those who have inadvertent exposure during early pregnancy.¹⁸
• Consider adding a systemic therapy when topical therapy has not been effective after 2-3 months, or if topical treatments only have a small chance of success such as with moderate to severe acne.
• Referral to a dermatologist can also be considered with refractory patients.

Summary

Acne remains a prevalent disease past the adolescence years. It is important to factor in the significant impact on quality of life for patients with this condition and to treat early to prevent complications such as dyspigmentation and scarring. Topical therapy is a cornerstone first-line treatment for mild to moderate acne. Education around proper application of the topical medicine and strategies to improve adherence should be reviewed with the patient. Maintenance treatment is important to prevent recurrence.

References

1. Canadian Dermatology Association. Acne. Fact sheet, available at www.dermatology.ca. Last accessed May 17, 2017.
2. Ramos-e-Silva M. Br J Dermatol. 2015 Jul;172(S1):20-6.
3. Perkins AC, et al. J Womens Health. 2012 Feb;21(2):223-30.
4. Zaenglien AL, et al. J Am Acad Dermatol. 2016 May;74(5):945-73.
5. Lynde C, et al. J Cutan Med Surg. 2014 Jul-Aug;18(4):243-55.
6. Kraft J, Frieman A. CMAJ. 2011 Apr 19;183(7):E430-5.
7. Gollnick HPM. J Eur Acad Dermatol Venereol. 2015 Jun;29(S5):1-7.
8. Brandstetter AJ, Maibach HI. J Dermatolog Treat. 2013 Aug;24(4):275-7.
9. Dréno B, et al. J Eur Acad Dermatol Venereol. 2013 Sep;27(9):1063-70.
10. Dréno B. J Eur Acad Dermatol Venereol. 2015 Jun;29(S5):14-9.
11. Kakita L. J Am Acad Dermatol. 2000 Aug;43(2 Pt 3):S51-4.
12. Rolewski SL. Dermatol Nurs. 2003 Oct;15(5)
13. Nyirady J, et al. Cutis. 2002 Nov;70(5):295-8.
14. Retin A Micro Product Monograph 2012.
15. Asai Y, et al. CMAJ. 2016 Feb;188(2):118-26.
16. Chien AL, et al. J Am Board Fam Med. 2016 Mar-Apr;29(2):254-62.
17. Bozzo P, et al. Can Fam Physician. 2011 June;57(6):665-7.
18. Kaplan YC, et al. Br J Dermatol. 2015 Nov;173(5):1132-41.

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

Introduction

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

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

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

Diagnosing HD – Important points to cover

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

Case

Case 1:

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

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

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

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

Case 2:

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

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

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

Case 3:

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

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

Case 4:

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

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

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

Conclusions

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

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

Acknowledgement

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

References

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

¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

²Department of Ophthalmology and Visual Science, University of British Columbia, Vancouver, BC, Canada

Conflict of interest disclosure: Dr. Humphrey and Dr. Carruthers are investigators, speakers and consultants for Kythera Biopharmaceuticals and Allergan Inc.
ABSTRACT

The chin and jaw line are integral parts of an individual’s aesthetic profile, and the presence of submental fat detracts from this and can lead to displeasure with one’s facial appearance. While liposuction and cosmetic surgery are regarded as the gold standard in treating submental fat, surgical intervention is not appealing to all patients and has potential surgical complications including longer recovery, and contour irregularities. Despite ample advances in aesthetic medicine to enhance the appearance of the face, very little is available in non-invasive options to reduce submental fat that has been supported by robust evidence. ATX-101, a proprietary formulation of deoxycholic acid that is synthetically derived, has been extensively explored in a vigorous clinical development program that has established the safety and efficacy of the injectable. It has recently received approval by regulatory authorities in Canada (Belkyra™) and the US (Kybella®) for the treatment of submental fat.

Key Words: adipocytolysis, ATX-101, deoxycholic acid, injectable, nonsurgical, submental fat

Introduction

Desirable features of the face are thought to follow the “golden
ratio” or Phi that is seen in natural formations.^1,2 What is viewed as
an attractive face in contemporary culture does not significantly
differ from ancient times.³ Think of the bust of Egyptian queen
Nefertiti. The ideal face appears as an inverted triangle that
contains a wide mid-face that tapers toward the chin.^4,5 A defined
chin denotes assertiveness, credibility, and leadership.⁶ A face that
has aesthetic balance is thought to feature a neck contour that
is pleasing to the eye.⁷ Individuals who have submental fullness
may be perceived as having an unattractive profile of the chin and
may experience reduced satisfaction with their appearance which
erodes their sense of well-being.^8,9 The presence of submental fat
superficially and deep to the platysma muscle is regarded as a sign
of aging of the lower face,^10,11 but there are individuals, both young
and old, whose morphology involves a round face which includes
deposits of submental fat. Still for others, a genetic predisposition
produces undesired submental fat that detracts from their profile
and remains even with weight loss and exercise.^1,7

Surgery has been the mainstay to treat submental fullness,
colloquially referred to as the “double chin”.⁸ Complications from
surgery however make it somewhat unappealing to patients.¹²
Indeed, alternatives to surgery would be well-received by both
clinicians and patients.

Discussion

It was first observed in cell cultures and porcine skin that
sodium deoxycholate, a bile salt that occurs in the body, acts as
the active ingredient in an injectable phosphatidylcholine and
sodium deoxycholate solution that treats the accumulation of
localized fat through adipocytolysis.¹³ Other investigators later
concluded that deoxycholic acid selectively targets fat tissue
while sparing other tissues like skin and muscle in the local
environment.¹⁴ The encouraging basic research has prompted
Kythera Biopharmaceuticals, Inc. to develop a synthetic form
of deoxycholic acid, with an aim to introduce a non-injectable
therapy designed to contour the chin-neck area through
decreasing submental fat.

The synthetic compound, known as ATX-101, is manufactured using a proprietary process, is indistinguishable from endogenous deoxycholic acid given it possesses an identical chemical structure, and does not contain any substances derived
from humans or animals. Chemical compounding that produces phosphatidylcholine/sodium deoxycholate formulations is not a process that guarantees a consistent formulation¹⁵ while the proprietary manufacturing process to prepare synthetic deoxycholic acid does achieve this.

In-depth study and evaluation of deoxycholic acid for the purposes of decreasing submental fat began in 2007 with preclinical investigations to first assess the safety and side effect profile of the compound, followed by research to elucidate the pharmacokinetic, pharmacodynamic, and optimal dosing of deoxycholic acid in a clinical setting. Safety data has assured that the subcutaneous injection of 100 mg deoxycholic acid, given via 0.2-ml injections spaced at 1-cm intervals, sees a temporary rise in deoxycholic acid plasma levels, but no increase beyond the normal range of variability for endogenous deoxycholic acid, with a return to baseline levels by 24 hours post dose.^16,17 Chief among the safety observations is that injection of synthetic deoxycholic acid does not result in elevations in lipids and adipokine concentrations that are clinically significant.¹⁷

The clinical development program associated with ATX-101 has
enrolled more than 2,600 patients, of whom 1,600 patients have
been treated with the synthetic compound. Investigators have
witnessed fast absorption of the compound, as well as a decline
in overall fat in the treated area. Where needed in clinical studies,
anesthesia with topical lidocaine preparations together with ice
were provided to patients and local lidocaine injections were
performed in some cases.¹⁷

Histological data reinforce the proposed mechanism of action,
adipocytolysis (Figure 1), for deoxycholic acid.¹⁸ Injections of the
synthetic compound into abdominal fat were observed to result
in fat lobule atrophy amongst other outcomes as well as near
resolution of inflammation at 28 days, which determined the
spacing of treatments of just under one month.¹⁸ The treatment
schedule was assessed in phase III clinical trials. No histological
effects were seen in the dermis or epidermis.¹⁸

Figure 1.
Mechanism of action of deoxycholic acid. Subcutaneous administration causes the destruction of fat cells.

Copyright 2015, Kythera Biopharmaceuticals, Inc., Used by permission. All rights reserved.

Of note, submental fat was not decreased any further when the
area-adjusted dose of deoxycholic acid was increased through
administration of a stronger concentration, larger injection volume, or shorter intervals between injections.^19,20 Self-reported
scales, which denoted patient dissatisfaction with appearance, and
clinician-reported scales, which reflect investigator evaluations of
submental fat were employed to determine baseline appearance
as it relates to the chin in randomized, double-blind, placebocontrolled,
phase III clinical trials.^21-25 In the two North American
trials, magnetic resonance imaging (MRI) was also employed to
assess a decrease in submental volume subsequent to deoxycholic
acid injection where MRI images were interpreted in a blinded
fashion.^23,24 Post-treatment evaluations were conducted using
patient-reported instruments to determine approval with facial
appearance and appearance of the chin. Submental fat change
and its psychological effect were also evaluated, and the adverse
psychological impact of submental fat was diminished with
deoxycholic acid injection. Assessments performed at 12 weeks
after the last treatment showed that the synthetic compound
decreased submental fat based on patient, clinician, and objective
evaluations. In the North American phase III trials 68.2% of
ATX-101 (2 mg/cm²) subjects demonstrated a simultaneous
improvement of at least one grade from baseline on clinician and
patient reported rating scales vs. 20.5% in placebo (p<0.001). The
proportion of MRI responders was more than eight-fold greater
with the compound than placebo in the REFINE-1 trial.^21-24

While there are predefined maximum treatments based on phase
III clinical data – four treatments based on European data and
six treatments based on North American data – fewer treatments
may be administered if efficacy is achieved earlier or if there
are safety concerns. After two treatments, 52.2% of subjects
achieved at least a one grade change from baseline in the clinician
submental fat ratings, and 71.5% after four treatments^21-24, endorsing the concept of tailored treatment of deoxycholic acid
for each patient, taking into account factors such as individual
anatomy and the fact the quantity of submental fat decreases over
time with successive treatments. See Figures 2a and 2b for before
and after images.^23,24 Durability is another favorable property
of deoxycholic acid therapy.²⁴ Data bear out that the effect of
treatment is sustained for up to 4 years after the last injection.²⁴

Figure 2a.
REFINE-2 (ATX-101-11-23) study – unretouched photos of clinical trial patient taken before and after treatment with ATX-101.

Subject details: Age: 35, Sex: F, Number of treatment cycles: 4, Composite grade change: 1-grade, Total dose: 16.2 ml

CR-SMFRS = Clinician-Reported Submental Fat Rating Scale; PR-SMFRS = Patient-Reported Submental Fat Rating Scale

Copyright 2015, Kythera Biopharmaceuticals, Inc., Used by permission. All rights reserved.

Figure 2b.
REFINE-1 (ATX-101-11-22) study – unretouched photos of clinical trial patient taken before and after treatment with ATX-101.

Subject details: Age: 55, Sex: F, Number of treatment cycles: 5, Composite grade change: 1-grade, Total dose: 22.0 ml

Copyright 2015, Kythera Biopharmaceuticals, Inc., Used by permission. All rights reserved.

The majority of adverse events in the four phase III trials
associated with deoxycholic acid injections were mild or
moderate, and transient. Pain, swelling, bruising, numbness,
erythema, and induration were some of the most frequent
side effects and were linked to the treatment area, route of
administration, the mechanism of action of the compound, and
expected tissue response. With repeated treatments, the incidence
and severity of pain and swelling declined.²³ Serious adverse
events were infrequent.²³ One adverse event, albeit rare, that did
differ between placebo-treated patients and deoxycholic acidtreated
patients was marginal mandibular nerve (MMN) paresis,
but most instances of MMN paresis were mild or moderate in
severity, lasting a median duration of 47.5 days.²³ No new signals
related to safety have been detected in extended follow up.

Phase III clinical trials demonstrated no exacerbation of skin
laxity, which is traditionally a worry when fat is extracted from
a targeted zone. In actual fact, skin laxity remained the same or
was improved in phase III clinical trials.^21,24 It has been suggested
the absence of exacerbation of skin laxity could be attributed to
the phenomenon of neocollagenesis,¹⁸ which was observed in
histologic samples after treatment with deoxycholic acid. Happily
for patients, the data indicate procedures for skin tightening to
address skin laxity are not necessary after submental fat decrease
with deoxycholic acid therapy.

Conclusion

As a first-in-class injectable therapy, deoxycholic acid, was
recently approved by Health Canada and the US Food and Drug
Administration, as Belkyra™ and Kybella®, respectively, to treat
submental fullness. It is not approved for use in other facial
areas or sites on the body. As a minimally invasive treatment,
it can be performed in the office, results are visible in two to
four treatments, and recovery is relatively quick. Different from
facial injectables like fillers and neuromodulators, maintenance
treatments with deoxycholic acid are not required to sustain
the effect over time or to reduce skin laxity. Clinicians should
ensure sufficient submental fat is present to justify injection of
deoxycholic acid. They should also be cautious to avoid injuring
anatomic structures in the submental region when injecting the
synthetic compound.

Acknowledgement

The authors wish to acknowledge Louise Gagnon for her editorial
assistance in the preparation of this manuscript.

References

1. Huettner F, Vasconez LO, de la Torre JI. Neck rejuvenation–anatomy and clinical correlation. Facial Plast Surg. 2012 Feb;28(1):40-51.
2. Ellenbogen R, Karlin JV. Visual criteria for success in restoring the youthful neck. Plast Reconstr Surg. 1980 Dec;66(6):826-37.
3. Sands NB, Adamson PA. Global facial beauty: approaching a unified aesthetic ideal. Facial Plast Surg. 2014 Apr;30(2):93-100.
4. Dayan SH, Arkins JP, Patel AB, et al. A double-blind, randomized, placebo-controlled health-outcomes survey of the effect of botulinum toxin type a injections on quality of life and self-esteem. Dermatol Surg. 2010 Dec;36 Suppl 4:2088-97.
5. Swift A, Remington K. BeautiPHIcation: a global approach to facial beauty. Clin Plast Surg. 2011 Jul;38(3):347-77, v.
6. Chin surgery skyrockets among women and men in all age groups. American Society of Plastic Surgeons. Press release dated April 16, 2012.
7. Raveendran SS, Anthony DJ, Ion L. An anatomic basis for volumetric evaluation of the neck. Aesthet Surg J. 2012 Aug;32(6):685-91.
8. Rohrich RJ, Rios JL, Smith PD, et al. Neck rejuvenation revisited. Plast Reconstr Surg. 2006 Oct;118(5):1251-63.
9. Schlessinger J, Weiss SR, Jewell M, et al. Perceptions and practices in submental fat treatment: a survey of physicians and patients. Skinmed. 2013 Jan-Feb;11(1):27-31.
10. Ascher B. Developments in management of facial and body lipoatrophy with exogenous volumetric injectables. In: Landau M, Rossi B, editors. Injection treatments in cosmetic surgery. London, UK: Informa Healthcare. 2008: p329-38.
11. Burgess CM. Principles of soft tissue augmentation for the aging face. Clin Interv Aging. 2006 1(4):349-55.
12. Koehler J. Complications of neck liposuction and submentoplasty. Oral Maxillofac Surg Clin North Am. 2009 Feb;21(1):43-52, vi.
13. Rotunda AM, Suzuki H, Moy RL, et al. Detergent effects of sodium deoxycholate are a major feature of an injectable phosphatidylcholine formulation used for localized fat dissolution. Dermatol Surg. 2004 Jul;30(7):1001-8.
14. Thuangtong R, Bentow JJ, Knopp K, et al. Tissue-selective effects of injected deoxycholate. Dermatol Surg. 2010 Jun;36(6):899-908.
15. Gupta A, Lobocki C, Singh S, et al. Actions and comparative efficacy of phosphatidylcholine formulation and isolated sodium deoxycholate for different cell types. Aesthetic Plast Surg. 2009 May;33(3):346-52.
16. Walker P, Fellmann J, Lizzul PF. A phase I safety and pharmacokinetic study of ATX-101: injectable, synthetic deoxycholic acid for submental contouring. J Drugs Dermatol. 2015 Mar;14(3):279-87.
17. Walker P, Lee D. A phase 1 pharmacokinetic study of ATX-101: serum lipids and adipokines following synthetic deoxycholic acid injections. J Cosmet Dermatol. 2015 Mar;14(1):33-9.
18. Walker P, Lee D, Toth BA. A histological analysis of the effects of single doses of ATX-101 on subcutaneous fat: results from a phase I open-label safety study of ATX-101. Poster presentation. 2013 Annual Meeting of the American Society for Dermatologic Surgery. October 3-6, 2013. Chicago, IL.
19. KYTHERA Biopharmaceuticals, Inc. FDA briefing document, April 30, 2015.
20. Goodman G, Smith K, Walker P, et al. Reduction of submental fat with ATX-101: a pooled analysis of two international multicenter, double-blind, randomized, placebocontrolled studies. J Am Acad Dermatol. 2012 Apr;66(4 Suppl 1):AB11.
21. Ascher B, Hoffmann K, Walker P, et al. Efficacy, patient-reported outcomes and safety profile of ATX-101 (deoxycholic acid), an injectable drug for the reduction of unwanted submental fat: results from a phase III, randomized, placebo-controlled study. J Eur Acad Dermatol Venereol. 2014 Dec;28(12):1707-15.
22. Rzany B, Griffiths T, Walker P, et al. Reduction of unwanted submental fat with ATX-101 (deoxycholic acid), an adipocytolytic injectable treatment: results from a phase III, randomized, placebo-controlled study. Br J Dermatol. 2014 Feb;170(2): 445-53.
23. Humphrey S, Sykes J, Kantor J, et. al. REFINE-2: A randomized, double-blind, placebocontrolled, phase III trial evaluating the efficacy and safety of deoxycholic acid injection (ATX-101) for submental contouring. J Am Acad Dermatol. (Submitted)
24. Jones DH, Carruthers J, Joseph JH, et al. REFINE-1, a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial with ATX-101, an injectable drug for submental fat reduction. Dermatol Surg. 2016 Jan;42(1):38-49.
25. Hoffmann K, et al. Reductions in submental fat achieved with ATX-101 (deoxycholic acid) are maintained over time. 13th Aesthetic & Anti-Aging Medicine World Congress. March 26-28, 2015. Monte Carlo, Monaco.