¹ Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
² Section of Dermatology, University of Manitoba, Winnipeg, MB, Canada

Introduction

Head lice infestations (Pediculosis capitis) are a worldwide problem with prevalence estimates typically ranging between 1-3% in elementary school aged children.^1,2 Although this obligate parasite is a nuisance, infestation does not pose a health risk. Infestations tend to occur more frequently in females,³ and less frequently in black children,⁴ as it may be more difficult for lice to grasp their oval-shaped hair shafts. It is not associated with poor hygiene. Infestation occurs across all levels of society, but occurs more frequently under conditions of overcrowding. Recent evidence suggests increasing frequency of topical treatment failure may be related to a growing resistance to the neurotoxic pediculicides that have been the first-line treatment for the last 40 years.⁵ Herein, we will review the current topical treatment options, including newer non-pediculicidal options.

Overview of Facts on Lice

• Pediculus humanus capitis (the head louse) is a 2-4 mm blood sucking, wingless insect.
• A louse cannot jump, but rather has 6 legs adapted for crawling along hairs at 23 cm per minute.⁶
• A louse will feed every 3-6 hours.
• Prior to feeding, the louse injects saliva into the skin.
• The life span is approximately 4 weeks and the female lays 6-8 eggs per day.
• Eggs hatch in 8 days, leaving their shell (“nit”) cemented to the base of the hair.
• Head lice spread by head contact, shared fabrics, shared combs, and other fomites that are commonly in contact with the scalp and hair.⁷
• A louse can survive 2-3 days away from a human host.
• Pets are not vectors.

Top

Diagnosis and Symptoms

Many affected individuals report no symptoms, but the most commonly reported symptom is scalp pruritus.⁸ The pruritus is thought to be caused by hypersensitivity to the louse saliva that is injected into the scalp during feeding, but the itching often does not begin until 1-4 weeks after infestation. Although any part of the scalp may be colonized, there seems to be a predilection for the nape of the neck and post-auricular areas.

Skin Findings

• Often there are no significant findings on the skin.
• Pruritic, papular lesions may be found at the nape of the neck.
• There may be excoriations on the scalp.
• Secondary staphylococcal infection is possible.
• Possible enlargement of cervical / nuchal lymph nodes.

Hair Findings

• True infestation is confirmed by the presence of live adult lice or nymphs (hatched immature lice) present on the scalp with nits.
• The presence of nits alone does not confirm infestation, as an empty nit can remain cemented to a hair even after the infestation has cleared.
• The distance of the nit from the scalp can be a clue to the duration of the infestation, as it moves with the hair away from the scalp when hair grows.
• A nit within 0.6 mm of the scalp is usually a viable egg.

Diagnosis is best made by wet or dry combing the scalp with a fine-toothed nit comb with teeth spaced 0.2 mm apart. One study comparing wet combing with visual inspection found that wet combing accurately diagnosed infestation 90.5% of the time, as compared to 28.6% with visual inspection.²

Directions for Detection by Wet Combing⁹

• Saturate hair with a conditioner.
• Remove tangles with a regular comb.
• With the nit comb against the scalp, comb to the end of the hair.
• Check the comb for lice after each pull by visual inspection and by cleaning the comb with a tissue and inspecting the contents.
• Dispose of the tissue in a plastic bag.
• Comb the entire scalp at least 5 times.
• Seal the plastic bag and dispose of it.
• If infestation is confirmed, rinse off all conditioner prior to treatment.

Treatment Options

Management

Traditionally, topical pediculicides have been the mainstay in the initial treatment of pediculosis. They are widely available without a prescription, which has contributed to the difficulty in gathering data on the true prevalence of infestation. Easy access and improper use has likely contributed to the significant resistance that has developed against topical pediculicides. Knockdown resistance (kdr) is a heritable insensitivity to dichlorodiphenyltrichloroethane (DDT), the pyrethrins, and the pyrethroids. A recent study examining lice collected in Quebec, Ontario, and British Columbia found the allele for resistance present in 97.1% of the 274 lice sampled.⁵ These findings suggest that a significant resistance to the traditional first-line treatment options exists within Canada.

In recognition of the developing resistance, there has been an increased interest within Canada to explore effective non-pediculicidal options. A recent study found the efficacy of isopropyl myristate 50% to be significantly higher (57%) than the standard treatment with pyrethrin 0.33% + piperonyl butoxide 4%.¹⁰

While non-pediculicidal therapy may be efficacious against treatment resistant infestations, re-infestation from close contacts and fomite transmission is a common problem. Along with treatment, it is important to decontaminate the environment.

Environmental Decontamination¹⁴

• Family members and close contacts should be examined and be treated for any infestation.
• Any clothing, linens, combs, toys, and fabrics used by the individuals in the 3 days preceding treatment should be decontaminated.
• Fabrics can be washed in high heat and put in a hot dryer for 20 minutes.
• Items that cannot be washed can be sealed in a plastic bag for 14 days or placed in the freezer for 24 hours.
• Brushes can be soaked in rubbing alcohol for 1 hour.
• Floors and furniture can be cleaned by vacuuming.
• Spraying the home with a pediculicide is not recommended.
• No nit policies at schools are unnecessary.

Management Tree

(scalp pruritus, papules at the nape of the neck, or known close contact with another infested individual)

Examine scalp using fine-toothed nit comb (0.2 mm spacing) Wet hair with lubricant, such as hair conditioner (optional), and comb front to back with the comb against the scalp

By wet or dry combing (presence of live adult louse or nymph)

Choose treatment (based on patient preference, age, and local resistance to topical pediculicides)

Take measures to decrease risk of reinfestation and spread (treat all family members, notify school, and decontaminate environment)

Manual Removal

Some patients may prefer to attempt mechanical treatments prior to topical therapy. Wet combing, as described earlier, can be both diagnostic and therapeutic. To attempt this method the patient should wet comb the entire scalp until no more lice are found every 3-4 days for 3 weeks, or at least 2 weeks after the last adult louse was found.¹⁴

Treatment Failure

Treatment failure is commonly a result of inadequate or improper treatment, resistance, or reinfestation. If environmental decontamination was performed and the treatment was properly administered, then immediate retreatment with a different agent is advised.

Conclusion

Head lice infestation is a common problem for children in Canada. The first-line treatment of using topical pediculicides is unfortunately not as effective as it once was because of a heritable resistance that seems to be rising in prevalence. Topical non-pediculicides may be an effective option in the case of failed treatment due to louse resistance to standard treatment.

References

1. Harris J, et al. Commun Dis Public Health 6(3):246-9 (2003 Sep).
2. Jahnke C, et al. Arch Dermatol 145(3):309-13 (2009 Mar).
3. Counahan M, et al. J Paediatr Child Health 40(11):616-9 (2004 Nov).
4. Centers for Disease Control and Prevention. Fact sheet: head lice. Available at: http://www.cdc.gov/lice/head/factsheet.html. Accessed June 28, 2010.
5. Marcoux D, et al. J Cutan Med Surg 14(3):115-8 (2010 May-Jun).
6. Ko CJ, et al. J Am Acad Dermatol 50(1):1-12 (2004 Jan).
7. Burkhart CN, et al. J Am Acad Dermatol 56(6):1044-7 (2007 Jun).
8. Mumcuoglu KY, et al. J Med Entomol 41(4):803-6 (2004 Jul).
9. District Health Authority Public Health Services of Nova Scotia. Guidelines for treatment of pediculosis capitis (head lice), August 2008.
10. Kaul N, et al. J Cutan Med Surg 11(5):161-7 (2007 Sep-Oct).
11. Mumcuoglu KY, et al. Isr Med Assoc J 4(10):790-3 (2002 Oct).
12. US Food and Drug Administration public health advisory on lindane.
13. Position Statement from Infectious Diseases and Immunization Committee, Canadian Paediatric Society. Paediatr Child Health 13(8):692-704 (2008 Oct).
14. Goldstein AO, et al. (2010 Jan). Available at: http://www.uptodate.com/home/index.html. Accessed July 3, 2010.

¹ Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
² Section of Dermatology, University of Manitoba, Winnipeg, MB, Canada

Introduction

Head lice infestations (Pediculosis capitis) are a worldwide problem with prevalence estimates typically ranging between 1-3% in elementary school aged children.^1,2 Although this obligate parasite is a nuisance, infestation does not pose a health risk. Infestations tend to occur more frequently in females,³ and less frequently in black children,⁴ as it may be more difficult for lice to grasp their oval-shaped hair shafts. It is not associated with poor hygiene. Infestation occurs across all levels of society, but occurs more frequently under conditions of overcrowding. Recent evidence suggests increasing frequency of topical treatment failure may be related to a growing resistance to the neurotoxic pediculicides that have been the first-line treatment for the last 40 years.⁵ Herein, we will review the current topical treatment options, including newer non-pediculicidal options.

Overview of Facts on Lice

• Pediculus humanus capitis (the head louse) is a 2-4 mm blood sucking, wingless insect.
• A louse cannot jump, but rather has 6 legs adapted for crawling along hairs at 23 cm per minute.⁶
• A louse will feed every 3-6 hours.
• Prior to feeding, the louse injects saliva into the skin.
• The life span is approximately 4 weeks and the female lays 6-8 eggs per day.
• Eggs hatch in 8 days, leaving their shell (“nit”) cemented to the base of the hair.
• Head lice spread by head contact, shared fabrics, shared combs, and other fomites that are commonly in contact with the scalp and hair.⁷
• A louse can survive 2-3 days away from a human host.
• Pets are not vectors.

Top

Diagnosis and Symptoms

Many affected individuals report no symptoms, but the most commonly reported symptom is scalp pruritus.⁸ The pruritus is thought to be caused by hypersensitivity to the louse saliva that is injected into the scalp during feeding, but the itching often does not begin until 1-4 weeks after infestation. Although any part of the scalp may be colonized, there seems to be a predilection for the nape of the neck and post-auricular areas.

Skin Findings

• Often there are no significant findings on the skin.
• Pruritic, papular lesions may be found at the nape of the neck.
• There may be excoriations on the scalp.
• Secondary staphylococcal infection is possible.
• Possible enlargement of cervical / nuchal lymph nodes.

Hair Findings

• True infestation is confirmed by the presence of live adult lice or nymphs (hatched immature lice) present on the scalp with nits.
• The presence of nits alone does not confirm infestation, as an empty nit can remain cemented to a hair even after the infestation has cleared.
• The distance of the nit from the scalp can be a clue to the duration of the infestation, as it moves with the hair away from the scalp when hair grows.
• A nit within 0.6 mm of the scalp is usually a viable egg.

Diagnosis is best made by wet or dry combing the scalp with a fine-toothed nit comb with teeth spaced 0.2 mm apart. One study comparing wet combing with visual inspection found that wet combing accurately diagnosed infestation 90.5% of the time, as compared to 28.6% with visual inspection.²

Directions for Detection by Wet Combing⁹

• Saturate hair with a conditioner.
• Remove tangles with a regular comb.
• With the nit comb against the scalp, comb to the end of the hair.
• Check the comb for lice after each pull by visual inspection and by cleaning the comb with a tissue and inspecting the contents.
• Dispose of the tissue in a plastic bag.
• Comb the entire scalp at least 5 times.
• Seal the plastic bag and dispose of it.
• If infestation is confirmed, rinse off all conditioner prior to treatment.

Treatment Options

Management

Traditionally, topical pediculicides have been the mainstay in the initial treatment of pediculosis. They are widely available without a prescription, which has contributed to the difficulty in gathering data on the true prevalence of infestation. Easy access and improper use has likely contributed to the significant resistance that has developed against topical pediculicides. Knockdown resistance (kdr) is a heritable insensitivity to dichlorodiphenyltrichloroethane (DDT), the pyrethrins, and the pyrethroids. A recent study examining lice collected in Quebec, Ontario, and British Columbia found the allele for resistance present in 97.1% of the 274 lice sampled.⁵ These findings suggest that a significant resistance to the traditional first-line treatment options exists within Canada.

In recognition of the developing resistance, there has been an increased interest within Canada to explore effective non-pediculicidal options. A recent study found the efficacy of isopropyl myristate 50% to be significantly higher (57%) than the standard treatment with pyrethrin 0.33% + piperonyl butoxide 4%.¹⁰

While non-pediculicidal therapy may be efficacious against treatment resistant infestations, re-infestation from close contacts and fomite transmission is a common problem. Along with treatment, it is important to decontaminate the environment.

Environmental Decontamination¹⁴

• Family members and close contacts should be examined and be treated for any infestation.
• Any clothing, linens, combs, toys, and fabrics used by the individuals in the 3 days preceding treatment should be decontaminated.
• Fabrics can be washed in high heat and put in a hot dryer for 20 minutes.
• Items that cannot be washed can be sealed in a plastic bag for 14 days or placed in the freezer for 24 hours.
• Brushes can be soaked in rubbing alcohol for 1 hour.
• Floors and furniture can be cleaned by vacuuming.
• Spraying the home with a pediculicide is not recommended.
• No nit policies at schools are unnecessary.

Management Tree

(scalp pruritus, papules at the nape of the neck, or known close contact with another infested individual)

Examine scalp using fine-toothed nit comb (0.2 mm spacing) Wet hair with lubricant, such as hair conditioner (optional), and comb front to back with the comb against the scalp

By wet or dry combing (presence of live adult louse or nymph)

Choose treatment (based on patient preference, age, and local resistance to topical pediculicides)

Take measures to decrease risk of reinfestation and spread (treat all family members, notify school, and decontaminate environment)

Manual Removal

Some patients may prefer to attempt mechanical treatments prior to topical therapy. Wet combing, as described earlier, can be both diagnostic and therapeutic. To attempt this method the patient should wet comb the entire scalp until no more lice are found every 3-4 days for 3 weeks, or at least 2 weeks after the last adult louse was found.¹⁴

Treatment Failure

Treatment failure is commonly a result of inadequate or improper treatment, resistance, or reinfestation. If environmental decontamination was performed and the treatment was properly administered, then immediate retreatment with a different agent is advised.

Conclusion

Head lice infestation is a common problem for children in Canada. The first-line treatment of using topical pediculicides is unfortunately not as effective as it once was because of a heritable resistance that seems to be rising in prevalence. Topical non-pediculicides may be an effective option in the case of failed treatment due to louse resistance to standard treatment.

References

1. Harris J, et al. Commun Dis Public Health 6(3):246-9 (2003 Sep).
2. Jahnke C, et al. Arch Dermatol 145(3):309-13 (2009 Mar).
3. Counahan M, et al. J Paediatr Child Health 40(11):616-9 (2004 Nov).
4. Centers for Disease Control and Prevention. Fact sheet: head lice. Available at: http://www.cdc.gov/lice/head/factsheet.html. Accessed June 28, 2010.
5. Marcoux D, et al. J Cutan Med Surg 14(3):115-8 (2010 May-Jun).
6. Ko CJ, et al. J Am Acad Dermatol 50(1):1-12 (2004 Jan).
7. Burkhart CN, et al. J Am Acad Dermatol 56(6):1044-7 (2007 Jun).
8. Mumcuoglu KY, et al. J Med Entomol 41(4):803-6 (2004 Jul).
9. District Health Authority Public Health Services of Nova Scotia. Guidelines for treatment of pediculosis capitis (head lice), August 2008.
10. Kaul N, et al. J Cutan Med Surg 11(5):161-7 (2007 Sep-Oct).
11. Mumcuoglu KY, et al. Isr Med Assoc J 4(10):790-3 (2002 Oct).
12. US Food and Drug Administration public health advisory on lindane.
13. Position Statement from Infectious Diseases and Immunization Committee, Canadian Paediatric Society. Paediatr Child Health 13(8):692-704 (2008 Oct).
14. Goldstein AO, et al. (2010 Jan).

Section of Dermatology, University of Manitoba, Winnipeg, MB, Canada

ABSTRACT

Psoriasis is a common skin disease affecting 1%-3% of the world’s population with significant impacts on quality of life. There is a great need for therapies that are efficacious and safe, not only for the short-term, but also for long-term management. Dovobet^®/ Daivobet^®/ Taclonex^® is a product combining two molecules, calcipotriol and betamethasone dipropionate, that may offer psoriatic patients with an option for maintenance therapy. The efficacy and safety of this combined formulation when used over a 4-week period is well documented. A recent publication in the British Journal of Dermatology discusses the safety of this product when used for 52 weeks.¹

Key Words:
Calcipotriol, Betamethasone Dipropionate, Psoriasis

Dovobet^®(Leo Pharma)/ Daivobet^®(Leo Pharma)/ Taclonex^®(Warner Chilcott) is a two-compound ointment containing calcipotriol 50ìg/gm and betamethasone dipropionate 0.5mg/gm. Hereafter, this ointment will be referred to as either “Dovobet^®” or “combination product” in this article.

Calcipotriol

Calcipotriol is a Vitamin D analog with a broad range of pharmacologic activities. Like vitamin D, calcipotriol inhibits keratinocyte proliferation, promotes epidermal differentiation and has a significant impact on cytokines and T-cells in the skin. Calcipotriol, however, has much less effect on calcium levels as compared to vitamin D. Topical calcipotriol 50ìg/gm has been used worldwide for over 15 years for the treatment of psoriasis vulgaris. A plethora of randomized controlled double-blind studies have confirmed its efficacy.^2,3

Topical calcipotriol has a good long-term safety profile and again there are many studies documenting this.^3,4 Most adverse reactions relate to initial application, irritation to or aggravation of existing psoriatic lesions. There have been isolated case reports of hypercalcemia,⁵ however this is uncommon when application is limited to <100gm/week in adults.

Corticosteroids

Topical corticosteroids have been the cornerstone of psoriasis therapy for many years. A recent study demonstrated that a super-potent steroid was used by 44% of psoriasis patients.⁶ Their efficacy and limitations are well known. Apart from concerns relating to systemic absorption, the major concern relating to long-term topical steroid use is cutaneous atrophy and its various clinical presentations.

Betamethasone dipropionate has been categorized by the World Health Organization as a group III (mid-high) potency steroid. It has been shown to be safe and effective in treating psoriasis vulgaris.

Combined Formulation

Initially, combining betamethasone dipropionate and calcipotriol in a vehicle proved difficult as these two substances are incompatible in aqueous and alcoholic media. In Dovobet^®, these molecules are combined in a water free vehicle, ensuring maximum stability and efficacy. It is also formulated to achieve optimal skin permeability.⁷

A recent study documented the effects of the molecules, in isolation and in combination, when used on psoriatic skin.⁸ Calcipotriol alone had a major effect on the proliferation marker Ki-67 and differentiation marker keratin-10 (K-10) while reducing T-cell subsets CD 45RO (+) and CD8 (+). Betamethasone dipropionate produced a highly significant increase of the K-10 positive epidermal surface without an effect on Ki-67 positive nuclei, and the effect on T-cell subsets was a reduction of natural cell to cell receptors CD94 and CD161 in the epidermis. Therapy involving both molecules showed no added effect in relationship to proliferation marker Ki-67 and keratinization marker keratin-10, but when amalgamated, they had a profound effect on all T-cell subsets. This suggested a different mode of action of the two molecules on psoriatic plaques at the molecular level and points to evidence that supports a synergistic effect when they are combined.

Dovobet^® has been proven to be highly effective in treating psoriasis vulgaris.⁹ A recent study suggested PASI 50 and PASI 75 response in greater than 80% and 50% of patients respectively, regardless of initial disease severity. The report combined data from six phase III studies involving more than 6500 patients.^10,11

Many recent reports have noted the profound effect that psoriasis has on the quality of life of patients. When applied once daily, Dovobet^® has been shown to be superior to calcipotriol applied twice daily in improving the quality of life of patients with psoriasis vulgaris.¹²

The majority of studies documenting the efficacy and safety of Dovobet^® have been limited to four-week periods of observation. As such, due to the chronic nature of psoriasis, detailed documentation to track long-term safety and efficacy is required by regulatory authorities.

Study Results

Recently, results of a 52-week randomized study of Dovobet^® in the treatment of psoriasis vulgaris were published in the British Journal of Dermatology.¹ The primary objective of this study was to investigate the safety of two treatment regimens involving the “as needed” use of Dovobet^® over 52 weeks. In particular, side-effects relating to the long-term use of a topical steroid were assessed by an adjudication panel consisting of three dermatologists not otherwise involved in the study.

Patients were randomized to one of the three double-blinded treatment groups:

• 52-weeks of combination product;
• 52-weeks of alternating 4-week periods of the combination product and calcipotriol ointment (alternating group); and
• 4-weeks of the combination product followed by 48 weeks of calcipotriol ointment (calcipotriol [non-steroidal control] group).

Treatment was limited to once daily application as required, and usage was limited to a maximum of 100gm/week per patient. Patients were seen every 4 weeks for assessment of adverse effects. A subset of 19 patients had adrenal function tests at baseline and after 4, 12, and 62 weeks.

The study was conducted from August 2002 to April 2004 and 634 patients were enrolled in 67 European centers and 10 Canadian centers. The treatment groups were similar with respect to age, sex, ethnic origin, duration of psoriasis, duration of previous topical steroid use and disease severity.

There were 21.7% of patients that developed adverse drug reactions in the Dovobet^® group, 29.6% in the alternating group, and 37.9% in the calcipotriol group. In addition to the aggravation of existing psoriatic lesions, the most common adverse reaction was application-related irritation. The most common adverse reactions with calcipotriol treatment are known to be irritation and pruritus, as was reflected in the calcipotriol group. This study indicates that the steroid molecule reduces the irritative effect of calcipotriol in the Dovobet^® group. The incidence of initial flare-ups of psoriatic lesions was similar in all groups.

There was one systemic event in the subset of 19 patients undergoing adrenal function testing. This one patient, who demonstrated adrenal insufficiency, was in the calcipotriol treatment group. Consequently, the event was considered unrelated to the therapy.

Skin atrophy was identified by the adjudication panel in 1.9% of the Dovobet^® group, 0.5% of the alternating group, and 1.0% in the calcipotriol group. The four patients identified in the Dovobet^® group demonstrated atrophy at 10–33 weeks of therapy and the condition resolved in three of the four patients. The fourth patient had used topical corticosteroids continuously for the previous 10 years prior to the study and continued to use Dovobet^® every other day, as needed, in the remaining 40 weeks of the study following identification of the atrophy. In addition, he was prescribed Dovobet^® once the study was completed. Folliculitis was noted by the adjudication panel in three patients in the Dovobet^® group and in one patient in the alternating group, however all cases were mild. One patient in the calcipotriol group developed cellulitis. There were two cases of depigmentation in the Dovobet^® group, one of which had resolved during the period of observation.

The study concluded that Dovobet®, when used for up to 52 weeks, was safe and well tolerated whether used as monotherapy, or alternating every 4 weeks with calcipotriol treatment.

Conclusion

The combination of calcipotriol and betamethasone dipropionate has been proven to be a very effective option for the topical treatment of psoriasis vulgaris.8-12 Recently published findings indicate its safety and tolerability for continuous use as needed for up to 52 weeks.¹

References

1. Kragballe K, Austad J, Barnes L, et al. A 52-week randomized safety study of a calcipotriol/betamethasone dipropionate two-compound product (Dovobet/Daivobet/Taclonex) in the treatment of psoriasis vulgaris. Br J Dermatol 154(6):1155-60 (2006 Jun).
2. Ramsay CA, Berth-Jones J, Brundin G, et al. Long-term use of topical calcipotriol in chronic plaque psoriasis. Dermatology 189(3):260-4 (1994 Jan).
3. Aaronson DS, Lebwohl M. Review of therapy of psoriasis: the prebiologic armamentarium. Dermatol Clin 22(4):379-88 (2004 Oct).
4. Cullen SI. Long-term effectiveness and safety of topical calcipotriene for psoriasis. Calcipotriene Study Group. South Med J 89(11):1053-6 (1996 Nov).
5. Georgiou S, Tsambaos D. Hypercalcaemia and hypercalciuria after topical treatment of psoriasis with excessive amounts of calcipotriol. Acta Derm Venereol 79(1):86 (1999 Jan).
6. Pearce DJ, Spencer L, Hu J, et al. Class I topical corticosteroid use by psoriasis patients in an academic practice. J Dermatolog Treat 15(4):235-8 (2004 Jul).
7. Simonsen L, Hoy G, Didriksen E, et al. Development of a new formulation combining calcipotriol and betamethasone dipropionate in an ointment vehicle. Drug Dev Ind Pharm 30(10):1095-102 (2004 Jan).
8. Vissers WH, Berends M, Muys L, et al. The effect of the combination of calcipotriol and betamethasone dipropionate versus both monotherapies on epidermal proliferation, keratinization and T-cell subsets in chronic plaque psoriasis. Exp Dermatol 13(2):106-12 (2004 Feb).
9. Papp KA, Guenther L, Boyden B, et al. Early onset of action and efficacy of a combination of calcipotriene and betamethasone dipropionate in the treatment of psoriasis. J Am Acad Dermatol 48(1):48-54 (2003 Jan).
10. Anstey AV, Kragballe K. Retrospective assessment of PASI 50 and PASI 75 attainment with a calcipotriol/betamethasone dipropionate ointment. Int J Dermatol 45(8):970-5 (2006 Aug).
11. Kragballe K, van de Kerkhof PC. Consistency of data in six phase III clinical studies of a two-compound product containing calcipotriol and betamethasone dipropionate ointment for the treatment of psoriasis. J Eur Acad Dermatol Venereol 20(1):39-44 (2006 Jan).
12. van de Kerkhof PC. The impact of a two-compound product containing calcipotriol and betamethasone dipropionate (Daivobet/Dovobet) on the quality of life in patients with psoriasis vulgaris: a randomized controlled trial. Br J Dermatol 151(3):663-8 (2004 Sep).