About the Author
Maha Dutil, MD, M.Ed, FRCPC
Dr. Dutil is a dermatologist in private practice. She received her medical degree and completed dermatology residency at the University of Toronto. She completed a Master of Education in 2006. Dr Dutil is an assistant professor of Medicine in the Division of Dermatology at the University of Toronto where she has served as co-director of the undergraduate dermatology program at the U of T medical school, and director of the Continuing Education Program in the Division of Dermatology. She is the President of the Toronto Dermatological Society and President of TWEAD (Toronto Women’s Education Association for Dermatologists) and the chair of the Women’s Dermatology Symposium which focuses on education related to women’s dermatologic health and disease.
Special Supplement, Canadian Dermatology Today, February, 2022
The Evolution Of Cal/BD Fixed Dose Combination Therapy For Psoriasis: A Case Study And Discussion
A fourteen-year-old boy presented with itchy thick red scaly plaques on his scalp, arms, legs, and torso. They had been present since the age of seven. The boy hid behind his long hair and made no eye contact with me; he was accompanied by his father who did all the speaking. The itching in his scalp was more intense than other areas. His only therapy at that point had been tar shampoo as well as topical steroid creams for his body, and neither offered much improvement in symptoms.
A family history revealed that his paternal uncle had severe psoriasis and psoriatic arthritis.
On physical examination, the patient had well-demarcated erythematous plaques with a thick silvery scale throughout the scalp, on the elbows, extensor forearms, knees, shins, and lower back. He was wearing a removable cast on his left forearm for a wrist fracture that had healed months ago. He was obese with a BMI of 43 and a BP of 140/80 mmHg. Blood work revealed a FBS 5.4 mmol/L, Cholesterol 5.61 mmol/L (↑ LDL, ↓HDL), Triglycerides 8.7 mmol/L, CRP 0.8 mg/L and elevated liver enzymes with suspected non-alcoholic steatohepatitis.
After discussion about the diagnosis and possible treatment options, the boy’s father asked me if I could write a note to his teacher to exempt him from gym class as his son’s classmates had been ridiculing him in the change room when they saw his skin condition on his arms and legs, which is why he had continued to wear his cast.
Psoriasis can have a tremendous impact on a child’s physical, emotional and social quality of life.1 For this particular patient, having psoriasis was devastating. In addition, his father felt the guilt of having passed this gene on to his son and the frustration of not having found adequate treatment to control his son’s psoriasis over the previous 7 years.
A treatment option that was effective, safe, and easy to use leading to better adherence was the desired solution. As much as the patient was interested in clearing his skin quickly, his father was equally concerned about the long-term risks of therapy given his brother’s long battle with severe disease associated with arthritis and some complications from systemic therapies he had used.
Parents may underestimate the emotional burden of psoriasis in their children and the requirement for counselling and support from their child’s dermatologist.1 After a long discussion focused on the skin condition itself and treatment options, calcipotriol/betamethasone dipropionate (Cal/BD) foam was prescribed for the patient’s scalp and body plaques and a 1-month follow-up was arranged to discuss potential comorbidities.
This article will review some highlights of psoriasis in children and adolescents as well as the rationale behind potential therapeutic treatment options.
Psoriasis is a chronic, immune-mediated, genetic inflammatory skin disease that occurs in 2-3% of the Canadian population, which is comparable in incidence and prevalence to Europe and the USA.3 It begins in childhood in almost a third of patients and the prevalence increases in a linear pattern from age 1 to age 18.4 The incidence continues to increase from the 2nd decade reaching a peak in the latter half of the 6th decade. The global incidence of psoriasis has increased over the past 30 years in both adults and children, especially in North America and Western Europe.5,6 As illustrated in this case, psoriasis is associated with comorbidities, such as hypertension, obesity, impaired glucose tolerance, hyperlipidemia, arthritis, and inflammatory bowel disease. These comorbidities occur in twice as many patients under the age of 20 with psoriasis as those without.7
The first line of treatment for mild-to-moderate psoriasis is topical therapy, which also complements systemic therapies in more severe disease.
Rationale for Cal/BD Fixed Dose Combination
Until recently, topical treatment options included steroids and calcipotriol as monotherapy, as well as tar, anthralin, and tazarotene. A stable formulation containing both Cal/BD in an ointment base was developed more than 20 years ago. It was thought that this combination might yield superior efficacy and that the calcipotriol and the topical steroid would have complementary effects on psoriatic inflammation. It was also hypothesized that the local irritation caused by calcipotriol might be alleviated via the anti-inflammatory effect of the steroid and that the skin atrophy from the corticosteroid might be reduced via the use of a Vitamin D analogue.8,9 (Box 1 and Table 1) Having two active ingredients in a single formulation would also improve patient adherence.
In a double-blind study, 1106 patients were randomized to receive combination Cal/BD ointment, BD ointment or Cal ointment twice daily for 4 weeks. The primary efficacy endpoint clearly demonstrated that the combination treatment was more effective than the individual active components. The mean decrease in PASI from baseline to the end of the double-blind phase was statistically significantly greater in the combination group compared to both the betamethasone and calcipotriol groups and showed a more rapid onset of action with statistically significant differences in PASI evident after 1 week.10
In another study, 1,603 patients randomised to one of the 4 double-blind treatments used a regimen composed of a once daily application for 4 weeks with either Cal 50 mcg/g + BD 0.5 mg/g combination ointment, or BD 0.5 mg/g ointment or Cal 50 mcg/g ointment or ointment vehicle. The results demonstrated the superiority of the combination group to the other three groups with the mean decrease in PASI being evident in the combination group after only 1 week.11 The mean decrease in PASI observed with the combination once-daily treatment in this study was similar to that seen with the combination twice-daily treatment in the previous study.
Cal/BD Fixed Dose Combination in Pediatrics
The efficacy and safety of Cal/BD has also been demonstrated in a pediatric population.12,13 In a study from 2014, seventy-three patients (mean age 10.8 years) with mild-to-moderate plaque psoriasis were treated with Cal/BD ointment for a median time of 35·0 weeks. At week 12, the mean PASI decreased 15·4% (from 5·2 to 4·4), BSA did not change in a meaningful manner, and median CDLQI decreased significantly from 5·5 to 4·0. VAS scores for pain and itch declined. At week 24, mean PASI decreased to 4·3 (17·3%). No related serious adverse events were observed in this study.12 Another study assessed the safety of once-daily application of fixed-combination Cal plus BD gel in adolescent scalp psoriasis. Patients in this study were aged 12-17 years with moderate-to-very severe scalp psoriasis according to Investigator’s Global Assessment (IGA) (≥ 10% of the scalp area affected). Results showed that 66 patients (85%) were clear or almost clear according to IGA. There was an 80% improvement in mean Total Sign Score from baseline to end of treatment. In total, at the end of treatment, 87% of patients rated their scalp psoriasis as clear or very mild, and 75 (96%) had no or mild pruritus compared with 14 (18%) at baseline (Figure 1).13
In a third study, the safety of the two-compound product, Cal/BD was assessed with results demonstrating that treatment up to 52 weeks appeared to be safe and well tolerated whether used on its own or alternating every 4 weeks with calcipotriol treatment.14 This is welcome news given that psoriasis is a chronic, relapsing and remitting disease that requires long-term management.14
Cal/BD Fixed Dose Combination in Scalp Psoriasis
Scalp psoriasis typically represents a therapeutic challenge. Itching and scaling represent the most distressing symptoms, and in some cases, scalp psoriasis can be associated with psoriatic alopecia, which can lead to scarring.15 Patient adherence to therapy is also a challenge based on the type of vehicle (greasy vehicles are less acceptable), and ease and frequency of application.
A multicenter, randomized, double-blind study of 1504 patients with scalp psoriasis was conducted to compare the clinical efficacy and safety of once-daily treatment for up to 8 weeks. The study randomized four treatments as follows: two-compound scalp formulation (calcipotriene 50 μg/g plus betamethasone 0.5 mg/g, as dipropionate) (n = 541), betamethasone 0.5 mg/g (as dipropionate) in the same vehicle (n = 556), calcipotriene 50 μg/g in the same vehicle (n = 272), or vehicle alone (n = 136). the The scalp formulation vehicle is less greasy than an ointment, which addresses patients’ concerns around cosmetic acceptability. Patients who used the two-compound scalp formulation achieved “absent” or “very mild” disease more quickly than any other group, and this efficacy advantage became evident after only 2 weeks of treatment. The effect was achieved using an average of 20 g less medication over the full study period than in the BD group (p = 0.023), indicating a potential steroid-sparing effect of the two-compound scalp formulation.16
A 52-week, international, double-blind study of 869 patients with moderate-to-severe scalp psoriasis demonstrated a high level of safety and efficacy in long-term management of scalp psoriasis with the two-compound scalp formulation (Cal 50 μg/g plus BD 0.5 mg/g).17
Cal/BD Aerosol Foam Formulation
To improve drug delivery further, an alcohol-free, surfactant-free aerosol foam formulation of Cal/BD, in which the active ingredients are dissolved in a mixture of volatile propellants (butane and dimethyl ether) to build a stable, supersaturated solution after the rapid evaporation of the propellants, was developed. The medication is in a non-skin-drying emollient vehicle in a pressurized spray can. This is associated with enhanced skin penetration and increased bioavailability.18 The foam is to be rubbed gently onto affected areas once-daily with usage not exceeding 15 g daily. Clinical studies have shown Cal/BD aerosol foam to be more efficacious than the vehicle19, more efficacious than Cal or BD aerosol foam alone20 and more efficacious than Cal/BD ointment in patients with psoriasis vulgaris.21,22 In the PSO-ABLE study, 4 weeks of Cal/BD aerosol foam was significantly more effective than 8 weeks of Cal/BD gel in patients with psoriasis (with lower drug consumption)23. This superiority was reached by week 1 and maintained throughout the 12-week treatment period.
Although the Cal/BD foam formulation has an increased bioavailability (as a result of the supersaturation and increased skin penetration), calcipotriol/ betamethasone foam was not associated with an increased risk of treatment-related adverse events compared with the individual components as foam or the fixed combination as topical gel or ointment formulations.24 In patients with extensive psoriasis vulgaris (15%-30% of body surface area, including ≥30% of scalp) who were treated once daily for 4 weeks, Cal/BD aerosol foam exhibited no clinically relevant impact on the hypothalamic– pituitary–adrenal (HPA) axis or calcium homeostasis. Results from this multicentre, single-arm, open-label, maximal-use systemic-exposure trial demonstrated that 49% of patients achieved treatment success (clear or almost clear status) when evaluated for efficacy. Cal/BD foam also demonstrated a favourable tolerability profile.25
The use of Cal/BD foam in adolescents is supported by a phase II, multicentre, prospective, open-label, non-controlled, single-group, 4-week trial in patients aged 12 to <17 years with plaque psoriasis on the body and scalp.26 Results from this study show that Cal/BD foam is generally well-tolerated in adolescent patients. Over 4 weeks of treatment with Cal/BD foam, 32 treatment-emergent adverse events (AEs) occurred in 22 patients (20.8%), all but two of which were mild in severity (no treatment-emergent AEs were serious or severe). No treatment-emergent AEs led to study withdrawal or death. The most frequently reported AEs were upper respiratory tract infection [eight (7.5%)], nasopharyngitis [four (3.8%)], and acne [two (1.9%) and expected in this age group]. There was no evidence for dysregulation of calcium homeostasis or the HPA axis in patients with moderate disease. Limitations of this study include the fact that it was not designed to determine a maximum tolerated dose and the open-label design could not exclude the possibility of investigator bias. Additionally, the lack of a placebo control group impaired the determination of the true efficacy and safety of Cal/BD foam in adolescents and no patients in the HPA-axis cohort had a PGA of severe disease.
Cal/BD Fixed Dose Combination in Elevated BMI
The use of Cal/BD foam in patients with an elevated BMI is supported by the sub-analysis from the PSO-FAST study demonstrating that Cal/BD aerosol foam, if used appropriately, is effective for the treatment of psoriasis independent of BMI and the extent or severity of disease.27
Case Study (Continued)
The 14-year-old patient returned after four weeks of Cal/BD foam use with marked improvement of the scalp and skin plaques; but many challenges remained and had to be discussed, including the disease’s potential to affect the cardiovascular system and metabolic pathways, as well as the lifelong psychosocial impact of psoriasis. Patients with early-onset psoriasis (age < 20 years) have been observed to be more anxious and depressed than patients with late-onset psoriasis.28 The use of Cal/BD foam may provide substantial benefit to adolescent patients and the risk-benefit profile of initiating such therapy should be discussed with patients and their families to ensure optimal outcomes considering all aspects of the disease’s impact on a patient’s life.
- Dogra S, Kaur I. Childhood psoriasis. Indian J Dermatol Venereol Leprol 2010; 76:357-65.
- Gitte Susanne Rasmussen, Knud Kragballe, Helle Terkildsen Maindal & Kirsten Lomborg (2020) Caring for young people with moderate to severe psoriasis: an interpretive description of parental perspectives, Journal of Dermatological Treatment, 31:3, 227-234, DOI:10.1080/0954663 4.2019.1590523.
- Eder L, Widdifield J, Rosen CF, Cook R, Lee KA, Alhusayen R, Paterson MJ, Cheng SY, Jabbari S, Campbell W, Bernatsky S, Gladman DD, Tu K. Trends in the Prevalence and Incidence of Psoriasis and Psoriatic Arthritis in Ontario, Canada: A Population-Based Study. Arthritis Care Res (Hoboken). 2019 Aug;71(8):1084-1091. doi: 10.1002/ acr.23743. Epub 2019 Jul 11. PMID: 30171803.
- Augustin M, Glaeske G, Radtke MA, Christophers E, Reich K, Schafer I. Epidemiology and comorbidity of psoriasis in children.Br J Dermat. 2010;162(3):633–6.
- AlQassimi et al. Global burden of psoriasis – comparison of regional and global epidemiology, 1990 to 2017 International Journal of Dermatology 2020, 59, 566–571.
- Tollefson MM, Crowson CS, McEvoy MT, Maradit Kremers H. Incidence of psoriasis in children: a population-based study. J Am Acad Dermatol. 2010;62(6):979–87.
- Augustin M, Glaeske G, Radtke MA, Christophers E, Reich K, Schafer I. Epidemiology and comorbidity of psoriasis in children.Br J Dermat. 2010;162(3):633–6.
- Segaert S, Shear NH, Chiricozzi A, et al. Optimizing Anti-Inflammatory and Immunomodulatory Effects of Corticosteroid and Vitamin D Analogue Fixed-Dose Combination Therapy. Dermatol Ther (Heidelb). 2017;7(3):265-279. doi:10.1007/ s13555-017-0196-z.
- Norsgaard H, Kurdykowski S, Descargues P et al. Calcipotriol counteracts betamethasone-induced decrease in extracellular matrix components related to skin atrophy. Arch Dermatol Res 2014; 306: 719–729.
- Douglas WS, Poulin Y, Decroix J, et al.A New Calcipotriol/Betamethasone Formulation with Rapid onset of Action was Superior to Monotherapy with Betamethasone Dipropionate or Calcipotriol in Psoriasis VulgarisActa Derm Venereol 2002; 82: 131–135.
- Kaufmann R, Bibby AJ, Bissonnette R, Cambazard F, Chu AC, Decroix J, Douglas WS, Lowson D, Mascaro JM, Murphy GM, Stymne B. A new calcipotriol/betamethasone dipropionate formulation (Daivobet) is an effective once-daily treatment for psoriasis vulgaris. Dermatology. 2002;205(4):389-93. doi: 10.1159/000066440. PMID: 12444337.
- van Geel MJ, Mul K, Oostveen AM, et al. Calcipotriol/betamethasone dipropionate ointment in mild-to-moderate paediatric psoriasis: long-term daily clinical practice data in a prospective cohort. Br J Dermatol. 2014;171(2):363–9.
- Gooderham M, Debarre JM, Keddy- Grant J, et al. Safety and efficacy of calcipotriol plus betamethasone dipropionate gel in the treatment of scalp psoriasis in adolescents 12–17 years of age. Br J Dermatol. 2014;171(6):1470–7.
- Kragballe K, Austad J, Barnes L, Bibby A, de la Brassinne M,Cambazard F, 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 2006;154:1155-60.
- van de Kerkhof PCM, de Hoop D, de Korte J, Kuipers MV. Scalp psoriasis, clinical presentations and therapeutic management. Dermatology 1998;197:326-34.
- Gemec, G et al. A new scalp formulation of calcipotriene plus betamethasone compared with its active ingredients and the vehicle in the treatment of scalp psoriasis: A randomized, double-blind, controlled trial J Am Acad Dermatol 2008;59:455-63.
- Luger T, A, Cambazard F, Larsen F, G, Bourcier M, Gupta G, Clonier F, Kidson P, Shear N, H: A Study of the Safety and Efficacy of Calcipotriol and Betamethasone Dipropionate Scalp Formulation in the Long-Term Management of Scalp Psoriasis. Dermatology 2008;217:321-328. doi: 10.1159/000155642.
- Lind, M., Nielsen, K.T., Schefe, L.H. et al. Supersaturation of Calcipotriene and Betamethasone Dipropionate in a Novel Aerosol Foam Formulation for Topical Treatment of Psoriasis Provides Enhanced Bioavailability of the Active Ingredients. Dermatol Ther (Heidelb) 6, 413–425 (2016). https:// doi.org/10.1007/s13555-016-0125-6.
- Leonardi C, Bagel J, Yamauchi P, et al. Efficacy and safety ofcalcipotriene plus betamethasone dipropionate aerosol foam in patients with psoriasis vulgaris – a randomized Phase III study (PSO-FAST). J Drugs Dermatol. 2015;14(12):1468–1477.
- Lebwohl M, Tyring S, Bukhalo M, et al. Fixed combination aerosol foam calcipotriene 0.005 % (Cal) plus betamethasone dipropionate 0.064% (BD) is more efficacious than Cal or BD aerosol foam alone for psoriasis vulgaris-a randomized, doubleblind, multicenter, three-arm, phase 2 study. J Clin Aesthet Dermatol. 2016;9(2):34–41.
- Koo J, Tyring S, Werschler WP, et al. Superior efficacy of calcipotriene and betamethasone dipropionate aerosol foam versus ointment in patients with psoriasis vulgaris—a randomized phase II study. J Dermatolog Treat. 2016;27:120–7.
- Queille-Roussel C, Olesen M, Villumsen J, Lacour JP. Efficacy of an innovative aerosol foam formulation of fixed combination calcipotriol plus betamethasone dipropionate in patients with psoriasis vulgaris. Clin Drug Investig. 2015;35:239–45.
- Paul, C,Stein Gold, L et al Calcipotriol plus betamethasone dipropionate aerosol foam provides superior efficacy vs. gel in patients with psoriasis vulgaris: randomized, controlled PSO-ABLE study. JEADV 2017, 31, 119–126.
- Kim, ES Frampton, JE. Calcipotriol/ Betamethasone Dipropionate Foam: A Review in Plaque Psoriasis Drugs (2016) 76:1485–1492.
- Karaska V, Tuppal R, Olesen M, et al. A novel aerosol foam formulation of calcipotriol and betamethasone has no impact on HPA axis and calcium homeostasis in patients with extensive psoriasis vulgaris. J Cutan Med Surg. 2015;20(1):44–51.
- Seyger M, Abramovits W, Liljedahl M, Hoejen MN, Teng J. Safety and efficacy of fixed-dose combination calcipotriol (50 lg/g) and betamethasone dipropionate (0.5 mg/g) cutaneous foam in adolescent patients (aged 12 to <17) results of a phase II, open-label trial. J Eur Acad Dermatol Venereol 2020; 34: 2026–2034.
- Stein Gold, L et al Calcipotriol Plus Betamethasone Dipropionate Aerosol Foam is Effective, Independent of Body Mass Index and the Extent and Severity of Psoriasis Dermatol Ther (Heidelb) (2016) 6:667–673.
- Remrod, C et al Psychological differences between early- and late-onset psoriasis: a study of personality traits, anxiety and depression in psoriasis British Journal of Dermatology (2013) 169, pp344–350.