L. C. Guenther, MD, FRCPC

The Guenther Dermatology Research Centre, London, ON, Canada

ABSTRACT


Scalp psoriasis occurs in 50%-75% of patients with plaque psoriasis. It may be the only area of the body affected, or it may be associated with disease elsewhere, including psoriatic arthritis. Most cases are treated topically, usually with steroids and/or calcipotriol. In 2008, Health Canada and the US FDA approved a stable, once-daily 2-compound gel containing calcipotriol and betamethasone dipropionate (Xamiol®, LEO Pharma; Taclonex Scalp®, Warner Chilcott). This once-daily therapy improves patient quality of life with a quick onset of action and greater efficacy than monotherapy with either ingredient or twice daily treatment with calcipotriol 0.005% (Dovonex®, LEO Pharma) scalp solution. The gel vehicle was developed for ease of use, improved cosmetic acceptability and absorption on the scalp. By 2 weeks, approximately 60%, and by 8 weeks, approximately 70% of patients have controlled disease (i.e., absent or very mild disease). At 8 weeks, the calcipotriol and betamethasone dipropionate gel formulation has a safety profile comparable with betamethasone dipropionate and is associated with significantly fewer adverse events than
calcipotriol. Xamiol® may be safely used for up to 52 weeks. No cases of atrophy, striae, or steroid purpura were noted in two 52-week studies.

Key Words:
calcipotriol, betamethasone dipropionate, steroid, vitamin D analogue, psoriasis, scalp psoriasis, fixed combination
therapy

Scalp Psoriasis

Psoriasis affects approximately 2% of the population,1
and in 50%-80% of cases, the scalp is affected.2 Scalp
involvement may occur in isolation, with plaque psoriasis
located elsewhere (most common), or with erythrodermic,
pustular or guttate psoriasis, and/or psoriatic arthritis.3 Single
or multiple, erythematous, pruritic, scaly plaques may occur
anywhere on the scalp. The entire scalp may be affected and
lesions may spread onto the forehead and behind the ears.
Quality of life can be severely compromised, particularly if
lesions are visible, scales fall onto clothes, and when pruritus
is intense. Hair loss due to telogen effluvium may rarely
occur.4 Scaling and hair, particularly with very thick hair,
may be obstacles to medications reaching the scalp.

Current Treatments for Scalp Psoriasis

Treatment is almost always topical, although systemic and
biologic therapy may be necessary, particularly if there is
also extensive psoriasis elsewhere on the body.3 Once-daily,
efficacious treatments have been associated with greater
adherence.5

Topical steroids are the most widely used treatment. They
are available in a number of formulations including lotions, solutions, gels, sprays, foams, shampoos, oils, ointments,
and creams. In a randomized controlled trial, superpotent
clobetasol propionate shampoo (Clobex®, Galderma) was
shown to control (i.e., clear/almost clear) the disease in
42.1% of the patients (compared with 2.1% using the
vehicle).6 In a double-blind, vehicle controlled study, 26% of
the patients showed complete clearance vs. only 1% of the
patients applying the vehicle.7 Foams are well tolerated and
efficacious. Of the patients in clinical trials 72%-74% were
controlled with betamethasone valerate8 or clobetasol foam.9
Salicylic acid may be added for its keratolytic effects (e.g.,
Diprosalic® lotion, Schering Plough).3,10

The unpleasant smell, yellow staining of white or grey hair,
and mutagenic potential limit the use of tars.11

Calcipotriol (Dovonex®, LEO Pharma), a topical vitamin
D derivative, may be safely used for 52 weeks.12 One study
showed that twice daily application has similar efficacy
to 1% betamethasone valerate,13 although other studies
showed that it was significantly less effective than 0.1%
betamethasone 17-valerate solution,14 and 0.05% clobetasol
propionate shampoo.15

Some patients are treated with a twice-daily application of
calcipotriol and corticosteroids to try to improve efficacy
and tolerability. However, mixing commercially available
topical steroids and calcipotriol is not advised, since the pH
of the resultant mixture would be different and most likely
both components would be inactivated.

Two small studies showed that a stable topical ointment
containing calcipotriol and betamethasone dipropionate
(Dovobet®, LEO Pharma) is efficacious.16,17 However, the
ointment base is generally not well accepted for scalp use,
since it makes the hair greasy and is difficult to wash out of
long hair.

Xamiol®, the Compound

Xamiol® is a lipophilic gel specially formulated for the
scalp. It contains the same active ingredients as Dovobet®
ointment, namely calcipotriol 0.005% and betamethasone
dipropionate 0.05%.18 This shear thinning gel sets when at
rest and gets thinner when shaken. It has 2 year stability at
room temperature, but should be used within 3 months of
opening.19 Systemic absorption is low.19

Mechanism of Action

Calcipotriol binds to the vitamin D receptor, then acts
as a heterodimer with the retinoid X receptor (RXR),20
normalizing differentiation and proliferation. It also reduces
CD45RO+ and T suppressor cells, and induces a Th1 to Th2
switch.21-24

Betamethasone dipropionate is a potent topical steroid. In
the cytoplasm, steroids bind to glucocorticoid receptors,
then rapidly translocate to the nucleus where they inhibit or stimulate genes that regulate inflammation.25
As a consequence, the production of cytokines, such as
interleukin–1 and –8, tumor necrosis factor alpha, and
gamma interferon are inhibited; nitric oxide, prostaglandins,
and levels of leukotrienes are reduced.23,26,27 Corticosteroids
can also regulate keratinocyte differentiation.28 Both
vitamin D and corticosteroids can increase the number of
T regulatory cells that are diminished in psoriatic skin.29,30

Clinical Efficacy of Xamiol®

This formulation has a quick onset of action and is an
effective long-term treatment. In the phase II trial (n=218),31
after 2 weeks, the total sign score (TSS = redness score +
thickness score + scaling score; range 0-12) decreased by
4.49 in the Xamiol® arm, and by 3.75 in the betamethasone
arms (p=0.005). Moreover, 67.6% of the Xamiol® group
compared with 52.7% in the betamethasone group were
clear/almost clear (p=0.025). At 8 weeks, the TSS was
reduced by 5.33 for the Xamiol® group vs. 4.76 for the
betamethasone arm (p=0.042); 83.3% of patients in the
Xamiol® group vs. 74.6% using betamethasone showed an
absence of disease or very mild disease.

STUDY Calcipotriol/
Betamethasone
dipropionate
O.D.
Betamethasone
dipropionate
O.D.
Calcipotriol
O.D.
Calcipotriol
scalp solution
B.I.D.
Vehicle
O.D.
Buckley, et al.31
(n=218)
83.3% 74.6%
Jemec, et al.32
(n=1505)
71.2% 64.0% 36.8% 22.8%
van der Kerkhof, et al.33
(n=1415)
68.4% 61.0% 43.4%
Kragballe, et al.34
(n=312)
68.6% 31.4%
Luger, et al.36
(n=869)
55.7% 31.8%
Tyring, et al.37
(n=175)
71.9% 40.5%
Table 1: Percent of patients with Investigator Global Assessment of absent/very mild at 8 weeks

The 2 phase III, international, multicenter, randomized,
blinded pivotal trials involved almost 3,000 patients and
showed that Xamiol® was more efficacious than its individual
ingredients.32,33 (Table 1)

Jemec et al.32 reported a reduction of 70.8% in TSS in the
Xamiol® group, 57.7% in betamethasone dipropionate
(p=0.12) group, 49.0% in the patients using calcipotriol
(p<0.0001), and 35.6% using the vehicle (p<0.0001). The
Investigator Global Assessment (IGA) was “absent/very mild” in 71.2% of the patients who were treated with
Xamiol® vs.:

  • 64.4% of those treated with betamethasone dipropionate (odds ratio [OR] 1.41, 95% confidence interval [CI]: 1.08-1.83, p=0.011)
  • 36.8% of those treated with calcipotriol (OR 4.13, 95% CI: 3.00-5.70, p<0.0001)
  • 22.8% of patients treated with the vehicle (OR: 8.65, 95% CI: 5.52-13.56, p<0.0001).

The onset of action was fast; at 2 weeks, 57.5% had
absent/very mild disease on Xamiol® compared with 47.1%
on betamethasone, 18.8% on calcipotriol, and 11.8% on
vehicle. The amount of study medication used during the
entire study was less for Xamiol® (139.1gm vs. 159.5gm for
betamethasone, 155.4gm for calcipotriol, and 176.4gm for
vehicle. The average weekly quantity of study medication
used was 17-22gm/week.

In a study by Kragballe et al., once-daily Xamiol® was
compared with twice daily Dovonex® scalp solution
(n=312).34 More than twice as many patients using Xamiol®
had controlled disease (i.e., absent/very mild; 68.6% vs.
31.4%). At 8 weeks, 56.3% of those whose condition was
very severe had controlled disease with Xamiol®, but none did on calcipotriol. In common with Jemec’s trial, a quick
onset was noted; at week 2, 49% on Xamiol® compared with
38.4% on steroids, and 15.7% on calcipotriol had absent/
very mild disease. Significant improvements in quality of
life, as measured by the short form-36 (SF-36) questionnaire,
were noted in the mental component at weeks 2, 4, and
8, but only at week 8 for calcipotriol scalp solution.35 In
addition, the amount of improvement in the Skindex 16 was
approximately twice as great with Xamiol®.

Two 52-week studies assessed long-term management.36,37 In
the first study, disease was absent/very mild/mild at 92.3%
of the visits in the Xamiol® arm vs. 80% in the calcipotriol
arm (p<0.0001).36 The withdrawal rate due to unacceptable
treatment efficacy was higher in the calcipotriol arm
(11.6% vs. 3.3%). The second long-term study (n=175) was
conducted in patients who were Hispanic/Latino (56%) or
African-American (44%).37 In the initial 8-week placebo
controlled portion, significantly more patients on Xamiol®
than vehicle had controlled disease (71.9% vs. 40.5%,
p<0.001). In patients treated with Xamiol® from the onset,
the median number of visits in which patients had clear,
minimal or mild disease was 100%.

STUDY Patients with at
least 1 AE
Patients with 1 AE
on calcipotriol or
vehicle
Patients with
perilesional AEs
Adverse Drug Reactions
Buckley, et al.31 74.6% ——— 10.3% Xamiol®
vs. 10.0%
betamethasone
8.l4% Xamiol® vs.
10.9% betamethasone
Jemec, et al. 34.4% Xamiol®
vs. 34.9%
betamethasone
(p=0.91)
46.2% calcipotriol
(p=0.0014) vs.
40% vehicle
(p=0.24)
4.7% Xamiol® vs.
5.3% betamethasone
vs. 13.2%
calcipotriol vs.
13.3% vehicle
7.9% Xamiol® vs.
8.4% betamethasone vs.
19.5% calcipotriol vs.
15.6% vehicle
van der Kerkhof, et al.33 38.7% Xamiol®
vs. 41.0%
betamethasone
(p=0.43)
46.1% calcipotriol
(p=0.04)
6.2% Xamiol® vs.
5.8% betamethasone
vs. 12.8%
calcipotriol
9.6% Xamiol® vs.
8.8% betamethasone vs.
18.4% calcipotriol
Kragballe, et al.34 34.5% Xamiol® 56.7% calcipotriol
scalp solution
(p<0.001)
3.4% Xamiol® vs.
19.2% calcipotriol
scalp solution
(p<0.001)
3.4% Xamiol® vs.
26.9% calcipotriol scalp
solution (p<0.001)
Luger, et al.36 66.8% 71.9% calcipotriol
(p=0.11)
11.9% Xamiol® vs.
21.6% calcipotriol
(p<0.001)
17.2% Xamiol® vs.
29.5% calcipotriol (p<0.001)
Tyring and Bibby37 36.7% Xamiol® vs.
34.2% vehicle
——— 3.1% Xamiol® vs.
2.6% vehicle
6.3% Xamiol® vs.
7.9% vehicle
Table 2: Adverse events reported for studies comparing Xamiol® with other treatments.

 

Patient Information

The Xamiol® bottle should be shaken. Then part hair to
expose the affected area of the scalp, then apply to dry skin
and gently rub in. Wash hands after applying. To remove
any excess gel vehicle from the hair, a mild, unmedicated
shampoo should be applied to dry hair and left on for a few
minutes. Then the hair should be washed normally. A second
shampooing may be required.18

Safety of Xamiol®

There were no significant changes in serum calcium, skin
atrophy, or striae in any of the trials. Table 2 summarizes
adverse events in the phase II and pivotal phase III trials.
A 52-week Xamiol® vs. calcipotriol study by Luger et al.36
showed similar results, although there were no differences in
the rates of AEs possibly related to long-term corticosteroid
use (e.g., rosacea, folliculitis, acne; 2.6% Xamiol® vs. 3.0%
corticosteroids). In the Hispanic/Latino/African-American
study, the Xamiol® and vehicle groups had similar AE rates
(36.7% and 34.2, respectively), adverse drug reactions (6.3%
and 7.9%, respectively) and perilesional/lesional adverse
events (3.1 and 2.6%, respectively) at 8 weeks.37

Conclusion

Xamiol® is a fast-acting, very efficacious, safe, oncedaily
treatment for scalp psoriasis ranging from mild to
very severe. It is more efficacious than calcipotriol in the
same base, or as the marketed solution (Dovonex® scalp
solution), betamethasone dipropionate, or the gel vehicle.
Approximately 60% of patients achieve absent or very
mild disease after only 2 weeks of therapy, and 70% after 8
weeks. The safety profile is similar to that of betamethasone
dipropionate and better than calcipotriol. Two 52-week
studies have shown that Xamiol® can be safely used longterm.
No cases of atrophy, striae, or senile purpura were
noted in any of the studies.

References

  1. Christophers E. Psoriasis: epidemiology and clinical spectrum. Clin Exp Dermatol 26(4):314-20 (2001 Jun).
  2. Papp K, Berth-Jones J, Kragballe K, et al. Scalp psoriasis: a review of current topical treatment options. J Eur Acad Dermatol Venerol 21(9):1151-60 (2007 Oct).
  3. Wozel G. Psoriasis treatment in difficult locations: scalp, nails, and intertriginous areas. Clin Dermatol 26(5):448-59 (2008 Sep-Oct).
  4. Schoorl WJ, van Baar HJ, van de Kerkhof PC. The hair root pattern in psoriasis of the scalp. Acta Derm Venereol 72(2):141-2 (1992).
  5. Zaghloul SS, Goodfield MJ. Objective assessment of compliance with psoriasis treatment. Arch Dermatol 140(4):408-14 (2004 Apr).
  6. Jarratt M, Breneman D, Gottlieb AB, et al. Clobetasol propionate shampoo 0.05%: a new option to treat patients with moderate to severe scalp psoriasis. J Drugs Dermatol 3(4):367-73 (2004 Jul-Aug).
  7. Olsen EA, Cram DL, Ellis CN, et al. A double-blind, vehicle-controlled study of clobetasol propionate 0.05% (Temovate) scalp application in the treatment of moderate to severe scalp psoriasis. J Am Acad Dermatol 24(3):443-7 (1991 Mar).
  8. Franz TJ, Parsell DA, Halualani RM, et al. Betamethasone valerate foam 0.12%: a novel vehicle with enhanced delivery and efficacy. Int J Dermatol 38(8):628-32 (1999 Aug).
  9. Melian EB, Spencer CM, Jarvis B. Clobetasol propionate foam, 0.05%. Am J Clin Dermatol 2(2):89-93 (2001).
  10. Høvding G. Treatment of psoriasis of the scalp with betamethasone 17, 21-dipropionate plus salicylic acid lotion (‘Diprosalic’). Pharmatherapeutica 3(1):61-6 (1981).
  11. van de Kerkhof PC, Franssen ME. Psoriasis of the scalp. Diagnosis and management. Am J Clin Dermatol 2(3):159-65 (2001)
  12. Barnes L, Altmeyer P, Fôrstrôm L, et al. Long-term treatment of psoriasis with calcipotriol scalp solution and cream. Eur J Dermatol 10(3):199-204 (2000 Apr-May).
  13. Duweb GA, Abuzariba O, Rahim M, et al. Scalp psoriasis: topical calcipotriol 50 micrograms/g/ml solution vs. betamethasone valerate 1% lotion. Int J Clin Pharmacol Res 20(3-4):65-8 (2000).
  14. Klaber MR, Hutchinson PE, Pedvis-Leftick A, et al Comparative effects of calcipotriol solution (50micrograms/ml) and betamethasone 17-valerate solution (1mg/ml) in the treatment of scalp psoriasis. Br J Dermatol 131(5):678-83 (1994 Nov).
  15. Reygagne P, Mrowietz U, Decroix J, et al. Clobetasol propionate shampoo 0.05% and clacipotriol solution 0.005%: a randomized comparison of efficacy and safety in subjects with scalp psoriasis. J Dermatolog Treat 16(1):31-6 (2005 Feb).
  16. Downs AMR. Overnight application of Daivobet® ointment is effective in scalp psoriasis. Br J Dermatol 151(Suppl 68):52 (2004 Jul).
  17. Emerson RM, Howlett C. Successful treatment of scalp psoriasis with Dovobet® ointment. Br J Dermatol 151(Suppl 68):52-3 (2004 Jul).
  18. Hats off to Xamiol. At: www.xamiol.com. Last accessed 15 January 2009.
  19. Xamiol® Product Monograph. Watermeadow Medical, Range Road, Witney, UK (2008).
  20. Bury Y, Ruf D, Hansen CM, et al. Molecular evaluation of vitamin D3 receptor agonists designed for topical treatment of skin diseases. J Invest. Dermatol 116(5):785-92 (2001 May).
  21. van de Kerkhof PC. Biological activity of vitamin D analogues in the skin, with special reference to antipsoriatic mechanisms. Br J Dermatol 132(5):675-82 (1995 May).
  22. van de Kerkhof PC. In vivo effects of vitamin D3 analogues. J Dermatolog Treat 9(Suppl 3):S25-9 (1998).
  23. Barna M, Bos JD, Kapsenberg ML, et al. Effect of calcitriol on the production of T-cell-derived cytokines in psoriasis. Br J Dermatol 136(4):536-41 (1997 Apr).
  24. 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 subset in chronic plaque psoriasis. Exp Dermatol 13(2):106-12 (2004 Feb).
  25. Beato M. Gene regulation by steroid hormones. Cell 56(3):335-44 (1989 Feb).
  26. Meltzer EO. The pharmacological basis for the treatment of perennial allergic rhinitis and non-allergic rhinitis with topical corticosteroids. Allergy 52(36 Suppl):33-40 (1997).
  27. Guyre PM, Girard MT, Morganelli PM, et al. Glucocorticoid effects on the production and actions of immune cytokines. J Steroid Biochem 30(1-6):89-93 (1988).
  28. Stojadinovic O, Lee B, Vouthounis C, et al. Novel genomic effects of glucocorticoids in epidermal keratinocytes: inhibition of apoptosis, interferon-gamma pathway, and wound healing along with promotion of terminal differentiation. J Biol Chem 282(6):4021-34 (2007 Feb).
  29. Hamdi H, Godot V, Maillot MC, et al. Induction of antigen-specific regulatory T lymphocytes by human dendritic cells expressing the glucocorticoid-induced leucine zipper. Blood 110 (1):211-9 (2007 Jul).
  30. Sugiyama H, Gyulai R, Toichi E, et al. Dysfunctional blood and target tissue CD4+CD25 high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 174(1):164-73 (2005 Jan).
  31. Buckley C, Hoffmann V, Shapiro J, et al. Calcipotriol plus betamethasone dipropionate scalp formulation is effective and well tolerated in the treatment of scalp psoriasis: a phase II study. Dermatology 217(2):107-13 (2008).
  32. Jemec GB, Ganslandt C, Ortonne JP, 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 59(3):455-63 (2008 Sep).
  33. van der Kerkhof PC, Hoffmann V, Anstey A, et al. A new scalp formulation of calcipotriol plus betamethasone dipropionate compared with each of its active ingredients in the same vehicle for the treatment of scalp psoriasis: a randomized, double-blind, controlled trial. Br J Dermatol 160(1):170-6 (2009 Jan).
  34. Kragballe K, Hoffmann V, Tan J, et al. Calcipotriene plus betamethasone dipropionate gel compared to calcipotriene solution in patients with scalp psoriasis. J Am Acad Dermatol 58(2 Suppl 2):AB131 (2008 Feb).
  35. Ortonne JP, Tan J, Nordin P, et al. Quality of life of patients with scalp psoriasis treated with calcipotriene plus betamethasone dipropionate gel compared to calcipotriene solution. J Am Acad Dermatol 58(2 Suppl 2):AB134 (2008 Feb).
  36. Luger TA, Cambazard F, Larsen FG, et al. A study of the safety and efficacy of calcipotriol and betamethasone dipropionate scalp formulation in the long-term management of scalp psoriasis. Dermatology 217(4):321-8 (2008).
  37. Tyring S, Bibby A. Calcipotriene/betamethasone dipropionate gel compared to gel vehicle in treatment scalp psoriasis in Hispanic/Latino and black/African American patients. J Am Acad Dermatol 58(2 Suppl 2):AB125 (2008 Feb).