Topical Combination Maintenance Therapy for Psoriasis

Safe and effective long-term therapy is important when treating patients with psoriasis and maintaining remission of this condition. Various formulations of topical agents can provide safe and effective treatment of plaque psoriasis in most patients with limited disease.1 

Recommendations pertaining to the use of topical corticosteroids, topical vitamin D analogues and their combination for initial disease control are based on consistent and good-quality, patient-oriented evidence.1 Accordingly, topical vitamin D analogue and corticosteroid combination therapy is commonly used as first-line treatment to achieve remission in patients with mild-to-moderate plaque psoriasis.1,2 

Once remission is achieved, the goal of a maintenance regimen is to prevent relapse. Long-term corticosteroid monotherapy is not recommended for this purpose because of the potential for adverse events (AEs).1 Numerous combinations and schedules for using vitamin D analogues and corticosteroids in maintenance therapy have been explored in clinical studies in an attempt to identify regimens that maintain efficacy while minimizing AEs.3-6 This article provides a perspective on the role of topical vitamin D analogue and corticosteroid combination treatment as long-term maintenance therapy.

Safety And Tolerability 

The use of topical corticosteroids for long durations may increase the risk of local cutaneous AEs, including skin atrophy and, infrequently, adrenal suppression.1,7 Corticosteroid-related AEs are more likely to occur with potent and superpotent corticosteroids that are applied to a large surface area for a long time.1 Short-term application of superpotent topical corticosteroids (twice-daily application for 2 or 4 weeks) in patients who have mild or moderate-to-severe psoriasis, or corticosteroid-responsive dermatoses, is associated with a low incidence of epidermal atrophy.8-12 Skin atrophy generally attenuates after treatment with corticosteroids is discontinued, whereupon skin thickness returns to normal.13

Reports of hypothalamic-pituitary-adrenal axis suppression with the use of superpotent topical corticosteroids (applied at doses consistent with the approved labeling) are minimal in the published literature spanning 1967 to 2011.7,12 

Patients in whom pathologic hypothalamic-pituitary-adrenal axis suppression has occurred have been treated with a superpotent corticosteroid at up to 6 times the maximum recommended dose, or have been continuously treated with the drug for 5 years for moderate-to-severe psoriasis.7 

In contrast to pathologic suppression, physiologic adrenal suppression (ie, prompt recovery of cortisol levels either during treatment or immediately after cessation of treatment) is a common occurrence in patients treated with topical corticosteroids that does not appear to have clinical significance. For patients with physiologic suppression, cortisol levels spontaneously normalized in approximately half of the patients, despite continuous therapy; the remaining patients had cortisol levels return to normal after discontinuation of the topical steroid. 

 Vitamin D is effective in treating psoriasis by inhibiting keratinocyte proliferation, inducing differentiation and decreasing inflammation. In addition, it offers an important advantage in topical combination treatment because of its potential to function as a corticosteroid-sparing agent.1 The addition of topical vitamin D to a corticosteroid may reduce corticosteroid-associated epidermal impairment.14,15 In a preclinical study, sequential application of topical calcitriol and clobetasol propionate to hairless mice restored corticosteroid-induced impairment in epidermal permeability and the antimicrobial barrier, as compared with clobetasol propionate alone.14 In another study, performed in miniature pigs, application of fixed-combination calcipotriol and betamethasone dipropionate counteracted epidermal thinning observed with betamethasone dipropionate alone.15 

In clinical use, topical vitamin D analogues are generally safe and well-tolerated; they are associated with mild, local AEs, including erythema and pruritus, and cause minimal skin discomfort.16 Cases of hypercalcemia have been reported with the use of calcipotriene or calcitriol, but they were not considered to be of clinical relevance.17 Even with long-term use (52 weeks) to treat mild-to-moderate psoriasis, calcipotriene was well-tolerated and had a favorable safety profile.18

Treatment Strategies After Achieving Remission

Corticosteroid Monotherapy: 6 Months 

Before the introduction of the vitamin D analogue calcipotriene to the psoriasis treatment armamentarium, it was common practice to prescribe a corticosteroid maintenance regimen designed to limit corticosteroid exposure.4 

Katz et al3 explored the efficacy and safety of betamethasone dipropionate for short-term maintenance therapy. In this study, patients who had successfully completed initial treatment of psoriasis with 3 to 4 weeks of betamethasone dipropionate 0.05% ointment twice daily were randomized to receive placebo or this ointment once weekly in 3 consecutive applications 12 hours apart for a maximum of 6 months. Remission was maintained in 65% of the patients treated with betamethasone dipropionate ointment but in only 20% of the patients who received placebo. No serious cutaneous atrophy or AEs related to the study drug were reported. 

Sequential Vitamin D Analogue Plus 

Corticosteroid: 6 Months

Two randomized, controlled trials have evaluated regimens involving weekday use of a vitamin D analogue and weekend use of a corticosteroid for maintenance therapy in patients with mild-to-moderate psoriasis of non-scalp regions.4,5 

In the first study, initial therapy consisted of calcipotriene ointment in the morning and halobetasol ointment in the evening for 2 weeks. Patients who were at least moderately (50% or greater) improved were randomly assigned to 1 of 2 groups for 6 months of maintenance therapy: calcipotriene twice daily on weekdays and halobetasol twice daily on weekends, or placebo twice daily on weekdays and halobetasol twice daily on weekends.4 The success rate was 76% (13/17) among the patients who were treated with both calcipotriene and halobetasol for maintenance but only 40% (8/20) among the patients who were treated with halobetasol only (P=.045).4 Mild AEs were reported in 4 patients treated with the combination regimen and 1 patient treated with halobetasol only. No AE-related discontinuations occurred. 

In the second study, patients with psoriasis on the trunk and extremities were initially treated twice daily with sequentially applied clobetasol 0.05% foam plus calcipotriene 0.005% ointment for 2 weeks.5 Patients who achieved remission received 6 months of maintenance therapy with calcipotriene twice daily on weekdays and were randomly assigned to receive either clobetasol or vehicle on weekends. Remission was maintained to a greater extent in the weekend clobetasol group than in the weekend vehicle group. Rates of improvement of lesions on the trunk and extremities were 92% (12/13) and 85% (11/13) in the weekend clobetasol group, as compared with 62% (8/13) and 69% (9/13) in the weekend vehicle group.     

Simultaneous Vitamin D Analogue Plus Corticosteroid: Up to 52 Weeks

A study of patients with scalp psoriasis who achieved complete remission using once-daily application of calcipotriol 0.005% and betamethasone dipropionate 0.064% topical fixed-combination gel evaluated use of the same product for maintenance therapy.19 In this randomized, controlled trial, patients applied the fixed-combination product either twice weekly or on-demand for 12 weeks. Although both treatment groups showed significant clinical improvement compared with baseline, at weeks 8 and 12 the twice-weekly combination group demonstrated a higher rate of clinical response (P<.05). The rate of relapse for the twice-weekly group was half that of the on-demand therapy group (19.5% vs 41.7%, respectively); differences and risk of relapse among the 2 groups were statistically significant (odds ratio, 0.47; 95% confidence interval, 0.37, 0.60). AEs were reported in 11 of the 394 patients in the twice-weekly group and in 7 of the 404 patients in the on-demand group. AEs leading to discontinuation of treatment occurred in 3 patients: 1 in the twice-weekly group and 2 in the on-demand group.

Long-term data are available from a 52-week study of the fixed-combination formulation containing calcipotriol 0.005% plus betamethasone dipropionate 0.064% in patients with moderate-to-severe scalp psoriasis.6 Patients were randomized in a 1:1 ratio to receive either the 2-compound formulation or calcipotriol alone once daily. Patients were treated until their psoriasis cleared. Cleared patients remained in the study and could be retreated at any time. The maximum dosage permitted was ≤100 g/week. Treatment with the 2-compound formulation over 52 weeks was efficacious, safe and well-tolerated. Disease was satisfactorily controlled (absence of disease, very mild disease or mild disease) in 92.3% of visits in the 2-compound group versus 80% in the calcipotriol alone group (P<.001). No cases of skin atrophy were reported. The proportion of patients reporting AEs was significantly lower in the patients treated with the 2-compound formulation (17.2%; 72/419) than in those treated with calcipotriol alone (29.5%; 127/431; P<.001). Approximately half as many patients in the combination group (21.4%) withdrew from the study as compared with the monotherapy group (39.8%).

Conclusion

When topical treatment for psoriasis is discontinued, lesions will recur.20 Thus, the primary goal of maintenance therapy is to prolong remission of psoriasis as long and as safely as possible. 

As discussed, treatment regimens consisting of sequential or simultaneous administration of vitamin D analogue and corticosteroid combination therapy are effective and well-tolerated in patients with mild-to-moderate psoriasis. Various strategies for using these agents in maintenance therapy have been explored. These regimens are intended to maximize the long-term beneficial effects. It is also important to keep in mind features of therapy that can affect real-world patient adherence, because adherence with topical treatment is known to be poor. Maintenance regimens that are less complicated enhance the potential for increased patient adherence and successful outcomes.21

Approaches such as alternating weekend and weekday treatment are mainly designed to limit corticosteroid exposure and minimize potential AEs. However, these strategies can be confusing for the patient. In my clinical practice, I prefer to simplify the regimen for the patient. I prescribe potent topical corticosteroids or, more preferably, a fixed-combination vitamin D/corticosteroid for use on weekends only to maintain long-term remission. Prescribing a vehicle that can be used on the scalp as well as the body further simplifies treatment. 

Patients find this to be a simple and convenient regimen, and their acceptance of it seems to contribute to persistence of use and successful outcomes. If they experience a relapse despite a prolonged response to this maintenance regimen, they can repeat daily treatments until remission is again achieved.

 

Dr. Stein Gold is with the division of dermatology at the Henry Ford Health System in West Bloomfield, MI.

 

Disclosure: Dr. Stein Gold is an advisor for Galderma, LEO Pharma Inc., Lilly, Novartis, Pfizer and Stiefel. She is also an investigator and speaker for Galderma, LEO Pharma Inc., Novartis and Stiefel as well as a consultant for Galderma, LEO Pharma Inc. and Stiefel. Editorial support was provided by Benjamin Dale, PhD, of p-value communications. 

 

References

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2. Davis SA, Feldman SR. Combination therapy for psoriasis in the United States. J Drugs Dermatol. 2013;12(5):546-550.

3. Katz HI, Prawer SE, Medansky RS, et al. Intermittent corticosteroid maintenance treatment of psoriasis: a double-blind multicenter trial of augmented betamethasone dipropionate ointment in a pulse dose treatment regimen. Dermatologica. 1991;183(4):269-274.

4. Lebwohl M, Yoles A, Lombardi K, Lou W. Calcipotriene ointment and halobetasol ointment in the long-term treatment of psoriasis: effects on the duration of improvement. J Am Acad Dermatol. 1998;39(3):447-450.

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8. Jarratt MT, Clark SD, Savin RC, et al. Evaluation of the efficacy and safety of clobetasol propionate spray in the treatment of plaque-type psoriasis. Cutis. 2006;78(5):348-354.

9. Kimball AB, Gold MH, Zib B, Davis MW. Clobetasol propionate emulsion formulation foam 0.05%: review of phase II open-label and phase III randomized controlled trials in steroid-responsive dermatoses in adults and adolescents. J Am Acad Dermatol. 2008;59(3):448-454.

10. Bernhard J, Whitmore C, Guzzo C, et al. Evaluation of halobetasol propionate ointment in the treatment of plaque psoriasis: report on two double-blind, vehicle-controlled studies. J Am Acad Dermatol. 1991;25(6 Pt 2):1170-1174.

11. Uliasz A, Zeichner J, Soung J, Wong V, Lebwohl M. A single-center, double-blind, randomized trial of the atrophogenic effects of fluocinonide cream 0.1% versus clobetasol propionate cream 0.05% in participants with corticosteroid-responsive dermatoses. Cutis. 2008;81(6):517-519.

12. Castela E, Archier E, Devaux S, et al. Topical corticosteroids in plaque psoriasis: a systematic review of risk of adrenal axis suppression and skin atrophy. J Eur Acad Dermatol Venereol. 2012;26(suppl 3):47-51.

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14. Hong SP, Oh Y, Jung M, et al. Topical calcitriol restores the impairment of epidermal permeability and antimicrobial barriers induced by corticosteroids. Br J Dermatol. 2010;162(6):1251-1260.

15. Norsgaard H, Gonzalez T, Duenstl G, Latta M, Røpke MA. Beneficial effects of the fixed combination of calcipotriol and betamethasone dipropionate on skin atrophy biomarkers. Presented at: 21st European Academy of Dermatology and Venereology Congress; September 27-30, 2012; Prague, Czech Republic. Poster PRA12-0845.

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17. Devaux S, Castela A, Archier E, et al. Topical vitamin D analogues alone or in association with topical steroids for psoriasis: a systematic review. J Eur Acad Dermatol Venereol. 2012;26(suppl 3):52-60.

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19. Saraceno R, Camplone G, D’Agostino M, et al. Efficacy and maintenance strategies of two-compound formulation calcipotriol and betamethasone dipropionate gel (Xamiol® gel) in the treatment of scalp psoriasis: results from a study in 885 patients. J Dermatolog Treat. 2014;25(1):30-33.

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21. Feldman SR, Horn EJ, Balkrishnan R, et al. Psoriasis: improving adherence to topical therapy. J Am Acad Dermatol. 2008;59(6):1009-1016.