¹Irvine School of Medicine, University of California, CA, USA
²Department of Dermatology, Psoriasis and Skin Treatment Center, University of California – San Francisco, San Francisco, CA, USA
³David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA, USA
⁴Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
⁵The Larner College of Medicine, University of Vermont, Burlington, VT, USA 

Conflicts of Interest:
JK is a speaker for AbbVie, Leo, and Celgene. JK conducts research for Amgen, Janssen, Novartis, Photomedex, Galderma, Pfizer and Merck. BF is an advisor for Cutanea. BF conducts research for Abbvie, Janssen, and Merck. JK and BF have no stocks, employment or board memberships with any pharmaceutical company. The other authors report no conflicts of interest.

ABSTRACT
While there are several commercially available treatment options for psoriasis and psoriatic arthritis, there remains a large number of individuals who are refractory to current modalities. In the recent past, there has been increasing evidence that interleukin (IL)-17 plays a vital role in the pathophysiology of psoriasis. Preclinical, phase II, and phase III studies of secukinumab (Cosentyx®) targeting IL-17 and its receptor have thus far proved to be promising. We reviewed the results of phase II and phase III clinical trials for secukinumab in the treatment of psoriasis and psoriatic arthritis. Only published studies were considered in the present review. We also performed an English language literature search from January 2003 to September 2015 using PubMed with any of the following key words: (secukinumab OR AIN457) AND (psoriasis OR psoriatic arthritis). In our review of the literature, seven phase III and five phase II clinical trials, as well as open-label extension studies with unpublished findings were found. Results from phase III clinical trials indicated secukinumab to be efficacious and safe for the treatment of psoriasis and psoriatic arthritis according to Psoriasis Area and Severity Index (PASI) and American College of Rheumatology (ACR) scores. The safety profile of this agent was similar across all studies, with the most frequently reported adverse events of nasopharyngitis, upper respiratory infections, headache, and injection site reaction. Secukinumab demonstrates rapid and robust clinical improvement accompanied by a favorable short- term safety profile. The results of the phase III trials continue to reinforce the theory that the IL-17 pathway is an essential target in psoriasis and psoriatic arthritis treatment. Additional extension studies of lower level evidence are needed to further understand the safety profile of the drug.

Key Words:
anti-interleukin-17, biologics, IL-17A, psoriasis, psoriatic arthritis, secukinumab, therapy

Introduction

Psoriasis is a common, multifaceted chronic inflammatory disease of the skin that affects 3-4% of the adult population in the United States, with 5-30% suffering from concurrent psoriatic arthritis.^1,2 The pathogenesis is largely multifactorial with a combination of immune dysregulation, genetic susceptibility, and environmental factors; thus, there is a wide range of disease severity and areas of involvement. While there are a number of available treatment options currently on the market, there are still many individuals who remain refractory to these modalities.

Since there still remains a large population of individuals who are resistant to current treatment methods, the need for further research to develop novel therapeutic modalities is great.^3,4The interleukin (IL)-17 pathway has demonstrated significant potential as a new target for treatment. As a proinflammatory cytokine, IL-17 is produced by type 17 helper (Th-17) T cells and is a downstream product of IL-23.^5-8 The IL-17 pathway mediates a diverse set of biological responses that contribute to the eventual in ammation, activation and recruitment of neutrophils, cessation of neutrophil apoptosis, and angiogenesis.^9-12 There has also been increasing research of IL-17, including the the IL-17 receptor, and its expression in synovial tissues, as well as its importance in the pathogenesis of psoriatic arthritis.^13-15 To futher support the role of IL-17 in psoriatic disease, studies have demonstrated elevated levels of IL-17 in both the serum and lesions of patients with active psoriasis.^16-21

One of the newest biologic agents approved by the US FDA for the treatment of psoriasis is secukinumab (Cosentyx®), a fully human monoclonal antibody. Secukinumab acts by inhibiting the effector function of IL-17A and has been shown in previous studies to be better than placebo and etanercept.²² Herein, we review the data regarding the efficacy and safety of secukinumab in patients with moderate-to-severe plaque psoriasis.

Mechanism of Action and Pharmacokinetics

Secukinumab is a human immunoglobulin G1 kappa (IgG1k) monoclonal antibody that binds and neutralizes IL-17A. IL-23 activates Th-17 cells, which release IL-17.23 IL-17 release increases expression of proinflammatory cytokines leading to recruitment of immune cells, activation of keratinocytes, and enhancement of angiogenesis. This can eventually lead to synovial inflammation and psoriatic plaque development.²³ Secukinumab has been administered either subcutaneously (SC) at a low, medium or high dose (75 mg, 150 mg, 300 mg) or intravenously (IV) at a dose of 10 mg/kg.²⁴ Secukinumab is available in 150 mg pre-filled syringes or injection pens. The FDA approved dosing for the treatment of psoriasis with secukinumab consists of SC injections with a loading dose of once weekly 300 mg injections for the first 4 weeks for induction, followed by 300 mg every 4 weeks thereafter for maintenance. A dose of 150 mg was acceptable for some patients.²³ For patients being treated for psoriatic arthritis, the dosing schedule is as follows: secukinumab is administered with a SC injection of 150 mg every week for the first 4 weeks as a loading dose, followed by 150 mg every 4 weeks thereafter. For patients with both psoriasis and psoriatic arthritis, the psoriasis dosing is recommended. Maximal plasma concentration is reached in approximately 6 days and the mean half-life is 27 days with an average bioavailability of 73%. Typically, secukinumab takes the form of a lyophilized formulation that can be reconstituted.²³ However, two clinical trials, FIXTURE and JUNCTURE, have detailed the various preparations and dosing forms of secukinumab, which includes a liquid formulation delivered either via pre- lled syringe or an auto-injector pen, respectively.^22,25

Methods

We reviewed the results of clinical trials for secukinumab in the treatment of psoriasis and psoriatic arthritis. Only completed studies were considered in the present review; recruiting, not yet recruiting, withdrawn and terminated trials were eliminated (Table 1). In order to identify any other studies that may have assessed secukinumab, we performed an English language literature search from January 2003 to September 2015 using PubMed with any of the following key words: (secukinumabWe reviewed the results of clinical trials for secukinumab in the treatment of psoriasis OR AIN457) AND (psoriasis OR psoriatic arthritis). We also reviewed citations within articles to identify relevant resources. Overall measures of efficacy and incidence of adverse events for each medication were calculated by tabulating values from independently conducted studies (Table 2). To the best of our knowledge there was only one open label extension study and no studies of lower level of evidence (3, 4, or 5), such as case series or case reports, commenting on the efficacy or side effects of secukinumab on a smaller scale.²⁶

Clinical Trials

Phase I/II Trials

Sun protection should also be recommended to acne patients.⁸ A systemic review found no convincing evidence that natural sunlight improves acne, although such studies are inherently difficult to conduct.⁹ Several oral acne treatments, including doxycycline and isotretinoin, are potentially photosensitizing.¹⁰ The US Food and Drug Administration official labelling for medications containing benzoyl peroxide and topical retinoids advises sun avoidance,^11,12 although no effect on ultraviolet Binduced erythema was shown with use of either benzoyl peroxide or adapalene in one study¹³. In addition to providing sun protection, the emollient component of the sunscreen may improve epidermal barrier function. Finally, sun protective measures may prevent or minimize postinflammatory hyperpigmentation, particularly in patients with higher skin types.¹⁴

Phase III Trials

Seven phase III clinical trials have been completed to determine the efficacy and safety of different doses of secukinumab for plaque psoriasis and psoriatic arthritis.^24,28,31-35 The most recent trials, FUTURE 1 and FUTURE 2, essentially validated IL-17A as a therapeutic target for the treatment of psoriasis and psoriatic arthritis. In the FUTURE 2 phase III, double-blind, placebocontrolled study, patients receiving the 300 mg, 150 mg and 75 mg doses were found to achieve a significantly higher American College of Rheumatology (ACR20) score at week 24 compared with placebo. The most common adverse events reported were urinary tract infections and nasopharyngitis.³¹ FUTURE 2 is the first large phase III trial for secukinumab. Data from week 52 suggests that the efficacy of the drug at higher dosages (300 mg and 150 mg) can be sustained over long periods of time.²⁸ In FUTURE 1, another randomized, double-blind phase III trial, the efficacy of IV secukinumab (10 mg/kg) followed by SC dosing vs. placebo was evaluated. In this study, patients with psoriatic arthritis received IV secukinumab at weeks 0, 2, and 4 followed by either placebo or a SC dose of either 150 mg or 75 mg every 4 weeks. The primary endpoint was a 20% improvement from baseline in the ACR20 by week 24. ACR20 scores at week 24 were significantly higher in the group receiving the SC secukinumab vs. the IV dosing paired with placebo. The most common adverse events were nasopharyngitis, headache, upper respiratory tract infection, and diarrhea. Serious adverse events included stroke (4), myocardial infarction (2) vs. no serious adverse events (AEs) in the placebo group.²⁴

ERASURE, a two-phase III double-blind, 52-week trial used the PASI75 to compare secukinumab to placebo. Langley et al. demonstrated that secukinumab at 300 mg and 150 mg SC was significantly superior in treating psoriasis compared to placebo. This trial showed that the 300 mg and 150 mg SC doses of secukinumab were markedly more effective in treating psoriasis than etanercept. In an ERASURE 52-week subanalysis published by Ohtsuki et al., secukinumab was found to be efficacious in the long-term treatment of plaque psoriasis in Japanese patients.^22,36

In a different study with a similar design by Langley et al., the FIXTURE trial compared secukinumab to placebo and etanercept. This trial showed that secukinumab 300 mg was superior to etanercept 50 mg twice weekly in terms of proportion of patients reaching PASI75 (77.1% vs. 44%, respectively) and PASI90 (54.2% vs. 20.7%, respectively) (P<0.001 for all groups compared to placebo).²²

FEATURE and JUNCTURE each compared the efficacy of secukinumab to placebo when administered by pre-filled syringe (FEATURE) and auto-injector pen (JUNCTURE). Both studies by Blauvelt et al. and Paul et al., respectively, demonstrated that secukinumab administration via either syringe or injector pen was effective with acceptable safety profiles.^25,33,34

The CLEAR trial compared secukinumab to ustekinumab, demonstrating secukinumab 300 mg was more efficacious than ustekinumab (45 mg for patients with a body weight ≤100 kg and 90 mg for patients >100 kg) in terms of proportion of patients achieving PASI75 (91% vs. 79.1%, respectively) and investigator’s global assessment (IGA) of 0 or 1 (80.8% vs. 65.1%, respectively). The SCULPTURE trial investigated the retreatment as-needed protocol vs. fixed interval regimen of secukinumab dosing. At week 12, patient outcomes were assessed with the PASI75, at which point participants were re-randomized to two new groups: retreatment as-needed or fixed interval dosings. The primary endpoint was maintaining PASI75 results until week 52. Mroweitz et al. demonstrated that secukinumab at fixed interval dosing (every 4 weeks after the initial loading dose) conferred clear benefit vs. the retreatment as-needed model. Both protocols showed that AEs were comparable to other trials with no serious AEs noted. Although both protocols require further study.^25,33,34

By week 12, the five studies comparing secukinumab to placebo each demonstrated statistically significant superiority of secukinumab over placebo at all SC dosings. Within these studies, the proportion of patients reaching PASI75 was statistically significant for all dosing levels of secukinumab (300 mg, 150 mg, and 75 mg) vs. comparators and placebo. Secukinumab was similarly superior to placebo in terms of IGA 0/1, ACR20, ACR50, PASI90, PASI100, and the Dermatology Life Quality Index (DLQI) (Table 2). The most common AEs among the studies were nasopharyngitis, headache, upper respiratory tract infection, and diarrhea. Mild and transient neutropenia, without associated infections, was noted in a minority of patients in each trial. Some serious adverse effects observed in the FUTURE 1 trials were stroke and myocardial infarction (Table 1).

Cost-Utility of Secukinumab

Currently, there have been only a few studies detailing the costbenefit analysis of secukinumab for moderate-to-severe plaque psoriasis. Lee et al. evaluated the cost utility of secukinumab, as well as other systemic biologic agents, compared with the standard of care, which was arbitrarily defined as methotrexate, cyclosporine, topical corticosteroids, or phototherapy.³⁷ The investigators demonstrated that secukinumab was associated with the second highest total cost ($70,313 Canadian dollars). The lowest cost was the standard of care. However, the highest quality of life (QoL) gains were found with secukinumab 300 mg. Thus, while the standard of care with non-biologics remains the most appropriate option in terms of cost analysis, Lee et al. posits that biologic agents, especially secukinumab, yield substantial QoL gains. Since psoriasis and psoriatic arthritis can be debilitating conditions in terms of their impact on QoL, productivity loss, psychosocial issues and individual burden of disease, biological agents such as secukinumab have the potential to replace the standard of care due to marked improvements in QoL.^{15,18-20,23,29,32-34,38-44}

Discussion

Secukinumab has the potential to address the unmet needs of patients with psoriasis refractory to current treatment modalities. The results of phase III clinical trials reinforce IL-17 as an essential therapeutic target and demonstrate the overall efficacy of secukinumab in the treatment of psoriasis and psoriatic arthritis. In the treatment of psoriasis, secukinumab was found to perform significantly better than several contemporary biologic agents currently in use, such as etanercept and ustekinumab. Within the context of these studies, there were no substantial differences noted in the safety profiles of secukinumab compared with other biologic agents; the most common AEs included nasopharyngitis, upper respiratory infection, and headache. However, there were several other AEs that were unique to secukinumab and not observed with etanercept, adalimumab, or ustekinumab. Some of the AEs unique to secukinumab were neutropenia, diarrhea and candidiasis, but was thought to be IL-17 specific. A small portion of patients experienced low-grade neutropenia with each of the agents, though these episodeswere self-controlled and transient. Mild or moderate Candida infections were more frequent with secukinumab compared with etanercept, ustekinumab, and placebo. No patients discontinued the study drug due to Candida infections and no serious or invasive fungal infections were reported in any of the studies.

Recent epidemiologic studies suggest that treating psoriasis with systemic immunosuppressant therapies leads to a reduction of cardiovascular events such as myocardial infarction and stroke. Interestingly, IL-17 has been measured in atherosclerotic plaques and thought to play an important role in overall plaque formation. Past studies have reported elevated levels of IL-17 in patients suffering from unstable angina and acute myocardial infarction. In tandem, these findings suggest that blocking the IL-17 pathway through biologic agents, such as secukinumab, has the potential to reduce the overall risk of cardiovascular events in patients with psoriasis. However, we do not yet have any long-term data for this medication, unlike the long-term safety and efficacy data available for other biologics like etanercept and adalimumab. While the initial clinical results reviewed here look promising, more long-term data is needed for secukinumab.^{15,18-20,23,29,32-34,38-44}

Conclusion

Secukinumab has the potential to address the unmet needs of patients with psoriasis and psoriatic arthritis recalcitrant to current treatment modalities. The phase III clinical trials suggest that anti-IL-17 inhibitors have improved efficacy compared to available biologic agents and placebo. Relative to the standard of care with non-biologic therapies, secukinumab is superior in terms of overall QoL scores. Further long-term studies are necessary to confirm the favorable efficacy and safety profiles of this biologic agent demonstrated in phase III trials.

References

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¹University of Utah School of Medicine, Salt Lake City, UT, USA
²Department of Dermatology, Psoriasis and Skin Treatment Center, University of California, San Francisco, San Francisco, CA, USA

Conflicts of Interest : Ms. Wong, Ms. Kamangar, and Mr. Nguyen have no financial conflicts of interest to report. Dr. Koo has the following
conflicts of interest: Abbott, Amgen, Leo, Galderma, GlaxoSmithKlein, Janssen, Novartis, PhotoMedex, Pfizer, and Teikoku.
ABSTRACT

Psoriasis is a chronic, inflammatory skin condition with negative impacts both physical and psychological. Scalp psoriasis, especially around the hairline, can cause significant impairment in quality of life due to its visibility. Options for treatment of facial psoriasis, including hairline involvement, are the use of low potency topical steroids, calcineurin inhibitors, and vitamin D analogues. Though the use of excimer laser for scalp psoriasis has been reported, there are no cases or studies specifically examining excimer laser phototherapy for the treatment of hairline psoriasis. We present a case of rapid improvement of hairline psoriasis using a regimen of 308 nm excimer laser with clobetasol spray and recommend an algorithm for the optimal treatment of scalp psoriasis utilizing currently available antipsoriatic therapies.

Key Words:
topical corticosteroid, excimer laser, phototherapy, scalp psoriasis

Introduction

Psoriasis is an inflammatory skin disease affecting approximately 2.6% of the U.S. population.¹ Psoriasis tends to remain stable throughout the patient’s lifetime or become gradually more widespread. It is associated with a high degree of morbidity, as well as having a negative impact on the lives of patients physically, psychologically, socially, and occupationally.^2,3 As it is a chronic condition, psoriasis often requires lifelong treatment.

Patients suffering from psoriasis have relatively high rates of depression and often report stigmatization, embarrassment, and self-consciousness.⁴ Plaques along the hairline and retroauricular regions are visible and resistant to therapy. Treatment of scalp psoriasis with laser has been reported, but this modality presents challenges due to the difficulty of penetration of photons through hair.⁵ Hence, such a limitation may discourage the use of excimer laser for scalp psoriasis. It must be noted, however, that because the forehead, hairline, and retroauricular areas are not entirely covered by hair, treatment with laser is a clearly viable option.

Targeted ultraviolet B (UVB) excimer laser phototherapy is one of the most cutting-edge advances in phototherapy. The xenon chloride laser produces a 308 nanometer (nm) monochromatic beam of light that is efficacious for the treatment of psoriasis.⁶ In contrast to traditional phototherapy, the UVB laser treats targeted areas while sparing the non-involved skin. Psoriatic plaques can tolerate increased dosimetry compared with non-involved skin, and a supra-erythmogenic dose (multiple times above the minimal erythema dose [MED]) can be delivered, resulting in faster clearance than with traditional UVB phototherapy.^6,7 We first present a case of rapid improvement and maintenance of hairline psoriasis treated with 308 nm excimer laser and clobetasol spray, followed by a discussion of current treatment options, and, finally, offer a recommended algorithm for the treatment of scalp psoriasis.

Case

A 68-year old Filipino female presented with a 16-year history of generalized plaque-type psoriasis. She reported that the most distressing region covered with psoriasis was her hairline because it caused severe pruritus and visible disfigurement. The patient failed past treatment on acitretin and topical therapies, including clobetasol ointment, fluocinonide 0.05% solution, calcipotriene ointment, and fluocinolone acetonide 0.01% oil. She had a past medical history of thyroid cancer with a thyroidectomy, stroke, and coronary artery bypass graft. She had no history of sun or other light sensitivity and no history of skin cancer. Her current medications included levothyroxine, metoprolol, warfarin, atorvastatin, and calcium and vitamin D supplements. She was not on any psoriasis therapies at the time of presentation.

On physical examination, there were thick, well-demarcated plaques of psoriasis with silvery scale over the lower and upper extremities bilaterally, back, abdomen, buttocks, scalp, and hairline, including over the forehead, retroauricular, and occipital area.

As the patient had a past history of cancer, she was not placed on immunosuppressive therapy. Topical therapy alone had not been sufficient for treating her psoriasis. Therefore, the patient was started on twice weekly excimer laser therapy (Photomedex XTRAC® Velocity) in conjunction with clobetasol propionate 0.05% (Clobex®) spray twice daily.

The patient was started on a dose of 400 millijoules per square centimeter (mJ/cm²) for laser therapy, which was increased to 500 mJ/cm² following her first treatment. After 2 weeks of therapy, with a total of 4 excimer laser treatments at a dose of 500 mJ/cm² and use of clobetasol spray to affected areas, she demonstrated marked improvement in hairline psoriasis. As the patient responded well to treatment without side effects or irritation, her dose was gradually increased to 666 mJ/cm². After 5 weeks of therapy (receiving a total of 9 laser treatments and using clobetasol spray twice daily), her hairline psoriasis completely cleared. The patient did not experience any side effects from laser therapy, such as blistering, burning, hyperpigmentation, or erythema. After 3 months without any subsequent therapy, the hairline psoriasis had not returned.

Figure 1: Algorithm for scalp psoriasis treatment Feldman SR, Koo JYM, Lebwohl MG, et al. The psoriasis and psoriatic arthritis pocket guide: treatment algorithms and management options. 2nd ed. 2005, p.76. National Psoriasis Foundation.12 Modified with permission.

Discussion

Phototherapy can be an effective treatment for generalized plaque psoriasis. However, one major limitation to the aggressiveness of therapy is the MED, which is the lowest dose that causes minimal erythema in non-psoriatic skin.⁷ The excimer laser overcomes the barrier of MED, which limits the efficacy of traditional phototherapy. The process by which this is achieved is the excimer laser only irradiates psoriatic plaques that typically require many times more light energy than MED when compared to traditional phototherapy. Thus, the excimer laser provides greater capacity for aggressive therapy, resulting in increased efficacy and significantly reduced number of treatments needed for disease improvement.^7-9

The medical literature provides a limited number of studies that have been performed for the specific treatment of hairline psoriasis.¹⁰ The Copenhagen Psoriasis Working Group recommended that the first-line treatment of facial psoriasis, including hairline involvement, should be low potency topical corticosteroids, calcineurin inhibitors, and vitamin D3 analogues.¹¹ However, for general scalp psoriasis, multiple studies have been performed. For mild disease, topical therapies are considered first-line treatments. Topical therapies include gentle care with medicated shampoos, steroids, salicylic acid, tars, calcipotriene/calcipotriol, tazarotene, anthralin, and various combinations of topical agents.¹² In addition, two 52-week studies demonstrated efficacy and safety of calcipotriol/betamethasone diproprionate gel (Xamiol®, Taclonex® scalp suspension) for scalp psoriasis.¹³ More recently, a multicenter, randomized, double-blind study of 81 moderate-to-severe psoriasis patients with scalp involvement evaluated the efficacy and safety of clobetasol spray.¹⁴ Forty-one patients applied clobetasol spray and 40 applied a control vehicle spray twice daily for up to 4 weeks. The study found that 85% (35/41) of the patients using clobetasol spray compared to 13% (5/40) of the control group were assessed as “cleared” or “almost cleared” as measured by the Global Severity Score (GSS).¹⁴

For severe or recalcitrant scalp psoriasis, systemic therapy is recommended, including acitretin, adalimumab, cyclosporine, etanercept, infliximab, and methotrexate.¹² A recent randomized, placebo-controlled study of 124 patients with stable plaque psoriasis and significant scalp psoriasis evaluated the efficacy and safety of etanercept.¹⁵ Sixty-two patients received etanercept 50 mg twice weekly for 12 weeks, followed by etanercept 50 mg once weekly and placebo once weekly. The remaining 62 patients received placebo twice weekly for 12 weeks, followed by etanercept 50 mg twice weekly for 12 weeks. The study found that etanercept was effective and well-tolerated for scalp psoriasis, showing a statistically significant difference in psoriasis scalp severity index (PSSI) between the experimental and control groups. At week 12, 86% in the experimental group achieved 75% improvement in PSSI in contrast to 11% in the control group.¹⁵

Despite concern that the efficacy of excimer laser may be limited by hair preventing maximal penetration of photons, two studies have shown improvement of scalp psoriasis with excimer laser. In an open comparative study of 13 patients with scalp psoriasis, patients were treated with a 308 nm excimer laser in conjunction with a hair blower to part the obstructed hair twice weekly for up to 15 weeks.¹⁶ Initial dosage was based on the MED, and subsequent doses were increased by increments of up to 20%. A statistically significant difference in mean decrease in modified Psoriasis Area and Severity Index (PASI) scores between the treated and control sites was found, and scores were 4 and 2.61 respectively.16 A retrospective study was performed on 35 patients with scalp psoriasis, who were treated by excimer laser using manual separation of the hair to increase exposure of the laser to the scalp.¹⁷ One-half of the scalp was treated, and the other half remained untreated to serve as a control. The results showed that 49% of the patients cleared >95% and 45% of patients cleared 50-95%.¹⁷ However, no studies have examined the use of excimer laser for the specific treatment of hairline psoriasis.

Based on our review of scalp psoriasis treatments and our experience with the excimer laser, we propose an updated algorithm for the treatment of scalp psoriasis, introducing excimer laser as part of the treatment algorithm (Figure 1). For mild scalp psoriasis, the first-line therapy remains topical treatments. However, when psoriasis is resistant to topical therapies or for severe scalp involvement, the combination of excimer laser with topical steroid (i.e., clobetasol spray) could be considered as a viable therapeutic option, as illustrated in our case and in two current studies using excimer laser alone.^16,17 Prior to initiating systemics that carry greater risks to patients, the use of the excimer laser may be an efficacious option for treating recalcitrant plaques along the hairline.

Conclusion

Our case and discussion demonstrates the use of excimer laser in conjunction with topical treatment as an effective and safe method for treating scalp psoriasis. One major limitation of the presented case is that there is a lack of a control arm and, therefore, it is difficult to predict whether the majority of the improvement in psoriasis was attributable to the excimer laser or to clobetasol spray. The clobetasol spray alone may have induced the significant improvements in psoriasis, as the patient had not used clobetasol spray in the past. Furthermore, a study by Sofen et al. showed 85% clearance of psoriasis with clobetasol spray alone.¹⁴ Therefore, the proposed update and addition to the scalp psoriasis treatment algorithm requires more substantiation through a study in which there is a controlled arm, such as comparing the application of clobetasol spray alone to clobetasol spray in conjunction with excimer laser therapy.

Nevertheless, when scalp psoriasis cannot be adequately controlled with topical therapy, the excimer laser can be used effectively to treat hairline plaques, visible lesions that can cause significant psychosocial distress to affected patients. For general scalp psoriasis treatment, clinicians may consider using excimer laser in combination with a topical steroid when topical agents alone do not achieve adequate disease control. This combined therapeutic method may also be considered prior to initiating systemic therapy for severe or intractable cases. Further studies should be performed to establish the safety and efficacy of excimer laser in the treatment of hairline psoriasis. In the future, this novel approach has the potential to become more widely used in clinical dermatology practices.

References

1. Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatol Clin. 1996 Jul;14(3):485-96.
2. de Arruda LH, De Moraes AP. The impact of psoriasis on quality of life. Br J Dermatol. 2001 Apr;144 Suppl 58:33-6.
3. Krueger G, Koo J, Lebwohl M, et al. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-membership survey. Arch Dermatol. 2001 Mar;137(3):280-4.
4. Van Voorhees AS, Fried R. Depression and quality of life in psoriasis. Postgrad Med. 2009 Jul;121(4):154-61.
5. Morison WL, Atkinson DF, Werthman L. Effective treatment of scalp psoriasis using the excimer (308 nm) laser. Photodermatol Photoimmunol Photomed. 2006 Aug;22(4):181-3.
6. Lee ES, Heller M, Kamangar F, et al. Current treatment options – phototherapy (Chapter 4). In Feldman SR, ed. Current and emerging treatments for psoriasis. London, UK: Future Medicine Ltd.; 2011:60-71.
7. Hong J, Malick F, Sivanesan P, et al. Expanding use of the 308-nm excimer laser for the treatment of psoriasis. Practical Dermatol. 2007 Apr: S13-6.
8. Gattu S, Pang ML, Pugashetti R, et al. Pilot evaluation of supra-erythemogenic phototherapy with excimer laser in the treatment of patients with moderate to severe plaque psoriasis. J Dermatolog Treat. 2010 Jan;21(1):54-60.
9. Feldman SR, Mellen BG, Housman TS, et al. Efficacy of the 308-nm excimer laser for treatment of psoriasis: results of a multicenter study. J Am Acad Dermatol. 2002 Jun;46(6):900-6.
10. Ortonne JP, Humbert P, Nicolas JF, et al. Intra-individual comparison of the cutaneous safety and efficacy of calcitriol 3 microg g(-1) ointment and calcipotriol 50 microg g(-1) ointment on chronic plaque psoriasis localized in facial, hairline, retroauricular or flexural areas. Br J Dermatol. 2003 Feb;148(2):326-33.
11. van de Kerkhof PC, Murphy GM, Austad J, et al. Psoriasis of the face and flexures. J Dermatolog Treat. 2007;18(6):351-60.
12. Feldman SR, Koo JYM, Lebwohl MG, et al. The psoriasis and psoriatic arthritis pocket guide: treatment algorithms and management options. 2nd ed. Portland, OR: National Psoriasis Foundation; 2005.
13. Guenther LC. Treatments for scalp psoriasis with emphasis on calcipotriol plus betamethasone dipropionate gel (Xamiol). Skin Therapy Lett. 2009 May;14(4):1-4.
14. Sofen H, Hudson CP, Cook-Bolden FE, et al. Clobetasol propionate 0.05% spray for the management of moderate-to-severe plaque psoriasis of the scalp: results from a randomized controlled trial. J Drugs Dermatol. 2011 Aug;10(8):885-92.
15. Bagel J, Lynde C, Tyring S, et al. Moderate to severe plaque psoriasis with scalp involvement: A randomized, double-blind, placebo-controlled study of etanercept. J Am Acad Dermatol. 2011 Oct 19.
16. Taylor CR, Racette AL. A 308-nm excimer laser for the treatment of scalp psoriasis. Lasers Surg Med. 2004;34(2):136-40.
17. Morison WL, Atkinson DF, Werthman L. Effective treatment of scalp psoriasis using the excimer (308 nm) laser. Photodermatol Photoimmunol Photomed. 2006 Aug;22(4):181-3.

¹ Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
² College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
³ Department of Dermatology, Psoriasis and Skin Treatment Center, University of California, San Francisco, CA, USA

ABSTRACT
Emotional stress may influence the development and exacerbation of psoriasis. The proportion of psoriasis patients who believe stress affects their skin condition (i.e., “stress responders”) is considerably high, ranging from 37% to 78%. Stress may worsen psoriasis severity and may even lengthen the time to disease clearance. Although a pathogenic association appears likely, additional well-controlled studies are necessary to confirm such a causal relationship. Dysregulation of the hypothalamus-pituitary-adrenal and sympathetic adrenomedullary systems has been proposed as one possible underlying cause of stress-induced flares of psoriasis. While stress may be an exacerbating factor, psoriasis itself may contribute to significant adverse psychological sequelae. Breaking this stress cycle may be an important part of any therapeutic approach. Thus, stress reduction through psychotherapy and pharmacotherapy may be useful in treating psoriatic patients who are stress responders.

Key Words:
anxiety, depression, chronic inflammatory disease, psoriasis, stress

Psoriasis is a chronic, inflammatory skin disease with an approximate 2-3% prevalence in the general population.¹ The etiology of psoriasis is not fully understood, but it appears to be multifactorial, involving both genetic and environmental influences. Among these factors, emotional stress (hereafter simply referred to as “stress”) is considered to play an important role in the onset and exacerbation of psoriasis.²

Stress has been indicated as a trigger in many dermatologic conditions, including atopic dermatitis, acne vulgaris, and chronic urticaria. With each of these conditions, one encounters both patients who experience a close chronologic association between stress and exacerbation of their skin disease, and patients for whom their emotional states seem to be unrelated to the natural course of their cutaneous disorder. These two groups are considered “stress responders” and “non-stress responders,” respectively.³

Just as in many dermatologic conditions, psoriasis appears to worsen with stress in a significant segment of patients. Studies report that the proportion of psoriasis patients who are stress-responders ranges from 37% to 78%.⁴

Significance of Stress

Studies define stress along three general categories: 1) major stressful life events (e.g., change of employment, major personal illness, financial problems), 2) psychological or personality difficulties, and 3) lack of social support.⁵ Regardless of how stress is defined, studies consistently support a relationship between stress and psoriasis.^5-12 Furthermore, a majority of patients consider stress to be the main cause for exacerbation of their psoriasis, ranking it above infections, trauma, medications, diet, or weather.⁶

For example, Seville⁷ examined 132 psoriasis patients whose psoriasis had completely cleared with anthralin therapy and were followed over 3 years. Fifty-one patients (39%) recalled specific incidents of stress within 1 month prior to psoriasis exacerbation. The study further observed that the incubation time from specific incidents of stress to psoriasis exacerbation was between 2 days to 1 month.⁷ In a subsequent study, Al’Abadie et al.8 assessed 113 psoriasis patients and determined the incubation time from stressful event to onset of psoriasis was significantly longer than that from stressful event to exacerbation of psoriasis.⁸

In a study of 127 psoriasis patients, Gupta et al.5 found differences between patients who reported that stress flared their psoriasis (stress responders) and patients who reported no association (non-stress responders). Stress-responders described significantly more flare-ups during the 6 months prior to admission, experienced more psoriasis-related daily stress, and relied more upon the approval of others. They also had more severe psoriasis in “emotionally charged” body areas, such as the scalp, face, neck, forearms, hands, and genital region. However, total percentage of body surface affected by psoriasis was not significantly different.

Similarly, Zachariae et al.9 showed that stress responders differed significantly from non-stress responders. Stress responders tended to self-report greater disease severity than non-stress responders, even though clinical measures of disease severity (e.g., Psoriasis Area Severity Index) did not vary between groups. Stress responders were, however, found to have more plaques of psoriasis on visible areas than non-visible regions.⁹

Unlike these above studies, Verhoeven et al.10 found a significant association between stress and disease severity. This prospective study of 62 psoriasis patients determined high levels of daily stressors to be related to an increase in disease severity 4 weeks later.¹⁰

Finally, stress may not only worsen psoriasis severity, but it may also adversely affect treatment outcomes. Fortune et al.¹³ found that psychological stress impaired the rate of clearance of psoriasis in patients undergoing psoralen + ultraviolet A (PUVA) treatment. Patients with high-levels of worry cleared with PUVA therapy almost two times slower than those with low-levels of worry.¹³

Physiologic Effects of Stress

Normal physiologic response to stress involves activation of the hypothalamus-pituitary-adrenal (HPA) axis and sympathetic adrenomedullary (SAM) axis, both of which interact with immune functions. Generally, in normal individuals, stress elevates stress hormones (i.e., increases cortisol levels). However, according to available studies, exposure to stress in psoriatic patients has been associated with diminished HPA responses and upregulated SAM responses.^14-17 More specifically, when psoriasis sufferers are under such emotional pressures lower plasma cortisol levels14 and higher epinephrine and norepinephrine levels¹⁵ can be induced, when compared with controls.

Similarly, Evers et al.16 found psoriasis patients had significantly lower cortisol levels at moments when daily stressors are at peak levels. The study also reported that psoriasis patients with overall high levels of daily stressors exhibited lower mean cortisol levels, as compared to psoriatics with overall low levels of daily stressors.¹⁶ Furthermore, Richards et al.¹⁷ observed physiologic differences in response to stress between psoriasis patients who are stress responders and those who are non-stress responders. Specifically, stress-responders had lower salivary and serum cortisol levels than non-stress responders following a social performance stressor.¹⁷

These blunted HPA axis and elevated SAM system responses to stress may be crucial in better understanding the inflammatory characteristics of psoriasis, particularly in stress-responders. For instance, decreased secretion of cortisol and increased levels of epinephrine and norepinephrine may stimulate the release of mast cells, affect skin barrier function, and upregulate proinflammatory cytokines, which could thereby maintain or exacerbate psoriasis severity.¹⁶ Some authors have commented that this decreased cortisol response may be similar to how psoriasis flares with steroid withdrawal, as evidenced by the well known phenomena of steroid-induced psoriasis rebound.¹⁷

Stress and Psoriasis: A Vicious Cycle

Psoriasis itself can serve as a stressor for patients. Psoriasis can be a disfiguring skin disease with much attached social stigmata. Accordingly, patients often suffer significant interpersonal and psychological distress. Patients commonly experience difficulties in social interactions, especially in meeting new individuals and forming romantic relationships. In general, most patients demonstrate adverse psychological consequences, including poor self-esteem, anxiety, depression, and for some, even develop suicidal ideation.¹⁸

As psoriasis can cause considerable stress for patients and increased levels of stress are likely to exacerbate psoriasis, the disease process, thus, becomes a self-perpetuating, vicious cycle.¹⁹ Therefore, treatment considerations for psoriasis should integrate methods of stress reduction, including psychotherapy and pharmacotherapy, especially for known stress responders.

Stress Evaluation and Management

The best approach to evaluating if an individual is a stress responder is to simply ask the patient, “Do you believe stress frequently worsens the severity of your psoriasis?” If the patient answers “yes” to this question, a clinician may want to consider further evaluating the impact of stress on the patient’s life. Useful questions may include: Have you experienced any recent stressful life events? Do you feel depressed or anxious? Do you have friends or family members that provide you with adequate social support? Do you feel you can manage the level of stress in your life? Ultimately, these questions should help guide a treating physician in determining if their patient is a stress responder. However, a clinician should be cognizant that the terms “stress responder” versus “non-stress responder” only refer to whether or not the patient’s psoriasis worsens with emotional stress. These terms do not indicate whether or not the patient has an underlying diagnosable psychiatric disorder, which is a separate issue requiring an alternate clinical approach.

As such, it is important to determine if the patient meets the diagnostic criteria for major depression, generalized anxiety, or other psychiatric disorders, as described by the Diagnostic and Statistical Manual of Mental Disorders (4th edition) published by the American Psychiatric Association.20 Obviously, all patients with diagnosable psychiatric disorders should be advised to seek appropriate mental health care. As for patients who are stress responders, but are otherwise psychologically well-functioning individuals, they should be made aware of the potential benefits of stress reduction in improving their skin condition. Some relatively easy and feasible stress reduction techniques are yoga, deep breathing exercises, and meditation, just to name a few. More intensive approaches to stress reduction, like psychotherapy or pharmacotherapy, may also be reasonable recommendations. Whether a patient is simply experiencing situational stress or suffering from a diagnosable psychiatric disorder, it may be advisable for that individual to consult a mental health professional as long as emotional factors (such as stress) play an important role in the natural history of their psoriasis.

Therapeutic Overview

Psychotherapy and Stress Reduction

Psychotherapy may be beneficial for psoriasis patients. Seng et al.²¹ found group therapy to be a useful and supportive treatment. Group therapy provided patients with knowledge about psoriasis and helped them better cope with their skin disease. Talking to other psoriasis patients enabled participants to learn how to manage disease-related stress and gain self-confidence.²¹

Case reports have described improvements in psoriasis severity with relaxation and stress reduction techniques, such as hypnosis and thermal biofeedback.^22,23 Likewise, Price et al.24 showed the potential efficacy of psychotherapy in a study of 11 patients, who completed an eight-session intervention consisting of relaxation and cognitive techniques. Patients reported a significant reduction in levels of anxiety and showed improvements in psoriasis severity based on a visual-analogue scale examining area of involvement, erythema, induration, and scaling.²⁴

Additionally, in a study of 37 patients treated with ultraviolet B (UVB) or PUVA therapy, Kabat-Zinn et al.²⁵ found that stress reduction may help accelerate the rate of clearance. Patients were randomly assigned to either an audiotape-guided, meditative stress reduction exercise during the light treatment, or a control group consisting of the light treatment alone. Study findings revealed that patients in the stress reduction group reached the clearing point (or the point at which less than 5% of the baseline level of psoriasis remained) more rapidly than controls in both UVB and PUVA therapies.²⁵

Pharmacotherapy and Stress Reduction

Pharmacotherapy may also be a helpful adjunct to psoriasis treatment. Studies have demonstrated improvements in psoriasis with oral administration of antidepressants, such as the tricyclic antidepressant (TCA) imipramine (Tofranil®), the monoamine-oxidase inhibitor (MAOI) moclobemide (Manerix®), and buproprion-SR (Wellbutrin®).^26-29

Modell et al.²⁹ found that the norepinephrine-dopamine uptake inhibitor buproprion-SR may be effective in treating non-depressed individuals with psoriasis. Ten patients were given buproprion-SR monotherapy at 150 mg/day for 3 weeks, and then increased to 300 mg/day for 3 more weeks. Only one patient remained on 150 mg/day dosing for all 6 weeks. Eight out of the 10 patients showed improvement from baseline after 6 weeks of therapy, with an average body surface area reduction of about 50%. Of these eight responders, disease severity worsened (towards pre-study baseline psoriasis coverage) within 3 weeks of discontinuing buproprion-SR.²⁹

In contrast, there are also a total of six cases reporting that the selective-serotonin reuptake inhibitors (SSRIs) fluoxetine (Prozac®) and paroxetine (Paxil®) may induce or exacerbate psoriasis.^30-32

Pharmacologic Treatment Recommendations

When pharmacologic treatment is deemed appropriate for stress reduction, SSRIs should be considered for first-line therapy. Despite the six reported cases of SSRI-associated flares of psoriasis,30-32 SSRIs have certain merits in the treatment of psoriasis patients experiencing depression. As well, these agents may possibly confer adjuvant benefits for non-depressed psoriatics who are stress responders. SSRIs, such as fluoxetine, paroxetine, sertraline (Zoloft®), and escitalopram (Lexapro®), are generally safe and better tolerated than other classes of antidepressants.³³

In stress responders, paroxetine may be preferential because of its anti-anxiety effects. It also offers the advantage of having minimal anticholinergic activity and no associated weight gain. Common side-effects include headache, gastrointestinal upset, and sexual dysfunction.33
TCAs, though effective antidepressants, can be lethal in overdose. Side-effects are common and include sedation, weight gain, orthostatic hypotension, and anticholinergic effects. MAOIs may be used to treat patients whose symptoms do not respond to first-line antidepressants (also known as, refractory depression). MAOIs should be prescribed with caution because of their potentially dangerous side-effects (i.e., serotonin syndrome and hypertensive crisis). Common side-effects include orthostatic hypotension, drowsiness, weight gain, sexual dysfunction, dry mouth, and sleep dysfunction.³³

In addition, anti-anxiety medications may be helpful for short-term use in specific stressful situations for stress responders. For instance, alprazolam (Xanax®) is a rapid-acting medication, with both anti-depressant and anti-anxiety effects, that may be beneficial in these situations. Because it has a shorter and more predictable half-life, as compared with other benzodiazepines, there is less risk of accumulation in the body when used over long periods of time. However, alprazolam can be highly sedating and potentially addictive,³⁴ and therefore, treatment should be limited to short-term use on the order of a few weeks to a maximum of a few months.

Conclusion

An extensive number of clinical studies exists supporting stress as an exacerbating factor in psoriasis.^5-12 One problem is that most investigations on stress are generally retrospective, primarily based on patient recall of past events, which may or may not be an entirely reliable measure. However, there are three prospective studies confirming an association between stress and psoriasis.^4,10
In sum, stress appears to be an important precipitating factor in the development and exacerbation of psoriasis. Patients who are identified as stress responders may especially benefit from stress reduction through psychotherapy and/or pharmacotherapy.

References

1. National Psoriasis Foundation website. About psoriasis: statistics. Available at: http:// www.psoriasis.org/netcommunity/learn/about-psoriasis/statistics. Last accessed: December 14, 2010.
2. Devrimci-Ozguven H, Kundakci TN, Kumbasar H, et al. The depression, anxiety, life satisfaction and affective expression levels in psoriasis patients. J Eur Acad Dermatol Venereol 14(4):267-71 (2000 Jul).
3. Koo JY. Psychodermatology: a practical manual for clinicians. Cur Prob Dermatol 6:204-32 (1995).
4. Picardi A, Abeni D. Stressful life events and skin diseases: disentangling evidence from myth. Psychother Psychosom 70(3):118-36 (2001 May-Jun).
5. Gupta MA, Gupta AK, Kirkby S, et al. A psychocutaneous profile of psoriasis patients who are stress reactors. A study of 127 patients. Gen Hosp Psychiatry 11(3):166-73 (1989 May).
6. Rigopoulos D, Gregoriou S, Katrinaki A, et al. Characteristics of psoriasis in Greece: an epidemiological study of a population in a sunny Mediterranean climate. Eur J Dermatol 20(2):189-95 (2010 Mar-Apr).
7. Seville RH. Psoriasis and stress. Br J Dermatol 97(3):297-302 (1977 Sep).
8. Al’Abadie MS, Kent GG, Gawkrodger DJ. The relationship between stress and the onset and exacerbation of psoriasis and other skin conditions. Br J Dermatol 130(2):199-203 (1994 Feb).
9. Zachariae R, Zachariae H, Blomqvist K, et al. Self-reported stress reactivity and psoriasis-related stress of Nordic psoriasis sufferers. J Eur Acad Dermatol Venereol 18(1):27-36 (2004 Jan).
10. Verhoeven EW, Kraaimaat FW, de Jong EM, et al. Individual differences in the effect of daily stressors on psoriasis: a prospective study. Br J Dermatol 161(2):295-9 (2009 Aug).
11. Naldi L, Chatenoud L, Linder D, et al. Cigarette smoking, body mass index, and stressful life events as risk factors for psoriasis: results from an Italian case-control study. J Invest Dermatol 125(1):61-7 (2005 Jul).
12. Jankovic S, Raznatovic M, Marinkovic J, et al. Risk factors for psoriasis: A case-control study. J Dermatol 36(6):328-34 (2009 Jun).
13. Fortune DG, Richards HL, Kirby B, et al. Psychological distress impairs clearance of psoriasis in patients treated with photochemotherapy. Arch Dermatol 139(6):752-6 (2003 Jun).
14. Arnetz BB, Fjellner B, Eneroth P, et al. Stress and psoriasis: psychoendocrine and metabolic reactions in psoriatic patients during standardized stressor exposure. Psychosom Med 47(6):528-41 (1985 Nov-Dec).
15. Buske-Kirschbaum A, Ebrecht M, Kern S, et al. Endocrine stress responses in TH1-mediated chronic inflammatory skin disease (psoriasis vulgaris)–do they parallel stress-induced endocrine changes in TH2-mediated inflammatory dermatoses (atopic dermatitis)? Psychoneuroendocrinology 31(4):439-46 (2006 May).
16. Evers AW, Verhoeven EW, Kraaimaat FW, et al. How stress gets under the skin: cortisol and stress reactivity in psoriasis. Br J Dermatol 163(5):986-91 (2010 Nov).
17. Richards HL, Ray DW, Kirby B, et al. Response of the hypothalamic-pituitary-adrenal axis to psychological stress in patients with psoriasis. Br J Dermatol 153(6):1114-20 (2005 Dec).
18. Russo PA, Ilchef R, Cooper AJ. Psychiatric morbidity in psoriasis: a review. Australas J Dermatol 45(3):155-9 (2004 Aug).
19. Kimball AB, Jacobson C, Weiss S, et al. The psychosocial burden of psoriasis. Am J Clin Dermatol 6(6):383-92 (2005).
20. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision. Washington, DC: American Psychiatric Association (2000).
21. Seng TK, Nee TS. Group therapy: a useful and supportive treatment for psoriasis patients. Int J Dermatol 36(2):110-2 (1997 Feb).
22. Winchell SA, Watts RA. Relaxation therapies in the treatment of psoriasis and possible pathophysiologic mechanisms. J Am Acad Dermatol 18(1 Pt 1):101-4 (1988 Jan).
23. Griffiths CE, Richards HL. Psychological influences in psoriasis. Clin Exp Dermatol 26(4):338-42 (2001 Jun).
24. Price ML, Mottahedin I, Mayo PR. Can psychotherapy help patients with psoriasis? Clin Exp Dermatol 16(2):114-7 (1991 Mar).
25. Kabat-Zinn J, Wheeler E, Light T, et al. Influence of a mindfulness meditation-based stress reduction intervention on rates of skin clearing in patients with moderate to severe psoriasis undergoing phototherapy (UVB) and photochemotherapy (PUVA). Psychosom Med 60(5):625-32 (1998 Sep-Oct).
26. Hardman R, Hopkins EJ, Pye AM, Solomon M, Solomon S. A trial of imipramine in the treatment of psoriasis. J Coll Gen Pract 10(3):315-6 (1965 Nov).
27. Hebel E. [Treatment of psoriasis with imipramine (Tofranil)]. Ugeskr Laeger 128(1):20-1 (1966 Jan 6).
28. Alpsoy E, Ozcan E, Cetin L, et al. Is the efficacy of topical corticosteroid therapy for psoriasis vulgaris enhanced by concurrent moclobemide therapy? A double-blind, placebo-controlled study. J Am Acad Dermatol 38(2 Pt 1):197-200 (1998 Feb).
29. Modell JG, Boyce S, Taylor E, et al. Treatment of atopic dermatitis and psoriasis vulgaris with bupropion-SR: a pilot study. Psychosom Med 64(5):835-40 (2002 Sep-Oct).
30. Tamer E, Gur G, Polat M, et al. Flare-up of pustular psoriasis with fluoxetine: possibility of a serotoninergic influence? J Dermatolog Treat 20(3):1-3 (2009).
31. Hemlock C, Rosenthal JS, Winston A. Fluoxetine-induced psoriasis. Ann Pharmacother 26(2):211-2 (1992 Feb).
32. Osborne SF, Stafford L, Orr KG. Paroxetine-associated psoriasis. Am J Psychiatry 159(12):2113 (2002 Dec).
33. Katon W, Ciechanowski P. Initial treatment of depression in adults. In: UpToDate. Waltham, MA.
34. DuPont RL, Greene W, Lydiard R. Sedatives and hypnotics: pharmacology and epidemiology. In: UpToDate. Waltham, MA.

Department of Dermatology, School of Medicine, University of California at San Francisco, San Francisco, CA, USA

ABSTRACT

Topical agents for the treatment of psoriasis are indicated for patients whose affected
area is < 10% of their skin. However, for long-term use, their effectiveness can be limited.
Topical sequential therapy involves the application of a class I corticosteroid and
calcipotriene in three different phases: the clearance phase, the transition phase and
the maintenance phase. It is an accepted and widely practiced technique that provides a balance between maximizing efficacy and minimizing side-effects thus offering patients rapid clearance of their psoriatic lesions and long-term maintenance of remission.

Key Words:
topical treatment, psoriasis, sequential therapy, calcipotriene, corticosteroids

Topical therapy is central in the treatment of psoriasis, and is indicated for most patients who have 20% or less of their body surface affected. Topical agents are associated with a lower side-effect burden compared with systemic therapies, which are generally reserved for patients with severe or non-responsive disease. However, individual topical agents have their own limitations. Topical corticosteroids, the most widely prescribed topical agents for psoriasis in the US, are highly effective in short-term use, but are associated with the potential for significant side-effects with long-term use, including atrophy, telangiectases, striae, and tachyphylaxis.

Sequential Therapy

The technique of sequential therapy was developed to maximize the shortterm efficacy of topical agents while minimizing side-effects associated with long-term maintenance therapy. Other topical agents, such as the vitamin D analog calcipotriene, are safer in long-term use, but they are also slower acting than commonly used high-potency topical steroids. Combining agents such as calcipotriene with corticosteroids in the context of sequential therapy is now widely practiced in the treatment of psoriasis. The utility of this approach has also been clearly demonstrated in recent trials.

As developed in clinical trials, sequential therapy involves three phases (Table 1).^1,2 The first phase, called the clearance phase, consists of short-term daily therapy with two topical agents. For example, a class I corticosteroid might be applied once or twice daily, followed by application of calcipotriene. Patients whose lesions respond to this daily combination therapy then enter the second or transition phase. During this phase, the use of the topical steroid is reduced from daily application to use only on weekends, while calcipotriene is applied

on weekdays, hence the terms “weekday-weekend” or “pulse” therapy. The length of this phase varies; recent trials describing sequential therapy for psoriasis have reported results extending up to 6 months, but longer duration of treatment may be indicated to prevent recurrence in some patients. Eventually, for the third or maintenance phase, only a non-steroid, namely calcipotriene, is used until the lesions clear completely.

Clinical Trials of Sequential Therapy

The technique of pulse therapy was developed in placebo-controlled trials over a decade ago. Katz and colleagues, for example, evaluated the use of betamethasone for extended maintenance therapy.³ Following short-term, twice-daily treatment for 2- 3 weeks, 38 of 59 enrolled subjects achieved 85% improvement from baseline and were rolled into the second phase of the study. Thereafter, subjects were randomized to weekend use of either betamethasone or placebo. Seventy-four percent of the betamethasone group and 21% of the placebo group maintained clinical remission for 12 weeks, suggesting that pulse dosing was safe and efficacious for long-term treatment.

Combination Therapy: Calcipotriene With
Corticosteroids

Some years later, following the introduction of calcipotriene, investigators focused on the addition of this vitamin D analog to sequential therapy with corticosteroids. Lebwohl and colleagues evaluated the daily use of both calcipotriene and halobetasol for the sequential treatment of mild-to-moderate psoriasis.⁴ After 2 weeks of daily combination therapy (i.e., clearing phase), 40 of 44 subjects demonstrated 50% or greater improvement, and were randomized to one of two groups: weekend halobetasol therapy with either weekday calcipotriene or weekday placebo. Through 6 months of treatment, 76% of subjects in the calcipotriene group maintained remission, compared with 40% of those in the placebo group (p=0.045). The results of this trial clearly demonstrated that calcipotriene in combination with a class I corticosteroid was tolerable to patients, and that this combination improved remission rates in the second phase of sequential therapy.

Other investigators have also demonstrated that combination therapy with calcipotriene and corticosteroids is more efficacious than monotherapy.⁵ Calcipotriene is moderately effective as a topical agent, and benefits from combination with other agents to maximize efficacy, particularly for initial treatment (i.e., the clearance phase of sequential therapy). The reasons for improved efficacy in combination with steroids are likely multifactorial. Steroids and vitamin D analogs act through different mechanisms of action that may be complementary. Corticosteroids have anti-inflammatory, immunosuppressive, antimitotic, and antipruritic actions, whereas calcipotriene reduces keratinocyte proliferation and acts as an immunomodulator. The side-effects of each agent also can be reduced through combination use. Because calcipotriene is safe for long-term use, it is an ideal agent for weekday use in combination with weekend steroid therapy, thus allowing for improved efficacy and reduced steroid side-effects. Furthermore, the most common side-effect of calcipotriene – irritation – may be reduced through concomitant use of topical steroids. Calcipotriene, therefore, is an ideal candidate for use with steroids in sequential therapy. The recent advent of combination agent capcipotriene + betamethasone (Dovobet®, LEO Pharma) also makes the use of the calcipotriene-corticosteroid combination easier. Dovobet® is approved for use in Canada and LEO Pharma, in conjuction with Warner Chilcott submitted an NDA to the US FDA in March 2005.

However, some authors have suggested that extemporaneous compounding of calcipotriene with other agents, such as steroids, may result in the degradation of the vitamin D analog.⁵ Data from several sources should minimize this concern. One in vitro study showed no enhanced degradation of calcipotriene when used immediately after application of a steroid foam.⁶ The results of recent clinical trials also indicate improved efficacy, rather than degradation, when calcipotriene is combined with topical steroids (see below).⁷

New Steroid Formulations and Sequential Therapy

New formulations of topical steroids have proliferated in recent years. Among these formulations is the introduction of foam vehicles such as the clobetasol propionate foam (Olux™, Connetics). This foam is a thermolabile vehicle that breaks down on contact with human skin and at body temperature, providing for convenient and elegant application. Data from a variety of in vitro studies indicate that this foam formulation is a more efficient vehicle for drug delivery than other topical formulations, including both creams and ointments.^8-11

Furthermore, because clobetasol foam is quickly absorbed and leaves no residue, it is an ideal vehicle for use in combination with other topical agents, such as calcipotriene. This relative lack of concern regarding incompatibility applies only to the foam vehicle agent and not to any other situation where the vehicle does not vanish. The utility of this combination – clobetasol foam and calcipotriene – was evaluated in a recently completed clinical trial of topical sequential therapy. The results of this trial were presented in two abstracts at the 2004 and 2005 meetings of the American Academy of Dermatology (AAD).^7,12 Part 1 of the study evaluated the twice-daily use of clobetasol foam and calcipotriene for the clearance phase of therapy.7 Eighty-six subjects were randomized to three groups: combination therapy, or monotherapy with either clobetasol foam or calcipotriene. Subjects in the combination group were directed to apply calcipotriene immediately after the clobetasol foam was absorbed. After 2 weeks of treatment, reductions in psoriasis severity scores for target lesions were significantly greater in the combination therapy group than in either monotherapy group:

• vs. clobetasol: p=0.0017 for trunk lesions, p < 0.0001 for extremity lesions
• vs. calcipotriene: p < 0.0001 for both trunk and extremity lesions.

As mentioned previously, the results also support in vitro data suggesting that degradation of calcipotriene does not occur when it used immediately following application of a topical steroid.⁶ At the 2005 AAD meeting, the results of the second phase of this trial were reported.12 In this part – the second phase of the sequential treatment approach – subjects who achieved at least 50% improvement in target lesions during part one were randomized to one of two groups: weekday calcipotriene b.i.d. with weekend use of either clobetasol foam (b.i.d.) or placebo. Through 6 months of treatment, the combination therapy group showed a consistent, although not statistically significant trend toward greater maintenance of remission compared with the monotherapy group. Because this trend was similar for all assessments used in the study, the authors suggested that there may be a positive effect associated with the combination of clobetasol foam and calcipotriene in pulse therapy. Given the consistency of these trends, it is possible that the results would have been statistically significant if a greater number of subjects had participated in the study (n=38, intent-to-treat population).

Conclusions

Topical sequential therapy is an accepted and widely practiced technique for rapid clearance of lesions and long-term maintenance of remission. This approach is a fruitful balance between maximizing efficacy and minimizing side-effects. Current sequential therapy paradigms are rooted in the synergistic effects of topical agents with different mechanisms of action and divergent side-effect profiles, in particular, the use of a class I corticosteroid with calcipotriene. Used together in daily application of the clearance phase, these agents complement one another and promote the rapid induction of remission. Subsequent weekend steroid therapy combined with weekday calcipotriene reduces the potential for steroid-related side-effects while improving the maintenance of remission.

Patients who remain stable may then be switched to the third phase of sequential therapy,
consisting of monotherapy with daily calcipotriene. Recent clinical trials support this approach. Newer steroid formulations, namely foam vehicles, further improve the convenience and efficacy of sequential therapy, eliminating concerns regarding dilution and
incompatibility through their rapid evaporation.

References

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2. Koo JYM. How and why to employ sequential therapy for psoriasis. Skin and Aging Suppl:16-21 (2000).
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