Dermatology Online Journal

The Efficacy of 308nm Laser Treatment of Psoriasis Compared to Historical Controls
Erin J Rodewald,¹ Tamara Salam Housman,¹ Beverly G Mellen,²and Steven R Feldman¹
Dermatology Online Journal 7(2): 4

1. Departments of Dermatology and 2. Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina

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Abstract

UVB treatment with a 308nm excimer laser has shown promise in the treatment of localized psoriasis. There is no placebo or comparison treatment controlled trial studying efficacy of the laser, however. The purpose of this report is to compare the results of a study of 308nm laser treatment of psoriasis to published results of other psoriasis treatments. Data on the efficacy of 308nm laser treatment of psoriasis were obtained from a previously published case series, supplemented by reanalysis of the data to estimate the median time to success using Kaplan-Meier methods. These results were compared to those from other studies identified by a Medline search. Treatment success was measured by estimating the percentage of patients who achieve 75% improvement in the severity of psoriasis. Patients treated in the 308nm laser study had similar disease severity as those in topical treatment studies and less severe disease than those treated in studies using standard phototherapy or systemic therapy. A greater percentage of patients achieved 75% improvement with the UVB laser treatments than was reported for other forms of phototherapy or systemic therapy with acitretin or low dose cyclosporine, and did so more rapidly. The UVB laser study patients achieved the 75% improvement endpoint in an average of 46% fewer treatments than was observed in other phototherapy studies. Laser treatment and topical calcipotriene had similar efficacies, and both were more effective than topical tazarotene or topical fluocinonide. As compared to topical therapies, the time to achieve 75% improvement favored the UVB laser. 308nm laser treatments for psoriasis are clearly more effective than placebo and are comparable to or more effective than many other standard treatments for psoriasis.

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Introduction

Figure 1
Figure 1: Laser treatment of a psoriatic plaque

UVB therapy is a well-accepted treatment of psoriasis and has a high benefit/risk ratio.[1] Disadvantages of standard UVB phototherapy include exposure of uninvolved skin and the cost and inconvenience of numerous office visits.[2] Despite these drawbacks of UVB therapy, it remains a mainstay for treating psoriasis because of advantages over other therapies for severe psoriasis. UVB is more effective than topical therapy and offers the potential for long remissions.[3,4]

Phototherapy has generally been reserved for patients with extensive psoriasis. Laser delivery of narrow band UVB offers patients with localized psoriasis the potential benefits of phototherapy. There are two additional benefits of laser delivery over UVB light. First, only the psoriasis is treated, so uninvolved skin is not subjected to the adverse effects of phototherapy. Second, psoriasis plaques are relatively resistant to UV compared to normal skin, limiting the dose of UV that can be given. Because laser delivery only treats the plaques, higher doses of UVB can be given-- several times the dose that induces burning of the normal skin (the minimal erythema doses [MED]). Doses as high as six times the minimal erythema dose (MED) for normal skin are well tolerated.[5] The use of multiple MED dosing with laser UVB therapy allows for psoriasis treatment in fewer UVB exposures, as clearing can occur with as few as four treatments.[5]

A recent study demonstrated the effectiveness of the 308 nm excimer UVB laser during a multicenter open trial.[6] While the outcome data were clinically and statistically significant, open trials are not regarded highly when evaluating studies based upon the criteria of levels of evidence. Unless controls are included in the study, treatments based upon case series are considered "experimental". In the five tiers of quality of clinical study evidence, randomized controlled trials (RCTs) are viewed with the most regard.[7]

This paper compares the UVB laser to historical controls in order to better demonstrate the efficacy of UVB laser treatments for psoriasis. Such historical controlled studies are a form of metaanalysis and represent the fourth tier in the five levels of clinical study evidence. While not as strong as the gold standard, first tier, randomized controlled trial, this study shows that UVB laser treatments are an effective treatment for localized psoriasis.

Methods

Case series data on 308nm UVB laser treatment of psoriasis were obtained from a published study using a XTRACTM XeCl excimer (PhotoMedex, Radnor PA) laser. Twice weekly 308nm UVB laser treatments were initiated at a dose of 3 MED and adjusted depending on response. Subjects had up to 10% body surface area affected. Treatments were given until clearing or up to a maximum of 10 treatments. Detailed methods of the study have been described.[6] The baseline severity of disease was measured using a modified Psoriasis Area and Severity Index (PASI) score based on the characteristics of target lesions. The original analysis examined rates of improvement based upon numbers of treatments needed to achieve the primary endpoint of 75% improvement in the disease as assessed by a physician's global evaluation.

A 75% improvement in PASI score is termed PASI75. Since first described in 1978, PASI has been a widely utilized tool for the objective evaluation of psoriasis.[8] The PASI score ranges from 0.1 to 72.0 on a scale representing the proportion of area involved and the severity of erythema, infiltration, and desquamation.[9] We compared rates of 75% improvement with UVB laser treatments to published results of PASI75 improvement with other treatments. We supplemented the original analysis with a reanalysis of the data to determine rates of improvement based on time to achieve 75% improvement in order to compare the results to published reports of topical and systemic psoriasis treatments.

Treatment	Percent achieving 75% improvement	Median number of treatments to 75% improvement	Mean PASI of study population	Reference
UVB laser	72	8	6	[6]
Near MED narrow band UVB	55	12	21^	[10]
Far MED narrow band UVB	27	16	19^	[10]
UVB + calcipotriol	61*	12	12	[11]
UVB + vehicle	58*	19	12	[11]

Table 1. Efficacy of treatments reported as number of treatments to 75% improvement

A Medline search was performed using key words 'psoriasis', 'randomized controlled trials', 'clinical trials', and all related words. The search was limited to articles written in English and pertaining to human subjects. We excluded all studies that did not report either PASI75 endpoints or the number of subjects who achieved a 75% improvement as an outcome measurement. We included one study that reported 75% improvement in Physician Global Assessment (PGA) rather than PASI75 (table 2). We also included studies that used a PASI 80 endpoint. In order to include data on tazarotene, we included on study reporting the number of subjects achieving 50% improvement in PASI. Improvement of 50% is a less stringent criterion of success and would serve as a lower limit for the relative efficacy of the treatment when compared to UVB laser treatment.

Treatment	Percent achieving 75% improvement	Number of days to 75% improvement	Mean baseline PASI of study population	Reference
UVB laser	72†	36	6	[6]
Systemic placebo	11, 8, 0, 0, 18	56, 70, 28, 56, 28	nd, nd, 20, 6, 20	[15, 19, 22, 23, 24]
Topical placebo	19†, 33**	56, 84	nd, 7	[12, 14]
Calcipotriene 0.005%	70†	56	nd	[12]
Tazarotene 0.1%	58**, 67**	84, 84	nd, 7	[13, 14]
Tazarotene 0.05%	50**, 53**	84, 84	nd, 7	[13, 14]
Fluocinonide 0.05%	68**	84	nd	[13]
Etretinate 0.5-0.75 mg/kg/day	88, 10	84, 70	18, 19	[17, 21]
Etretinate 40 mg	61	98	nd	[16]
Acitretin 10-25 mg	0	56	nd	[15]
Acitretin 50-75 mg	25	56	nd	[15]
Etretinate 50 mg then PUVA	79	98	nd	[16]
Etretinate 45 mg then etretinate 34 mg + PUVA	84	98	nd	[16]
PUVA	80	98	nd	[16]
Cyclosporine 1.25 mg/kg/day	18*, 24, 12,	84-252, 84, 70	15, 25, nd,	[9, 18, 19]
Cyclosporine 2.5-3 mg/kg/day	50*, 52, 30, 48, 47	84-252,84, 70, 84, 70	15, 25, nd, 25, 18	[9, 18, 19, 20, 21]
Cyclosporine 5-5.5 mg/kg/day	68*, 97, 88, 89, 83	84-252, 84, 84, 42, 28	15, 18, 25, 25, 20	[9, 17, 18, 20, 22]
Etanercept 25mg	26	56	10^	[23]
Infliximab 5 mg/kg	82	28	22	[24]
Infliximab 10 mg/kg	73	28	27	[24]

Table 2. Efficacy of treatments reported as number of days to 75% improvement

Adverse reactions were also evaluated (table 3). In order to compare side effects between all studies, adverse effects were only compared if the study reported the percentage of patients experiencing each side effect.

Therapy	Adverse event (AE)	Percent reporting	Patients dropping due to AE	Reference
UVB laser	erythema	51%	0	[6]
	blister	45%	[6]
	hyperpigmentation	38%	[6]
	shallow erosion	25%	[6]
Topical placebo	rash	8%	3-6**%	[12,14]
	pruritus	8%	[14]
	burning	6%	[14]
UVB + calcipotriol	burn, pruritus, and/or erythema	28%	0	[11]
UVB + vehicle	burn, pruritus, and/or erythema	41%	0	[11]
Calcipotriene 0.005%	erythema	11%	4**%	[12]
	rash	12%	[12]
Tazarotene 0.05-0.1%	erythema	7-11%	11-18%	[13,14]
	pruritus	9-23%	[13,14]
	burning	9-19%	[13,14]
Fluocinonide 0.05%	burning	7%	2%	[13]
Etretinate 40 mg	elevated liver enzymes	20%	3%	[17]
	elevated triglycerides	20%	[17]
	elevated cholesterol	10%	[17]
	cutaneous desquamation	8%	[17]
	elevated uric acid	8%	[17]
	elevated creatinine	5%	[17]
Acitretin 10-75 mg	elevated triglycerides	35%	0	[15]
	elevated cholesterol	15%	[15]
	elevated liver enzymes	16%	[15]
Cyclosporine 1.25-3 mg/kg/day	elevated creatinine	1-68%	0-10%	[9,19,20]
elevated uric acid	4-28%	3%	[9,20]
	elevated cholesterol	12-21%	12%(20)	[9,20]
	elevated liver enzymes	8-20%	nd	[9,20]
	Hypertension	6-21%	4%(20)	[9,20]
Cyclosporine 5-5.5 mg/kg/day	elevated creatinine	13-55%	0-10%	[9,17,20,22]
elevated uric acid	6-43%	2%	[9,17,20]
	elevated cholesterol	6-25%	nd	[9,17]
	elevated liver enzymes	0-53%	6%(20)	[9,17,22]
	Hypertension	8-28%	6%	[9,17,20,22]
	Hypertrichosis	11-27%	0	[20,22]
Etanercept 25mg	injection site reaction	20%	0	[23]
	Fatigue	13%	0	[23]
Inflximab 5 mg/kg	Headache	9%	0	[24]
	Rash	9%	9%(1)	[24]
Inflximab 10 mg/kg	Headache	64%	0	[24]
	elevated liver enzymes	18%	0	[24]
	Fever	18%	0	[24]

Table 3. Adverse events

A limitation of the reported 308nm UVB laser study was that a significant number of subjects withdrew before completion of the trial (for reasons unrelated to safety or efficacy). Because of the extent of censored data, we limited the analysis strategy to time-to-event analysis using the Kaplan-Meier method. Of the fifteen studies that reported the methods of their statistical analysis, 7 (47%) also used a method of analysis to account for censored data.

To compare the populations throughout studies, the baseline PASI scores were compared from those studies that reported the mean baseline PASI scores. Two studies used median rather than mean PASI score at baseline (see tables 1 and 2). Baseline PASI scores were then compared as a mean value between the different treatment groups of photo, topical, and systemic therapies.

Results

The efficacy of UVB laser treatment was first compared with results obtained from other forms of phototherapy. These studies did not include placebo-controls, at least in part because of the difficulty in creating a placebo control for a phototherapy treatment. There were differences in the patient populations between the UVB laser phototherapy study and other phototherapy studies. As expected for a treatment used for localized psoriasis, the UVB laser study population had the lowest baseline PASI (6, standard deviation 1.4). The comparative UVB study populations had a relatively high mean PASI score (mean 16, standard deviation of the means 4.7).[10,11]

More patients achieved 75% improvement with the UVB laser treatments than was observed in the conventional phototherapy studies (table 1). Adjunctive topical therapy is often used to make conventional phototherapy more effective. UVB laser treatments resulted in more patients achieving the 75% improvement endpoint than was observed in other phototherapy studies, including those that used adjunctive topical therapy. Compared with UVB laser treated patients, the next best treatment, near erythemogenic narrow band UVB required 50% more treatments to achieve 75% improvement endpoint.

The efficacy of systemic and topical therapies for psoriasis is reported on the basis of the number of days until response is achieved, not on the basis of the number of treatments. We reanalyzed the UVB laser treatment data and determined the estimated median time to the 75% clearing endpoint of 36 days (table 2). This was then compared to the results for topical and systemic therapies that reported the PASI75 outcome (table 2). Again, there were differences in the severity of psoriasis in the patient populations of the different studies (table 2). However, the mean baseline PASI score (overall mean 8, standard deviation of the means 0.8) of the topical therapy studies were more similar to the UVB laser study population as both are indicated for the treatment of localized psoriasis.

Placebo-treated patients in the topical treatment studies showed relatively low PASI75 scores compared to the UVB laser treated patients (table 2). Topical calcipotriene reported the highest PASI75 response (70%), comparable to that reported in the UVB laser study. The time to achieve the 75% improvement favored the UVB laser. Topical tazarotene was less effective than topical calcipotriene. A study comparing tazarotene to the topical corticosteroid fluocinonide reported the number of patients achieving 50% improvement in PASI.13 The number of patients achieving this PASI50 endpoint was similar to the number achieving PASI75 with the UVB laser and with calcipotriene. The time to achieve the PASI50 endpoint for tazarotene and fluocinonide was longer than the time to achieve PASI75 for both the UVB laser and calcipotriene.

Of the systemic therapies reporting PASI75 outcomes, retinoids and etanercept exhibited lower efficacy. The 75% improvement response of UVB laser treatment subjects was greater than the responses of both the active and placebo treated subjects in the retinoid and etanercept trials (table 2). High dose cyclosporine showed the greatest percentage of patients achieving PASI75 and is considered among the most effective psoriasis treatments. However, this therapy causes numerous systemic side effects and is reserved for patients with severe disease. The difference in patient populations between cyclosporine studies and the UVB laser study is considerable. Patients treated with systemic therapies had a relatively high mean PASI (mean 20, standard deviation of the means 5). Nevertheless, the similarity of 75% improvement response between patients treated with the UVB laser and patients treated with moderate doses of cyclosporine supports the overall efficacy of UVB laser treatments. Infliximab also shows a high percentage of patients achieving PASI75, and in a similar time period as UVB laser. In contrast to high-dose cyclosporine, reported side effects with infliximab were less frequent (table 3).

Discussion

With the rapid development of new medical technology, some insurance companies use screening criteria when making determinations of whether to cover new therapies. Many companies have adopted evidence-based decision making and prefer outcomes data from controlled clinical trials.[25-27] This is laudable, however it may discriminate against forms of therapy, such as phototherapy, for which placebo controls are difficult. The comparison of the efficacy of excimer laser treatments to historical controls obtained from previously published randomized controlled trials demonstrates that the treatment is better than placebo and gives some sense of the relative efficacy of the laser treatment (albeit subject to potential differences in the patient populations that were treated). Using the published study outcomes, the excimer laser was clearly more efficacious than placebo. While the potential for differences in patient populations must be kept in mind, the 308 nm laser treatments appear comparable to or more effective than many other standard treatments for psoriasis.

The limitations and difficulties of performing a historical control comparison are considerable. Comparing data from different studies is complicated by differences in study population, study design and the variation among studies for interpreting and reporting data. A recent article examining the adequacy of reporting amongst RCTs found that only 1 in 122 recently published RCTs described randomization adequately.[28] This process becomes even more difficult because articles reporting the treatment of psoriasis encompass a considerable time-span, and the methods of reporting outcomes measures have changed considerably over time. The most common method utilized in psoriasis studies is the PASI. However, few studies reported the PASI in the same manner. The most common methods of reporting the PASI were the mean change from baseline, a graph of PASI over time, and time to clearing (often defined as PASI90).

The most recent studies of psoriasis efficacy use the PASI75 as a clinical efficacy endpoint. This is based on the proposition that treatments should be approved only if they result in a clinically significant improvement in a statistically significant number of patients. The advantage of PASI75 over other psoriasis assessments is that a 75% or greater improvement in psoriasis indicates that the patient has achieved a clinically significant improvement. An additional advantage of this approach is that it allows for time-to-event analyses of the data that take into account censored data, facilitating the comparison of results of 308nm laser treatment to results from other psoriasis treatment studies. While we used 75% improvement as the primary outcome, there was still some variation in the efficacy measures used in different studies-- some using PASI80 or PASI50, and others, including the UVB laser study, which used a physician global assessment of percent improvement.

In addition to its value for assessing efficacy, the comparison with historical controls is informative concerning adverse effects. Treatment with the 308nm excimer laser is expected to have similar side effects to other methods of UVB phototherapy. However, although well-tolerated, a higher degree of local irritation was seen with the 308nm laser. This is likely due to the relatively high MED doses achieved by the laser. The associated risks of photoaging and cutaneous malignancies are low with UVB phototherapy and theoretically may be further reduced with 308nm laser treatment because normal skin is not exposed to the laser's radiation. Overall, the side effect profile of 308nm laser treatment appears relatively benign.

The major limitation of this study is that patient populations are not necessarily similar between the different studies; patient populations in different studies vary greatly in activity of disease, percentage of body involved and many other characteristics. However, our analysis of baseline PASI scores indicates that studies of topical therapies are most likely to include similar populations of patients with localized psoriasis. These studies clearly show that placebo-treated patients with psoriasis are unlikely to achieve a PASI75 endpoint. This study shows that UVB laser treatments are an effective treatment for localized psoriasis. This study will facilitate patient access to this therapy by providing insurers the ³fourth tier² evidence they consider adequate proof of efficacy.

The study was funded by grants from PhotoMedex. Dr. Feldman has received grant support from Bristol-Myers Squibb Dermatology and Novartis and has been a consultant to Allergan.

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