Recent advances in phototherapy for psoriasis

The immunoregulatory effects of phototherapy: possible pathways

Psoriasis is caused by abnormal interactions among innate immune cells, T cells, and keratinocytes, leading to activation of the T helper cell type 1/T helper cell type 17 (Th1/Th17) immune axes and related cytokines. This contributes to the hyperproliferation and inflammation seen in psoriasis. There are various mechanisms by which phototherapy may be effective for psoriasis¹³. First, UV light induces apoptosis of keratinocytes and T cells in the epidermis and dermis¹⁴. Second, UV light promotes immunosuppression by promoting migration of Langerhans cells out of the epidermis¹⁵ as well as decreasing mast cell degranulation and histamine release¹⁶. Lastly, UV light induces alterations in the cytokine profile of psoriasis.

Research in the last 5 years has led to a better understanding of the specific pathways and cytokines that are altered by phototherapy. Phototherapy shifts the immune response away from the Th1/Th17 pathway, toward the counter-regulatory Th2 axis¹⁷. The Th1/Th17 pathway is suppressed by NB-UVB, leading to decreased levels of interleukin-12 (IL-12), IL-17, IL-20, IL-22, and IL-23¹⁸. These effects on cytokines appear to be systemic and not just localized to psoriatic lesions. PUVA and NB-UVB lower plasma levels of tumor necrosis factor-alpha, IL-17, IL-22, and IL-23 at the end of 6 weeks of treatment¹⁹. Furthermore, regulatory T (Treg) cells of patients with severe psoriasis display an enhanced propensity to convert into IL-17A-producing cells, which is linked to loss of forkhead box P3 (Foxp3)²⁰. UVB increases Foxp3-positive Treg cells in psoriatic skin lesions²¹. This increase in Foxp3 expression improves Treg cell stability and reduces pro-inflammatory Th1/Th17 cytokines in psoriatic skin lesions.

Handheld phototherapy: targeting difficult-to-treat psoriasis in the office and at home

Whole-body phototherapy is limited in that there can be needless exposure of uninvolved skin and no benefit to unexposed skin (such as the hair-covered scalp). In the last decade, various portable and lightweight handheld phototherapy units have become available for the treatment of localized psoriasis in the office and at home (Table 1)^22,23. These handheld devices, as compared with full-body irradiance in a booth or by a panel, have the added benefit of limiting skin exposure to UV light. The handheld devices are useful for the treatment of scalp psoriasis as well as recalcitrant localized psoriasis plaques. For example, the Dermalight 90 by National Biological Corporation has a comb attachment that permits direct application of light to scalp lesions. Although large-scale clinical trials are lacking, such light combs appear to be efficacious with longer remission compared with topical treatments^24,25. The handheld devices typically deliver NB-UVB, but some devices use BB-UVB or UVA. The DuaLight by Theralight, Inc. and Psoria-Light by Psoria-Shield can deliver both UVB and UVA, but these devices are for use only in an office setting.

Two concerns for home administration of phototherapy are patient adherence and the possibility of overuse, underuse, and inappropriate use²⁶. Fortunately, various features have been developed in recent years to increase safety of home phototherapy. Features such as an integrated timer and automated calibration can limit the length of time of treatment sessions and number of treatment sessions between follow-up visits with the physician. However, proper screening of candidates and patient education continue to be important to ensure safety and compliance²⁷. For the physician, an increasing number of resources are now available to increase knowledge and ease of prescribing home phototherapy units²³.

The excimer laser: a potential new indication and a novel dosimetry protocol

In addition to targeted therapy in the form of handheld devices, the 308 nm excimer laser was developed in 1997 as a targeted NB-UVB source for the treatment of psoriasis²⁸. The advantage to using the excimer laser is that because psoriasis plaques can take higher doses of light compared with normal skin, targeted treatment of psoriasis lesions using higher doses permits quicker time to clearance. In a multicenter open-label trial, 72% of patients with mild to moderate psoriasis achieved at least 75% improvement of the target plaque in an average of 6.2 treatments²⁹. Compared with traditional whole-body phototherapy, the excimer laser required fewer visits²⁹. In another study, 13 out of 26 patients with plaque-type psoriasis had continued clearance or long-term improvement after 1 year³⁰.

These initial studies tested the excimer laser in patients with localized psoriasis and thus the excimer laser is currently US Food and Drug Administration indicated for the treatment of mild to moderate psoriasis. However, the excimer laser may also be safe and effective for use in generalized, moderate to severe psoriasis³¹. In a single-center pilot study, patients with greater than 10% but less than 30% body surface area involvement (moderate to severe psoriasis) were treated with excimer laser twice weekly for 12 weeks for a total of 24 treatment sessions. Fifty-four percent achieved PASI-75 and 83% achieved PASI-50, which was maintained without further treatment for 6 months³². However, the downside to treating moderate to severe psoriasis is the long duration required per session to treat a large body surface area, which may not be feasible in many dermatology office settings.

Another area of recent advancement for the excimer laser is in the dosimetry protocol. The current accepted starting dose is typically based on the patient’s MED or Fitzpatrick skin type as well as location and thickness of the psoriatic lesion²⁸. The dose is increased as tolerated according to degree of erythema at each treatment session²⁸. A limitation to the current dosing method is that because the MED and Fitzpatrick skin type are based on normal skin, the starting dose is typically an underestimate. It typically takes 5 to 10 treatments of incremental dose increase just to reach the ideal maximum dose of the plaque. A recent study has attempted to develop a new dosing protocol called “plaque-based sub-blistering dosimetry”, in which the patient’s psoriatic plaque, rather than uninvolved skin, is tested with incrementally increasing doses to determine the dose at which blistering is observed³². The patients then are treated just below that dose. This allows plaques to be treated at the most aggressive possible dose (though still a tolerable one) to achieve faster clearing. The starting dose used in this protocol is 8 to 16 times the MED, compared with 2 to 4 times the MED of the currently accepted dosing protocol. The use of this “plaque-based sub-blistering dosimetry” can result in achievement of PASI-75 in a patient with moderate psoriasis after only two treatment sessions³².

Phototherapy and biologic agents: combination therapy for recalcitrant psoriasis

Although several biologic agents showing excellent efficacy in the treatment of moderate to severe psoriasis have been developed in the last decade, phototherapy appears to play an important role in a subset of patients with severe, recalcitrant psoriasis despite treatment with a biologic agent. Several studies have demonstrated the efficacy of using etanercept and NB-UVB in combination^33–38. These studies evaluated this combination therapy in patients who had not previously received treatment, patients who had an inadequate response with etanercept alone (50 mg once-weekly or 50 mg twice-weekly dosing), or patients who had an inadequate response to NB-UVB alone. Overall, combination therapy was superior and time to clearance was reduced. A study by Lynde et al. also demonstrated the importance of high adherence to the NB-UVB regimen in order to achieve significant clinical improvement³⁶. High adherence to the NB-UVB regimen was defined as missing not more than two treatments in any 4-week period.

One study to date has failed to establish efficacy of combination therapy of etanercept and NB-UVB. This head-to-head pilot study by Park et al., who examined combination treatment with NB-UVB and etanercept 50 mg twice weekly compared with etanercept monotherapy, did not demonstrate significantly enhanced improvement with combination therapy³⁹. However, this study was limited by a small sample size of 13 patients. Furthermore, the patients all had a body mass index (BMI) of greater than 30, and studies have reported a suboptimal response to etanercept in psoriasis patients with a BMI of greater than 30^40,41.

Adalimumab or ustekinumab in combination with NB-UVB has also been investigated in a limited number of studies. A study by Bagel et al. evaluated the combination of adalimumab and NB-UVB⁴², and another study, by Wolf et al., evaluated adalimumab and the excimer laser⁴³. Both studies demonstrated that phototherapy significantly accelerates therapeutic response and improves the clearance of psoriatic lesions in patients who received adalimumab treatment. One study to date has evaluated the combination of ustekinumab with the excimer laser⁴⁴. This was an intra-individual, half-body comparison study in which PASI-75 was achieved significantly more often on the UV-irradiated half than on the non-irradiated half at week 6 in patients on ustekinumab.

In general, combination therapy involving a biologic agent with NB-UVB phototherapy was very well tolerated. The most common side effect was erythema. Although long-term studies do not currently exist, no skin cancers were reported throughout the duration of the above-mentioned trials.