Journal of the American Academy of Dermatology
Volume 49 • Number 2 • August 2003
Copyright © 2003 American Academy of Dermatology, Inc.



Phototherapy treatment of psoriasis today


Michael Zanolli, MD a,b, *


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a Dermatology Consultants PC
Nashville, Tennessee, USA

b Division of Dermatology
Vanderbilt University Medical Center
Nashville, Tennessee, USA

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* Reprint requests: Michael Zanolli, MD, Dermatology Consultants PC, Suite 609 East, 4230 Harding Road, Nashville, TN 37205USA.
Funding sources: None.Disclosure: Dr Zanolli has been a participant in clinical trials for the following companies: Genentech, Amgen, Biogen, IDEC, Allergan, and MedImmune, and has served as a consultant to Genetech and Centecor. He also participated in the early clinical trials of the EXTRAC laser.
PII S0190-9622(03)01139-3

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The use of the various forms of phototherapy remains an essential treatment option for psoriasis vulgaris. Expertise concerning the mechanisms involved with the actions of therapeutic ultraviolet light and the proper delivery of office-based treatments resides within the specialty of dermatology. New therapies for the treatment of moderate to severe psoriasis will soon become available which have specific actions on the cutaneous immune system. A better understanding of the known mechanisms of action for ultraviolet light therapy makes it appropriate to include this area of treatment with new biologic agents. Photochemotherapy and various forms for delivery of narrow band ultraviolet B can be used as treatments, either as monotherapy or in combination with other agents, to effectively treat moderate and severe psoriasis.


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Phototherapy remains an essential treatment option for patients with moderate to severe psoriasis. The refinement of ultraviolet (UV) light delivery has continued during the past century, primarily based on the observation of beneficial effects that natural and artificial light sources have on disease severity. We are now entering a therapeutic era of psoriasis treatment with very specific mechanisms of action which target the inflammatory pathway of cutaneous immunology. How does intervention with ultraviolet light enter into this discussion? What are the proposed mechanisms of action for ultraviolet B (UVB), UV laser, and psoralen plus ultraviolet A (PUVA) therapy? Will phototherapy still be an important treatment option when all of the new biologic agents discussed in this supplement become available? This discussion is not meant to be a complete treatise on the full range of phototherapy treatment options. The intent is to give insight into the current understanding of the effects of phototherapy on the skin, current treatments for moderate to severe psoriasis, and how combination with phototherapy may compliment the use of existing and new therapeutic agents.

Office-based delivery of phototherapy
The genesis of office-based phototherapy relates to the availability of fluorescent tubes as a light source. The refinement of the phosphor in the inner lining of the glass tubes, stimulated by the radiation emitted when an electric current is passed through a mercury vapor, allowed for differing spectra of UV light to be generated at a low voltage and relatively low amount of heat. The use of multiple lamps allowed for greater irradiance and thus shorter treatment times. Before the development of systemic retinoids and cyclosporine, there were few tenable choices for systemic agents, except for methotrexate (MTX). The delivery of UVB therapy in the office, despite the poor dosimetry in the early years of use, provided effective treatment of patients without the need for systemic agents. Inpatient centers with specialized staffs delivered traditional Goeckerman therapy with excellent results, although it required hospitalization for weeks. Office treatments with UVB and petrolatum or day care centers for outpatient therapy of psoriasis were essential options for patients who were not candidates for MTX, or who chose not to take systemic agents.

The advancement and development of photochemotherapy with psoralens was a major therapeutic achievement thirty years ago. Compared to traditional UVB or Goeckerman therapy, the use of PUVA was remarkably effective, acting rapidly and allowing patients to continue a relatively normal lifestyle, even if special protective glasses were required on the days of treatment. The acute side effects associated with PUVA therapy were tolerated by patients because of an improvement of their skin disease. PUVA remains a very effective therapy and is still the most effective form of phototherapy for severe extensive disease, with average remissions longer than currently approved systemic therapies. However, the advent of rapidly acting, effective systemic agents such as cyclosporin, the availability of more effective UVB, and the need for caution in patients who have received long term PUVA treatment has resulted in a decline in the frequency of PUVA use over the past five years.

Applying specific wavelengths of UV light based on the psoriasis action spectrum in treating psoriasis has been the most important aspect of phototherapy in the last decade. The development of narrow band (NB) UV fluorescent tubes made delivery of a treatment almost as effective as PUVA without the problems associated with the concomitant use of a psoralen molecule, thereby making office use of UV therapy much easier to perform, with fewer side effects. Our European colleagues have been using NB phototherapy units for a decade, and it is clearly the choice for UVB therapy in Europe. In North America, the majority of purchases for new phototherapy units demonstrates the preference for NB units either as combination units with the ability to deliver UVA and NBUVB or as a dedicated NBUVB unit.

The most recent progression of delivery of UV light therapy has been the delivery of laser light in the UV region or high fluence for a narrow spectrum of UV light in or near the most effective wavelengths for treatment of psoriasis. The practical application of such units will depend on the demonstration of improved delivery, efficacy, decreased side effects, and cost effectiveness.

Perspectives on the mechanisms of ultraviolet light therapy for psoriasis
It is a uniform observation that natural sunlight improves psoriasis in the majority of patients. This is the basis for climatotherapy at the Dead Sea and the use of natural sunlight to benefit psoriasis, especially for people who live in the northern latitudes. Early UV light treatments attempted to reproduce these effects through the development of artificial sources for UV light. Carbon arc lamps were used by Niels Finsen in the first therapeutic interventions with artificial UV light in 1893, although he was treating cutaneous mycobacterial infection on the face (lupus vulgaris). He won the Nobel Prize in 1903 for his pioneering application of UV light as a medical treatment. Hot quartz lamps were employed as one of the mainstays of treatment throughout the twentieth century in the form of Goeckerman therapy, in which UV light was combined with tar under occlusion, and for the Ingram method of treatment, which combined UV light and anthralin under occlusion. It was not until after 1945 that modern fluorescent UV lamps were developed. Further application and modification of fluorescent lamps and high output metal halide lamps in the 1980s have provided the foundation for therapeutic delivery of UVA and UVB light for treatment of skin diseases.

The determination of a therapeutic action spectrum for psoriasis provides the basis for selecting the best wavelengths of UV light for treatment of psoriasis. In addition, insight into the mechanisms involved with the pathogenesis of the disease is derived from this information. Turkel Fisher, in 1976, reported on the action spectrum for psoriasis.[1] Although somewhat limited by the few numbers of wavelengths tested, his work demonstrated beneficial effects of some of the wavelengths for plaque-type psoriasis. His experiments indicated that the wavelength of 313 nanometers was the most effective in treating the disease. In 1981, Parish[2] expanded this line of investigation, adding to it appreciably by including a more extensive number of UVC, UVB, and UVA wavelengths. This pivotal work, in conjunction with Fisher’s data, helped focus the development of current phototherapy devices, resulting in more efficient and effective treatment for psoriasis. The current devices are designed to deliver wavelengths between 310 and 315 nanometers, which Parish found to be the most effective for treatment of plaque-type psoriasis. An important observation made during these experiments was that erythemogenic doses below 300 nanometers produced significant clearing; however, these wavelengths also produce the most amount of erythema and burning. The wavelengths within the action spectrum for psoriasis which produce the best therapeutic response at suberythemogenic doses of UV light therapy are between 310 and 315 nm.

Recent insight into the pathogenesis of psoriasis provides a better understanding of how UVB therapy may affect the cutaneous immune system as the primary mechanism responsible for the observed therapeutic response in psoriasis. If high doses of UV light cause severe damage and destruction of cells in the skin, producing apoptosis of immune competent cells, then high doses of erythemogenic light may also serve to clear psoriasis. Low dose UV light may not cause apoptosis of cells, but could affect the cutaneous immune system through the modification of secondary signals of the immune response without producing broad injury to the skin. Relevant to our discussion is an excellent review of ultraviolet effects on the human immune system.[3] This review is beneficial because it looks at the skin as the milieu for these UV effects on the immune system, rather than focusing on isolated photochemical reactions. It is important to correlate broad effects of UV on the complicated system of the skin, rather than trying to assign broad ranging actions on observations from isolated photochemical reactions. As defined in other articles in this supplement, there is a complex balance between the first and second signals necessary to produce an adequate immune response. In fact, the balance of the cytokines and the secondary effectors that modify the activation of T cells can be disrupted at very specific points by very small molecules, as evidenced by the clinical effects of some of the new biologic agents.

The effects of UV light can result in two main categories of observable changes. One category consists of rapid changes, which include membrane damage, induction of cytoplasmic transcription factors, DNA damage, and isomerization of urocanic acid. The second category of subacute changes includes alteration of antigen-presenting cell populations and the modification of intracellular and intercellular signaling mechanisms. This overall effect creates a change in the environment in the cytokine patterns of the dermis and epidermis, which is more favorable for development of a T helper Th-2 cell-like response as a result of UV effects on the skin.[3]

Even though the new biologics may not have a direct effect on urocanic acid (UCA), it is worth mentioning in this context because UCA is one of the major chromophores of UV light in the skin and is a known immune modifier. UVB light within the range of 290 to 341 nm causes UCA to be isomerized from trans UCA to cis UCA. It is maximal between 290 and 310 mn. The transformation from trans to cis UCA is dose dependent until equal parts of both are present in the skin.[4] [5] The presence of cis UCA helps to promote a change in the cytokine production from a Th-1 to a Th-2 environment in the skin.[3]

Ultraviolet B therapy
The use of UVB continues to be one of the most important therapeutic interventions for mild to moderate psoriasis. As previously mentioned, the use of Goeckerman therapy when done on a daily basis with occlusive tar is still one of the standards by which other therapies are measured, because of the long duration of remission and the high rate of clearing. The maturation and development of the forms of UVB therapy now have led us to the use of the more precise wavelengths within UVB range that have the most effective therapeutic benefit for psoriasis.

Despite evidence that the most effective wavelength for treatment of psoriasis is between 310 and 315 nm, it was not until ten years ago that commercially processed lamps with the proper phosphor to emit a refined narrow band of UVB became available. This lamp is the Philips TL01 lamp (Philips Medical Systems, Bothell, Wash) which has a peak emission between 310 and 313 nm. The clinical use of such lamps has been primarily in Europe and the initial clinical trials demonstrated efficacy for treatment of plaque-type psoriasis.[6] [7]

The progress of applying this advancement in UVB therapy has been very slow in North America, primarily because the lamps were not available in the US until 1998. The demonstrable studies done in North America using half body comparisons between broad band UVB and NBUVB showed a superiority in the response and efficacy for NBUVB in a well-controlled study.[8] Additional trials and half body comparisons with NB and PUVA have also been done showing that NB is almost as effective as PUVA, although the duration of remission is much shorter than with the use of photochemotherapy.[9] In addition to clinical trials showing efficacy, research has provided insight into the mechanisms involved with the actions of NBUVB therapy. Immunohistochemical data showed a positive correlation of clearing of psoriasis with apoptosis of CD3 cells in the epidermis and the dermis. Further, in vitro studies on T cells showed that the T cells were affected by very low doses of narrow band wavelength of light within the range of 50 to 100 mj/cm2.[10]

As a result of its demonstrated efficacy, the use of NB therapy is becoming more widespread in North America. Although protocols used for NB therapy are similar to those used for broad band therapy, there are important differences because of the narrow spectral output of the NB UV light units. The dose range to produce erythema with a narrow band UVB is from 400 to above 1800 mj/cm2. This is a much higher and broader range than that used in with broad band UVB, primarily because broad band UVB has much lower wave lengths contained within its spectral distribution provoking erythema at much lower doses. The erythema is the limiting step in the practical delivery of broad band UVB therapy, as patients do not tolerate the smarting reaction associated within repetitive sunburn-like reactions. In addition, the range of the dose to produce erythema with NBUVB varies greatly from one skin type to another using Fitzpatrick’s skin type assignment.

To still remain effective, yet limit the side effects of having repetitive erythemogenic doses, it is standard in NBUVB therapy to first obtain a minimal erythema dose. The usual starting dose for NBUVB therapy ranges from 50% to 70% of the minimal erythema dose (MED). The MED is determined by a simple procedure that takes a total of 15 to 20 minutes. Delivery of the doses for the MED can be done at the time of the initial visit and the first full body dose of UVB therapy with NB may be initiated 24 hours later. This does not delay treatment more than one day and it gives a very important starting point for the delivery of UVB.

Once the MED and initial dosage is determined, the treatment protocols can range from treatments of three to five times weekly. Comparison trials to determine the most effective methods for the delivery of NBUVB showed no real statistical difference, although there might be a slight improvement with more frequent doses of treatments five times weekly.[11] The more aggressive use of NBUVB therapy, using 70% to 90% of the MED, was not statistically superior to a 50% of the MED when the near versus far erythemogenic doses of NBUVB were used.[12] Other important factors for the most effective use of NBUVB therapy include lubrication of the skin with a non-UVB absorbing lubricant, such as mineral oil, which decreases reflectance from the scale on the psoriatic plaques. Caution must be applied not to use agents containing salicylic acid, which would be a UVB absorber.

Treatments using NBUVB therapy are advanced by increasing the dose of each successive treatment by at least 10% of the MED. Some centers increase the dose by more than 10%, up to 20%, or even 25% of the MED, and use clinical response on a daily basis, such as pinkness of the skin or the patient’s complaint of burning, to determine their degree of advancement. Typically 15 to 20 treatments may be necessary to achieve greater than 50% improvement in psoriasis. Some patients do not clear with NBUVB because of the severity of their psoriasis or their intolerance to UV light therapy. Combination therapy, other modalities of UV light therapy, or systemic treatments may be considerations for such resistant cases. A summary of the treatment protocol for NBUVB is given in Table I .



Table I. Treatment protocol for NBUVB
MED for starting dose

Treatments 3-5 × a week
Initial treatment at 50% of MED
Lubricate before treatment
Advance treatment by 10% of MED


Photochemotherapy
The discussion concerning photochemotherapy will be limited to the use of PUVA therapy. PUVA is the combination of a psoralen molecule plus ultraviolet A light. Photopheresis will not be considered. PUVA has been one of the most effective therapeutic interventions for moderate to severe psoriasis over the past thirty years. It has been an advancement in the use of phototherapy since its recognition as a therapy for psoriasis. Features of PUVA that have maintained it as one of the standard treatments for psoriasis are as follows: it is effective, long-term emissions can be obtained as compared with UVB, and it is an alternative for darker-skinned individuals. Because of such benefits, PUVA has been used as one of the most efficient office-based phototherapy treatments for psoriasis. In addition, many other skin conditions can be treated with PUVA. There are special concerns when using PUVA, however.

These broad concerns can be divided into acute side effects and long-term side effects. The use of PUVA requires ingestion of a psoralen molecule, which in North America is 8-methoxypsoralen. The use of this molecule requires timing of drug ingestion and also a mandatory use of eye protection whenever the psoralen molecule is used. The use of 5-methoxypsoralen (5-MOP) in Europe has been increasing, and in some centers it is the molecule of choice because of the decreased gastrointestinal side effects associated with its use while still maintaining good efficacy. The real advantage of 5-MOP is the decease in gastrointestinal side effects, because 8-MOP can produce nausea in more than 30% of patients, which results in the discontinuation of therapy in a significant number of patients. To help make PUVA therapy more efficient, modifications of the delivery of 8-methoxypsoralen from a crystalline to a liquid form in gelatin capsules were done in the 1990s, which provided better absorption and more predictable blood levels. In addition to the nausea, another parameter that makes the use of photochemotherapy more difficult is variable serum levels of the psoralen molecule, even on a treatment by treatment basis. It is very important that patients undergoing photochemotherapy have a consistent approach to the ingestion of the molecule, including the foods or liquids taken with the molecule and consistent timing of the dose prior to delivery of UVA. Problems associated with the absorption of psoralens and effects of foods are set forth in an article reviewing this topic.[13]

Interest in the mechanisms of actions of PUVA on a T cell–mediated disease, such as psoriasis, is an important consideration as with other forms of UV light therapy. PUVA therapy can produce oxygen dependent and oxygen independent photochemical reactions. Type I reactions are oxygen independent. This reaction is exemplified by the formation of DNA crosslinks and development of cyclobutane rings. A DNA crosslink is a covalent bond that remains as a defect in the DNA. The increased numbers of DNA cross links in the epidermis are important in the predisposition to develop squamous cell carcinoma with excessive long-term treatment over years. The type II reaction is dependent upon the generation of reactive oxygen species, which primarily results in membrane damage at cell membranes and mitochondrial membranes. Significantly, lymphocytes appear to be more susceptible than keratinocytes to the effects of PUVA, and depletion of CD3 lymphocytes in the epidermis correlates with the clinical response to PUVA.[14]

There are standard methods for delivering PUVA in North America, especially with the use of 8-methoxypsoralen. The delivery of the dose and selection of the dose of the UVA after the proper ingestion and timing of the oral psoralen dose is dependent upon the skin type, based on Fitzpatrick’s response to UV light. The routine delivery of PUVA is done three times a week, and there is usually a significant early response after six to eight treatments. PUVA is a very effective treatment for psoriasis and good response is expected in 75% of patients. Variations in the delivery of PUVA can be made. Topical application of a psoralen molecule instead of ingestion of the drug has been shown to be very effective, thereby removing the common side effect of nausea seen after ingestion of the psoralen. This method of PUVA is utilized more commonly in Scandinavian countries with expertise in the delivery of PUVA in the form of bath PUVA, which requires both a specialized facility and a very compliant patient population.

The more recent concerns regarding PUVA therapy relate to the potential for long-term side effects and the reports regarding the increased incidents of cutaneous malignancies in patients receiving long-term high dose PUVA. There are very few patient populations within the field of dermatology that have been followed for such a long duration and with the degree of follow-up as occurred with the PUVA Cohort, which was established in 1975. The series of articles drawn from the data collected from the PUVA Cohort, led by Dr Rob Stern, have shown that patients receiving high numbers of treatments are more susceptible to development of squamous cell carcinomas of the skin.[15] This is especially true for squamous cell carcinomas on the genital area. Protection of the genitals has been standard and routine for the past two decades because of these reports.

The increased risk of melanoma associated with PUVA treatment has been reported in this PUVA Cohort. The factors which put a patient is this higher risk category are a high number of treatments, Fitzpatrick skin types I through III, and long-term use. The rise in the incidence has a latency period of 15 years before the demonstrable increase above the estimated incidence for melanoma of the general population. However, the results have been questioned. Other groups of PUVA patients in European studies have not had a significant increase in the incidence of melanoma as with the North American PUVA Cohort. Currently, the number of treatments that would place an individual into the high dose category for PUVA treatments is 200. In addition, patients with lower skin types are preferentially affected, although skin types III and IV have been documented to have melanomas, including melanoma in situ. There is a recent report outlining these findings with the inherent treatment methods bias of the North American PUVA Cohort study.[16]

Given the known increase in the development of squamous cell carcinomas and the potential long-term risk of melanoma if the patient approaches the high dose category, practitioners and centers giving PUVA have modified the approach of PUVA. It is now general practice that PUVA can be used as a very effective modality of treatment for moderate to severe psoriasis with the special benefit of having the possibility of longer term remissions and greater efficacy than are possible with NBUVB therapy alone. Once there is an advancing number of treatments, there can be a rotation of therapies and use of other modalities of treatment to theoretically decrease the incidence of side effects resulting from one therapy alone. There is a caveat with the use of other potent broad immunosuppressant therapy, however. That relates to the use of agents such as cyclosporin, which have a broad immunosuppressant effect, not only on the cutaneous immune system but also related to immune surveillance for tumors. It is known that solid organ transplant patients with long-term cyclosporin already have an increased risk and incidence of squamous cell carcinomas on the skin, whether or not PUVA was used. These patients would then have a very likely chance of developing squamous cell carcinoma if a second immunosuppressive agent is continued in light of high risk PUVA.

PUVA has been and remains a very effective therapeutic modality for the treatment of psoriasis. There have been modifications in the treatment approach to PUVA based on experiences obtained over the past twenty years. These include limiting long-term maintenance periods with PUVA and maintaining the total number of treatments at less than 200. PUVA remains a vital treatment alternative for patients with psoriasis. With a better understanding of the mechanisms and the potential for long-term side effects, its use will continue to be modified to further diminish the likelihood of long-term side effects, especially the development of cutaneous malignancies.

Lasers and enhancement of ultraviolet light delivery
Lasers utilizing specific wavelengths and other enhancements of UV light can be used for the treatment of psoriasis. More recent reports and prospective studies concerning the efficacy of very specific wavelengths of light within the action spectrum of psoriasis have enhanced the range of phototherapy devices utilized. The best example of enhancement of phototherapy treatment of psoriasis has been the use of the 308 nanometer excimer laser. Other approaches with high output&ndashUVB delivered at three and four times the minimal erythema dose exemplified by the BClear Targeted PhotoClearing System (Lumenis, Inc, Santa Clara, Calif) have also been utilized. Photodynamic therapy for the treatment of psoriasis is a potential area of investigation and in need of further refinement for resistant plaque psoriasis.

Specialized, high-energy use of UV light relies mainly on the types of effects erythemogenic or super erythemogenic doses of UV light have on the skin. The histologic changes that occur with multiples of erythemogenic doses of UV light are injury to the epidermis and dermal collagen with apoptosis of cells. The production of these changes is much more acute and more readily apparent by light microscopy than the suberythemogenic doses that have effects on the processing of antigens and secondary cytokine production. This has been discussed in more detail in the introduction regarding mechanisms of therapy. Consequently, the rational conclusion is that multiples of erythemogenic doses results in more inherent cell death than do doses of UV light within the action spectrum that might modify the immunologic response without such tissue injury.


Excimer laser approach to psoriasis treatment
The clinical use of excimer laser for treatment of psoriasis was first reported in a letter to The Lancet.[17] Subsequent interest in this modality, including a small series of patients, was reported in a dose ranging study.[18] A very interesting observation reported as part of the dose study was that at the very high multiples of the MED, such as 4 and 6 × MED, there appeared to be an initial long term remission in some patients. Subsequent experience with the use of this excimer laser device shows efficacy for plaque-type psoriasis; although the duration of remission has not been uniformly extended and further studies are needed to accurately define the duration of remission.[19] It does appear, however, that the use of the excimer laser is associated with a somewhat longer duration of remission than is achieved with conventional narrow band therapy. Another apparent benefit of the use of excimer laser for psoriasis is the consistent low number of treatments that may be necessary to have clearing as compared with conventional NBUV therapy. Within six to ten treatments, there is usually a greater than 50% improvement in the individual plaques of psoriasis treated. However, widespread surface areas are generally not treated with this modality because the spot size is less than two square centimeters.


Narrow band ultraviolet light enhanced
An approved device for the delivery of NBUVB therapy within an effective range of approximately 300 to 320 nanometers has recently been developed by Lumenis and others. This device, with a filamentous light source at high energy, is delivered through fiberoptic cables to a hand piece, which can then deliver measured doses of UV light of short duration. The approach is similar to that described in the preceding section on the excimer laser, with the difference being that this is not a coherent light, but rather a limited range of UVB with a different light source than the normal fluorescent tube. Clinical experience of the delivery of 2, 3, and 4 × MED are currently in press. The response to this approach, as with the other localized forms of UV therapy, would be most suitable for those patients with resistant plaques who are receiving other treatment and/or those having hard to treat localized areas such as the hands, feet, knees, and elbows.


Photodynamic therapy
There are ongoing investigations in clinical trials regarding the use of photodynamic therapy, both systemic and topical, for the treatment of resistant plaque psoriasis. Currently, there are no approved photodynamic treatments for psoriasis. However, with the further development of more specific chromophores and the possibility of more selective concentration of these molecules within plaques of psoriasis, this may be a future therapeutic option within the realm of effective UV light treatments.

Combination phototherapy
This section on combination therapy discusses selected systemic agents in combination with phototherapy. Certainly, topical agents can and are used on a daily basis with phototherapy. In fact, it is rare for phototherapy to be used alone without the combination of a topical agent. Even the use of mineral oil prior to the delivery of phototherapy enhances the overall effect of the UV and produces better results. However, for patients with moderate to severe psoriasis who are not responsive to UV therapy alone, the use of systemic agents with or without phototherapy should be considered.


Acitretin plus ultraviolet light
The most effective agents commonly used in combination with ultraviolet light are the systemic retinoids. There have been reports of clinical trials concerning the use of systemic retinoid plus UVB therapy or combined with PUVA treatments dating back to the late 1980s in European reports and 1991 in North American dermatologic literature.[20] [21] The overall findings of the combination of UV therapy with systemic retinoids demonstrate that lower numbers of treatments are required to produce the same amount of clearing. Consequently, this therapy provides a lower total dose of UV during a treatment course. Even low-dose acitretin can enhance the overall effect of UV therapy, thereby making the systemic retinoid easier to tolerate because of decreased retinoid side effects.[23] Retinoid side effects are covered fully in the article by Lowe et al in this supplement.

The overall approach for the use of systemic retinoids plus UVB or PUVA therapy seeks to maximize the effect and decrease the potential side effects associated with each of the treatments. Specifically, because of the retinoid effect of decreasing the thickness of the stratum corneum and epidermis, there should be a two-week initial treatment with systemic retinoid therapy before the initiation of UV light therapy. A thinner epidermis would make an individual more susceptible to the effects of UVB. This pre-use of the systemic retinoid should be followed by MED determinations before the initiation of treatment with UVB. Treatment can then proceed according to standard methods. Caution must be used both in UVB and PUVA therapy when treatment is combined with a retinoid because of a patient’s enhanced susceptibility to phototoxic reactions. It is also important to adjust the dose of either UVB or PUVA during the course of therapy if a retinoid is to be added to an ongoing treatment schedule. In this circumstance, specific recommendations concerning the reduction in dose of the phototherapy treatments included in Table II should help to decrease the potential phototoxic reactions. The overall recommendations regarding combination retinoid plus UV light, as well as the addition of retinoid during the course of an UV light treatment, are contained in the report of a consensus conference on combination therapy with acetretin.[24]



Table II. Treatment protocol for acetretin plus UV
Start therapy with retinoid 2 weeks before UV treatment

25mg/day if >70 kg, 10mg/day if <70
Obtain MED if using BBUVB or NBUVB
Deliver PUVA by selecting low skin-type assignment
Reduce dose of UV (50%) if acitretin is added after UV initiated


Methotrexate plus UV
This can be a very helpful combination therapy, especially if there are episodes of mild exacerbation of disease activity during the long-term course of MTX treatment. For example, during the winter months, there might be increased activity of psoriasis in a limited manner over the trunk or extremities. As an alternative to raising the dose of MTX to higher levels, a two- to three-week short course of UVB therapy might be added to MTX to bring this back under control. Combination phototherapy was reported with MTX in the early 1980s.[25] Another instance when MTX may be effectively used in combination with UVB is as a pretreatment for very thick, hard to control areas of psoriasis. The effects of MTX initially would help thin the plaque and decrease scale, thereby facilitating the delivery and penetration of UVB to the epidermis and upper dermis, which are the sites for effective therapy. Care must be taken to use only suberythemogenic doses when MTX is combined with UV therapy to avoid the potential for a MTX sunburn recall reaction. Even though this is a very uncommon side effect, the development of a generalized erythema would cause marked discomfort for the patient and require days to subside. Additional articles combining MTX plus PUVA have also been published.[26] However, the long-term combination of these two relative immunosuppressive agents would theoretically have a more profound effect on the potential for cutaneous squamous cell carcinoma. Unfortunately, no long-term study specifically addresses this question. The recommendations regarding the use of MTX plus UV are also included in Table III .



Table III. Treatment protocol for methotrexate plus UV
Pretreatment with MTX for 3-4 weeks

Do MED and use suberythemogenic doses of BBUVB or NBUVB
Low dose is usually adequate (10-15 mg/wk)


Cyclosporin and ultraviolet light therapy
This combination therapy is mentioned because of the potential for problems, especially in patients who have previously undergone long-term PUVA therapy. As has already been discussed, there is a known increased risk of squamous cell carcinoma in psoriasis patients who have had more than 200 PUVA therapies over time. Accordingly, it is important to obtain a proper treatment history before the initiation of long-term therapy with cyclosporin. This issue has been previously discussed in the PUVA section.


Potential for new biologic and systemic agents plus phototherapy
Currently, the best systemic combination therapy is UV treatment with systemic retinoids. The development of new retinoid therapies for the treatment of psoriasis vulgaris theoretically would be a very good choice for use in combination with phototherapy because of the shared mechanisms of action among retinoids. This is discussed elsewhere in this supplement by Lebwohl. Because of the need for development of new medications and the due diligence necessary to evaluate new therapeutic agents in phase II and III studies as a monotherapy, there are no current combination therapies with biologic agents available for direct discussion.

To be able to rationally select the best combination of new biologic agents and phototherapy for a given patient, one must have a good understanding of the reported known effects of the agents on the skin and their specific location of inhibition at each stage of immune activation. Of particular importance is whether or not the biological agent would be lymphocyte-depleting or selectively acting on secondary signals and cytokine activation. If a particular new drug was known to be nonlymphocyte-depleting, it might be a good candidate for use in combination with high dose UVB or PUVA phototherapy, because the CD3 cells both in the dermis and epidermis tend to decrease with aggressive UVB treatment. This would attack two different points along the immune activation and possibly enhance efficacy of the systemic and phototherapy treatment. Historically and by necessity, more specific recommendations regarding the combination therapies with UV light treatment will become possible as experience is gained with each of the new biological agents. The utilization of combination therapy will remain very important even with the availability of the new biologic therapeutic agents. The use of UV light therapy to localized areas with erythemogenic doses of effective wavelengths would be a safe and additive therapeutic option.

Phototherapy in its various forms, including PUVA, is likely to continue to play an important role in the approach to treatment of psoriasis. Despite the concerns for long term PUVA therapy and skin carcinogenesis, the duration of remission obtained with PUVA make it a continued viable option. NBUV therapy delivered by conventional fluorescent tubes, lasers, or other methods will serve as a very useful adjunct for treatment of resistant localized plaques of psoriasis or hard to clear areas. The combination of UV therapy with the new biologic agents for long term control of psoriasis will allow for an overall approach to therapy that only a dermatologist would be able to deliver with expertise.[22]

References

1. Fisher T. UV-light treatment of psoriasis. Acta Derm Venereol 1976;56:473-9.
2. Parrish JA, Jaenicke KF. Action spectrum for phototherapy of psoriasis. J Invest Dermatol 1981;76:359-62. Abstract
3. Duthie MS, Kimber I, Norval M. The effects of ultraviolet radiation on the human immune system. Br J Dermatol 1999;140:995-1009. Abstract
4. Kammeyer A, Teunissen MB, Pavel S, de Rie MA, Bos JD. Photoisomerisation spectrum of urocanic acid in human skin and in vitroeffects of simulated solar and artificial untraviolet radiation. Br J Dermatol 1995;132:884-91. Abstract
5. Gibbs ND, McCloone RP, Simics E. An action spectrum for urocanic acid isomerisation in human skin in vivo. Photochem Photobiol 1997;65:103S-4S.
6. Green C, Ferguson J, Lakshmipathi T, Johnson BE. 311 nm UVB phototherapy-an effective treatment for psoriasis. Br J Dermatol 1988;119:691-6. Abstract
7. Larko O. Treatment of psoriasis with a new UVB lamp. Acta Derm Venereol 1989;69:357-9. Abstract
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Adnan Alabdulkarim, MD