Phototherapy and photochemotherapy

doi:10.1016/j.clindermatol.2007.11.004

Clinics in Dermatology

Volume 26, Issue 5, September–October 2008, Pages 464-476

https://doi.org/10.1016/j.clindermatol.2007.11.004 Get rights and content

Abstract

Phototherapy, whose first application for psoriasis dates back to almost a century now, is still an actual mainstay of treatment. We discuss in detail the radiophysical aspects involved in the therapy, the different treatment modalities, and all aspects related to clinical application of phototherapy. By looking at new insights on the molecular mode of action, it becomes evident that phototherapy is in fact the oldest “biological” therapeutic strategy, whose target is directly the T-cell–mediated immunopathology of psoriasis. In an outlook, we discuss finally the current cost effectiveness calculations, important issues in times of increasingly tight public health budgets. In summary, this review points out that phototherapy is clearly a first-line therapy that is safe and effective. Guidelines in the patient management still have to be harmonized, however, and further trials to improve the fine tuning of irradiation protocols are still necessary.

Introduction

Around the turn of the 19th century, Sardemann used for the first time ever a carbon arc lamp to treat psoriasis in a patient.¹ In 1923, Alderson then described “heliotherapy in psoriasis”. He used a quartz-jacketed mercury discharge lamp to treat his first patients.² William Goeckermann, a dermatologist at the Mayo Clinic (Rochester, Minn) followed and introduced a combination of coal tar and subsequent UV-B, which soon came to fame as the “Goekermann regimen”.³ Roughly 70 years later, in 1974, the combination of oral psoralen intake and subsequent UV-A irradiation was reported by the groups of Parrish⁴ and Wolff,⁵ publications that mark the initiation of modern psoralen–UV-A (PUVA) photochemotherapy for psoriasis. Phototherapy is thus an old and established treatment modality for this disease, which bothers 2% of the world's population.⁶ Since the beginnings, it has been subject to a continuous refinement process over the many years of its clinical application. This has kept its place in the dermatologist's arsenal until today. That is justified, as we will show. We enter now an age of new biologicals being appraised as novel therapy for psoriasis. These new bioengineered medications carry a large potential but also a substantial risk. For example tumor necrosis factor (TNF) α–blocking strategies can lead to fatal systemic infections such as legionellosis.⁷ Biologicals are extremely valuable for some indications. They are very expensive, however, and their broad use is not justified in our view. All of this in times of reduced public budgets for health care makes the old phototherapy modalities far from being redundant. In fact, phototherapy is also, strictly seen, a “biological” therapy. The photons and free radicals induced by UV radiation directly tackle the molecular pathology of psoriasis without the side effect of profound systemic immunosuppression.

Section snippets

Radiophysical aspects of phototherapy and photochemotherapy

Ultraviolet radiation clears psoriasis with varying efficacy depending on the wavelength. Wavelength dependency was determined with monochromatic UV radiation and resulted in the action spectrum for psoriasis as established by Parrish,² who picked up and expanded earlier investigations by Fisher and Alsins.⁸ This action spectrum revealed that the most efficient wavelengths against psoriasis in the UV-B range are 304 and 313 nm.⁹ Wavelengths of less than 300 nm also achieve significant clearing

“Biological” “mode of action” for phototherapy

Since 1967, it has been known that already, a single dose of UV-B leads to a reduced synthesis of DNA, RNA, and proteins that entails a decreased rate of mitosis of the epidermal cells.13, 14 This short-term effect is then reversed when the repair starts 48 to 72 hours after irradiation, and the cells proliferate again at full speed. From this fact, one can directly deduce that an efficient UV-B phototherapy needs at least a session every other day to be effective. Another effect of

Natural phototherapy

Natural sunlight has been used as a UV source throughout history for a long time before modern phototherapy was developed. Even today, sunbathing at the dead sea is very popular among patients. From a photobiologist's point of view, there is indeed a rationale for this. The specific geographic location of the dead sea provides a favorable spot for natural phototherapy.⁴⁹ Because of the southern latitude, the sunlight has relatively high energy in the UV-B range, which is a fact caused by the

Broadband UV-B

The traditional broadband UV-B sources were the first to be used for phototherapy in psoriasis. Nowadays, they have lost their popularity, but in some units, they are still used.1, 12 In comparative studies, they are clearly less efficient than narrow-band UV-B or PUVA.³ For patient safety, broadband UV-B therapy, which implies significant exposure to wavelength spectra of less than 300 nm and even less than 280 nm (UV-C), carries in theory a greater risk of long-term development of nonmelanoma

Narrow-band UV-B (UV-B 311 nm)

Narrow-band UV-B phototherapy has replaced the traditional broadband UV-B therapy. The success of narrow-band UV-B started in Europe with the invention of the Phillips TL01 lamp. In the United States, the invention was much delayed by the fact that these devices only became available in 1998 in the US market.¹⁰ That fact probably explains why the mentioned broadband UV-B protocol is still around in the United States.⁴⁹ At least 6 independent studies have found the new narrow-band UV-B equipment

The history of PUVA therapy

Already, in ancient Egyptian times, plant extracts containing psoralens were used to treat patients with vitiligo. Psoralen–UV-A therapy thus looks back to more than a 3500-year history. Interestingly, it took until 1947 to finally invent PUVA in its modern form, first again for treating vitiligo.²² In 1951, Pinkus was then the first to use psoralens for the treatment of patients with psoriasis, but it took until 1974 for the first PUVA study with oral 8-methoxypsoralen (MOP) intake in patients

What is PUVA?

Psoralen–UV-A is basically a controlled and repeated induction of phototoxic reactions that has proven its efficacy in virtually all subtypes of psoriasis.³ Only generalized pustular psoriasis and erythemogenic psoriasis are difficult to treat with PUVA alone and normally need a combination therapy with retinoids such as etretinate. Phototoxic reactions are delayed, with an erythema reaction peaking 48 to 72 hours after irradiation. Therefore, accurate UV-A dosimetry is distinctly required for

Oral PUVA therapy

The first clinical trials in the 1970s were set up using oral PUVA therapy. In the United States and in Europe, 2 slightly differing protocols of oral PUVA were evaluated in these trials, and both proved their efficacy.73, 74 Their characteristics are shown in Table 3. The main differences between the 2 protocols are the UV-A starting dose and the increment scheme. The European study used the individually determined minimal phototoxic dose (MPD) as starting point, whereas the Americans used a

Bath PUVA therapy

Topical application of psoralen was first described by Fischer and Alsins⁸, and then Hannuksela and Karvonen⁸¹ demonstrated its high efficacy in a first comparative study with systemic PUVA in 1978. Several studies have confirmed this and rated bath PUVA equally or even better than systemic PUVA.²¹ Most of these trials, however, contained small patient numbers and did not meet basic International Conference on Harmonization standards for equivalence trials, a fact that has lead to disapproval

Combinations of phototherapy with other treatment strategies

Ultraviolet B and PUVA can be combined with several other agents used for psoriasis. Ultraviolet B together with methotrexate (MTX) in 26 patients worked very well, with 15 mg MTX per week with MTX started 3 weeks before initiating UV-B. When psoriasis is cleared, MTX should be stopped.⁵⁹ One has to be aware, however, of the rare, but serious side effect of a generalized phototoxic reaction with this combination.⁴⁹ Methotrexate has also been used together with PUVA, but because of the

Balneophototherapy

This new variant is basically a combination of salt water bathing and subsequent UV-B 311 nm irradiation and thus an imitation of the natural heliotherapy and bathing at the dead sea already discussed. The patient is bathed in a brine of 5% to 15% magnesium-rich salt and irradiated subsequently with UV-B 311 nm while the skin is still wet. The magnesium ions in the brine supposedly help to decrease antigen presentation in the skin.⁹⁶ The salt-water–soaked skin requires less UV-B irradiation,

New phototherapy strategies: the excimer laser

The xenon chloride excimer laser is in fact nothing different from a monochromatic 308-nm–emitting UV-B source. Because its wavelength is right in between the 2 action spectrum optima of 304 and 131 nm, it offers a highly efficient UV therapy without other interfering spectra. Only a few studies have been conducted so far with small patient samples. Two studies found more than a 75% improvement of the target plaque and more than a 90% improvement of the target lesion in 50% of cases. These

Photodynamic therapy

Photodynamic therapy (PDT) is a new treatment modality that has recently also been tried out for psoriasis. It involves the topical application of 5-aminolaevulinic acid and subsequent irradiation with visible light. There are several light sources used; a common spectrum is the range of 600 to 750 nm.¹⁰² The irradiation causes a photochemical reaction in the skin during which the 5-aminolaevulinic acid creates reactive oxygen species. Thus, PDT has some parallels with conventional PUVA in

Cost-effectiveness issues of phototherapy

In times of increasingly tight health budgets, economic issues become more and more important for clinicians, especially when working in an office-based environment. Economic data therefore supplement clinical management decisions today. So far, only little data are available on the costs of common treatments for psoriasis and especially on the phototherapy treatment.¹⁰⁵ The total expenditure for the treatment of patients with psoriasis per year is difficult to calculate. Estimations for the

Which therapy to choose

Patients with psoriasis experience difficulty and desire a quick and efficient improvement of their disease. The impact of psoriasis on the quality of patients' lives has been shown to be similar to that of other major diseases such diabetes and heart failure.¹⁰⁹ Phototherapy improves the quality of life and thus achieves this treatment goal. If one looks at current guidelines of international consensus conferences, biologicals, traditional systemic agents, and phototherapy are all set on the

Conclusions

Patients with psoriasis require individual management and long-term planning of therapeutic strategies. The risk-vs-benefit ratio in many cases speaks in favor of phototherapy, the cost-effectiveness issue as well, and so far, no single other treatment strategy for psoriasis has been accepted as equally safe as narrow-band UV-B and PUVA.3, 115 Phototherapy is the oldest and best established “biological” therapy for psoriasis around. There is still a lot to establish in terms of clinical

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Phototherapy and photochemotherapy

Abstract

Introduction

Section snippets

Radiophysical aspects of phototherapy and photochemotherapy

“Biological” “mode of action” for phototherapy

Natural phototherapy

Broadband UV-B

Narrow-band UV-B (UV-B 311 nm)

The history of PUVA therapy

What is PUVA?

Oral PUVA therapy

Bath PUVA therapy

Combinations of phototherapy with other treatment strategies

Balneophototherapy

New phototherapy strategies: the excimer laser

Photodynamic therapy

Cost-effectiveness issues of phototherapy

Which therapy to choose

Conclusions

Pharmacol Ther

J Am Acad Dermatol

J Invest Dermatol

Biochim Biophys Acta

Dermatol Clin

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

Cytokine

Dermatol Clin

J Am Acad Dermatol

J Am Acad Dermatol

Lancet

J Invest Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

Lancet

J Invest Dermatol

An appraisal of ultraviolet lamps used for the phototherapy of psoriasis

Br J Dermatol

Phototherapy for psoriasis

Clin Exp Dermatol

Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light

N Engl J Med

Treatment of psoriasis with trioxsalen baths and dysprosium lamps

Acta Derm Venereol

Phototherapy treatment of psoriasis today

J Am Acad Dermatol

A comparison of the efficacy and relapse rates of narrowband UVB (TL-01) monotherapy vs. etretinate (re-TL-01) vs. etretinate-PUVA (re-PUVA) in the treatment of psoriasis patients

Br J Dermatol

Guidelines for dosimetry and calibration in ultraviolet radiation therapy: a report of a British Photodermatology Group workshop

Br J Dermatol

Effect of ultraviolet light on RNA and protein synthesis in differentiated epidermal cells

Nature

Defect in DNA synthesis in skin of patients with xeroderma pigmentosum demonstrated in vivo

Science

Psoriasis. Transcapillary and interstitial transport of plasma proteins, cutaneous blood, flow, and effect of phototherapy

Dan Med Bull

History of psoriasis response to sunlight does not predict outcome of UVB phototherapy

Clin Exp Dermatol

Narrowband UV-B phototherapy clears psoriasis through a combination of local and systemic effects

Arch Dermatol

Psoralen plus black light inhibits epidermal DNA synthesis

Arch Dermatol

UV-induced oxidative stress and photoaging

Curr Probl Dermatol

Phototherapy of psoriasis: review and update

Acta Dermatovenerol Croat

Psoriasis: dysregulation of innate immunity

Br J Dermatol

Misbehaving macrophages in the pathogenesis of psoriasis

J Clin Invest

Pathogenic role for skin macrophages in a mouse model of keratinocyte-induced psoriasis-like skin inflammation

J Clin Invest

Activated macrophages are essential in a murine model for T cell–mediated chronic psoriasiform skin inflammation

J Clin Invest

Psoriasis induced at the injection site of recombinant interferon gamma. Results of immunohistologic investigations

Arch Dermatol

Immunopathogenesis of psoriasis