|Year : 2013 | Volume
| Issue : 3 | Page : 229-235
Photochemotherapy: A review
Pattammal Elumalai Chandra Mouli1, Thulasiraman Selvakumar2, S Manoj Kumar2, S Parthiban3, R Priya3, M Deivanayagi3
1 Department of Oral Medicine and Radiology, Sri Venkateswara Dental College and Hospital, Chennai, Tamil Nadu, India
2 Department of Oral and Maxillofacial Surgery, Sri Venkateswara Dental College and Hospital, Chennai, Tamil Nadu, India
3 Department of Oral Medicine and Radiology, Ragas Dental College and Hospital, Chennai, Tamil Nadu, India
|Date of Submission||19-Jun-2012|
|Date of Acceptance||07-Aug-2012|
|Date of Web Publication||10-Jul-2013|
Pattammal Elumalai Chandra Mouli
Department of Oral Medicine and Radiology, Sri Venkateswara Dental College and Hospital, OMR Road, Off Navalur, Thalambur, Chennai 603 103, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Photochemotherapy (PUVA) is a type of ultraviolet radiation (UVA). Treatment (phototherapy) used for severe skin diseases. PUVA is a combination treatment, which consists of Psoralens (P) and then exposing the skin to long wave UVA. PUVA has become a useful alternative in dermatologic therapy. Starting from historical date up to modern era the safe and useful modes of PUVA has been documented in many immunological disorders. PUVA is useful for patients with various skin disorders, including psoriasis, dermatitis, polymorphic light eruption, and mycosis fungoides. The number and the frequency of PUVA treatments will depend on the condition being treated and individual factors. Despite side effects and potential long-term hazards, PUVA is shown in clinical routine as an effective alternative to conventional immunosuppressive therapy. A wide range of diverse field for its possible utility provides an alternative armamentarium in many immunological disorders for dermatologist and also for oral diagnostician.
Keywords: Psoralens, photochemotherapy, ultraviolet radiation
|How to cite this article:|
Mouli PC, Selvakumar T, Kumar S M, Parthiban S, Priya R, Deivanayagi M. Photochemotherapy: A review. Int J Nutr Pharmacol Neurol Dis 2013;3:229-35
|How to cite this URL:|
Mouli PC, Selvakumar T, Kumar S M, Parthiban S, Priya R, Deivanayagi M. Photochemotherapy: A review. Int J Nutr Pharmacol Neurol Dis [serial online] 2013 [cited 2019 Aug 25];3:229-35. Available from: http://www.ijnpnd.com/text.asp?2013/3/3/229/114840
| Introduction|| |
Photochemotherapy (PUVA) is the treatment method in which radiation of appropriate wavelength is used to induce a therapeutic response in the presence of a photosensitizing drug. The radiation must be absorbed by a target molecule-a chromopher, which is an exogenous drug in PUVA. Ultraviolet and visible radiation are u sed therapeutically in dermatology; UVC-100-290 nm is absorbed by the ozone layer, UVB-292-320 nm for phototherapy, UVA-320-400 nm for PUVA (Psoralens plus UVA) and visible light − 400 to 800 nm for photodynamic therapy. ,
| Photochemotherapy - History|| |
PUVA using plant extracts and subsequent exposure to sunlight as a form of treatment in vitiligo has been used since ancient times, as early as 1500 BC in India and Egypt. However, the first scientific use of phototherapy dates back to 1948 AD, when Fahmy et al., in the University of Cairo, isolated three chemical compounds from the fruit of a plant Ammi majus. They named these three compounds as Ammoidin (8-methoxypsoralen [8-MOP]), Ammidin, and Majudlin (5-methoxypsoralen [5-MOP]).  Lerner in 1953 further documented the role of PUVA in patients with vitiligo.  The first synthetic psoralens and trimethylpsoralen (TMP) was introduced in 1964 and used for treatment of vitiligo. In 1974, Parrish et al., reported successful treatment of severe psoriasis with 8-MOP (p) with UVA and coined by acronym PUVA. The modern form of PUVA using high intensity UV-A sources was introduced at the Harvard-Massachusetts General Hospital Dermatology Laboratories. 
| Photochemotherapy Chemistry|| |
Psoralens belong to the furocoumarin class of compounds, which are derived from fusion of furan with a coumarin found naturally in certain plant species or synthesized in vitro. It occurs naturally in many plants including limes, lemons, and parsnips. Among the three psoralens, the trimethyl derivative is only synthesized in vitro, 8-MOPs (methoxysalens), 5-MOPs (Bergapten), and 4, 5, 8 TMPs (trioxsalen); the trimethyl derivative is not found naturally and is synthesized in vitro.  The structure of psoralens was originally deduced using its degradation reactions. It exhibits the normal reactions of the lactone of coumarin, such as ring opening by alkali to give a coumarinic acid or coumaric acid derivative. Potassium permanganate causes oxidation of the furan ring, whereas other methods of oxidation produce furan-2,3-carboxylic acid [Figure 1]. IUPAC name for psoralens is 7 H-furo [3,2-g] chromen-7-one.
One isomer of psoralens is angelicin and most furocoumarins can be regarded as derivatives of psoralens or angelicin. Some important psoralens derivatives are xanthotoxin, bergapten, and nodekenetin [Figure 2]. Another important feature of this class of compounds is its ability in generating singlet oxygen.
|Figure 2: Structure of psoralens derivatives – angelicin, xanthotoxin, bergapten, and nodekenetin|
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The psoralens are absorbed rapidly after oral administration. Absorption of psoralens is dependent upon many factors namely the formulation of drug, coexistent food intake, first pass effect in liver, and individual differences in absorption of drug but this accounts partly for the rare cases, which not gives respond expectedly to PUVA therapy in the usual dose. ,, After absorption, psoralens get distributed to all tissues and are excreted in the urine within an average of 12 hours. Peak levels of psoralens in the blood after oral intake are seen within 1-8 hours with a mean of 2 hours. This forms the basis for giving UV radiation after 2 hours of oral intake in PUVA therapy.  Photosensitivity on average is maximal 1-2 hours after ingestion of methoxsalen. Liquid formulation are superior to the previously used crystalline preparation and produce more rapid, higher, and more reproducible peak serum level. Methoxysalen has a serum half life of approximately 1 hour, but the skin remains sensitive to light to 8-12 hours. Despite widespread distribution of drug throughout the body, it is activated on the skin, where the UVA penetrates. When psoralens are applied topically they rapidly penetrate the skin and can be detected in the urine after about 4 hours. 
Mechanism of action
The action spectrum for oral PUVA is between 320 and 400 nm. Two types of reaction are involved in causing photosensitivity after PUVA. (a) an anoxic reaction that affects cellular deoxyribonucleic acid (DNA) with formation of photo adducts that may inhibit the proliferation of epidermal cells and induce apoptosis, and (b) an oxygen dependent reaction that give rise to free radicals and reactive oxygen that may damage membrane by lipid per oxidation. PUVA promotes melanogenesis in normal skin, increased pigmentation results from the transfer of melanosomes from melanocytes to epidermal cells, however, there is no change in the size of melanosomes or in their distribution. ,,,, In vitiligo, a stimulatory effect on melanocytes secondary to action on c-AMP pathway is postulated. There is an effect on DNA synthesis, proliferation of cells, immunological alternation and on the biosynthesis of prostaglandin in the skin. Psoralens act much more on cells that are actively dividing than on resting cells. This explains why they are effective only in the active stage of scleroderma and not in the fibrotic stage. Action on actively dividing or activated immune cells especially on T cell, explain their action in immune mediated disease like psoriasis, lichen planus, graft versus host disease. ,,,,
Fundamentals of PUVA therapy
The therapy usually consists of oral administration or topical application of psoralens followed by exposure to UV-A light (320-400 nm wavelengths) at a time when the concentration of the psoralens in the tissues is adequate. The main aim of PUVA therapy is to bring about a controlled, persistent phototoxic reaction. For this purpose UV-A sources having an action spectrum 320-380 nm is given. In case of oral PUVA therapy the drug is given usually on an empty stomach and the patient is exposed to UV light after 1-3 hours, the initial UV-A dose determined either by skin typing or by phototoxicity testing. In case of phototoxicity testing the patient's minimal phototoxic dose (MPD) is first calculated and this usually forms the initial does of UV-A exposure. MPD is defined as the least possible dose of UV-A that causes a barely perceptible erythema of skin in an individual patient.  The UVA dose is then sequentially increased as per the protocol followed (European, American, or any other). The frequency of UV-A exposure is either 3 or 4 times per week and this frequency of treatment is usually continued till the patient goes into remission. After attaining remission, especially in immune mediated diseases like psoriasis, lichen planus, etc., the frequency of exposure is then reduced and the last UV-A dose is continued during the maintenance therapy. The duration of this maintenance therapy depends upon the disease being treated and its propensity to relapse. With topical treatment the psoralens rapidly penetrates the epidermis, within approximately 10 minutes in normal skin and presumably faster in psoriatic skin. 
Frequency of treatment remains the same as in oral PUVA, that is, about 3-5 times per week. Several regimens exists for PUVA therapy, the most commonly being administration of 8-MOP 0.6 mg/kg body weight, on alternate days followed by 2 hours or later by exposure to UV range.  A lotion containing 1% Methoxsalen (oxsoralen) also is available for topical application. It can be diluted for bath water delivery, a method that produces low systematic psoralens level. A combination of etretinate and PUVA (RE-PUVA) is popular.  It causes faster clearing of skin lesions with fewer side effects. , In both American and European multicenter cooperative studies of PUVA for the treatment of psoriasis, initial success rates close to 90% were achieved. 
Indications of PUVA therapy
PUVA finds its use in a number of cutaneous and systematic diseases at present. The disorder in which PUVA has been used till date include: (1) Psoriasis specially in cases with greater than 20% body surface area involvement (2) Vitiligo (3) Lichen planus (4) Cutaneous T cell lymphoma (CTCL) (5) Morphea (6) Chronic graft vs host disease (7) Dermatitis herpetiformis (8) Histocytosis X (9) Prevention of photosensitive disorders like solar urticaria, chronic actinic dermatitis, polymorphic light eruption (PLE) (10) Mycosis fungoides (11) Prurigo nodularis (12) PLE (13) Chronic palmoplantar pustulosis (14) Eosinophilic folliculitis and other pruritic eruptions of human immunodeficiency virus (HIV) infection (15) Granuloma annulare (16) Morphea and localized skin lesions associated with scleroderma (16) Necrobiosis lipoidica (17) Photodermatoses (18) Pityriasis lichenoides (19) Severe refractory atopic dermatitis/eczema (20) Severe refractory pruritis of polycythemia vera, and (21) Severe urticaria pigmentosa (cutaneous mastocytosis). PUVA can induce melanocyte pigmentation in vitiligo, resulting in cosmetic pigmentation. ,,
Psoriasis is the most common indication for UVB and for PUVA. PUVA is more effective than broadband UVB, but not much different in efficacy compared with narrowband UVB. In general, PUVA is used only when UVB, administered appropriately, fails to adequately clear psoriasis or when the duration of remission is short. In view of the cumulative exposure-related skin cancer risks known to be associated with PUVA, UVB is preferred, particularly for younger patients. Neither of the therapy is curative, and remissions of on average 6 months can be expected.
UVB is indicated
- For patients who have extensive disease on limbs and body, which makes practical use of topical therapy difficult
- If topical therapy has not worked.
PUVA should be used instead of UVB
- If UVB is ineffective
- If the duration of remission following three consecutive UVB courses is consistently short (e.g., <2 months)
- For palmoplantar pustular psoriasis, PUVA appears more effective.
- UVB and PUVA are effective treatments for atopic eczema/dermatitis. The rules for psoriasis can broadly be applied to this condition. It is used:
- For particularly extensive truncal and limb eczema
- When standard topical therapies are not the controlling activity or only resulting in short-term remissions
- As steroid-sparing therapy when potent or very potent topical steroids are otherwise required continuously to maintain disease control.
As for psoriasis PUVA should be reserved for older patients and those who are not helped by UVB. In general, treatment courses often have to be more gentle, with lower increments and more prolonged in comparison to those used for psoriasis. Topical therapy with corticosteroids should be continued, although the need for this will reduce as the disease is brought under control with phototherapy. If your phototherapy department is not air-conditioned, then heat particularly in the summer months may be a reason for apparent treatment failure, because sweating can be a factor in aggravating the eczema.
Polymorphic light eruption
Mild PLE is usually managed with advice on behavioral, clothing, and topical sunscreen photo protection measures. However, when it is more severe and impairing life quality, prophylactic PUVA or UVB phototherapy administered in spring is beneficial. Narrowband UVB is as effective as PUVA, and generally preferable for its convenience and greater safety. However, PUVA is more effective than broadband UVB. Patients need to know before starting treatment that it is common for PLE to be provoked during the course. This can usually be managed by adjusting the doses used, treating only sites requiring therapy (e.g., treating patients wearing shorts and a T-shirt, the same ones each treatment), and if necessary applying a potent topical corticosteroid immediately after each treatment. If PLE is very readily provoked by UVB, then PUVA may be better, and vice versa.
Cutaneous T cell lymphoma
The effect of PUVA on the long-term prognosis of CTCL is unknown. The finding of "solar signature" p53 mutations in tumor stage CTCL raises possible concerns about use of phototherapy and PUVA, although there is no evidence to suggest that treatment with either adversely affects the natural history. If simple treatment approaches with topical steroids have been unhelpful, PUVA is an effective treatment for symptomatic (pruritic) early stage I and Ia patch and plaque disease. The effect appears to be localized to exposed sites, and "sanctuary site" disease does not clear. It is also useful, sometimes in combination with other therapies such as retinoids or interferon, in the palliation of later stage disease. Narrowband UVB is effective for patch stage disease but once lesions are palpably thickened PUVA is more likely to be effective.
Narrowband UVB and PUVA can both induce repigmentation. Up to 70% of patients with vitiligo benefit if they are treated continuously for a year or more. Those with trichrome pattern vitiligo, that is, those with areas of reduced pigment as well as areas of normal skin and of complete pigment loss, tend to respond better. Acral sites respond poorly. Patients repigment in a perifollicular fashion initially. In patients with skin photo types II-V, there is a danger that, if complete repigmentation does not occur, the problem will be made worse by exaggeration of contrast between vitiligo and surrounding skin, and there could be scattered macules of follicular pigment if partial repigmentation occurs. However, if the patient is well motivated, has a good understanding of their condition and what to expect from this treatment, and has a pattern of vitiligo, which is likely to respond, then UVB or PUVA can greatly improve quality of life. Some of those in whom successful repigmentation is achieved keep their pigmentation after an initial prolonged course of treatment, but others lose it again and require repeated courses.
It should be remembered that a course of PUVA for vitiligo may easily give a patient a high cumulative dose with 150-200 treatments given twice weekly over 1-2 years. A frank discussion with the patient of the risks of therapy - the risk of more pronounced lesional adverse effects with "burning" and blistering, and the possibility of an increased skin cancer risk compared with unaffected skin - is a must before embarking on prolonged courses of phototherapy for vitiligo.
| Puva Regimen|| |
Choice of psoralens and its route of administration
The psoralens most widely used is 8-MOP, administered by mouth. If the microcrystalline tablet formulation is used, UVA treatment is usually given 2 hours after the tablets (0.6 mg/kg or a dose based on a surface area nomogram) are taken. Nausea is a frequent side effect of 8-MOP: This is usually not a problem if the tablets are taken with food, but some patients need to be changed to 5-MOP tablets which rarely, if ever, cause this adverse effect. It is because it is not certain that 5-MOP PUVA is as effective as 8-MOP PUVA (and 5-MOP is more expensive) that 8-MOP is generally the standard first-line psoralens.
The psoralen can also be administered topically, by application as a bath-water solution for whole-body treatment or as soaks, paint, or cream for localized treatment (e.g., for hands and feet). In the UK, 8-MOP is the psoralens currently most widely used for bath PUVA, although in some areas TMP is favored. Bath PUVA is more time-consuming for patients and staff than oral PUVA, but may be preferred when the patient is on medications, such as warfarin, which might interact with an oral psoralen or if the eye protection necessary for oral PUVA will be particularly problematic. Moreover, when psoralens are applied topically they reach a higher skin concentration, and shorter UVA exposures are needed for the same effect: This is particularly true for TMP, and is an advantage if short treatment times are important (e.g., for very frail or claustrophobic patients), but can be a disadvantage in that the risk of phototoxic erythema reactions after natural sunlight UVA exposure is greater.
Starting dose - minimal phototoxic dose determination
The starting dose should ideally be based on each individual's MPD. The reasons for doing this are similar to those described for performing MED testing before UVB phototherapy. Additionally, for oral PUVA, MPD assessment ensures that the psoralens dose given does cause a phototoxic reaction. If it does not then MPD testing should be repeated after an increased psoralens dose or a switch to topical PUVA made. Although not ideal, oral PUVA is sometimes started at a low UVA dose without prior MPD determination. Bath PUVA should never be started without the MPD being determined first because of the particularly severe photosensitivity that can result, and which cannot be predicted by skin phototype or any other patient characteristics.
Frequency of treatment
Treatment with PUVA is normally twice weekly (based on the time course of PUVA erythema, which peaks later than UVB erythema), although in some countries thrice-weekly treatment is customary. When necessary for patient convenience, once-weekly treatment can also be effective, although it takes longer to see the benefit.
Patients treated with PUVA need to be careful to avoid natural UV exposure (including exposure through window-glass and cloud) throughout the course. Following psoralen tablets, eye protection (UVA-absorbing spectacles) is advised for 24 hours, and following bath psoralen application if an inflammatory dermatosis treated is very extensive (and significant systemic absorption possible), to minimize the risk that a psoralens-UVA reaction in eye lenses could lead to cataracts.
Combinatorial usage of PUVA
The most common treatment combinations for use in early CTCL (stages I-IIa) are PUVA with either Inteferon alpha (IFNα) or bexarotene, although alternatives include other retinoid compounds and denileukin diftitox (Ontak) [Figure 3]. A review of studies with IFNα monotherapy in a total of 207 patients with MF or Sézary syndrome (SS) reported an overall complete response rate of 52%, but the rate was only slightly higher (60%) in 102 patients who received this drug in combination with a retinoid.  A considerably higher complete response rate of 82% was achieved when IFNα was combined with PUVA in a multicenter study of 98 patients with stages I and II MF, or small- to medium-sized pleiomorphic T-cell lymphoma. This was superior to the combination of IFNα and retinoids, investigated in the same study, for which the complete response rate was 49%.  Nevertheless, the IFNα plus retinoid combination produced a marked response in some patients.
|Figure 3: Treatment combinations. (a) Possible treatments that can be used in combination in early stage Cutaneous T-Cell Lymphoma (CTCL), (b) possible bexarotene treatment modalities, (c) photopheresis combinations in stage III CTCL or Sézary syndrome|
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A comparison of PUVA plus IFNα vs PUVA alone in 96 patients with CTCL stages I and II showed that the combination therapy produced a complete response rate of 80%, compared with 72% for PUVA alone.  Although this treatment difference was not significant, the cumulative dose of UV-A was significantly lower for the combination therapy than for PUVA alone, which is important in long-term treatment. Moreover, the recurrence-free time was 113 weeks for PUVA plus IFNα compared with 56 weeks for PUVA alone. Similar results were reported in a study of 89 patients with stage Ia-IIa MF treated with IFNα, 6-18 MIU, plus PUVA over 14 months.  The rate of complete remission was 84%, and continuous remission was seen in 20% of this group. The combination of IFNα plus PUVA therapy is therefore a safe and effective treatment for early disease stages. This combination therapy could both reduce treatment dose, and therefore toxicity, and increase the recurrence-free time, compared with monotherapy.
- Pregnancy and lactation
- Severe liver disease
- Renal failure
- Xeroderma pigementosum
- Systemic Lupus Erythematosis SLE or porphyrias
- Family history of melanoma. 
- PUVA lentigo is a persistent, pale brown macule appearing 6 months or longer after the start of PUVA therapy for psoriasis. The lesions resemble solar lentigines, but they often have more irregular borders and may mimic ephelides. The occurrence of lesions is closely associated with greater cumulative doses of PUVA, and the lesions may occur on all treatment sites. The most common areas include the upper part of the chest and back, groin, buttocks, glans penis, and penile shaft. The axillae, palms, soles, and gluteal cleft are spared. The lesions vary from 3 to 8 mm in diameter, but stellate lesions can be as large as 3 cm in diameter. The lentigines may persist for 3-6 months after therapy is discontinued. In contrast, stellate lesions can persist longer than 2 years.
Toxicity and monitoring
The major acute side effects of PUVA include nausea, blistering, and painful erythema.  PUVA-induced inflammation is more delayed and reaching a peak of 48-72 hours after exposure. Chronic effects occur within the skin like actinic keratosis, photo aging, hypertrichosis, lichenoid eruption and lichen planus, development of multiple keratoacanthoma, bullous pemphigoid, Koebhner phenomenon, systemic lupus erythematous may develop during PUVA therapy or existing potential lesion may exacerbated. ,,,, Squamous cell carcinomas occur as the most potential hazards of PUVA therapy. ,
Extracorporeal photophoresis (ECP) was introduced in 1987 as a treatment option for CTCL. It is a variant of PUVA in which irradiation of selective blood fractions is done outside the human body in presence of a psoralens. The process combines leukopheresis with either oral administration of 8-MOP or injection of liquid 8-MOP into the leukocyte rich fraction of blood followed by selective irradiation of the leukocyte fraction. In case the psoralens (8-MOP) is administered orally, its level in the blood needs to be measured at the time of the procedure and this level should ideally be more than 50 μg/ml of blood. ECP has been found to be an effective therapeutic option in a wide range of cutaneous disorder like atopic dermatitis, CTCL, bullous pemphigoid, graft versus host disease, epidermolysis bullous aquista, morphea, erosive lichen planus, pemphigus vulgaris and foliaceous, psoriasis, scleroderma, and in systemic disorder like SLE, systemic sclerosis, dermatomyositis, rheumatoid arthritis, chronic HCV infection, multiple sclerosis, leukemias, and lymphomas. ,
| Conclusion|| |
The present overviews regarding PUVA provide a sound idea in over all aspects from historical age to modern era as one of the alternative effective therapy for many immunological disorder and systematic disease. To be on a safer side, steps should be taken to lower the dose of PUVA by changing the dose schedule, reducing the unnecessary maintaining dose and by adding a psoralens, or oral retinoids to the regimen. PUVA therapy is best avoided in patients with a history of skin cancer or those, who require a higher maintaining dose.
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[Figure 1], [Figure 2], [Figure 3]