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Monday, August 10, 2009

Phototherapy in 2009

Pr Pierre Thomas (Lille)

Phototherapy today in France

In France, there are currently 1298 dermatologists practicing phototherapy (PUVA and UVB), and a similar number have access to lasers, mainly for cosmetic purposes.
Photodermatology had its glory days in the 1930s, with Finsen’s Nobel Prize and Jean Saidman’s Institut d’Actinologie.
Most physicians used UV to treat tuberculosis and rickets. With the advent of antibiotics and vitamin therapy, phototherapy fell into disuse.

When I first began to get involved in photobiology, I developed a solar simulator based on a Cinérama projection lamp, and I rigged up an array of 12 Blacklight tubes for phototherapy and in so doing, I was, like «Monsieur Jourdain», performing PUVAtherapy without knowing it.
The dramatic results of PUVA in psoriasis, published by Fitzpatrick in the early 1970s, proved convincing and allowed the use of this technique to expand.

Our first Dixwell cabin, acquired in 1974, worked from 7 a.m. to 10 p.m. … including Saturdays!
We now have two TL09-TL01mixed cabins. Bath-PUVAtherapy is very widely used, because it is more effective with fewer sessions and a lower cumulative dose, and does not have the drawbacks that accompany the oral administration of psoralen (need for eye protection, nausea, drug interactions).
One needs appropriate premises (a separate bath in a connecting room adjacent to the cabin) and dedicated staff; however, this can be justified for a University Hospital as long as the Health Service funding is appropriate.
Oral route PUVA is usually performed by private dermatologists to whom we refer patients for reasons of local proximity in the context of a health-care partnership.
TL01 phototherapy is extensively used for vitiligo, psoriasis, and prurigo, and a combination of UVA-TL01 for atopic patients. We use a UVA lamp for flares of atopic eczema, and localized scleroderma, extensive forms being treated by Bath-PUVA.
A considerable proportion of our activity is Bath-PUVA, which is rarely performed outside a hospital, but it is also very useful for palmoplantar psoriasis and alopecia areata.

In 2007, out of the 3313 phototherapy sessions carried out in our department, 1456 involved localized Bath-PUVA (palmoplantar and alopecia), 885 TL01 (psoriasis and vitiligo), 610 whole-body Bath-PUVA (psoriasis, lymphomas), and 205 sessions of UVA1-therapy (scleroderma, necrobiosis lipoidica), but there were only 156 sessions of oral-route PUVA (psoriasis).
Outside the hospital setting, phototherapy in the community is used mainly to treat psoriasis and polymorphous light eruption in the summer. The other indications are lichen planus, vitiligo and atopic eczema.

Phototherapy and psoriasis

Dermatologists still use phototherapy as a front-line treatment for psoriasis, but over time, many patients have reached the limit maximum total dose.
In these cases, the usual option is methotrexate rather than cyclosporin. The combination of phototherapy up to the limit dose, followed by cyclosporin leads to cumulative carcinogenic risks of immunosuppression. In the case of methotrexate, it is the hepatic and hematological risks that restrict its use, and previous phototherapy does not restrict the indication.
The biotherapies are developing rapidly, but in practice, are usually prescribed to patients who have been shown to be resistant to phototherapy or exceeded the limit doses.
The results are no better than those of PUVA, and the potential risks, which are still poorly assessed, have to be balanced against the known, dose-dependent risks of UV. The respective places of systemic treatments (retinoids, methotrexate), of phototherapy and biotherapies remain to be defined. Having reached the limit total dose of UV is not the best indication for biotherapies, particularly as psoriasis-sufferers tend to practice heliotherapy, sometimes combined with PUVA despite our advice. Therapeutic escape from methotrexate treatment appears to constitute a better indication.
Phototherapy, like the biotherapies, must be used as part of the revolving treatment of psoriasis, because they are only symptomatic treatments.

Psoriasis: PUVAtherapy or UVB phototherapies ?

In psoriasis with large, thick plaques, PUVA is more effective than TL01 phototherapy, with remission being achieved in 90% after 15 to 30 oral route sessions for a cumulative dose of 100 J/cm2, versus 15 to 20 sessions of Bath-PUVA for a cumulative dose of 25 J/cm2.
TL01 phototherapy is proposed from the outset in psoriasis with extensive, small superficial plaques. This is the preferred treatment for children and pregnant women. No cutaneous or ocular photoprotection measures are required, and it has less phototoxicity and probably less carcinogenicity.
Nevertheless, the PUVA session - UVB session equivalence must be retained when calculating the number of sessions, because calculating the sum of the UVA and UVB doses is meaningless. Concomitant retinoid-PUVA treatment is not used sufficiently, even though it makes it possible to reduce the doses, and to provide maintenance with retinoids alone as soon as a sufficient response has been obtained.
For palmoplantar psoriasis it is required in association with Bath-PUVA.

Phototherapy and vitiligo

The results of phototherapy in vitiligo depend equally on the technique and on the patient’s motivation and the physician’s conviction. Physicians and patients have different assessments of the results. The percentage of repigmentation and the PASI score can be useful for comparing different methods in psoriasis, but have no real meaning for patients.
For a patient, even partial repigmentation seems to offer the hope of achieving repigmentation.
The best results are obtained in highly motivated patients with a dark phototype.
PUVA induces hyperpigmentation in normal skin, which accentuates the contrast, which distresses the patient, something that does not happen with TL01 phototherapy. TL01 phototherapy is also more effective and more convenient.
In practice, it takes a trial period of at least 3 months with 3 sessions per week to find out whether the patient is a good responder. To improve compliance, this can be reduced to 2 sessions a week, beginning with 0.075 J/cm2 (vitiliginous skin corresponds to phototype I skin, regardless of the subject’s phototype), and increasing by 20% per session until slight erythema is obtained, which should be maintained.
In practice problems arise in good responders who reach 150 sessions, and then cannot continue due to the risk of cancer. The combination of tacrolimus-TL01 cannot be recommended, because although it produces better repigmentation, it also increases the carcinogenicity risk.
However, skin cancer is extremely rare in cases of vitiligo treated with TL01, because fortunately these patients tend to limit their exposure to the sun in order to avoid the contrast with a suntan.

In practice, for fair skin, I recommend keeping out of the sun in order to limit the contrast. I prescribe a self-tanning product appropriate to the phototype, and an antioxidant intended to limit the destruction of melanocytes.
In subjects with a dark phototype, I recommend trying TL01 phototherapy for 3 months with photographic follow-up using a Wood’s lamp in order to provide an objective measure. If both the physician and the patient find the results significant, I continue this for a year, with treatment-free intervals of 2 months between 3-month courses of treatment.
In most cases, I have seen progression halted during treatment and some repigmentation obtained in 60% of cases (complete repigmentation in only 10% of cases). In the absence of repigmentation, I do not continue the phototherapy.
In children, in a context of recent vitiligo I prescribe topical corticosteroids for 2 months, and for long-standing vitiligo I prescribe topical tacrolimus for 3 months. Melanocyte transplants are restricted to segmental local forms or those occurring in a context of poliosis, when there is no longer any follicular contingent, or to zones resistant to UV.
In practice this is difficult to organize, because it is very demanding for both the patient and the physician.

PUVAtherapy and skin cancers

The interaction between the psoralens and DNA is mutagenic in bacteria and mammalian cells.
In animals, a combination of 8-MOP and UVA is more carcinogenic when applied topically or by intra-peritoneal injection, than by the oral route.
A correlation has been demonstrated between high doses and the development of human skin cancers. The risk, which is dose- dependent, is increased 5 to 10-fold, depending on the studies, for squamous cell carcinomas, and 2-fold for basal cell carcinomas.
Overall, it is similar to that for organ transplant patients, and calls for the same monitoring. Squamous cell carcinomas due to PUVA occur in younger subjects in unexposed areas, and seem to be more aggressive. In practice they affect subjects with a fair phototype who have had more than 250 sessions. In the case of TL01 phototherapy, the risk appears to be doubled, and is greater than that for wide-spectrum UVB for equally-erythemal doses.
For UVA (TL10 or high pressure UVA) used for tanning purposes, the risk is increased 4 fold for basal cell carcinomas and 10 fold for squamous cell carcinomas.

This risk means that co-carcinogens (arsenic, tacrolimus, cyclosporine…) must not be used concomitantly, and that the doses and number of sessions must be limited. What needs to be taken into account, rather than the dose received, is the number of sessions (of PUVA or TL01), as overall the risk is the same. Exposure to sunlight and to UVA tanning parlors must also be taken into account.
The patient must be clearly informed that the risks are cumulative. It is necessary to limit the doses and the number of sessions (Bath-PUVA and concomitant retinoids), not to administer maintenance treatment, not to use phototherapy for a local recurrence, and to limit the number of sessions to 200 regardless of the type of phototherapy used.
The patient is legally obliged (by a decision of the French Supreme Court) to provide us with complete information as part of a Care Contract, but is allowed to change dermatologist without admitting how many sessions he or she has already had! Fortunately the health insurance authorities should have a record of the sessions paid for by the public health fund. This provides a justification that is medical rather than finance-driven for refusing to pay for care! Perhaps this is the way to exercise medical control?

Phototherapy and acne

In the North of France it is still the physician who decides what treatment to use, but the patient is entitled to information (Act of 4 March 2002, article L1111-2 of the [French] Public Health Code).
Acne is improved by sunshine in 70% of cases. This is true for inflammatory lesions, but not for comedo-type lesions which tend to be exacerbated by the hyperkeratinization induced by UV. Hence the idea of using light alone. Light reacts with the coproporphyrin secreted by Propionibacterium acnes. This is a type-II photodynamic reaction involving the production of an oxygen singlet that induces lipid peroxidation of the membrane system of P. acnes.

Clinical trials are still at a preliminary stage, but several light sources are already on the market, because phototherapy sources, like lasers, do not require FDA approval, but simply have to comply with safety standards. Papageorgiou’s single-blind study comparing the blue light (415 nm), a mixture of blue and red light (660 nm), white light (15 min of irradiation/day for 12 weeks) and benzoyl peroxide. Inflammatory lesions improved by 50 to 60% in response to the mixed blue and red light and benzoyl peroxide versus 25% to white light. The improvement was quicker (from the 4th week) with light than with benzoyl peroxide. There was less improvement in retentional lesions.

The contribution of PDT using the application of delta-aminolevulinic acid in the treatment of acne is controversial. In an open prospective study of 22 patients suffering from dorsal acne, Hongcharu demonstrated a significant reduction in bacterial fluorescence and sebaceous excretion for 10 weeks, with 1 cycle, and for 20 weeks with several cycles. These results have not been confirmed by other studies.
In practice, the efficacy of this technique, which does not induce resistance to the cyclines, is neither spectacular in the few patients that we have treated, nor definitely established. The conventional treatments are still relevant, on condition that they are combined with cyclines, topical tretinoin and benzoyl peroxide. Trying to get teenagers to stay out of the sun is something of a pipe dream, and the repeated application of sunscreens with a high SPF is potentially comedogenic. So at the end of vacations, I resume the treatment for a few months to compensate for the post-summer flare.

Clarification on artificial tan

We only have one skin and it has to last a lifetime.
We should look after it! Skin aging and skin cancer are due to UV. These facts are known to the general public and to the Health authorities. However, one cannot ban everything, and negative messages have proved ineffective: smoking is no longer allowed in public places, don’t drink if you are going to drive, don’t expose yourself to the sun, don’t use sun beds, don’t have unprotected sex, … In fact, what is dangerous is the abuse. This justifies legislative regulation of commercial use (Order No. 97-617 of 30 May 1997, and the Order dated 10 September 1997).
The message from dermatologists must remain restrictive, but not excessively so in campaigns that target the general public. On the other hand, on an individual basis, dermatologists must advise their patients not to use UV lamps, taking into account their phototype, and whether they take photosensitizing medication....
In practice, it is better to limit the number of sessions rather than trying to ban them completely. Low-pressure UVA is not less dangerous than high-pressure UVA, but it takes at least 20 to 30 min to deliver the dose received in 3 min with high-pressure lamps, which deliver 16 to 23 times the dose of solar UVA. High-risk subjects have a contraindication. A certificate to show that one does not have a contraindication is required to take part in sport, so why not for undergoing UVA tanning?

We could require the following information poster to be on display (Campagne des Dermatologistes de Franche Comté):

- Ultraviolet irradiation can lead to skin cancer and can seriously damage your eyes
- You must wear protective goggles
- Intense and repeated exposure to ultraviolet irradiation can lead to premature aging of the skin and an increased risk of skin cancer.
- It causes irreversible skin damage
- Exposure to UV for esthetic purposes is prohibited in minors and pregnant women
- Some drugs and cosmetics may trigger adverse skin reactions that can sometimes be serious if you expose your skin to UVA
- Do not use any device that emits UVA if you are highly sensitive to the sun, or have skin cancer or any precancerous conditionWith regard to solar photoprotection, relative avoidance between 11 a.m. and 2 p.m. remains justified, as is the wearing of protective clothing.

The use of a sunscreen is no more than a complement. In practice, they are actually used to get a tan. People must be reminded that sunscreens protect against sunburn, but must not be used to prolong exposure.
The use of a self-tanning agent, whether combined with a sunscreen or not, is a good way to limit the excessive exposure of fair skin in the hope of getting a suntan, that imposes too high a cost on the skin. Protection against UVA is an advantage, but it is pointless unless one also reduces UVB protection in order to reduce overexposure.
Solar erythema may be a natural protection against excess!

The phototherapy material in medical practice

The main thing is that he or she must be educated about the equipment and techniques as a resident. Overwhelmed by their work in the wards, residents tend to neglect this training. They have to have used phototherapy themselves to grasp its problems and advantages. Fortunately there is the annual phototherapy course organized by the SFPD and the photodermatology book!

The investment required is at least 20 000 to 30 000 euros for a cabin plus an appropriate consulting room. The best solution is for a group of dermatologists to work together in a medical center. It is also necessary to take local demand into account. There is no need for a cabin every 10 km, but there has to be at least one in every district. The other dermatologists in the district can send their patients to the phototherapist, and each can specialize in a different field (ionophoresis, laser, dermatological surgery etc.).
The regulation of medical demographics also involves access to phototherapy. It is not right for there to be such a dearth of local phototherapy outside hospitals. If, in a given district, several practices are already equipped with cabins, the recently installed practitioner could opt for local phototherapy using small modules…

The cost-effectiveness of the investment remains an important point.
Leasing at 2% of the total cost is the best option to avoid long-term credit payments over too long a period relative to the initial investment. The main distributors supply efficient and safe cabins. For an investment of 20,000 Ä, and a charge of 19.20 Ä session, it would take 20 sessions per month - i.e. 2 to 3 patients treated - to pay off the purchase over 3 to 4 years!