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E-STUDY
Year : 2014  |  Volume : 59  |  Issue : 2  |  Page : 209
Evaluation of PUVA-induced skin side effects in patients referred to the Imam Reza Hospital of Mashhad in 2005-2007


1 Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
2 Research Center for Skin Diseases and Cutaneous Leishmaniasis, Mashhad University of Medical Sciences, Mashhad, Iran
3 Department of Dermatology, Arak University of Medical Sciences, Arak, Iran
4 Department of Dentistry, Arak University of Medical Sciences, Arak, Iran

Date of Web Publication21-Feb-2014

Correspondence Address:
Hamid Hamidi
Arak University of Medical Sciences, Arak
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.127708

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   Abstract 

Background: Systemic oral psoralens plus UVA therapy (PUVA) is a therapeutic method used with considerable success in many different skin disorders. PUVA therapy causes some cutaneous and noncutaneous side effects and in the present research we deal with cutaneous side effects. Aims: Evaluation of patients to know the different skin side effects of PUVA and their importance. Materials and Methods: All patients referred to the phototherapy unit of Imam Reza Hospital of Mashhad entered the research and skin examination was taken place initially and every 3 months thereafter. Whenever any side effect appeared, it was recorded in the information sheet. Results: One hundred and twenty-eight patients were included in the research, 61 were male between 15 and 75 years and 67 were female between 10 and 61 years of age. Age of female patients at the time of cutaneous side effect appearance was less than male patients. The most common early side effect was pruritus (34.3%) and the rarest was telangiectasia (0.7%). One case of late side effect in the form of squamous cell carcinoma was observed in a patient who had received other carcinogenic drugs as well. Complications such as skin dryness, pruritus, erythema and burning sensation occurred at low doses of UVA, while dermatitis, severe limb pain and acne at moderate doses and PUVA lentigines, hypertrichosis and lichenoid lesions appeared at high doses of UVA. Conclusion: Considering the significant therapeutic effects and few serious side effects, PUVA therapy is a suitable and safe method for treatment of certain skin diseases.


Keywords: Lentigines, Psoralen plus UVA, side effect


How to cite this article:
Maleki M, Yazdanpanah MJ, Hamidi H, Jokar L. Evaluation of PUVA-induced skin side effects in patients referred to the Imam Reza Hospital of Mashhad in 2005-2007. Indian J Dermatol 2014;59:209

How to cite this URL:
Maleki M, Yazdanpanah MJ, Hamidi H, Jokar L. Evaluation of PUVA-induced skin side effects in patients referred to the Imam Reza Hospital of Mashhad in 2005-2007. Indian J Dermatol [serial online] 2014 [cited 2019 Sep 22];59:209. Available from: http://www.e-ijd.org/text.asp?2014/59/2/209/127708

What was known?
It was accepted that PUVA therapy is relatively safe method for treatment of some skin diseases but still some side effects may appear during or after treatment which need more attention.



   Introduction Top


Oral psoralens plus UVA therapy (PUVA) has been used to treat several skin disorders for years. For the first time in 1974, PUVA was used to treat psoriasis successfully. [1] Since then many different dermatoses such as vitiligo, atopic dermatitis, mycosis fungoides, lichen planus, GVHD, etc., have been treated with this method. [2] Because UVA (320-400 nm) only penetrates down to the dermis, the depth of activation of psoralens is limited to the dermis as well. Once psoralens enters an excited state induced by UVA radiation, it forms cross-links with DNA that inhibit DNA replication. In addition to antiproliferative effects, PUVA also has anti-inflammatory and cutaneous immunosuppressive properties. [3] PUVA also directly affects cell-surface membranes and inhibits epidermal growth factor binding, which may further downregulate the hyperproliferative state. PUVA generates reactive oxygen species, causes mitochondrial dysfunction, induces apoptosis of both keratinocytes and lymphocytes, and is toxic to Langerhans' cells. [4]

As any other procedures, PUVA therapy has some side effects which should be kept in mind while using this treatment for any patient and these can be divided into cutaneous and noncutaneous side effects.

Cutaneous side effects including erythema, pruritus, burning, dermatitis, onycholysis, etc., are important because some of them are indicators of higher than safe UVA dose and some others are bordering and disturbing the usual patients' activities.


   Materials and Methods Top


All patients referred to the phototherapy unit of Imam Reza Hospital of Mashhad entered the research. Since the research had no effect on treatment protocol and regular examination was beneficial for patients, there was no limitation or patient selection. The patients had been referred to the phototherapy unit after confirmation of their disease with skin biopsy. After recording the data, patients' skin was examined by a dermatologist and any cutaneous signs and symptoms and previous history of skin problem were recorded. Since then, cutaneous examination was repeated every 3 months; meanwhile each week patients were asked about any cutaneous side effect.


   Results Top


During 2 years of research, 128 patients between 10 and 75 years of age were enrolled (mean 30.8 ± 12.2), 61 males (47.6%) between 15 and 75 years and 67 females (52.3%) between 10 and 61 years. With regular skin examination every 3 months, in 87 patients (67.9%) cutaneous side effects appeared from which 29 were males (33.3%) and 58 were females (66.7%).

For patients with side effects minimum and maximum age were 10 and 75, respectively, (mean 32.03 ± 13.67), male patients with side effect of 16-75 years and female patients of 10-61 years.

The age distribution was normal (P = 0.221) so for age comparison we used T-test. There was no significant difference primarily (P = 0.211) so we used T-test with pooled variance estimate and significant difference was found (P = 0.005) between age of male and female patients according to side effect appearance.

All patients used methoxsalen tablets 2 hours before UVA therapy. Comparison of different doses of methoxsalen in patients with side effect is seen in [Table 1] and [Table 2].
Table 1: Doses of methoxsalen in vitiligo patients with side effect

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Table 2: Doses of methoxsalen in psoriasis patients with side effect

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The patients with side effects were compared with regard to their disease in [Table 3].
Table 3: Frequency of patients with side effect regarding their disease

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Early cutaneous side effects were pruritus, burning, erythema, skin dryness, PUVA lentigines, hypertrichosis, onycholysis, dermatitis, hair loss, lichenoid eruption, severe pain, acne, nail pigmentation, telangiectasia, nail Beau's line, nail thinning and the single late cutaneous side effect seen in our patients was squamous cell carcinoma (SCC).

Frequency of different cutaneous side effects occurrence is shown in [Table 4].
Table 4: Frequency of different cutaneous side effects

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Patients were compared with regard to their gender which is seen in [Table 5].
Table 5: Comparison of patients with regard to their gender

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   Discussion Top


PUVA therapy is one of the most effective modality for treatment of different skin diseases. A very small study comparing narrow band (NB)-UVB and PUVA suggested that NB-UVB and PUVA have similar efficacies, [5] but the two largest published head-to-head comparison studies involving approximately 100 patients each showed significant efficacy advantage of PUVA over NB-UVB.

The first study by Gordon, et al., [6] (N = 100) demonstrated that PUVA is not only more effective than NB-UVB, but also requires fewer treatments to clearance (mean of 16.7 vs. 25.3 sessions) and has a longer remission time (35% in remission with PUVA after 6 months vs. 12% with NB-UVB). The second large-scale trial (N = 93) by Yones et al., [7] corroborated the results of Gordon et al., [6] PUVA was more effective, needed fewer treatments, and demonstrated longer remission times than NB-UVB.

The present research is a descriptive-analytical with easy sampling method from patients referred to the phototherapy unit of Imam Reza Hospital of Mashhad from 2005 to 2007.

One hundred and twenty-eight patients (61 males and 67 females) entered the research. During 2 years of research, 87 patients afflicted by cutaneous side effects (67.9%) and considering that most of these side effects were mild and controllable, therefore at least for early cutaneous side effects, PUVA therapy seems relatively safe.

From 87 patients with side effects 29 were male (33.3%) and 58 were female (66.7%) which means females affected twice as males, while this comparison is not mentioned in any reference books. The reason for this difference may be that female patients pay more attention to the mild cutaneous signs like pruritus and erythema.

Age comparison of male and female patients by T-test with pooled variance was statistically significant (P = 0.005) which means that female patients were affected in younger age than males.

In the range of 10-20 years from 25 patients, 19 were affected (76%) and in 31-40 years from 37 patients, 24 were affected (64.8%) and in 21-30 years from 46 patients 26 were affected (56.5%) by cutaneous side effects. Comparing these data shows that appearance of side effect under the age of 20 is more common. Although in 41-50 years every 8 patients (100%) and over the age of 51 from 12 patients 10 were affected (83.3%), but because of small number of patients in these groups, it is not possible to give definite suggestion about them, besides skin dryness in old age can predispose them to the phototherapy side effects and this may be a confounding factor.

All patients received oral methoxsalen 2 hours before UVA therapy. In vitiligo group, from 58 patients 49 (84.5%) received 20 mg methoxsalen, 4 (6.9%) received 25 mg, 3 (5.2%) received 30 mg and 2 (3.4%) 15 mg. In psoriasis group, from 18 patients 11 (61.1%) received 20 mg methoxsalen, 5 (27.8%) received 30 mg and 2 (11.1%) received 25 mg. Comparing these data shows that methoxsalen dose in vitiligo patients is considerably lower than psoriasis patients and if we compare that with range of methoxsalen dose in vitiligo and psoriasis patients which is 0.25-0.5 mg/kg and 0.6 mg/kg, respectively, it will appear that our patients received relatively suitable dose. [2]

The phototherapy cutaneous side effects are divided into two groups of early and late side effects. In present research mainly the early cutaneous side effects were considered because the research has taken place during 2 years and also from the beginning of phototherapy in Imam Reza Hospital to the end of the research about 9-10 years is passed and this period is not enough for evaluation of late side effects.

Patients were examined every 3 months for cutaneous side effects and observed side effects are shown according to their prevalence in [Table 5]. The most common side effect was pruritus with 34.3% and the rarest was telangiectasia with 0.7%.

Prevalence of some side effects is mentioned in reference books such as erythema 30%, pruritus 25% and dermatitis 5% [2],[3],[8],[9] which, in some cases is near to our data and in some others is far, considering the personal and genetic differences between our people and Americans or Europeans and different life style, prevalence of side effects is definitely different and of course some more research is needed to take precise data about cutaneous side effects in our people.

Pigmentation is the commonest cutaneous change observed, and is dose related. It may be diffuse, poikiloderma-like, or in a naevus spilus-like pattern producing gross freckling (PUVA lentigines). [10],[11]

From late cutaneous side effects of PUVA therapy which are skin tumors, only one case of SCC was observed on the flank of a male patient and was confirmed by pathologist. Although the patient had received high dose of UVA (1884j) and the number of phototherapy sessions was 538 and long time had been passed from the beginning of his phototherapy (about 8 years) which means that all risk factors were present, [12],[13] but since he was the case of Mycosis Fungoides and had received Neotigason, Interferon, Methotrexate, Prednisolon and Nitrogen mustard during this period because of his disease exacerbations and of course some of them are carcinogenic and some others are not, and also Neotigason has even protective effect for skin cancers, appearance of SCC could not be considered the side effect of PUVA therapy.

A case of nail Beau's line in form of transverse depression of finger nail observed in a female patient. This condition comes from transient disruption of nail formation and the causes can be trauma, inflammation and neurological problems (involvement of one or several nails) or systemic problems such as coronary thrombosis, measles, mumps and pneumonia (involvement of all nails) and appears several weeks later. [14],[15] In our patient one nail was involved and none of the above-mentioned causes was present, considering that in the dermatological reference books this condition is not in the list of phototherapy side effects, and also only one nail was involved, it is unlikely that the Beau's line is a side effect of phototherapy but its confirmation needs more information from future researches.

Comparison of cutaneous side effects prevalence with regard to the patients sex shows that some of these side effects such as dry skin are more common in males and some others like lichenoid lesions are more common in females and this was statistically significant (P < 0.05).

For some side effect like skin dryness, erythema, skin burning, hypertrichosis and dermatitis which were seen in relatively high number of patients, difference between male and female is significant besides in case of lichenoid lesions and severe limb pain which happened only in females, it is also significant but for other side effects, although the difference was statistically significant, because of very low number of patients it is difficult to reach any conclusion and more research is needed.

According to the [Table 6] skin dryness and burning is more common in males and erythema, hypertrichosis, onycholysis, dermatitis, lichenoid lesions and severe limb pain is more common in females.
Table 6: Cutaneous side effects prevalence with regard to the patient's sex

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In case of appearance of any side effect total dose of UVA was calculated and number of phototherapy sessions was recorded which can be seen in [Table 7].
Table 7: UVA dose at the time of cutaneous side effects appearance

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As expected, some side effects like pruritus, skin dryness and erythema appeared in low doses of UVA, so one should consider them at the beginning of phototherapy and some others appeared at high UVA doses such as PUVA lentigines, onycholysis and lichenoid lesions and so they are expected in patients under long-time phototherapy.

Severe limb pain is an uncommon side effect which can occur within 4-8 weeks of starting phototherapy [16],[17] but in our patients this side effect appeared later (session 36 and afterwards) this difference may come from our different race comparing with Americans or Europeans and also our patients in some cases did not continue their phototherapy regularly so the side effect appeared later.


   Conclusion Top


The present research on 128 patients during 2 years showed that although PUVA therapy can cause some side effects but most of them are not serious or life threatening and can be controlled with simple measures. Cutaneous side effects appear in female patients in younger age compare with males consequently choosing young female patients for phototherapy should be done with caution.

Evaluation of early cutaneous side effects in our patients showed that most of these are not hazardous and easily controllable and it is not necessary to hold the phototherapy. The only exception is PUVA lentigines in which atypical melanocytes may predict the possibility of skin cancer appearance and phototherapy should be stopped. Thus it can be concluded that PUVA therapy with regard to its great therapeutic effects on different skin disorders and few side effects, is a suitable and safe method. The late cutaneous side effects could not be evaluated in this research and is suggested that further follow-up is considered for patients up to about 15 years and then evaluation of late side effects should be done.

The patients, who had received long-time phototherapy from the beginning of Imam Reza Hospital phototherapy unit working, were followed for possible skin tumor appearance. Some of them were examined and no skin problem was detected but in some others because of some limitations we could not get enough information. Our limitations were, although the addresses and phone numbers of patients were recorded, changes of these parameters were not reported by the patients in some cases, so finding the new addresses or phone numbers were sometimes impossible and in two cases after finding the new phone numbers and explaining the importance of follow-up, the patients did not return for further examination. These cases, although not too many, showed that patient's information should be recorded completely and meticulously and any change should be considered and its importance also should be emphasized for the patients.

Unfortunately the patients were not serious enough about their follow-up and this is the duty of medical personnel and even the media to show the importance of this process because the best way to find the late side effects which are life threatening is by regular skin examination by dermatologist.


   Acknowledgments Top


We specially thank those colleagues who were involved in recording patient`s information and side effects and also patients who had co-operated during the study period.

 
   References Top

1.Parrish JA, Fitzpatrick TB, Tanenbaum L, Pathak MA. Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light. N Engl J Med 1974;291:1207-11.  Back to cited text no. 1
    
2.Morison WL. psoralens ultraviolet A therapy in 2004. Photodermatol Photoimmunol Photomed 2004;20:315-20.  Back to cited text no. 2
    
3.Lauharanta J. Photochemotherapy. Clin Dermatol 1997;15:769-80.  Back to cited text no. 3
    
4.Erkin G, Uður Y, Gürer CK, Aþan E, Korkusuz P, Sahin S, et al . Effect of PUVA, narrow-band UVB and cyclosporin on inflammatory cells of the psoriatic plaque. J Cutan Pathol 2007;34:213-9.  Back to cited text no. 4
    
5.Sivanesan SP, Gattu S, Hong J, Chavez-Frazier A, Bandow GD, Malick F, et al. Randomized, double-blind, placebo-controlled evaluation of the efficacy of oral psoralens plus ultraviolet A for the treatment of plaque-type psoriasis using the Psoriasis Area Severity Index score (improvement of 75% or greater) at 12 weeks. J Am Acad Dermatol 2009;61:793-8.  Back to cited text no. 5
    
6.Gordon PM, Diffey BL, Matthews JN, Farr PM. A randomized comparison of narrow-band TL-01 phototherapy and PUVA photochemotherapy for psoriasis. J Am Acad Dermatol 1999;41:728-32.  Back to cited text no. 6
    
7.Yones SS, Palmer RA, Garibaldinos TT, Hawk JL. Randomized Double-blind trial of the treatment of chronic plaque psoriasis: efficacy of psoralens-UV-A therapy vs narrowband UV-B therapy. Arch Dermatol 2006;142:836-42.  Back to cited text no. 7
    
8.Griffiths C. Camp R. Barker J. Psoriasis. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook`s Textbook of Dermatology. 7 th ed. Oxford: Blackwell; 2004.p. 35.1-35.68.  Back to cited text no. 8
    
9.Parrish JA, Fitzpatrick TB, Shea C, Pathak MA. Photochemotherapy of vitiligo. Use of orally administered psoralens and a high-intensity long-wave ultraviolet light system. Arch Dermatol 1976;112:1531-4.  Back to cited text no. 9
    
10.Helland S, Bang G. Nevus spilus-like hyperpigmentation in psoriatic lesions during PUVA therapy. Acta Derm Venereol 1980;60:81-3.  Back to cited text no. 10
    
11.Miller RA. Psoralens and UV-A-induced stellate hyperpigmented freckling. Arch Dermatol 1982;118:619-20.  Back to cited text no. 11
    
12.McKenna KE, Patterson CC, Handley J, McGinn S, Allen G. Cutaneous neoplasia following PUVA therapy for psoriasis. Br J Dermatol 1996;134:639-42.  Back to cited text no. 12
    
13.Lever LR, Farr PM. Skin cancers or premalignant lesions occur in half of high-dose PUVA patients. Br J Dermatol 1994;131:215-9.  Back to cited text no. 13
    
14.Beau JHS. Note sur certain caractères de séméiologie rétrospective présentés par les ongles. Arch Gén Méd 1846;11:447-9.  Back to cited text no. 14
    
15.Weismann K. Lines of Beau: Possible markers of zinc deficiency. Acta Derm Venereol 1977;57:88-90.  Back to cited text no. 15
    
16.Tegner E. Severe skin pain after PUVA treatment. Acta Derm Venereol 1979;59:467-70.  Back to cited text no. 16
    
17.Miller J, Munro DD. Severe skin pain following PUVA. Acta Derm Venereol 1980;60:187.  Back to cited text no. 17
    

What is new?
Although some side effects do appear during or after phototherapy, most of them are not hazardous and controllable with exception of PUVA lentigine in which atypical melanocytes are present. In our patients females affected twice as males and female patients showed side effects in younger age than males.



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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