Policy. Number: *Pleasesee amendment forpennsylvaniamedicaidattheend ofthis CPB.

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1 1 of 49 Number: 0205 Policy *Pleasesee amendment forpennsylvaniamedicaidattheend ofthis CPB. PUVA Aetna considers psoralens and ultraviolet A light (PUVA) treatments medically necessary for the following conditions after conventional therapies have failed: Last Review: 04/12/2018 Effective: 03/12/1998 Next Review: 02/14/2019 Review History Alopecia areata; Chronic palmoplantar pustulosis; Cutaneous T cell lymphoma (mycosis fungoides); Cutaneous manifestations of graft versus host disease; Eosinophilic folliculitis and other pruritic eruptions of HIV infection; Granuloma annulare; Morphea (circumscribed scleroderma) and localized skin lesions associated with scleroderma; Necrobiosis lipoidica; Definitions Clinical Policy Bulletin Notes

2 2 of 49 Photodermatoses; Pityriasis lichenoides; Polymorphous light eruption; Severe lichen planus; Severe parapsoriasis; Severe refractory atopic dermatitis/eczema; Severe refractory pruritus of polycythemia vera; Severe urticaria pigmentosa (cutaneous mastocytosis); Severely disabling psoriasis (i.e., psoriasis involving 10 % or more of the body, or severe psoriasis involving the hands, feet, or scalp); Vitiligo. Generally 2 to 3 PUVA treatments per week for up to 23 weeks are considered medically necessary for psoriasis. After 23 weeks, the medically necessary frequency of PUVA therapy is 1 treatment every 1 to 3 weeks with the majority of persons treated once every 3 weeks for an indefinite period. If the psoriasis fails to improve after 2 months of PUVA therapy, continued treatment is generally not considered medically necessary due to lack of efficacy. Note: Home PUVA treatment is considered experimental and investigational because of insufficient evidence of its safety and effectiveness. Aetna considers PUVA treatment experimental and investigational for all other indications. There is inadequate evidence in the peer reviewed medical literature of the effectiveness of PUVA in any of these conditions (not an allinclusive list): Acne; Eosinophilic cellulitis (Wells syndrome); Keratosis follicularis (Darier disease or Darier White disease); Lichen amyloidosis; Lichen myxedematosus; Melasma;

3 3 of 49 Necrobiotic xanthogranuloma; Necrobiosis lipoidica; To increase skin tolerance to sunlight. UVA/UVB Aetna considers phototherapy with UVA medically necessary for the following indications: Acne; Eczema (atopic dermatitis); Eosinophilic folliculitis and other pruritic eruptions of HIV infection; Lichen planus; Morphea (circumscribed scleroderma); Parapsoriasis; Photodermatoses; Pityriasis lichenoides; Pityriasis rosea; Prurigo nodularis; Psoriasis Scleredema that is functionally limiting or symptomatic. Aetna considers the use of UVA experimental and investigational for infectious keratitis, lymphomatoid papulosis, uremic pruritus, and all other indications because there is inadequate evidence in the peer reviewed medical literature of the effectiveness of UVA in any of these conditions. Aetna considers narrow band UVB phototherapy medically necessary for the following indications: Atopic dermatitis (atopic eczema); Chronic urticaria; Early stage mycosis fungoides; Morphea (circumscribed scleroderma); Photodermatoses (e.g., actinic dermatitis and solar urticaria;

4 4 of 49 Psoriasis; Polymorphous light eruption For narrow band UVB phototherapy for vitiligo, see CPB 0422 Vitiligo (../400_499/0422.html). Aetna considers narrow band UVB phototherapy experimental and investigational for all other indications (e.g., acquired perforating dermatitis, alopecia mucinosa chemical dermatitis/contact dermatitis, cholestasis of pregnancy, dermatographic urticaria (also known as dermographism and dermatographism), graft versus host disease, granuloma annulare, Hailey Hailey disease, hidradenitis suppurativa, lichen simplex chronicus, papular urticaria, progressive macular hypomelanosis, pruritus, scleroderma, skin hypopigmentation from scarring, superficial mixed cell dermatitis, and uremic pruritus; not an all inclusive list) because there is inadequate evidence in the peer reviewed medical literature of the effectiveness of narrow band UVB in any of these conditions. Aetna considers UVB with the addition of topical coal tar (also known as the Goeckerman regimen) or petrolatum medically necessary for persons with severe psoriasis (defined as psoriasis that affects more than 10 % of body surface area). Aetna considers UVB with the addition of topical coal tar or petrolatum experimental and investigational for all other indications (e.g., pemphigoid, pruritis). Aetna considers home phototherapy (UVB) treatment medically necessary DME for persons with severe psoriasis with a history of frequent flares who are unable to attend on site therapy or those needing to initiate therapy immediately to suppress psoriasis flares. Home ultraviolet light booths or ultraviolet lamps, as well as replacement bulbs sold by prescription only, are considered medically necessary for persons eligible for home UVB phototherapy.

5 5 of 49 For excimer laser treatment of psoriasis, see CPB 0577 Laser Treatment for Psoriasis and Other Selected Skin Conditions (../500_599/0577.html). Aetna considers tanning beds for home UVB phototherapy not medically necessary. Unlike tanning beds, home UVB devices are designed solely for the medical treatment of skin diseases and emit a different wavelength of ultraviolet light than tanning beds. Note: In addition, tanning beds do not meet Aetna's definition of covered durable medical equipment in that they are of use in the absence of illness or injury. See also CPB 0656 Photodynamic Therapy for Acne (../600_699/0656.html). Background Psoralens and ultraviolet A light (PUVA) therapy is contraindicated in any of the following conditions: (i) history of arsenic exposure; or (ii) history of ionizing radiation exposure; or (iii) history or presence of melanoma or other skin cancer; or (iv) pregnancy. The National Institute for Health and Clinical Excellence's procedure guidance on "Photochemical corneal collagen cross linkage using riboflavin and ultraviolet A for keratoconus" (NICE, 2009) concluded that "[c]urrent evidence on the safety and efficacy of photochemical corneal collagen cross linkage using riboflavin and ultraviolet A (UVA) for keratoconus is inadequate in quantity and quality. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research". Khan and colleagues (2011) presented the first 3 cases of Acanthamoeba keratitis (AK), unresponsive to medical treatment, that were successfully treated with a novel adjunctive therapy using UVA and riboflavin (B2). Two patients with confirmed AK and 1 patient with presumptive AK, which were all refractive to multi drug conventional therapy were included in this study. Two treatment sessions involving topical

6 6 of 49 application of 0.1 % B2 solution to the ocular surface combined with 30 mins of UVA irradiation focused on the corneal ulcer were carried out. Main outcome measures were clinical examination by slit lamp, confocal microscopy, and histopathology, when available. All patients in these series showed a rapid reduction in their symptoms and decreased ulcer size after the first treatment session. The progress of the clinical improvement began to slow after 1 to 3 weeks of the first application and was then renewed after the second application. All ancillary signs of inflammation mostly resolved after the second treatment session. The ulcers in all patients continued to decrease and were closed within 3 to 7 weeks of the first application. Two patients developed dense central corneal scars, and penetrating keratoplasty was performed for visual rehabilitation. Histopathological examination of the excised tissue revealed no Acanthamoeba organisms. The remaining patient had no symptoms or signs of infection, both clinically and by confocal microscopy, and was left with a semitransparent eccentric scar that did not affect visual acuity. The authors concluded that adjunctive use of UVA and B2 therapy seems to be a possible alternative for selected cases of medication resistant AK. Moreover, they noted that further research is needed and currently underway to examine how best to use photochemical therapy for the treatment of infectious keratitis. Lowe (1992) stated that home UV phototherapy is extremely popular with many psoriasis patients. However, it is essential that they understand the need for regular skin examination by the dermatologist. Patients with psoriasis are not trained nor are many non dermatologist physicians to recognize the early features of many skin cancers, and continued home UV therapy in the presence of such skin cancers is clearly unwise for the safety of that patient. The use of UVA tanning salon treatments in the therapy of psoriasis is usually unsuccessful and is extremely unwise with concomitant psoralen and drug therapy. This is to be discouraged, and the patient should always be treated with PUVA in the dermatologist's office with carefully monitored UVA machines and staff trained in the administration

7 7 of 49 of PUVA phototherapy. In an open label, randomized controlled trial, van Coevorden et al (2004) examined if oral PUVA with a portable tanning unit at home is as effective as hospital administered bath PUVA in patients with chronic hand eczema. A total of 158 patients with moderate to severe chronic hand eczema (more than 1 year in duration) were included in this study. The primary outcome was clinical assessment by a hand eczema score (evaluation of desquamation, erythema, vesiculation, infiltration, fissures, itch, and pain, each on a 4 point scale) after 10 weeks of treatment. The secondary outcome was hand eczema score at 8 weeks of follow up, after completion of treatment. The tertiary outcome was travel cost and time off work. Both groups showed a comparable and substantial decrease in hand eczema score (meaningful clinical improvement). This decrease was maintained during the follow up period. Patients treated with oral PUVA at home had lower travel costs and less time off work. The authors concluded that oral PUVA at home has a clinically relevant efficacy, similar to that of hospitaladministered bath PUVA. This effect was maintained during an 8 week follow up period. It resulted in lower travel costs and less time off work. These promising results need to be validated by more research. Dermatographic urticaria (also known as dermographism and dermatographism) is a skin disorder observed in 4 to 5 % of the population and is one of the most common types of urticaria, in which the skin becomes raised and inflamed when stroked, scratched, rubbed, and sometimes even slapped. Dermatographic urticaria can be treated by anti histamines, which may need to be given as a combination of H1 antagonists, or possibly with an H2 receptor antagonist such as cimetidine. Therapies may also include immunosuppressive agents and steroids. There is a lack of evidence regarding the clinical value of narrow band UVB phototherapy in the treatment of this condition. Kreutz et al (2012) noted that depletion of host Langerhans

8 8 of 49 cells (LCs) prevents cutaneous graft versus host disease (GVHD) in mice. These researchers analyzed whether UVB irradiation is tolerated during the course of human allogeneic hematopoietic cell transplantation and whether depletion of LCs by broadband UVB could improve GvHD outcome. A total of 17 patients received 6 whole body UVB irradiations with 75 % of the individually determined minimal erythemal dose after conditioning with a reduced intensity protocol. Langerhans cells, dermal dendritic cells (DCs), and macrophages were analyzed before and after UVB irradiation by immunohistochemical analysis. Circulating blood cells and serum factors were analyzed in parallel. In striking contrast to previous data, this irradiation protocol was well tolerated in all patients. Treatment with UVB decreased the number of LCs and also affected dermal DCs. Patients treated with UVB also had significantly higher 25 hydroxyvitamin D3 serum levels and higher numbers of circulating CD4+ FoxP3+ regulatory T cells. Strikingly, 9 out of 9 patients with complete LC depletion (less than 1 LC per field) developed only grade I GVHD or no GVHD up to day 100. The authors concluded that these results strongly suggest that prophylactic UVB irradiation posttransplant is safe and should be further explored as a clinical strategy to prevent acute (skin) GVHD. Duarte et al (2010) noted that progressive macular hypomelanosis (PMH) is a common dermatosis; its cause is unknown and proposed treatments have had little effect. These researchers examined epidemiological aspects of PMH in patients referred to a phototherapy clinic between 1997 and 2008 and evaluated therapeutic response to PUVA (psoralen + UVA) photochemotherapy or narrow band ultraviolet B (NB UVB) phototherapy. A total of 84 patients with PMH were evaluated. After 16 phototherapy sessions, therapeutic response was classified as: unchanged, slightly improved (less than 50 % of re pigmentation), moderately improved (50 to 79 % of re pigmentation), much improved (80 to 99 %) or cured (100 %). After a minimum of 3 months, patients whose response was classified as cured or much improved were contacted by telephone to evaluate the persistence of the

9 9 of 49 therapeutic response. Most of the patients were women (79 %) and white (85 %). Age at onset of PMH ranged from 13 to 36 years. PUVA was prescribed for 27 patients and NB UVB phototherapy for 57. No significant difference was found between the outcomes obtained with PUVA and those obtained with NB UVB phototherapy (Fisher's exact test; p < 0.05). The majority of patients (81 %) had 50 % or more re pigmentation, with 65 % being classified as cured or much improved. Nevertheless, there was a recurrence of the lesions in 72 % of patients. The authors concluded that the fact that no patients were over 40 years of age suggested that PMH is a self limiting disease. Both PUVA and NB UVB are effective therapeutic options; however, they do not prevent recurrence of the disease. The main drawback of this study was its uncontrolled nature and small sample size. Montero et al (2011) stated that PMH is an acquired disorder of skin pigmentation, which is mostly under diagnosed. It is characterized by nummular hypo pigmented lesions appearing on the trunk in young persons. Several treatment options are available, although topical clindamycin and benzoyl peroxide have been used traditionally. However, good results have recently been achieved using NB UVB phototherapy. These researchers presented the case of a 13 year old girl with hypopigmented lesions on the trunk and limbs that had progressed over 1 year and that were diagnosed as PMH. The patient was initially treated with topical clindamycin and benzoyl peroxide. However, little improvement was seen and treatment was then started with NB UVB phototherapy. After 25 sessions, with a total cumulative dose of 18 J/cm(2), the patient showed almost total re pigmentation of the lesions. The treatment of PMH is often difficult, and very little is currently known about the treatment response in this disorder, as most reports have very small series of patients with a short disease progression time. The authors concluded that NB UVB phototherapy has been shown to be effective, as seen in this patient, although in many cases, there is recurrence after the cessation of treatment. Kim et al (2012) examined the clinical features of PMH in

10 10 of 49 Koreans and determined the therapeutic efficacy of NB UVB therapy in the management of PMH. These investigators performed an uncontrolled prospective study designed to evaluate the usefulness of NB UVB therapy in PMH. A total of 23 patients with PMH were enrolled in the study. Of these, 17 patients underwent treatment with NB UVB therapy once or twice weekly and were eligible for analysis. The remaining 6 patients were lost to follow up before completion of the treatment. Re pigmentation was evaluated by 2 dermatologists using photographic documentation. Narrow band UVB therapy was used successfully in 9 of 16 patients (56.2 %), who showed more than 90 % re pigmentation. They found that 13 of 16 patients (81.3 %) experienced at least 50 % re pigmentation. The re pigmented sites showed an excellent color match. No signs of recurrence have been detected in 11 of these 16 patients (68.7 %) up to the present time (13.2 +/ 8.2 months of follow up). The authors concluded that the findings of this study suggested that NB UVB therapy is an effective and safe method for use in the treatment of PMH. Drawbacks of this study included a small number of subjects examined, and it was an uncontrolled and non double blind study. Berg et al (1994) carried out a study in 22 patients with polymorphous light eruption (PMLE) who were prophylactically treated with UVA with and without trimethylpsoralen; 12 of the patients were treated during 2 consecutive springs with placebo during one spring and psoralens during the other. Eighteen of the patients improved after the therapy, but there was no clear cut difference between the 2 regimens. As many as 12 patients got light eruptions during the treatment, but all but 1 continued with the therapy. The authors concluded that the findings of this study indicated that UVA alone is as good prophylactic therapy for PMLE as PUVA with trimethylpsoralen. However, because of the high incidence of provoked eruptions during therapy, the treatment may be difficult to handle for the patients themselves, at least during the initial treatment. Fesq and colleagues (2003) stated that management of PLE should focus on basic preventative measures and additional

11 11 of 49 therapeutic approaches, depending on the clinical condition. Polymorphous light eruption can be classified into 4 severity groups: (i) mild, (ii) moderate to severe, (iii) severe, and (iv) therapy resistant. These classifications are useful for determining appropriate prophylactic measurements. No specific laboratory tests were available for the diagnosis of PLE, therefore, a clinician must rely on the clinical appearance of the disorder (e.g., clinical symptoms, the location of the lesions, the relationship of the occurrence of the lesions with sun exposure and the time course of the lesions) as well as a patient's medical history in order to make a diagnosis. Basic preventative management of PLE consists of adequate sun protection comprising avoidance of sun exposure, the use of textile sun protection and the application of broadband sunscreens with high UVA protection potential. Other supportive measurements have to be managed individually and are dependent on the patient's medical history and the severity of the disease. Topical anti oxidants, systemic immunomodulation, photo(chemo)therapy and systemic immunosuppression may be required in some cases of PLE. Topical anti oxidants represent a new treatment approach for moderate to severe PLE and are an effective and well tolerated option for this patient population. Severe PLE also requires photo(chemo)therapy. Phototherapy can be in the form of 311 nm UVB or UVA1 irradiation. In cases where 311 nm UVB or UVA1 are ineffective, psoralen plus UVA (PUVA) bath therapy may be used. However, PUVA bath therapy must be used with caution because it is associated with acute and long term adverse effects. In rare exceptions we would consider using oral PUVA therapy. However, in our outpatient department, quality of life of most patients is improved with the treatment regimens that are recommended for patients with moderate tosevere PLE, without the need for photo(chemo)therapy. An UpToDate review on Polymorphous light eruption (Elmets, 2013) states that that PUVA plus psoralens is considered second line therapy for PMLE. First line therapies Includes the following:

12 12 of 49 Sun protection Sun protection is first line therapy for patients with PMLE and includes sun avoidance, sun protective clothing, and sunscreens. Sunscreens should be broad spectrum, with both UVA and UVB protection. A sunscreen with an SPF (sun protection factor) of at least 30 should be regularly applied. Products containing photostabilized avobenzone or ecamsule (Mexoryl SX) offer improved protection against UVA, and have been effective in preventing PMLE eruptions. Sunscreens that contain the non micronized form of zinc oxide or titanium dioxide also offer photoprotection that extends throughout the UV and into the visible spectrum. Examples of broad spectrum sunscreens containing photostabilized avobenzone or ecamsule, or zinc oxide and titanium oxide are provided. Topical corticosteroids No randomized trials have evaluated the efficacy of topical corticosteroids for PMLE. Clinical experience suggests that potent topical corticosteroids (groups one to three) may be used for symptomatic relief, and may be sufficient pharmacologic therapy for mild cases. Facial lesions should be treated with lower potency topical corticosteroids (groups six to seven). Second line therapies include the following: Phototherapy Prophylactic phototherapy with low dose PUVA (psoralens plus UVA) or UVB in early spring to induce tolerance to sun exposure may be an option for patients who are expected to develop significant symptoms during the spring or summer. Treatments are usually given 2 to 3 times per week over 5 to 6 weeks. PUVA therapy is superior to broadband UVB. In one randomized trial, treatment was successful in 92 % of patients treated with PUVA, compared with 62 % of patients treated with broadband UVB. In contrast, a small randomized trial showed narrowband UVB to be as effective as PUVA. Because narrowband UVB is easier to administer, it is often preferred to PUVA therapy for patients with PMLE. Narrowband UVB phototherapy can be administered 3 times per week, starting with a dose equivalent to 50 to 70

13 13 of 49 % of the MED. The dose is increased during subsequent treatments as tolerated by the patient. Treatment induced exacerbations may occur early in the course of phototherapy. If these occur, potent topical corticosteroids (groups one to three) or a short course of oral glucocorticoid therapy (e.g., prednisone 1 mg per kg for 7 to 10 days) may be required Samson et al (2003) reviewed the evidence regarding NB UVB for the treatment for vitiligo, pruritus, and inflammatory dermatoses. This was a retrospective review of the treatment outcomes of 117 consecutive patients with vitiligo, pruritus, and other inflammatory dermatoses, excluding those with psoriasis and cutaneous T cell lymphoma (CTCL), who were treated with NB UVB between 1998 and 2001 at the authors institution. Approximately 80 % of all patients showed improvement in their condition. Narrow band UVB phototherapy was well tolerated, with no serious adverse effects. In patients with vitiligo, 6.4 % had an abnormal thyroidstimulating hormone level and 6.5 % had anemia. The authors concluded that NB UVB may be considered as a viable therapeutic option in the treatment of vitiligo, pruritus, and other inflammatory dermatoses. Moreover, they stated that long term adverse effects and cost benefit analysis of NB UVB therapy compared to other treatment modalities remain to be determined. Gambichler et al (2005) provided an update on clinical experiences in NB UVB of non psoriatic skin conditions, and established its current position within the spectrum of competing photo(chemo)therapeutic options. The computerized bibliographic database PubMed, without time limits, and other sources were screened for clinical trials on NB UVB. Included were research articles of randomized controlled trials (RCTs), open prospective studies, and retrospective observations on NB UVB in skin disorders other than psoriasis. A total of 28 articles met eligibility criteria including 6 RCTs, 16 open prospective studies, and 6 retrospective observations.

14 14 of 49 Narrow band UVB is effective in patients with chronic atopic dermatitis (AD) (n = 719) and generalized vitiligo (n = 305) and appears to have some advantages over competing photo(chemo)therapeutic regimens. Narrow band UVB also seems to be effective in patients with PMLE (n = 25), early stages of CTCL (n = 108), chronic urticaria (n = 88), lichen planus (n = 15), pruritus associated with polycythemia vera (n = 10), seborrheic dermatitis (n = 18), actinic prurigo (n = 6), and acquired perforating dermatosis (n = 5). The quality of evidence determined for the afore mentioned diagnoses ranged from high to moderate to very low. The authors concluded that the best currently available data on NB UVB in non psoriatic conditions exist for AD and generalized vitiligo. In view of its efficacy, benefit/risk profile, and costs, NB UVB may be considered the first line photo(chemo)therapeutic option for moderately severe AD and widespread vitiligo. In the treatment of most other non psoriatic conditions, NB UVB appears to be effective, but current data allow no definitive conclusions as to whether NB UVB should be preferred to competing photo(chemo)therapeutic options such as PUVA regimens. Because NB UVB may have a wider indication spectrum, including AD, vitiligo, and early stage CTCL, and appears to be equally effective or even more effective than broad band UVB (BB UVB), a switch from BB UVB to NB UVB seems to be justified. This study had a small number of patients with PMLE (n = 25) Pugashetti and colleagues (2010) noted that BB UVB phototherapy has demonstrated effectiveness in the treatment of cutaneous disorders including psoriasis, AD, uremic pruritus and idiopathic pruritus. In the last decade, there has been a rapidly escalating process of replacing BB UVB phototherapy units with NB UVB equipment, as studies have demonstrated that NB UVB (ranging from 311 mm to 312 nm) is more effective in the treatment of psoriasis. Nevertheless, it is important to recognize the efficacy of BB UVB phototherapy in the treatment of uremic pruritus, idiopathic pruritus, eosinophilic folliculitis and other inflammatory pruritic conditions. Furthermore, as high lighted in this report, there

15 15 of 49 was a small but significant proportion of psoriasis and AD patients who do not tolerate NB UVB but demonstrated an excellent clinical response to BB UVB. It is critical for dermatologists to recognize the role of BB UVB as a complement to NB UVB phototherapy for patients who cannot tolerate or experience an inadequate therapeutic response from NB UVB. This study did not mention PMLE as an indication of BB UVB or NB UVB. Walker and Jacobe (2011) stated that dermatologists are presented with a diversity of therapeutic modalities for the treatment of inflammatory, sclerosing, and neoplastic conditions, but with the development of various new irradiation devices that utilize specific parts of the electromagnetic spectrum, phototherapy has become a more viable, accessible, and effective option in the treatment of these conditions. The UV range (10 to 400 nm) is further sub divided into UVA and UVB, each of which has been particularly useful in a number of skin conditions. The most commonly used forms of UV irradiation are UVA1, PUVA, and NB UVB. Each of these modalities differ in their mechanism of action, indications, and side effect profiles, and it is important that clinicians be familiar with these differences. Today, phototherapy is a valuable option in the treatment of many non psoriatic conditions including AD, sclerosing skin conditions such as morphea, vitiligo, and mycosis fungoides. Due to its relative safety, phototherapy may be used in most populations, including children and pregnant women. However, contraindications and side effects are known and should be considered before patients begin a phototherapeutic regimen. Again, this study did not mention PMLE as an indication of BB UVB or NB UVB. Veith et al (2011) noted that phototherapy is used for the medical care of cutaneous conditions that do not respond to topical or systemic medical agents, and for conditions that require broad exposure to UV as a stabilizing agent for disease. Numerous wavelengths and delivery devices of UV light are used in childhood. This article was a brief overview of the medical usage of phototherapy in childhood. In the neonatal

16 16 of 49 nursery blue light (459 to 460 nm) is used to reduce bilirubin levels and prevent kernicterus. While PUVA has been demonstrated to be effective in a variety of pediatric skin conditions, NB UVB therapy (311 nm) has largely replaced PUVA as initial choice in full body phototherapy for children. The latter is easier to deliver, with less resultant erythema than systemic PUVA, which requires strict use of 24 hour protective eyewear. Narrowband UVB is therefore preferred for stabilization and clearance of a variety of inflammatory and autoimmune conditions especially AD, psoriasis and vitiligo. Conditions with lymphocytic infiltration, including mycosis fungoides, alopecia areata and pityriasis lichenoides can improve with NB UVB as well. Alternatively, localized delivery of NB UVB can be performed using the Excimer laser (308 nm), which has been described for the therapy of vitiligo and alopecia areata in childhood. Some diseases with dermal infiltration including morphea and mastocytosis may do better with PUVA or UVA1. Delivery of psoralens can also be performed topically for said conditions and in the setting of alopecia areata, thereby limiting UVA exposure, while retaining efficacy. Phototherapy can be a helpful adjunct in pediatric skin disease, but is limited by compliance issues. Parents can act as partners in the safe and effective delivery of phototherapy by standing outside the booth or inside with the child to ensure lack of movement and to aid in maintenance of eyewear. Choice of type of phototherapy and close monitoring, with parental partnership, is the key to successful treatment. Again, this study did not mention PMLE as an indication of BB UVB or NB UVB. Also, an UpToDate review on Polymorphous light eruption (Elmets, 2013) does not mention the use of photochemotherapy/goeckerman treatment as therapeutic options. The review provides several Summary and Recommendations : UVA is the most common inciting spectrum of light, but UVB and visible light may also provoke PMLE in some patients Primary treatment for PMLE includes sun avoidance, sun

17 17 of 49 protective clothing, and sunscreen. Broad spectrum sunscreens with an SPF of at least 30 should be regularly used For patients with active lesions, we suggest treatment with potent topical corticosteroids (groups one to three). An alternative in patients with infrequent exacerbations, particularly those who require rapid improvement, is a short course of systemic glucocorticoids For patients who develop frequent exacerbations during the spring and summer, we suggest prophylactic phototherapy in early spring Juvenile spring eruption is a variant of PMLE that is manifested by erythematous papules or bullae typically on ears of children or adolescents after sun exposure. Symptoms are self limited and resolve within several weeks Note: Regarding UVB in the treatment of prurigo nodularis, Ferrandiz et al (1997) reported that an excellent response was obtained after an average of 32 UVB courses. Note: Delrosso et al (2008) reported that an aggressive bath PUVA treatment is not substantially more effective in clearing chronic plaque type psoriasis than a milder therapeutic approach. Tan et al (2010) reviewed the efficacy and tolerability of NB UVB phototherapy in children at a tertiary center in New Zealand, and determined if there were any factors that differentiated responders from non responders. These researchers performed a prospective analysis of children (less than 16 years old) who had undergone phototherapy over a 15 year period. A total of 116 children received phototherapy with a total of 144 courses. Mean age was 11.0 years with the majority being European and having skin phototype II. Atopic dermatitis was the most common indication for treatment followed by psoriasis, pityriasis lichenoides, nodular prurigo, morphea, vitiligo, urticaria pigmentosa and erythropoietic porphyria. Treatment was effective in the majority of children (72 %). Most received only 1 course. For responders, the mean

18 18 of 49 number of treatments was The mean dose per treatment to achieve clearance was 886 mj/cm(2) and the mean maximum treatment dose per treatment was 1,328 mj/cm(2). All children tolerated treatment well with 36 % developing brief, minimally symptomatic, erythema. Only 2 children experienced exacerbations of their underlying dermatoses. The authors concluded that the findings of this study showed that phototherapy is an effective and well tolerated treatment modality in children. Weibel (2012) stated that localized scleroderma or morphea is a sclerosing connective tissue disease of the skin, which may affect underlying tissues such as subcutis, muscle and bone. Many patients show extra cutaneous symptoms and antinuclear antibodies, however, secondary transformation into systemic sclerosis does not occur. Localized scleroderma usually begins in childhood with a wide variation in its clinical spectrum. The linear variant is the most common subtype in children, associated with a progressive course and increased risk of complications. The disease may progress over years and result in severe functional and cosmetic disability. The etiology of localized scleroderma remains unknown. A genetic background is suspected, while triggers such as trauma, vaccinations and infections may lead to secondary immunologic phenomena. Localized scleroderma often remains unrecognized for a long time, resulting in substantial delay in treatment. The combination of systemic corticosteroids and methotrexate has been established as first line therapy for progressive (usually linear) disease, whereas phototherapy (UVA 1 or NB UVB) is suitable for adolescents with superficial circumscribed subtypes. Newland and Marshman (2012) stated that post irradiation morphea is a rare but under recognized complication of radiotherapy treatment for breast cancer. Management of this condition is difficult, and many cases are recalcitrant to therapy. A 43 year old woman with breast cancer received radiotherapy following a mastectomy and partial axillary lymph node dissection, shortly after which she developed a hot,

19 19 of 49 tender, erythematous and indurated plaque at the mastectomy site. Subsequently the skin became retracted, depressed and hyper pigmented. The clinical features, along with histological findings, were consistent with post irradiation morphea. Treatment with NB UVB and acitretin 10 mg daily was commenced 5 years following radiotherapy. After 2 months of therapy the patient reported significant improvement in tenderness and range of left arm movement. Objectively the plaque was less indurated and softer to palpation. The authors proposed that this treatment regimen is an option in the management of post irradiation morphea. Spalek et al (2015) noted that radiation induced morphea (RIM) is a rare and under recognized skin complication of radiotherapy. It is commonly wrongly diagnosed as other dermatological conditions or malignancy because of similar clinical characteristics. This literature review analyzed 66 cases that have been reported in the literature since The clinical appearance often includes pain and disfiguration of affected area, which may influence the patient's quality of life. There is no clear connection between the radiotherapy dose, the fractionation scheme, the use of a boost, age, the presence of other dermatological conditions or other connective tissue diseases and the occurrence of RIM. Its pathogenesis is still unclear, but several theories are proposed to explain this phenomenon. The available data suggested that the abnormally high secretion of some cytokines (interleukin 4, interleukin 5, transforming growth factor) induced by radiation causes an extensive fibrosis after an activation of fibroblasts. Histological confirmation is crucial in distinguishing RIM from similar looking diseases, such as chronic radiation dermatitis, cancer recurrence, radiation, recall dermatitis, new carcinoma or cellulitis. There is no clear treatment regimen for this condition. Clinical outcome after therapy is often unsatisfactory. The commonly used methods and agents include: topical and systemic steroids, calcineurin inhibitors, systemic immunosuppressants including methotrexate, tacrolimus, heparin, hyaluronidase, phototherapy (UVA, UVA1, UVB, PUVA), systemic antibiotics, imiquimod, mycophenolate

20 20 of 49 mofetil, photopheresis. The differential diagnosis is challenging and requires a multi disciplinary approach to avoid misdiagnosis and to plan appropriate treatment. Mizuno et al (2014) noted that Hailey Hailey disease (HHD) is a rare autosomal dominant disorder characterized by development of recurrent blisters, erosions, and crustations in the intertriginous areas. The treatment of HHD is often challenging, and various methods have been tried. These investigators reported the case of a 45 year old woman with a generalized form of HHD that was dramatically improved and well controlled by NB UVB phototherapy. This preliminary finding needs to be validated by well designed studies. An UpToDate review on Hailey Hailey disease (benign familial pemphigus) (Morrell, 2014) does not mention phototherapy/nb UVB as a therapeutic option. Treister et al (2015) evaluated the safety and effectiveness of intra oral NB UVB phototherapy in the management of oral chronic GVHD (cgvhd). Patients with oral cgvhd were treated using a custom NB UVB unit for a course of 24 phototherapy sessions. Treatments were initiated at 50 mj/cm2 and increased by 10 % at each visit unless toxicity was noted. Toxicity and response were assessed weekly. A total of 11 patients received a median of 22 (range of 4 to 39) NB UVB treatments; 5 patients completed 24 treatments and elected to receive a median of 7 additional treatments. Median symptom scores (0 to 10) for sensitivity, pain, and dryness at baseline/end of therapy were 7.5, 3, 1, and 3, 1, 2, respectively. Taking into account all patient reported outcomes, 7/11 patients had improvement and 2/11 worsened. At least partial improvement was reported in 8/11 patients with none reporting worsening. Over treatment occurred in 10/11 patients with all graded mild or moderate and resolving in 1 to 2 days. The authors concluded that intra oral NB UVB may be effective for management of refractory oral cgvhd. They stated that further optimization of treatment parameters, as well as minimal erythema dose testing, and inclusion of a

21 21 of 49 control arm are needed in the consideration of future studies. UVB for the Treatment of Photodermatoses: Collins and Ferguson (1995) reported that 20 patients with photodermatoses [actinic prurigo (n = 6), hydroa vacciniforme (n = 4), idiopathic solar urticaria (n = 1), amiodarone induced photosensitivity (n = 1) and a range of cutaneous porphyrias (n = 8)] were treated with a hardening course of narrow band ultraviolet (UV) B (TL 01) phototherapy in springtime. The response to phototherapy was monitored subjectively, by interviewing patients after the summer, and objectively by monochromator photo testing, before and after phototherapy. Fifteen patients reported that treatment was worthwhile. Monochromator photo testing after phototherapy revealed a 4 fold increase in the minimal erythema dose (MED) in those with abnormal photosensitivity to ultraviolet A wavebands. Adverse effects included erythema (n = 7), pruritus (n = 5) and provocation of the eruption (n = 4). The authors concluded that they now routinely consider narrow band UVB phototherapy for problem photodermatoses. Gupta et al (2000) stated that hydroa vacciniforme (HV) is a rare, sporadic, idiopathic photodermatosis characterized by vesicles and crust formation after sunlight exposure. The lesions typically heal with vacciniform scarring. These researchers identified and reviewed the clinical features and follow up data of Scottish patients with HV and reported on the prevalence of this condition. They noted that this was the largest recent study of HV patients from a single center. In this retrospective study, patients with HV were identified by means of the diagnostic database from the Photobiology Unit, Dundee. Patients were contacted and details of clinical features, duration of disease, results of investigations, and treatment were recorded. At review, disease progress was assessed. Between 1973 and 1997, a total of 17 patients (9 males and 8 females) with a diagnosis of HV were investigated. Data from 15 patients showed a mean age at onset of 7.9 years (range of 1 to 16 years), with females (mean of 6.7 years; range

22 22 of 49 of 2 to 12 years) having an earlier onset than males (mean of 8.7 years; range of 1 to 16 years). A bi modal age distribution was also identified with onsets between the ages of 1 and 7 years and 12 and 16 years. At review, spontaneous clearing had occurred in 9 patients (60 %) with mean duration of disease being 9 years (range of 4 to 17 years). Males had longer disease duration (mean of 11 years; range of 5 to 17 years) than females (mean of 5 years; range of 4 to 7 years). Eight patients (53 %) were sensitive in the UVA wave band on monochromator photo testing, and 6 (40 %) experienced papulo vesicular lesions on repetitive broad spectrum UVA irradiation. All patients received broad spectrum sunscreens with variable results. Of the 5 patients treated with narrow band UVB (TL 01) phototherapy, 3 reported beneficial results with an increase in tolerance to sunlight exposure and associated reduction in disease severity. The authors concluded that the estimated prevalence of HV was at least 0.34 cases per 100,000 with an approximately equal sex ratio. Males had a later onset and longer duration of disease than females. Photo testing showed abnormal responses in the UVA wavebands in 53 % of cases, whereas 60 % of patients treated with prophylactic TL 01 phototherapy found it beneficial. Dummer et al (2003) stated that polymorphous light eruption (PLE), a type of idiopathic photodermatoses, is an eruption induced by ultraviolet (UV) radiation (UVR). These researchers evaluated the clinical aspects, diagnostic criteria of PLE in a major Swiss referral center. A total of 25 patients (22 women and 3 men) with PLE were tested with a standardized protocol for the assessment of photodermatoses. Papular and papularvesicular eruptions were the most common clinical presentations; 6 of 25 patients had a reduced MED for UVA and 8 of 25 patients had a reduced MED for UVB. Photoprovocation was positive in 11 of 20 patients for UVA and 7 of 20 patients for UVB. Photo hardening with narrow band UVB was successful in 8 of 10 patients. Combined UVA/UVB therapy had a satisfactory effect in 10 of 15 patients. Narrow band UVB therapy was still successful after ineffective UVA/UVB therapy. The authors concluded that MED was of no value for the

23 23 of 49 diagnosis of PLE. The typical lesions were reproduced by UVA and UVB photo provocation. These investigators recommended photo hardening with narrow band UVB (311 nm). Fesq et al (2003) stated that optimal management of patients with PLE, the most frequent photodermatosis, requires knowledge of the individual clinical course of the disease and pathogenic factors. As PLE often causes problems during leisure time activities and holidays, resulting in a substantial loss of quality of life, prophylaxis is the most important therapeutic approach. Management of PLE must, therefore, focus on basic preventative measures and additional therapeutic approaches, depending on the clinical condition. PLE can be classified into 4 severity groups (mild, moderate tosevere, severe and therapy resistant), which are useful for determining appropriate prophylactic measurements. No specific laboratory tests are available for the diagnosis of PLE, therefore, a clinician must rely on the clinical appearance of the disorder (e.g., clinical symptoms, the location of the lesions, the relationship of the occurrence of the lesions with sun exposure and the time course of the lesions) as well as a patient's medical history in order to make a diagnosis. Basic preventative management of PLE consists of adequate sun protection comprising avoidance of sun exposure, the use of textile sun protection and the application of broad band sunscreens with high UVA protection potential. Other supportive measurements have to be managed individually and are dependent on the patient's medical history and the severity of the disease. Topical antioxidants, systemic immunomodulation, photo(chemo)therapy and systemic immunosuppression may be required in some cases of PLE. Topical antioxidants represent a new treatment approach for moderate to severe PLE and are an effective and well tolerated option for this patient population. Severe PLE also requires photo(chemo)therapy. Phototherapy can be in the form of 311 nm UVB (narrow band UVB) or UVA1 irradiation. In cases where 311 nm UVB or UVA1 are ineffective, psoralen plus UVA (PUVA) bath therapy may be used. However, PUVA bath therapy must be used with caution because it is associated with

24 24 of 49 acute and long term adverse effects. In rare exceptions the authors would consider using oral PUVA therapy. However, in their outpatient department, quality of life of most patients is improved with the treatment regimens that are recommended for patients with moderate to severe PLE, without the need for photo(chemo)therapy. Khaled et al (2011) stated that chronic actinic dermatitis (CAD) is a debilitating photodermatosis with characteristic clinical, histological and photo biological features (reduced MED). Its management involves various therapeutic approaches, among them there is phototherapy. Efficacy of psoralen ultraviolet therapy (PUVA therapy) was previously demonstrated but there are no current data on the use of narrowband UVB therapy (NB UVB) in CAD. NB UVB has already been proven to be effective and safe in several other photodermatoses. These researchers reported the findings of 2 dark skinned patients (skin type IV and V) with CAD, successfully treated with an incremental regimen of NB UVB phototherapy coupled to a 3 month course of systemic steroids (1 mg/kg/day). The authors concluded that their protocol of NB UVB with steroids appeared to be effective for the management of CAD with a good short term safety profile. An UpToDate review on Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment (Elmets, 2015) states that Actinic prurigo Phototherapy with narrowband UVB or psoralen plus ultraviolet A (PUVA) is a therapeutic option in patients with persistent symptoms. Chronic actinic dermatitis Low dose PUVA or narrowband UVB, initially given with oral glucocorticoids to decrease treatment induced flares, has been effective in small case series. Solar urticaria Pharmacologic therapy or photodesensitization with low dose PUVA or narrowband UVB initially given with oral glucocorticoids is usually required for management.. PUVA for Eosinophilic Cellulitis (Wells Syndrome):

25 25 of 49 Raßler et al (2016) noted that eosinophilic cellulitis (Wells syndrome) is a rare inflammatory skin disease defined by erythematous, tender, sometimes urticarial plaques, possibly with vesicles and bullae, and granulomatous eosinophilic infiltrates in the dermis. Usually the disease has a benign course with spontaneous remission within a few weeks. Nevertheless, recurrences are quite frequent and may occur for several years. These investigators reviewed the therapeutic options for Wells syndrome in a systematic manner, which was based on a search on Medline, Embase and Cochrane Central Register for English and German articles from 1970 to Advices on the treatment of Wells syndrome were limited predominately to case reports or to small case series studies. There were no RCTs, and control groups were missing. A variety of therapeutic options for Wells syndrome were reported including anti histamines, anti malarial medications, azathioprine, colchicine, cyclosporine, dapsone, doxycycline, griseofulvin, interferon alpha and gamma, minocycline, oral tacrolimus/topical tacrolimus, PUVA therapy, sulfasalazine, tumor necrosis factor (TNF) alpha inhibitors, as well as topical and systemic corticosteroids. As well designed RCTs are missing, no guidelines for the treatment of this disease can be given. The authors noted that due to the small number of patients and the frequent misdiagnosis of this clinical entity, the aim of this systematic overview was to call attention to this rare condition and to help clinicians to diagnose and treat Wells syndrome effectively. The authors concluded that due to the good prognosis and tendency to resolve, systemic treatment should be limited to cases resistant to local therapy or with widespread lesions. PUVA for Necrobiotic Xanthogranuloma: Miguel and colleagues (2017) stated that necrobiotic xanthogranuloma (NXG) is an uncommon non Langerhans cell histiocytosis involving skin and extracutaneous tissues. The lesions are usually asymptomatic and commonly appear in the peri orbital area. Paraproteinemia is closely associated with NXG and its pathogenesis remains unclear. NXG prognosis is

26 26 of 49 poor with several treatments showing variable results. Treatment of monoclonal gammopathy with alkylating agents does not necessarily influence the activity of the skin disease and vice versa. These researchers summarized all reported treatments of necrobiotic xanthogranuloma of the skin, with or without underlying malignant condition and based on articles from the PubMed database using the query necrobiotic xanthogranuloma treatment, both in English and German, about human subjects and published between 1980 and 2014, documenting adequate treatment for NXG. Mainly individual case reports, small case series and retrospective studies were found. Therapeutic options include azathioprine, chlorambucil, cladribine, cyclophosphamide, extracorporeal photopheresis, fludarabine, high dose intravenous immunoglobulin (IVIG), hydroxychloroquine, infliximab, interferon alpha, laser therapy, melphalan, methotrexate, plasmapheresis, PUVA, radiotherapy, rituximab, surgery, thalidomide, as well as topical and systemic corticosteroids. The authors stated that RCTs and studies on long term outcomes after treatment were not found and are needed to focus on in the future. Phototherapy for Scleredema: An UpToDate chapter on scleredema (Kreuter, 2017) states that, for patients with functionally limiting or symptomatic scleredema that is not expected to resolve spontaneously, initial treatment with phototherapy is suggested. This is a grade 2C recommendation based upon a retrospective study and case reports. The authors stated that, when available, they prefer to use UVA1 phototherapy. Improvement in scleredema has also been reported with PUVA and narrowband UVB phototherapy. Kalfa and associates (2015) noted that scleredema is a rare connective tissue disorder of unknown pathogenesis; and 3 types of scleredema have been described, based on its association with post infection, monoclonal gammopathy and diabetes mellitus. These investigators reported a case of