Phototherapy in Scleroderma.

Systemic and localized scleroderma are difficult to manage diseases with no accepted gold standard of therapy to date. Phototherapeutic modalities for scleroderma show promise. A PubMed search of information on phototherapy for scleroderma was conducted. The information was classified into effects on pathogenesis and clinical outcomes. Studies on photopheresis were excluded. There were no randomized, double-blind, placebo-controlled studies, and only three controlled studies. The vast majority of identified studies evaluated ultraviolet A1 (UVA1) phototherapy. More rigorous studies are needed to evaluate phototherapy in the treatment of scleroderma. Based on the limited studies available, 20-50 J/cm2 of UVA1 therapy 3-4 times a week for 30 treatments is recommended.

Introduction: Background on Morphea/Scleroderma

Scleroderma is a chronic autoimmune disease associated with cutaneous, joint, and internal organ involvement. Cutaneous scleroderma is characterized by enhanced fibroblast activity leading to hypertrophic dermal collagen. There are localized and systemic forms of scleroderma. The localized forms include morphea and linear scleroderma. Localized scleroderma has a better prognosis and does not involve internal organs. There are currently no curative treatments for scleroderma. Current treatments include immunosuppressants; intralesional, topical, and oral steroids; topical vitamin D; and phototherapy. This review serves to provide insight into the use of phototherapy in the management of scleroderma. This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Phototherapy in Dermatology

Phototherapy modalities utilize specific wavelengths of the electromagnetic spectrum to disrupt the dysfunctional and pathologic tissue that has developed in some patients with skin disease. Various phototherapy modalities possess anti-inflammatory effects [1]. The longer the wavelength of phototherapy, the deeper in the dermis it penetrates [2]. Current phototherapeutic modalities being used for dermatoses include broadband ultraviolet B (UVB 290–320 nm), narrowband UVB (311–313 nm), excimer laser (308 nm), ultraviolet A (UVA 320–400 nm), ultraviolet A1 (UVA1 340–400 nm), psoralen and UVA (PUVA), and extracorporeal photochemotherapy.

Mechanism Behind Phototherapeutic Modalities Used in Scleroderma

A common theory behind the mechanism of phototherapy in scleroderma is that light is converted to chemical energy resulting in the increase of reactive oxygen species or singlet oxygen production, which can modulate the expression of cytokines [3, 4]. Ultraviolet radiation includes UVA and UVB therapy, with UVA1 studied the most. UVA1 can have an output categorized as low (10–30 J/cm2), moderate (40–70 J/cm2), or high (up to 130 J/cm2).

UVA1 radiation increases collagenase [also known as the matrix metalloproteinase-1 (MMP-1)] gene, mRNA, and protein expression by fibroblasts [5-9]. In mice models, UVA1 radiation reduces fibroblast proliferation in a dose-dependent fashion [10, 11]. Additionally, UVA1 radiation administered three times a week showed decreased hydroxyproline and collagen levels in a dose-dependent fashion [11]. The quality of the collagen is altered after UVA1 therapy, as collagen appears less dense and smoother compared to before treatment [12]. Decorin (a proteoglycan component of connective tissue) mRNA levels are lower in lesional scleroderma versus non-lesional skin, and decorin levels are increased after UVA1 phototherapy [13]. Transforming growth factor beta (TGF-β) protein levels (TGF-β is profibrotic) are inversely correlated with decorin levels. On the other hand, another study showed that after UVA1 phototherapy, decorin was decreased in the upper to middle dermis, although decorin slightly increased in the papillary dermis [14]. In patients, UVA has been shown to reduce collagen I, collagen III, and TGF-β and increase interferon-γ [9]. UVB radiation increases alpha melanocyte-stimulating hormone (α-MSH) receptor synthesis in keratinocytes and melanocytes [15]. Human fibroblast dermal cultures treated with α-MSH demonstrated an increase in MMP-1 mRNA, indicating that α-MSH may be one of UVB's mediators of anti-fibrosis [16].

The source of the mediators that contribute to the reduction in sclerosis comes mostly from the dermis. Subsequently, certain parts of the dermis may be impacted more than others. An image analyzer showed a greater reduction in collagen fibers in the upper and middle dermis and less reduction in the lower dermis [12]. In 18 patients treated with UVA1, the MMP-1 level was higher in the papillary layers and lower in the reticular layers [17]. The anti-fibrotic effects of phototherapy may not come exclusively from the dermis. Samples taken 18 h after the final UVA1 treatment in a set of patients showed an increase in interstitial collagenase in the upper layer of keratinocytes, melanocytes, and endothelial cells [5].

Evidence supports the regimen of multiple UVA1 therapy sessions a week. The anti-sclerotic effects of a single exposure of UVA1 effects are typically seen to last less than 1 week. In human skin, mRNAs of type I and III procollagen were decreased and MMP-3 was increased after 3 days of a single UVA1 dose [18]. MMP-1 and MMP-3 were upregulated for 3 to 5 days, while procollagen levels were suppressed for at least 7 days [18]. In this small study, anti-fibrotic responses became refractory to multiple UVA1 exposures over the course of 1 week, as repeated exposures weekly showed no reduction in type I procollagen levels [18].

UVA1 therapy can have an immunomodulatory effect on lesional skin. UVA1 can reduce inflammation in the dermis [12]. UVA1 causes apoptosis of T-cells [19]. Patients with morphea exposed to UVA1 with a dose of 30 J/cm2 and a cumulative dose of 900 J/cm2 were found to have an increase in CD34+ dendritic cells [20]. Human beta defensin[s] (HBD), interleukin (IL)-6 and IL-8 are downregulated in patients with localized scleroderma treated with UVA1 phototherapy [6]. On the other hand, another study showed that UVA1 induces MMP-1 through a mechanism involving IL-1 and IL-6 [21].

UVA1 radiation may induce oxidative stress, as evidenced by an increase in UVA1-induced heme oxygenase-1 in fibroblasts [7]. Glutathione was lower in systemic sclerosis (SSc) fibroblasts than control samples, but glutathione was increased and became equivalent between normal and SSc fibroblasts after in vitro irradiation with UVA1 [8]. Thus, the SSc fibroblasts may be more susceptible to phototherapy-induced oxidative stress than normal fibroblasts [8]. Additionally, heme oxygenase-1 may reduce fibrotic conditions via TGF-β [22]. UVA1 may play a role in angiogenesis. In patients exposed to UVA1 phototherapy for 14 weeks, there was an increase in CD34+ cells and an increase in vascular endothelial growth factor (VEGF) [23]. The neuroendocrine system may be involved, as UVA1 therapy decreases dermal expression of neuron-specific enolase, which correlated with softening of skin lesions in patients with SSc with acral lesions [24].

UVB phototherapy results in DNA damage, forming cyclobutane pyrimidine dimers between nucleotides [25]. There is evidence that broadband UVB can induce interstitial collagenase, stromelysin, and IL-6 [26]. There may be an interplay between these enzymes and cytokines [26]. Broadband UVB radiation can induce production of MMP-1 in fibroblasts [27]. When keratinocytes are exposed to UVB, there is an increase in IL-1α and IL-6, which induced MMP-1 [27]. Human keratinocytes cultured in a model system exposed to 300 J/cm2 of broadband UVB produced IL-1α, IL-6, and tumor necrosis factor alpha (TNF-α) [28].

PUVA is another modality that can be used for scleroderma. PUVA can lead to apoptosis of T-cells in the dermis [19]. In patients with SSc treated with PUVA, the majority of patients experienced an increase in circulating TNF-α levels, E-selectin, and vascular cell adhesion molecule (VCAM). In the majority of patients, there was a reduction in VEGF and TGF-β [29]. On the other hand, in patients with morphea treated with PUVA, there was a fall in serum VCAM molecules and an increase in TNF-α in most patients [30]. In a bleomycin-induced scleroderma rat model, PUVA treatment reduced dermal thickness and hydroxyproline content and downregulated expression of type I and III collagen genes [10]. In one patient with SSc, treatment with oral PUVA therapy three times a week for 4 weeks resulted in loosening of collagen, reduction in edema, and decreased CD34+ cells [31]. Bath PUVA treatment has effects on collagen cross-links in human skin samples of scleroderma, reducing hydroxylysylpyridinoline and lysylpyridinoline [32]. UVA1 treatment affected collagen fibrils mostly in the upper reticular dermis [33], whereas PUVA affected collagen fibrils in the upper and middle reticular layers [33]. Additionally, collagen fibrils decreased and new fibrils developed, suggesting UVA1 and PUVA phototherapies’ impact on sclerotic lesions occurs via collagen degradation and new collagen synthesis [33].

Other modalities have also been studied. Photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA) treatment of scleroderma fibroblasts increased MMP-1 and MMP-3, and there was a decrease in collagen type 1 mRNA as early as 6 h after treatment [34]. Keratinocytes exposed to PDT with 5-ALA had an increase in IL-1α and TNF-α [35]. In fibroblasts that were incubated with keratinocytes pre-exposed to PDT with 5-ALA, there was an increase in MMP-1 and MMP-3; Karrer et al. [35] subsequently suggested paracrine signaling between the phototherapy exposed keratinocytes and the fibroblasts. Furthermore, an IL-1 antagonist reversed the induction of MMP-1 and MMP-3 in fibroblasts [35]. Blue light up to 453 nm is toxic to cultured T cells, causing apoptosis, but was nontoxic for other skin cell types [36].

The Use of Phototherapy in Dermatology

Phototherapy is commonly used for many dermatoses, but there is less usage for scleroderma. Of 653 patients using phototherapy in a Brazilian clinic, 11 were there for scleroderma treatment [37]. In a multi-center response from 155 British pediatric physicians, PUVA was the most popular phototherapy modality (38%), followed by narrowband UVB (23%) and UVA1 (16%) for morphea [38]. These same clinicians were also asked what would be the best treatment option overall in their opinion for active morphea: 17% responded phototherapy and about 2/3 of these responses were for UVA1, which was only accessible to 27% of respondents [38]. Phototherapy for adult skin disorders is almost exclusively provided by dermatologists [39]. In a survey of physicians treating juvenile localized scleroderma in the UK, 19 of 28 pediatric dermatologists used UV therapy, whereas 0 of 10 pediatric rheumatologists used UV therapy [40]. A self-reported survey of dermatologists and rheumatologists revealed that 20% of dermatologists (n = 40) and 10.6% of pediatric dermatologist (n = 47) used phototherapy [41].

Clinical Evidence of Phototherapy’s Efficacy

Search Method

A PubMed search was performed with the Boolean search terms ‘scleroderma’ OR ‘morphea’ OR ‘crest’ AND ‘phototherapy.’ The search years yielded were from 1978 to 2016. Clinical articles in a non-English language were excluded.

UVA1

UV therapy for patients with localized scleroderma was introduced as PUVA in 1994 [42]. In 1995, Kerscher et al. [43] reported that low-dose UVA1 phototherapy could be used in linear scleroderma. It is unclear whether there is an association between initial skin disease duration and response to UVA1 therapy. A study of ten patients with sclerodermic lesions determined that there was no correlation between disease duration and clinical response with UVA1 [44].

Table 1 lists the clinical reports of UVA1′s efficacy in scleroderma or morphea. It is important to note that covered sclerotic lesions show less improvement after UVA1 therapy [45]. Ultrasound is an objective measure used to assess skin thickness in several UVA studies. Fourteen patients with localized scleroderma treated with UVA1 were evaluated with a 13-MHz ultrasound, and dermal thickness was increased before therapy and decreased from 3.11 ± 1.54 to 2.26 ± 0.86 [46]. Other studies have also supported a correlation of a decrease in dermal thickness when treating with UVA1 therapy [47].

Table 1

Studies of UVA1, UVB, and PUVA treatment in patients with scleroderma or morphea

Study (clinical trial, case report, etc.)	Patientsa	Disease	Treatment modality	Treatment duration	Cumulative dose (J/cm2)	Duration of phototherapy	Total treatments	Improvement outcome (clinical, radiologic)	Was the patient(s) reported to be on another treatment concurrently?	Author
Randomized, controlled, single-blinded controlled study	9	Systemic sclerosis (acrosclerosis)	UVA1	40 J/cm2 3 times a week	1680	14 weeks	42	Modified Rodnan skin scoring: no improvement seen in control vs. placebo	No	Durand et al. [69]
Randomized, controlled trial	64	Localized scleroderma	UVA1/UVB	Twenty-seven patients received 20 J/cm2 UVA1; 18 patients received 50 J/cm2 UVA1; 19 patients received narrowband UVB. All phototherapy was performed 5 times a week	Low dose 800, medium dose 2000	8 weeks	40	Reduction in clinical scores in all groups. No statistical difference between the UVA groups. There was a statistically significant difference between UVB and medium dose UVA1	No	Kreuter et al. [70]
Controlled study	8	Localized scleroderma	UVA1	48 J/cm2 4 times a week	960	5 weeks	20	At 12 weeks no significant difference between skin elasticity in treated versus control skin. Fast Fourier transform did not show a significant change after 12 weeks. Skin softening was clinically noted after 7 weeks	No	de Rie et al. [71]
Prospective uncontrolled study	18	Systemic sclerosis (acrosclerosis)	UVA1	30 J/cm2 4 times a week for 8 weeks, then 3 times a week for 6 weeks	1500	14 weeks	50	Improvement in clinical score and dermal thickness in 16 patients with softening of the skin and increased finger mobility. Follow-up in 6 months showed stable clinical outcome in most patients	Eight patients were on other systemic medications	Kreuter et al. [17]
Prospective uncontrolled study	14	Localized scleroderma	UVA1	20 and 70 J/cm2 were given 4 times a week for 5 weeks, then 2 times a week for 5 weeks	Low dose 600, medium dose 2100	10 weeks	30	Skin thickness decreased in patients in both groups, but more so in the higher dosage group at a 12-month follow-up	No	Sator et al. [45]
Prospective uncontrolled study	35	Localized scleroderma	UVA1	30 J/cm2 3–5 times a week	900–1350 (mean 1180.29)	10–15 weeks	30–45 (mean 41.14)	The mean follow-up period was 21.63 months. In five patients, a partial relapse was observed. Two of the five patients reported reappearance of new lesions after 12 months. Softening of plaques and improvement in 29 of 35 patients (82.85%). Dermal thickness decreased after therapy in 14 of 35 patients	No	Su et al. [46]
Prospective uncontrolled study	20	Localized scleroderma	UVA1	20 J/cm2 4 times a week for 6 weeks and once a week for another 6 weeks	600	12 weeks	30	More than 80% of the lesions disappeared in 18 patients. Decreased dermal thickness	No	Kerscher et al. [47]
Prospective uncontrolled study	10	Localized scleroderma	UVA1	20 J/cm2 4 times a week	480	6 weeks	24	Lesions started to regress after 15 treatments. More than 80% of lesions regressed after 24 treatments	No	Kerscher et al. [43]
Prospective uncontrolled study	34	Localized scleroderma	UVA1	6 patients were treated with medium dose and 28 were treated with high dose. Both groups treated 3 times a week	5234 ± 3611	Unavailable	Unavailable	Patients reported an improvement of at least 25%	Unknown	Jacobe et al. [48]
Prospective uncontrolled study	17	Localized scleroderma	UVA1	Ten patients with high dose 130 J/cm2. Seven patients with low-dose 20 J/cm2. Patients treated 4 times a week during 5 weeks, then twice a week for 5 weeks	Low dose 600, high dose 3900	10 weeks	30	Softening of skin lesions in all high dose patients, and complete clearance in four of ten patients. Three months after treatment, nine of ten patients have clinical stability. Two of seven patients in the low-dose group reported improvement or had clinical signs of improvement. Skin thickness by ultrasound was reduced in all patients	No	Stege et al. [72]
Prospective uncontrolled study	13	Localized scleroderma	UVA1	Unavailable	750–1250	3–5 weeks	20.8 ± 4.0	Modified Rodnan score improvement. Reduction of skin thickness in 11 patients. Skin elasticity increased in ten patients	No	Andres et al. [73]
Prospective uncontrolled study	7	Morphea	UVA1	30 J/cm2 3 times a week	900	10 weeks	30	Clinical improvement in induration of all patients. One patient reported improved elbow joint mobility. After a 6–9-month follow-up, there was clinical stability	No	Camacho et al. [20]
Prospective uncontrolled study	3	Morphea	UVA1	20 J/cm2 4 times a week for 6 weeks, then once a week for 6 weeks	600	12 weeks	30	Resolution of sclerotic plaques in all patients. No signs of recurrence after 2 year follow-up	No	Gruss et al. [74]
Prospective uncontrolled study	19	Childhood morphea	UVA1	20 J/cm2 4 times a week	800	10 weeks	40	Mean clinical score (skin inspection and palpation every week) improved–relative reduction of 67.1%. The treatment outcome remained stable for at least 1 year in all patients	Topical calcipotriol 0.005% twice a day	Kreuter et al. [64]
Prospective uncontrolled study	47	Morphea	UVA1	Six were treated with medium dose (50–60 J) and 41 were treated with high dose (120 J) UVA1; 3 times a week	5329 ± 4398	Unavailable	Unavailable	Patients reported an improvement of at least 25%	May/may not	Jacobe et al. [48]
Prospective uncontrolled study	30	Morphea	UVA1	3 times a week, 21 cases of morphea were treated with UVA 20 J/cm2 for 20 sessions. Nine cases of morphea received 10 J/cm2	High dose 400, low dose 200	6 + weeks	20	No difference in improvement between the 10 and 20 J/cm2 group. Overall, 18 patients reported softening of the skin lesions. Twelve patients reported moderate improvement, four patients reported good improvement, and two patients reported very good improvement	No	El-Mofty et al. [9]
Prospective uncontrolled study	49/M	Morphea	UVA1	70 J/cm2 5 times a week	1400	4 weeks	Unavailable	Durometer scores improved significantly during first 3 weeks, and borderline significantly the last week. Improvements were maintained at 4-month follow-up	No	Kroft et al. [44]
Prospective uncontrolled study	4	Systemic sclerosis	UVA1	60 J/cm2 5 times a week	510–1740	Unavailable	9–29	Skin elasticity before treatment was improved as assessed by cutometer. The mean thermography and joint passive range of motion both increased after treatment	Unknown	Morita et al. [75]
Prospective uncontrolled study	83	Morphea (63), systemic sclerosis (15)	UVA	5, 10, and 20 J/cm2	100, 200, 400	6 + weeks	20	Clinical improvement. No difference between the groups	No	El-Mofty et al. [51]
Prospective uncontrolled study	12	Morphea	UVA	20 J/cm2 3 times a week	400	6 + weeks	20	90% cure of early lesions, 50% cure of “late” lesions	No	El-Mofty et al. [12]
Prospective uncontrolled study	11	Scleroderma	Oral + topical PUVA, Narrowband UVB	Unavailable	Unavailable	Unavailable	Mean 10	Most lesions had a decreased dermal thickness on ultrasound at 12 weeks	Unknown	Buense et al. [56]
Prospective uncontrolled study	12	Systemic sclerosis	PUVA, bath or oral	Unavailable	Median cumulative exposure 68.25	Unavailable	Median 24	Improvement in 11 patients	No	Usmani et al. [29]
Prospective uncontrolled study	4	Localized scleroderma	PUVA cream	4 times a week. Maximum single dose of 3.5 J/cm2	89.5 (range 67.5–121)	Unavailable	30	Decrease in dermal thickening	No	Grundmann-Kollmann et al. [76]
Prospective uncontrolled study	4	Systemic sclerosis	PUVA oral	3 times a week for 10 weeks	Mean of 70.5 (range 50.5–92.0)	10 weeks	30	Improvement of skin, joint mobility, grip strength, and skin thickness in three of four patients	No	Hofer and Soyer [77]
Prospective uncontrolled study	17	Localized scleroderma	PUVA bath	0.2–0.5 J/cm2 up to 1.2–3.5 J/cm2 per treatment. First 20 treatments 4 times a week, twice a week for the following ten treatments, and once a week for the last four treatments	Mean UVA dose of 41.5 (range 15.7–64.3)	15 weeks	25–35	Clinical and ultrasound improvement noted in 13 patients. In most patients, softening of sclerotic lesions was noted at the 15th treatment. Patients were followed up regularly for more than a year; there were two cases of recurrence	No	Kerscher et al. [54]
Prospective uncontrolled study	5	Localized scleroderma	3% ALA + PDT (10 J/cm2)	Once or twice weekly	Unavailable	3–6 months	25–43	A reduction of skin hardness and pruritus in lesions. In two patients, joint mobility was improved. One control plaque was untreated, and showed no signs of regression	No	Karrer et al. [78]
Retrospective study	8	Localized and systemic scleroderma	UVA1	15 J/cm2 3 times a week. Then increased up to maximum dose of 30 J/cm2 for seven patients and 40 J/cm2 for three patients	Range 529–1029.4	Unavailable	Range 26–32	Modified Rodnan skin score percentage improvement was 57%. One in remission for 12 months, four were in remission for 24 months	One patient on mycophenolate mofetil, one patient on pulsed cyclophosphamide, methotrexate, and ciclosporin. One patient on azathioprine	Rose et al. [79]
Retrospective study	17	Localized scleroderma	UVA1	5 times weekly	750–1400	3–6 weeks	19.3 ± 3.8	Fourteen patients reported clinical improvement	No	Andres et al. [73]
Retrospective study	3	Systemic scleroderma	UVA1	Mean dose of 29.5 J/cm2	Mean cumulative dose 1160 (range 660–1695)	Unavailable	Mean 26	Patients showed an improvement in the modified Rodnan scoring system. One patient had complete remission	Unknown	Pereira et al. [80]
Retrospective study	18	Morphea	UVA1	Mean dose of 31 J/cm2	Mean cumulative dose of 1662 (range 310–4270)	Unavailable	Mean 33	77.8% had marked improvement, 11.1% had moderate improvement, 5.6% had slight improvement, and 5.6% had no improvement	Unknown	Pereira et al. [80]
Case series	8	Systemic sclerosis	UVA1	30 J/cm2 4 times a week for 8 weeks, then 3 times a week for 6 weeks	1500	14 weeks	50	Modified Rodnan skin score improved after treatment. Seven patients experienced improvement in sclerosis in 6 months. Resulting in marked softening of skin and clinically significant improvement including finger mobility	Unknown	Von Kobyletzki et al. [81]
Case series	37	Morphea	UVA1	Treatments varied 2–5 times a week; 13 patients received 20 J/cm2 of UVA1. Eleven patients received 50–60 J/cm2 UVA1. Ten patients received medium-dose increased to high-dose 50–120 J/cm2. One patient received low-dose, followed by medium-dose UVA1 (60 treatments), and two patients received low-dose increased to high-dose UVA1 (mean 23.5 treatments, mean cumulative dose 2090 J/cm2)	20 J/cm2 group mean 683.9, 50–60 J/cm2 group mean 1468.5, 50–120 J/cm2 group 2560	Ranged	20 J/cm2 group 11–78 (mean 35), 50–60 J/cm2 group 13–36 (mean 27.8), 50–120 J/cm2 group 9–41 (mean 20.7)	26–100% improvement was found in 46.2% of patients treated with low-dose UVA1 phototherapy compared with 72.7% and 70% treated with medium and medium to high-dose UVA1, respectively	Unknown	Tuchinda et al. [85]
Case series	6	Morphea/SS/CREST	UVA1	Unavailable	Unavailable	Unavailable	30–60	Dermal thickness had decreased in five patients	No	Oikarinen and Knuutinen [82]
Case series	54	Scleroderma	UVA1	59.81 ± 27.40 J/cm2	1203.15 ± 1133.95	Unavailable	21.10 ± 13.1	Clinical improvement was noted by physician in 79.6% of patients	Unknown	Rombold et al. [83]
Case series	8	Localized scleroderma	UVA1	50 J/cm2 5 times a week	2000	8 weeks	40	The modified skin score improved in all patients	Unknown	Kreuter et al. [84]
Case series	14	Localized scleroderma	UVA1	20 J/cm2 5 times a week	800	8 weeks	40	The modified skin score improved in all patients	Unknown	Kreuter et al. [6]
Case series	12	Systemic sclerosis/CREST	UVA1	Treatments varied 2–5 times a week	Unavailable	Unavailable	Unavailable	41.7% of patients experienced 51–100% improvement	Unknown	Tuchinda et al. [85]
Case series	2	Localized scleroderma	PUVA	0.2 J/cm2 up to a maximum dose of 20 J/cm2, 4 times a week over 5 weeks, then 2 times per week for an additional 5 weeks	Unavailable	10 weeks	30	Skin lesions cleared, ultrasound revealed normal ratio of treated skin thickness to uninvolved skin	No	Kerscher et al. [42]
Case series	4	Localized scleroderma	PUVA	The initial daily UVA doses were 1–1.5 J/cm2	Range 242–405.5	12 weeks of PUVA daily, then maintenance PUVA treatment given twice or once per week for 3 months	57–72	The modified skin score improved after therapy	Acitretin	Ozdemir et al. [86]
Case series	13	Localized morphea	PUVA	Two patients treated with bath PUVA and all other patients with oral PUVA. Treatment was given twice weekly.	Mean 135 (range 42–244)	7–15 weeks	14–30	Mean reduction of 62.9% in modified Rodnan score	Five patients had concurrent therapies	Usmani et al. [30]
Case series	23	Localized morphea	PUVA	Patients were treated with a weekly regimen of bath immersion in 0.2 mg/l water solution of 8-methoxypsoralen, followed by irradiation with UVA 3 times a week with an initial UVA dose of 0.3 J/cm2, with subsequent increments of 0.3 J/cm2 added every 2–3 treatments up to a maximum dose of 10.0 J/cm2	Mean 115	Unavailable	Mean 71	Eleven patients (39%) showed complete remission. Partial response in 14 patients (50%). In the complete remission group; no recurrence was observed in seven patients after a mean follow-up period of 7 months (range 1–18 months)	No	Pavlotsky et al. [87]
Case series	4	Linear and generalized morphea	PUVA oral	3 times a week. UVA dose ranged from 42.5–94 J/cm2. After improvement (loss of induration), then maintenance treatment weekly and biweekly was given	Unavailable	Unavailable	44–88	Number of treatments to show clearance ranged from 44–88. UVA dose to clear lesions ranged from 358–838.5 J/cm2	No	Morison et al. [88]
Case series	2	En coup de sabre	PUVA topical	Initial dose was 0.3 J/cm2. 3 times a week. And UVA dose was increased after 3 days with 0.2 J/cm2	71	Unavailable	40	Softening of lesions after 90 days	Topical calcipotriol twice a day	Gambichler et al. [100]
Case series	7	Six with localized scleroderma, one with systemic scleroderma	PUVA topical	4 times a week. Highest UVA dose per treatment mean was 3.5 J/cm2	Mean 53.5	Unavailable	Mean 25 (range 14–39)	Marked improvement in softening of sclerotic plaques in all patients	Unknown	Pasic et al. [89]
Case series	10	Scleroderma	Water-filtered infrared A plus visible light treatment	Total irradiance was 180–200 mW/cm2. Treatment was done 2–5 times a week.	Unavailable	Unavailable	16–48	Seven patients reported improvement, follow-up was 1–7.5 years after treatment	Unknown	Von Felbert et al. [90]
Case report	16/F	Nodular morphea	PUVA topical	Unavailable	2.32	Unavailable	Unavailable	Slight improvement of regression of nodules. The patient was lost to follow-up	Penicillin G for 10 days	Kauer et al. [91]
Case report	12/F	Localized scleroderma	PUVA topical	0.2–4.0 J/cm2 to total dose of 62.8 J/cm2. Initiated for 10 days, then subsequently once a week for 4 months	Unavailable	4 months	Unavailable	Rodnan score + range of motion of affected joint improvement	Oral prednisolone	Uchiyama et al. [92]
Case report	43/F	Systemic sclerosis	PUVA topical	UVA dose started at 0.6 J/cm2 then gradually increased to 2.4 J/cm2. Treatments were given once a week	167.3	Unavailable	107	Significant softening of the affected areas, and normalization of skin temperature	No	Morita et al. [93]
Case report	58/M	Systemic sclerosis	PUVA topical	0.10 J/cm2 3 times a week, increasing to a maximum single dose of 8 J/cm2	272.3	29 weeks	Unavailable	Decreased necrosis in fingers, reduced symptoms of swelling, erosions, crusting, and induration in fingers. Follow-up at 5 months showed slight swelling of both hands without new fingertip lesions	Sildenafil 150 mg daily	Mohanna et al. [94]
Case report	65/F	Generalized morphea	PUVA	0.4 J/cm2 3 times a week	Unavailable	8 weeks	24	Hand closure and skin sclerosis index. Score went from three to one. Disease free after 2-year follow-up with weekly maintenance therapy	No	Kanekura et al. [95]
Case report	61/M	Progressive systemic sclerosis	PUVA	0.25 J/cm2 4 times a week. Total dose of 5 J/cm2.	Unavailable	5 weeks	20	Hand closure and skin sclerosis index improved from 4 to 1	No	Kanekura et al. [95]
Case report	42/M	Progressive systemic sclerosis	PUVA	PUVA 0.4 J/cm2 6 times a week. Total dose of 7.2 J/cm2.	Unavailable	3 weeks	18	Hand closure and skin sclerosis index improved from 3 to 0	No	Kanekura et al. [95]
Case report	32/F	Progressive systemic sclerosis	PUVA	PUVA 0.25 J/cm2 twice a week. Total dose of 3.5 J/cm2.	Unavailable	7 weeks	14	Skin sclerosis index improved from 3 to 1	No	Kanekura et al. [95]
Case report	80/M	Localized scleroderma	PUVA	Initial 3 times weekly UVA dose of 4 J/cm2, which was gradually increased, weekly, to a maximal single dose of 18 J/cm2	Unavailable	11 months	127	After 9 months, the skin plaques were softening. Treatment was then continued twice every week for another 2 months. After 127 treatments, there was clearance of the lesion. Clinical stability remained after 8 months	No	Garcia-Bustinduy et al. [96]
Case report	7/F	Pansclerotic morphea	PUVA	0.6 mg/kg for 4 times a week. Dose started at 0.5 J/cm2 and was gradually increased to 2.0 J/cm2 over 2 months	Unavailable	10 weeks	Unavailable	After 10 weeks her condition worsened with spread of disease, ulceration and contraction deformities	Penicillamine 20 mg/kg/day	Todd et al. [97]
Case report	56/F	Systemic sclerosis	PUVA	3 times a week. Then once a week for maintenance therapy once improvement seen	483	19 months	Unavailable	100% improvement (patient self-evaluation)	No	Baum et al. [98]
Case report	66/M	Systemic sclerosis	PUVA	3 times a week then once a week for maintenance therapy once improvement seen	20	1.5 months	Unavailable	>70% response rate (patient self-evaluation)	No	Baum et al. [98]
Case report	27/M	Generalized morphea	PUVA	3 times a week, then once a week for maintenance therapy once improvement seen	288	10 months	Unavailable	>70% response rate (patient self-evaluation)	No	Baum et al. [98]
Case report	40/M	Diffuse morphea	PUVA	Twice weekly at 5 J/session	115	23 months	N/A	Increased mobility, reduced progression of plaques and sclerosis	Cyclosporine for 2 years. Then transitioned to mycophenolate mofetil for 1 year and phototherapy discontinued	Rose and Goodfield  [99]
Case report	64/F	Disseminated scleroderma	PUVA	Initial dose of 0.76 J/cm2, maximum tolerated dose 10 J/cm2. The first 28 treatments were conducted 4 times a week. Then twice a week during the following ten treatments	Unavailable	Unavailable	Unavailable	The skin sclerosis index was a four before therapy, and a one or two after therapy. Improvement was also noted from infrared thermography before and after treatment. No recurrence approximately 2 years later	No	Aragane et al. [101]
Case report	27/F	Localized scleroderma	PUVA	0.4 J/cm2 up to a total dose of 5 J/cm2	Unavailable	Unavailable	Unavailable	Clinical improvement observed with reduced hardness. No recurrence after 20-month follow-up	No	Yamaguchi et al. [102]
Case report	12/M	Pansclerotic morphea	PUVA	Unavailable	Unavailable	Unavailable	Unavailable	Improvement in skin and ulceration that lasted 1.5 years	Unknown	Wollina et al. [103]
Case report	40/F	Post-radiation morphea	PUVA	Twice weekly for 22 treatments (107.8 J/cm2). Patient subsequently had 47 treatments of UVA1. This was started at medium dose (35 treatments at 50 J/cm2) and progressed to high dose (12 treatments at 80 J/cm2	2633.6	Unavailable	69	Patient reported better improvement with high-dose UVA1 then medium-dose UVA1	No	Lim et al. [104]
Case report	8/F	Pansclerotic morphea	PUVA	UVA dose 0.5 J/cm2, which was gradually increased to 1.8 J/cm2 during the next 2 months using four irradiations weekly. She was maintained on two treatments per week for 6 months	Unavailable	Unavailable	68	Softening of skin was observed within 1st month. Improved healing of ulcers and joint mobility. No evidence of relapse after a 14 month follow-up	No	Scharffetter-Kochanek et al. [105]
Case report	72/F	Traumatic scleroderma	UVA1	70 J/cm2 5 times a week	1400	4 weeks	Unavailable	Durometer scores improved significantly during first 3 weeks and borderline significantly the last week. Remission after >31 months	No	Kroft et al. [44]
Case report	8/F	Pansclerotic morphea	UVA1	5 J/cm2 3 times a week. Then the doses were increased gradually to a maximum of 20 J/cm2	480	Unavailable	Unavailable	Improvement was seen at 10–12 sessions. Softening of sclerotic lesions. Hypopigmented areas began to have pigmentation	No	Yildirim et al. [106]
Case report	45/F	Systemic sclerosis	UVA1	50 J/cm2 2–3 times a week	2222	Unavailable	40	Microstomia had improved; all of her sclerotic lesions were softer. She could articulate words normally and had reduced furrowing around the mouth	Unknown	Tewari et al. [107]
Case report	19/F	Scleroderma	UVA1	20 J/cm2 5 times a week	Unavailable	Unavailable	Unavailable	Softening of fibrotic skin, improved mobility of joints	Methylprednisolone, methotrexate, pentoxiflyin, asprin, and piascledine	Forsea, et al. [108]
Case report	71/M	Pansclerotic morphea	UVA1	30 J/cm2 3 times a week	1350	15 weeks	45	Softening, increased elasticity	No	Herzinger et al. [109]
Case report	16/M	Pansclerotic morphea	UVA1	20 J/cm2 4 times a week	640	8 weeks	32	Within 3 weeks there was softening of the skin on the trunk and head. There was an increase in joint mobility. Therapeutic effects lasted for 6 months	No	Gruss et al. [110]
Case report	42/F	Progressive systemic sclerosis	UVA	20 J/cm2 3 times a week	Unavailable	Unavailable	Unavailable	Softening of facial sclerosis softening and decreased pruritus at 3 week. At 2 months, lesions on her abdomen and upper legs softened	Unknown	Steger and Matthews [111]
Case report	11/M	Localized scleroderma	UVA	20 J/cm2 4 times a week for 6 weeks, then once weekly for 6 weeks	Unavailable	12 weeks	Unavailable	Lesion cleared with softening, tanning, and thinning of the skin. At 3-month follow-up the lesion is still in remission	No	Steger and Matthews [111]
Case report	32/F	En coup de sabre	Narrowband UVB	3 times a week	Unavailable	24 weeks	N/A	Prevented progression of disease. Patient remained stable for a year off of UVB, but then disease recurred and had to resume UVB and oral colchicine	No	Brownell et al. [112]
Case report	22/F	Secondary cicatricial alopecia/scleroderma	Non-ablative fractional laser	Fluence of 6–8 mJ and a density of 300 spots/cm2/pass. For ablative fractional laser, a fluence of 30–50 mJ was delivered to the affected area 150 spots/cm2	Unavailable	Non-ablative/ablative laser with a 4 week interval between treatments	15	Eight treatments before clinical improvement observed. 26–50% clinical improvement assessment	Topical calcipotriol cream 0.005%	Cho et al. [113]
Case report	34/M	Secondary cicatricial alopecia/scleroderma	Non-ablative fractional laser	Fluence of 6–8 mJ and a density of 300 spots/cm2/pass. For ablative fractional laser, a fluence of 30–50 mJ was delivered to the affected area 150 spots/cm2	Unavailable	Non-ablative/ablative laser with a 4 week interval between treatments	20	Five treatments before clinical improvement observed. 26–50% clinical improvement	Topical calcipotriol cream 0.005%	Cho et al  [113]
Case report	41/F	Morphea	585-nm long pulsed (1.5 ms) dye laser	Four treatments, 2 weeks between treatments. 5 J/cm2 fluence	Unavailable	8 weeks	4	Softening of the plaque noted after each treatment. 6 months after 1st treatment, there was clinical stability	No	Eisen and Alster [114]

ALA aminolevulinic acid, F female, M male, PDT photodynamic therapy, PUVA psoralen and ultraviolet, UVA ultraviolet A, UVA1 ultraviolet A1, UVB ultraviolet B

aTotal number, if case report age/gender

Skin darkness or darkening likely has no effect on UVA1’s efficacy. Forty-seven patients with morphea and 35 with SSc treated with UVA1 phototherapy were analyzed to see whether Fitzpatrick skin type makes an impact on the outcome, with the result being that medium- to high-dose UVA1 had similar efficacy in skin types I–V [48]. There was also no correlation noted for Fitzpatrick skin type and cumulative dose or clinical improvement.

The current evidence suggests that UVA1 effects are dose-related. In an observational report for patients with SSc who completed at least ten treatments, 20% of those treated with low-dose (20–40 J/cm2) UVA1 (n = 5), 83.3% of those treated with medium-dose (>40–80 J/cm2) UVA1 (n = 6), and 100% of those treated with high-dose (>80–120 J/cm2) UVA1 (n = 5) reported improvement [49]. A 14-patient study showed a 70-J/cm2 dose was more effective in treating localized scleroderma lesions than a 20 J/cm2 dose [45]. In six patients with localized scleroderma treated two to three times a week, three patients experienced complete remission [50]. Two of the three received high-dose 100 J UVA1 therapy, of which one of them received 67 treatments and relapsed after 6 months, compared to one patient which received low-dose UVA1 twice weekly for 6 weeks for a total of 39 irradiations and did not relapse after 84-month follow up [50]. A broadband UVA trial examined 63 patients with morphea and 15 patients treated with UVA1 5, 10, or 20 J/cm2 with cumulative doses of 100, 200, and 400 J/cm2, respectively [51]. Clinical improvement was observed in all patients, but there was no comparable difference between the UVA doses.

Long-term outcome of UVA1 therapy is unclear. In a cohort study of 37 patients with morphea with positive clinical benefits from UVA1 treatment 44.5% recurred at 2 years, and 48.4% recurred at 3 years [52]. There was no difference between medium- (60–90 J/cm2) and high-dose (>90 J/cm2) UVA1 phototherapy with respect to recurrence. There was a 1.15-times higher chance of disease recurrence for an increment of 1 year in duration of morphea prior to UVA1 treatment [52].

Broadband UVA

Twelve patients with morphea were treated with low-dose (20 J/cm2) broadband UVA 3 times a week for a total of 20 sessions [12]. Improved softness of skin lesions assessed by palpation was reported as early as three treatments and as late as ten treatments. Longer standing lesions did not respond as well as therapy. As a control, some lesions in the same patients were covered to prevent UVA1 exposure during treatment, and less softening was reported in these covered lesions. After a 1-year follow-up, only two patients reported a reappearance of lesions. Lesions on skin creases or over joints did not respond as well to therapy [12].

PUVA

A 15-year-old male with scleroderma with indurated patches on the trunk and joint restrictions was recalcitrant to hydroxychloroquine, prednisolone, and methotrexate [53]. PUVA at a dose of 0.6 mg/kg twice weekly was subsequently added for 20 sessions over 10 weeks at a cumulative dose of 25.4 J/cm2. Methotrexate was subsequently administered for 7 months. After this period, he was able to make a full fist and increase to a normal range of motion in the ankles; his skin was less indurated and has maintained clinical stability for 2 years [53]. Table 1 lists additional PUVA treatment studies in scleroderma/morphea. PUVA’s effects may be due to local effects rather than systemic effects, as Kerscher et al. [54] noted that residual sclerotic lesions remained in patients in areas hidden from UVA exposure such as parts of the elbow in patients undergoing PUVA.

UVB

A 43-year-old female with radiation-induced morphea was given acitretin daily and UVB three times a week [55]. Two months afterwards there was less induration of her plaque, decreased tenderness, and improved range of motion of the left arm [55]. Eleven patients that underwent phototherapy treatment (seven treated with PUVA and four treated with narrowband UVB) for an average of ten sessions experienced a 48% improvement of their localized scleroderma as indicated by a clinical pinching test [56]. Additionally, the ultrasound examination showed a dermal thickness reduction ranging from 20% to 100% [56]. There was no correlation between the type of phototherapy and clinical response rate [56]. Additional studies on UVB therapies are included in Table 1.

Targeted Phototherapy

Targeted phototherapy is a modality that spares non-lesional skin and is able to deliver a higher fluence. A patient with limited scleroderma and elbow mobility restrictions was treated 2–3 times a week for 13 weeks with 940-nm low-level light therapy with millisecond pulsing and continuous wave modes. Using a sequential pulsing dose on one elbow and continuous wave mode on the other, better results were seen with the pulsing mode showing improvement in skin thickness [57].

Five patients with a total of 11 plaques were treated with a 308-nm monochromatic excimer laser for 4 weeks at a power density of 48 mW/cm2 with a maximum irradiation area of 512 cm2 [58]. The mean number of treatments was seven, and the dose per session was 1.5 J/cm2. The mean total dose was 10 J/cm2. After 4 weeks, 3 out of 5 patients experienced marked improvement with residual hyperpigmentation [58].

A 27-year-old Hispanic female had a contracture of her knee with sclerotic bands on her left lower leg, ankle, and foot that were recalcitrant to methotrexate, UVA1, topical calcipotriene, intralesional triamcinolone acetonide, and physical therapy [59]. The patient was treated with a single treatment of 10.6 µm carbon dioxide laser with a 50 J/cm2 pulse energy, while remaining on methotrexate and topical agents [59]. After 1 week, she experienced an increase in range of motion. After 4 months of follow-up, there was softening of her contracture, and she regained full plantar flexion of her left foot. After a 1-year follow-up, she maintained a full range of motion [59].

Four patients with microstomia and SSc were treated with intense pulsed light. 530–570 mm, 11–14 J/cm2; 10–14 pulse durations was used for the patients every 4 weeks [60]. Patients were followed for 4 months. Three patients experienced an increased interincisal distance of ~1 mm per treatment [60]. One patient did not have improved interincisal distance, but did note activities of daily living became easier. One patient did report recurrence of the stiffness after 3 weeks [60]. Table 1 lists additional reports of targeted phototherapy.

Photodynamic Therapy

In six patients, 20% 5-ALA was applied under occlusion to areas of morphea for 5 h. A band width of 570–670 nm, peak 635-nm light was given. A dose of 25 J/cm2 was given for a total of six weekly treatments. In four of the patients there was clinical improvement as determined by skin scoring, although only one of these patients showed histologic evidence of improvement. The side effects patients reported included burning sensation, dryness, erythema, pigmentation, and pruritus [61]. Table 1 lists an additional study.

Discussion

There are mostly care reports of UVA1, UVB, PUVA (bath and topical), and targeted phototherapies in cases of scleroderma. UVA1 appears to be the most efficacious, but it is also the most studied. There are not many studies on high-dose UVA1, and this needs to be investigated further to assess the optimal dose of UVA to use in scleroderma. Additionally, longer term studies are needed to study the long-term outcome and safety of these treatments. A similar literature review study delineated UVA and PUVA’s efficacy and safety in the context of SSc, localized scleroderma, extragenital lichen sclerosus et atrophicus, sclerodermoid graft-versus-host disease, lupus erythematosus, and other rare sclerotic diseases [62]. This review also asserts that there need to be more rigorous studies to help establish a guide for UVA’s indications as well as its efficacy compared to other conventional medical therapies [62].

Based on the studies available, a reasonable regimen is UVA1 therapy 20–50 J/cm2 3–4 times a week for a total of 30 treatments. There were no double-blind, placebo-controlled trials available, and only three controlled trials. Adverse effects thus far do not correlate with the intensity of therapy. The side effects noted in scleroderma phototherapy include fatigue, a burning sensation, hyperpigmentation, pruritus, erythema, edema, headaches, gastrointestinal upset, and joint and muscle pain. Additionally, one patient undergoing UVA1 phototherapy for disseminated morphea developed bullous pemphigoid after 29 treatments [63]. The long-term effects of UVA1 on patients have not reported skin cancer [64]. Phototherapy should be safe in pregnancy [65] although folate may need to be supplemented as reports show that UVB and solar UV radiation may cause photodegradation [66, 67]. Multiple treatments, as well as limited availability of in-office phototherapy, are barriers to treatment. In a review by Bielsa Marsol [68], it was pointed out that most of the studies for UVA1 therapy were performed in countries where patients are predominantly Fitzpatrick types I–III, although, as noted earlier, the Fitzpatrick skin type thus far has not been shown to have an impact on therapy. Phototherapy may not be as useful for sclerotic diseases that affect structures deeper than the dermis.