Pre-treatment with topical 5-fluorouracil increases the efficacy of daylight photodynamic therapy for actinic keratoses - A randomized controlled trial.

BACKGROUND: Daylight photodynamic therapy (dPDT) and topical 5-fluorouracil (5-FU) are each effective treatments for thin grade I actinic keratosis (AKs), but less so for thicker grade II-III AKs. Prolonged topical treatment regimens can be associated with severe skin reactions and low compliance. This study compares the efficacy of sequential 4 % 5-FU and dPDT with dPDT monotherapy for multiple actinic keratoses. METHODS: Sixty patients with a total of 1547 AKs (grade I: 1278; grade II: 246; grade III: 23) were treated in two symmetrical areas (mean size 75 cm2) of the face or scalp, which were randomized to (i) 4% 5-FU creme twice daily for 7 days before a single dPDT procedure and (ii) dPDT monotherapy. Daylight exposure was either outdoor or indoor daylight. RESULTS: Twelve weeks after treatment 87 % of all AKs cleared after 5-FU+dPDT compared to 74 % after dPDT alone (p<0.0001). For grade II AKs, the lesion response rate increased from 55 % with dPDT monotherapy to 79 % after 5-FU+dPDT (p<0.0056). Moderate/severe erythema was seen in 88 % 5-FU+dPDT areas compared to 41 % of dPDT areas two days after dPDT. Twelve weeks after treatment 75 % of the patients were very satisfied with both treatments. CONCLUSIONS: Sequential 5-FU and dPDT was more effective than dPDT monotherapy in the treatment of AKs, especially for grade II AKs. Local skin reactions were more pronounced after combination treatment, but no patients discontinued the treatment. The combination of 5-FU and dPDT is an effective treatment of large treatment areas with high compliance and satisfaction.

Treatment of Familial Benign Chronic Pemphigus With Superficial Radiotherapy.

IMPORTANCE: Hailey-Hailey disease (HHD) is a chronic genodermatosis with recurrent vesicles and erosions mainly in the intertriginous areas. Hailey-Hailey disease severely affects patient quality of life. Standard treatments attempt to control the flares, but often do not result in long-term remission of the disease. OBJECTIVE: To describe outcomes of treatment with superficial radiotherapy (SR) for severe treatment-refractory HHD. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case-series included 13 patients with severe HHD with a mean (SD) duration of 24 (14) years whose treatments with SR and follow-up were conducted at the Department of Dermatology at Bispebjerg University Hospital (Copenhagen, Denmark) from January 2015 to April 2021. INTERVENTIONS: Patients were treated with SR (20 kilovolt; 8 fractions of 2 gray was equal to 1 cycle) with a total dose of 16 gray in each treatment cycle. Patients received 1 to 6 treatment cycles with 1 to 5 separate body areas treated in each cycle. Sixty-two separate body areas were treated with SR. MAIN OUTCOMES AND MEASURES: Complete long-term remission, defined as no relapse during follow-up of at least 12 months. RESULTS: For the 13 participants (mean [SD] age, 52 [18] years; 8 women [62%]), 56 of 62 treated areas (90%) achieved long-term remission, and the mean (SD) follow-up was 32 (12) months for the successfully treated areas. Nine of 13 patients (69%) responded with complete remission of all treated areas after the first treatment cycle and an additional 3 patients experienced complete remission after the second SR cycle. One patient with partial remission in 1 of 2 treated skin areas experienced such an improvement in HHD that they chose to abstain from retreatment. The treatment was followed by severe inflammation lasting for up to 1 month followed by temporary slight hyperpigmentation of the treated areas. The average Dermatology Life Quality Index score before treatment with SR was 22 (the disease having extremely large effect on the patient's life) and decreased to an average of 3 (small effect on the patient's life) after treatment with SR. CONCLUSIONS AND RELEVANCE: The results of this case series suggest that treatment with SR was associated with remission in patients with severe HHD and may provide a long-term improvement of treated skin areas.

Short-term chemical pretreatment cannot replace curettage in photodynamic therapy.

BACKGROUND: Guidelines for photodynamic therapy (PDT) recommend pretreatment with curettage/debulking to enhance intracellular formation of protoporphyrin IX (PpIX). However, studies suggest that new chemical pretreatment procedures may replace curettage/debulking. PURPOSE: To investigate how pretreatment with curettage and two combination ointments containing calcipotriol/betamethasone and salicylic acid/betamethasone affect PpIX fluorescence after the application of methyl aminolevulinate MAL and 5-aminolevulinic acid (BF-200 ALA). METHODS: Four fields on the forearms of 30 healthy volunteers were pretreated with curettage or short-term application of calcipotriol/betamethasone or salicylic acid/betamethasone for 20 min. Two fields were not pretreated, thus serving as reference. After pretreatment, MAL or BF-200 ALA was applied for 24 h, and PpIX fluorescence was measured hourly from 1 to 5 h and after 18, 21 and 24 h. RESULTS: Curettage significantly enhanced PpIX fluorescence for MAL from 1 to 21 h (P < 0.0041). For BF-200 ALA, curettage enhanced fluorescence from 1 to 5 h (P < 0.000064), while fluorescence was lower from 18 to 24 h. Pretreatment with salicylic acid/betamethasone and calcipotriol/betamethasone before BF-200 ALA application did not increase PpIX fluorescence from 1 to 5 h compared to no pretreatment, and both were significantly inferior to curettage (P < 0.0017 and 0.0024, respectively). CONCLUSION: Curettage significantly enhances PpIX fluorescence from 1 to 5 h and is superior to short-term chemical pretreatment. Our results support curettage as standard pretreatment in PDT.

Update on photodynamic treatment for actinic keratosis.

Photodynamic therapy (PDT) is an attractive treatment option for actinic keratoses (AKs), as large skin areas can be treated with high response rates and superior cosmetic outcome. The efficacy of 5-aminolevulinic acid (ALA)-PDT and methyl aminolevulinate (MAL)-PDT for AK has been proven in multiple studies, and this treatment is recommended in numerous consensus works and therapy guidelines. Moreover, a self-adhesive ALA patch has been approved for the PDT of AK. In a phase III study, ALA-patch-PDT was superior to cryotherapy and placebo in the treatment of mild to moderate AK on the face and scalp, and pre-treatment of the lesions and additional light occlusion was unnecessary when using the patch. ALA with a proprietary nanoemulsion is another newly marketed ALA gel that has been approved for the treatment of mild to moderate AK on the head. ALA was combined with a nanoemulsion to achieve increased chemical stability of the active ingredient and to enhance skin penetration. One study found that ALA was superior to MAL in the treatment of AK on the face or scalp. Daylight-PDT is a simpler and more tolerable treatment procedure for PDT, and three randomised studies have shown that daylight-PDT is an effective and pain-free treatment for AK; however, the procedure is limited by the need for a sufficient light dose and outdoor temperature. Ablative fractional laser resurfacing prior to MAL has been used to improve the PDT response of thick AK. However, more intense acute skin reactions and long-term adverse events in ablative fractional laser resurfacing-PDT compared with PDT-treated skin were found, which might limit the use of the intensified treatment.

Continuous ultra-low-intensity artificial daylight is not as effective as red LED light in photodynamic therapy of multiple actinic keratoses.

BACKGROUND/PURPOSE: Daylight-mediated photodynamic therapy (PDT) is a simple and tolerable treatment of nonmelanoma skin cancer. It is of interest which light intensity is sufficient to prevent accumulation of protoporphyrin IX (PpIX) and effectively treat actinic keratoses (AKs). We compared the efficacy of PDT with light-emitting diode (LED) to daylight-mediated PDT with very low-intensity artificial daylight ('daylight') in the treatment of multiple AKs in the face or scalp. METHODS: Twenty patients were treated with conventional methyl aminolevulinate (MAL) PDT in one area. Another area was, after half an hour of occlusive treatment with MAL, illuminated for 2.5 h with low-intensity 'daylight' (0.5 mW/cm(2) -3.7 mW/cm(2)) that corresponds to midday outdoor intensity in the Scandinavian winter. RESULTS: After 3 months, with a response rate of 52%, low-dose artificial daylight was less effective than conventional LED-PDT (63%) (P = 0.0017). The mean PpIX light dose during 'daylight' exposure was 2.23 J/cm(2) and the lower the PpIX light intensity, the higher the accumulation of PpIX (P = 0.003). CONCLUSIONS: Even very low-intensity/dose artificial daylight-mediated PDT of multiple AKs resulted in a response rate of more than 50%. However, to ensure efficacies equivalent to conventional LED-PDT, the treatment should not be conducted on very overcast days.

Cold water and pauses in illumination reduces pain during photodynamic therapy: a randomized clinical study.

Pain is the main acute adverse event during photodynamic therapy of skin lesions. The objective of this randomized study was to evaluate the pain-relieving effect of pauses and cooling during illumination. Twenty-four patients with actinic keratoses were treated with photodynamic therapy in two symmetrical areas and cooled with either cold-water-spray or cold-water-pack (CoolPack). Treatment areas were cooled during either the first or second period of illumination, which were separated by a 3-min pause in illumination. Pain intensity was scored from 0 to 10. Water-spray reduced the mean pain score by 1.2 points (p=0.030) and CoolPack by 1.3 points (p=0.007) during the first half of the illumination. Pain intensity decreased during the pause by 3.7 points in water-spray patients (p<0.0001) and 3.0 points in CoolPack patients (p<0.0001). In conclusion, cooling resulted in a minor reduction in pain intensity, while adding the intermediate pause in illumination reduced the pain considerably. Use of pauses and cooling during illumination is an easy and inexpensive way to make photodynamic therapy more tolerable for the patient.

Long-pulsed dye laser versus long-pulsed dye laser-assisted photodynamic therapy for acne vulgaris: A randomized controlled trial.

BACKGROUND: Long-pulsed dye laser (LPDL)-assisted photodynamic therapy has been suggested to be superior to laser alone for acne vulgaris but no evidence is available. OBJECTIVE: To evaluate the efficacy and safety of LPDL alone versus LPDL in photodynamic therapy with methylaminolevulinic acid (MAL-LPDL) for acne vulgaris. METHODS: Fifteen patients received a series of 3 full-face LPDL treatments and half-face prelaser MAL treatments; the latter being randomly assigned to the left or right side. RESULTS: Inflammatory lesions were reduced more on MAL-LPDL-treated than on LPDL-treated sides (week 4: 70% vs 50%, P = .003; week 12: 80% vs 67%, P = .004). Noninflammatory lesions reduced similarly. Patient satisfaction was slightly greater with MAL-LPDL versus LPDL treatments (scale 0-10: week 4: 7 vs 6, P = .034; week 12: 8 vs 7.5, P = .034). Fluorescence measurements detected photobleaching with MAL-LPDL (35.3%) and LPDL (7.3%) treatments (P < .001). Erythema, edema, and pustular eruptions intensified from MAL incubation. No patients experienced pigment changes or scarring. LIMITATIONS: The sample size was limited. The split-face design in this randomized controlled trial does not allow us to draw conclusions about the efficacy of the LPDL, only about the efficacy of MAL-LPDL compared with LPDL alone. CONCLUSIONS: MAL-LPDL is slightly superior to LPDL for the treatment of inflammatory acne.

Transepidermal water loss after photodynamic therapy, UVB radiation and topical corticosteroid is independent of inflammation.

BACKGROUND/PURPOSE: Photodynamic therapy (PDT) and ultraviolet radiation cause an inflammatory reaction of the skin. This may lead to disruption of the skin barrier function. We examined the acute effect of PDT and short-wave ultraviolet radiation (UVB) on the barrier function of the epidermis. Furthermore, we explored the effect on the skin barrier of topical corticosteroid previous to UVB exposure. METHODS: Eight patients with acne vulgaris of the face were treated with PDT two times, and eight patients were left untreated. The transepidermal water loss (TEWL) was measured before treatment and at three control visits after PDT over 12 weeks. Twenty healthy volunteers were irradiated with UVB in two areas on the back. One area was treated with topical high-potency corticosteroid before irradiation. TEWL was measured before, 15 min and 24 h after UVB exposure. RESULTS: TEWL did not differ significantly between the various visits in each acne group and no significant difference in the TEWL between PDT-treated patients and the control group was found at any visit (P>0.05). TEWL was not significantly altered 15 min and 24 h after a single exposure to UVB and no positive relationship was found between UV-induced erythema and change in TEWL (P>0.05). Application of topical corticosteroid before UVB did not affect the skin barrier function significantly (P>0.05). CONCLUSION: Neither PDT nor a single exposure to UVB damaged the permeability barrier function of the skin and no effect on the TEWL was found when topical corticosteroid was applied previous to UVB irradiation.

Morphine gel 0.3% does not relieve pain during topical photodynamic therapy: a randomized, double-blind, placebo-controlled study.

There is a demand for pain relief during photodynamic therapy. We therefore investigated the efficacy and side-effects of topical morphine gel 0.3% for pain relief during topical photodynamic therapy in a randomized, double-blind, placebo-controlled study. The study involved 28 patients with actinic keratoses or basal cell carcinomas. Each patient was treated with photodynamic therapy after superficial curettage of 2 treatment areas that were randomized to morphine gel or placebo gel. The gels were applied 15 min before illumination. Pain was assessed pre-illumination, during, and immediately after illumination, using a numeric rating scale. Skin redness was determined by reflectance spectrophotometry and the size of the treated area by protoporphyrin IX fluorescence. There were no differences between the areas according to accumulation of protoporphyrin IX (p =0.34), size of fluorescence areas (p =0.84), or skin redness (p =0.95). There was no significant pain relief of topical morphine gel compared with placebo gel (p >0.23). This negative result suggests that opioid receptors may not be involved in the pain induced by photodynamic therapy.

Photodynamic therapy of acne vulgaris using 5-aminolevulinic acid versus methyl aminolevulinate.

BACKGROUND: Recent studies have shown that photodynamic therapy (PDT) is effective in the treatment of acne vulgaris. No studies have compared the treatment effect of aminolevulinic acid-PDT (ALA-PDT) and methyl aminolevulinate-PDT (MAL-PDT). OBJECTIVE: We sought to compare the treatment effect and tolerability of ALA-PDT versus MAL-PDT in the treatment of acne vulgaris in a controlled randomized investigator-blinded trial. METHODS: Fifteen patients with at least 12 facial inflammatory acne lesions had one split-face PDT treatment with MAL and ALA. RESULTS: Twelve weeks after treatment we found a 59% decrease in inflammatory lesions from baseline, with no significant differences in effectiveness between the two treatments. All patients experienced moderate to severe pain during illumination and developed erythema, pustular eruptions, and epithelial exfoliation after treatment, which were more severe and uniform in the ALA-PDT-treated area. LIMITATIONS: The study is paired and controlled, but the results should be evaluated with consideration given for the number of participating patients. CONCLUSION: PDT appeared to be an effective treatment for inflammatory acne vulgaris with no significant differences in the response rate between ALA-PDT and MAL-PDT. ALA-PDT resulted in more prolonged and severe adverse effects after treatment.

Pain associated with photodynamic therapy using 5-aminolevulinic acid or 5-aminolevulinic acid methylester on tape-stripped normal skin.

BACKGROUND: Pain during and after topical photodynamic therapy (PDT) is one of the few severe adverse effects of the new treatment of skin diseases. OBJECTIVE: To compare the pain experienced in normal skin treated with 5-aminolevulinic acid (ALA) PDT and 5-aminolevulinic methylester (ALA-ME) PDT. DESIGN: Double-blind randomized trial. INTERVENTIONS: Twenty healthy volunteers were treated randomly with ALA-PDT on one forearm and ALA-ME-PDT on the other forearm after tape stripping of the sun-exposed skin areas. MAIN OUTCOME MEASURES: Pain was scored using a numerical scale ranging from 0 to 10 during illumination, immediately after illumination, and each day in the following week. In addition, we measured erythema, pigmentation, and protoporphyrin IX (PpIX) fluorescence. RESULTS: ALA-PDT generated significantly more pain than ALA-ME-PDT during and after illumination (P =.001 and P =.05, respectively). ALA-PDT induced a larger decrease in PpIX fluorescence than ALA-ME-PDT (P =.009). There was no correlation between pain and peak PpIX fluorescence or absolute decrease in peak PpIX fluorescence. Both treatments lead to erythema immediately after illumination and increased pigmentation 1 week after PDT. There was no correlation between pain and degree of erythema or pigmentation. CONCLUSIONS: ALA-ME-PDT was less painful than ALA-PDT when performed on tape-stripped normal skin. The pain scores did not correlate with the intensity of peak PpIX fluorescence in the skin or with the degree of erythema after illumination, suggesting that pain was not caused by activation of PpIX alone. The theory that ALA and not ALA-ME is transported by gamma-aminobutyric acid receptors into the peripheral nerve endings may explain the higher pain scores in ALA-PDT-treated areas.