Systematic review of photodynamic therapy for the treatment of hidradenitis suppurativa

Sofiya Reshetylo; Shanthi Narla; Caitlin Bakker; Thomas Freeman; Ronda S Farah; Iltefat H Hamzavi; Noah Goldfarb

doi:10.1111/phpp.12812

. 2022 Jul 24;39(1):39–50. doi: 10.1111/phpp.12812

Systematic review of photodynamic therapy for the treatment of hidradenitis suppurativa

Sofiya Reshetylo ¹, Shanthi Narla ², Caitlin Bakker ³, Thomas Freeman ^1,⁴, Ronda S Farah ¹, Iltefat H Hamzavi ⁵, Noah Goldfarb ^1,^4,^6,^✉

PMCID: PMC10087637 PMID: 35713108

Abstract

Objective

To perform a systematic review of available literature regarding the use of 5‐aminolevulinic acid (ALA) and ALA derivative photodynamic therapy (PDT) in the treatment of hidradenitis suppurativa (HS) and provide recommendations on its use.

Methods

A systematic review was performed of all published studies up to September 1, 2019 from nine databases, including PubMed, that evaluated PDT in the treatment of HS. For each study, quality of evidence and risk of bias was evaluated. Recommendations from the body of evidence were created based on Strength of Recommendation and Taxonomy (SORT) criteria.

Results

Eighteen studies met inclusion criteria. The majority of studies had a high risk of bias. Blue light PDT with 20% ALA and red light PDT with 16% methyl aminolevulinate (MAL) demonstrated some benefit based on a small number of poor‐quality studies with a high risk of bias (Grade C, level III evidence). The most promising results were for 1%–5% ALA with intralesional diode, with good to complete response in 78%–94% of anatomic sites treated (Grade B, level II evidence).

Limitations

The majority of studies contained high levels of bias, with significant heterogeneity between studies. Conclusions are limited by small samples sizes, lack of randomized controlled trials, and differing protocols.

Conclusion

Further studies are needed to determine the clinical efficacy of 20% ALA with blue light and MAL with red light. Intralesional diode PDT shows the most promise and warrants further investigation in larger, randomized controlled trials.

Keywords: 5‐aminolevulinic acid, blue light, hidradenitis suppurativa, intense pulsed light, intralesional diode, methyl aminolevulinate, photodynamic therapy, pulsed dye laser, red light

1. INTRODUCTION

Hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory skin condition that typically affects intertriginous sites, consisting of inflammatory nodules, abscesses, and draining tunnels. ¹ , ² The pathogenesis is not fully elucidated but is likely due to a combination of genetic factors, androgens, and complex interplay between hair follicle anatomy, localized immune response, and commensal bacteria. ¹ First‐line treatment options include topical and systemic antibiotics (e.g., tetracyclines and clindamycin), anti‐androgen therapy (e.g., spironolactone), biologics (i.e., anti‐tumor necrosis factor [TNF]‐α inhibitors), Nd:YAG (neodymium‐doped yttrium aluminum garnet) laser treatments, and surgical excision or deroofing. ³ , ⁴ , ⁵ , ⁶ Adalimumab, a TNF‐α inhibitor, is the only medication currently approved by the United States (US) Food and Drug Administration (FDA) for HS; however, many patients are reluctant to use systemic, immunosuppressive medications, and others do not tolerate or respond to adalimumab. ⁷ Therefore, new FDA‐approved treatments are desperately needed. While new medications including interleukin (IL)‐1, IL‐17, and Janus Kinase (JAK) inhibitors are currently being studied in clinical trials, adjuvant or alternative non‐immunosuppressive options are also essential. ⁸

Photodynamic therapy (PDT) is of interest as a potential treatment option for HS. PDT is FDA approved for the treatment of actinic keratoses (AK) but has also been utilized off‐label by dermatologists to treat several other conditions including non‐melanoma skin cancer and inflammatory skin diseases. ⁹ , ¹⁰ PDT involves administration of a topical or systemic photosensitizing agent followed by irradiation by a light source to create reactive oxygen species. While several photosensitizers and light sources have been evaluated for AKs, only two photosensitizers are currently available in the US and FDA approved for topical use, including 20% 5‐aminolevulinic acid (ALA) solution (Levulan® Kerastick®, DUSA Pharmaceuticals, MA, USA) used with blue light (BLU‐U®, DUSA Pharmaceuticals, MA, USA), and a 10% ALA gel (Ameluz®, Biofrontera Inc, MA, USA) used with BF‐RhodoLED® (Biofrontera Inc, MA, USA), a narrow spectrum, approximately 635 nm, red light. ¹¹ , ¹² A 16.8% methyl aminolevulinate (MAL) cream (Metvixia®, Photocure, Oslo, Norway) used with Aktilite® CL‐128 (Galderma SA, Zug, Switzerland), a red light device, was previously approved by the FDA, but is no longer available in the United States. ¹³ Four topical ALA and ALA‐derived formulations are available and approved in Europe including Ameluz® (Biofrontera AG, Leverkusen, Germany), Metvix® (Galderma, Zug, Switzerland), and Luxerm® 16% MAL cream (Galderma, Zug, Switzerland), and an 8 mg ALA patch (Alacare®, Photonamic GmbH und Co. KG, Pinneberg, Germany). ¹⁰

There are several studies that examine and discuss the results of various PDT treatments for HS, however many of the studies are isolated case reports or case series, and randomized controlled trials are lacking. In 2015, the European S1 guidelines for the treatment of HS did not make a recommendation regarding PDT for the treatment HS, stating that more studies were needed to “establish the role of PDT.” ¹⁴ Later, the 2017 Swiss HS Practice Recommendations were published, which made no mention of PDT as a potential treatment. ¹⁵ In 2018, the HS ALLIANCE working group again did not provide a recommendation for PDT due to the limited data available. ¹⁶ It was not until 2019 that the North American HS Guidelines recommended PDT with a C strength of recommendation and level II/II evidence, based on the Strength of Recommendation Taxonomy (SORT) criteria. ⁴ To our knowledge, there have been no systematic reviews exclusively evaluating PDT in HS to help guide treatment recommendations and future studies. Therefore, the objective of this study was to perform a systematic review of current available literature regarding the usage of ALA and ALA derivative PDT as an HS treatment modality.

2. METHODS

2.1. Literature search

The study was exempt from institutional review board approval at the University of Minnesota as data were gathered from published literature. In accordance with Methodological Expectations of Cochrane Intervention Reviews (MECIR) guidelines, ¹⁷ the search was developed to include both natural language and controlled vocabulary to reflect the concepts of photodynamic therapy and hidradenitis suppurativa (Table S1). The search was implemented in nine resources: Medline (Ovid), PubMed, Embase (Ovid), Cochrane Library (Wiley), Web of Science Core Collection, Scopus, Global Index Medicus, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP). The search was conducted in September 2019, and no restrictions on language, date of publication, or study design were employed in the search strategy (Table S1). To ensure that no potentially relevant items were excluded, we also performed a hand search of reference lists of included and related publications. The systematic review was registered with PROSPERO (CRD42020183029).

2.2. Eligibility criteria and selection of studies

Abstracts were chosen for inclusion based on article titles by two blinded reviewers (SR, SN). Disagreements on article inclusion were reconciled by a third party (NG) upon discussion with the two reviewers. On full‐text review, articles were chosen for inclusion or exclusion by three blinded review team members (SR, SN, NG). Disagreements on article inclusion were reconciled through a discussion with a fourth party (IH). The systematic review included studies with at least one participant diagnosed with HS by a dermatologist treated with PDT using ALA or an ALA derivative. To be included in the systematic review, studies needed to report the type of photosensitizer and light source used. Conference abstracts, articles that did not include original data, and articles that included patients that had surgery performed on their HS lesions were excluded.

2.3. Data extraction and risk of bias

The following data were extracted from the studies: study title, study author, publication year, study type, number of patients, number of males and females, Hurley stages of patients included, photosensitizer used, incubation time, light source, medium, dosage, number of sessions and interval between sessions, time to follow‐up, outcome measures evaluated, and results. Risk of bias for all studies included in the systematic review was evaluated to determine if they had low risk of bias, rated as good and deeming results valid; some bias, rated as fair and not sufficient to invalidate results; or high risk of bias, rated as poor and indicating that the results may be invalid. Risk of bias and study quality for each study was assessed by two blinded review team members (SR, SN), with disagreements reconciled through discussion among the two review team members and a third party (NG). Risk of bias was evaluated based on the National Heart, Lung, and Blood Institute's quality assessment tools ¹⁸ and quality was rated as good, fair, or poor.

2.4. Level of evidence and strength of recommendations

Study quality was assessed using the Strength of Recommendations Taxonomy (SORT) ¹⁹ which includes a strength of recommendation and a level of evidence. Each study was assigned level of evidence from one to three. Level one corresponded to good‐quality patient‐oriented evidence. Level two corresponded to limited quality patient‐oriented evidence, and level three corresponded to other evidence. The body of literature for each treatment modality was evaluated for consistency, defined as coherent conclusions amongst studies. Consistency was reported as not applicable if there was only one study reviewed. A recommendation and strength of recommendation for each treatment modality were determined based on level of evidence and consistency. Strength of recommendation was graded as A if based on consistent and good‐quality patient‐oriented evidence; B if based on inconsistent or limited‐quality patient‐oriented evidence; C if based on consensus, usual practice, opinion, disease‐oriented evidence, or case series. Strength of recommendation was reported as insufficient if the data were too inconsistent to be able to provide a recommendation or if there was no data available for the specific light source and photosensitizer combination. The recommendation and strength of recommendation were decided upon through discussion with SN, SR, IH, and NG.

3. RESULTS

3.1. Study selection

The study selection process is summarized in Figure 1. Four hundred and seventy‐two non‐duplicate articles were identified in the database search. Thirty‐four studies were included following review of titles and abstracts. Sixteen studies were excluded during full‐text review: one using the wrong photosensitizer, one with the photosensitizer not specified, four conference abstracts, three studies that included patients who underwent surgery combined with PDT, four in which the outcomes were not discussed, two review articles, and one study that did not include HS patients. Eighteen studies met inclusion criteria and were included in the systematic review: four case series, five case reports, eight pre‐post studies, and one split‐body controlled study. The studies were separated into categories according to light source: blue light PDT, red light PDT, intralesional diode PDT, pulsed dye laser (PDL) PDT, and multiple modalities including PDT. Improvement was measured by validated and non‐validated outcome measures, including Dermatology Life Quality Index (DLQI), modified Sartorius score, median hidradenitis severity score, visual analog scale (VAS), lesion size and count, symptomatic improvement, mean global severity scores, and pain and disease activity scale. Adverse effects and recurrence were also noted when reported. The studies included a total of 118 participants: 52 males, 56 females, and 10 were unspecified. Multiple studies did not specify Hurley stage but of those that did, the majority of patients were Hurley stage II or III.

PRISMA flowchart of article selection process

3.2. Blue light PDT

Three case series examining the use of blue light PDT were included (Table 1). ²⁰ , ²¹ , ²² One study used multiple modalities, but patients treated with only blue light PDT were included in this section. ²² The three studies were comprised of a total of 13 patients, one male, five females, and seven unspecified. Hurley stages were not specified for any of the participants. Each study used 20% ALA with an incubation period ranging from 15 min to 1.5 h. Settings for the light source were not specified. While all three studies were consistent in demonstrating efficacy of blue light PDT with level III evidence, all studies were rated as poor quality with high risk of bias. There were few studies, each with small sample size. Due to the consistency of results amongst the three case series, blue light PDT received a grade C strength of recommendation for the treatment of HS with level III evidence (Table 5).

TABLE 1.

Studies using blue light PDT

Study (First author, year)	Study design (Level of Evidence; Bias)	N (M:F)	Hurley Stages	Photosensitizer	Incubation Time (+/− occlusion)	Light Source = wavelength [nm], medium (Brand)	Settings [J/cm²] (Time [min])	Sessions (Interval)	Follow‐up	Outcome Measure (validated/non‐validated)	Results	Comments/Recurrence
Gold et al, 2004 ¹⁹	Case series (III; Poor)	4 (0:4)	NA	20% ALA (Levulan)	15–30 min (NA)	407–420 nm (Clearlight photoclearing system, Lumenis, Santa Clara, CA)	NA (NA)	3–8 (1–2 wks)	3 mo	Clearance (non‐validated)	Cases 1,2,4: 75% clearance	All patients maintained response at 3 months
Gold et al, 2004 ¹⁹	Case series (III; Poor)	4 (0:4)	NA	20% ALA (Levulan)	15–30 min (NA)		NA (NA)	3–8 (1–2 wks)	3 mo	Improvement in symptoms (non‐validated)	Case 3: 100% improvement	Only case 3 had 8 sessions
Rivard et al, 2006 ²⁰	Case Series (III; Poor)	2 (1:1)	NA	20% ALA (Levulan)	1–1.5 hrs (NA)	BLU‐U Blue Light (DUSA Pharmaceuticals) PDT illuminator model 4170	NA (10–18 min)	1–3 (NA)	NA	Symptoms (non‐validated)	Case 1: less drainage	Case 1: 2 x 60% glycolic acid peels
										Symptoms (non‐validated)	Case 2: improved	Case 2: Also treated with Candela 595 nm V‐beam laser (4–5 J/cm²; 6 msec pulse duration, 10 mm spot size)
										Lesion size (non‐validated)	Case 1: markedly smaller lesion
Schweiger et al, 2011 ²¹	Case Series (III; Poor)	7	NA	20% ALA	45 min (NA)	417 nm blue light (NA) or 415 nm blue light from a light‐emitting diode (NA)	NA	4 (1 wk)	8 wks	Mean lesion counts (SD) (non‐validated)	Pre: 11.4 (10.9) Post: 8.1 (8.6)	More severe disease improved more than mild disease
										Mean Global Severity Scores (SD) (non‐validated)	Pre: 2.1 (0.9) Post: 1.7 (1.3)	Blue light better tolerated than IPL
										DLQI (Validated)	Pre: 16.7 (7.2) Post: 13.1 (6.0)	Data also presented in Table 5

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Abbreviations. ALA, aminolevulinic acid; cm, centimeter; DLQI, Dermatology Life Quality Index; F, female; IPL, intense pulse light; J, joules; M, male; min, minutes; mm, millimeter; msec, millisecond; mo, months; N, number of participants; nm, nanometer; NA, not available; PDT, photodynamic therapy; SD, standard deviation; wk, week; wks, weeks.

TABLE 5.

Level of evidence, consistency, and recommendations

PDT Light Modalities	Level of Evidence	Consistency	Strength of Recommendation	Is Treatment Recommended?
Blue light
20% ALA	III	Consistent	C	Yes
Red light
5% ALA	II, III	Inconsistent	Insufficient	No
20% ALA	II, III	Inconsistent	Insufficient	No
MAL	III	Consistent	C	Yes
595 nm pulsed dye laser
MAL	III	NA	C	No
630 nm intralesional diode
1%–5% ALA	II, III	Consistent	B	Yes
633‐nm external diode laser
20% ALA	II	NA	Insufficient	No
Intense pulsed light
20% ALA	III	NA	Insufficient	No

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Abbreviations. ALA, aminolevulinic acid; NA, not applicable; nm, nanometer; NA, Not applicable; PDT, photodynamic therapy.

3.3. Red light PDT

Three pre‐post studies, one case series, and five case reports examining red light PDT were included (Table 2). The nine studies and reports were comprised of 24 patients, with Hurley stage II or III HS. There was one case of broadband red light PDT used in a larger series of patients utilizing multiple modalities including PDT (Table S2). ²³ As the individual outcome data for this patient was not provided, this case was not included in the red light PDT section and instead was presented in the table for multiple modalities including PDT (Table S2).

TABLE 2.

Studies using red light PDT

Study (First author, year)	Study design (Level of Evidence; Bias)	N (M:F)	Hurley Stages	Photosensitizer	Incubation Time (+/− occlusion)	Light Source = wavelength [nm], medium (Brand)	Settings (J/cm²) (Time [min])	Sessions (Interval)	Follow‐up	Outcome Measure (validated/non‐validated)	Results	Comments
5% ALA
Zhang et al, 2016²³	Pre‐Post (II; Poor)	3 (3:0)	III	5% ALA (Shanghai Fudan‐Zhangjiang Bio‐Pharmaceutical Co. Ltd., Shanghai, China)	4 hrs (occluded)	633 nm+/−6 nm (LED device, red Omnilux Revive, Photo Therapeutics Ltd., Manchester, UK)	126 J/cm² (NA)	3 (2 wks)	1 yr	Lesion clearance (Excellent:> 90%; moderate: 50–89%, slight: 20–49%, poor: <20% or worse) (non‐validated)	All 3 had poor response	No worsening or improvement
										DLQI (validated)	No change
										Adverse Events (non‐validated)‐itching, pain, and edematous erythema	All, 1–7 days after treatment
Zhang et al, 2018²⁴	Case Report (III; Poor)	1 (1:0)	NA	5% ALA	4 hrs (occluded)	630 +/− 5 nm	96 J/cm² (20 min)	9 (10–15 days)	NA	Improvement (non‐validated)	Resolution of skin lesions
						LED‐1A (Yage Optic And Electronic Technique Co., Ltd, Wuhan, China)					Ulcer healing
											Disappearance of symptoms
20% ALA
Andino Navarrete et al, 2013²⁵	Pre‐Post (II; Fair)	5 (1:4)	II/III	20% ALA (Oldex, Recalcine)	1.5 hrs (NA)	635 nm (PDT 1200 L, Herbert Waldmann GmbH & Co.)	37 J/cm² (~9 min)	4 minimum (7–14 days)	8 wks	Modified Hidradenitis Suppurativa Score/ Modified Sartorius Score (mean [SD]) (validated)	Baseline: 35 (5) 8 wk: 18 (8)	All patients refractory to at least 2 medical treatments
										Mean DLQI (SD) (validated)	Baseline: 28.8 (2.68) 8 wks: 7.49 (2.79)	Response noted in all patients by week 4
										Mean Pain and Disease Activity Scale (SD) (non‐validated)	Baseline: 3 (0) 8 wks: 0.80 (0.45)
										Adverse events (non‐validated)	2 with mild burning during tx
Lau et al, 2014²⁶	Case Report (III; Poor)	1 (NA)	NA	20% ALA [w/w in Unguentum M; Crawfords Pharmaceuticals, Milton Keynes, UK]	3–5 hrs (NA)	632 nm LED source (Aktilite; Galderma [UK] Lts, Herts, UK)	75 J/cm² (~16 min)	2 (14 days)	NA	Improvement (non‐validated)	Initial improvement	Relapsed when stopped
Sotiriou et al, 2009²⁷	Pre‐Post (II; Poor)	5 (3:2)	II/III	20% ALA (Medac GmBh, Hamburg, Germany)	3 hrs (occluded)	570–670 nm, noncoherent light source (Waldmann PDT 1200; Waldmann‐Medizin‐Technik, Villingen‐Schwenningen, Germany)	20 J/cm² (NA)	4 (14 days)	2 mo	Mean Sartorius score (validated)	Baseline: 18.8 2 mo: 17.2	None had significant improvement
										Mean visual analog scale (validated)	Baseline: 2.4 2 mo: 2.1	All patients had significant HS scarring
										Mean DLQI reduction (validated)	6.4%
										Adverse Events (non‐validated)
										‐Pain/burning	All during treatment
										‐Erythema	All, up to 1 week after
										Swelling and Blistering	2, lasted 8–10 days
MAL
Calzavara‐Pinton et al, 2013²⁹	Case‐series (III; Poor)	6 (1:5)	NS	MAL (Metvix)	3–4 hrs (occluded)	635 ± 18 nm, diode lamp (Aktilite CL128, PhotoCure ASA, Oslo, Norway)	37 J/cm² (NA)	4.8 +/− 2.9 (18.8 +/− 8.4 days)	2.6 ± 0.55 mo	Improvement (Marked:>75%; Mod: 50–75%; Poor: < 50%) (non‐validated)	Marked: 2 (33%) Mod: 3 (50%)Poor: 1 (17%)	Only 1 patient maintained marked response at follow‐up
						Polychromatic light sources (PDT S‐630 lamp, Alpha Strumenti Srl, Melzo, Italy; PDT 1200 L, Waldmann GmbH, Villingen‐Schwenningen, Germany)	Equivalent doses to diode			Adverse events (non‐validated)
										‐Local reaction:	Marked 0 (0%) Mod: 5 (83%) Absent: 1 (17%)
										‐Pain/burning during treatment	None: 0 (0%) Mild: 2 (33%) Mod: 4 (67%) Marked: 0 (0%)
Guglielmetti et al, 2010³⁰	Case Report (III; Poor)	1 (0:1)	III	MAL (Metvix)	3 hrs (occluded)	630 nm (Aktilite, PhotoCure ASA)	37 J/cm² (8 min)	2 (10 days)	12 mo	Inflammation/ exudate (non‐validated)	Decrease 90–100%	Mild relapse at 12 mo follow‐up
										Adverse events (non‐validated)
										‐Pain/burning during treatment	Moderate burning and pain
										‐Erythema	Immediately after, lasting 2 days
Perez Wilson et al, 2010³¹	Case Report (III; Poor)	1 (0:1)	NA	MAL (Metvix)	3 hrs (occluded)	630 nm LED (Aktilitie)	37 J/cm² (NA)	4 (15–20 days)	1 yr	Clinical response (non‐validated)	>90% improvement	No recurrence at 1 yr follow‐up
Saraceno et al, 2009³²	Case Report (III; Poor)	1 (1:0)	NA	MAL (Metvix, Galderma, Agrate Brianza, Italy)	3 hrs (occluded)	570–670 nm	37 J/cm² (8 min)	9 (15 days)	6 mo	Clearance (non‐validated)	80%	Improvement also noted for pilonidal cyst
										Itching and discomfort (non‐validated)	Complete resolution
										Adverse events (non‐validated)	Complete resolution
										‐Pain/burning	During treatment
										‐Erythema	Mild, day after

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Abbreviations. ALA, aminolevulinic acid; cm, centimeter; DLQI, Dermatology Life Quality Index; F, female; F/U, follow up; hrs, hours; J, joules; M, male; min, minutes; mo, months; N, number of participants; NA, not applicable; nm, nanometer; NA, Not available; PDT, photodynamic therapy; SD, standard deviation; tx, treatment; wk, week; wks, weeks; yr, year.

Two studies, with a total of four participants, used 5% ALA with an incubation period of 4 h under occlusion. ²⁴ , ²⁵ The light source was set to 96–126 J/cm². While one patient had resolution of skin lesions, the three others had a poor response with no change in clinical symptoms. The two studies provide level II/III evidence, with inconsistent results and high risk of bias, providing insufficient evidence for the use of 5% ALA with red light PDT for the treatment of HS. (Table 5).

Three studies with a total of 11 participants, used 20% ALA with an incubation period of 1.5–5 h. ²⁶ , ²⁷ , ²⁸ Only one of these studies specified that the incubation was done under occlusion. ²⁸ The light source was set to 20–75 J/cm². Of the three studies, one study reported that none of the five participants had significant improvement, but the authors commented that all patients had significant scarring. ²⁸ Of note, in this study there was a 6.4% reduction in mean dermatology quality of life index, which is greater than the minimal clinically important difference of 4 for the DLQI. ²⁸ , ²⁹ A second study reported initial improvement in a single patient with relapse after stopping treatment, ²⁷ and the third study reported improvement in all five participants. ²⁶ These three studies provided insufficient evidence, neither in favor of or against the use of 20% ALA with red light PDT for the treatment of HS. Due to the inconsistency of results and high risk of bias, 20% ALA with red light PDT is not recommended at this time for the treatment of HS. ²⁶ , ²⁷ , ²⁸ (Table 5).

Four studies with a total of nine participants used MAL with an incubation period of 3–4.5 h under occlusion. ³⁰ , ³¹ , ³² , ³³ The light source was set to 37 J/cm². One study reported moderate or marked improvement in five out of six participants on follow‐up. ³⁰ Another reported improvement in one patient with mild relapse at 12‐month follow‐up. ³¹ The two remaining case reports showed improvement in two patients without relapse noted at 6‐month and 1‐year follow‐up, respectively. ³² , ³³ These four studies provided level III evidence in favor of the use of MAL with red light PDT for the treatment of HS, with consistent results but studies with high risk of bias. (Table 5).

3.4. Pulsed dye laser PDT

Only one split‐body controlled study was included that used 595 nm pulsed dye laser (PDL), which did not report overall improvement (Table 3). ³⁴ The study was comprised of four patients. The number of males, females and Hurley stage was not specified. The study used MAL with an incubation period of 3 h under occlusion. The light source was set to 7.5 J/cm², spot size 7 mm, and pulse duration of 10 msec. Inflammatory lesions were treated with double stacking. Of the four patients included in the study, three did not show improvement and one reported worsening of disease requiring surgical treatment. The study was rated as poor with high risk of bias, providing level III evidence against the use of pulse dye laser‐mediated PDT in the treatment of HS. As none of the four patients in the literature had improvement of their HS, and one had worsening, pulse dye laser‐mediated PDT for the treatment of HS is not recommended with a grade C strength of recommendation with level III evidence (Table 5).

TABLE 3.

Studies using pulsed dye laser

Study (First author, year)	Study design (Level of Evidence; Bias)	N (M:F)	Hurley Stages	Photosensitizer	Incubation Time (+/− occlusion)	Light Source = wavelength [nm], medium (Brand)	Settings (J/cm²)	Sessions (Interval)	Follow‐up	Outcome Measure (validated/non‐validated)	Results	Comments
Passeron et al, 2009³³	Split‐body controlled study (III; Poor)	4 (NA)	NA	MAL	3 hrs (occluded)	595 nm pulsed dye laser (Vbeam; Candela)	7.5 J/cm²; spot size 7 mm, pulse duration 10 msec	3 (1 mo)	3 mo	Sartorius Score (validated)	PDTPre: 7, 18, 8, 12Post: 7, NA, 6, 14ControlPre: 6, 18, 6, 14Post: 8, NA, 6, 12	Double stacking for inflammatory lesions One patient (NA) had worsening and required surgical treatment.
Passeron et al, 2009³³	Split‐body controlled study (III; Poor)	4 (NA)	NA	MAL	3 hrs (occluded)	595 nm pulsed dye laser (Vbeam; Candela)	(DCD 30/20)	3 (1 mo)	3 mo	Adverse Events ‐Pain during treatment (VAS) (validated)	Mean 8 (range: 6–9)	PDT was in conjunction with other therapies

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Abbreviations. ALA, aminolevulinic acid; cm, centimeter; DCD, dynamic cooling device; F, female; hrs, hours; J, joules; M, male; MAL, methyl aminolevulinate; mo, months; msec, millisecond; N, number of participants; NA, not applicable; nm, nanometer; NA, Not available; PDT, photodynamic therapy; VAS, visual analog scale.

3.5. Intralesional diode PDT

One case series and two pre‐post studies examining the use of PDT with a 630 nm intralesional diode were included (Table 4). ³⁵ , ³⁶ , ³⁷ The three studies were comprised of 68 patients, 39 males and 29 females. One study included patients with Hurley stages I to III, ³⁶ but the other two did not specify. ³⁵ , ³⁷ Two studies used 1% ALA (0.1–0.2 ml/cm³) with an incubation period of 3 h under occlusion. ³⁵ , ³⁷ The third study used 5% ALA funneled into tunnels and 1% ALA injected into nodules with an incubation period of 2 h under occlusion. ³⁶ All three studies used a light source set to 180 J/cm². The case series presented three patients with resolution of lesions and symptoms without recurrence, providing level III evidence supporting the use of PDT with intralesional diode, with high risk of bias. ³⁵ The pre‐post studies provided level II evidence in favor of PDT with intralesional diode, one with high risk of bias, ³⁷ and the other deemed as having low risk of bias. ³⁶ Due to the consistency of results amongst the three studies with good to complete response in 78–94% of anatomic sites treated, PDT with intralesional diode was recommended for the treatment of HS with a grade B strength of recommendation with level II/III evidence.

TABLE 4.

Studies using PDT with intralesional diode

Study (First author, year)	Study design (Level of Evidence; Bias)	N (M:F)	Hurley Stages	Photosensitizer (+/− intralesional)	Incubation Time (+/− occlusion)	Light Source = wavelength [nm], medium (Brand)	Settings (J/cm2)	Sessions (Interval)	Follow‐up	Outcome Measure (validated/non‐validated)	Results	Comments
Rodriguez‐Prieto, 2013³⁴	Case Series (III; Poor)	3 (3:0)	NA	1% ALA (0.1–0.2 mL/cm³ intralesional)	3 hrs (occluded)	630 nm diode (intralesional)	180 J/cm³ (3 min)	1–3 (NA)	NA	Inflammation/symptom (non‐validated)	Resolution of inflammation/symptoms for all patients	One patient received PDT previously with no help
Rodriguez‐Prieto, 2013³⁴	Case Series (III; Poor)	3 (3:0)	NA	1% ALA (0.1–0.2 mL/cm³ intralesional)	3 hrs (occluded)	630 nm diode (intralesional)	180 J/cm³ (3 min)	1–3 (NA)	NA	Clinical Recurrence (non‐validated)	No clinical recurrence after 7–14 mo for any patient	Two patients had resolution of treated tunnels
Suárez Valladares et al, 2016³⁵	Pre‐post (II; Good)	38 (20: 18)	I‐III	5% ALA gel (Intrala, IDP Light, S.L. Alicante, Spain) for fistulas (intralesional)	2 hrs (occluded)	630 nm diode (intralesional) (Multidiode 630 PDT, Intermedic, Barcelona, Spain)	180 J/cm³ (NA)	NA (5–7 wks)	26.21 mo (21.07–68.57 mo)	Median Hidradenitis Severity Score (IQR) (validated)	Pre: 28.5 (11.75–38.5)Post: 0 (0–45)	18/38 (47.3%) had only one session
				1% ALA solution for nodules (intralesional)						Median DLQI (IQR) (validated)	Pre: 10 (7–17)Post: 1 (0–2.25)	Those needing repeated session were treated over a mean of 18.2 wks (+/−30.6)
										Adverse effects
										Pain VAS (During treatment)	3 (2–5.25)
										Persistence (non‐validated)	8/38 (21%)
										Remission (non‐validated)	29/38 (76%)
										Recurrence (non‐validated)
										Recurrence (non‐validated)	1/38 (3%)

Valladares‐Narganes et al, 2015³⁶	Pre‐post (II; Poor)	27 (16: 11)	NA	1% 5‐ALA in saline, 0.2 ml/cm³ (intralesional)	3 hrs (occluded)	630 cm diode (LasAX630, INTERmedic, Barcelona, Spain)	180 J/cm³ (3 min)	NA (NA)	6 mo	Mean localized Modified Sartorius score (SD) (validated)	Pre: 20.7 (14.4)Post: 8.8 (11.0)	Axilla had best results (6/8 with complete response)
										Modified Sartorius Response (non‐validated) (Complete ≥75%; good: 50–75%; partial: 25–50%; No response: <25%)	Complete: 10Good: 11Partial: 5	Adverse effects: postoperative pain, erythema, mild swelling, flu‐like reaction
										Adverse Effects Pain VAS (during treatment) (validated) (Severe: ≥9; Moderate: 6–9; Low: 1–6)	Severe: 1Moderate: 4Low: 22

Open in a new tab

Abbreviations. ALA, aminolevulinic acid; cm, centimeter; DLQI, Dermatology Life Quality Index; F, female; IQR, interquartile range; J, joules; M, male; min, minutes; ml, milliliter; mo, months; N, number of participants; NA, not applicable; nm, nanometer; NA, Not available; PDT, photodynamic therapy; SD, standard deviation; VAS, visual analog scale; wks, weeks.

3.6. Multiple modalities including PDT

Two pre‐post studies comparing multiple modalities were included (Table S2). ²² , ²³ The two studies were comprised of 16 patients, 3 males, 9 females, and 4 unspecified. Hurley stages were not specified. Both studies used 20% ALA, one with an incubation period of 45 min and the other with an incubation period of 4 h under occlusion. The first study used intense pulsed light (IPL) alone, blue light alone, and mixed IPL and blue light. ²² This study demonstrated small improvements in mean lesion counts, global severity score, and dermatology life quality index (DLQI) scores for both blue light alone, IPL‐mediated PDT alone, and both modalities combined. Greater improvement was noted in patients with more severe HS. They also noted that blue light PDT was better tolerated than IPL. ²² Given the limited number of patients treated with IPL‐mediated PDT and high risk of the study, it was deemed that there was insufficient evidence for or against IPL‐mediated PDT in the treatment of HS.

The second study, which used a 633 nm diode laser for three patients and a broadband red light (15 J/cm²) for one patient, did not demonstrate an overall improvement in any patients. ²³ This study provided level II evidence against PDT using an external diode laser, with too few patients to conduct statistical analyses on and high risk of bias. Given the limited number of patients treated with an external diode laser, it was deemed that there was insufficient evidence for or against the use of PDT using an external diode laser in the treatment of HS (Table 5).

4. DISCUSSION

The majority of studies examining PDT for the treatment of HS were of poor quality. Blue light PDT with 20% ALA demonstrated benefit (Grade C, level III evidence), supported by consistent improvement in 13 of 13 patients in three studies. All of these studies employed low‐quality study designs, using non‐validated outcome measures, with high risk of bias, providing the lowest level of evidence in support of blue light PDT. Similarly, red light PDT using MAL also demonstrated benefit in eight of nine participants over four studies, providing Grade C, level III evidence with consistent data in support of its use, albeit with data with high risk of bias. Red light PDT with 5% and 20% had insufficient evidence for or against its use in the treatment of HS, respectively. These findings are overall consistent with the recommendations made in the North American clinical management guidelines, which recommend PDT for HS with grade C, level III evidence. ⁴ Of note, none of the studies in this review examined the effect of skin color on the efficacy of PDT. Given the impact of melanin on light absorption, it remains unknown how skin type influences PDT efficacy. Thus, it will be important that future studies on PDT for HS include and examine the efficacy for participants with a wide range of skin types.

The mechanism of action of blue and red light PDT for HS remains unknown. Protoporphyrin IX, a metabolite of ALA, has been found to preferentially accumulate in sebaceous glands, and to a lesser extent in the hair follicles and epidermis. ³⁸ Accumulation of protoporphyrin IX has a direct cytotoxic effect on these cells with a preference for those that rapidly proliferating. ³⁹ Blue and red light PDT have also demonstrated antimicrobial effects on several bacterial species, including Cutibacterium acnes (C. acnes), a gram‐positive anaerobic bacilli that plays an important role in the pathogenesis of acne. ³⁸ In addition, IPL‐mediated PDT with 5% ALA increases the expression of anti‐inflammatory cytokines, IL‐10 and transformation growth factor‐beta (TGF‐β1) by keratinocytes. ⁴⁰

Pulsed dye laser‐mediated PDT was only evaluated in four patients in a single study with no appreciable difference between treated compared to control body sites, with worsening in one patient. Based on this level III evidence, it was deemed that there was sufficient evidence to recommend against PDL‐mediated PDT. For both PDT using a 633 nm external diode laser and IPL‐mediated PDT, it was deemed that there was insufficient evidence to recommend either of these modalities. PDT using a 633 nm external diode laser was only evaluated in three patients in a single study with no appreciable difference between pre‐ and post‐treatment. IPL‐mediated PDT demonstrated some improvement in mean lesion counts and DLQI pre‐ to post‐treatment, but there were only three patients evaluated in a single study, too few to make any meaningful recommendations.

The most encouraging results were for 1–5% ALA with 630 nm intralesional diode. Due to the consistency of results amongst the three studies, with good to complete response in 78–94% of anatomic sites treated, PDT with 630 nm intralesional diode for the treatment of HS was recommended with a grade B strength of recommendation with level II/III evidence. This modality first entails either funneling 1–5% ALA gel or solution down an HS tunnel via a catheter or canula, or injecting 1% ALA into an inflammatory nodule. Next, the lesions are irradiated intralesionally with a 630 nm diode laser via a fiber optic cable transmitted to the tissue via a needle. The mechanism of action for the 630 nm intralesional diode for HS is not well understood, but may reduce inflammation via selective photothermolysis targeting either the blood vessels or hair follicle. Larger, randomized trials are needed to further validate this treatment modality for HS.

In conclusion, most of the data currently available examining the use of PDT for the treatment of HS contains high levels of bias and has a significant amount of variability between studies in severity of disease, protocols (photosensitizer concentration, incubation time, occlusion, light source settings), number of sessions, and length of follow‐up. In addition, many studies contained small sample sizes, were not randomized controlled trials, and did not specify severity of disease, making it difficult to compare outcomes and draw meaningful conclusions. Based on the limited data available 20% ALA with blue light and MAL with red light PDT should be further explored as potential treatment modalities for HS. 630 nm intralesional diode PDT shows the most promise and warrants further investigation in larger, randomized controlled trials.

CONFLICT OF INTEREST

Sofiya Reshetylo, Shanthi Narla, Thomas Freeman have no conflicts of interest to report. Ronda Farah is an employee of the University of Minnesota Department of Dermatology, which has received equipment and funding from Syneron Candela. Iltefat Hamzavi is the president of the HS Foundation and has served as an advisory board member, investigator, and/or has received research funding from AbbVie, Pfizer Inc., Bayer, Lenicura, Incyte, UCB, HS Foundation, and Boehringer Ingelheim. Noah Goldfarb participates in clinical trials with Abbvie, Pfizer, Chemocentryx and Balter Medical and has served on advisory board for Novartis.

Supporting information

Table S1

Click here for additional data file.^{(20.2KB, docx)}

Table S2

Click here for additional data file.^{(19.4KB, docx)}

Reshetylo S, Narla S, Bakker C, et al. Systematic review of photodynamic therapy for the treatment of hidradenitis suppurativa. Photodermatol Photoimmunol Photomed. 2023;39:39‐50. doi: 10.1111/phpp.12812

Sofiya Reshetylo and Shanthi Narla contributed equally.

Iltefat H. Hamzavi and Noah Goldfarb contributed equally.

Funding information

This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Minneapolis, MN. The contents of this publication do not represent the views of the Department of Veterans Affairs or the United States Government.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1

Click here for additional data file.^{(20.2KB, docx)}

Table S2

Click here for additional data file.^{(19.4KB, docx)}

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

[phpp12812-bib-0001] 1. Zouboulis CC, Benhadou F, Byrd AS, et al. What causes hidradenitis suppurativa ?‐15 years after. Exp Dermatol. 2020;29(12):1154‐1170. [DOI] [PubMed] [Google Scholar]

[phpp12812-bib-0002] 2. Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med. 2012;366(2):158‐164. [DOI] [PubMed] [Google Scholar]

[phpp12812-bib-0003] 3. Golbari NM, Porter ML, Kimball AB. Antiandrogen therapy with spironolactone for the treatment of hidradenitis suppurativa. J Am Acad Dermatol. 2019;80(1):114‐119. [DOI] [PubMed] [Google Scholar]

[phpp12812-bib-0004] 4. Alikhan A, Sayed C, Alavi A, et al. North American clinical management guidelines for hidradenitis suppurativa: A publication from the United States and Canadian Hidradenitis Suppurativa Foundations: Part I: Diagnosis, evaluation, and the use of complementary and procedural management. J Am Acad Dermatol. 2019;81(1):76‐90. [DOI] [PMC free article] [PubMed] [Google Scholar]

[phpp12812-bib-0005] 5. van Straalen KR, Tzellos T, Guillem P, et al. The efficacy and tolerability of tetracyclines and clindamycin plus rifampicin for the treatment of hidradenitis suppurativa: Results of a prospective European cohort study. J Am Acad Dermatol. 2021;85(2):369‐378. [DOI] [PubMed] [Google Scholar]

[phpp12812-bib-0006] 6. Nazzaro G, Zerboni R, Passoni E, et al. High‐frequency ultrasound in hidradenitis suppurativa as rationale for permanent hair laser removal. Skin Res Technol. 2019;25(4):587‐588. [DOI] [PubMed] [Google Scholar]

[phpp12812-bib-0007] 7. Hambly R, Kirby B. Biologic survival in hidradenitis suppurativa: much done, more to do. Br J Dermatol. 2021;185(1):16‐17. [DOI] [PubMed] [Google Scholar]

[phpp12812-bib-0008] 8. Frew JW, Marzano AV, Wolk K, et al. A systematic review of promising therapeutic targets in hidradenitis suppurativa: a critical evaluation of mechanistic and clinical relevance. J Invest Dermatol. 2021;141(2):316‐324.e2. [DOI] [PubMed] [Google Scholar]

[phpp12812-bib-0009] 9. Taub AF. Photodynamic therapy: other uses. Dermatol Clin. 2007;25(1):101‐109. [DOI] [PubMed] [Google Scholar]

[phpp12812-bib-0010] 10. Monfrecola G, Megna M, Rovati C, et al. A critical reappraisal of off‐label use of photodynamic therapy for the treatment of non‐neoplastic skin conditions. Dermatology. 2021;237(2):262‐276. [DOI] [PubMed] [Google Scholar]

[phpp12812-bib-0011] 11. DUSA Pharmaceuticals, Inc . Levulan Kerastick (aminolevulinic acid HCl) [package insert]. U.S. Food and Drug Administration website. Revised December 1999. Accessed May 18, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/20965lbl.pdf

[phpp12812-bib-0012] 12. Biofrontera Inc . Ameluz (aminolevulinic acid hydrochloride) [package insert]. U.S. Food and Drug Administration website. Revised May 2016. Accessed Accessed May 18, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208081s000lbl.pdf

[phpp12812-bib-0013] 13. Galderma Laboratories, L.P. Metvixia (methyl aminolevulinate) [package insert]. U.S. Food and Drug Administration website. Revised November 2012. Accessed May 18, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021415s004lbl.pdf

[phpp12812-bib-0014] 14. Zouboulis CC, Desai N, Emtestam L, et al. European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa. J Eur Acad Dermatol Venereol. 2015;29(4):619‐644. [DOI] [PubMed] [Google Scholar]

[phpp12812-bib-0015] 15. Hunger RE, Laffitte E, Läuchli S, et al. Swiss practice recommendations for the management of hidradenitis suppurativa/acne inversa. Dermatology. 2017;233(2–3):113‐119. [DOI] [PubMed] [Google Scholar]

[phpp12812-bib-0016] 16. Zouboulis CC, Bechara FG, Dickinson‐Blok JL, et al. Hidradenitis suppurativa/acne inversa: a practical framework for treatment optimization ‐ systematic review and recommendations from the HS ALLIANCE working group. J Eur Acad Dermatol Venereol. 2019;33(1):19‐31. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[phpp12812-bib-0019] 19. Ebell MH, Siwek J, Weiss BD, et al. Strength of recommendation taxonomy (SORT): a patient‐centered approach to grading evidence in the medical literature. J Am Board Fam Pract. 2004;17(1):59‐67. [DOI] [PubMed] [Google Scholar]

[phpp12812-bib-0020] 20. Gold M, Bridges TM, Bradshaw VL, Boring M. ALA‐PDT and blue light therapy for hidradenitis suppurativa. J Drugs Dermatol. 2004;3(1 Suppl):S32‐S35. [PubMed] [Google Scholar]

[phpp12812-bib-0021] 21. Rivard J, Ozog D. Henry Ford Hospital dermatology experience with Levulan Kerastick and blue light photodynamic therapy. J Drugs Dermatol. 2006;5(6):556‐561. [PubMed] [Google Scholar]

[phpp12812-bib-0022] 22. Schweiger ES, Riddle CC, Aires DJ. Treatment of hidradenitis suppurativa by photodynamic therapy with aminolevulinic acid: preliminary results. J Drugs Dermatol. 2011;10(4):381‐386. [PubMed] [Google Scholar]

[phpp12812-bib-0023] 23. Strauss RM, Pollock B, Stables GI, et al. Photodynamic therapy using aminolaevulinic acid does not lead to clinical improvement in hidradenitis suppurativa. Br J Dermatol. 2005;152(4):803‐804. [DOI] [PubMed] [Google Scholar]

[phpp12812-bib-0024] 24. Zhang L, Wang P, Shi L, et al. Topical 5‐aminolevulinic acid photodynamic therapy improved refractory acne conglobata and perifolliculitis capitis abscedens et suffodiens rather than hidradenitis suppurativa. J Innov Opt Health Sci. 2016;9(1):1640002. [Google Scholar]

[phpp12812-bib-0025] 25. Zhang Y, Yang Y, Zou X. Photodynamic therapy for Hidradenitis Suppurativa/acne inversa: Case report. Photodiagn Photodyn Ther. 2018;22:251‐252. [DOI] [PubMed] [Google Scholar]

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PERMALINK

Systematic review of photodynamic therapy for the treatment of hidradenitis suppurativa

Sofiya Reshetylo

Shanthi Narla

Caitlin Bakker

Thomas Freeman

Ronda S Farah

Iltefat H Hamzavi

Noah Goldfarb

Abstract

Objective

Methods

Results

Limitations

Conclusion

1. INTRODUCTION

2. METHODS

2.1. Literature search

2.2. Eligibility criteria and selection of studies

2.3. Data extraction and risk of bias

2.4. Level of evidence and strength of recommendations

3. RESULTS

3.1. Study selection

FIGURE 1.

3.2. Blue light PDT

TABLE 1.

TABLE 5.

3.3. Red light PDT

TABLE 2.

3.4. Pulsed dye laser PDT

TABLE 3.

3.5. Intralesional diode PDT

TABLE 4.

3.6. Multiple modalities including PDT

4. DISCUSSION

CONFLICT OF INTEREST

Supporting information

DATA AVAILABILITY STATEMENT

REFERENCES

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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