Photodiagnosis and Photodynamic Therapy 38 (2022) 102752
Available online 14 February 2022
1572-1000/© 2022 Elsevier B.V. All rights reserved.
A prospective study of adverse reactions of ALA-PDT for acne vulgaris
Lei Shi
1, Jiayi Yang
1, Linglin Zhang , Yunfeng Zhang , Guorong Yan , Haiyan Zhang , Xiaojing Liu , Jin Yang , Peiru Wang , Guolong Zhang , Zhongxia Zhou , Xiuli Wang
*Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 1278 Baode Road, Shanghai 200092, China
A R T I C L E I N F O Keywords:
Photodynamic therapy ALA-PDT
Adverse reaction Acne vulgaris
A B S T R A C T
Background: Acne vulgaris is a chronic inflammatory skin disease around pilosebaceous unit. 5-Aminolaevulinic acid photodynamic therapy (ALA-PDT) is an effective therapy for severe acne vulgaris. However, the lack of detailed information of adverse reactions limits the promotion of ALA-PDT in clinic.
Objective: To systemically investigate the adverse reactions relating to ALA-PDT for acne vulgaris.
Methods: A prospective study was performed at the Shanghai Skin Disease Hospital.
Results: In the prospective study, 35 patients with acne vulgaris completed the trial. The adverse reactions were first divided into acute-phase adverse reactions, including erythema (94.3%), post-treatment pain (91.4%), burning skin (91.4%), dry skin (91.4%), itching (85.7%), pustule (82.9%), edema (20%) and blister (11.4%), or recovery-phase adverse reactions, which included crust (65.6%), exudation (48.6%) and hyperpigmentation (42.7%). Younger patients were more likely to have pustules (P<0.05). Male patients were represented itching more often than female patients (P<0.05). The efficacy of ALA-PDT for severe acne was positively related to the severity of acute-phase adverse reactions. The duration of pain was shortest. Crusting and hyperpigmentation lasted considerably longer.
Conclusion: In the present study, we recorded the relative incidence of various adverse reactions following ALA- PDT for acne vulgaris. The severity of adverse reactions tended to decrease with increased patient age, except for itching and hyperpigmentation. Light-to-moderate adverse reactions might be the inflammatory reactions of ALA-PDT, predicting a good efficacy. A form for evaluation of adverse reactions based on the present study could assist dermatologists in predicting and managing adverse reactions for greater efficacy and higher patient satisfaction.
1. Introduction
5-Aminolaevulinic acid photodynamic therapy (ALA-PDT), a rela- tively novel and non-invasive therapy, is now widely used to treat severe acne vulgris [1,2]. The photosensitizer preferentially accumulates in target cells, then following a period of incubation, photons of an appropriate wavelength initiate the evolution of reactive oxygen species (ROS), promoting the photodynamic reaction [3,4]. ALA-PDT has been included in many guidelines for the treatment for moderate to severe acne vulgaris [5,6].
ALA-PDT is considered a relatively safe treatment, generally only inducing topical adverse reactions in skin and does not cause adverse systemic reactions. Pain is the most common adverse effect of ALA-PDT [7]. Severe pain affects patients experience, causing treatment
interruption that affects its efficacy. This issue is now gradually being addressed with daylight and modified ALA-PDT [8,9]. However, addi- tional to pain, other topical adverse reactions, such as erythema, burning skin, dry skin, itching, pustule, edema, blister, crust, exudation and hyperpigmentation are observed, whose incidence, severity, occurrence, and duration remain unclear [10–12]. Because of the incomplete identification of adverse reactions and the lack of systematic health education, patients are anxious, or even fear the ALA-PDT pro- cedure where adverse reactions do not elicit medical attention or any intervention. Therefore, the lack of a complete picture of possible adverse reactions limits the use and promotion of ALA-PDT in clinic [13, 14].
The aim of the study was to systemically investigate the detailed evidence of adverse reactions relating to ALA-PDT for acne vulgaris. A
* Corresponding author.
E-mail address: [email protected] (X. Wang).
1 These authors contributed equally to this work.
Contents lists available at ScienceDirect
Photodiagnosis and Photodynamic Therapy
journal homepage: www.elsevier.com/locate/pdpdt
https://doi.org/10.1016/j.pdpdt.2022.102752
Received 21 December 2021; Received in revised form 26 January 2022; Accepted 4 February 2022
prospective study were performed at Shanghai Skin Disease Hospital to clarify the incidence, severity, time of occurrence and duration of adverse reactions associated with ALA-PDT. The systematic research will help dermatologists predicte and manage adverse reactions for greater efficacy and higher patient satisfaction..
2. Methods
The study was conducted at Shanghai Skin Disease Hospital and was designed as a prospective trial to observe the adverse reactions of ALA- PDT for facial acne vulgaris. The study protocol was approved by the Fig. 1. Severity, occurrence and duration time of adverse reactions following ALA-PDT.
Fig. 2. Manifestations of various adverse reactions following ALA-PDT.
Photodiagnosis and Photodynamic Therapy 38 (2022) 102752
Ethics Committee of Shanghai Skin Disease Hospital (No. 2020–04) and is registered on the Clinical Trials website (ID: NCT04709289). Written informed consent and photo consent were obtained from every patient.
The inclusion criteria were as follows: (1) Individuals over 18 years of age with acne vulgaris on their face diagnosed as moderate to severe (Pillsbury grade III) or severe (Pillsbury grade IV) were included; (2) Those who had read the instructions and were willing to follow the program requirements. The exclusion criteria were as follows: (1) In- dividuals with a history of photosensitivity; (2) Patients who had received oral isotretinoin over the previous 3 months, used oral con- traceptives, or antibiotics and had undergone local or facial surgery over the previous 4 weeks; (3) Female patients who were pregnant or lactating.
Prior to ALA-PDT, all patients cleaned their faces with soap and photographed themselves using a VISIA-CR™ system (Canfield, USA;
using a 6500 K standard white polarized light source). The lesions were coated with 5% ALA for 90 min, then wiped prior to exposure with red light at a wavelength of 630 nm ±5 nm and intensity of 60 mW/cm2, 100 J/cm2. The procedure was repeated at one-week intervals. Every patient had 4 sessions of PDT. After each ALA-PDT session, erythema, pain, burning skin, dry skin, itching, pustules, edema, blisters, crusting, exudation, and hyperpigmentation were evaluated by two senior der- matologists. Severity was scored 0–3 for none, mild, moderate, and severe.
Fig. 3. Severity of adverse reactions following ALA-PDT and their relationship with patient age.
Fig. 4. Severity of different adverse reactions in each session of ALA-PDT. * P<0.05.
L. Shi et al.
2.1. Statistical analysis
The incidence and severity of adverse reactions were evaluated using a chi-squared test, and their time of occurrence and duration using a Kruskal Wallis test. The relationship between adverse reactions from ALA-PDT and patient characteristics was evaluated by linear regression analysis. All analyses were performed using GraphPad Prism 8.0. Sta- tistical significance was set at P<0.05.
3. Results
3.1. Characteristics of patients and efficacy of ALA-PDT
A total of 40 individuals diagnosed with moderate to severe acne with a mean age of 23.5 years (range 18~31 years) were selected for the prospective study. Five were excluded due to the exclusion criteria and thus 35 patients completed the trial. There were more male patients (60%) than female (40%). After 4 sessions of ALA-PDT, the mean rate of clearance of total lesions, inflammatory lesions and non-inflammatory lesions was 73.94%±8.89%, 75.23%±11.06%, and 65.13%±15.65%, respectively.
3.2. Time, incidence, severity, and correlation analysis of adverse reactions
Erythema, Pain, burning skin, dry skin, itching, pustules, edema, blisters, exudation, crusting, and hyperpigmentation following ALA- PDT were recorded. Depending on the point at which the adverse re- actions occurred, they were divided into acute or recovery-phase. Ery- thema, Pain, burning skin, itching, blisters, or edema were experienced first, then dry skin or pustules. Recovery-phase reactions, including crusting, exudation, and hyperpigmentation, always occurred last (P<0.05). Of all the above adverse reactions, the duration of Pain was shortest, for no more than 1 day. Crust and hyperpigmentation lasted considerably longer, for more than 4 days (P<0.05) (Fig. 1). Hyper- pigmentation did not dissipate until the subsequent session, and possibly as long as 6 months. Acute-phase reactions generally occurred in 2 days following ALA-PDT, including erythema, Pain, burning skin, dry skin, Itching, pustules, edema, and blistering, which were encountered in 94.3%, 91.4%, 91.4%, 91.4%, 85.7%, 82.9%, 20%, and 11.4%. Adverse reactions during the recovery phase included crusting, exudation, and hyperpigmentation, which occurred in 65.7%, 48.6%, and 42.7% of patients. Their manifestations are displayed in Fig. 2.
As shown in Fig. 1, the severity of erythema, Pain, burning skin, itching, and pustules were similar, higher than that of dry skin, exuda- tion, crusting, and hyperpigmentation (P<0.05). In addition, linear analysis demonstrated that younger patients were likely to suffer lighter erythema, itching, or hyperpigmentation, but the converse for other adverse reactions (Fig. 3). For each session of ALA-PDT, the severity of pain, erythema, dry skin, edema, and crusting was similar, while the severity of itching, pustules, and blisters decreased. However, the severity of hyperpigmentation, burning skin, and exudation became severer (Fig. 4).
3.3. Efficacy of ALA-PDT is positively correlated with the severity of adverse reaction
There was a positive correlation between clearance rate and the severity of erythema, Pain, burning skin, dry skin, itching, pustules, crust, hyperpigmentation, edema, and blisters, although the difference was not always significant (Table 1). The severer the therapeutic reac- tion described above, the higher the clearance rate. Conversely, lighter exudation was consistent with higher clearance rates. This suggests that the efficacy of ALA-PDT has a positively related tendency to the severity of the majority of adverse reactions.
Table 1 Linear analysis of the clearance rate of lesions with the incidence of adverse reactions following ALA-PDT. Characteristics n (N) Acute phase adverse effects N (%)
Recovery phase adverse effects N (%) Erythema 33 (94.3) Post-Pain 32 (91.4) Burning skin 32 (91.4) Dry skin 32 (91.4)
Itching32 (85.7) Pustule 29 (82.9) Edema 7 (20) Blister 4 (11.4) Crust 23 (65.7) Exudation 17 (48.6)
Hyperpigmentation 15 (42.7) r P r P r P r P r P r P r P r P r P r P r P Total (N) 35 The clearance Total lesions 0.019 0.214 0.056 0.168 0.014 0.254 0.006 0.561 0.011 0.027 0.014 0.173 0.005 0.560 0.005 0.995 0.017 0.166 ¡0.007 0.438 0.030 P<0.05 rate
Inflammatory lesions
0.015 0.218 0.045 0.167 0.018 0.067 0.007 0.390 0.009 0.244 0.011 0.198 0.006 0.391 −0.001 0.816 0.021 P<0.05 ¡0.001 0.940 0.012 ¡0.186
Non- inflammatory lesions 0.006 0.488 0.028 0.270 0.004 0.619 −0.002 0.761 0.005 0.404 −0.002 0.973 −0.001 0.760 0.001 0.685 ¡0.002 0.793 ¡0.006 0.323 0.014 P ≤0.05 SEM: standard error of the mean. p <0.05 was considered significant.
Photodiagnosis and Photodynamic Therapy 38 (2022) 102752
4. Discussion
ALA-PDT is known to be effective for treating a variety of skin dis- eases. However, topical adverse reactions affect the effectiveness and experience of the treatment. In our experience, patients have refused subsequent sessions of ALA-PDT because of pain, pigmentation, or exudation, especially where PDT was provided as a cosmetic procedure for acne. Postoperative care of patients with acne treated with ALA-PDT appears particularly important, including the incidence, severity, occurrence, and duration of adverse reactions following ALA-PDT.
In the prospective study, significant pustules were more likely to occur in younger patients, possibly related to more active sebaceous gland secretions in these patients. The explanation of severe itching in the elderly may be due to differences in the stratum corneum barrier function, more alkaline pH, and less active sebaceous and sweat glands (Fig. 1) [15]. Additionally, the more ALA-PDT was applied, the severer the hyperpigmentation that developed, emphasizing the crucial role of early preventive measures (Figs. 3 and 4). Therefore, patients should be warned to reduce exposure to sunlight after each session of ALA-PDT.
Adverse reactions following ALA-PDT were classified as acute or recovery-phase, which could further assist dermatologists in better predicting and periodically managing them prior to ALA-PDT to improve the experience and efficacy of treatment.
A positive relationship between the severity of adverse reactions and the efficacy of ALA-PDT was observed in the present study. Interestingly, efficacy and exudation were negatively associated, contrary to other reactions. Light-to-moderate adverse reactions, considered the normal response to therapy, may predict good treatment efficacy (Table 1) [3, 16]. Of all therapeutic responses, erythema appears early after ALA-PDT with little systemic impact in humans, so erythema could be used for monitoring. If the response to therapy is not apparent, the intensity of
subsequent ALA-PDT could be adjusted to achieve better treatment ef- ficacy, and so an evaluation form reporting adverse reactions associated with ALA-PDT is required, to benefit future treatments of ALA-PDT (Table 2). Novel treatment protocols, which reduce adverse reactions without affecting treatment efficacy, such as Daylight or modified PDT, would drive additional use of ALA-PDT. The present study was limited due to its small sample size and narrow spectrum of diseases studied by the prospective study. Thus, further prospective studies are required.
In summary, in the present study, we recorded the relative incidence of various adverse reactions following ALA-PDT for acne vulgaris and their relationship with patient clinical characteristics. Depending on the point at which erythema, Pain, burning skin, dry skin, itching, pustules, edema, blisters, crusting, exudation, and hyperpigmentation occurred, adverse reactions can be divided into acute or recovery-phase reactions.
The efficacy of ALA-PDT for severe acne was positively related to the severity of acute-phase adverse reactions. Details of the adverse re- actions could assist in refining our understanding of them, and repre- sents a reference that will enable clinicians to resolve them in order that patients can receive additional sessions of ALA-PDT.
CRediT authorship contribution statement
Lei Shi: Writing – review & editing, Investigation, Funding acqui- sition, Resources, Data curation. Jiayi Yang: Writing – review & editing, Writing – original draft, Investigation, Data curation. Linglin Zhang:
Funding acquisition, Resources. Yunfeng Zhang: Resources, Project administration, Investigation. Guorong Yan: Data curation, Investiga- tion, Methodology. Haiyan Zhang: Supervision, Investigation, Data curation. Xiaojing Liu: Data curation, Investigation, Methodology. Jin Yang: Software, Resources, Methodology, Investigation. Peiru Wang:
Supervision, Validation, Visualization. Guolong Zhang: Supervision, Table 2
Evaluation form of adverse reactions of ALA-PDT.
Adverse Reaction Management Form (AR-MF)
Name Age Gender Diagnosis Intensity of ALA-PDT ALA-PDT session
Efficacy Total lesion Inflammatory lesion Non-inflammatory lesion Advice
Acute-phase adverse
reaction None Mild Moderate Severe Occurrence Time Remission Time
Erythema Post-Pain Burning skin Itching Pustule Exudation Edema Blister Others
Recovery-Phase adverse reaction Dry skin
Crust
Hyperpigmentation Herpes simplex Hypopigmentation Others
Systemic adverse reaction Fever
Psoriasis Allergic contact
dermatitis Pemphigus vulgaris Transient amnesia Others
Tips —Patients in different characteritics should pay more attention to different adverse reactions as follows.
Groups of skin diseases Skin cancer or precancerosis lesions:@@@@HPV-related skin diseases:@@@@Skin appendage disorders:
@@@@Others:
In-Pain, erythema, pigmentation issue;@@@@In-Pain, erythema, edema, exudation;
@@@@In-Pain, erythema, hyperpigmentation;@@@@In-Pain, erythema, edema, exudation
Gender Female: Edema, hypopigmentation, fever
Age Younger patient:@@@@Older patient: In-Pain, Post-Pain, burning skin, dry skin, edema, pustule, blister, crust, exudation,
fever;@@@@Itching, pigmentation issue
ALA-PDT session Subsequent session Itching, pustule, hyperpigmentation
L. Shi et al.
Resources, Data curation. Zhongxia Zhou: Data curation. Xiuli Wang:
Resources, Investigation, Validation, Supervision, Project administration.
Declaration of Competing Interest None declared.
Acknowledgements
This work was partly supported by the grants from National Natural Science Foundation (82073463, 81872212, 82073013, 81901204), Shanghai Shenkang Hospital Development Center (SHDC12019130) and Leading talent project of Shanghai Jingan District.
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