Light and Laser-based Treatments for Hidradenitis Suppurativa: A Systematic Review

1 Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada 2 Faculty of Medicine, University of Toronto, Toronto, ON, Canada 3 Vancouver General Hospital, Vancouver, BC, Canada 4 Photomedicine Institute and Centre for Clinical Epidemiology & Evaluation, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada 5 British Columbia Children’s Hospital Research Institute, Vancouver, BC, Canada

Hidradenitis suppurativa (HS) is characterized by painful, recurrent papules and nodules occurring mainly in intertriginous areas. The pain, odor, and disfigurement caused by HS significantly impacts patients' quality of life and is associated with increased rates of anxiety and depression. 1-3 Moreover, the symptoms of HS can be physically limiting and interfere with employment and personal functioning. 4, 5 Early diagnosis and management of HS reduces the risk of disease progression. 6 Treatment for HS are often multimodal and include medical, surgical, and laser and light-based therapies. Although treatment with tumor necrosis factor inhibitors, interleukin-1 inhibitors, antibiotics and others have been reported, these INTRODUCTION treatments may be associated with significant cost, adverse effects, declining efficacy, and possible drug-drug interactions. In practice, patients may express the preference to avoid systemic treatments if possible. Light and laser-based management is known to be a safe and effective treatment option for many dermatological conditions. Furthermore, light and laser-based treatment provides the advantage of avoiding the adverse effects and drug interactions associated with systemic therapies. Light and laser-based treatments commonly employed for HS include psoralen plus ultraviolet A (PUVA), photodynamic therapy (PDT), neodymiumdoped yttrium aluminum garnet (Nd:YAG) laser, carbon dioxide (CO2) laser, and others 7-10 . These treatments are thought to reduce HS lesions by debulking tissue and by reducing the amount of hair follicles, sebaceous glands, and bacterial load. 11 Although laser and light-based treatments for HS have been reported, little is known about their comparative effectiveness. The aim of this systematic review is to summarize outcomes for light and laser-based treatments used for HS, enabling physicians to better predict clinical response.
A systematic review of the literature was conducted adhering to PRISMA reporting guidelines. 12 The study protocol was registered in the PROSPERO database (CRD42020223612).

Study eligibility criteria
Eligibility criteria for this review were: • Population: individuals of any age and sex with HS • Intervention (exposure): Nd:YAG laser, PDT, CO2 laser, intense pulse light (IPL), PUVA • Comparator: patients with HS not exposed to intervention • Outcomes: pain, lesion count, hidradenitis severity score (HSS), visual analogue scale (VAS), dermatology life quality index (DLQI), recurrence, healing time, physician global assessment (PGA), sartorius score, lesion area and severity index (LASI), patient satisfaction, clinical response • Study design: cohort, cross-sectional, and case-series

Literature search and screening
MEDLINE, Embase, the Cochrane Database of Systematic Reviews, and PubMed were searched on June 12, 2020 using variations of the keywords "hidradenitis suppurativa" and "light" (Tables S1-S4). No date or language restrictions were applied. Title, abstract, and full-text screening were conducted by two independent reviewers (I.M., S.M.) using Covidence online systematic review software (www.covidence.org). Any conflicts between reviewers were resolved by discussion until a consensus was reached.
After data collection, we determined that quantitative evidence synthesis was not feasible due to differences between the studies included in our review. Specifically, differences in study design, HS severity, heterogeneity in treatment modalities, patient populations, and outcome measurement. Instead, our results are presented in narrative form for each outcome

Study selection
Our literature search yielded 460 articles, 405 of which were excluded based on title and abstract review (Figure 1). Of the 55 studies retrieved for full text screening, 15 were excluded. A total of 40 studies were ultimately included in the review, 6 of which were conference abstracts.
The included studies were published between 1987 and 2020 and included 5 randomized within-patient controlled trials, 1 randomized controlled trial, and 34 case series ( Table 1). The majority of studies were conducted in Spain (n=7), North America (n=6), United Kingdom (n=5), and Italy (n=4) ( Table 1).

Patient characteristics (age/sex)
In total, our pooled analysis includes 821 patients, 87% (n=623/716) females, with mean age of 33 years, ranging from 15 to 73 years of age.

Targeted phototherapy
A total of 22 studies 14-35 included in our review reported on targeted phototherapy using lasers and energy-based devices in patients with HS, representing a sample size of 724 patients with a mean age of 37.2 years (range: 14-73), and 76.3% (n=497/651 † ) were female. Overall, targeted phototherapy improved lesions in 77.6% (n=413/532) of HS patients. Adverse effects were reported in 22.9% (n=122/532) of treated patients ( Table  2).

CO2
CO2 laser was employed in 10 studies (n=396), with 78.5% (n=311/396) of patients showing improvement ( Table 2). 15-17, 19-21, 24-26, 28 Adverse events were reported in 26.2% of cases (n=103/393). All 10 studies found that CO2 laser was an effective treatment modality. In a study of 24 patients, Lapins et al. showed that CO2 laser treatment with healing by secondary intention was safe, beneficial, and rapidly effective with a mean resolution period of 4 weeks. The majority of patients (91.7%, n=22/24) experienced no recurrence in treated areas. Overall, all patients reported satisfaction with this treatment modality. 24 The treatments were well tolerated in all patients, and average healing time post procedure was 8.8 weeks. 21 Among patients with recurrent HS, Mikkelsen et al. found that CO2 laser surgery with healing by secondary intention was effective with high patient satisfaction rates (94.8%, n=55/58). Improvement was reported as great in 75.8% (n=44/58) of patients and mild in 19.0% (n=11/58). Overall, 91.4% (n=53/58) of patients stated they would recommend the procedure. 28

Nd:YAG
Four studies consisting of 92 patients reported on the use of Nd:YAG in HS 27,29,32,33 . Among studies with reported outcomes, 85% (n=30/35) of treated patients showed improvement ( Table 2) and adverse events were reported in 15% of cases (n=8/53). Overall, 3 of the 4 studies found that Nd:YAG laser The studies included in our review reported on patients with both moderate and advanced disease. Many of the studies included in our review utilize laser-based treatments for surgery of affected sites in patients with advanced disease resistant to other therapies. Our results suggest that laser-based surgery is associated with a moderate response rate based on a large sample of pooled patients. Furthermore, many of the studies employing laser devices for surgery of HS lesions included patients with long standing and recalcitrant disease, suggesting that these treatment modalities can be employed an adjuncts with success even in patients with advanced disease.

RESULTS
Likewise, treatment modalities that utilize laser-based field therapy of affected areas using Nd:YAG, IPL, or diode laser were associated with a mild response rate based on a large sample of pooled patients. Laser field treatments for HS were employed in patients with both early and advanced disease, suggesting that this treatment modality is appropriate both to treat advanced disease and as a prophylactic therapy to target follicular inflammation and prevent disease progression.
A number of adverse events were reported in the studies included in our review. Overall, PDT was associated with the highest rates of reported adverse events (36%). Laser field treatments had less reported adverse events compared to lasers employed for surgical treatment of HS lesions (18% vs 25%). A number of factors may contribute to this observed difference, including differences in study quality and reporting of adverse events, given that only 105 out of 424 patients treated with laser surgery for HS had adverse events recorded. Some of the adverse events reported for laser surgery included pain, infection, hypertrophic scaring, contracture and wound dehiscence. Side effects associated with PDT included pain, erythema, blistering, burning. Bath PUVA was generally well tolerated, although two patients reported erythema and claustrophobia. Collectively, these findings suggest that while light therapy is a moderately effective treatment modality, adverse events are not uncommon, and patients should be counselled on the risks and benefits of light therapy.
While the mechanism underlying the effectiveness of light-based treatments for HS are not well understood, several possibilities have been suggested. CO2 laser vaporization and excision removes epithelial sinus tracts which may contain debris and bacteria that can lead to relapse. 53 Nonablative lasers cause thermal damage to the dermis, which may initiate a wound-healing response with upregulation of procollagen mRNA, matrix metalloproteinases, and cytokines that contribute to wound healing. 54 Our study has several limitations. Many studies did not report on the side effects of light-based therapies, which restricts our analysis on treatment tolerability. Secondly, some studies reported aggregate data and outcomes for individual patients could not be extracted. Moreover, different outcome measures were used in the studies included in our review, further challenging comparisons between studies. Finally, the majority of the included studies were case series, which limits the generalizability of our analysis.
Despite these limitations, our review provides important information that must be DISCUSSION CONCLUSION interpreted in a clinical context. First, lightbased treatments show moderate benefit in both early and advanced disease. Second, laser devices and PDT have moderate clearance rates for patients with HS, however access to the technology and impractical treatment delivery (especially with extensive disease) may be a barrier. Third, adverse events are not uncommon with light therapy and patients should be counselled on these risks. Though randomized control trials would be the ideal way to validate our findings, studies with treatment comparators are needed to further delineate the therapeutic ladder for HS.