DATE: 26 August 2013 CONTEXT AND POLICY ISSUES

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1 TITLE: Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa: A Review of the Clinical Effectiveness, Cost-Effectiveness, and Safety DATE: 26 August 2013 CONTEXT AND POLICY ISSUES Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory disease that, while not rare, is relatively uncommon, with an estimated prevalence between one and four percent in European countries. 1,2 HS primarily affects the flexor surfaces of the skin. It is a chronic disabling condition that can cause social isolation and depression, 2 and while the exact cause of the disease is unknown, it is generally agreed to be a follicular disease with secondary apocrine gland involvement. 3 HS is more common in women, by a ratio of three to one. HS is most frequently categorized based on the Hurley Staging system. The system divides patients into three stages, with stage one being the mildest and stage three being the most severe disease involvement. 1,2 For disease monitoring during intervention trials, however, a more dynamic and detailed scale has been developed, which involves the counting of nodes and fistulas. 2 Treatment options for HS include antibiotics, such as topical clindamycin and systemic tetracycline; biologics, such as infliximab; botulinum toxin, hormone modulators, and laser therapies. 1,2 Most of these treatments are based on treatments for similar diseases, such as acne congoblada and pilonidal sinus; there is no universally accepted primary treatment for HS. 1 Surgical procedures, which are generally quite successful, are other treatment options for HS, however, they are associated with high morbidity. 2 Though generally used for hair removal, the neodymium:yttrium-aluminium-garnet (Nd:YAG) laser has recently shown promise for the treatment of HS lesions. The possible mechanism of action being follicular ablation and the destruction of inflammatory lesions through photothermolysis. 4 The objective of this report is to review the clinical effectiveness, costeffectiveness, and safety of the Nd:YAG laser for the treatment of HS. Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 RESEARCH QUESTIONS 1. What is the clinical effectiveness of the long-pulsed neodymium:yttrium-aluminium-garnet (Nd:YAG) laser for the treatment of patients with hidradenitis suppurativa? 2. What is the safety of the long-pulsed Nd:YAG laser for the treatment of patients with hidradenitis suppurativa? 3. What is the cost-effectiveness of the long-pulsed Nd:YAG laser for the treatment of patients with hidradenitis suppurativa? KEY FINDINGS Evidence suggests that monthly long-pulsed Nd:YAG laser therapy is effective and welltolerated in the short- to medium-term (3 to 6 months) for the treatment of hidradenitis suppurativa. The results should be interpreted with caution due to small sample sizes and short length of follow-up. No cost-effectiveness information was identified. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2013, Issue 7), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2008 and July 26, Rapid Response reports are organized so that the evidence for each research question is presented separately. Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed for relevance. Full texts of any relevant titles or abstracts were retrieved, and assessed for inclusion. The final article selection was based on the inclusion criteria presented in Table 1. Population Intervention Comparator Outcomes Table 1: Selection Criteria Patients with hidradenitis suppurativa; any age group or disease stage Long-pulsed Nd:YAG laser (as primary or adjunct treatment) Standard of care interventions: pharmaceutical agents or surgery or no comparator Q1: Improved patient outcomes Q2: safety; adverse events Q3: cost-effectiveness Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 2

3 Study Designs Table 1: Selection Criteria HTA, SR, MA, RCT, NRS, Economic evaluations HTA = health technology assessment, MA = meta-analysis; Nd:YAG: neodymium: yttrium-aluminium-garnet; NRS = non-randomized studies; RCT = randomized controlled trial; SR = systematic reviews Exclusion Criteria Studies were excluded if they did not fit the selection criteria, were duplicate publications, were examined in an included systematic review, or were published prior to Critical Appraisal of Individual Studies Critical appraisal of the included studies was based on study design. The methodological quality of the included systematic reviews and meta-analyses was evaluated using the assessment of multiple systematic reviews (AMSTAR). 5 AMSTAR is an 11-item checklist that has been developed to ensure reliability and construct validity of systematic reviews. The quality of RCTs was assessed using the Downs and Black checklist. 6 A numeric score was not calculated for each study. Instead, strengths and limitations of each study were summarized and described. SUMMARY OF EVIDENCE Quantity of Research Available A total of seven potential citations were identified by searching the bibliographic database, with two citations being excluded during the title and abstract screening based on their irrelevance to the questions of interest. The full text documents of the remaining five articles were retrieved. One additional article was identified by grey literature and hand search. Of the six articles examined in full text, two did not meet the inclusion criteria and were excluded; leaving four articles that reported one systematic review (SR) and three randomized controlled trials (RCTs). No cost-effectiveness information was identified. A PRISMA diagram illustrating the study selection process is presented in Appendix 1. Summary of Study Characteristics Study Design One systematic review 7 and three randomized controlled trials 3,4,8 met the inclusion criteria. The systematic review examined all treatments for HS and included one RCT pertaining to the Nd:YAG laser. 9 In all of the included randomized trials, the patients acted as their own controls, as randomization occurred either by body part affected by HS, or by side of the body. One of the included randomized trials 4 reported 6 month outcomes for the patients who participated in the RCT included in the systematic review (which reported 3 month outcomes). No relevant cost-effectiveness information was identified. Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 3

4 Population The patient populations in the included studies were generally comparable. One study included patients with at least stage I disease, 8 two included patients with stage II HS, 3,4 and one study included both stages II and III. 7 The number of patients included in most of the studies was relatively small: 6, 8 20, 3 and 22 patients. 4,7 Follow-up periods were two, 3 three, 7 four, 8 and six months. 4 Interventions and Comparators All of the included studies used monthly long-pulse Nd:YAG laser treatment for patients with HS. 3,4,7,8 Topical co-treatments were also part of the treatment protocols for all of the included studies. One study did not specify the co-treatment, 3 one study treated with 1% clindamycin gel, and the patient population examined in both the SR 7 and one of the included RCTs 4 was treated with benzoyl peroxide wash 10% and 1% clindamycin lotion. In all of the studies, both the Nd:YAG-treated body parts and the control parts were treated with the topical interventions. Outcomes The main efficacy outcome of interest in the included studies was disease severity based on either the Modified Hidradenitis Suppurativa Lesion Area and Severity Index (HS-LASI) 3,4,7 or a modified version of the modified HS-LASI. 8 Patient satisfaction and patient-rated improvements were examined in two studies 4,8 and adverse events such as pain, swelling, and thermal injury were examined in three studies. 3,4,8 One of the RCTs presented outcomes only for the Nd:YAG laser-treated sites and not control sites. 3 Details regarding study characteristics are presented in Appendix 2. Summary of Critical Appraisal Overall, the quality of the included studies was moderate. The systematic review, 7 which included one relevant RCT, 9 was well-conducted and included a comprehensive literature review, a clear description of the inclusion and exclusion criteria, as well as a rating of the scientific quality of the included studies. The analysis did not pool data, as limited information was found for relevant treatments. The main limitations were that it was not clear if there was a priori design and publication bias was not assessed. The RCT 9 included in the SR reported three month outcomes for the population for which six month outcomes were reported in one of the RCTs 4 included in this review and has the same strengths and limitations. The main strengths of the RCTs 3,4,8 were that the interventions, comparators, and findings were clearly described, that subjects were likely representative of the population affected by HS, and compliance with the treatment was reliable. One of the main limitations of all of the included trials was the lack of an attempt to blind the patients to the treatment and the lack of reporting as to whether or not assessors were blinded. A sham laser could have been used on control body parts in order to blind the patients, and while it wasn t reported and therefore it is unclear whether blinding occurred, blinding the assessor would have been possible. One of the RCTs had limited power to detect clinical differences due to small sample size. 8 Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 4

5 Details regarding the critical appraisal are presented in Appendix 3. Summary of Findings What is the clinical effectiveness of the long-pulsed Nd:YAG laser for the treatment of patients with hidradenitis suppurativa? Two-month outcomes In the RCT that presented results for patients after two-months of treatment, statistically significantly lower disease activity was seen lesions treated with the Nd:YAG laser when compared with the control lesions. 3 The decrease in the modified HS-LASI rating was 31.6% for all anatomic sites, 24.4% for axillary sites, and 36.8% for inguinal sites. HS-LASI ratings were not presented for the control sites. Histopathological results were also presented, and of the 18 patients for which histopathological results were available, 12 patients had minimal inflammatory reaction. Three-month outcomes The SR presented the three month RCT outcomes. 7 The decrease in HS-LASI rating in Nd:YAG treated areas was 65.3% for all sites, 62% for axillary sites, 73.4% for inguinal sites, and 53.2% for inframammary sites. These changes were significant, whereas changes in control-site lesions were not. Four-month outcomes In the RCT that reported outcomes after four months, 8 HS severity ratings increased (though not significantly) both after Nd:YAG and control treatments. 80% of patients were very satisfied with the treatment, whereas 20% were not satisfied. This study included the smallest number of participants (n = 6; 5/6 completed the study) and was not adequately powered to detect differences. Six month outcomes The RCT that reported six month outcomes 4 included the same cohort of patients as the SR that reported the three month outcomes. 7 Like the three month results, at the six month follow-up, a decrease in HS-LASI rating was observed after Nd:YAG treatment. The percent change from baseline in the treatment group versus control group was: 72.7% (SD: 13.0, P > 0.001) vs. 22.9% (SD: 38.9, P < 0.001) for all anatomic sites; 70.2% (SD: 13.0, P = 0.001) vs. 11.3% (SD: 29.4, P < 0.044) for axillary sites; 74.5% (SD: 14.4, P < 0.001) vs. 35.8% (SD: 39.3, P < 0.005) for the inguinal sites; and 73.5% (SD: 11.3, P = 0.004) vs. 16.2% (SD: 56.6, P < 0.406) for inframammary sites. While the improvement in both treatment sites and control sites was statistically significant, for the combination of all anatomic sites, improvements were significantly higher in the Nd:YAG treated sites compared with control. 92% of patients associated the Nd:YAG treatment with improvements in their disease. What is the safety of the long-pulsed Nd:YAG laser for the treatment of patients with hidradenitis suppurativa? Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 5

6 While the authors of most of the included studies reported the laser to be tolerable, two of the included studies 4,8 reported specific safety outcomes. Four month outcomes At four months, 8 none of the 5 patients who completed the study reported an adverse event within 48 hours of laser treatment, nor were there any reports of pain, swelling, or redness at the laser site. Six month outcomes In the study reporting six-month outcomes, 4 60% of patients did not experience treatmentrelated pain and those who did, did not find that it interfered with daily activity. Furthermore, there was no histopathological evidence of thermal injury. What is the cost-effectiveness of the long-pulsed Nd:YAG laser for the treatment of patients with hidradenitis suppurativa? No relevant cost-effectiveness information was identified. Details regarding both effectiveness and safety outcomes are presented in Appendix 4. Limitations As HS is a relatively uncommon condition, one of the primary limitations of all of the included studies and of the body of literature regarding HS treatments is small sample size. While all but one of the studies was powered to detect differences in clinical effectiveness, none of the studies was powered to detect statistical differences in safety. This may not be important, however, as the device is unlikely to cause serious safety concerns. All of the studies used monthly laser treatments and no study had a follow-up period beyond six months. Therefore, the results are generalizable only to short- and medium-term follow-up. Additionally, the lack of blinding in the included studies means the results should be interpreted with caution. All of the studies allowed for topical therapies in conjunction with the Nd:YAG laser and excluded patients who were taking systemic therapies. Thus, the ability to draw conclusions regarding when to initiate Nd:YAG laser therapy is limited based on the evidence in this review. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING One systematic review 7 and three randomized controlled trials 3,4,8 were included in this review. All of the studies examined the use of long-pulsed Nd:YAG laser treatment versus topical treatment controls on patients with stages I through III HS. After reviewing the evidence regarding many treatments for HS, including one RCT examining the Nd:YAG laser, the authors of the systematic review recommended a multidisciplinary approach that comprises both medical and surgical treatments. They found that for patients with stage I disease, Nd:YAG was considered appropriate, for patients with stage II disease monthly treatment with Nd:YAG, for at least three to four months, was recommended, and that a shift to biological agents would be appropriate if the laser treatment is not successful. They concluded that there was not enough strong evidence to make a recommendation for stage III disease. Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 6

7 The conclusions made by the authors of the systematic review based on an RCT with a threemonth follow-up were similar to the results found in the additional RCTs included in this review. Based on studies with a limited number of patients, with a maximum of six-months of follow-up, Nd:YAG was found to be a promising treatment option for patients with HS. Only the study with the fewest number of subjects, which was not powered to detect differences, found no effect of the Nd:YAG laser on HS lesions. Patients were also generally satisfied with Nd:YAG treatment. As long-pulsed Nd:YAG laser treatment is non-invasive, and was found to be both well-tolerated and satisfactory to patients, it is likely a reasonable treatment option for patients with HS. Studies with longer follow-up are needed in order to determine its long-term effectiveness and economic studies are needed in order to determine its cost-effectiveness. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 7

8 REFERENCES 1. Liu Y, Eisen DB. Treatment of hidradenitis suppurativa: what's new? Cosmet Dermatol [Internet] May [cited 2013 Jul 31];24(5): Available from: 2. van der Zee HH. Hidradenitis suppurativa: pathogenesis and treatment [Internet]. Rotterdam, The Netherlands: Erasmus Universiteit Rotterdam; 2011 Dec. [cited 2013 Jul 31]. Available from: 3. Xu LY, Wright DR, Mahmoud BH, Ozog DM, Mehregan DA, Hamzavi IH. Histopathologic study of hidradenitis suppurativa following long-pulsed 1064-nm Nd:YAG laser treatment. Arch Dermatol Jan;147(1): Mahmoud BH, Tierney E, Hexsel CL, Pui J, Ozog DM, Hamzavi IH. Prospective controlled clinical and histopathologic study of hidradenitis suppurativa treated with the long-pulsed neodymium:yttrium-aluminium-garnet laser. J Am Acad Dermatol Apr;62(4): Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet] [cited 2013 Jul 19];7:10. Available from: 6. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet] Jun [cited 2013 Aug 13];52(6): Available from: 7. Rambhatla PV, Lim HW, Hamzavi I. A systematic review of treatments for hidradenitis suppurativa. Arch Dermatol Apr;148(4): Nosrati N, Hunter L, Kelly E. Efficacy of Nd:YAG laser for the treatment of hidradenitis suppurativa. J Cosmet Dermatol Sci Appl [Internet] [cited 2013 Aug 6];2(2):83-7. Available from: 9. Tierney E, Mahmoud BH, Hexsel C, Ozog D, Hamzavi I. Randomized control trial for the treatment of hidradenitis suppurativa with a neodymium-doped yttrium aluminium garnet laser. Dermatol Surg Aug;35(8): Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 8

9 APPENDIX 1: Selection of Included Studies 7 citations identified from electronic literature search and screened 2 citations excluded 5 potentially relevant articles retrieved for scrutiny (full text, if available) 1 potentially relevant reports retrieved from other sources (grey literature, hand search) 6 potentially relevant reports 2 reports excluded: -outcomes not of interest (1) -already included in at least one of the selected systematic reviews (1) 4 reports included in review Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 9

10 APPENDIX 2: Study Characteristics Objective, Type of study, Length of follow-up Rambhatla, Examine the effectiveness of available treatments for HS. Systematic Review Any follow-up length. (one included RCT 9 examined Nd:YAG laser treatment at 3 month follow-up) Table 2: Characteristics of the Included Studies Patient Characteristics Intervention, Cointervention Comparator For the included RCT: Stage II to III disease, bilateral or symmetric disease, one or more sites of involvement. (no systemic use of HS treatments) Disease site: 15, groin; 12 axillary; 7 inframammary; Mean age 41 years Long-pulsed Nd:YAG, 4 treatments at monthly intervals. Entire area treated in a single pass, triple stacking used for inflammatory nodules, abscesses, and fistulae Co-intervention: Benzoyl peroxide wash 10% and clindamycin 1% lotion Benzoyl peroxide wash 10% and clindamycin 1% lotion Outcomes Considered Disease severity Nostrati, To examine the efficacy of the Nd:YAG to treat patients with any degree of axillary HS. RCT (Randomized to L or R side treatment; opposite side used as control) 4 month follow-up Xu, To assess both the clinical and histopathological effects of Nd:YAG laser 86.4% women At least Hurley stage I disease of axilla. Mean age 37.6 years >80% female enrolled (5/6 patients) Hurley stage II disease, no concomitant systemic treatment, no stage III Long pulsed 1064-nm Nd:YAG single pass, monthly treatments for 3 months plus one month follow-up. Laser setting chosen based on Fitzpatrick skin type. (Topical cooling gel used, no anesthetics). Co-treatment: 1% clindamycin gel Long-pulsed 1064-nm Nd:YAG single pulse for treatment area; double 1% Clindamycin gel Adverse events, visual improvement of HS, disease severity (based on HS-LASI, but modified); patient satisfaction. No treatment (topical treatments acceptable) Visual improvement of HS, disease severity using HS-LASI); Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 10

11 Objective, Type of study, Length of follow-up treatment for HS. RCT (Randomized to L or R side treatment if both sides involved, randomized to body part treatment with second affected body part serving as control if both sides not involved) 2 month follow-up Mahmoud, To assess both the clinical and histopathological effects of Nd:YAG laser treatment for HS. RCT (Randomized to L or R side treatment with the other acting as a control) 6 month follow-up Table 2: Characteristics of the Included Studies Patient Characteristics Intervention, Cointervention Comparator disease. stacking inflamed lesions on first treatment, triple Disease site: stacking inflamed lesions 42.1% axilla; 57.9% groin on second treatment. Laser setting chosen Mean age 37 years based on Fitzpatrick skin type. (Topical cooling gel 84.2% female used, no anesthetics) Stage II disease, bilateral or symmetric disease, one or more sites of involvement. (no systemic use of HS treatments) Disease site: 12 axillary, 7 inframammary, 15 groin Mean age 41 Topical co-treatment acceptable Long-pulsed Nd:YAG, 4 treatments at monthly intervals. Entire area treated in a single pass, triple stacking used for inflammatory nodules, abscesses, and fistulae Co-intervention: benzoyl peroxide wash 10% and clindamycin 1% lotion Benzoyl peroxide wash 10% and clindamycin 1% lotion Outcomes Considered histopathological findings; tenderness/pain, percentage improvement Disease severity based on Modified HS-LASI; patientrated disease activity, patient-rated adverse events/pain related to the laser, histopathological outcomes 86.4% women CO 2 = carbon dioxide; HS = Hidradenitis Suppurativa; HS-LASI = Modified Hidradenitis Suppurativa Lesion Area and Severity Index; Nd:YAG = neodymium:yttrium-aluminium-garnet; nm = nanometer; NRS = non-randomized study; RCT = randomized controlled trial a Pilonidal sinus not relevant to this review and thus results not reported Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 11

12 APPENDIX 3: Summary of Critical Appraisal Table 3: Summary of Critical Appraisal Strengths Limitations Systematic Review Rambhatla 7 Duplicate study selection and data extraction Comprehensive literature search performed status of publication used as an inclusion criterion Were the characteristics of the included studies provided but not tabulated Scientific quality of the included studies assessed and documented Scientific quality of the included studies used appropriately in formulating conclusions Methods used to combine the findings of studies appropriate (very mixed, therefore, no meta-analysis) Conflict of interest included Randomized Controlled Trials Nosrati 8 REPORTING Objective clearly described Main outcomes clearly described Patient characteristics clearly described Interventions clearly described Main findings clearly described Important adverse events reported Patient lost to follow-up partially described EXTERNAL VALIDITY Subjects likely close to representative of the entire population (ratio of women to men who have HS is 3:1) Staff, places, facilities for treatment likely representative of what the majority of patients could receive laser is relatively common. INTERNAL VALIDITY (bias) Follow-up period the same for all patients Statistical tests appropriate paired t-test used. Compliance with intervention was reliable INTERNAL VALIDITY (confounding/selection bias) Patients acted as their own controls, therefore were recruited from the same population and same period of time Unclear if a priori design List of excluded studies not provided Likelihood of publication bias not assessed REPORTING Distributions of principal confounders in each group of subjects to be compared not clearly described Estimates of the random variability in the data for the main outcomes not clearly described P values not reported; however, results were not significant INTERNAL VALIDITY (bias) Blinding was not attempted Attempt to blind those measuring the main outcomes of the intervention not reported INTERNAL VALIDITY (confounding/selection bias) Unclear if there was adequate adjustment for confounding in the analyses from which the main findings were drawn One patent withdrew, no analysis based on this patient POWER Study had limited power to detect statistical significance. Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 12

13 Table 3: Summary of Critical Appraisal Strengths Limitations Treatment was randomized within the patient to the side of the body (computer generated) Outcomes used accurate Xu 3 REPORTING Objective clearly described Main outcomes clearly described Patient characteristics clearly described Intervention clearly described Main findings clearly described Characteristics of patients lost to follow-up partially described Probability values reported EXTERNAL VALIDITY Subjects recruited likely close to representative of the entire population from which they were recruited Staff, places, facilities for treatment likely representative of what the majority of patients could receive laser is relatively common. INTERNAL VALIDITY (bias) Follow-up period the same for all patients Statistical tests appropriate Compliance with intervention was reliable Main outcomes are accurate INTERNAL VALIDITY (confounding/selection bias) Patients acted as their own controls, therefore were recruited from the same population and same period of time Randomization was based on body part or side of the body POWER Study had sufficient power to detect clinically important effects where the probability value for a difference being due to chance is less than 5%. Power calculation reported Mahmoud 4 REPORTING Objective clearly reported Main outcome measures clearly described Characteristics of patients fairly clearly described Interventions clearly described REPORTING Patients acted as own controls, therefore, distributions of principal confounders in each group likely not relevant Estimates of the random variability not reported Important adverse events not reported INTERNAL VALIDITY (bias) Blinding was not attempted Unclear if an attempt made to blind those measuring the main outcomes Not clear if any of the results of the study were based on data dredging INTERNAL VALIDITY (confounding/selection bias) Randomization was not concealed Unclear if randomized intervention assignment concealed from both patients and health care staff until recruitment was complete and irrevocable Unclear if adequate adjustment for confounding in the analyses from which the main findings were drawn Patients lost to follow up were removed from the analysis. REPORTING Patients acted as own controls, therefore, distributions of principal confounders in each group likely not relevant Estimates of the random variability not reported Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 13

14 Table 3: Summary of Critical Appraisal Strengths Limitations Main findings clearly described Important adverse events reported Characteristics of patients lost to follow-up mostly described Actual probability values for main outcomes reported EXTERNAL VALIDITY Subjects likely representative of the entire population Staff, places, facilities were likely representative of the treatment most patients can receive INTERNAL VALIDITY (bias) Follow-up time was the same for all subjects Statistical tests used to assess the main outcomes were appropriate Compliance to the intervention was reliable Main outcome measures accurate INTERNAL VALIDITY (confounding/selection bias) Patients acted as their own controls, therefore were recruited from the same population and same period of time Randomization based on side of the body POWER Study had sufficient power to detect a clinically important effect where the probability value for a difference being due to chance is less than 5% INTERNAL VALIDITY (bias) Blinding of patients not attempted Unclear if blinding of the raters or evaluators was attempted INTERNAL VALIDITY (confounding/selection bias) Unclear if randomized intervention assignment concealed from both patients and health care staff until recruitment was complete and irrevocable Unclear if adequate adjustment for confounding in the analyses from which the main findings were drawn Unclear if losses of patients to follow-up taken into account in the analysis Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 14

15 APPENDIX 4: Summary of Findings Table 4: Summary of Effectiveness and Safety Outcomes Author, Year Main Effectiveness Outcomes Main Safety Outcomes Author Conclusions Systematic Review Rambhatla, Decreases in disease activity after 3 months: 65.3% for all sites 73.4% for groin 62% for axillary 53.2% for inframammary Changes were significant in the treatment, but not control group Randomized Controlled Trials Nostrati, /6 patients completed study Disease rating: tx: increased from 2.4 (SD 0.33) to 2.75 (SD 2.56) control: increased from 3.05 (SD: 1.89) to 3.15 (SD: 2.77) (difference not significant) Patient satisfaction: 80% very satisfied with treatment 20% unsatisfied with treatment Xu, /20 patients completed the study; 18 patients had 2 month histopathological results Modified HS-LASI change at 2 months: NR Multidisciplinary approach (medical and surgical) for treatment of HS recommended. Stage I disease: Monthly therapy with Nd:YAG considered appropriate Stage II disease: Monthly (minimum 3 to 4 sessions) treatment with Nd:YAG considered efficacious, shift to biological agents if not tolerated or refractory disease continues Stage III disease: No strong evidence available No patient reported an adverse event within 48 hours of treatment No pain, swelling, redness, crusting, changes in skin pigmentation Withdrawal was not due to an adverse event Pain and adverse events not reported Nd:YAG was found to be safe, even when using high fluences Patients were satisfied, requested further treatment No objective response seen in this study Laser seemed to speed healing of active lesions Nd:YAG was found to be a well-tolerated, effective, non- Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 15

16 Table 4: Summary of Effectiveness and Safety Outcomes Author, Year Main Effectiveness Outcomes Main Safety Outcomes Author Conclusions -31.6% (P<.001) for all anatomic sites % (P = 0.008) for axillary regions -36.8% (P = 0.001) for inguinal Histopathological results at 2 months: 12/18 had minimal (mainly deep) inflammatory reaction 6/18 had scarring and fibrosis 1/18 had inflammation around apocrine glands invasive treatment option for patients with HS Mahmoud, /22 competed the study Change from baseline on treated vs. control side: -72.7% (SD: 13.0, P>0.001) vs % (SD: 38.9, P<0.001) for all anatomic sites -70.2% (SD: 13.0, P = 0.001) vs % (SD: 29.4, P<0.044) for axillary sites -73.5% (SD: 11.3, P = 0.004) vs % (SD: 56.6, P <0.406) for inframammary sites -74.5% (SD: 14.4, P<0.001) vs % (SD: 39.3, P < 0.005) for the inguinal fold Continued progression occurred throughout the study, with treatment being more significant than control (P <0.001) for the combination of all sites. 92% of patients associated the laser treatment with improvements in disease 3 patients developed cellulitis and withdrew due to the need for systemic medication 60% of patients did not experience pain Those who experienced pain did not find it to interfere with daily activity No histopathological evidence of thermal injury Laser seemed to improve preexisting lesions, prevent new lesions Improvements maintained for at least 2 months Nd:YAG laser was a safe and effective modality to treat HS, should be incorporated into standard treatment options for HS, especially moderate disease. Dermal edema present after 1 and 4 weeks HS = Hidradenitis Suppurativa; HS-LASI = Modified Hidradenitis Suppurativa Lesion Area and Severity Index; Nd:YAG = neodymium:yttrium-aluminium-garnet; nm = nanometer; SD = standard deviation Nd:YAG Laser for the Treatment of Patients with Hidradenitis Suppurativa 16