Endpoints and Outcomes for Localized Scleroderma/Morphea: A Scoping Literature Review

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Torok, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4138373/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Aug, 2024 Read the published version in Pediatric Rheumatology → Version 1 posted 5 You are reading this latest preprint version Abstract Background Current treatment for localized scleroderma (LS) has been shown to halt disease activity, but little is still known about patient experiences with these treatments, nor is there consensus about optimal measurement strategies for future clinical trials. Objective Conduct a scoping review of the literature for the types of outcomes and measures (i.e. clinician-, patient-, and caregiver-reported) utilized in published treatment studies of LS. Methods Online databases were searched for articles related to the evaluation of treatment efficacy in LS with a special focus on pediatrics. Results Of the 168 studies, the most common outcomes used were cutaneous disease activity and damage measured via clinician-reported assessments. The most frequently cited measure was the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT). Few patient-reported outcome measures (PROMs) were used. Limitations: Some studies only vaguely reported the measures utilized, and the review yielded a low number of clinical trials. Conclusion In addition to evaluating disease activity with clinician-reported measures, the field could obtain critical knowledge on the patient experience by including high-quality PROMs of symptoms and functioning. More clinical trials using a variety of outcomes and measures are necessary to determine the most suitable course of treatment for LS patients. juvenile localized scleroderma localized scleroderma scleroderma rheumatic condition morphea treatment outcomes CAPSULE SUMMARY Existing treatments for localized scleroderma halt disease activity but little is known about patient experiences with these treatments. Clinician-reported measures are over represented in published trials. Better integration of patient-reported measures, alongside clinical outcomes, would more completely evaluate treatment efficacy in future trials by incorporating the patient perspective. Introduction Localized scleroderma (LS) or morphea is a rare rheumatic condition that causes atrophy, fibrosis, and sclerosis of the skin and underlying tissues. 1 Morbidity is common for individuals with LS, who can be adversely impacted via skin damage, physical deformity and dysfunction (especially during childhood onset), permanent cosmetic issues, and extracutaneous manifestations. 2 3 The conduct of clinical trials for LS encounters a number of challenges common for rare diseases, including hard to reach patient populations, low sample sizes, and a lack of consensus regarding clinical outcome assessments (COAs). Currently, there are no FDA approved treatments for LS, although consensus-based groups have started compiling evidence across clinical sites. Current regimens have been shown to be efficacious at halting disease activity, 4 but recent qualitative work has shed light on the negative experiences of patients under treatment, including side effects and overall burden. 5 6 Further, recent attempts at meta-analyses have been unsuccessful due to the wide variation in how successful treatment efficacy has been defined across studies, clinics, and registries. 7 Much needed clinical trials to find efficacious treatments or comparable treatments with lower burden cannot occur without the identification of relevant patient-centered outcomes and high-quality clinical outcome assessments (COAs; i.e. the measures themselves). This study aims to explore and catalogue the current and past outcomes and COAs used to evaluate treatment efficacy in children and adults diagnosed with LS, with particular focus on pediatric patients who have a higher cumulative disease burden, 8 and the use of patient-reported outcomes (PROs). We expect this review to spur important clinical research into this population and identify new areas for measurement developers to pursue. We also expect to be able to discuss and provide recommendations for researchers on best practices for citing quality evidence supporting outcome/endpoint choices. Methods Design This work is a scoping review. It was carried out using the Cochrane Handbook for Systematic Reviews of Interventions 9 and was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement: an updated guideline for reporting systematic reviews. 10 The search was developed and conducted by a professional medical librarian in consultation with the author team and included a mix of keywords and subject headings representing localized scleroderma, morphea, and pediatrics. Search hedges or database filters were used to remove publication types such as editorials, case reports, comments and animal-only studies as was appropriate for each database. The databases searched included MEDLINE (PubMed), Embase (Elsevier), and Web of Science (Clarivate). The search was conducted on September 19, 2019 and updated on April 20, 2022 and found 3,212 citations. Complete reproducible search strategies, including date ranges and search filters are detailed in the Supplementary Materials. Eligibility Criteria To be included in the review, studies had to meet all inclusion criteria as follows 1) the inclusion of human subjects, 2) at least some participants were diagnosed with LS, 3) reported on the treatment of patients, 4) reported at least one outcome that was linked to treatment, and 5) were available in English. Studies also were required to be primary data sources. Eligible studies included observational cohorts, case studies with 3 or more individuals, randomized clinical trials, and reports on large registries. The focus of the study was on juvenile LS, with the expectation that most studies would be have at least some pediatric patients, however, studies that included only adults with LS were not excluded to maximize the number of relevant articles. Study Selection After the search, all identified studies were uploaded into Covidence (Veritas Health Innovation, Melbourne, Australia). The duplicates were removed by the software (n = 1,190) and a final set of 2,022 citations were left to be screened in the title/abstract phase. Study selection was carried out independently by two authors. The article selection is presented by flowchart as per PRISMA guidelines (Fig. 1). For the full-text screening stage, papers were also reviewed in detail by two independent reviewers and were excluded if they did not meet the inclusion criteria. At any stage, all disagreements were resolved by discussion, consensus, and later on by the study investigator. Data Extraction Data elements of interest included general study information (i.e. year of publication, type of study), quality of study, sample size/number of LS patients, age of patients, types and subtypes of morphea/LS, treatment, and information on outcomes and COAs. As per the National Institutes of Health Biomarkers, Endpoints, and other Tools (BEST) glossary, 11 an ‘outcome’ was defined as the domains of symptoms and functioning defined by the authors of the included articles (e.g. ‘disease activity’), while the COA was defined as the overall system of measurement including the survey/questions, the method for obtaining measurement, and the method of interpretation. Of particular interest, the type of COA was recorded and results are reported separately for different types of clinical outcome measures as defined in Table 1 . Table 1 Clinical outcome assessment (COA) types and definitions. Clinical Outcome Assessment Type Abbreviation Definition 1 N (%) 3 Clinical assessment of treatment outcomes - Any clinical assessment of treatment benefit. This categorization included formal and informal evaluations by clinicians that did not explicitly utilize a COA, as well as those that utilized named ClinRO measures. 99 (58.9) Clinician-reported outcome measures 2 ClinRO A standardized measurement based on a report that comes from a trained health-care professional after observation of a patient’s health condition. 31 (18.5) Patient-reported / Observer-reported outcome measures PRO /ObsRO Any measurement of health taken directly from the patient or an observer (defined here as a parent or caregiver, not a clinician). 43 (25.6) Performance-based outcome measures PerfO A measurement based on standardized task(s) actively undertaken by a patient according to a set of instructions. 9 (5.4) Other measures of health - Any measurement of health status that utilized external equipment such as thermography, ultrasound, MRI, photographs, and laboratory tests. 67 (39.9) 1 Definitions adapted from the NIH Best Resource [15]. 2 As defined, ClinRO measures are a subset of those counted as “Clinical Assessment of Treatment Outcomes’. 3 Studies could utilize multiple COAs; thus percentages add up to more than 100% Quality Assessment To assess the methodological quality of the cited evidence for the COAs being utilized, we intended to take a modified COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) approach 12 13 However, due to general lack of details included in the articles, the quality assessment of the validity evidence cited was binary (yes - any reliability or validity information was cited in the methods to support use of the measure, or no – no support was cited). Further, quality at the study level was evaluated using the following criteria: 1) the research question was clearly stated, 2) the sample size was justified, 3) the treatment protocol was standardized, 4) there was a control/placebo group, and 5) blinding of the treatment condition was present. Synthesis Methods Specific variables were catalogued across studies using pre-specified definitions. Additionally, for each outcome and COA, specific characteristics were extracted and tabulated for each category. For example, studies could and often did include multiple outcomes, meaning that the frequencies and percentages for reported outcome categories add up to more than 100%. Due to inconsistencies across articles in how outcomes and COAs were reported, we also include descriptive narratives of our findings for each type of COA. Results Study characteristics and quality assessment The 168 studies in the final evaluation sample were conducted in a total of 35 countries (~ 30% of studies conducted in the United States). Almost half (78/168) of studies were retrospective, i.e. medical chart reviews. As such, in terms of study quality, 90% of articles stated the research question, but the majority of articles did not include a sample size justification (93%), a control group (92%), or any masking of the treatment effect (76%). Further, only 46% of articles reported on efficacy of a standardized treatment regimen. Further detail on study characteristics can be found in Supplemental Materials. Patients included in the studies comprised all subtypes, with craniofacial scleroderma and generalized morphea being the most commonly reported (Table 2 ). The majority of treatments evaluated in the studies were systemic medications, followed by phototherapy/UV therapy, topical creams, or reconstructive surgery (Table 2 ). More than half of studies (56%) reported on multiple treatments. Table 2 Frequency and percentages across the 168 included articles for reported subtypes of LS and evaluated treatments. N (%) 1 Types/Subtypes Craniofacial scleroderma 100 (59.5) Generalized morphea 95 (56.5) Linear morphea, unspecified 60 (35.7) Circumbscribed morphea, unspecified 51 (30.4) Mixed subtype 42 (25.0) Linear morphea, trunk/limb 35 (20.8) Circumscribed morphea, deep 23 (13.7) Pansclerotic morphea 22 (13.1) Eosinophilic Fasciitis 13 (7.7) Circumbscribed morphea, superficial 8 (4.8) Unspecified 16 (9.5) Treatments Corticosteroids (oral and parenteral) 76 (45.2) Methotrexate 72 (42.9) Phototherapy / UV therapy 50 (29.8) Topical creams / medications 37 (22.0) Plastic / reconstructive surgery 35 (20.8) Mycophenolate Mofetil (MMF) 20 (11.9) Antibiotic 4 (2.4) Traditional Chinese medicine 2 (1.2) Acupuncture 1 (0.6) Other 66 (39.3) 1 Studies could report multiple subtypes and treatments; percentages add up to more than 100% Outcomes and Endpoints Treatment outcomes The most common outcome reported across all articles was “disease activity” (111/168), although the operationalization of this term varied across studies (Table 3 ). Other outcomes names by authors to determine treatment efficacy included “disease damage”, “skin thickness”, “lesion size”, “surgical outcomes”, and “clinician satisfaction”. Outcomes utilized to evaluate other aspects of treatment from the patient perspective commonly included “health-related quality of life” and “patient satisfaction/success” (Table 3 ). Table S1 Included studies by country. Country N (%) United States of America 50 (29.8) Other/Unclear 1 13 (7.7) Italy 12 (7.1) Germany 11 (6.5) United Kingdom 10 (6.0) Canada 9 (5.4) China 7 (4.3) Brazil 6 (3.6) Netherlands 6 (3.6) Egypt 5 (3.0) Turkey 5 (3.0) France 4 (2.3) Korea 4 (2.3) Israel 4 (2.3) Australia 4 (2.3) Poland 3 (1.8) Multiple Countries 3 (1.8) Ireland 2 (1.2) Japan 2 (1.2) Mexico 2 (1.2) Portugal 2 (1.2) South Korea 2 (1.2) Switzerland 2 (1.2) 1 Countries with n of 1 are included in the ‘other’ category. Table S2 Study type. N (%) Study Type Existing data 78 (46.4) Prospective observational 57 (33.9) Case study (3 or more patients) 13 (7.7) Non-randomized clinical trial 9 (5.4) Randomized clinical trial 8 (4.8) Survey 1 (0.6) Existing data + survey 1 (0.6) Clinical trial 1 (0.6) Table 3 Treatment outcomes as categorized by authors of included articles. N (%) 1 Outcomes Treatment Efficacy Disease activity (cutaneous/global) 111 (66.1) Skin Thickness (separate outcome, not part of overall disease activity) 26 (15.5) Disease damage (cutaneous/global) 23 (13.7) Other aspect categorized as reflecting disease activity (not part of overall disease activity score) 23 (13.7) Lesion size/body surface area 7 (4.2) Disease severity 2 (1.2) Surgical outcome (general) 15 (8.9) Clinician satisfaction/success 8 (4.8) Patient perspective Health-related quality of life 20 (11.9) Functional outcomes 1 (0.6) Adverse side effects 1 (0.6) Other 26 (15.5) 1 Studies could include multiple outcomes; percentages add up to more than 100% Supplemental Files SI. Full search strategy Search Strategy Report : Searcher: Leila Ledbetter, MLIS, AHIP, Duke University Medical Center Library Initial Search Date: 9/19/2019 Updated Search Date: 4/20/2022 Database (including vendor/platform): MEDLINE (via PubMed) Inclusive Date Coverage: 1966 to present, and selected coverage of literature prior to that period Table S3 Quality of studies. Quality Variable Yes (%) Research question clearly stated 16 (9.5) Reporting justification for sample size 11 (6.5) Treatment regimen was standardized 78 (46.4) Control/placebo group 13 (7.7) Blinding of treatment condition 40 (23.8) Types of COAs The most common way treatment outcomes were measured were via clinical assessments that were both informal and formal/standardized (59%) along with other measures of health (40%; blood tests, imaging; Table 1 ). Patient- or observer-reported measures (like those completed by a parent) were used more infrequently (26%). Clinical assessment of treatment outcomes. Almost 59% percent of articles (99/168) included some type of clinical assessment of treatment benefit that was commonly conceptualized as improvement, progression, and/or change in disease status (e.g. activity or damage). Disease progression typically included the appearance of new lesions or the expansion of pre-existing lesions over a specific period of time. Disease improvement typically was defined as lesions getting smaller or disappearing. Change in disease status was often conceptualized as a “halt” in disease activity or progression. The clinical assessments within this category included clinical evaluations that both did and did not explicitly utilize a COA. Some clinical assessments were described as being less formal in nature and did not utilize specific criteria or time frame when reporting on the clinical evaluation. Other clinical assessments for disease activity were more formal and did include specific criteria that was utilized to categorize patients. For example, another study 14 evaluated defined clinical improvement in activity as the absence of the criteria suggested by Careta and Romiti: appearance of new lesions in the last 3 months, expansion of the pre-existing lesion in the last 3 months, moderate or severe erythema or skin lesions with erythematous borders, violaceous lesion or lesion border, increased induration of the lesion border, and worsening of the hair loss on the scalp, eyebrows or eyelashes. Other clinical assessments described in the articles included the evaluation of surgical outcomes or general clinician satisfaction/success by assessing facial symmetry, complications, and need for surgical revisions. Clinician-reported outcome measures. The most frequently named ClinRO(s) across studies was the Localized Scleroderma Assessment Tool (LoSCAT) 15 16 and/or its components (18.5%; 31/168), the modified Localized Skin Severity Index (mLoSSI), which measures disease activity, and the Localized Scleroderma Damage Index (LoSDI), which measures disease damage. All studies that utilized the LoSCAT or its components cited validity and/or reliability information in the article, including general PRO measure development, content validity, reliability, and responsiveness. The LoSCAT was most often used in association with disease activity. Physician-global assessments (PGAs) 15 16 were utilized in 10.7% of studies (18/168), and often together with the LoSCAT, focused on disease activity. Other named ClinROs included skin scores (7.1%; 12/168), such as the modified Rodnan Skin Score (mRSS), most often utilized to assess skin thickness, and other clinical activity scores (e.g. ‘CAS’ or LS Cutaneous Activity Measure; 1.8%; 3/168). Other named ClinROs that were utilized infrequently were the Quantitative facial symmetry score and the Derriford Appearance Scale (both n = 1) which were linked to surgical outcomes. Patient-reported / Observer-reported outcome measures Patient-reported outcomes (PROs) and/or observer-reported outcomes (ObsROs; typically a child’s caregiver) were included in about 26% of the manuscripts (43/168). PROs were most often used to evaluate treatment outcomes described as health-related quality of life (HRQOL) and patient satisfaction/success. Some of the PROs/ObsROs utilized to evaluate HRQOL were listed as the the World Health Organization Quality of Life (WHOQOL-110), 17 the Children’s Dermatology Life Quality Index (CDLQI), 18 the Scleroderma Health Assessment Questionnaire (SHAQ), 19 Child Health Assessment Questionnaire (CHAQ), 20 Pediatric Quality of Life (family impact, generic, rheumatology module), 21 22 and visual analog scales (VAS) for symptoms. Many of the patient satisfaction outcomes were measured using patient satisfaction with surgery and did not utilize specific PROs, but instead noted if the patient was satisfied. For example, one study had patients rate their satisfaction using ( 1 ) very good/very satisfied, ( 2 ) good/satisfied, ( 3 ) bad/not satisfied, and ( 4 ) very bad/very dissatisfied. 23 Some studies used unnamed ObsROs and PROs to assess if the patient (or caregiver) noticed an improvement, no change, or worsening of the disease. Performance-based outcome measures Performance-based outcome measures (PerfOs) were infrequently utilized to evaluate treatment benefit (5.4%; 9/168), and when included, typically were related to measuring joint mobility/range of motion before and after treatment. Other measures of health Other measures of health were included in about 40% of articles (67/168). The most frequent external equipment used to assess outcomes were magnetic resonance imaging (MRI), ultrasound, thermography, and photographs. In one study 24 , MRI was used before and after 6 months of treatment to evaluate the depth and thickness of the soft-tissue structures and the degree of inflammation and edema. The MRI images were graded from 0 to 10 by an experienced and blinded radiologist. The MRI scores were also compared and scored from 0 (no improvement) to 10 (total healing) by investigators. These outcome measures were often used as a supplement to other COAs. Additionally, authors commonly reported using photographs when evaluating surgical outcomes. Discussion While the field of LS research has been historically limited to case studies and retrospective chart reviews, with the development of large, multi-site research registries and coordination among international clinical experts, our understanding of the molecular basis of LS/morphea and the efficacy of treatments has grown. The more recent studies have started to recognize the importance of switching our focus from only inclusion of traditional clinical outcomes (i.e. disease activity) to clinical outcomes alongside complementary and critical patient experience data. As stated in the U.S. Food & Drug Administration’s new Patient-Focused Drug Development Guidances, patient-reported outcome measures are “useful for assessment of symptoms, functioning, events, or other aspects of health from the patient’s perspective.” 25 26 Further, as new research studies are planned and executed, the field can improve in terms of the published justifications to support use of a specific COA. Quite a few published studies in this review did not report use of existing COAs, and thus, there is little record of their thought process when conceptualizing these important outcomes. Additionally, the field is starting to gather information on the reliability and validity of outcome measures used in this population, with the LoSCAT and the Localized Scleroderma Quality of Life Instrument (LoSQI) 27–29 being two measures with support specifically with LS patients. While PerfOs were the least utilized COA, a large number of studies used other measures of health as part of their evaluation. Although the intention of using equipment is to provide a more objective evaluation of treatment, some of these measures (e.g. MRIs and photographs) required the output to be graded by a rater, perhaps giving the illusion of objectivity, but having the same possibility for error as other types of subjective measures. One limitation of this review is publication bias, in which investigators might have used certain outcome measures, but chose not to report on them. We also did not include articles published in languages other than English, which may have contained useful information. Some manuscripts in this review were vague and could not be reproduced due to lack of reporting on how exactly they assessed treatment. Most importantly, our review did not yield many randomized clinical trials, which supports the low utilization of control groups and blinding. This reveals more clinical trials evaluating treatment efficacy for this population are needed. Conclusion This review demonstrates a critical need for high quality, well-designed randomized clinical trials and comparative effectiveness studies to evaluate treatment efficacy of new and legacy treatments in patients with LS. Past and current studies have focused primarily on secondary data collection, and when prospective studies are conducted, patient-reported outcomes or other measures collected from patients and families are less of a focus, although important strides have been made recently. As the field moves forward, it is imperative to use validated and high quality COAs to evaluate meaningful aspects of treatment and for publishing authors to include stronger justifications and support for their choice of measures. The inclusion of complementary ClinROs, PROs, and ObsROs will go a long way to ensure future research and clinical care is patient-centered, and that we are able to compare treatments on their ability to control disease activity but also to improve (and not worsen) patient symptoms and negative side effects. Abbreviations CAS Cutaneous Activity measure CDLQI Children’s Dermatology Life Quality Index CHAQ Child Health Assessment Questionnaire ClinROs Clinician–reported outcome measures COAs Clinical outcome assessments COSMIN COnsensus–based Standards for the selection of health Measurement Instruments HRQoL health–related quality of life LoSCAT Localized Scleroderma Assessment Tool LoSDI Localized Scleroderma Damage Index LoSQI Localized Scleroderma Quality of Life Instrument LS Localized scleroderma mLoSSI modified Localized Skin Severity index MRI magnetic resonance imaging mRSS modified Rodnan Skin Score ObsRO Observer–reported outcome PROs Patient–reported outcomes PerfOs Performance–based outcome measures PGA Physician global assessment PRISMA Preferred Reporting Items for Systematic Reviews and Meta–Analyses SHAQ Scleroderma Health Assessment Questionnaire WHOQOL 110–World Health Organization Quality of Life VAS visual analog scale Declarations Funding sources: None Conflicts of Interest: Drs. Zigler & Torok developed the Localized Scleroderma Quality of Life Instrument, and if it is commercially successful in the future, they may benefit financially. Ethics approval and consent to participate: Not applicable Availability of data and materials: The datasets created and analysed during the current study available from the corresponding author on reasonable request. Consent for publication: Not applicable Authors’ contributions: All authors contributed towards the design of the study. AH, LZP, LL, and CKZ performed the literature search and data extraction. AH, LZP, CKZ, and KT contributed to the analysis of the data. All authors read and approved the final manuscript. Acknowledgements: We would like to acknowledge the contributions of Courtney Mann, Kirsten Bahnson, and Ashley Wilson. References Laxer RM, Zulian F. Localized scleroderma. Curr Opin Rheumatol 2006:18(6):606–13. Li SC, Higgins GC, Chen M, et al. 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Br J Dermatol. 2019 doi. 10.1111/bjd.18512 . Zigler CK, Ardalan K, Hernandez A, et al. Exploring the impact of paediatric localized scleroderma on health-related quality of life: Focus groups with youth and caregivers. Br J Dermatol. 2020 doi. 10.1111/bjd.18879 . Zigler CK, Lin L, Ardalan K, et al. Cross-sectional quantitative validation of the paediatric Localized Scleroderma Quality of Life Instrument (LoSQI): A disease-specific patient-reported outcome measure. J Eur Acad Dermatol Venereol. 2023;37(7):1406–14. 10.1111/jdv.19059 . [published Online First: 2023/03/24]. Cite Share Download PDF Status: Published Journal Publication published 21 Aug, 2024 Read the published version in Pediatric Rheumatology → Version 1 posted Editorial decision: Major revision 26 Apr, 2024 Reviewers agreed at journal 10 Apr, 2024 Reviewers invited by journal 10 Apr, 2024 Editor assigned by journal 09 Apr, 2024 First submitted to journal 04 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4138373","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":289741855,"identity":"fa0e8635-5650-4a2e-94c5-2c1052a22b09","order_by":0,"name":"Alexy Hernandez","email":"","orcid":"","institution":"Duke University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Alexy","middleName":"","lastName":"Hernandez","suffix":""},{"id":289741856,"identity":"4634e324-dc4e-41a9-bdf4-122785b3e6c5","order_by":1,"name":"Leslie Zapata Leiva","email":"","orcid":"","institution":"Duke University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Leslie","middleName":"Zapata","lastName":"Leiva","suffix":""},{"id":289741857,"identity":"01899285-a18b-41e1-948f-d998225a2a8d","order_by":2,"name":"Maria Mutka","email":"","orcid":"","institution":"Duke University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Mutka","suffix":""},{"id":289741858,"identity":"1c950990-46f1-4f61-a7a5-c33379229bc4","order_by":3,"name":"Kathryn S. Torok","email":"","orcid":"","institution":"Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center: Children's Hospital of Pittsburgh of UPMC","correspondingAuthor":false,"prefix":"","firstName":"Kathryn","middleName":"S.","lastName":"Torok","suffix":""},{"id":289741859,"identity":"40952499-a841-46b4-96c2-ec5f8f54c5ac","order_by":4,"name":"Leila Ledbetter","email":"","orcid":"","institution":"Duke University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Leila","middleName":"","lastName":"Ledbetter","suffix":""},{"id":289741860,"identity":"f6de5745-9f16-48c7-93ba-d65de5e45c19","order_by":5,"name":"Christina K Zigler","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAnklEQVRIiWNgGAWjYDACHgbGBzwMCSCmAdFamA1I1sImQZoW/p7jzyretqXJMbA3b5MgSovE2Ya0m3PbcowZeI6VEafFgJ/h2G3etorEBokcM2K1MLYVA7XUN8i/IVYLbzMbM29bTgKDBA+RWiTOHGOWnHMuzbCNJ63Ygigt/D3pDz+8KUuW52c/vPEGUVrggI005aNgFIyCUTAK8AIAHEknXekUPZAAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-8996-7757","institution":"Duke University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Christina","middleName":"K","lastName":"Zigler","suffix":""}],"badges":[],"createdAt":"2024-03-20 15:57:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4138373/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4138373/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12969-024-01014-x","type":"published","date":"2024-08-21T15:56:51+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":63300032,"identity":"a677c1c2-b9df-4d06-8bd0-a9dfc33014c7","added_by":"auto","created_at":"2024-08-26 16:09:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":622269,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4138373/v1/c3051369-3817-4658-bced-4ac7724a31c8.pdf"}],"financialInterests":"","formattedTitle":"Endpoints and Outcomes for Localized Scleroderma/Morphea: A Scoping Literature Review","fulltext":[{"header":"CAPSULE SUMMARY","content":"\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eExisting treatments for localized scleroderma halt disease activity but little is known about patient experiences with these treatments.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eClinician-reported measures are over represented in published trials. Better integration of patient-reported measures, alongside clinical outcomes, would more completely evaluate treatment efficacy in future trials by incorporating the patient perspective.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"Introduction","content":" \u003cp\u003eLocalized scleroderma (LS) or morphea is a rare rheumatic condition that causes atrophy, fibrosis, and sclerosis of the skin and underlying tissues.\u003csup\u003e1\u003c/sup\u003e Morbidity is common for individuals with LS, who can be adversely impacted via skin damage, physical deformity and dysfunction (especially during childhood onset), permanent cosmetic issues, and extracutaneous manifestations. \u003csup\u003e2 3\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe conduct of clinical trials for LS encounters a number of challenges common for rare diseases, including hard to reach patient populations, low sample sizes, and a lack of consensus regarding clinical outcome assessments (COAs). Currently, there are no FDA approved treatments for LS, although consensus-based groups have started compiling evidence across clinical sites. Current regimens have been shown to be efficacious at halting disease activity,\u003csup\u003e4\u003c/sup\u003e but recent qualitative work has shed light on the negative experiences of patients under treatment, including side effects and overall burden.\u003csup\u003e5 6\u003c/sup\u003e Further, recent attempts at meta-analyses have been unsuccessful due to the wide variation in how successful treatment efficacy has been defined across studies, clinics, and registries.\u003csup\u003e7\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMuch needed clinical trials to find efficacious treatments or comparable treatments with lower burden cannot occur without the identification of relevant patient-centered outcomes and high-quality clinical outcome assessments (COAs; i.e. the measures themselves). This study aims to explore and catalogue the current and past outcomes and COAs used to evaluate treatment efficacy in children and adults diagnosed with LS, with particular focus on pediatric patients who have a higher cumulative disease burden,\u003csup\u003e8\u003c/sup\u003e and the use of patient-reported outcomes (PROs). We expect this review to spur important clinical research into this population and identify new areas for measurement developers to pursue. We also expect to be able to discuss and provide recommendations for researchers on best practices for citing quality evidence supporting outcome/endpoint choices.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign\u003c/h2\u003e \u003cp\u003e This work is a scoping review. It was carried out using the Cochrane Handbook for Systematic Reviews of Interventions\u003csup\u003e9\u003c/sup\u003e and was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement: an updated guideline for reporting systematic reviews.\u003csup\u003e10\u003c/sup\u003e The search was developed and conducted by a professional medical librarian in consultation with the author team and included a mix of keywords and subject headings representing localized scleroderma, morphea, and pediatrics. Search hedges or database filters were used to remove publication types such as editorials, case reports, comments and animal-only studies as was appropriate for each database. The databases searched included MEDLINE (PubMed), Embase (Elsevier), and Web of Science (Clarivate). The search was conducted on September 19, 2019 and updated on April 20, 2022 and found 3,212 citations. Complete reproducible search strategies, including date ranges and search filters are detailed in the Supplementary Materials.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEligibility Criteria\u003c/h2\u003e \u003cp\u003eTo be included in the review, studies had to meet all inclusion criteria as follows 1) the inclusion of human subjects, 2) at least some participants were diagnosed with LS, 3) reported on the treatment of patients, 4) reported at least one outcome that was linked to treatment, and 5) were available in English. Studies also were required to be primary data sources. Eligible studies included observational cohorts, case studies with 3 or more individuals, randomized clinical trials, and reports on large registries. The focus of the study was on juvenile LS, with the expectation that most studies would be have at least some pediatric patients, however, studies that included only adults with LS were not excluded to maximize the number of relevant articles.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy Selection\u003c/h2\u003e \u003cp\u003eAfter the search, all identified studies were uploaded into Covidence (Veritas Health Innovation, Melbourne, Australia). The duplicates were removed by the software (n\u0026thinsp;=\u0026thinsp;1,190) and a final set of 2,022 citations were left to be screened in the title/abstract phase. Study selection was carried out independently by two authors. The article selection is presented by flowchart as per PRISMA guidelines (Fig.\u0026nbsp;1). For the full-text screening stage, papers were also reviewed in detail by two independent reviewers and were excluded if they did not meet the inclusion criteria. At any stage, all disagreements were resolved by discussion, consensus, and later on by the study investigator.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData Extraction\u003c/h2\u003e \u003cp\u003eData elements of interest included general study information (i.e. year of publication, type of study), quality of study, sample size/number of LS patients, age of patients, types and subtypes of morphea/LS, treatment, and information on outcomes and COAs. As per the National Institutes of Health Biomarkers, Endpoints, and other Tools (BEST) glossary,\u003csup\u003e11\u003c/sup\u003e an \u0026lsquo;outcome\u0026rsquo; was defined as the domains of symptoms and functioning defined by the authors of the included articles (e.g. \u0026lsquo;disease activity\u0026rsquo;), while the COA was defined as the overall system of measurement including the survey/questions, the method for obtaining measurement, and the method of interpretation. Of particular interest, the type of COA was recorded and results are reported separately for different types of clinical outcome measures as defined in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical outcome assessment (COA) types and definitions.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical Outcome Assessment Type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbbreviation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDefinition\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN (%)\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eClinical assessment of treatment outcomes\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAny clinical assessment of treatment benefit. This categorization included formal and informal evaluations by clinicians that did not explicitly utilize a COA, as well as those that utilized named ClinRO measures.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e99 (58.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eClinician-reported outcome measures\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClinRO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eA standardized measurement based on a report that comes from a trained health-care professional after observation of a patient\u0026rsquo;s health condition.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e31 (18.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePatient-reported / Observer-reported outcome measures\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePRO /ObsRO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAny measurement of health taken directly from the patient or an observer (defined here as a parent or caregiver, not a clinician).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e43 (25.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePerformance-based outcome measures\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePerfO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eA measurement based on standardized task(s) actively undertaken by a patient according to a set of instructions.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (5.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eOther measures of health\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAny measurement of health status that utilized external equipment such as thermography, ultrasound, MRI, photographs, and laboratory tests.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e67 (39.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e1\u003c/sup\u003e Definitions adapted from the NIH Best Resource [15]. \u003csup\u003e2\u003c/sup\u003eAs defined, ClinRO measures are a subset of those counted as \u0026ldquo;Clinical Assessment of Treatment Outcomes\u0026rsquo;. \u003csup\u003e3\u003c/sup\u003eStudies could utilize multiple COAs; thus percentages add up to more than 100%\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eQuality Assessment\u003c/h2\u003e \u003cp\u003eTo assess the methodological quality of the cited evidence for the COAs being utilized, we intended to take a modified COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) approach\u003csup\u003e12 13\u003c/sup\u003e However, due to general lack of details included in the articles, the quality assessment of the validity evidence cited was binary (yes - any reliability or validity information was cited in the methods to support use of the measure, or no \u0026ndash; no support was cited). Further, quality at the study level was evaluated using the following criteria: 1) the research question was clearly stated, 2) the sample size was justified, 3) the treatment protocol was standardized, 4) there was a control/placebo group, and 5) blinding of the treatment condition was present.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSynthesis Methods\u003c/h2\u003e \u003cp\u003eSpecific variables were catalogued across studies using pre-specified definitions. Additionally, for each outcome and COA, specific characteristics were extracted and tabulated for each category. For example, studies could and often did include multiple outcomes, meaning that the frequencies and percentages for reported outcome categories add up to more than 100%. Due to inconsistencies across articles in how outcomes and COAs were reported, we also include descriptive narratives of our findings for each type of COA.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStudy characteristics and quality assessment\u003c/h2\u003e \u003cp\u003eThe 168 studies in the final evaluation sample were conducted in a total of 35 countries (~\u0026thinsp;30% of studies conducted in the United States). Almost half (78/168) of studies were retrospective, i.e. medical chart reviews. As such, in terms of study quality, 90% of articles stated the research question, but the majority of articles did not include a sample size justification (93%), a control group (92%), or any masking of the treatment effect (76%). Further, only 46% of articles reported on efficacy of a \u003cem\u003estandardized\u003c/em\u003e treatment regimen. Further detail on study characteristics can be found in Supplemental Materials.\u003c/p\u003e \u003cp\u003ePatients included in the studies comprised all subtypes, with craniofacial scleroderma and generalized morphea being the most commonly reported (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The majority of treatments evaluated in the studies were systemic medications, followed by phototherapy/UV therapy, topical creams, or reconstructive surgery (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). More than half of studies (56%) reported on multiple treatments.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFrequency and percentages across the 168 included articles for reported subtypes of LS and evaluated treatments.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN (%)\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTypes/Subtypes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCraniofacial scleroderma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e100 (59.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeneralized morphea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e95 (56.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLinear morphea, unspecified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e60 (35.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCircumbscribed morphea, unspecified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e51 (30.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixed subtype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLinear morphea, trunk/limb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35 (20.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCircumscribed morphea, deep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23 (13.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePansclerotic morphea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22 (13.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEosinophilic Fasciitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13 (7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCircumbscribed morphea, superficial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8 (4.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnspecified\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16 (9.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatments\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorticosteroids (oral and parenteral)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e76 (45.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMethotrexate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e72 (42.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhototherapy / UV therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50 (29.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTopical creams / medications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37 (22.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlastic / reconstructive surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35 (20.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMycophenolate Mofetil (MMF)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (11.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibiotic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (2.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTraditional Chinese medicine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcupuncture\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e66 (39.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e1\u003c/sup\u003eStudies could report multiple subtypes and treatments; percentages add up to more than 100%\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes and Endpoints\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003eTreatment outcomes\u003c/h2\u003e \u003cp\u003eThe most common outcome reported across all articles was \u0026ldquo;disease activity\u0026rdquo; (111/168), although the operationalization of this term varied across studies (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Other outcomes names by authors to determine treatment efficacy included \u0026ldquo;disease damage\u0026rdquo;, \u0026ldquo;skin thickness\u0026rdquo;, \u0026ldquo;lesion size\u0026rdquo;, \u0026ldquo;surgical outcomes\u0026rdquo;, and \u0026ldquo;clinician satisfaction\u0026rdquo;. Outcomes utilized to evaluate other aspects of treatment from the patient perspective commonly included \u0026ldquo;health-related quality of life\u0026rdquo; and \u0026ldquo;patient satisfaction/success\u0026rdquo; (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable S1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIncluded studies by country.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eN (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eUnited States of America\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (29.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther/Unclear\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e13 (7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e12 (7.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e11 (6.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnited Kingdom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e10 (6.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e9 (5.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e7 (4.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e6 (3.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNetherlands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e6 (3.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEgypt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e5 (3.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTurkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e5 (3.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e4 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKorea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e4 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsrael\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e4 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAustralia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e4 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3 (1.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple Countries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3 (1.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIreland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e2 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e2 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMexico\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e2 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePortugal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e2 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSouth Korea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e2 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSwitzerland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e2 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003e1\u003c/sup\u003eCountries with n of 1 are included in the \u0026lsquo;other\u0026rsquo; category.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable S2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStudy type.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStudy Type\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExisting data\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78 (46.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProspective observational\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57 (33.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase study (3 or more patients)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-randomized clinical trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (5.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRandomized clinical trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (4.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurvey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExisting data\u0026thinsp;+\u0026thinsp;survey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment outcomes as categorized by authors of included articles.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN (%)\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOutcomes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTreatment Efficacy\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease activity (cutaneous/global)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e111 (66.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin Thickness (separate outcome, not part of overall disease activity)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26 (15.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease damage (cutaneous/global)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23 (13.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther aspect categorized as reflecting disease activity\u003c/p\u003e \u003cp\u003e(not part of overall disease activity score)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23 (13.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLesion size/body surface area\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease severity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical outcome (general)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (8.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinician satisfaction/success\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8 (4.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePatient perspective\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHealth-related quality of life\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (11.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFunctional outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse side effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26 (15.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e1\u003c/sup\u003eStudies could include multiple outcomes; percentages add up to more than 100%\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cb\u003eSupplemental Files\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cb\u003eSI.\u003c/b\u003e Full search strategy\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cb\u003eSearch Strategy Report\u003c/b\u003e:\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eSearcher: Leila Ledbetter, MLIS, AHIP, Duke University Medical Center Library\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eInitial Search Date: 9/19/2019\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eUpdated Search Date: 4/20/2022\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eDatabase (including vendor/platform): MEDLINE (via PubMed)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eInclusive Date Coverage: 1966 to present, and selected coverage of literature prior to that period\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable S3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eQuality of studies.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQuality Variable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResearch question clearly stated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (9.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReporting justification for sample size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (6.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment regimen was standardized\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78 (46.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControl/placebo group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlinding of treatment condition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (23.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eTypes of COAs\u003c/h2\u003e \u003cp\u003eThe most common way treatment outcomes were measured were via clinical assessments that were both informal and formal/standardized (59%) along with other measures of health (40%; blood tests, imaging; Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Patient- or observer-reported measures (like those completed by a parent) were used more infrequently (26%).\u003c/p\u003e \u003cp\u003e \u003cem\u003eClinical assessment of treatment outcomes.\u003c/em\u003e Almost 59% percent of articles (99/168) included some type of clinical assessment of treatment benefit that was commonly conceptualized as improvement, progression, and/or change in disease status (e.g. activity or damage). Disease progression typically included the appearance of new lesions or the expansion of pre-existing lesions over a specific period of time. Disease improvement typically was defined as lesions getting smaller or disappearing. Change in disease status was often conceptualized as a \u0026ldquo;halt\u0026rdquo; in disease activity or progression.\u003c/p\u003e \u003cp\u003eThe clinical assessments within this category included clinical evaluations that both did and did not explicitly utilize a COA. Some clinical assessments were described as being less formal in nature and did not utilize specific criteria or time frame when reporting on the clinical evaluation.\u003c/p\u003e \u003cp\u003eOther clinical assessments for disease activity were more formal and did include specific criteria that was utilized to categorize patients. For example, another study \u003csup\u003e14\u003c/sup\u003e evaluated defined clinical improvement in activity as the absence of the criteria suggested by Careta and Romiti: appearance of new lesions in the last 3 months, expansion of the pre-existing lesion in the last 3 months, moderate or severe erythema or skin lesions with erythematous borders, violaceous lesion or lesion border, increased induration of the lesion border, and worsening of the hair loss on the scalp, eyebrows or eyelashes. Other clinical assessments described in the articles included the evaluation of surgical outcomes or general clinician satisfaction/success by assessing facial symmetry, complications, and need for surgical revisions.\u003c/p\u003e \u003cp\u003e \u003cem\u003eClinician-reported outcome measures.\u003c/em\u003e The most frequently named ClinRO(s) across studies was the Localized Scleroderma Assessment Tool (LoSCAT)\u003csup\u003e15 16\u003c/sup\u003e and/or its components (18.5%; 31/168), the modified Localized Skin Severity Index (mLoSSI), which measures disease activity, and the Localized Scleroderma Damage Index (LoSDI), which measures disease damage. All studies that utilized the LoSCAT or its components cited validity and/or reliability information in the article, including general PRO measure development, content validity, reliability, and responsiveness. The LoSCAT was most often used in association with disease activity.\u003c/p\u003e \u003cp\u003ePhysician-global assessments (PGAs)\u003csup\u003e15 16\u003c/sup\u003e were utilized in 10.7% of studies (18/168), and often together with the LoSCAT, focused on disease activity. Other named ClinROs included skin scores (7.1%; 12/168), such as the modified Rodnan Skin Score (mRSS), most often utilized to assess skin thickness, and other clinical activity scores (e.g. \u0026lsquo;CAS\u0026rsquo; or LS Cutaneous Activity Measure; 1.8%; 3/168). Other named ClinROs that were utilized infrequently were the Quantitative facial symmetry score and the Derriford Appearance Scale (both n\u0026thinsp;=\u0026thinsp;1) which were linked to surgical outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003ePatient-reported / Observer-reported outcome measures\u003c/h2\u003e \u003cp\u003e Patient-reported outcomes (PROs) and/or observer-reported outcomes (ObsROs; typically a child\u0026rsquo;s caregiver) were included in about 26% of the manuscripts (43/168). PROs were most often used to evaluate treatment outcomes described as health-related quality of life (HRQOL) and patient satisfaction/success. Some of the PROs/ObsROs utilized to evaluate HRQOL were listed as the the World Health Organization Quality of Life (WHOQOL-110),\u003csup\u003e17\u003c/sup\u003e the Children\u0026rsquo;s Dermatology Life Quality Index (CDLQI),\u003csup\u003e18\u003c/sup\u003e the Scleroderma Health Assessment Questionnaire (SHAQ),\u003csup\u003e19\u003c/sup\u003e Child Health Assessment Questionnaire (CHAQ),\u003csup\u003e20\u003c/sup\u003e Pediatric Quality of Life (family impact, generic, rheumatology module),\u003csup\u003e21 22\u003c/sup\u003e and visual analog scales (VAS) for symptoms.\u003c/p\u003e \u003cp\u003eMany of the patient satisfaction outcomes were measured using patient satisfaction with surgery and did not utilize specific PROs, but instead noted if the patient was satisfied. For example, one study had patients rate their satisfaction using (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) very good/very satisfied, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) good/satisfied, (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) bad/not satisfied, and (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) very bad/very dissatisfied.\u003csup\u003e23\u003c/sup\u003e Some studies used unnamed ObsROs and PROs to assess if the patient (or caregiver) noticed an improvement, no change, or worsening of the disease.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003ePerformance-based outcome measures\u003c/h2\u003e \u003cp\u003ePerformance-based outcome measures (PerfOs) were infrequently utilized to evaluate treatment benefit (5.4%; 9/168), and when included, typically were related to measuring joint mobility/range of motion before and after treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eOther measures of health\u003c/h2\u003e \u003cp\u003eOther measures of health were included in about 40% of articles (67/168). The most frequent external equipment used to assess outcomes were magnetic resonance imaging (MRI), ultrasound, thermography, and photographs. In one study\u003csup\u003e24\u003c/sup\u003e, MRI was used before and after 6 months of treatment to evaluate the depth and thickness of the soft-tissue structures and the degree of inflammation and edema. The MRI images were graded from 0 to 10 by an experienced and blinded radiologist. The MRI scores were also compared and scored from 0 (no improvement) to 10 (total healing) by investigators. These outcome measures were often used as a supplement to other COAs. Additionally, authors commonly reported using photographs when evaluating surgical outcomes.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWhile the field of LS research has been historically limited to case studies and retrospective chart reviews, with the development of large, multi-site research registries and coordination among international clinical experts, our understanding of the molecular basis of LS/morphea and the efficacy of treatments has grown. The more recent studies have started to recognize the importance of switching our focus from only inclusion of traditional clinical outcomes (i.e. disease activity) to clinical outcomes \u003cem\u003ealongside\u003c/em\u003e complementary and critical patient experience data. As stated in the U.S. Food \u0026amp; Drug Administration\u0026rsquo;s new Patient-Focused Drug Development Guidances, patient-reported outcome measures are \u0026ldquo;useful for assessment of symptoms, functioning, events, or other aspects of health from the patient\u0026rsquo;s perspective.\u0026rdquo;\u003csup\u003e25 26\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFurther, as new research studies are planned and executed, the field can improve in terms of the published justifications to support use of a specific COA. Quite a few published studies in this review did not report use of existing COAs, and thus, there is little record of their thought process when conceptualizing these important outcomes. Additionally, the field is starting to gather information on the reliability and validity of outcome measures used in this population, with the LoSCAT and the Localized Scleroderma Quality of Life Instrument (LoSQI)\u003csup\u003e27\u0026ndash;29\u003c/sup\u003e being two measures with support specifically with LS patients.\u003c/p\u003e \u003cp\u003eWhile PerfOs were the least utilized COA, a large number of studies used other measures of health as part of their evaluation. Although the intention of using equipment is to provide a more objective evaluation of treatment, some of these measures (e.g. MRIs and photographs) required the output to be graded by a rater, perhaps giving the illusion of objectivity, but having the same possibility for error as other types of subjective measures.\u003c/p\u003e \u003cp\u003eOne limitation of this review is publication bias, in which investigators might have used certain outcome measures, but chose not to report on them. We also did not include articles published in languages other than English, which may have contained useful information. Some manuscripts in this review were vague and could not be reproduced due to lack of reporting on how exactly they assessed treatment. Most importantly, our review did not yield many randomized clinical trials, which supports the low utilization of control groups and blinding. This reveals more clinical trials evaluating treatment efficacy for this population are needed.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003e This review demonstrates a critical need for high quality, well-designed randomized clinical trials and comparative effectiveness studies to evaluate treatment efficacy of new and legacy treatments in patients with LS. Past and current studies have focused primarily on secondary data collection, and when prospective studies are conducted, patient-reported outcomes or other measures collected from patients and families are less of a focus, although important strides have been made recently. As the field moves forward, it is imperative to use validated and high quality COAs to evaluate meaningful aspects of treatment and for publishing authors to include stronger justifications and support for their choice of measures. The inclusion of complementary ClinROs, PROs, and ObsROs will go a long way to ensure future research and clinical care is patient-centered, and that we are able to compare treatments on their ability to control disease activity but also to improve (and not worsen) patient symptoms and negative side effects.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCutaneous Activity measure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCDLQI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChildren\u0026rsquo;s Dermatology Life Quality Index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCHAQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChild Health Assessment Questionnaire\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eClinROs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eClinician\u0026ndash;reported outcome measures\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOAs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eClinical outcome assessments\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOSMIN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCOnsensus\u0026ndash;based Standards for the selection of health Measurement Instruments\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHRQoL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehealth\u0026ndash;related quality of life\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLoSCAT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLocalized Scleroderma Assessment Tool\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLoSDI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLocalized Scleroderma Damage Index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLoSQI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLocalized Scleroderma Quality of Life Instrument\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLocalized scleroderma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003emLoSSI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emodified Localized Skin Severity index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emagnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003emRSS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emodified Rodnan Skin Score\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eObsRO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eObserver\u0026ndash;reported outcome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePROs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePatient\u0026ndash;reported outcomes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePerfOs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePerformance\u0026ndash;based outcome measures\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePGA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePhysician global assessment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePRISMA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePreferred Reporting Items for Systematic Reviews and Meta\u0026ndash;Analyses\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSHAQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eScleroderma Health Assessment Questionnaire\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWHOQOL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e110\u0026ndash;World Health Organization Quality of Life\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003evisual analog scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding sources:\u003c/strong\u003e None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e Drs. Zigler \u0026amp; Torok developed the Localized Scleroderma Quality of Life Instrument, and if it is commercially successful in the future, they may benefit financially.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe datasets created and analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u0026nbsp;\u003c/strong\u003eAll authors contributed towards the design of the study. AH, LZP, LL, and CKZ performed the literature search and data extraction. AH, LZP, CKZ, and KT contributed to the analysis of the data. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e We would like to acknowledge the contributions of Courtney Mann, Kirsten Bahnson, and Ashley Wilson.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLaxer RM, Zulian F. Localized scleroderma. Curr Opin Rheumatol 2006:18(6):606\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi SC, Higgins GC, Chen M, et al. Extracutaneous involvement is common and associated with prolonged disease activity and greater impact in juvenile localized scleroderma. Rheumatology. 2021;60(12):5724\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZigler CK, Ardalan K, Lane S, et al. A novel patient-reported outcome for paediatric localized scleroderma: a qualitative assessment of content validity. 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[published Online First: 2023/03/24].\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"proj","sideBox":"Learn more about [Pediatric Rheumatology](http://ped-rheum.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/proj/default.aspx","title":"Pediatric Rheumatology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"juvenile localized scleroderma, localized scleroderma, scleroderma, rheumatic condition, morphea, treatment, outcomes","lastPublishedDoi":"10.21203/rs.3.rs-4138373/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4138373/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCurrent treatment for localized scleroderma (LS) has been shown to halt disease activity, but little is still known about patient experiences with these treatments, nor is there consensus about optimal measurement strategies for future clinical trials.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eConduct a scoping review of the literature for the types of outcomes and measures (i.e. clinician-, patient-, and caregiver-reported) utilized in published treatment studies of LS.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eOnline databases were searched for articles related to the evaluation of treatment efficacy in LS with a special focus on pediatrics.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf the 168 studies, the most common outcomes used were cutaneous disease activity and damage measured via clinician-reported assessments. The most frequently cited measure was the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT). Few patient-reported outcome measures (PROMs) were used.\u003c/p\u003e\u003ch2\u003eLimitations:\u003c/h2\u003e \u003cp\u003eSome studies only vaguely reported the measures utilized, and the review yielded a low number of clinical trials.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIn addition to evaluating disease activity with clinician-reported measures, the field could obtain critical knowledge on the patient experience by including high-quality PROMs of symptoms and functioning. More clinical trials using a variety of outcomes and measures are necessary to determine the most suitable course of treatment for LS patients.\u003c/p\u003e","manuscriptTitle":"Endpoints and Outcomes for Localized Scleroderma/Morphea: A Scoping Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-18 18:47:46","doi":"10.21203/rs.3.rs-4138373/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2024-04-26T11:40:13+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-04-10T16:33:51+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-10T14:02:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-09T09:32:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Rheumatology","date":"2024-04-04T15:18:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"proj","sideBox":"Learn more about [Pediatric Rheumatology](http://ped-rheum.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/proj/default.aspx","title":"Pediatric Rheumatology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"29a1877d-3d0f-4b72-b277-b4da10e07a1c","owner":[],"postedDate":"April 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-26T15:59:22+00:00","versionOfRecord":{"articleIdentity":"rs-4138373","link":"https://doi.org/10.1186/s12969-024-01014-x","journal":{"identity":"pediatric-rheumatology","isVorOnly":false,"title":"Pediatric Rheumatology"},"publishedOn":"2024-08-21 15:56:51","publishedOnDateReadable":"August 21st, 2024"},"versionCreatedAt":"2024-04-18 18:47:46","video":"","vorDoi":"10.1186/s12969-024-01014-x","vorDoiUrl":"https://doi.org/10.1186/s12969-024-01014-x","workflowStages":[]},"version":"v1","identity":"rs-4138373","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4138373","identity":"rs-4138373","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}