Article Text
Abstract
Objectives Patient-reported outcome measures (PROMs) are important for clinical practice and research. Given the high unmet need, our aim was to develop a comprehensive PROM for systemic sclerosis (SSc), jointly with patient experts.
Methods This European Alliance of Associations for Rheumatology (EULAR)-endorsed project involved 11 European SSc centres. Relevant health dimensions were chosen and prioritised by patients. The resulting Systemic Sclerosis Impact of Disease (ScleroID) questionnaire was subsequently weighted and validated by Outcome Measures in Rheumatology criteria in an observational cohort study, cross-sectionally and longitudinally. As comparators, SSc-Health Assessment Questionnaire (HAQ), EuroQol Five Dimensional (EQ-5D), Short Form-36 (SF-36) were included.
Results Initially, 17 health dimensions were selected and prioritised. The top 10 health dimensions were selected for the ScleroID questionnaire. Importantly, Raynaud’s phenomenon, impaired hand function, pain and fatigue had the highest patient-reported disease impact. The validation cohort study included 472 patients with a baseline visit, from which 109 had a test–retest reliability visit and 113 had a follow-up visit (85% female, 38% diffuse SSc, mean age 58 years, mean disease duration 9 years). The total ScleroID score showed strong Pearson correlation coefficients with comparators (SSc-HAQ, 0.73; Patient’s global assessment, Visual Analogue Scale 0.77; HAQ-Disability Index, 0.62; SF-36 physical score, −0.62; each p<0.001). The internal consistency was strong: Cronbach’s alpha was 0.87, similar to SSc-HAQ (0.88) and higher than EQ-5D (0.77). The ScleroID had excellent reliability and good sensitivity to change, superior to all comparators (intraclass correlation coefficient 0.84; standardised response mean 0.57).
Conclusions We have developed and validated the EULAR ScleroID, which is a novel, brief, disease-specific, patient-derived, disease impact PROM, suitable for research and clinical use in SSc.
- scleroderma
- systemic
- patient reported outcome measures
- quality indicators
- health care
- immune system diseases
Data availability statement
Data are available on reasonable request. On request, and subject to review by the steering committee, access can be granted to the anonymised raw data and the R code. Deidentified data will be made available via secure data transfer. Data requests may be sent to the ScleroID steering committee, represented by OD, Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland. Email oliver.distler@usz.ch.
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- scleroderma
- systemic
- patient reported outcome measures
- quality indicators
- health care
- immune system diseases
Key messages
What is already known about this subject?
Patient-reported outcome measures (PROMs) are important to integrate the patient’s view into routine care.
They are an integral part of clinical trials and required for registration of novel treatments.
A brief and specific validated PROM for overall systemic sclerosis (SSc) is lacking.
What does this study add?
It develops and validates the Systemic Sclerosis Impact of Disease (ScleroID), a disease-specific PROM that captures patient experience and SSc complexity in an easy to apply format for clinical care and clinical trials.
How might this impact on clinical practice or future developments?
ScleroID can be used to integrate patient experience to improve decision making in clinical practice.
Further studies are needed to validate ScleroID as a potential PROM for future clinical trials in SSc.
Introduction
Systemic sclerosis (SSc) is characterised by a chronic and frequently progressive course and by a high patient-to-patient variability.1 SSc has one of the highest morbidities and case-specific mortalities among the connective tissue diseases.2 3 Overall, general health (as measured by the Short Form-36 (SF-36) and EuroQol Five Dimensional (EQ-5D) questionnaires), as well as quality of life and functional abilities (as measured by the Health Assessment Questionnaire Disability Index, HAQ-DI) are significantly reduced in SSc.4–6
A disease-specific, patient-reported outcome measure (PROM) for use in clinical trials and in clinical practice in SSc that covers the different disease features of this multiorgan autoimmune disease is lacking.7 The European Medicines Agency recommends that sufficient evidence needs to be provided on the patient benefit by PROMs before granting approval of a new therapeutic agent,8 and PROMs need to be included as outcome measures in therapeutic randomised controlled trials (RCTs). Thus, the lack of sensitive, disease-specific PROMs covering the overall disease is currently one of the greatest challenges for drug development in this devastating disease. In addition, published data show that systematic use of PROMs in clinical practice improves patient-physician communication and decision making, as well as patients’ satisfaction.9
Research in the field of other autoimmune diseases provides the basis for the successful development of disease-specific PROMs. For rheumatoid arthritis, the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire,10 11 and for psoriatic arthritis, the Psoriatic Arthritis Impact of Disease (PsAID) questionnaire,12 were designed to capture the burden of disease that is most important to patients. Furthermore, the RAID has been successfully used to identify thresholds for symptom states acceptable for patients, as well as evaluating onset of response to medication.13 14
In this study, we aimed to develop a novel, patient-derived PROM for SSc that is able to cover the global disease burden—the EULAR Systemic Sclerosis Impact of Disease (ScleroID). Furthermore, we validated the ScleroID by the Outcome Measures in Rheumatology (OMERACT) filter in a large, multicentric, clinical cohort study.15
Methods
The development of the European Alliance of Associations for Rheumatology (EULAR) ScleroID follows approaches used in the EULAR-endorsed RAID and PsAID questionnaires, as well as in the Pancreatic Cancer Disease Impact Score (PACADI),10–12 16 17 with some modification given the differences between these diseases and SSc. Validation of the EULAR ScleroID follows the internationally recommended methodology of the OMERACT filter15 (online supplemental file). This is a longitudinal, multicentric project, involving 11 European expert SSc centres and patient research partners. The project workflow and process are presented in figure 1.
Supplemental material
Patient and public involvement
Patient research partners were involved in all the stages of the ScleroID project, starting with project design (KF and ATK), to the identification of the relevant health dimensions, and development and validation of the ScleroID including item reduction by weighting. These steps are detailed in the sections below. Furthermore, the dissemination of the study has been supported by the patient organisation Federation of European Scleroderma Associations (FESCA) by invited presentations of the preliminary results at patient congresses.
Part 1: development of the ScleroID questionnaire
Identification, prioritisation and selection of the health dimensions for the ScleroID
Initially, 24 patients with SSc participated in a nominal group technique exercise and selected candidate health dimensions with the highest impact on their disease status. First, the expert investigators (RD, MB and TH) presented a review of the literature on PROMs used in SSc. The patient representatives thereafter suggested health dimensions on which the disease has an important impact, according to their personal perception. On day one, 66 health dimensions were collected. On the second day, these were discussed and grouped by the patients according to the main concept that they are referring to, under moderation by TH. Finally, 17 candidate dimensions were unanimously selected (further details in online supplemental annex 2).
Subsequently, the identified health dimensions were evaluated by a larger group of SSc patients from all 11 participating centres. The objective of this exercise was to optimise face validity and to prioritise the dimensions. The health dimensions were translated by the investigators and patient research partners into each language (online supplemental file). Patients were presented with the list of candidate health dimensions in a random order and asked to rank them according to a decreasing order of importance. The top 10 dimensions based on median ranking were selected by the steering committee (MB, RD, KF, ATK, TH and OD) for the final ScleroID. The limitation to 10 dimensions was chosen based on ranking and aiming for a better feasibility of the final questionnaire and focussing on the most relevant health dimensions reported by the SSc patient research partners.
Development of the ScleroID questionnaire
The experts (MB, RD, TH and OD) developed one question with Numeric Rating Scales (NRS) to assess each of the selected top 10 health dimensions. The ScleroID questionnaire was subsequently translated into all applicable languages following the protocol detailed in online supplemental file.
Supplemental material
Part 2: weighting of the dimensions and validation of ScleroID
Study design
A cross-sectional international observational cohort study with longitudinal reliability and sensitivity to change arms was performed. Patients above 18 years of age fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) 2013 classification criteria for SSc were prospectively included.18 Patients with severe comorbidities not related to SSc were excluded (eg, concomitant inflammatory disease, organ failure, recent acute cerebrovascular event, serious psychiatric or neurological disease). All patients signed written informed consent.
The sample target for the cohort study was 500 patients for the cross-sectional arm and 100/150 patients for reliability/sensitivity to change longitudinal arms, respectively, based on previous experiences with RAID and PsAID. As comparator questionnaires for the ScleroID, the most frequently used global PROMs applied in SSc were selected (online supplemental file).
Data collection
Clinical and demographic data were collected according to the European Scleroderma Trials and Research group (EUSTAR) standards19 (online supplemental file). In addition, patients completed the ScleroID questionnaire, the selected comparators (SSc-HAQ, EQ-5D, SF-36), patient’s global assessment on a Visual Analogue Scale (VAS), specific questions on the state of disease and a minimal clinically important difference question (online supplemental table S1) at all visits (online supplemental file).20–25 For the weighting procedure, in order to assess the relative impact of the health dimensions, patients were asked to distribute 100 points between the 10 dimensions of the ScleroID according to the perceived impact on their health (online supplemental file). This was the basis for calculation of the ScleroID score (see statistical methods). Patients considered to be in a stable state by the physician and with no foreseeable change in treatment or medical intervention in the next 10 days following the baseline visit were included into the reliability arm, and asked to complete the reliability questionnaire at 7±3 days after the baseline visit (online supplemental annex). Patients considered to have active disease by the treating physician were included into the sensitivity to change arm and completed the respective questionnaire at the 12 months visit and/or at the 6 months visit, if available (online supplemental annex).
Supplemental material
Statistical analysis
The calculation of the ScleroID score was based on the ranking of the weights, as performed in RAID, PsAID and PACADI.10–12 16 17 Mean and median weights were calculated for each health dimension, after which mean and median ranks were computed for the whole cohort. These represent the basis for calculating the final weight, which is multiplied by the value on the NRS for each dimension/item and summed up for the final ScleroID score, which is then divided by 100.
The validation of ScleroID psychometric properties was performed according to the OMERACT filter, which assesses three main features: feasibility, truth and discrimination.15 Feasibility addresses the applicability of the ScleroID questionnaire. Truth encompasses face validity (does the measure make sense), and content validity (eg, distribution of the score, floor/ceiling effect). As other measures of truth, internal consistency using Cronbach’s alpha and construct validity (concurrent validity) with Pearson correlations to other scores (SSc-HAQ, SF-36, EQ-5D) were calculated. Construct validity was also investigated using a confirmatory factor analysis (online supplemental file). In addition, we assessed reliability and sensitivity to change. In the reliability arm, patients, who reported themselves as ‘stable’, were included in the test–retest reliability (reproducibility) analysis by assessing the intraclass correlation coefficient and agreement by Bland-Altman plot. In the sensitivity to change arm, patients reporting themselves as ‘not stable’ were included in the sensitivity to change (responsiveness) analysis by the standardised response mean (SRM, which is the difference in the baseline and follow-up mean values divided by the SD of the change scores). CIs were obtained by bootstrapping.
Results
Part 1: development of the ScleroID questionnaire
Identification and prioritisation of health dimensions for the ScleroID
In the initial nominal group exercise, 24 patient research partners selected 17 health dimensions reflecting the impact of SSc (table 1). An additional cohort of 108 patients (online supplemental table S2) subsequently prioritised these health dimensions. The selected health dimensions and their prioritisation are summarised in table 1.
Selection of health dimensions and development of the ScleroID questionnaire
The steering committee agreed unanimously to include the ten health dimensions rated with the highest priority into the ScleroID questionnaire. One question with appropriate anchors to assess each of the selected ten health dimensions was developed by the steering committee (MB, RD, KF, ATK, TH and OD). These questions formed the ScleroID questionnaire (table 2), which was also agreed on by the patient research partners.
Part 2: weighting and validation of the ScleroID questionnaire
Cohort study
In total, 472 SSc patients from nine countries (France, Italy, Hungary, Poland, Romania, Spain, Sweden, Switzerland, UK) were included in the cross-sectional cohort study.
Most patients were female (84.8%), more than one-third had diffuse cutaneous SSc (dcSSc, 37.5%) and the median age was 57 years. The various disease manifestations, including lung fibrosis (42.6%), pulmonary arterial hypertension (7%), gastrointestinal (GI) involvement (>60% of patients with oesophageal symptoms), articular involvement (4.4% with synovitis) and digital ulcers (24.0% with previous ulcers, 13.0% with current ulcers) were well represented, reflecting a typical SSc population (table 3).
Weighting of the health dimensions and calculation of the ScleroID score
Overall, valid data on weighting was provided by 446 (94%) patients, and 462 (98%) patients provided complete data on the ScleroID questionnaire.
The health dimensions which were assigned the highest weights (and thus highest impact) by the patients were Raynaud’s phenomenon, fatigue, hand function and pain, followed by upper and lower GI symptoms (table 4), confirming the results from the prioritisation.
The mean ranks given in table 4 were rescaled to sum up to 1 for the final weights. The ScleroID was calculated as a composite score of the selected 10 dimensions. For each dimension, the NRS score was multiplied by the specific weight for this item and the weighted scores were summed up (see example in table 5).
Performance of ScleroID by the OMERACT filter
Feasibility
The ScleroID showed feasibility in the application, given the low proportion of missing data: ten patients (2.1%) had missing items, compared with 36 and 37 patients with missing data for SF-36 physical/mental component summary (PCS), 8 for EQ-5D, 12 for HAQ-DI and 16 for SSc-HAQ (online supplemental table S3). The majority of participants (462 or 98%) had complete data on the ScleroID questionnaire. Missing data were evenly distributed among the ScleroID items (no item had significantly higher missing values).
In daily practice, single items of questionnaires are frequently missing. We therefore assessed how imputation of single items affects the overall ScleroID score. When one missing item of the ScleroID score was imputed by the mean of the remaining cohort for this item, the error was minimal (up to 0.29/10 or <10%, (online supplemental table S4)).
Truth
Face validity was ensured by the involvement of patient research partners in all steps of the ScleroID development.26
The ScleroID score range is 0–10, the actual median and IQR in our patients was 3.2 (1.9–4.7) at baseline. The median and IQ for lcSSc patients was 3.3 (2.0–4.7) and for difusse cutaneous SSc (dcSSc) patients 3.3 (1.7–4.8; online supplemental figure S2). In total, eight patients recorded a ScleroID score of 0, while the highest observed value was 9.4. There was no relevant floor or ceiling effect, which would be assumed if >15% of patients scored either the minimum or maximum value (27 online supplemental figure S2). The ScleroID questionnaire showed a good construct validity when correlated with the comparators (SSc-HAQ r=0.73; EQ-5D r=−0.48; Patient’s global assessment, VAS r=0.77; HAQ-DI r=0.62; SF-36 PCS r=−0.62; each p<0.001, table 6).
The internal consistency as another measure of construct validity was also strong: Cronbach’s alpha for the ScleroID was 0.87, similar to the SSc-HAQ (0.88) and higher than for the EQ-5D (0.77, online supplemental table S2). We also performed a confirmatory factor analysis which suggested a bifactor model (one general factor with additional two or three factors) with good model fit indices (online supplemental table S6 and figure S2). The omega indices, which are thought to be superior to Cronbach’s alpha,28 29 suggested not only good model fit for the bifactor models (online supplemental table S7), but also supported our claim for sufficient unidimensionality to justify the use of a sum score (see also online supplemental file).
Test–retest reliability
In total, 109 patients were included in the longitudinal reliability arm and completed a second visit at 7±3 days after baseline. The ScleroID had a very good test–retest reliability, with an intraclass correlation coefficient of 0.84 (ranging 0.61–0.79 for the individual items), superior to all comparators (online supplemental table S8); see also Bland-Altman plot for agreement in online supplemental figure S5).
Sensitivity to change
A total of 113 patients were included and had a median follow-up visit at 12.2 (IQR 11.5–13.1) months. The sensitivity to change for the ScleroID was estimated using the SRM between baseline and follow-up, using only those patients (n=37) reporting disease status as not-stable (table 7). The SRM is computed for all patients regardless of whether they report improved/worsened disease state, and then separately for those with improved and worsened state (table 7). The ScleroID performed better than all other comparator PROMs in indicating overall change. This performance was even better in patients who experienced improvement (table 7).
Discussion
PROMs are being developed to capture the patient’s aspects of a disease, that is, the specific patient experience beyond the disease manifestations that are in the physician’s focus, which are typically lethal or associated with high morbidity. Especially in SSc, which has a high morbidity and mortality as well as a high work disability, there is a discordance between the patient’s experience and the physician’s assessment, exemplified by differences in the patient’s and physician’s global assessment.30–32 This was also observed in this study, underlining the need to implement PROMs in the clinical assessment and shared decision making. Most PROMs used in SSc are legacy questionnaires adapted from other diseases and not SSc-specific instruments.
Hence, specific PROMs are needed, although some have tried to incorporate the patient’s view.7 33
We have developed and validated the ScleroID questionnaire as a global measurement tool to assess the disease burden in SSc patients. The questionnaire is simple and easy to apply, has high internal consistency and shows good correlation with the patient global assessment and the SSc-HAQ. Although weighting reflects patient experience, it does not significantly change the overall score. It is planned to develop a calculator (or app) to provide final scores. The ScleroID health dimensions have a high face validity due to the inclusion of SSc patient research partners throughout the development and validation process. Notably, main dimensions of the ScleroID questionnaire such as dyspnoea, pain, digital ulcers, GI symptoms or fatigue were also associated with a high self-reported disability and high disease burden in other reports from the literature.5 34
The ScleroID questionnaire has a very good retest reliability, which is even better than comparators and has better sensitivity to change than the comparators used. This is especially important as a high percentage of patients are relatively stable, but progression of the disease drives mortality and morbidity.35 In addition, other frequently used major outcomes of SSc studies, such as the mRSS, show a relatively low sensitivity to change, which might partially explain the many randomised clinical trials with borderline significance using the mRSS as a primary outcome.36
Comparison to other PROMs
In contrast to other validated PROMs that have not been developed specifically for SSc (such as Patient-Reported Outcomes Measurement Information System-29; PROMIS-29)37–39 or have only been adapted to SSc (such as the Scleroderma Health Assessment Questionnaire (SHAQ))39 40, the ScleroID questionnaire was specifically developed, with involvement of SSc patient research partners. Although other specific PROMs for SSc have been developed, the Symptom Burden Index and the Systemic Sclerosis Questionnaire (SySQ) did not involve the target population for dimension/item generation. The Scleroderma Assessment Questionnaire (SAQ), which is based on the SysQ, had only partial involvement of patients.41 42 However, these questionnaires have only been partially validated, mostly lacking a discriminant validity analysis, and are partly not validated in English (SysQ and SAQ). The recently published PROM Cochin Scleroderma Functional scale 17, a 17-item PROM that focused on mobility and general task aspects of SSc, was also developed with involvement of SSc patients.43 It has been evaluated in a smaller cohort than the ScleroID and in French only, with data on discriminant validity (sensitivity to change) still missing.
Limitations of the study
Although patients with diverse disease manifestations participated in the nominal group exercise, disease-related or demographic data were not prospectively collected at this early stage. Patients included in the cross-sectional analysis had to fulfil the ACR/EULAR 2013 classification criteria for SSc but there were no recommendations concerning disease subtype or organ involvement. The final selection of participants by the centres has an impact on the weighting of the ScleroID dimensions and the cross-sectional part included mainly patients with longstanding disease. However, our cohort reflects other observational cohorts such as the EUSTAR registry, etc, indicating that it is a representative SSc population. Although SSc patients often acquire expert knowledge about their disease and are aware that the questionnaire evaluates SSc-related burden, it might be difficult at times to distinguish symptoms related to SSc from common, unrelated symptoms, for example, as in the case of GI problems. This is however common to all PROMs.
Another potential limitation is the relative paucity of patients who experience change of their disease status, who then enter the sensitivity to change analysis. As this change was anchored by the patients themselves, there were no prior data to guide selection of these patients.
The ScleroID was designed as an overall measure of disease impact. It was derived from patients under routine clinical care and as such, it is still to be validated in clinical trials aiming at overall disease modification. If the ScleroID questionnaire can also be used for clinical trials focusing on organ-specific disease progression is subject to further analysis.
In summary, the ScleroID questionnaire is a unique, easy to apply, SSc-specific PROM that has been successfully validated in a large European clinical cohort using multiple translations. It should be further validated for clinical trials and in large registries and has the potential to measure disease impact that will be more meaningful for patients and health authorities than currently used approaches.
Data availability statement
Data are available on reasonable request. On request, and subject to review by the steering committee, access can be granted to the anonymised raw data and the R code. Deidentified data will be made available via secure data transfer. Data requests may be sent to the ScleroID steering committee, represented by OD, Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland. Email oliver.distler@usz.ch.
Ethics statements
Patient consent for publication
Ethics approval
The project was approved by the ethics committee in each participating centre.
Acknowledgments
We sincerely thank the patients’ representatives who contributed to the study, without whom this project would not have been possible: Ann Kennedy, Kim Fligelstone, Heleen Lever, Yanne Perriault, Anna Vegh, Susanne Tuppeck, Silvia-Daniela Sandulescu, Mervat Gaafar, Barbara Zappitello, Rachida Amrouch, Grazia Tassini, Helene Kambourakis, Elisabeth Scheel, Stephan Houbertz, Beata Garay Toth, Ana Marcela Badea, Stefana Dumitru, Alicia García Oliva, Begoña María Gorricho Corta, Johanna Berglind, Natalie Perruchoud, Alice Martins Correia, Richard Dodds, Nicola Whitehill. Our thoughts go to Mr. Richard Dodds, who unfortunately is no longer with us.
References
Supplementary materials
Supplementary Data
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Footnotes
Handling editor Josef S Smolen
MOB and RD contributed equally.
TH and OD contributed equally.
Presented at Part of this work has previously been presented, as follows: Presentations: The EULAR Systemic Sclerosis Impact of Disease score – a new patient-reported outcome measure under development, 4th Scleroderma World Congress, Patient Congress, Lisbon, Feb 18th – 20th, 2016, Poster EULAR 2016, Poster ACR 2016, Abstract book EULAR 2017, Poster ACR 2017, Poster Patients’ Congress SWC 02/2018 Bordeaux, Abstract book EULAR 2018. Meetings: Working group patients and PIs inkl. teleconference – Rome, 06/2015, Task force meetings, EULAR 06/2016 London, ACR 11/2016 Washington, EULAR 06/2017 Madrid, EULAR 2020 Online E-Congress.
Contributors The authors as listed on the title page of the manuscript have all made substantial contributions which qualifies them as authors. All authors contributed to critical revisions and approved the final version of the manuscript. MB: design of the study, acquisition of data, analysis, interpretation of data, drafting and revising the article. RDo: design of the study, acquisition of data, analysis, interpretation of data, drafting and revising the article. AG: analysis, interpretation of data, drafting and revising the article. RDe: interpretation of data, revising the article. KF: design of the study, acquisition of data, interpretation of data, revising the article. ATK: design of the study, acquisition of data, interpretation of data, revising the article. AR: acquisition of data, interpretation of data, revising the article. YA: acquisition of data, analysis, interpretation of data, revising the article. PEC: acquisition of data, analysis, interpretation of data, revising the article. LC: acquisition of data, analysis, interpretation of data, revising the article. CPD: acquisition of data, analysis, interpretation of data, revising the article. RH: acquisition of data, analysis, interpretation of data, revising the article. GS: acquisition of data, analysis, interpretation of data, revising the article. OK-B: acquisition of data, analysis, interpretation of data, revising the article. CB: acquisition of data, analysis, interpretation of data, revising the article. MM-C: acquisition of data, analysis, interpretation of data, revising the article. CM: acquisition of data, analysis, interpretation of data, revising the article. AMG: acquisition of data, analysis, interpretation of data, revising the article. UM-L: acquisition of data, interpretation of data, revising the article. JS: design of the study, analysis, interpretation of data, revising the article. TKK: design of the study, analysis, interpretation of data, revising the article. TH: design of the study, acquisition of data, analysis, interpretation of data, drafting and revising the article. OD: design of the study, acquisition of data, analysis, interpretation of data, drafting and revising the article, guarantor.
Funding The development and validation of the ScleroID was in part supported by a grant from EULAR.
Competing interests MB personal fees from Amgen and Bayer, outside the submitted work. RDo reports grants from Articulum Fellowship, sponsored by Pfizer (2013-2014), grants from Actelion, personal fees from Actelion and Boehringer-Ingelheim, outside the submitted work. AG none with respect to the study. RDe none with respect to the study.KF none with respect to the study. ATK none with respect to the study. AR none with respect to the study. YA reports grants and personal fees from Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Curzion, Inventiva, Roche and Sanofi during the conduct of the study. PEC reports consultancy relationship and/or research grants from: Abbvie, Actelion, Bayer, Boehringer Ingelheim, Corbus Pharma, Emerald Health Pharmaceuticals, Galapagos, Gesynta Pharma, Inventiva, iQvia, Mitsubishi Tanabe Pharma, MSD, Roche and Sanofi Genzyme. LC none with respect to the study. CPD reports grants and personal fees from GSK, Mitsubishi Tanabe Pharma, Boehringer-Ingelheim, Servier, Arxx Therapeutics, Bayer, Inventiva, Galapagos, Horizon, Roche, CSL Behring, Sanofi during the conduct of the study.RH reports personal lecture fees from Actelion Pharmaceuticals Sweden AB, Boehringer-Ingelheim Sweden AB, and Roche Sweden AB, and has been co-investigator in clinical trials for United Therapeutics and Actelion Pharmaceuticals Sweden AB, and has been involved in research advisory boards for Actelion Pharmaceuticals Sweden AB and Boehringer-Ingelheim Sweden AB. GS none with respect to the study. OK-B reports personal fees and/or congress support from Bayer, Boehringer Ingelheim, CSL Behring, Gilead, Inventiva, Medac, MSD, Novartis, Pfizer, Roche, Sandoz, outside the submitted work. CB reports personal fees from Actelion, personal fees from Boehringer-Ingelheim, personal fees from Eli Lilly, grants from Gruppo Italiano Lotta alla Sclerodermia (GILS), grants from New Horizon Fellowship, grants from European Scleroderma Trials and Research (EUSTAR), grants from Foundation for Research in Rheumatology (FOREUM), grants from Fondazione Italiana per la Ricerca sull’Artrite (FIRA), outside the submitted work. MM-C reports grants and personal fees from Actelion, personal fees from Biogen, personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from CSL Behring, personal fees from Eli-Lilly, outside the submitted work. CM reports personal fees from Boehringer Ingelheim, Eli-Lilly, Mepha, MEDTalks Switzerland and congress support from Actelion and Roche, outside the submitted work. AMG reports consultancy fees from Boehringer-Ingelheim and congress support from Abbvie and Novartis, outside the submitted work. UM-L none with respect to the study. JS none with respect to the study. TKK none with respect to the study. TH reports no conflicts of interest.OD has/had consultancy relationship and/or has received research funding in the area of potential treatments of scleroderma and its complications from (last three years): Abbvie, Acceleron Pharma, Alexion, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Bayer, Boehringer Ingelheim, Catenion, Drug Development International, CSL Behring, ChemomAb, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, Italfarmaco, iQvia, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Target Bio Science and UCB In addition, he has a patent mir-29 for the treatment of systemic sclerosis issued (US8247389, EP2331143).
Provenance and peer review Not commissioned; externally peer reviewed.
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