K. Fligelstone

WWF United Kingdom, Londinium, England, United Kingdom

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Publications (11)108.25 Total impact

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    ABSTRACT: Objectives The aim was to update the 2009 EULAR recommendations for the treatment of systemic sclerosis (SSc) [1] with a distinct focus on new therapeutic aspects. Methods Revision and update of the previous recommendations were performed according to the EULAR standard operating procedures. The task force consisted of 30 SSc experts from Europe and USA, two patients nominated by the pan-European patients association FESCA, a clinical epidemiologist and 3 fellows for systematic literature research. All centers from the EULAR Scleroderma Trials and Research (EUSTAR) group were invited to submit and select research questions concerning SSc treatment using a Delphi approach. A set of 46 research questions addressing 26 different interventions was selected for systematic literature research. The new recommendations were developed in a meeting, based on the available evidence while using a consensus procedure. Results Sixteen recommendations were developed (instead of 14 in 2009) which address treatments of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis, and gastrointestinal involvement. Compared with the 2009 recommendations, the 2015 recommendations include phosphodiestase-5 (PDE5) inhibitors in the treatment of SSc-related RP and DUs, riociguat and new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE5 inhibitors for SSc-related PAH. The new recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressing SSc were added. In addition, the statement regarding sitaxentan for PAH was removed, because it was withdrawn from the market. A web-based internal evaluation of the new recommendations revealed high level of approval among task force members (average score >7 out of maximum 9) for all statements except the one regarding fluoxetine for RP (average score of 6,1). In addition, several comments regarding other treatments addressed in research questions and suggestions for the future SSc research agenda were formulated by the experts. Conclusions These updated and improved, data- and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations will also facilitate the directions for future clinical research in SSc. References Acknowledgements The project is funded by a research grant of EULAR to the EUSTAR SSc recommendation group. All contributing experts will be listed as full coauthors on the respective presentations and publications. Disclosure of Interest O. Kowal-Bielecka Speakers bureau: Abbvie, Actelion, Pfizer, Roche, J. Fransen: None declared, J. Avouac: None declared, M. Becker Consultant for: Actelion, A. Kulak: None declared, Y. Allanore Consultant for: Bayer Pharma, Actelion, Pfizer, Sanofi-Aventis, CSL Behring, Roche, O. Distler Consultant for: 4D Science, Actelion, Active Biotec, Bayer-Schering, Biogen, Biovitrium, BMS, Boehringer Ingelheim Pharma, EpiPharm, Ergonex, GSK, Inventiva, Medac, Novartis, Pfizer, Pharmacyclics, Roche/Genentech, Sanofi/Genzyme, Serodapharm, Sinoxa and United BioSource Corporation., L. Czirjak Consultant for: MSD, Pfizer, Roche, Abbvie, UCB, BMS, Servier, Medac, Richter, Egis, C. Denton Grant/research support from: Actelion, CSL Behring, Novartis, Consultant for: Actelion, GSK, Bayer, Inventiva, Takeda, K. Fligelstone: None declared, J. Welling: None declared, U. Mueller-Ladner Grant/research support from: EULAR grant
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Calcinosis is a disabling, rarely discussed manifestation of SSc for which the natural history and management is poorly understood. This investigation is the 1st phase of a multi-tiered project to understand calcinosis from patients' perspectives creating the groundwork for a SSc-calcinosis PROM. Methods Five focus groups and individual interviews in the US and UK were recorded and transcribed verbatim. Pathophysiologic and life impact were elicited with: 1. Since developing calcinosis how has your life changed over time? 2. How has calcinosis changed over time? A final probe was a request for questions that a clinician could ask to understand if calcinosis was better, worse or same. Transcripts were analysed by hand (highest method) by an iterative inductive process (content drives coding) by at least 5 independent analysts including at least one patient research partner. Concepts were triangulated until a comprehensive set of concepts emerged. Occurrence was quantified per participant. Results Twenty-three patients (29/31 female, 27/31 white, with mean disease duration 18.1 years) were consented and interviewed. Responses spanned broadly to include concepts of self-management strategies and recurrent hypotheses relating calcinosis development to trauma, Raynaud's and cold exposure (tables 1 & 2). Cold exposure and Raynaud's were a perceived association to calcinosis severity - “when they are cold mine always open back up”. A majority of patients engage in strategies to extrude calcinosis with either pressure +/- soaking or at home surgical techniques. “I actually have homemade surgical tools to get these out.” The following anchors were consistently suggested for physicians to assess calcinosis severity: pain level, size, frequency, number and functional impairment. A 2-step question was suggested to help differentiate ulcer, infection and calcinosis symptoms: 1st regarding predomiant wound character and then target the related calcinosis. Conclusions These results provide the groundwork for and conclude the 1st steps (item collection) in PROM development. As suggested by patients, a composite of scales anchored in pain, size, frequency, number and related impairment may reasonably serve as an interim instrument for SSc calcinosis. Next steps are validating content with a large subject base and questionniare development with subsequent validation. Very importantly, patients' observations and self-management behavior provide opportunities to learn from and to preemptively educate physicians and patients. Patients are eager for self-management guidance. An essential deliverable of this work will be a patient-physician education guide on calcinosis management. Acknowledgements In memory of Anne Mawdsley, founder: Raynaud's & Scleroderma Association UK – tireless engine for education and advocacy raising >£10 million for SSc research. Disclosure of Interest A. Christensen: None declared, S. Khalique: None declared, S. Cenac: None declared, K. Fligelstone: None declared, V. Jaeger: None declared, A. Mawdsley: None declared, R. Kaufman: None declared, T. Frech: None declared, J. Gordon: None declared, V. Steen: None declared, A. Aubin: None declared, M. Baron: None declared, E. Busman: None declared, L. A. Saketkoo Grant/research support from: ACR/EULAR Exchange Awardee
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
  • L. Shapiro · L.A. Saketkoo · J. Farrell · K. Fligelstone
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    ABSTRACT: Background Scleroderma renal crisis (SRC) is a devastating complication of SSc. The introduction of effective treatment with ACE inhibition (ACE-I) in 1979 dramatically reduced death as a near-immediate consequence of SRC. However, poor outcomes still occur with great frequency including chronic or temporary dialysis or death. Individuals with early, rapidly progressive diffuse disease and RNA polymerase III antibody positivity are at high risk for SRC. Prophylactic use of ACE-I in high risk patients has not demonstrated improved outcomes and may have negative consequences. Our goals were to identify associative causes of poor outcome and develop a targeted preventive intervention to address in accordance with findings. Methods A retrospective chart review at Royal Free Hospital scleroderma clinic between 1994-1999 identified and stratified 44 cases of SRC for long term outcomes (death, long-term dialysis, short-term dialysis, and no dialysis). Cases were then assessed for factors potentially related to outcomes: onset of symptoms, time to medical attention, and therapeutic management. Results directed development of SRC preventive intervention. Results Death or long-term dialysis was the outcome in approximately 50% of the cases reviewed. Three subgroups emerged as associative with poor outcomes: Poor outcomes were correlated to delayed therapy, rather than drug failure. All patients in the “no dialysis/death” group were treated with ACE-I according to protocol. From these findings, a “scleroderma renal crisis prevention card” was developed. The card is dual-sided with one side for patients and the other for physicians unfamiliar with patient. Conclusions Despite availability of effective therapy, SRC is associated with poor outcomes often consequential to treatment delay and lack of knowledge of initial treating physicians. A “renal crisis prevention card” may improve health outcomes of high-risk patients as a method of educating patients and health care providers. Disclosure of Interest L. Shapiro: None declared, L. A. Saketkoo Grant/research support from: ACR/EULAR Exchange Awardee, J. Farrell: None declared, K. Fligelstone: None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background SSc is a complex, diffuse, devastating health condition of vascular injury, inflammation and fibrosis resulting in multiple organ involvement with high impact on survival and quality of life. Demonstrated research activity tends to define SSc Centers of Excellence (SCoE) certification. However, SSc complications require coordinated high-level multi-specialty expert care. The Scleroderma Foundation, Scleroderma Australia and Scleroderma Society UK engaged SSc patients and SSc health providers (HPs) in a multi-tiered process to assess priorities in recognition of SCoEs. Methods A mixed methods design ensured comprehensive item collection in addressing “important qualities and services in a certified SSc Center of Excellence”. A core of 35 patients & SSc HPs from 8 countries initiated the study through an iterative process using nominal group technique with rounds of item revision until saturation and satisfaction of proposed survey content was achieved and subsequently field-tested with a 5 point scale (critical to low importance). Participation was screened and “gate-controlled” with online survey access through a unique one-time link. Telephone interview was offered. Responses from SSc patients and HPs were compared by Pearson's χ2 or Fisher's exact tests as appropriate. Results Initial phases yielded a 54 item survey and field-tested in 15 SSc patients & HPs. 400 patients and SSc HPs received surveys of which 299 from 19 countries (75% response rate) were completers. Expert care superseded research as a priority of “critical importance” by HPs & patients respectively at 69% & 48% (p=0.02) and by 94% & 89% (p=0.8) when “critical to very important” were collapsed. 3 questions provided internal cross-validation of this query. “SCoEs should engage in research” received 57% of patients and 48% of HPs (p=0.37) as being critical. Further, education, rehabilitative services and support networks were consistently highly rated items with topics stratified by ratings (tables 1 & 2). Discrepant areas of importance between patients and HPs are highlighted in tables. Conclusions Participation was robust in all project stages emphasizing the perceived global importance of this effort. Though research is of clear importance, quality expert care incorporating rehabilitative and educational provisions is a SCoE operational priority. These findings signal the need to redefine SCoE certification standards and provide a roadmap to SCoE development. Acknowledgements Dedicated to the memory of Anne Mawdsley. Disclosure of Interest V. Jaeger: None declared, A. Aubin: None declared, N. Baldwin: None declared, K. Fligelstone: None declared, R. Sims: None declared, J. Welling: None declared, R. Burrill: None declared, K. Connolly: None declared, J. Gordon: None declared, T. Frech: None declared, T. Ngcozana: None declared, M. Kowalczyk: None declared, M. Lammi: None declared, J. Lasky: None declared, U. Walker: None declared, L. A. Saketkoo Grant/research support from: ACR/EULAR Exchange Awardee
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background A recent consensus project (Saketkoo et al, Thorax 2014) recommended a minimum core set of outcome measures for use in future clinical trials of CTD-ILD and IPF. The World Health Organization (WHO) introduced the International Classification of Functioning, Disability, and Health (ICF) as a scientific method of disability data collection and a universal framework of >1200 categories describing disability in terms of the bio-psycho-social model with consideration of environmental and personal factors. For accurate representation of disease, ease of healthcare provision and fair allocation of resources, it is essential that ICF Core Sets be established for rare and complex diseases. Methods Per updated ICF linkage rules, each instrument from the published CTD-ILD and IPF core sets were deconstructed to meaningful concepts and independently linked by 2 health professionals experienced in ICF linkage (RE, LAS). Inter-linker agreement on independent linkages was analyzed (KK). A 3rd linker (OD) arbitrated if irreconcilable linkages occurred. Results Eighty-two ICF categories were identified under the 4 ICF domains for 6 patient questionnaires and 3 traditional objective measures. The proportion of agreement ranged from 0.79 (95% CI: 0.62, 0.91) to 0.93 (0.76, 0.99) (Table 1) with the overall proportion of inter-linker agreement 0.86 (0.82, 0.89). 20 new “Personal Factors” and 7 suggested modifications were generated to capture important disease-specific qualities not elsewhere described in ICF, e.g. “pf_embarrassed by cough”; “pf_panic/afraid when can't get breath”; pf_fear of hurting self by overexertion; d4508_walking pace or b469_bouts of coughing to describe paroxysmal coughing spells that are often disabling in this condition. Conclusions This is the first effort to map CTD-ILD and IPF outcome measures to the ICF. ICF Core Sets provide stream-lined disease-specific coding of disability data that support global, regional and personal health-related parity across cultures, age and socioeconomic status; enabling fair assessment of disability for policy-making, service provision, funding and rural/urban infrastructural modifications. Validation steps are planned for item analysis and potential development of a single composite instrument for clinical trials and clinical practice. The availability of ICF Core Sets in CTD-ILD and IPF will afford clinicians a smoother transition to ICD-11 which is under development and will meld diagnostic coding with the ICF. Disclosure of Interest L. A. Saketkoo Grant/research support from: ACR/EULAR Exchange Awardee, R. Escorpizo: None declared, K. Keen: None declared, K. Fligelstone: None declared, S. Birring: None declared, M. Lammi: None declared, J. Lasky: None declared, D. LeSage: None declared, E. Renzoni: None declared, A. M. Russell: None declared, C. Sarver: None declared, M. B. Scholand: None declared, J. Varga: None declared, O. Distler: None declared
    Full-text · Conference Paper · May 2015
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    ABSTRACT: OBJECTIVES: To outline rationale and potential strategies for rheumatology experts to be able to develop disease-specific Core Sets under the framework of the International Classification of Functioning, Disability and Health (ICF). ICF is a universal framework introduced by the World Health Organization (WHO) to describe and quantify the impact and burden on functioning of health conditions associated with impairment/disability. METHODS: A combined effort of the EULAR Scleroderma Clinical Trial and Research and the ICF Research Branch was initiated to develop an ICF language for scleroderma. From our Medline literature review, using the abbreviation and spelled out version of ICF, we assembled approaches and methodological reasoning for steps of core set development. RESULTS: The ICF can be used for patient care and policy-making, as well as the provision of resources, services and funding. The ICF is used on institutional, regional, national and global levels. Several diseases now have ICF Core Sets. Patients with complex rheumatologic diseases will benefit from a disease-specific ICF Core Set and should be included in all stages of development. ICF Core Set development for rheumatic diseases can be conducted from a number of feasible strategies. CONCLUSION: This overview should help to clarify useful processes leading to development of an ICF Core Set, and also provide a platform for expert groups considering such an endeavour.
    Preview · Article · Aug 2012 · Rheumatology (Oxford, England)
  • L. A. Saketkoo · R. Escorpizo · K. Keen · K. Fligelstone · O. Distler
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    ABSTRACT: Background SSc affects multiple organ systems resulting in an unlimited combination of types and degrees of disability in patients. Skin fibrosis, ischemic pain, ulceration, arthritis, contractures of small and large joints, and myopathy as well as cardiopulmonary, renal and gastrointestinal effects carry significant burden on emotional, social and physical functioning. ICF is a universal framework introduced by the World Health Organization (WHO) to describe and quantify the impact caused by health conditions on functioning and disability. The ICF uses a standardized alphanumerical language to describe health states in terms of the bio-psycho-social model. The ICF is accepted by national and international health care and policy-making systems to assess the impact of disease on personal, scientific, economic and service levels. Methods A comprehensive literature search in PubMed was performed with the following keywords: outcome measures, SSc, health, rehabilitation, function, quality of life, mental, sexual, pain and disease activity to identify 5 validated measures representing the broadest range of SSc manifestations (OD, LAS). Meaningful concepts were identified in the instruments and linked to the ICF by two health professionals familiar with ICF linking rules (RE, LAS). Their agreement was analyzed (KK). Results Nine new codes were created to address the absence of ICF codes to describe the SSc disease experience as contained within the instruments. ICF codes were linked to 5 validated SSc instruments:5 ICF codes to the Hand Mobility in Scleroderma Test, 5 the Modified Rodnan Skin Score, 9 to the Raynaud’s Condition Score, 40 to the Scleroderma Health Assessment Questionnaire, and 25 to the SSc Gastrointestinal Tract Instrument. These 5 instruments identified 71 distinct categories for the folllowing domains: 26 for Body Function, 6 for Body Structure, 33 for Activity and Participation and 6 for External Factors. The proportion of agreement ranged from 0.8611 (95% CI: 0.7500, 0.9444) for HAMIS to 0.9647 (0.9175, 1.000) for mRSS, when corrected for chance ranged from 0.7097 (0.5291, 0.8835) to 0.8964 (0.7631, 1.0000). Overall, the proportion of agreement was 0.9359 (0.9172, 0.9506), which when adjusted for chance was 0.7230 (0.6453, 0.7797). By either measure, the degree of agreement between the linkers, a physiotherapist and a rheumatologist, was high. Conclusions This first step, in a methodological series to establish an ICF language for SSc, was successful in both high agreement of linking and in exploring the potential challenges of linking a complex multi-organ system disease. Further face, content and construct validation strategies are now underway. Of the diseases already linked to ICF, SSc is the most complex thus requiring precise strategies to gain knowledge from SSc experts– including patients, rehabilitation and nurse experts. A composite of all validated SSc outcome measures is soon to be available for ICF engaged health systems. Thus, the global, regional and personal impact of SSc across cultures, age and socioeconomic status may be assessed fairly for use in policy making and provision of services and funding. Disclosure of Interest L. A. Saketkoo Grant/Research support from: Actelion, United Therapeutics, R. Escorpizo: None Declared, K. Keen Speakers Bureau: Merck, K. Fligelstone: None Declared, O. Distler Consultant for: Actelion, BMS, Fibrogen, Egonex, Pfizer, Sonofi Aventis, Genetech, Active Biotech, Novartis, UCB, 4D Science
    No preview · Article · Jun 2012 · Annals of the Rheumatic Diseases
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    ABSTRACT: The European League Against Rheumatism Scleroderma Trials and Research Group (EUSTAR) has established an online database with clinical data of currently more than 8200 patients with systemic sclerosis (SSc). In addition to clinical research, EUSTAR fosters biomolecular studies to develop novel biomarkers and therapies for SSc. High-quality biospecimens are the basis for successful biomolecular studies. The EUSTAR biobanking group has therefore developed recommendations to standardise the collection, storage and distribution of SSc biospecimens at EUSTAR centres. These recommendations consider the scientific challenges associated with biomolecular research in SSc and the organisational requirements of EUSTAR. They were approved by the EUSTAR executive committee as well as the EUSTAR board. Once they become effective, these recommendations will be the basis for international EUSTAR studies with large numbers of SSc biospecimens. These recommendations might also be followed by other SSc consortia to enable exchange of biosamples between different SSc initiatives and might serve as a template for biobanking initiatives in other rheumatic diseases.
    Full-text · Article · Feb 2011 · Annals of the rheumatic diseases
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    ABSTRACT: Early diagnosis of systemic sclerosis (SSc) may allow the start of treatment that could slow disease progression. For this reason early diagnosis of the disease is of pivotal importance. However, the lack of diagnostic criteria and valid predictors significantly limit patient evaluation and the use of potentially effective drugs in the earliest phase of SSc. Early SSc may be suspected on the basis of Raynaud's phenomenon, puffy fingers, autoantibodies and SSc capillaroscopic pattern. In practice, the aim is to have criteria for the diagnosis of very early SSc. The criteria that are proposed are obviously provisional and need to be validated: (a) initially through a Delphi technique; (b) thereafter perhaps using already available datasets; but (c) of critical importance, through prospective studies. Only after prospective studies can these potential criteria be considered validated. The consensus on criteria for the classification of very early SSc might be part of the evolving EULAR/ACR project of reclassification of SSc.
    No preview · Article · Oct 2009 · Annals of the rheumatic diseases
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    ABSTRACT: The optimal treatment of systemic sclerosis (SSc) is a challenge because the pathogenesis of SSc is unclear and it is an uncommon and clinically heterogeneous disease affecting multiple organ systems. The aim of the European League Against Rheumatism (EULAR) Scleroderma Trials and Research group (EUSTAR) was to develop evidence-based, consensus-derived recommendations for the treatment of SSc. To obtain and maintain a high level of intrinsic quality and comparability of this approach, EULAR standard operating procedures were followed. The task force comprised 18 SSc experts from Europe, the USA and Japan, two SSc patients and three fellows for literature research. The preliminary set of research questions concerning SSc treatment was provided by 74 EUSTAR centres. Based on discussion of the clinical research evidence from published literature, and combining this with current expert opinion and clinical experience, 14 recommendations for the treatment of SSc were formulated. The final set includes the following recommendations: three on SSc-related digital vasculopathy (Raynaud's phenomenon and ulcers); four on SSc-related pulmonary arterial hypertension; three on SSc-related gastrointestinal involvement; two on scleroderma renal crisis; one on SSc-related interstitial lung disease and one on skin involvement. Experts also formulated several questions for a future research agenda. Evidence-based, consensus-derived recommendations are useful for rheumatologists to help guide treatment for patients with SSc. These recommendations may also help to define directions for future clinical research in SSc.
    No preview · Article · Feb 2009 · Annals of the rheumatic diseases
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    ABSTRACT: To describe methods and procedures used for the development of the European League Against Rheumatism (EULAR)/EULAR Scleroderma Trial and Research group (EUSTAR) recommendations for the treatment of systemic sclerosis. In particular, the results of a web-based Delphi exercise aimed at selection of research questions and evidence from systematic literature research, as parts of the development of these recommendations, are presented in detail. In agreement with the EULAR standard operating procedures a Task Force was created that consisted of the EUSTAR board members, 10 systemic sclerosis (SSc) experts invited from outside the EUSTAR board and representing Europe, the USA and Japan, a clinical epidemiologist, 2 patients with SSc and 3 fellows for literature research. All EUSTAR centres were invited to contribute to the development of recommendations through submission and preliminary selection of the research questions. The systematic literature research was performed using the Pubmed, Medline, EMBASE and Cochrane databases. Retrieved trials were evaluated according to the Jadad classification, and the level of evidence was graded from 1 to 4. Outcome data for efficacy and adverse events were abstracted and effect size, number needed to treat (NNT) and number needed to harm (NNH) were calculated when appropriate. In all, 65 EUSTAR Centres provided 304 research questions concerning SSc treatment. These questions were aggregated, subdivided into 19 treatment categories and then subjected to preliminary selection by a web-based Delphi technique. The final set of 26 research questions was created by the Expert Committee based on the results of the Delphi exercise and the expert's experience. This paper is a comprehensive summary of the methods we used to build recommendations for the drug treatment of systemic sclerosis, combining an evidence based approach and expert opinion.
    No preview · Article · Nov 2008 · Annals of the rheumatic diseases