Open access Original research Early indicators of disease progression in Fabry disease that may indicate the need for disease-­specific treatment initiation: findings from the opinion-­ based PREDICT-­FD modified Delphi consensus initiative Derralynn A Hughes,1,2 Patricio Aguiar,3,4 Patrick B Deegan,5,6 Fatih Ezgu,7 Andrea Frustaci ‍ ‍,8 Olivier Lidove,9 Aleš Linhart,10 Jean-­Claude Lubanda,10 James C Moon,11 Kathleen Nicholls,12,13 Dau-­Ming Niu,14,15 Albina Nowak,16,17 Uma Ramaswami,1 Ricardo Reisin,18 Paula Rozenfeld,19 Raphael Schiffmann,20 Einar Svarstad,21,22 Mark Thomas,23 Roser Torra,24 Bojan Vujkovac,25 David G Warnock,26 Michael L West,27 Jack Johnson,28,29 Mark J Rolfe ‍ ‍,30 Sandro Feriozzi31 To cite: Hughes DA, ABSTRACT Aguiar P, Deegan PB, et al. Strengths and limitations of this study Objectives The PRoposing Early Disease Indicators for Early indicators of disease Clinical Tracking in Fabry Disease (PREDICT-­FD) initiative progression in Fabry disease ►► A globally representative panel of clinician-­experts aimed to reach consensus among a panel of global experts that may indicate the need in Fabry disease (FD) was recruited. for disease-­specific treatment on early indicators of disease progression that may justify ►► Group interaction bias was minimised by the anony- initiation: findings from the FD-­specific treatment initiation. mous consensus process. opinion-­based PREDICT-­FD Design and setting Anonymous feedback from panellists ►► The response rate was >95% at each round of the modified Delphi consensus via online questionnaires was analysed using a modified consensus process. initiative. BMJ Open Delphi consensus technique. Questionnaires and data ►► Scoring of FD indicators reflects the real-­ world 2020;10:e035182. doi:10.1136/ were managed by an independent administrator directed bmjopen-2019-035182 views of clinicians. by two non-­voting cochairs. First, possible early indicators ►► Prepublication history and of renal, cardiac and central/peripheral nervous system additional material for this (CNS/PNS) damage, and other disease and patient-­ gastrointestinal symptoms suggestive of gastrointestinal paper are available online. To reported indicators assessable in routine clinical practice neuropathy; (other) pain in extremities/neuropathy, view these files, please visit were compiled by the cochairs and administrator from angiokeratoma; (patient-­reported) febrile crises, the journal online (http://​dx.​doi.​ panellists’ free-­text responses. Second, the panel scored progression of symptoms/signs. Panellists revised and org/​10.​1136/​bmjopen-​2019-​ approved proposed chronologies of when the consensus indicators for importance (5-­point scale: 1=not important; 035182). 5=extremely important); indicators scoring ≥3 among indicators manifest. The panel response rate was >95% at Received 21 October 2019 >75% of panellists were then rated for agreement all stages. Revised 19 June 2020 (5-­point scale: 1=strongly disagree; 5=strongly agree). Conclusions PREDICT-­FD captured global opinion Accepted 16 July 2020 Indicators awarded an agreement score ≥4 by >67% of regarding current clinical indicators that could prompt panellists achieved consensus. Finally, any panel-­proposed FD-­specific treatment initiation earlier than is currently refinements to consensus indicator definitions were practised. adopted if >75% of panellists agreed. © Author(s) (or their Results A panel of 21 expert clinicians from 15 countries INTRODUCTION employer(s)) 2020. Re-­use provided information from which 83 possible current Fabry disease (FD) affects individuals defi- permitted under CC BY-­NC. No indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, commercial re-­use. See rights cient in lysosomal alpha-­galactosidase A. The 13; other, 16; patient reported, 24) were compiled. Of 45 and permissions. Published by indicators meeting the importance criteria, consensus disease is X-­linked, with an estimated preva- BMJ. lence of up to 1 in 40 000, and its multisystem was reached for 29 and consolidated as 27 indicators For numbered affiliations see (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient pathology is caused by intracellular accumu- end of article. lation of globotriaosylceramide (Gb3).1 FD reported, 3) including: (kidney) elevated albumin:creatinine Correspondence to ratio, histological damage, microalbuminuria; (cardiac) presents with highly variable symptomatology Professor Derralynn A Hughes; markers of early systolic/diastolic dysfunction, elevated ranging from patients who are asymptomatic ​rmgvdah@​ucl.​ac.​uk serum cardiac troponin; (CNS/PNS) neuropathic pain, to those severely affected with multiorgan Hughes DA, et al. BMJ Open 2020;10:e035182. doi:10.1136/bmjopen-2019-035182 1 Open access damage.1 The rate at which FD progresses also varies widely used, validated technique for developing expert considerably.1 This poses a major challenge for physicians consensus when evidence is limited and has generated in determining prognosis, and consequently a diagnosis simple, robust clinical guidance, including for the diag- of FD does not automatically merit initiation of FD-­spe- nosis and management of patients with FD.1 16–18 The cific treatment with enzyme replacement therapy (ERT) stepwise use of questionnaires and the maintenance of or chaperone therapy. Instead, physicians must monitor anonymity of the experts consulted minimises data distor- patients regularly to identify signs that may warrant treat- tion that can arise from the pressure on individuals within ment initiation. The decision whether to treat may be a group to conform to a dominant view.19 As well as exam- complicated by the high costs of FD-­specific treatments2 ining the most relevant early clinical indicators of FD and by the considerable patient burden associated with progression, we also aimed to gain agreement on when hospital treatment if home therapy is unavailable or inap- to initiate and to stop FD-­specific treatment in different propriate.3 4 patient groups in different scenarios. The intention is that In 2015, the European Fabry Working Group (EFWG) these findings will raise awareness among specialist and published consensus criteria for initiation and withdrawal general physicians of the early clinical cues that should of ERT in patients with FD.1 The general recommen- prompt consideration of disease-­specific treatment initi- dation applied to classically affected males and females ation in patients with FD, so that disease progression and and to non-­classically affected males, and was to initiate irreversible organ damage in these patients is minimised treatment when clinical signs of kidney, heart or central or avoided. nervous system (CNS) involvement, pain or gastrointes- tinal symptoms first appeared.1 Treatment of classically affected males aged ≤16 years could also be considered in METHODS the absence of signs or symptoms of organ involvement, The modified Delphi process used in PREDICT-­ FD is as could treatment of non-­classically affected females with described below and summarised in figure 1. early clinical signs attributed to FD.1 Initiation or contin- uation of FD-­specific treatment was to be considered on Selection of chairs and expert panel an individual basis, and certain recommendations were Two leading global experts in FD were invited to be made to withhold treatment (eg, in patients with end-­ non-­voting cochairs of the PREDICT-­FD initiative. The stage renal disease with no option for renal transplant cochairs selected an international group of FD experts to and advanced heart failure, or in patients with severe form the voting panel. Panel members were nominated cognitive decline).1 based on track record and demonstrated expertise in The EFWG guidelines provide a valuable framework the field, according to factors such as research activities, for clinical decision making in FD, but important recent participation in national or regional FD management advances in the field suggest that revising these recom- initiatives and authorship of relevant peer-­reviewed publi- mendations may now be appropriate. An increasing cations. Nominated panellists were recruited on behalf body of evidence supports the early initiation of ERT of the initiative cochairs by an independent third-­party in patients with FD,5–8 and several studies show that the administrator (Oxford PharmaGenesis, Oxford, UK). best outcomes of ERT are in patients with the least organ damage at treatment initiation.5 6 9–12 A study comparing Modified Delphi process response to FD-­ specific treatment after 1 year among Under the direction of the PREDICT-­FD cochairs, the treatment-­ naïve men starting ERT before the age of third-­party administrator drafted a study protocol, which 25 years with that among men who started treatment later, was reviewed and approved by both cochairs and by a found a significantly greater reduction in plasma levels of patient representative before commencement of the globotriaosylsphingosine (lyso-­Gb3; a marker of disease initiative. A non-­exhaustive literature search was also severity in FD) in the group treated early.13 conducted by the administrator for the cochairs and was As well as new clinical outcome data, new imaging tech- used to inform aspects of the initiative (see online supple- niques such as cardiac MRI (cMRI)14 and 123I-­metaiodo- mentary appendix). All stages of the initiative, including benzylguanidine single-­photon emission CT15 will likely content development, data collation, data processing and offer the means to detect very early FD-­related organ reporting, were overseen by the cochairs and conducted damage not identified by traditional assessment methods. by the independent third-­ party administrator. Expert Such approaches facilitate FD-­specific treatment initia- panel responses were gathered anonymously via an online tion before more advanced signs appear and irreversible survey platform (SurveyMonkey, SurveyMonkey Europe, organ damage occurs. Dublin, Ireland). For tracking purposes, the adminis- We conducted the international PRoposing Early trator knew the identities of responding panellists, but no Disease Indicators for Clinical Tracking in Fabry Disease identifying information was shared with the cochairs or (PREDICT-­ FD) modified Delphi initiative to establish other panel members. Panellists remained anonymous to expert consensus on early clinical indicators that may each other throughout the Delphi stages. Circulation of prompt when FD-­specific treatment should be initiated the questionnaires, and collection and processing of the in treatment-­ naïve patients. The Delphi process is a panel’s responses was conducted between January and 2 Hughes DA, et al. BMJ Open 2020;10:e035182. doi:10.1136/bmjopen-2019-035182 Open access Figure 1 PREDICT-­FD modified Delphi consensus methodology. aA threshold median likelihood score of 7.5 was set a priori. For questions about the likelihood of initiating treatment, agreement for initiation was sought in round 2 if a scenario was awarded a median score of ≥7.5 and agreement not to initiate treatment sought if the score was <7.5. Similarly, for questions about cessation of treatment, agreement to stop treatment was sought in round 2 if a scenario was awarded a median score ≥7.5 and agreement not to stop treatment sought if the score was <7.5. PREDICT-­FD, PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease. September 2018. Except for comment fields included in likelihood that they would start or stop FD-­specific treat- the questionnaires, all questions were compulsory. No ment in different patient groups and clinical scenarios controlled feedback was provided to panellists between proposed by the cochairs. rounds. Among questions in round 1 that solicited free-­text Further details on the design of the modified Delphi responses, the administrator identified similar themes initiative, including all questionnaires, are provided in among the responses and created provisional groupings the online supplementary appendix. Achieving consensus for review by the cochairs. The cochairs checked and with three rounds of questionnaires was planned. In revised the groupings to exclude indicators that are not round 1, information was solicited regarding panellists’ widely used, are known to be of greater relevance in late-­ stage than in early-­stage disease or are poorly indicative of FD clinical practices, number of years spent treating FD status and progression. The administrator generated patients with FD and number of patients with FD typically lists of indicators and compiled responses from the panel managed in their practices. Panellists provided free-­text regarding attitudes to FD-­specific treatment initiation or responses to open questions soliciting suggestions for cessation in different patient groups, determining the early indicators of renal, cardiac and CNS damage that panel’s median likelihood scores for starting or stopping can be assessed in current routine clinical practice, or FD-­specific treatment. that are not assessed routinely at present, but might be In round 2, panellists rated the importance of each in the future. Additional round 1 questions explored indicator on a 5-­point Likert scale (1=not important; symptoms experienced by patients with FD that could 2=slightly important; 3=important; 4=very important; contribute to initiating FD-­specific treatment. Attitudes 5=extremely important). Regarding scenarios for towards FD-­ specific treatment initiation or cessation initiation or cessation of FD-­specific treatment, if a were also investigated by asking panellists to rate on an scenario was awarded a median likelihood score of ≥7.5 11-­point scale (0=not at all likely; 10=extremely likely) the in round 1, agreement was sought whether to start or Hughes DA, et al. BMJ Open 2020;10:e035182. doi:10.1136/bmjopen-2019-035182 3 Open access to stop FD-­specific treatment. In contrast, if the score Patient and public involvement statement was <7.5, agreement was sought whether to start or to A leadership representative from the Fabry Interna- stop treatment. Panellists rated their level of agree- tional Network (FIN), JJ, was invited to participate in ment using a 5-­point Likert scale (1=strongly disagree; the project in a non-­voting role. The representative 2=disagree; 3=neither agree nor disagree; 4=agree; reviewed and approved the initial protocol and round 5=strongly agree). Importance and agreement ratings 1 questionnaire, and facilitated the involvement of were compiled by the administrator. It was specified a three patients with FD (one from the USA and two priori that indicators awarded an importance score of from outside the USA) in reviewing these materials. ≥3 by >75% of the panel would be tested for consensus This ensured that any appropriate feedback from the in round 3, and that agreement on treatment recom- patients could be incorporated into materials before mendations would be reached if an agreement score distributing the round 1 questionnaire. Additional of ≥4 was awarded by >67% of the panel. All ratings roles of the FIN representative included capturing compiled by the administrator were reviewed by the these patients’ views on the outcomes of the initiative, cochairs as per the predefined scores and consistent and reviewing and approving the final study report. with previous Delphi initiatives20 21; agreement on treatment recommendations concluded in round 2. In round 3, panellists rated their level of agreement with RESULTS each indicator that had met the designated impor- PREDICT-FD expert panel demographics and clinical tance criteria in round 2, using the 5-­point Likert scale experience already described. Consensus was established using In total, 23 experts were invited to join the expert panel; the same a priori criteria already described. Agree- one declined to participate, and one did not complete ment scores were compiled by the administrator and round 1 and was excluded from the analysis. Thus, the reviewed by the cochairs. panel comprised 21 physicians representing 15 countries Round 4 was included post hoc to capture the panel’s (Argentina, Australia, Canada, Czech Republic, France, level of agreement with certain indicators that met the Italy, Norway, Portugal, Slovenia, Spain, Switzerland, importance criteria in round 2 but which were inadver- Taiwan, Turkey, UK, USA). All panellists had managed tently omitted from round 3. Panel members were also male and female patients with FD; most panellists had asked whether they agreed or disagreed with refine- experience of managing both patients with classical and ments proposed for several indicators that achieved those with non-­classical FD (table 1). consensus in round 3 and these were adopted if >75% The majority of panellists (18 (85.7%)) practised in of the panel agreed; refinements were informed by public teaching hospitals. Panellists had treated patients comments made by panel members during the first with FD for a mean of 15.5 years and four panellists three rounds. Panellists’ responses were compiled by (19.0%) had >20 years of clinical experience with FD. the administrator, reviewed by the cochairs, and any Specialties most commonly represented were nephrology new consensus terms combined with those identified (8 (38.1%)), metabolic diseases (5 (23.8%), of whom 3 in round 3. (14.3%) also specialised in genetics) and cardiology (4 Chronology of signs and symptoms (19.0%)); haematology, immunology, neurology, paedi- After generating the refined list of consensus indicators, atrics, internal medicine, biochemistry and angiology timelines were developed under the direction of the were also represented. Overall, the panel managed an cochairs showing when each indicator typically mani- estimated 2079 patients, 40.7% of whom were male; fests during the disease course in relation to established 64.5% of patients had classical FD (table 1). A response indicators currently recommended as triggers for treat- rate of 95.5% (21/22) was achieved during round 1 of ment initiation. Indicators manifesting before and after the modified Delphi process; thereafter all 21 panellists established indicators were termed ‘early’ and ‘late’, responded. respectively. Indicators featuring in the chronologies were grouped as renal, cardiac or patient reported/ Consensus on current and potential future indicators of other. The cochairs agreed a draft chronology for each disease progression in FD group, and these proposals were submitted to each Indicators achieving consensus in round 3 of the modi- panel member for comment and amendment. Panel fied Delphi process were further refined in round 4 (see responses were collated, and the chronologies revised section ‘Refinements to consensus indicators’ for further by the administrator then approved by the cochairs. information); the final list of consensus indicators is The chronologies were developed between December summarised in table 2. Results by organ system and cate- 2018 and January 2019; Delphi consensus techniques gory are described below. were not applied to this part of the initiative. Indicators of renal damage Statistical analyses Following consolidation by the cochairs, 15 indicators of The study was exploratory; no hypotheses were tested and early renal damage in current use and 19 potential future only descriptive statistical analyses were performed. indicators were collated from round 1. Of these, seven 4 Hughes DA, et al. BMJ Open 2020;10:e035182. doi:10.1136/bmjopen-2019-035182 Open access time on cMRI; elevated serum cardiac troponin; and Table 1 PREDICT-­FD modified Delphi expert panel clinical experience elevated serum N-­terminal probrain natriuretic peptide (NT-­pro-­BNP). The other important current indicators Clinical experience (n=21) were: markers of early systolic/diastolic dysfunction; early Main clinical practice* indicators of left ventricular hypertrophy (LVH); histo-  Private teaching hospital 1 (4.8) logical damage (lesions associated with Gb3 deposition)  Private hospital 0 in endomyocardial biopsies; late gadolinium enhance- ment on cMRI; abnormal ECG; abnormal echocardio-  Public teaching hospital 18 (87.5) gram; and, specifically, abnormal wall motion revealed by  Public non-­teaching hospital 0 echocardiogram.  Research centre 6 (28.6) Duration of FD clinical experience, years Indicators of peripheral nervous system damage In round 1 following consolidation, 13 current and 13  Mean (SD) 15.5 (7.5) future indicators were identified, with 5 and 2 indica-  0–10 6 (28.6) tors, respectively, subsequently meeting the importance  11–20 11 (52.4) criteria in round 2 (see online supplementary table S3).  21–30 4 (19.0) Consensus was reached for neuropathic pain and gastro- Number of patients with FD managed intestinal symptoms suggestive of gastrointestinal neurop- athy as current indicators; no consensus was achieved for  Mean (SD) 99 (81) future indicators.  1–50 4 (19.0)  51–100 12 (57.1) Other indicators  101–200 3 (14.3) When asked for further information about early indi- cators of FD, such as non-­ organ-­specific symptoms,  >200 2 (9.5) consensus was reached for five indicators (see online Patient summary† supplementary table S4): pain in extremities/neurop-  Male 847 (40.7) athy; angiokeratoma; organ biopsy (including skin biopsy  Female 1232 (59.3) for small-­ fibre neuropathy); gastrointestinal symptoms  Classical FD 1341 (64.5) (including bloating, pain, diarrhoea/frequent diarrhoea or constipation); and sweating abnormalities or heat/  Non-­classical FD 738 (35.5) exercise intolerance. Data are shown as number (%) of respondents unless otherwise stated. Patient-reported indicators *Respondents could select more than one option. Panellists were asked to list what they considered to be †Patient n (%) values are estimates, derived from total patient the earliest signs and symptoms relevant to FD progres- numbers and estimated sex and FD-­type breakdown reported by each panellist. sion and FD-­specific treatment initiation, and also to list FD, Fabry disease; PREDICT-­FD, PRoposing Early Disease patient-­reported signs and symptoms relevant to FD-­spe- Indicators for Clinical Tracking in Fabry Disease. cific treatment initiation. When the responses were combined, consensus was achieved for the following six patient-­reported indicators: stroke/transient ischaemic current and two future indicators met the predefined attack; febrile crises; patient-­ reported progression of importance criteria in round 2. Consensus was reached symptoms/signs of FD (such as acral burning paraes- for the following current indicators (see online supple- thesias, heat intolerance, impaired sweating, fatigue, mentary table S1): elevated urine albumin:creatinine depression, pain, gastrointestinal symptoms, shortness ratio; histological damage (lesions associated with Gb3 of breath, palpitations, peripheral oedemas); diarrhoea/ deposition); microalbuminuria; abnormal glomerular frequent diarrhoea; angiokeratoma; and neuro-­otological filtration rate (GFR); decline in iohexol GFR and podo- abnormalities (see online supplementary table S5). cyte inclusions in renal biopsies. Consensus was not Based on consensus reached in round 4, stroke/tran- achieved for any future indicators. sient ischaemic attack and diarrhoea/frequent diarrhoea were reclassified among ‘other indicators’, and neuro-­ Indicators of cardiac damage otological abnormalities was discarded (see ‘Refinements After consolidation at the end of round 1, 15 current and to consensus indicators’). 14 future indicators of early cardiac damage were iden- tified, and 12 current and 3 future indicators met the Indicators under research importance criteria in round 2. Consensus was reached for Of the eight indicators that were the focus of experimental 10 current indicators, 3 of which also reached consensus studies or ongoing research, five were deemed important, as future indicators (see online supplementary table S2). and two achieved consensus (see online supplementary The indicators deemed important, both currently and table S6): reduced quality of life and high gastrointestinal in the future, were: reduced myocardial T1 relaxation symptom scores. Hughes DA, et al. BMJ Open 2020;10:e035182. doi:10.1136/bmjopen-2019-035182 5 6 Table 2 Indicators for which consensus was achieved in PREDICT-­FD Open access Current early indicators of damage Kidney Cardiac PNS Other Patient reported Elevated urine albumin:creatinine Markers of early systolic/diastolic dysfunction†‡ Neuropathic pain†§ Pain in extremities/neuropathy¶ Febrile crises ratio* Histological damage Elevated serum cardiac troponin† Painful gastrointestinal symptoms Stroke/transient ischaemic attack** Patient-­reported (kidney biopsy)* suggestive of gastrointestinal neuropathy progression of symptoms/ related to FD†§ signs†† Microalbuminuria*† Early indicators of left ventricular hypertrophy   Angiokeratoma Angiokeratoma Abnormal glomerular filtration rate Early indicators of histological damage (heart   Organ biopsy¶¶ (Neuro-­otological biopsy)‡‡§§ abnormalities)*** Decline in iohexol glomerular Late gadolinium enhancement on cardiac MRI   Non-­pain gastrointestinal symptoms (including   filtration rate diarrhoea/frequent diarrhoea) related to FD Podocyte inclusions Elevated serum N-­terminal probrain natriuretic   Sweating abnormalities or heat/exercise intolerance   peptide†   Reduced myocardial T1 relaxation time on cardiac       MRI   Abnormal ECG‡,‡‡         Abnormal echocardiogram†‡         Abnormal wall motion on echocardiography       Early cardiac indicators of FD that may be used in future Early indicators of FD subject to ongoing research Reduced myocardial T1 relaxation time on cardiac MRI Reduced quality of life Elevated serum cardiac troponin† High gastrointestinal symptom scores Elevated serum N-­terminal probrain natriuretic peptide† *It was noted in round 4 that the prognostic significance of this indicator is different in male and female patients. †It was noted in round 4 that a causal relationship between this indicator and FD is required to justify treatment initiation. ‡Including decreased myocardial strain and strain rate, tissue Doppler abnormalities,enlarged left atrium or pulmonary venous flow abnormalities on echocardiogram. §Recategorised as PNS in round four because no indicators of CNS damage achieved consensus. ¶Including acroparaesthesias. **Previously under ‘patient-­reported indicators of FD’, recategorised in round 4 under ‘other early indicators of FD’ because such indicators would need to be confirmed clinically. ††Renamed ‘patient-­reported progression of symptoms/signs’ from ‘symptom/sign progression’ in round 4. ‡‡Including a shortened PR interval, non-­sustained ventricular tachycardia and symptomatic bradycardia. §§Cardiac histological changes have been reported in FD, but cardiac biopsy is too invasive to be recommended. ¶¶Including skin biopsy for small-­fibre neuropathy, and kidney and heart biopsy nominated in other categories. ***This indicator is included because it achieved consensus but was subsequently excluded in round 4. It refers to a cluster of indicators (vertigo, hearing loss and tinnitus) that did not achieve consensus individually. †††Originally grouped under ‘patient-­reported indicators of FD’; combined with ‘non-­pain gastrointestinal symptoms’ under ‘other early indicators of FD’ in round 4. ‡‡‡Including bloating, pain, diarrhoea/frequent diarrhoea or constipation, that are causally related to FD. CNS, central nervous system; PNS, peripheral nervous system; PREDICT-­FD, PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease. Hughes DA, et al. BMJ Open 2020;10:e035182. doi:10.1136/bmjopen-2019-035182 Open access Refinements to consensus indicators damage are summarised in table 4 and online supplemen- During the first three rounds, panellists offered addi- tary figure S1B. Agreement was reached that treatment tional information about the indicators, typically to should be initiated in patients with evidence of damage to define broad indicators more precisely. Comments on the a single organ system, irrespective of whether that organ current indicators that achieved consensus were reviewed system was being treated by a non-­Fabry-­specific interven- by the cochairs, and proposed clarification on 23 of these tion (eg, renal replacement therapy, kidney transplant or was circulated to the panel in round 4, either to endorse cardiac pacemaker, etc), and that FD-­specific treatment of new information or to provide an opportunity to include such patients should not be stopped, were such a therapy additional information. The panel reached agreement on to become necessary. Agreement was also reached that refinements to 19 of these indicators (see online supple- FD-­specific treatment should be initiated and should not mentary table S7; ‘neuro-­ otological abnormalities’ was be stopped in patients receiving separate therapies for excluded from the consensus because it encompassed damage to multiple organ systems (such as a combination the other indicators ‘vertigo’, ‘hearing loss’ and ‘tinnitus’ of renal replacement therapy, kidney transplant and/or that had not achieved consensus (see online supple- cardiac pacemaker, etc). The group in which the panel mentary tables S4,S5). The current and potential future was least likely to initiate or to stop FD-­specific treatment indicators, as well as those under research, that achieved was that comprising patients who were receiving no sepa- final consensus are summarised in table 2; explanatory rate therapy for multiple organ system damage. However, table footnotes describe the refinements made in round no agreement was reached for either scenario. The panel 4 based on feedback from the panel. also did not reach agreement on the question of whether all patients with FD should remain on disease-­specific Chronology of manifestation of indicators during the disease treatment, irrespective of organ damage or any related course treatment (mean (median) agreement score, 2.2 (2); Indicators that achieved consensus were allocated to agreement score ≥4, 6 (28.6%)). three groups: renal; cardiac; and patient reported/ other, and a chronology was developed for each group (figure 2A–C). DISCUSSION The PREDICT-­FD panel was convened to identify early Initiation and cessation of FD-specific treatment in patients clinical indicators that could prompt disease-­specific treat- with FD ment initiation in patients with FD, thereby minimising In round 1, the panel rated the likelihood of initiating disease progression. The panel reached consensus on 27 FD-­ specific treatment in different scenarios (patients early renal, cardiac, peripheral nervous system (PNS), asymptomatic for organ damage, symptomatic patients patient-­reported and other indicators of disease progres- not meeting guideline criteria, patients meeting guide- sion that can currently be assessed in FD clinics (table 2). line criteria) in five different patient groups (defined Other indicators that were considered important but by sex, age group, and classical or non-­classical FD) (see where no consensus was reached or that were categorised online supplementary figure S1A). The panel’s level of as being of no importance, are summarised in the supple- agreement in round 2 with proposals that treatment mentary tables. Three indicators of cardiac damage should or should not be started in different patient were also identified that might be adopted more widely groups in different scenarios is summarised in table 3. for routine use in future and the utility of two other Agreement was reached in round 2 that FD-­ specific consensus indicators are the focus of ongoing research. treatment should be initiated in all males aged ≥16 years In the opinion of the panellists, treatment should be initi- with classical disease, and in males of any age with clas- ated in any male patients with classical FD aged at least sical disease and with early indicators of organ damage, 16 years, and in younger males with classical disease if irrespective of whether these symptoms meet the EFWG early signs of organ damage appear. Female patients and recommendations for treatment initiation.1 Agreement male patients with non-­classical disease should be treated that FD-­specific treatment should be initiated was also based on existing guideline recommendations. reached for all female patients and for male patients with Detection of renal histological damage requires a non-­classical disease with indicators meeting the EFWG biopsy, which is highly invasive, so the presence of other, guideline criteria.1 Agreement not to start treatment was less invasive early indicators could be sufficient grounds reached only for asymptomatic females with non-­classical to start FD-­specific treatment without biopsy data. The FD (table 3). However, when asked if all patients who panel reached a consensus that early indicators of renal meet the EFWG guideline criteria1 should receive FD-­spe- damage included microalbuminuria, glomerular hyper- cific treatment, the panel did not reach agreement (mean filtration and podocyte inclusions in the presence of (median) score, 3.4 (4); score ≥4, 11 (52.4%)), including other renal lesions, such as signs of glomerulosclerosis or for female patients with classical FD and male patients vasculopathy, which may occur even in patients without with non-­classical FD. microalbuminuria (figure 2).22 23 The panel’s responses regarding starting or stopping Regarding cardiac indicators, consensus was reached on FD-­ specific treatment in scenarios relating to organ several early indicators of cardiac damage, including ECG Hughes DA, et al. BMJ Open 2020;10:e035182. doi:10.1136/bmjopen-2019-035182 7 Open access Figure 2 Chronology of consensus indicators. (A) *Indicator tested for, but not achieving, consensus in round 3. (B) †Indicators in red text achieved consensus both as currently used, and suitable for future adoption, because they are not available in all centres. Two further indicators (abnormal PET/MRI and increased serum lyso Gb3) that were included in round 2 of the initiative but were not taken forward to round 3 are not shown here based on guidance from the cochairs. (C) *Indicator tested for, but not achieving, consensus in round 3. Other indicators tested for, but not achieving, consensus, and which are not included here owing to their lack of specificity were: biomarkers; patient-­reported outcomes; absenteeism owing to ill health; and palpitations. a Indicators that currently would be likely to trigger FD-­specific treatment initiation. bIn isolation, probably insufficient justification for FD-­specific treatment initiation. cMicroalbuminuria could be a trigger for further investigation, such as confirmatory biopsy, and subsequent initiation of disease-­specific treatment. dIncluding decreased myocardial strain and strain rate, tissue Doppler abnormalities, enlarged left atrium, abnormal wall motion or pulmonary vein abnormalities. eIncluding shortened PR interval, non-­SVT and symptomatic bradycardia. ACR, albumin:creatinine ratio; AF, atrial fibrillation; FD, Fabry disease; GFR, glomerular filtration rate; LGE, late gadolinium enhancement; LVH, left ventricular hypertrophy; lyso Gb3, globotriaosylsphingosine; NT-­pro-­ BNP, N-­terminal probrain natriuretic peptide; PET, positron emission tomography; SVT, sustained VT; VT, ventricular tachycardia. abnormalities (eg, shortened PR interval) elevated cardiac is an established sign of cardiac involvement in FD, any troponin, elevated NT-­ pro-­ BNP and low myocardial T1 tests revealing early stages of hypertrophy could be valu- relaxation times on cMRI, although the utility of the last able in informing treatment decisions and could help to may be limited by the low availability of T1 mapping by slow cardiac disease progression on treatment.25 Elevated cMRI in specialist FD centres. Grade 1 diastolic dysfunc- high-­sensitivity cardiac troponin and NT-­pro-­ BNP levels tion in early FD24 may be a useful indicator of cardiac are early signs of cardiac damage that might be detect- changes, but perhaps only in young patients. Because LVH able before signs that can be seen with cMRI. A concern 8 Hughes DA, et al. BMJ Open 2020;10:e035182. doi:10.1136/bmjopen-2019-035182 Table 3 Treatment initiation in different patient groups and scenarios Males aged <16 years Males aged ≥16 years Females with classical Males with non-­ Females with non-­ Scenario with classical FD with classical FD FD classical FD classical FD Asymptomatic for organ involvement Likelihood of starting treatment  Mean (median) score 5.4 (5) 7.1 (8) 2.8 (2) 3.3 (2) 1.6 (1) Agreement Do not start Start Do not start Start Do not start Start Do not start Start Do not start Start treatment treatment treatment treatment treatment treatment treatment treatment treatment treatment  Mean (median) score 2.5 (2)     4.2 (4) 3.2 (3)   3.2 (4)   3.8 (4)    Score ≥4, n (%) 5 (23.8)     18 (85.7) 10 (47.6)   11 (52.4)   15 (71.4)   Early indicators of organ involvement Likelihood of starting treatment Mean (median) score 7.6 (8) 8.6 (10) 6.6 (7) 6.6 (7) 5.3 (5) Hughes DA, et al. BMJ Open 2020;10:e035182. doi:10.1136/bmjopen-2019-035182 Agreement Do not start Start Do not start Start Do not start Start Do not start Start Do not start Start treatment treatment treatment treatment treatment treatment treatment treatment treatment treatment  Mean (median) score   4.4 (5)   4.8 (5) 1.7 (2)   1.7 (2)   2.1 (2)    Score ≥4, n (%)   19 (90.5)   21 (100) 0 (0)   1 (4.8)   2 (9.5)   Guideline indicators for FD-­specific treatment initiation Likelihood of starting treatment  Mean (median) score 9.4 (10) 9.7 (10) 9.4 (10) 9.1 (10) 8.5 (10) Agreement Do not start Start Do not start Start Do not start Start Do not start Start Do not start Start treatment treatment treatment treatment treatment treatment treatment treatment treatment treatment  Mean (median) score   4.5 (5)   4.6 (5)   4.6 (5)   4.3 (4)   4.1 (4)  Score ≥4, n (%)   20 (95.2)   20 (95.2)   20 (95.2)   19 (90.5)   16 (76.2) Where the median likelihood score awarded for starting treatment was ≥7.5 in round 1, panellists were asked in round two to rate their level of agreement with starting treatment. Where the median likelihood score awarded for starting treatment was <7.5 in round 1, panellists were asked in round two to rate their level of agreement with not starting treatment. Green shading: consensus that FD-­specific treatment should be initiated. Orange shading: consensus that FD-­specific treatment should not be initiated. No shading: no consensus was achieved. n=21. FD, Fabry disease. Open access 9 Open access raised by panellists was that later manifestations of cardiac Start treatment Do not start treatment Start treatment Stop treatment Do not stop treatment Stop treatment Multiorgan damage, not receiving damage do not typically respond to FD-­specific treatment. *For example, renal replacement therapy, kidney transplant or cardiac pacemaker. Where the median likelihood score awarded for starting or stopping treatment was ≥7.5 in round 1, panellists were Histological markers have the potential to reveal very early cardiac tissue changes, but undertaking a cardiac biopsy is asked in round 2 to rate their level of agreement with that course of action. Where the median likelihood score awarded was <7.5 in round 1, panellists were asked in round 2 to rate their level of         too invasive to be recommended as a routine screen for FD therapy for those organs progression. agreement with not taking that course of action. Green shading: scenarios in which consensus was reached that either treatment should start or treatment should not be stopped. n=21. Other clinical and patient-­reported early indicators of FD, such as neuropathic pain, gastroenterological symp- toms and difficulties with hearing or balance, are well-­ known signs and symptoms experienced by patients with 13 (61.9) 3 (14.3) FD. Such clinical features could contribute to a physi- 6.3 (7) 2.3 (2) 4.8 (4) 3.7 (4) cian’s decision to treat but may respond only partially to FD-­specific treatment. Multiorgan damage, receiving therapy Implications of the consensus indicators for the start of 18 (85.7) treatment 4.1 (4)     The panel reached a consensus on initiating FD-­specific treatment in predefined patient groups. In particular, the panel agreed that treatment should be initiated for Do not start treatment Do not stop treatment all males ≥16 years of age with the classical FD mutation for those organs regardless of symptom status. Similarly, the panel agreed that treatment should be initiated among males <16 years of age with classical FD demonstrating early or guideline-­ 16 (76.2) associated indicators. However, there was no consensus 7.1 (8) 3.9 (3) 4.0 (4)     on initiating treatment in asymptomatic males <16 years of age. In particular, consensus regarding early renal and Start treatment Stop treatment cardiac indicators of disease progression could encourage Damage to one organ system, not FD centres to monitor for these indicators, pre-­empting 16 (76.2) receiving therapy for that organ accrual of irreversible organ damage. Furthermore, 3.8 (4)     agreement among the panel about the most suitable patient groups for FD-­specific treatment initiation indi- cates that the current guideline recommendations1 could Start treatment Do not start treatment Stop treatment Do not stop treatment be updated, and the impact of early intervention could Treatment initiation or cessation in patients with organ damage* be audited for beneficial outcomes. Likewise, policy-­ makers can use observational and longitudinal data to examine the cost–benefit implications of early treatment 16 (76.2) 7.0 (8) 3.9 (5) 4.0 (4) of patients for avoidable complications, as well as appro-     priate cessation of therapy in specific patient groups. Results of the PREDICT-FD initiative in context receiving therapy for that organ The PREDICT-­ FD modified Delphi initiative represents 19 (90.5) Damage to one organ system, 4.3 (4) the broadest evaluation of early indicators of FD-­ spe-     cific treatment initiation to date. Previous Delphi initia- tives have evaluated indicators specific to renal or cardiac Do not start treatment Do not stop treatment organ damage,17 18 with a focus on tissue biopsy evaluation. However, biopsies are invasive and other approaches are available to aid early identification of disease progression. The use of biopsies in the diagnosis of FD was also key in a 18 (85.7) Likelihood of stopping treatment Delphi initiative exploring diagnosis, treatment and adverse Likelihood of starting treatment  Mean (median) score 8.1 (9)  Mean (median) score 2.8 (2)  Mean (median) score 4.3 (4)  Mean (median) score     event management.16 This Delphi panel reached conclu- sions similar to those of the PREDICT-­FD panel regarding initiation of treatment.16 Both the cardiac and renal Delphi Stopping treatment Starting treatment panels recognised serum lyso Gb3 levels as a potential indi-  Score ≥4, n (%)  Score ≥4, n (%) cator, although it might have limited specificity in kidney damage.17 18 Lyso Gb3 has also been proposed as a poten- Agreement Agreement tial primary biomarker for FD in other studies.26 27 In the Table 4 PREDICT-­FD panel, there was no consensus on the use of lyso Gb3 as an early indicator of organ damage or treatment 10 Hughes DA, et al. BMJ Open 2020;10:e035182. doi:10.1136/bmjopen-2019-035182 Open access 4 initiation, with the strongest marker of the importance of Medicine Department, University of Lisbon, Lisbon, Portugal 5 lyso Gb3 observed for cardiac damage. Lysosomal Disorders Unit, Addenbrooke’s Hospital, Cambridge, UK 6 Department of Medicine, University of Cambridge, Cambridge, UK 7 Department and Laboratory of Paediatric Metabolic Disorders, Gazi University, Strengths and weaknesses of the PREDICT-FD modified Delphi Ankara, Turkey initiative 8 Department of Cardiovascular, Respiratory, Nephrologic, Geriatric and The anonymised nature of Delphi methodology should Anesthesiologic Sciences, University of Rome La Sapienza, Rome, Italy minimise the possibility of bias often seen in face-­to-­face 9 Department of Internal Medicine-­Rheumatology, Croix Saint Simon Hospital, Paris, group interactions, thereby strengthening the validity of the France 10 consensus process. However, clinicians in a relatively small Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic and highly specialised field may well be aware of the opin- 11 Cardiac Imaging Department, Barts Heart Centre, London, UK ions of their peers, which may have influenced the responses 12 Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia provided in our study. With this qualification, the anonymity 13 Department of Medicine, The University of Melbourne - Parkville Campus, of the panellists was maintained until the Delphi stages Melbourne, Victoria, Australia 14 were complete and the disease chronologies circulated Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan 15 for comment. Furthermore, the overall response rate was Institute of Clinical Medicine, National Yang-­Ming University, Taipei, Taiwan 16 Department of Endocrinology and Clinical Nutrition, University Hospital Zurich and >95%, indicating that panellists’ knowledge and opinions University of Zurich, Zurich, Switzerland were well represented. However, because the importance- 17 Department of Internal Medicine, Psychiatry University Hospital Zurich, Zurich, and agreement-­rating steps in this Delphi consensus were Switzerland opinion based, it is possible that a different consensus would 18 Department of Neurology, British Hospital of Buenos Aires, Buenos Aires, Argentina 19 have been reached, had the panel comprised different Instituto de Estudios Inmunológicos y Fisiopatológicos, UNLP - CONICET, La Plata, medical specialties. Thus, the generalisability of our findings Argentina 20 Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA is influenced by the panel composition and by the degree 21 Department of Clinical Medicine, University of Bergen, Bergen, Norway to which each panellist’s perspective represents that of FD 22 Department of Medicine, Haukeland University Hospital, Bergen, Norway specialists not polled. Such shortcomings are implicit in the 23 Department of Nephrology, Royal Perth Hospital, Perth, Western Australia, Australia Delphi process and the findings require further evaluation 24 Inherited Renal Diseases Unit, Autonomous University of Barcelona, Barcelona, in real-­world clinical practice to confirm their relevance. Spain 25 Weaknesses of the methodology were the absence of a Department of Internal Medicine, General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia neutral response option for those unfamiliar with the rele- 26 Division of Nephrology, University of Alabama at Birmingham, Birmingham, vance of an indicator during the importance rating stage, Alabama, USA and that no controlled feedback was provided to panellists 27 Medicine, Dalhousie University, Halifax, Nova Scotia, Canada between rounds. Another was that no attempt was made to 28 Fabry Support & Information Group, Concordia, Missouri, USA 29 achieve consensus on the utility of indicators that did not Fabry International Network, Beveren, Belgium 30 meet the consensus criteria. Conceivably, this would have Oxford PharmaGenesis, Oxford, UK 31 Division of Nephrology, Belcolle Hospital, Viterbo, Italy led to some indicators being completely discounted, leaving others whose utility remains to be proven. Acknowledgements This initiative is endorsed by the Fabry International Network. The authors are grateful to Oxford PharmaGenesis, Oxford, UK, for Conclusion and implications for future research providing administrative and project management support for the PREDICT-­FD The PREDICT-­ FD modified Delphi initiative achieved initiative and for medical writing, editorial support and project management consensus on 27 early renal, cardiac, PNS, patient-­reported support in preparation of this manuscript. This research and support from Oxford PharmaGenesis were funded by an unrestricted independent medical and other indicators of disease progression that could education grant (IME-­GBR-15474) from Shire International (now part of Takeda prompt FD-­ specific treatment initiation earlier than is Pharmaceutical Company), Zug, Switzerland. The authors chose independently to currently practised. These findings should raise awareness work with Oxford PharmaGenesis, without input from Shire International GmbH. among physicians of the early clinical cues that should Contributors DAH and SF provided expert clinical insight throughout the prompt consideration of disease-­specific treatment initia- development of the PREDICT-­FD modified Delphi initiative, advised on the tion in FD, so that disease progression and irreversible organ recruitment for the panel members and contributed to the concept, design and development of the initiative and the development of the questions for each round, damage in these patients is minimised or avoided. Empiri- as well as to the interpretation of the findings. MJR contributed to the design and cally, early treatment is associated with better outcomes development of the initiative and the development of the questions for each round, than delaying treatment of FD, but there is currently scant as well as to the interpretation of the findings. JJ provided expert guidance on the information about the responsiveness to treatment of many initiative design and questions for each round, and the interpretation of the findings. PA, PBD, FE, AF, OL, AL, J-­CL, JCM, KN, D-­MN, AN, UR, RR, PR, RS, ES, MT, RT, BV, of the early indicators of disease progression identified in DGW and MLW were voting members of the panel, and provided expert input at PREDICT-­FD. Further evidence is needed to understand each round and on the interpretation of the findings. All authors contributed to the the latest stage at which treatment can be initiated to mini- development and approval of the manuscript. mise the long-­term complications of FD. Funding Administration and coordination of the PREDICT-­FD initiative and medical writing support were funded by an unrestricted independent educational grant Author affiliations (IME-­GBR-15474) from Shire International GmbH, Zug, Switzerland, now part of 1 Lysosomal Storage Disorders Unit, Royal Free Hospital, London, UK Takeda Pharmaceutical Company. Shire/Takeda was not involved in the planning, 2 Department of Haematology, University College London, London, UK design or delivery of the initiative. No reimbursement or funding was offered to 3 Inborn Errors of Metabolism Reference Center, North Lisbon Hospital Center, the voting panel, to the cochairs or to any other organisation participating in the Lisbon, Portugal initiative. Hughes DA, et al. BMJ Open 2020;10:e035182. doi:10.1136/bmjopen-2019-035182 11 Open access Competing interests DAH: advisory boards for Amicus, Sanofi, Shire (now part 3 Hughes DA, Mlilligan A, Mehta A. Home therapy for lysosomal of Takeda); consulting fees from Amicus, Idorsia, Sanofi and Shire (now part storage disorders. Br J Nurs 2007;16:1384–9. of Takeda); honoraria from Amicus, Sanofi and Shire (now part of Takeda). PA: 4 Milligan A, Hughes D, Goodwin S, et al. Intravenous enzyme research grant and honoraria from Shire (now part of Takeda); honoraria from replacement therapy: better in home or hospital? Br J Nurs 2006;15:330–3. Amicus, Biomarin, Sanofi and Ultragenyx. PBD: speaker honoraria from and 5 Germain DP, Charrow J, Desnick RJ, et al. Ten-­year outcome of advisory boards for Takeda and Sanofi; consultancy for Sanofi. FE: travel grants and enzyme replacement therapy with agalsidase beta in patients with speaker honoraria from Pfizer, Sanofi Genzyme and Takeda. AF: research grants Fabry disease. J Med Genet 2015;52:353–8. from Amicus and Shire. OL: travel grants and speaker honoraria from Amicus, 6 Hopkin RJ, Cabrera G, Charrow J, et al. Risk factors for severe Sanofi Genzyme and Shire HGT. AL: speaker’s honoraria or consultation fees from clinical events in male and female patients with Fabry disease treated Amicus, Sanofi Genzyme and Takeda. J-­CL: speaker’s honoraria and consultation with agalsidase beta enzyme replacement therapy: data from the fees from Shire. JCM: research grant and speaker honoraria from Sanofi Genzyme; fabry registry. Mol Genet Metab 2016;119:151–9. 7 Weidemann F, Niemann M, Sommer C, et al. Interdisciplinary advisory board for, and honoraria from ST; consulting fees from 4DMT. KN: research approach towards female patients with Fabry disease. Eur J Clin support and/or honoraria from Amicus, Idorsia, Protalix, Sanofi and Shire (now part Invest 2012;42:455–62. of Takeda); advisory boards for Amicus, Sanofi and Shire (now part of Takeda). 8 Hopkin RJ, Jefferies JL, Laney DA, et al. The management and D-­MN: research funding from Shire (now part of Takeda) and Sanofi. AN: honoraria treatment of children with Fabry disease: a United States-­based and research support from Sanofi Genzyme and Shire (now part of Takeda). UR: perspective. Mol Genet Metab 2016;117:104–13. advisory boards for Amicus, Chiesi, Idorsia and Shire; travel grants and honoraria 9 Talbot AS, Lewis NT, Nicholls KM. Cardiovascular outcomes in from Amicus, Genzyme and Shire. RR: travel grants and speaker honoraria from Fabry disease are linked to severity of chronic kidney disease. Heart Amicus and Shire HGT (now part of Takeda). PR: advisory board, consulting fees 2015;101:287–93. 10 Kim JH, Lee BH, Hyang Cho J, et al. Long-­term enzyme replacement and research grant from Shire (now part of Takeda). RS: advisory boards for Amicus, therapy for Fabry disease: efficacy and unmet needs in cardiac and Sanofi, Shire (now part of Takeda); honoraria from Amicus and Shire; research renal outcomes. J Hum Genet 2016;61:923–9. funding from Idorisia, Protalix, Sanofi Genzyme and Takeda. ES: speaker’s fees and 11 Arends M, Biegstraaten M, Hughes DA, et al. Retrospective study of travel support from Amicus, Sanofi Genzyme and Shire; advisory board honoraria long-­term outcomes of enzyme replacement therapy in Fabry disease: from Amicus and Sanofi Genzyme. MT: advisory boards for Amicus, Sanofi and analysis of prognostic factors. PLoS One 2017;12:e0182379. Shire (now part of Takeda); travel grants and speaker’s honoraria from Amicus, 12 Lenders M, Schmitz B, Stypmann J, et al. Renal function predicts Sanofi and Shire; research funding from Amicus, AVROBIO and Idorsia. RT: travel long-­term outcome on enzyme replacement therapy in patients with grants, speaker’s honoraria or consultation fees from Amicus, Sanofi Genzyme and Fabry disease. Nephrol Dial Transplant 2017;32:2090–7. 13 Arends M, Wijburg FA, Wanner C, et al. Favourable effect of Takeda. BV: speaker’s fees and travel support from Greenovation, Sanofi Genzyme early versus late start of enzyme replacement therapy on plasma and Shire/Takeda; advisory board honoraria from Sanofi Genzyme. DGW: advisory globotriaosylsphingosine levels in men with classical Fabry disease. boards for Amicus, Avrobio, Freeline Therapeutics, 4D-­MT Technology, Idorsia and Mol Genet Metab 2017;121:157–61. Protalix; honoraria and travel expenses from Amicus, Protalix and Sanofi; and equity 14 Kozor R, Grieve SM, Tchan MC, et al. Cardiac involvement interest in Reata Pharmaceuticals. MLW: advisory boards for Amicus, Sanofi and in genotype-­positive Fabry disease patients assessed by Shire (now part of Takeda); honoraria from Amicus, Sanofi and Shire; research cardiovascular MR. Heart 2016;102:298–302. funding from Amicus, Idorisia, Protalix and Shire. JJ: honoraria from Sanofi; travel 15 Imbriaco M, Pellegrino T, Piscopo V, et al. Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients expenses from Amicus and Sanofi. MJR is an employee of Oxford PharmaGenesis with Anderson-­Fabry disease. Eur J Nucl Med Mol Imaging (Oxford, UK). SF: advisory boards for Amicus; consulting fees from Shire (now part 2017;44:2266–73. of Takeda); contracted research from Shire (now part of Takeda); honoraria from 16 Concolino D, Degennaro E, Parini R, et al. Delphi consensus on Amicus, Sanofi and Shire (now part of Takeda); speaker’s bureau for Amicus, Sanofi the current clinical and therapeutic knowledge on Anderson-­Fabry and Shire (now part of Takeda); travel expenses from Amicus, Sanofi and Shire (now disease. Eur J Intern Med 2014;25:751–6. part of Takeda). 17 Smid BE, van der Tol L, Cecchi F, et al. Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left Patient and public involvement Patients and/or the public were involved in the ventricular hypertrophy and genetic variants of unknown significance. design, or conduct, or reporting, or dissemination plans of this research. Refer to Int J Cardiol 2014;177:400–8. the Methods section for further details. 18 van der Tol L, Svarstad E, Ortiz A, et al. Chronic kidney disease and an uncertain diagnosis of Fabry disease: approach to a correct Patient consent for publication Not required. diagnosis. Mol Genet Metab 2015;114:242–7. Ethics approval No patient-­level data were used in this study and no ethical 19 Hsu CC, Sandford BA. The Delphi technique: making sense of approval was sought. consensus. Pract Assess Res Eval 2007;12:1–8. 20 Bousquet J, Winchester C, Papi A, et al. Inhaled corticosteroid/ Provenance and peer review Not commissioned; externally peer reviewed. long-­acting β₂-agonist combination therapy for asthma: attitudes of specialists in Europe. Int Arch Allergy Immunol 2012;157:303–10. Data availability statement No data are available. All key data for this study are 21 Mehta A, Kuter DJ, Salek SS, et al. Presenting signs and patient included in this article or uploaded as online supplementary information. co-­variables in Gaucher disease: outcome of the Gaucher earlier Open access This is an open access article distributed in accordance with the diagnosis consensus (GED-­C) Delphi initiative. Intern Med J Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which 2019;49:578–91. 22 Tøndel C, Bostad L, Hirth A, et al. Renal biopsy findings in children permits others to distribute, remix, adapt, build upon this work non-­commercially, and adolescents with Fabry disease and minimal albuminuria. Am J and license their derivative works on different terms, provided the original work is Kidney Dis 2008;51:767–76. properly cited, appropriate credit is given, any changes made indicated, and the use 23 Ramaswami U, Bichet DG, Clarke LA, et al. Low-­dose agalsidase is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. beta treatment in male pediatric patients with Fabry disease: a 5-­year randomized controlled trial. Mol Genet Metab 2019;127:86–94. ORCID iDs 24 Weidemann F, Beer M, Kralewski M, et al. Early detection of Andrea Frustaci http://​orcid.​org/​0000-​0002-​5748-​0725 organ involvement in Fabry disease by biomarker assessment in Mark J Rolfe http://​orcid.​org/​0000-​0002-​9248-​1563 conjunction with LGE cardiac MRI: results from the SOPHIA study. Mol Genet Metab 2019;126:169–82. 25 Goker-­Alpan O, Longo N, McDonald M, et al. An open-­label clinical trial of agalsidase alfa enzyme replacement therapy in children with Fabry disease who are naïve to enzyme replacement therapy. Drug REFERENCES Des Devel Ther 2016;10:1771–81. 1 Biegstraaten M, Arngrímsson R, Barbey F, et al. Recommendations 26 Nowak A, Mechtler TP, Desnick RJ, et al. Plasma LysoGb3: a for initiation and cessation of enzyme replacement therapy in useful biomarker for the diagnosis and treatment of Fabry disease patients with Fabry disease: the European Fabry working group heterozygotes. Mol Genet Metab 2017;120:57–61. consensus document. Orphanet J Rare Dis 2015;10:36. 27 Maruyama H, Miyata K, Mikame M, et al. Effectiveness of plasma 2 Rombach SM, Hollak CEM, Linthorst GE, et al. Cost-­effectiveness of lyso-­Gb3 as a biomarker for selecting high-­risk patients with Fabry enzyme replacement therapy for fabry disease. Orphanet J Rare Dis disease from multispecialty clinics for genetic analysis. Genet Med 2013;8:29. 2019;21:44–52. 12 Hughes DA, et al. BMJ Open 2020;10:e035182. doi:10.1136/bmjopen-2019-035182