Breaking down the fences among registries on Autoinflammatory diseases: the E-Merge project

doi:10.21203/rs.3.rs-2483165/v1

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Breaking down the fences among registries on Autoinflammatory diseases: the E-Merge project

https://doi.org/10.21203/rs.3.rs-2483165/v1

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published 17 Jul, 2023

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Background. Between the various number of different AIDs, the absolute majority remains to be rare, with a single representative among big populations. Project, endorsed by PRES and supported by the EMERGE fellowship program, performed in line with the Metadata registry for the ERN RITA (MeRITA), had an objective to perform data harmonization attempt of the most relevant research questions regarding clinical features, diagnostic strategy, and optimal management of the autoinflammatory diseases.

Results. Analysis of 3 large European registries: Eurofever, JIR-cohort, and AID-Net with total coverage of 7825 patients from 278 participating centers all over the world was performed in the context of the epidemiological and clinical data merging. Information summarized in the registries covers not only pediatric patients, but as well adults, with newly diagnosed AID. General aspects of the existing epidemiological data were discussed in the context of patient distribution around the world, potential diagnostic delay, access to genetic testing, and availability of the treatment.

Conclusions. Overall work results indicate great potential for upcoming collaborative work using existing data in cohorts, which will definitely benefit the quality of medical care performed for patients with autoinflammatory diseases.

autoinflammatory diseases

disease registry

Eurofever

JIR-cohort

AID-Net.

Systemic autoinflammatory diseases (SAIDs) are a cluster of monogenic and polygenic/acquired inflammatory diseases associated with dysregulations in the innate immune system [1]. The first international series of patients affected with genetically determined conditions Familial Mediterranean Fever (FMF), TNF receptor 1-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD) have been described from 1999 onwards [2–3].

The first formal international registry for an autoinflammatory disease was settled in the Netherlands to collect clinical and laboratory data on Hyper-IgD syndrome, transformed into HIDSnet. Information from this registry allowed summarizing the existing clinical knowledge, defining treatment algorithms and providing data on the follow-up of the patients. Similarly, an international European consortium (EUROTRAPS) was developed to collect data from 6 different countries (Austria, France, Germany, Israel, Italy, United Kingdom), with the aims to gain insights about TRAPS [4–5]. In 2008 Hofer established a web-based multicentric registry for PFAPA, as an international collaboration in the context of the working party "periodic fevers" of PRES [6]. Data from the above registries provided pivotal information on these newly discovered conditions. In 2009 Ben-Chetrit and Touitou launched an international cohort of FMF patients aimed to define the epidemiological, genetic and clinical characteristics of FMF [7].

The extraordinary increase of the number of SAID in the last 20 years, thanks to the novel achievements in medicine and especially genetics, highlighted the limits of carrying unique registries for each condition, prompting the need of establishing common registries able to enrol patients with different diseases and flexible enough to include the newly identified conditions [8–9].

The Eurofever registry, a multi-national clinical registry hosted by the Pediatric Rheumatology International Trials Organization (PRINTO; www.printo.it) was held in the context of the Pediatric Rheumatology European Society (PRES) since 2009 [10]. At the same time, a German national database for autoinflammatory diseases, the AID-NET, was set up [11]. This registry collected information and samples of German patients with SAID for 10 subsequent years, until 2018. In 2013, the JIR Cohort, a multicenter prospective data repository for patients with systemic inflammatory or rheumatological disease, was created in the context of francophone countries, and subsequently extended towards other countries. A specific module dedicated to AID was developed in 2016, and patients from the main centers of expertise for autoinflammatory diseases in France and Switzerland have been enrolled.

Although each register has its own rationale, it appears nevertheless - due to the extreme rarity of these conditions that merging of data collected would be useful in order to obtain a more robust body of evidence on these conditions.

The aim of this E-Merge project was to test the possibility for a group analysis of data collected among different registries analyzing the strengths and the limitations of this approach.

The three registries (Eurofever, JIRcohort and AID-net) collect information on SAID patients in Europe and in extra-European countries. The list of variables subject to the evaluation of the present study were discussed in a consensus meeting held in Chateau d’Oex (Switzerland) in October 2021 (supplementary table 1).

Basic set of the epidemiological data was extracted anonymously by each coordinator, provided and analysed as aggregated data (e.g. no individual patient’s data provided).

As well, each registry representative provided information about cohort design, duration and procedure of patients follow-up, chapters about main epidemiological, clinical and laboratory information, data collection methods, process of IT-support, etc. This study as well included the review of published articles with studies based on registry data. Evaluation of the extracted information was descriptive, more than comparative.

IBM SPSS (SPSS Inc. Chicago, IL, 29.0) and excel were used for descriptive statistics including frequencies for categorical variables; median (first and third quartiles) for numerical variables.

Data analysis was conducted by YV during a 6-months PReS EMERGE fellowship, with attendance at CHUV Lausanne (Switzerland), IRCCS Istituto Giannina Gaslini in Genoa, and UKM in Muenster (Germany), each for 2 months respectively.

Origin and structure of the three registries

Eurofever

The Eurofever project was promoted in 2008 by the SAID working group of the Paediatric Rheumatology European Society (PRES) and supported by the Executive Agency for Health and Consumers (EAHC, project 2007332). The electronic data capturing (EDC) system of the Registry has been developed by PRINTO in November 2009. All centres belonging to the PRINTO network dealing with AID were offered the possibility to participate to the registry. In addition, adult centres involved in the management of SAID were also invited to participate.

The original structure of the registry consisted of 2 parts – demographic information and clinical manifestations. In 2015 a protocol amendment updated the registry with the new AID, and with the elaboration of a longitudinal observational part.

The quality control applied to the registry consists of a routinely check of the completeness and coherence of the data by the PRINTO staff; if any relevant query is raised during the check, a question is addressed to the Investigator to confirm or modify the data. Collection of the information has longitudinal prospective design, with regular onsite supervision of the PRINTO technical support. Registry continues its active recruitment activity with collection of the demography and clinical information on AIDs.

AID-Net

In 2009, the research initiative AID-Net (Network for Inflammatory Diseases), funded by the German Federal Ministry of Education and Research (BMBF project 01GM08104) was established. The network was structured into five basic research and three clinical research projects located at 12 institutions all over Germany. The main unit of the collaborative clinical research core of AID-Net was the patient registry.

Recruitment of patients with AID was prompted via this online registry, additionally patient material was collected and stored in a central biomaterial banks for DNA and serum. Data of the registry and the biobanks are connected in the online user interface. The patients’ biomaterial was used for the identification of genetic or serological markers of AID.

All members of the GKJR (German Society for Pediatric Rheumatology) were invited to participate in the project. In addition, immunological and molecular genetics laboratories had their own access to the online system for documentation of sample management.The online registry was operating by EDC with easy handling. All data were entered via remote data entry software ProMISe (Project Manager Internet Server) version 2.0, which had been developed by R Brand. Technical and operating support of the registry was provided by Sabrina Fühner and Elke Lainka. Data check and validation were provided on demand within particular scientific projects.

JIR cohort

The JIR cohort is an initiative of Belgium, French and Swiss pediatric rheumatologists and was endorsed by the scientific societies “SOFREMIP” (French speaking pediatric rheumatology society) and “PRS” (Pediatric Rheumatology Switzerland). The registry launched in 2013, was designed for patients with rheumatic diseases with childhood-onset. The primary goal was to improve patients’ care through the streamlining and evaluation of the outcome of pediatric rheumatic diseases. The initial financial support for the creation of the JIR platform was the “Aquira Award” in 2013. The first 24 participating centers were recruited through the SOFREMIP and PRS networks during the period of 2013–2016. From 2016 onwards, thanks to the implementation of a bilingual French-English interface, non-French speaking centres could also be recruited to participate in the registry.

From the onset, the registry is organized through 3 managing committees – steering, scientific and executive with members representative from the participating countries. The registry is hosted by the Foundation RES whose goals are to support research and training in pediatric rheumatology.

Registry data are collected by the investigating physician or clinical research technician in a prospective manner, and in a few centres the register serves as a medical record. The registry is composed of a common core for all diseases and specific modules collecting disease-specific data (autoinflammatory diseases, systemic onset JIA, JIA, uveitis, lupus). All the data before 2013 was collected retrospectively, after 2013 the register functions as a longitudinal observational cohort.

The registry works on “OCQMS” – a software developed by Swiss IT company Seantis Gmbh, a software already successfully used by the Swiss adult rheumatology registry (SCQM). Technical support is provided by Seantis Gmbh. Data cross-checking is performed when the data is exported for scientific purpose and is usually performed either by the clinical researcher performing the project, or by the physician requesting the data, dependent on particular situation.

All participating centres to the 3 named registry received approval by the related ethics committee and consent/assent have been obtained by patients and their families.

Demographic data

In total, all 3 registries cover 7825 patients with different AID from 278 participating centers all over the world (Fig. 1).

AID-Net is a national registry involving 36 main pediatric rheumatology centers in Germany. JIR and Eurofever are multi-national cohorts, covering about 40 countries in total. Data collection in AID-Net was completed in 2009, but JIR and Eurofever continue active recruitment and follow-up children previously included. Information summarized in the registries covers not only pediatric patients, but as well adults, with newly diagnosed AID and different proportion of the last (table 1).

The most commonly met AID in the registries are FMF, PFAPA, SURF (Undefined Recurrent Fever), CRMO, SoJIA, CAPS, TRAPS and MKD, which demonstrates a general trend in the population. At the same time, other exclusively rare AIDs such as PAPA, DADA2, Blau syndrome, HA20, PASH, DIRA, etc., were also presented in the Eurofever and JIR cohort, which are of particular interest for further evaluation of the newly described diseases (supplementary table 2).

The distribution of patients among registries was not uniform. Of the 125 centers participating in the JIR cohort, 23 centers from Switzerland and France enrolled more than 90% of all patients. Patients from Eurofever were most scattered with most patients coming from centers in Southern Europe (43%), and the remaining from Western Europe (26%), Northern Europe (8.7%) and the Middle East (9%) with a tendency toward lower incidence in Eastern Europe countries (suppl. Figure 1).

Evaluation of patient ethnicity revealed a predominance of Caucasians in all registries, with up to 20% of others not immediately definable (Table 2).

Epidemiologic characteristics of patients in the registries included diagnostic delay. In all registries, there was a significant delay between disease onset and diagnosis, with a much shorter trend in children (Fig. 2).

The highest rate of diagnostic delay was observed for the “classical” monogenic AID, as TRAPS, MKD and CAPS (table 3).

The finding of diagnostic delay in a given patient group is related to the availability of genetic testing in different time periods. Eurofever reported 5955 tests performed in 2605 (57.2%) patients. The following methods were reported for the structure of genetic testing: major exon testing 2763 (41.1%), NGS – 1463 (21.8%), complete gene screening 1092 (16.2%), whole-exome sequencing – 174 (2.4%) and in 463 (6.9%) the testing method was unknown. The JIR cohort reported 1687 genetic tests in 1172 patients (61.7%), with pathologic findings in 789 (46.7%) of the tests performed. Sanger sequencing was performed in the majority – 1003 (59.5%), NGS – 193 (11.4%) tests, and in 491 (29.1%) the method was unknown. In the AID network, 735 (53.4%) patients were tested, with most relevant exons in 406 (55.2%), complete gene screening in 88 (12%), whole exome sequencing in 23 (3.1%), and most relevant point mutation in 9 (1.2%). In 209 (28.4%) results, the testing method was unknown. The process of the clinical data merging among the registries can be more complicated than previously expected, depending on the depth of the information required to be analyzed (Table 4).

The availability of data related to the treatment was also investigated. Drugs included for treatment of AID were divided for main groups: steroids, synthetic DMARDS, biologic DMARDS and NSAIDs. In table 5, the distribution of the most frequent treatment is reported.

In this study, we provide the evidence on the actual possibility to merge demographic, genetic, and clinical data from different registries on rare conditions taking as an example three “historical” registries in the context of autoinflammatory diseases. The study explores the degree of homogeneity among the three registries and the possibility to retrieve scientifically relevant information from their demographic part.

Many critically important questions arise around clinical features, diagnostic strategy and optimal management of the AID. Due to low incidence of the diseases no single registry will be able to answer all these questions and they must follow defined purpose that reflects the process of data collection and items being collected.

We were able to show in this study that registers for auto-inflammatory diseases, developed independently in specific contexts and countries, nevertheless present an important homogeneity in the variables recorded: all of them include main epidemiological data (with a focus on the date of diagnosis, age, gender, origin), similar clinical part, involving manifestations from the main systems and organs, part of the laboratory investigations, genetic testing availability, and treatment. The possibility of data merging is performed at the example of ethnicity characteristic (tabl. 2) and demonstrates, that type of data collection may significantly influence resulting outcome.

At the cost of a reclassification of some data, we have shown that merging data from different registries is possible and provides cohorts with many patients, even for exceptional diseases (suppl. table 2). The main and global problem of the AID is their rarity, which makes patient enrolment and data collection complicated, especially from the point of the treatment strategy evaluation, when medications are new or to perform cohort studies when information should be merged from couple of resources. Two of the three registries continue active recruitment, at the same time availability of the biobank of AID-Net allows them to be counted active as well. But with the majority of the centers in Western and Southern Europe, the Eastern part of Europe is less involved, which shows the potential of further cooperation, underestimate problem with diagnosing AID in the region, or low activity of the specialized centers, so these should be further discussed. The number of the important geographic areas from North America and Asia are as well less involved in any of the networks, but their participation potentially may significantly increase the number of the recruited patients which will allow them conducting of more global studies for AID.

Challenges:

Identifying patients that have been entered into different registries is potentially noticeable according to the distribution of the centers (Fig. 1). Our study was not aimed to detect possible multiple entries of the same patient into different registries. However, this possibility should mandatory in any process of merging data coming from different registries This issue can be addressed with mechanisms similar to those used by the recent ERN RITA project, named MERITA automatic system that allows to reduce and exclude duplicated data should be used for all studies to provide further more accurate collaborative work. These questions should be addressed to IT support or discussed at the site level, before collaborative studies, because the presence of encrypted information made not possible a manual check.
Very detailed analyses remain difficult. Indeed, the granularity of the data is not identical. It’s possible to follow the simplest questions regarding particular clinical signs of the disease or describe the presence of specific tests. Combining data from different cohorts definitely increases the statistical power of the results, but must be done carefully, cause usually similar points of view don`t provide similar result outcomes. Different methods of outcome ascertainment (collection of clinical information, symptoms details, results of investigations, treatment) may cause a significant difference in results even if the primary working model was similar. Standardization or unification of the clinical data on AID will allow overcoming the problems of data merging in future
Longitudinal collection of the information should provide correct outcomes over time, identify clinical changes or predict short and long-term outcomes and evaluate treatment effectiveness and safety. Collection of the data set at the baseline is helpful for epidemiological or general overviewing studies. But further investigation of the disease outcomes and evolution of the diagnoses over time is possible just in case of controlled regular follow-up monitoring.
The possibility to express the results in tables as aggregated data from each registry (as shown in the results) surely overcome many limitations concerning the informed consent of single patients. However, this approach has the relevant limitation to reduce the possibility of more sophisticated statistical analyses. This project as well didn`t consider into account differences in health care systems, clinical expertise of AID. Further collaborative studies can be extremely useful as far will be able to recognize the difference and showing potential pitfalls on the geographical and economic levels, to improve quality of the medical care in the future.

This study conducted an overview of 3 historical AID registries in Europe. Many of the challenges regarding data collection and its comparison had been analyzed. New approaches to optimize data collection, taking into account possibilities of genetic testing, treatment options, with avoiding data doubling will be crucial to set new possibilities in AID studies. But overall work results indicate great potential for upcoming collaborative work, using existing data in cohorts, that will benefit in the quality of medical care performed for patients with AID.

PRES Pediataric Rheumatology European Society

ERN RITA European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases

FMF Familial Mediterranean fever

MKD Mevalonate kinase deficiency

PFAPA Periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome

SAID Systemic autoinflammatory disease

TRAPS Tumor necrosis factor receptoreassociated periodic syndrome

CAPS Cryopyrin-associated periodic syndrome ¼ NLRP3-associated autoinflammatory disease (NLRP3-AID)

SoJIA Systemic onset juvenile idiopathic arthritis

SURF Syndrome of undifferentiated recurrent fever

CRMO Chronic recurrent multifocal osteomyelitis

DADA2 ADA2 deficiency

DIRA Deficiency of the IL-1 receptor antagonist

DITRA Deficiency of the IL-36 receptor antagonist

HA20 A20 haploinsufficiency

Acknowledgements. The authors would like to thank Francois Hofer from JIR for technical assistance and support. Elisa Patrone and Alessio Giacobbe from PRINTO for their enthusiastic secretarial assistance and IT support. Sabrina Fuhner from UKM for assistance with data exporting and research assistance.

Authors’ contributions and information: YV: collection, analysis, interpretation of data; wrote manuscript draft. VH, MG, DF, HW, MH: checked and revised manuscript. RC, KT, EL, NR, EM: checked and approved the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding. This project is supported by PRES/Autoinflammation working party.

Funding for the project was additionally provided for Investigator initiated Research by Novartis Pharma GmbH.

Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate. Patients were not involved in the research process of this study. Ethics approval was obtained from the centers before the participation in registries.

Consent for publication The article is original, has not already been published in a journal, and is not currently under consideration by another journal. The authors agree to the terms of the BioMed Central Copyright and License Agreement and Open Data policy. All authors of the manuscript have read and agreed to its content and are accountable for all aspects of the accuracy and integrity of the manuscript in accordance with ICMJE criteria.

Competing interests The authors declare that they have no competing interests.

Grateau G, Hentgen V, Stojanovic KS, et al. How should we approach classification of autoinflammatory diseases? Nat Rev Rheumatol. 2013;9(10):624–9.
Wong M. What has happened in the last 50 years in immunology. J Paediatr Child Health. 2015;51(2):135–9.
Ben-Chetrit E, Gattorno M, Gul A, et al. Consensus proposal for taxonomy and definition of the autoinflammatory diseases (AIDs): a Delphi study. Ann Rheum Disease. 2018;77:1558–65.
JC, van der Hilst EJ, Bodar KS, Barron et al. Long-Term Follow-Up, Clinical Features, and Quality of Life in a Series of 103 Patients With Hyperimmunoglobulinemia D Syndrome Medicine (Baltimore). 2008 Nov;87(6):301–10
Lachmann HJ, Papa R, Gerhold K, Obici L, et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases fromthe Eurofever/EUROTRAPS international registry. Ann Rheum Dis. 2014 Dec;73(12):2160–7.
Hofer MF, Pillet P, Berg S et al. International PFAPA syndrome registry: cohort of 214 patients from 15th Paediatric Rheumatology European Society (PreS) Congress London, UK. 14–17 September 2008
Chetrit E, Ben, Touitout I. Familial Mediterranean Fever in the World Arthritis & Rheumatism (Arthritis Care & Research) Vol. 61, No. 10, October 15, 2009, pp 1447–14538.
Tucker LB, Niemietz I, Mangat P, et al. Children with systemic autoinflammatory diseases have multiple, mixed ethnicities that reflect regional ethnic diversity. Clin Exp Rheumatol. 2021;39(Suppl 132):124–S128.
Gattorno EBen-ChetritM, Gul A, et al. Consensus proposal for taxonomy and definition of the autoinflammatory diseases (AIDs): a Delphi study. Ann Rheum Dis. 2018;77(11):1558–65.
Ozen S, Frenkel J, Ruperto N, Gattorno M. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445–52.
Lainka E, Bielak M, Hilger V, Basu O, Neudorf U, Wittkowski H, Holzinger D, Roth J, Niehues T. Dirk Foell. Translational research network and patient registry for autoinflammatory diseases. Rheumatology (Oxford). Jan; 2011;50(1):237–42.
Natasa, Toplak et al. 1 Joost Frenkel,2 Seza OzenAn international registry on autoinflammatory diseases: the Eurofever experience. Ann Rheum Dis. 2012;71(7):1177-82.
Ruperto N, Martini A. Networking in paediatrics: the example of the Paediatric Rheumatology International Trials Organisation (PRINTO). Arch Dis Child. 2011;96:596–601.
Lainka E, Bielak M, Hilger V, et al. Translational research network and patient registry for auto-infl ammatory diseases. Rheumatology (Oxford). 2011;50:237–42.
Dingulu G, Hentgen V, et al. Validation of the new classification criteria for hereditary recurrent fever in an independent cohort: experience from the JIR Cohort Database. Rheumatology. 2020;59(10):2947–52.
Akre C, Suris J-C, Hofer M. Building a transitional care checklist in rheumatology: A Delphi-like survey. Joint Bone Spine. 2018;85(4):435–40.
Heon-Klin V. European reference networks for rare diseases: what is the conceptual framework? Orphanet J Rare Dis. 2017;12(1):137.
Beukelman T, Anink J, Berntson L, et al. A survey of national and multinational registries and cohort studies in juvenile idiopathic arthritis: challenges and opportunities. Pediatr Reumatology. 2017;15:3118.
Dolezalova P, Anton J, Avcin T, et al. The European network for care of children with paediatric rheumatic diseases: care across borders. Rheumatology (Oxford). 2019;21:1188–95.
Papa R, Cant A, Klein C, Little M, Wulffraat N, Gattorno M, Ruperto N. Towards European harmonisation of healthcare for patients with rare immune disorders: outcome from the ERN RITA registries survey.Orphanet Journal of Rare Diseases 2020, Vol.15. https://doi.org/10.1186/s13023-020-1308-x

Tables 1 to 5 are available in the Supplementary Files section.

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You are reading this latest preprint version

Breaking down the fences among registries on Autoinflammatory diseases: the E-Merge project

Status:

Journal Publication

Version 1

Abstract

Figures

Background

Materials And Methods

Origin and structure of the three registries

Eurofever

AID-Net

JIR cohort

Results

Demographic data

Discussion

Conclusions

Abbreviations

Declarations

References

Tables

Supplementary Files

Status:

Journal Publication

Version 1