Molecular reclassification to find clinically useful biomarkers for systemic autoimmune diseases


Systemic autoimmune diseases (SADs) such as rheumatoid arthritis and lupus affect 1-3% of the population, and while treatments exist, these are costly and have a number of serious side effects. There is growing evidence that many of these conditions may be incorrectly classified. The PRECISESADS project studied over 2 000 people with various autoimmune diseases, gathering data on the molecular causes of their disease as well as their clinical symptoms. Using this information, they will identified potential new classifications of these diseases, something that could allow doctors to offer patients more personalised treatments at an earlier stage of their disease.

Systemic autoimmune diseases (SADs) are a group of chronic inflammatory conditions where the immune system malfunctions and attacks the body’s tissues. With autoimmune aetiology and many common clinical features, the diseases are difficult to diagnose because of clinical overlap, and hard to treat, despite the significant improvement of available drugs. SADs are one of the leading causes of disability and can occasionally be fatal. With no effective cure in sight, there is a clear unmet need to get the right treatment to the right patient, and to better understand those conditions, so that in future, the right medicine can be produced.

PRECISESADS explored the idea that the conventional disease definition is an outdated concept in the current medical environment. The aim was to define clusters of individuals who share similar molecular pathways for their disease and therefore could be treated in a targeted and personalised way. By evaluating the molecular and clinical data, the project aspired to deliver new biomarkers for use in more targeted clinical trials, and ultimately, pave the way for new, tailored therapies for patients suffering from these life-long, debilitating diseases.

In-depth molecular study

With the hypothesis that the identification of specific molecular signatures in patients with SADs will enable clinicians to tailor therapies according to the specific aetiological pathways at the root of the pathology in each individual case, the focus was on the SADs that have been little studied, but that share pathogenic mechanisms. The researchers analysed over 2 000 patients living with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren’s syndrome (Sjs), rheumatoid arthritis (RA), primary antiphospholipid syndrome (PAPS) and mixed connective tissue disease (MCTD), gathering data on the molecular causes of their disease as well as their clinical symptoms and making comparisons with over 600 healthy controls.

By using the power of ‘OMICS’ (genomics, transcriptomics, epigenomics, metabolomics, proteomics), and bioinformatics to identify new classifications for SADs known to share common pathophysiological mechanisms, PRECISESADS scientists conducted an in-depth molecular study unprecedented in immunology research. Moreover, they addressed several questions relating to pathology within more defined ‘tissue’ entities, such as the kidneys or skin. In addition, cell-specific information was used to further help in the classification of the disease clusters.

New molecular classification

The idea that SADs may be usefully reclassified according to their molecular pathology led to the main result of the project, the discovery of a new molecular classification of SADs. Scientist realised that the SADs’ molecular patterns or ‘clusters’ do not fit the diagnoses based on traditional clinical criteria and that many different diseases as diagnosed by conventional clinical definitions are represented in each of the clusters. They found out that the patterns are stable, meaning that an individual with active disease or an ongoing pathogenic process maintains the same molecular pattern, i.e. each individual has one molecular pathway of disease. In addition, integrative analysis of patient OMICS data revealed that there are four clusters of patients, and each of them contains all studied diseases. The four molecular patient patterns (adaptive immune pattern, inflammatory pattern, interferon/innate immune pattern and those with no clear pattern), were compared with SADs patient blood biomarker profiles including autoantibodies, cytokines, chemokines, inflammatory marker and metabolites. This identified molecular pathways that may be common to SADs currently classified as different based on clinical phenotype.

Identification of clustered biomarker signatures that better describe a molecular classification of SADs than existing traditional definitions could empower physicians to precisely tailor therapy to individual patients. This novel taxonomy may also increase the likelihood of more successful clinical trials, through the pre-selection of participants most likely to respond.

Another important achievement for the PRECISESADS consortium was the discovery of new biomarkers at tissue level for scleroderma and lupus nephritis. Analysing the results of diseased tissue matching to the patients’ blood and urine samples, led to the identification of novel diagnostic and prognostic biomarkers. Moreover, in order to perform extensive OMICS approaches, researchers carried out multi-parameter flow cytometry analyses in 11 different laboratories across Europe, which required the precise tuning of all instruments. This effective multi-centre harmonisation enabled the formation of the cytometry database for the identification of specific molecular signatures in individuals with SADs.

PRECISESADS scientists also developed protocols that allow the harmonisation of sample collection and data quality controls that may be used for clinical studies and clinical trials, along with procedures and guidelines to help sites in conducting the trial and to ensure the overall quality of the study results.

Other achievements from the project include:

  • development of methods for the detection and prediction of lupus nephritis;
  • determination of an easy to use test to classify SADs patients by flow cytometry;
  • a calibration method for the harmonisation of flow cytometers across different instruments and locations;
  • comparative OMICS characterisation of several models of SLE was performed to determine similarities and differences between the models, and how these compare to the identified human clusters - this information will support the selection of the most appropriate animal models for drug discovery and development;
  • database and the sample collection, to be used in further research.

Next steps

PRECISESADS proved that taxonomies of SADs can be changed, and this will hopefully contribute in the long term to more precise treatments and hence improved patient care.

In addition, the consortium created a new resource that will include not only all publicly available data for autoimmune diseases but also the PRECISESADS data once the clusters are published into the Autoimmune Disease Explorer (ADEx). This will allow an in-depth exploration of the data and comparisons with other data sources, and together with the clinical molecular profiles, it will facilitate the selection of appropriate animal models for drug discovery and development. Effective collaboration between physicians, scientists and bioinformaticians from 21 academic and 5 industrial partners, and 2 SMEs, helped reinforce the multidisciplinary demands of the era of “big data” and has implications for future drug development and medicine in general.

Achievements & News

Identification of patient subgroups could pave way for personalised Sjögren’s syndrome treatments

There is currently no treatment for primary Sjögren’s syndrome (pSS), an autoimmune disease that can affect a range of organs and tissues. New findings from IMI’s PRECISESADS project could help to change that.###

In recent years, scientists have run clinical trials of a number of treatments for pSS, but none of these proved successful, and to date there is no approved treatment for pSS. One reason for the clinical trial failures could be the diversity of pSS patients; some treatments may work for certain sub-groups of patients – the challenge is to identify these subgroups and match them up with appropriate treatments.

Now, a new paper in Nature Communications suggests that there could be four sub-groups of pSS patients. The team arrived at this conclusion after drawing up detailed molecular profiles from blood samples from over 300 pSS patients and comparing these with profiles from 330 healthy volunteers. The team also offer suggestions as to which kinds of treatments could work best for the different subgroups, effectively paving the way for more personalised treatments for pSS.

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Proposed ‘clustering’ of patients offers hope for better understanding of autoimmune diseases

There is evidence that many autoimmune conditions (such as rheumatoid arthritis, lupus, and Sjögren's syndrome) may share molecular mechanisms. IMI’s PRECISESADS project carried out painstaking analysis of molecular and clinical data and were able to reclassify around 2 000 individuals affected by systemic autoimmune diseases (SADs) into four different clusters of molecular groupings.###

‘We were able to show that these different diseases can be joined together into groups,’ said project coordinator Marta E. Alarcón-Riquelme of the Centre for Genomics and Oncological Research in Granada, Spain. ‘There were four different groups of patients, formed by all the patients with the different autoimmune diseases. This was new.’ The four groups are inflammatory, undefined, lymphoid group and an interferon group. The interferon group was already known for lupus, and it was known that some patients with rheumatoid arthritis or scleroderma could also have the interferon signature. To go further and build on these new insights, more research is needed. ‘In another study we would need to look into whether by classifying the patients into in this way, we could actually find which treatment would be best for which patient,’ said Dr Alarcón-Riquelme.

By going beyond classical clinical signs and symptoms and grouping people by underlying drivers, the work of the team will help ensure better diagnosis and treatment for people with SADs in the future.

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Fast, effective treatment for autoimmune rheumatic diseases

Affecting around 2 % of the population, autoimmune rheumatic diseases can have severe symptoms, including painful and swollen joints, fever, rashes, fatigue and sensitivity to the sun, with patients needing regular check-ups. ###Diagnosis can take a number of years from the onset of symptoms – too long to prevent negative outcomes. Moreover, wide variations exist between patients in terms of severity, prognosis and response to treatment, which renders therapy a trial-and-error process.

Researchers in IMI’s PRECISESADS project are gathering data on the molecular causes of various autoimmune rheumatic diseases and different patients’ clinical symptoms in order to facilitate the delivery of precision medicine based on earlier and more accurate diagnosis.  ‘Blood samples from over 3 000 patients from across Europe with different autoimmune diseases have undergone in-depth analyses, unprecedented in the field of rheumatology research,’ explains project coordinator John Ioannou of UCB Biopharma in Belgium. ‘Data on genome, transcriptome, proteome, methylome and other biological parameters have been analysed with the identification of novel clusters of molecular signatures, which could form the basis for a brand new classification of these diseases and pave the way towards more tailored therapy.’

PRECISESADS hits 1000 mark on patient recruitment

IMI project PRECISESADS has now recruited over 1 000 people into its pan-European clinical study on systemic autoimmune diseases such as rheumatoid arthritis and lupus. The milestone means that the project is well on track to recruit a total of 2 500 people from 9 countries into the study.### In the project, patients with the diseases under study as well as healthy people are giving blood and urine samples which are analysed in detail. ‘This will allow us to gain a full molecular profile of the patients and (hopefully) allow us to cluster the patients into groups based on their molecular profile instead of their clinical symptoms,’ explains project coordinator Marta Alarcón Riquelme of GENYO in Spain. ‘This would then allow clinicians to tailor the therapies to the specific pathways to be targeted in a sort of personalised medicine.’ The project hopes to recruit all patients needed for the study by the middle of 2017.

IMI projects working on a new way of defining diseases

The work of IMI’s PRECISESADS and AETIONOMY projects on disease taxonomy is spotlighted in a new Nature Reviews Discovery comment piece.### Currently, most diseases are still defined largely on the basis of their symptoms, yet while two patients may share the same diagnosis, the underlying causes of their symptoms may be very different. This means that a treatment that works in one patient may prove ineffective in another. The AETIONOMY and PRECISESADS projects are pioneering a new approach to the classification of disease; for AETIONOMY, in the field of Alzheimer’s and Parkinson’s diseases, and for PRECISESADS, in the field of systemic autoimmune diseases (such as rheumatoid arthritis and lupus). Although the projects are tackling the problem in different ways, their overall goal is the same: to pave the way towards a new taxonomy of disease that is based on the underlying causes of disease. In the long term, this will help to diagnose patients more accurately and provide them with a treatment that works for them.

Join PRECISESADS for a conference on the genomics of complex diseases
IMI’s PRECISESADS will hold a conference on the genomics of conference diseases in Granada, Spain on 10-11 March 2016. PRECISESADS is working on a new classification of autoimmune diseases such as rheumatoid arthritis and lupus, and the study will pave the way for more personalised treatments. ### The conference will provide an overview of the genetic, epigenetic, regulatory and functional aspects of genomics studies as well as the new challenges posed by next generation sequencing and bioinformatics in the understanding of complex diseases, focused on systemic autoimmune diseases. The scientific program will include updates on genetic susceptibility of lupus and other autoimmune diseases, studies around immune cells and autoimmune disease and drug repositioning and other interesting topics. In addition, PhD students and post-docs are invited to submit abstracts for the event. Deadline for registration: 31 December 2015. 


  Show participants on map
EFPIA companies
  • Bayer Aktiengesellschaft, Leverkusen, Germany
  • Eli Lilly And Company LTD, Basingstoke, United Kingdom
  • Institut De Recherches Internationales Servier Iris, Suresnes, France
  • Sanofi-Aventis Recherche & Developpement, Chilly Mazarin, France
  • UCB Biopharma, Brussels, Belgium
Universities, research organisations, public bodies, non-profit groups
  • Agencia Estatal Consejo Superior De Investigaciones Cientificas, Madrid, Spain
  • Centro Hospitalar Universitario Do Porto Epe, Porto, Portugal
  • Charite - Universitaetsmedizin Berlin, Berlin, Germany
  • Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Barcelona, Spain
  • Fondazione Irccs Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy
  • Fundacio Institut D'Investigacio Biomedica De Bellvitge, Hospitalet De Llobregat, Spain
  • Fundacion Publica Andaluza Progreso Y Salud M.P., Seville , Spain
  • Karolinska Institutet, Stockholm, Sweden
  • Katholieke Universiteit Leuven, Leuven, Belgium
  • Klinikum Der Universitaet Zu Koeln, Cologne, Germany
  • Kypriako Idryma Erevnon Gia Ti Myiki Distrofia, Nicosia, Cyprus
  • Medizinische Hochschule Hannover, Hannover, Germany
  • Medizinische Universitaet Wien, Vienna, Austria
  • Servicio Andaluz De Salud, Sevilla, Spain
  • Servicio Cántabro de Salud, Santander, Spain
  • Szegedi Tudomanyegyetem, Szeged, Hungary
  • Universidad De Granada, Granada, Spain
  • Universita Degli Studi Di Milano, Milano, Italy
  • Universite Catholique De Louvain, Louvain-La-Neuve, Belgium
  • Universite De Bretagne Occidentale, Brest, France
  • Universite De Geneve, Genève 4, Switzerland
Small and medium-sized enterprises (SMEs)
  • Atrys Health, SA, Madrid, Spain
  • Quartz Bio S.A., Plan-les-Ouates, Switzerland
Third parties
  • Centre Hospitalier Regional Et Universitaire De Brest, Brest, France

NameEU funding in €
Agencia Estatal Consejo Superior De Investigaciones Cientificas846 180
Atrys Health, SA243 425
Centro Hospitalar Universitario Do Porto Epe153 324
Charite - Universitaetsmedizin Berlin378 985
Consorci Institut D'Investigacions Biomediques August Pi I Sunyer145 320
Deutsches Rheuma Forschungszentrumberlin (left the project)49 453
Fondazione Irccs Ca' Granda - Ospedale Maggiore Policlinico388 612
Fundacio Institut D'Investigacio Biomedica De Bellvitge1 026 782
Fundacion Publica Andaluza Progreso Y Salud M.P.1 826 852
Karolinska Institutet434 450
Katholieke Universiteit Leuven229 400
Klinikum Der Universitaet Zu Koeln129 800
Kypriako Idryma Erevnon Gia Ti Myiki Distrofia252 540
Medizinische Hochschule Hannover217 924
Medizinische Universitaet Wien45 520
Quartz Bio S.A.893 562
Servicio Andaluz De Salud556 740
Servicio Cántabro de Salud127 950
Szegedi Tudomanyegyetem67 350
Universidad De Granada480 780
Universita Degli Studi Di Milano254 040
Universite Catholique De Louvain341 995
Universite De Bretagne Occidentale534 715
Universite De Geneve270 140
Third parties
NameFunding in €
Centre Hospitalier Regional Et Universitaire De Brest103 484
Total Cost9 999 323