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Original research
Proximity extension assay-based discovery of biomarkers for disease activity in chronic inflammatory demyelinating polyneuropathy
  1. Luuk Wieske1,2,
  2. Milou R Michael1,
  3. Sjors G J G in 't Veld3,
  4. Allerdien Visser3,
  5. Ivo N van Schaik1,4,
  6. Filip Eftimov1,
  7. Charlotte E Teunissen3
  1. 1 Department of Neurology and Neurophysiology, Amsterdam Neuroscience, Amsterdam UMC Location AMC, Amsterdam, Noord-Holland, The Netherlands
  2. 2 Department of Clinical Neurophysiology, Sint Antonius Hospital, Nieuwegein, The Netherlands
  3. 3 Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC Location VUmc, Amsterdam, Noord-Holland, The Netherlands
  4. 4 Sanquin Bloedvoorziening, Amsterdam, Noord-Holland, The Netherlands
  1. Correspondence to Dr Luuk Wieske, Department of Neurology, Amsterdam UMC, location AMC, Amsterdam, Netherlands; l.wieske{at}amsterdamumc.nl

Abstract

Background Objective disease activity biomarkers are lacking in chronic inflammatory demyelinating polyneuropathy (CIDP), impacting treatment decisions in clinical care and outcomes in clinical trials. Using a proximity extension assay, we aimed to identify candidate serum protein biomarkers for disease activity in CIDP.

Method We collected clinical data and serum of 106 patients with CIDP. Patients starting induction treatment (n=53) and patients on maintenance treatment starting treatment withdrawal (n=40) were assessed at baseline and at 6 months (or at relapse). Patients in remission (n=13) were assessed once. Clinical disease activity was defined based on improvement or deterioration by the minimal clinically important difference on the inflammatory Rasch-built Overall Disability Scale in combination with either grip strength or the Medical Research Council sum score. Using a proximity extension assay (Olink Explore platform), 1472 protein levels were analysed in serum. Candidate proteins were selected based on fold change>0.5 or <−0.5 and p<0.05 between clinically active and inactive disease. Longitudinal changes of candidate proteins between baseline and follow-up were analysed.

Results We identified 48 candidate proteins that differed between clinically active and inactive disease on cross-sectional comparison. Five of these proteins (SUGT1, IRAK4, DCTN1, 5'-nucleotidase cytosolic IIIA (NT5C3A), glutaredoxin (GLRX)) also showed longitudinal changes consistent with disease activity changes. IRAK4 was also identified in a sensitivity analysis, using another definition for disease activity.

Conclusion Our results indicate that IRAK4 and possibly SUGT1, DCTN1, NT5C3A and GLRX are candidate biomarkers for monitoring clinical disease activity in CIDP.

  • NEUROPATHY
  • CLINICAL NEUROLOGY
  • NEUROBIOLOGY
  • NEUROIMMUNOLOGY

Data availability statement

Data are available upon reasonable request. Data will be made available upon reasonable request by a qualified researcher in accordance with privacy regulations.

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Data availability statement

Data are available upon reasonable request. Data will be made available upon reasonable request by a qualified researcher in accordance with privacy regulations.

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Footnotes

  • LW and MRM are joint first authors.

  • LW and MRM contributed equally.

  • Contributors LW and MRM contributed equally to this paper and conceptualised and designed the study, recruited patients, contributed data, carried out statistical analyses, interpreted the results and drafted and edited the manuscript. SGJGiV and AV were involved in conceptualising of and carrying out statistical analyses. SGJGiV, AV, INvS, FE and CET revised all versions critically for important intellectual content. All authors gave approval for the final version to be published. LW is responsible for the overall content as guarantor.

  • Funding This study was supported by an International Research Grant by the GBS|CIDP foundation.

  • Competing interests CET reports the following grants: Research of CET is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (IMI 2 Joint Undertaking (JU), grant No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance), Alzheimer Association, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands. CET is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). CET has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, PeopleBio, Roche, Siemens, Toyama, Vivoryon. She is editor in chief of Alzheimer Research and Therapy and serves on editorial boards of Medidact Neurologie/Springer, and Neurology: Neuroimmunology & Neuroinflammation. She had speaker contracts for Roche, Grifols, Novo Nordisk. FE reports grants from ZonMw (Dutch Governmental Agency) and Prinses Beatrix Spierfonds (Dutch Charity Organization) and grants from CSLBehring, Kedrion, Terumo BCT, Grifols and Takeda Pharmaceutical Company, outside the submitted work. Grants were paid to institution and are used for investigator-initiated randomized controlled trials and studies within INCbase, an international CIDP registry. In addition, he received consultancy fee from UCB Pharma, Grifols, Sanofi and Dianthus Therapeutics paid to institution, outside the submitted work. INS reports grants from Dutch Governmental grant (ZonMw/Rational Pharmacotherapy program), non-financial support from Sanquin Plasma Products B.V., and grants from CSL-Behring, all outside the submitted work on of competing interest. LW received research grants from Grifols and the GBS/CIDP Foundation for the study of disease activity biomarkers in CIDP. The remaining authors have nothing to disclose.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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