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The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual “window of treatment success” in RA patients

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Bianka Marklein, Madeleine Jenning, Zoltán Konthur, Thomas Häupl, Franziska Welzel, Ute Nonhoff, Sylvia Krobitsch, Debbie M. Mulder, Marije I. Koenders, Vijay Joshua, Andrew P. Cope, Mark J. Shlomchik, Hans Joachim Anders, Gerd R. Burmester, Aase Hensvold, Anca I. Catrina, Johan Rönnelid, Günter Steiner, Karl Skriner

Original languageEnglish
Article number239
JournalArthritis Research and Therapy
Issue number1
PublishedDec 2021

Bibliographical note

Funding Information: We thank Prof. Gary Brewer (Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA) who provided the AUF1p45 clone, Prof. Edward K.L. Chan (Department of Oral Biology, University of Florida, Gainesville, USA) for providing ?-RCK/p54 antibody and Dr. Stefan B?nziger (Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, Zurich, Switzerland) for providing mice sera from C57BL/6 (-/+ R848). Thanks to Prof. Gerhard Kr?nke from Erlangen, who provided additional sera of risk-RA. We wish to thank EIRA study participants and the EIRA study group for their contributions, Professor Lars Klareskog for establishing the EIRA study and for support and scientific input, and Sarah Ohrendorf for comments reading the manuscript. Funding Information: The work was supported by grants from the project ArthroMark (grant number 01EC1401A) and the project ProgRATE (KMU-innovativ-8) (grant number 0315941C) of the Federal Ministry for Education and Research (BMBF) and the IMI EU funded project BTCure (grant number 115142-2), additional KMU-innovativ: tIVDiRA FKZ 13GW0194CA with the project partner: Charité and the RTCure project. RTCure (Rheuma Tolerance for Cure) is a large, pan-European collaborative initiative funded by the Innovative Medicines Initiative (IMI). IMI is the world’s biggest public-private partnership (PPP) in the life sciences. It is a partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA). The RTCure project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777357. Open Access funding enabled and organized by Projekt DEAL. Publisher Copyright: © 2021, The Author(s).

King's Authors


Background: There is a need for biomarker to identify patients “at risk” for rheumatoid arthritis (risk-RA) and to better predict the therapeutic response and in this study we tested the hypothesis that novel native and citrullinated heterogeneous nuclear ribonucleoprotein (hnRNP)-DL autoantibodies could be possible biomarkers. Methods: Using protein macroarray and ELISA, epitope recognition against hnRNP-DL was analysed in sera from different developed RA disease and diagnosed SLE patients. Toll-like receptor (TLR) 7/9 and myeloid differentiation primary response gene 88 (MyD88)-dependency were studied in sera from murine disease models. HnRNP-DL expression in cultivated cells and synovial tissue was analysed by indirect immunofluorescence, immunoblot and immunohistochemistry. Results: HnRNP-DL was highly expressed in stress granules, citrullinated in the rheumatoid joint and targeted by autoantibodies either as native or citrullinated proteins in patient subsets with different developed RA disease. Structural citrullination dependent epitopes (SCEs) of hnRNP-DL were detected in 58% of the SLE patients although 98% of these sera were α-CCP-2-negative. To obtain a specific citrullinated signal value, we subtracted the native antibody value from the citrullinated signal. The citrullinated/native index of autoantibodies against hnRNP-DL (CNDL-Index) was identified as a new value for an “individual window of treatment success” in early RA and for the detection of RF IgM/α-CCP-2 seronegative RA patients (24–46%). Negative CNDL-index was found in SLE patients, risk-RA and early RA cohorts such as EIRA where the majority of these patients are DAS28-responders to methotrexate (MTX) treatment (87%). High positive CNDL-values were associated with more severe RA, shared epitope and parenchymal changes in the lung. Specifically, native α-hnRNP-DL is TLR7/9-dependent, associated with pain and ROC analysis revealed an association to initial MTX or etanercept treatment response, especially in seronegative RA patients. Conclusion: CNDL-index defines people at risk to develop RA and the “window of treatment success” thereby closing the sensitivity gap in RA.

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