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Novel autoantibodies identified in ACPA-negative rheumatoid arthritis
  1. Ketian Li1,2,
  2. Wenxiu Mo3,
  3. Lijun Wu4,
  4. Xunyao Wu1,2,
  5. Cainan Luo4,
  6. Xinyue Xiao1,
  7. Xinmiao Jia1,
  8. Huaxia Yang1,2,
  9. Yunyun Fei1,
  10. Hua Chen1,2,
  11. Fengchun Zhang1,
  12. Yongzhe Li5,
  13. Lidan Zhao1,2,
  14. Xuan Zhang2,6
  1. 1 Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
  2. 2 State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Dongcheng-qu, Beijing, China
  3. 3 Department of Rheumatology and Immunology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
  4. 4 Department of Rheumatology and Immunology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
  5. 5 Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
  6. 6 Clinical Immunology Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
  1. Correspondence to Professor Xuan Zhang, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Dongcheng-qu, Beijing, China; zxpumch2003{at}sina.com; Professor Lidan Zhao, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China; zhaolidan{at}hotmail.com; Professor Yongzhe Li, Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China; yongzhelipumch{at}126.com

Abstract

Objectives Lack of effective biomarkers in anti-citrullinated protein antibody (ACPA)-negative rheumatoid arthritis (RA) impedes early diagnosis and treatment. This study aimed to identify novel autoantibodies in RA and verify their diagnostic values in ACPA-negative RA based on protein microarray technology.

Methods A total of 1011 sera from 559 RA (276 ACPA-positive and 283 ACPA-negative), 239 disease controls (DCs) and 213 healthy controls (HCs) were collected and sampled on two sequential microarrays and ELISA and western blot (WB) detection, for novel autoantibodies discovery, validation and verification, respectively. The high-density protein microarray printed with a broad spectrum of recombinant human proteins was first employed to screen candidate autoantibodies, then focused microarrays composed of candidate autoantigens were used for validation, followed by ELISA and WB to verify the presence of the most promising candidates in ACPA-negative RA.

Results Nine novel autoantibodies were identified by two sequential microarrays with positivity 17.93%–27.59% and specificities >90% in ACPA-negative RA. Among these, anti-PTX3 and anti-DUSP11 autoantibodies presented with the highest sensitivity and were consistently verified by ELISA and WB. Pooling samples of all cohorts, the positivities of anti-PTX3 and anti-DUSP11 in ACPA-negative RA were 27.56% and 31.80%, respectively, similar to those in ACPA-positive RA, and significantly higher than in HCs (4.69% and 2.35%) and DCs (10.04% and 8.49%) (p<0.0001). Combination of anti-PTX3 with anti-DUSP11 significantly increased the diagnostic sensitivity (38.00%) with specificity of 88.72%, regardless of ACPA status.

Conclusion Anti-PTX3 and anti-DUSP11 autoantibodies are newly identified biomarkers for diagnosis of ACPA-negative RA.

  • arthritis
  • rheumatoid
  • autoantibodies
  • anti-citrullinated protein antibodies

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Data are available from the corresponding author (email: zxpumch2003@sina.com ORCID: https://orcid.org/0000-0001-8775-1699) upon reasonable request.

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Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Data are available from the corresponding author (email: zxpumch2003@sina.com ORCID: https://orcid.org/0000-0001-8775-1699) upon reasonable request.

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Footnotes

  • Handling editor Josef S Smolen

  • KL, WM and LW contributed equally.

  • Contributors XZ, Y-zL, L-dZ, K-tL, W-xM and L-jW conceived the project and designed experiments. W-xM, K-tL and W-xY carried out experiments with help from X-yX; K-tL, W-xM and X-mJ analysed experimental results. L-jW, C-nL, H-xY, Y-yF, HC and F-cZ provided the clinical samples. K-tL, L-dZ, Y-zL and XZ wrote the manuscript. XZ supervised work and acquired funding.

  • Funding This study was supported by grants from the National Natural Science Foundation of China (81788101, 81630044, 81771763, 82071840), Chinese Academy of Medical Science Innovation Fund for Medical Sciences (CIFMS2016-12M-1-003, 2017-12M-1-008, 2017-12M-3-011, 2016-12M-1-008), Beijing Capital Health Development Fund (2020-2-4019), China Postdoctoral Science Foundation Grant (2018M630105), and the Construction Project of National Traditional Chinese Medicine Clinical Research Base of SATCM, and Clinical Cooperative Project of Chinese and Western Medicine for Major and Knotty Diseases of SATCM.

  • Competing interests Two patents application “ACPA-negative RA diagnostic marker and application thereof” (PCT/CN2017/111043, PCT/CN2017/111044) have been filed by Peking Union Medical College Hospital.

  • 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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