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Original research
Urine and serum S100A8/A9 and S100A12 associate with active lupus nephritis and may predict response to rituximab treatment
  1. Jennifer C Davies1,
  2. Angela Midgley1,
  3. Emil Carlsson1,
  4. Sean Donohue1,
  5. Ian N Bruce2,
  6. Michael W Beresford1,3 and
  7. Christian M Hedrich1,3
  1. 1 Department of Women’s and Children’s Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
  2. 2 Arc Epidemiology Unit, University of Manchester, Manchester, UK
  3. 3 Department of Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
  1. Correspondence to Christian Hedrich; christian.hedrich{at}liverpool.ac.uk

Abstract

Background Approximately 30% of patients with the systemic autoimmune/inflammatory disorder systemic lupus erythematosus (SLE) develop lupus nephritis (LN) that affects treatment and prognosis. Easily accessible biomarkers do not exist to reliably predict renal disease. The Maximizing SLE Therapeutic Potential by Application of Novel and Systemic Approaches and the Engineering Consortium aims to identify indicators of treatment responses in SLE. This study tested the applicability of calcium-binding S100 proteins in serum and urine as biomarkers for disease activity and response to treatment with rituximab (RTX) in LN.

Methods S100A8/A9 and S100A12 proteins were quantified in the serum and urine of 243 patients with SLE from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR) study and 48 controls matched for age using Meso Scale Discovery’s technology to determine whether they perform as biomarkers for active LN and/or may be used to predict response to treatment with RTX. Renal disease activity and response to treatment was based on BILAG-BR scores and changes in response to treatment.

Results Serum S100A12 (p<0.001), and serum and urine S100A8/A9 (p<0.001) levels are elevated in patients with SLE. While serum and urine S100 levels do not correlate with global disease activity (SLE Disease Activity Index), levels in urine and urine/serum ratios are elevated in patients with active LN. S100 proteins perform better as biomarkers for active LN involvement in patients with SLE who tested positive for anti-double-stranded DNA antibodies. Binary logistic regression and area under the curve analyses suggest the combination of serum S100A8/A9 and S100A12 can predict response to RTX treatment in LN after 6 months.

Conclusions Findings from this study show promise for clinical application of S100 proteins to predict active renal disease in SLE and response to treatment with RTX.

  • Arthritis
  • Juvenile
  • Arthritis
  • Psoriatic
  • Cytokines
  • Inflammation
  • Lupus Erythematosus
  • Systemic
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Footnotes

  • MWB and CH contributed equally.

  • Correction notice This article has been corrected since it was published online.

  • Contributors Clinical information and serum/urine samples from patients with SLE were provided by the following BILAG-BR centres and local clinical information systems: Dr Mohammed Akil, Royal Hallamshire Hospital, Sheffield; Prof Ian N Bruce, NIHR Manchester Musculoskeletal Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester; Dr Bhaskar Dasgupta, Southend University Hospital, Westcliff-on-Sea, Essex; Dr Shirish Dubey, University Hospital of Coventry and Warwickshire, UK; Dr Nicole Erb, Dudley Group of Hospitals NHS Foundation Trust, West Midlands; Dr Mary Gayed, Heart of England NHS Foundation Trust, Birmingham; Dr Patrick Gordon, King’s College Hospital, London; Dr Bridget Griffiths, Freeman Hospital, Newcastle upon Tyne; Dr Peter Hewins, Queen Elizabeth Hospital, Birmingham; Dr Michelle Hui, Countess of Chester Hospital NHS Foundation Trust, Chester; Prof David Isenberg, University College Hospital, London; Dr David Jayne, Addenbrooke’s Hospital, Cambridge; Dr Rachel Jeffrey, Northampton General Hospital, Northampton; Dr Munther Khamashta, St Thomas’s Hospital, London; Dr Peter Lanyon, Nottingham University Hospitals NHS Trust, Nottingham; Dr Neil McHugh, Royal United Hospitals Bath NHS Foundation Trust, Bath; Dr Athiveer Prabu, Sandwell and West Birmingham Hospitals NHS Trust & Worcestershire Acute Hospitals NHS Trust; Dr Marian Regan, Royal Derby Hospital, Derby; Dr Shireen Shaffu, Leicester Royal Infirmary, Leicester; Dr Robert Stevens, Doncaster and Bassetlaw Hospitals NHS Foundation Trust, Doncaster; Dr Steven Young-Min, Portsmouth Hospitals National Health Service Trust, Portsmouth; Dr Asad Zoma, Hairmyres Hospital, Lanarkshire.

  • Funding This work was funded by the Medical Research Council, grant MR/M01665X/1 “Maximizing SLE Therapeutic Potential by Application of Novel and Systemic Approaches and the Engineering (MASTERPLANS). BILAG-BR has been funded by unrestricted educational donations from Roche, GSK and LUPUS UK. This work was supported by the UK’s Experimental Arthritis Treatment Centre for Children (supported by Versus Arthritis, Alder Hey Children’s NHS Foundation Trust, LUPUS UK, the Alder Hey Charity and the University of Liverpool) and supported also by the National Institute for Health Research (NIHR) Alder Hey Clinical Research Facility. INB is a National Institute for Health Research (NIHR) Senior Investigator and is funded by the NIHR Manchester Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

  • Competing interests None declared.

  • Patient consent for publication Not required.

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

  • Data sharing statement Data are available upon reasonable request.

  • Contributors The project was planned by CMH, MWB and AM on behalf of the MRC MASTERPLANS Consortium. JCD, SD and AM carried out the work presented in this article. All authors were involved in data analysis and interpretation, and provided valuable discussion. JCD, AM, EC and CMH wrote the manuscript, and all authors read and approved the final version.

  • Patient and Public involvement The MRC MASTERPLANS Consortium included patient and public involvement (PPI) representatives from early stages of project planning and establishment of the wider consortium. This happened through focus group meetings and personal conversations which established that patients with SLE wish and require treatment that includes no or significantly lower steroid doses alongside target-directed and individualised approaches. It was agreed that, though outcome measures used are standard for SLE, discussion about other measures reflecting patients’ perception of improvement are necessary. PPI representative provided advice and input into patient-facing information, ethics application, and discussion about importance of including sufficient different ethnic groups. Furthermore, patient representatives commented and advised on ‘acceptable levels’ of blood volumes required, biopsies, frequency and timing of clinic and study visits. Dissemination of results from MASTERPLANS-related projects is guaranteed through close links with the LUPUS UK charity (regular progress reports already publicised). Patients are already involved in writing patient summaries with various academic authors. The entire MRC MASTERPLANS Consortium committed to presenting information in a way which is accessible to patients and the public. Some patients have professional experience in various types of media and will have opportunities to broaden the usual academic approach to publication, not just with patients and the public but with other important stakeholders, including NICE, as well as NHS England, Scotland and Wales.

  • 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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