S100A12 Is Associated with Response to Therapy in Juvenile Idiopathic Arthritis

Faekah Gohar; Janneke Anink; Halima Moncrieffe; Lisette W A Van Suijlekom-Smit; Femke H M Prince; Marion A J van Rossum; Koert M Dolman; Esther P A H Hoppenreijs; Rebecca Ten Cate; Simona Ursu; Lucy R Wedderburn; Gerd Horneff; Michael Frosch; Dirk Foell; Dirk Holzinger

doi:10.3899/jrheum.170438

S100A12 Is Associated with Response to Therapy in Juvenile Idiopathic Arthritis

J Rheumatol. 2018 Apr;45(4):547-554. doi: 10.3899/jrheum.170438. Epub 2018 Jan 15.

Authors

Faekah Gohar^{1

2}, Janneke Anink^{1

2}, Halima Moncrieffe^{1

2}, Lisette W A Van Suijlekom-Smit^{1

2}, Femke H M Prince^{1

2}, Marion A J van Rossum^{1

2}, Koert M Dolman^{1

2}, Esther P A H Hoppenreijs^{1

2}, Rebecca Ten Cate^{1

2}, Simona Ursu^{1

2}, Lucy R Wedderburn^{1

2}, Gerd Horneff^{1

2}, Michael Frosch^{1

2}, Dirk Foell^{1

2}, Dirk Holzinger^{3

4}

Affiliations

¹ From the Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster, Germany; Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital Rotterdam, Rotterdam, the Netherlands; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA; Emma Children's Hospital, Academic Medical Centre and Amsterdam Rheumatology and Immunology Centre, Reade location, Jan van Breemen Institute; Department of Pediatrics/Pediatric Rheumatology, Onze Lieve Vrouwe Gasthuis, Amsterdam; Department of Pediatrics/Pediatric Rheumatology, St. Maartenskliniek and Radboud University Medical Centre, Nijmegen; Leiden University Medical Centre, Leiden, the Netherlands; School of Biological Sciences, Royal Holloway, University of London; Infection, Immunity, Inflammation Programme, University College London (UCL) Great Ormond Street (GOS) Institute of Child Health; UK National Institute for Health Research (NIHR) GOS Hospital Biomedical Research Centre (BRC); Arthritis Research UK Centre for Adolescent Rheumatology at UCL, London, UK; Centre of Pediatric Rheumatology, Department of General Pediatrics, Asklepios Clinic Sankt Augustin, Sankt Augustin; German Pediatric Pain Centre, Children's and Adolescents' Hospital, Datteln; Klinik für Kinderheilkunde III, Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Essen, Essen, Germany.
² F. Gohar, MD, Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster; J. Anink, MD, PhD, Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital Rotterdam; H. Moncrieffe, PhD, Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati; L.W. Van Suijlekom-Smit, MD, PhD, Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital Rotterdam; F.H. Prince, MD, PhD, Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital Rotterdam; M.A. van Rossum, MD, PhD, Emma Children's Hospital, Academic Medical Centre and Amsterdam Rheumatology and Immunology Centre, Reade location, Jan van Breemen Institute; K.M. Dolman, MD, PhD, Department of Pediatrics/Pediatric Rheumatology, Onze Lieve Vrouwe Gasthuis; E.P. Hoppenreijs, MD, Department of Pediatrics/Pediatric Rheumatology, St. Maartenskliniek and Radboud University Medical Centre; R. ten Cate, MD, PhD, Leiden University Medical Centre; S. Ursu, PhD, School of Biological Sciences, Royal Holloway, University of London; L.R. Wedderburn, MD, PhD, Infection, Immunity, Inflammation Programme, UCL GOS Institute of Child Health, UCL; G. Horneff, MD, Centre of Pediatric Rheumatology, Department of General Pediatrics, Asklepios Clinic Sankt Augustin; M. Frosch, MD, German Pediatric Pain Centre, Children's and Adolescents' Hospital; D. Foell, MD, Department of Paediatric Rheumatology and Immunology, University Children's Hospital Münster; D. Holzinger, MD, Department of Paediatric Rheumatology and Immunology, University Children's Hospital Münster, and Klinik für Kinderheilkunde III, Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Essen.
³ From the Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster, Germany; Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital Rotterdam, Rotterdam, the Netherlands; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA; Emma Children's Hospital, Academic Medical Centre and Amsterdam Rheumatology and Immunology Centre, Reade location, Jan van Breemen Institute; Department of Pediatrics/Pediatric Rheumatology, Onze Lieve Vrouwe Gasthuis, Amsterdam; Department of Pediatrics/Pediatric Rheumatology, St. Maartenskliniek and Radboud University Medical Centre, Nijmegen; Leiden University Medical Centre, Leiden, the Netherlands; School of Biological Sciences, Royal Holloway, University of London; Infection, Immunity, Inflammation Programme, University College London (UCL) Great Ormond Street (GOS) Institute of Child Health; UK National Institute for Health Research (NIHR) GOS Hospital Biomedical Research Centre (BRC); Arthritis Research UK Centre for Adolescent Rheumatology at UCL, London, UK; Centre of Pediatric Rheumatology, Department of General Pediatrics, Asklepios Clinic Sankt Augustin, Sankt Augustin; German Pediatric Pain Centre, Children's and Adolescents' Hospital, Datteln; Klinik für Kinderheilkunde III, Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Essen, Essen, Germany. Dirk.Holzinger@uk-essen.de.
⁴ F. Gohar, MD, Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster; J. Anink, MD, PhD, Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital Rotterdam; H. Moncrieffe, PhD, Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati; L.W. Van Suijlekom-Smit, MD, PhD, Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital Rotterdam; F.H. Prince, MD, PhD, Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital Rotterdam; M.A. van Rossum, MD, PhD, Emma Children's Hospital, Academic Medical Centre and Amsterdam Rheumatology and Immunology Centre, Reade location, Jan van Breemen Institute; K.M. Dolman, MD, PhD, Department of Pediatrics/Pediatric Rheumatology, Onze Lieve Vrouwe Gasthuis; E.P. Hoppenreijs, MD, Department of Pediatrics/Pediatric Rheumatology, St. Maartenskliniek and Radboud University Medical Centre; R. ten Cate, MD, PhD, Leiden University Medical Centre; S. Ursu, PhD, School of Biological Sciences, Royal Holloway, University of London; L.R. Wedderburn, MD, PhD, Infection, Immunity, Inflammation Programme, UCL GOS Institute of Child Health, UCL; G. Horneff, MD, Centre of Pediatric Rheumatology, Department of General Pediatrics, Asklepios Clinic Sankt Augustin; M. Frosch, MD, German Pediatric Pain Centre, Children's and Adolescents' Hospital; D. Foell, MD, Department of Paediatric Rheumatology and Immunology, University Children's Hospital Münster; D. Holzinger, MD, Department of Paediatric Rheumatology and Immunology, University Children's Hospital Münster, and Klinik für Kinderheilkunde III, Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Essen. Dirk.Holzinger@uk-essen.de.

Abstract

Objective: Around one-third of patients with juvenile idiopathic arthritis (JIA) fail to respond to first-line methotrexate (MTX) or anti-tumor necrosis factor (TNF) therapy, with even fewer achieving ≥ American College of Rheumatology Pediatric 70% criteria for response (ACRpedi70), though individual responses cannot yet be accurately predicted. Because change in serum S100-protein myeloid-related protein complex 8/14 (MRP8/14) is associated with therapeutic response, we tested granulocyte-specific S100-protein S100A12 as a potential biomarker for treatment response.

Methods: S100A12 serum concentration was determined by ELISA in patients treated with MTX (n = 75) and anti-TNF (n = 88) at baseline and followup. Treatment response (≥ ACRpedi50 score), achievement of inactive disease, and improvement in Juvenile Arthritis Disease Activity Score (JADAS)-10 score were recorded.

Results: Baseline S100A12 concentration was measured in patients treated with anti-TNF [etanercept n = 81, adalimumab n = 7; median 200, interquartile range (IQR) 133-440 ng/ml] and MTX (median 220, IQR 100-440 ng/ml). Of the patients in the anti-TNF therapy group, 74 (84%) were also receiving MTX. Responders to MTX (n = 57/75) and anti-TNF (n = 66/88) therapy had higher baseline S100A12 concentration compared to nonresponders: median 240 (IQR 125-615) ng/ml versus 150 (IQR 87-233) ng/ml, p = 0.021 for MTX, and median 308 (IQR 150-624) ng/ml versus 151 (IQR 83-201) ng/ml, p = 0.002, for anti-TNF therapy. Followup S100A12 could be measured in 44/75 MTX-treated patients (34/44 responders) and 39/88 anti-TNF-treated patients (26/39 responders). Responders had significantly reduced S100A12 concentration (MTX: p = 0.031, anti-TNF: p < 0.001) at followup versus baseline. Baseline serum S100A12 in both univariate and multivariate regression models for anti-TNF therapy and univariate analysis alone for MTX therapy was significantly associated with change in JADAS-10.

Conclusion: Responders to MTX or anti-TNF treatment can be identified by higher pretreatment S100A12 serum concentration levels.

Keywords: BIOLOGICAL MARKERS; BIOLOGICAL THERAPY; JUVENILE IDIOPATHIC ARTHRITIS; PEDIATRIC RHEUMATIC DISEASES.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Antirheumatic Agents / pharmacology
Antirheumatic Agents / therapeutic use*
Arthritis, Juvenile / blood*
Arthritis, Juvenile / drug therapy*
Biomarkers / blood
Child
Child, Preschool
Female
Follow-Up Studies
Humans
Linear Models
Logistic Models
Male
Methotrexate / therapeutic use*
Multivariate Analysis
S100A12 Protein / blood*
Statistics, Nonparametric
Treatment Outcome
Tumor Necrosis Factor-alpha / antagonists & inhibitors

Substances

Antirheumatic Agents
Biomarkers
S100A12 Protein
S100A12 protein, human
Tumor Necrosis Factor-alpha
Methotrexate

Abstract

Publication types

MeSH terms

Substances

Grants and funding