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Anticarbamylated protein (anti-CarP) antibodies are present in sera of juvenile idiopathic arthritis (JIA) patients
  1. P C E Hissink Muller1,
  2. J Anink2,
  3. J Shi3,
  4. E W N Levarht3,
  5. T H C M Reinards1,
  6. M H Otten2,
  7. M J D van Tol1,
  8. C M Jol-van der Zijde1,
  9. D M C Brinkman1,
  10. C F Allaart3,
  11. E P Hoppenreijs4,
  12. Y Koopman-Keemink5,
  13. S S M Kamphuis2,
  14. K Dolman6,
  15. J M van den Berg7,
  16. M A J van Rossum7,
  17. L W A van Suijlekom-Smit2,
  18. M W Schilham1,
  19. T W J Huizinga3,
  20. R E M Toes3,
  21. R ten Cate1,
  22. L A Trouw3
  1. 1 Department of Pediatrics/Pediatric Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2 Department of Pediatrics/Pediatric Rheumatology, Sophia Children's Hospital Erasmus Medical Center, Rotterdam, The Netherlands
  3. 3 Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  4. 4 Department of Pediatrics/Pediatric Rheumatology, St Maartenskliniek and Radboud University, Nijmegen, The Netherlands
  5. 5 Department of Pediatrics, Hagaziekenhuis Juliana Children's Hospital, The Hague, The Netherlands
  6. 6 Department of Pediatrics/Pediatric Rheumatology, St Lucas Andreas Hospital and Reade Location Jan van Breemen, Amsterdam, The Netherlands
  7. 7 Department of Pediatrics/Pediatric Rheumatology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands
  1. Correspondence to Dr L A Trouw, Department of Rheumatology, C1-R, Leiden University Medical Center (LUMC), PO Box 9600, Leiden 2300 RC, The Netherlands; l.a.trouw{at} PCEHM, JA and JS contributed equally

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In juvenile idiopathic arthritis (JIA) patients there is a lack of markers that predict severe disease. Although anticitrullinated protein antibodies (ACPA) have contributed substantially to the understanding of rheumatoid arthritis (RA),1 their detection in JIA has not been equally useful as incidence rates in JIA patients are low2 and merely confined to the polyarticular immunoglobulin (Ig)M-rheumatoid factor (RF)-positive category resembling RA. Recently, anticarbamylated protein (anti-CarP) antibodies were detected in 45% of RA patients and importantly also in 16%–20% ACPA-negative patients.3–5 Within the ACPA-negative patients, anti-CarP antibodies were associated with more severe radiographic progression.3 Since most JIA patients are ACPA-negative we investigated whether anti-CarP antibodies are present in the sera of JIA patients and how they are related to ACPA and IgM-RF.

JIA patients from three Dutch sources were included: the BeSt for Kids trial (NTR 1574, a treatment strategy study) (n=33), a previously described cohort6 (n=48) and the Arthritis and Biologicals in Children (ABC) register7 (n=153). Healthy controls (n=107) (mean age/range 11/(2–20)) are stem-cell graft donors. Written informed consent was obtained from all patients and controls. Blood collection and storage are comparable among different cohorts. Cross-sectionally obtained sera from 234 JIA patients at variable time points in disease course were analysed. All International League against Rheumatism JIA categories were included8 with polyarticular JIA over-represented. Median disease duration at the time of serum collection was 2.3 years (IQR 0.7–6.8) (table 1). Patients’ disease characteristics were collected from patient files. Anti-CarP antibodies and ACPA were measured by ELISA as described previously.3

Table 1

Disease characteristics of 234 juvenile idiopathic arthritis (JIA) patients

We observed that 8.1% (19/234) of the JIA patients were positive for anti-Ca-FCS antibodies versus 4.7% (5/107) of controls (p=0.20); 13.2% (31/234) of patients versus 2.8% (3/107) of controls were positive for anti-Ca-Fib antibodies (p=0.003); 16.7% (39/234) of patients versus 8/107 (7.5%) of controls were positive for at least one anti-CarP antibody (p=0.028); and 11/234 (4.7%) versus 0 of controls (p=0.017) were positive for both anti-CarP reactivities. Both anti-Ca-FCS and anti-Ca-Fib antibodies were predominantly present in polyarticular IgM-RF-positive patients compared with other JIA categories (p<0.0001) (figure 1). Additionally, 53% (8/15) of ACPA-positive patients and 42.1% (8/19) of IgM-RF-positive patients were also positive for anti-CarP antibodies. Importantly, anti-CarP antibodies were also found in ACPA and IgM-RF-negative patients as 57.9% (11/19) of anti-CarP-positive patients were negative for ACPA and 27.3% (3/11) were negative for IgM-RF. In total, nine JIA patients were positive for IgM-RF, ACPA and anti-CarP (Ca-FCS and/or Ca-Fib) antibodies. All triple positive patients were part of the ABC register.

Figure 1

IgG anticarbamylated protein (anti-CarP) antibodies are present in juvenile idiopathic arthritis (JIA) sera. A cut-off for positivity (horizontal line) was determined using the mean plus two times the SD of the healthy controls. Antibodies against Ca-FCS (A) and Ca-Fib (B) in the sera of JIA patients and healthy controls are depicted in aU/mL. (C) Results of anti-CarP antibodies: positivity above cut-off per JIA category in absolute number, percentage and significance (NS, not significant, *p<0.05, **p<0.01). FCS, fetal calfs serum; RF, rheumatoid factor.

Disease duration at sample collection, anti-nuclear antibodies status or age was not associated with the presence of anti-CarP antibodies. In the second cohort,6 we did not find an association of anti-CarP positivity with disease activity measured by time-in-active-disease at the time of sampling. Within the ABC register cohort, no association was found between the presence of anti-CarP antibodies and ACR-Pedi 30 response9 or reaching inactive disease10 at 15 months after starting anti-TNF treatment. The cross-sectional nature of these three cohorts did not allow a more indepth analysis on the association with clinical outcome.

This is the first study showing the presence of anti-CarP antibodies in JIA stimulating future studies on the diagnostic and prognostic value of anti-CarP antibodies in JIA.


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  • Contributors PCEHM, JA, JS, THCMR, MHO, MJDvT, CMJvdZ, EPH, YK-K, SSMK, KD, JMvdB, MAJvR, LWAvS-S, MWS and RtC all contributed data. DMCB, CFA, LWAvS-S, PCEHM, JA, JS, TWJH, RtC, REMT and LAT contributed to the design of the study. PCEHM, JA, JS and EWNL performed tests. PCEHM, JA and JS performed analyses. PCEHM, JA, JS and LAT wrote the manuscript. All authors critically reviewed the draft manuscript and approved the version to be published.

  • Funding This study was also supported by the Netherlands Genomics Initiative (NGI) as part of the Netherlands Proteomics Center (NPC) and the Center for Medical Systems Biology (CMSB). LAT was financially supported by a VIDI grant from NWO-Zon-MW and a fellowship from Janssen Biologics. REMT was financially supported by a VICI grant from NWO-Zon-MW. PCEHM and The BeSt for Kids study are financially supported by Pfizer. RtC received research grants by the Dutch Arthritis Association. The ABC register is receiving unconditional support of The Board of Health Insurances (2003-2006), Pfizer (since 2007) and Abbott (since 2010). The authors wish to acknowledge the support of the European Union (FP6 integrated project Autocure, FP7 integrated project Masterswitch and IMI JU funded project BeTheCure, contract no 115142-2).

  • Competing interests None.

  • Ethics approval Institutional Review Board of Leiden University Medical Center.

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