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The window of opportunity in ACPA-positive rheumatoid arthritis is not explained by ACPA characteristics
  1. Annemiek Willemze1,
  2. Michael P M van der Linden1,
  3. Saskia le Cessie2,
  4. Leendert A Trouw1,
  5. Rene E M Toes1,
  6. Tom W J Huizinga1,
  7. Annette H M van der Helm-van Mil1
  1. 1Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department of Clinical Epidemiology and Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Annemiek Willemze, Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; a.willemze{at}

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Very early therapy of rheumatoid arthritis (RA) with disease-modifying antirheumatic drugs is associated with lower levels of joint destruction and a higher chance of achieving remission.1,,5 Having symptoms for >12 weeks at treatment initiation is a strong and independent risk factor for a persistent disease course.1 3,,5 These observations have led to the concept of the 'window of opportunity'.2 This hypothesis presumes that underlying disease processes are not fully matured in the very early stage of arthritis, making modulation more successful. However, putative biological mechanisms remain unexplored.

Anti-citrullinated protein antibodies (ACPA) precede arthritis development and are associated with a severe disease course.6 We hypothesised that the ACPA response broadens within the very early phase of RA and in doing so limits the 'window of opportunity'. Therefore, it was examined whether patients who were assessed within 12 weeks of symptom onset had a less broadened ACPA response than patients with longer symptom duration.

Three hundred and nine ACPA-positive patients (defined by anti-CCP2 positivity) fulfilling the 1987 ACR criteria for RA and included in the Leiden Early Arthritis Clinic7 were studied for the association between symptom duration and the progression in joint destruction over 7.5 years, with symptom onset as the starting point.3 Yearly radiographs of hands and feet were scored according to the Sharp-van der Heijde method.7 A repeated measurement analysis was used with a random person and time effect; the fixed effect of time was modelled with linear spline functions with knots at each year.3 Adjustments were made for age, gender and treatment strategy. RA patients who presented with <12 weeks or ≥12 weeks of symptoms were compared for level, isotype usage and fine specificity of ACPA at inclusion. Antibody reactivity against peptides derived from human proteins (the citrullinated (Cit) and the uncitrullinated form of two linear peptides derived from vimentin (Vim1-16: STCitS VSSS SYCitCit MFGG and Vim59-74: VYAT CitSSA VCitLCit SSVP), two linear peptides derived from fibrinogen (Fib-α27-43: FLAE GGGV Cit GPR VVER H and Fib-β36-52: NEEG FFSA CitGHR PLDK K), one linear peptide derived from α-enolase (Eno5-20: KIHA CitEIF DSCitG NPTV) and myelin basic protein (MBP)) were determined by ELISA and described previously.3 7,,9 Anti-CCP3 and anti-MCV (mutated citrullinated vimentin) were also measured by ELISA (Quanta Lite CCP version 3.1 for IgG/IgA; Inova Diagnostics San Diego, California, USA and Orgentec Diagnostika, Mainz, Germany).

ACPA-positive RA patients who presented <12 weeks of symptom onset had less progression in joint destruction over 7.5 years (p=0.04) (figure 1). Patients with symptoms <12 weeks revealed no differences in anti-CCP2 level, isotype usage or fine specificity recognition profile compared with patients with longer symptom duration (table 1).

Figure 1

Joint destruction (Sharp/van der Heijde scores) over time in ACPA-positive RA patients with <12 or ≥12 weeks of symptoms at first presentation at the rheumatologist. The date of symptom onset is used as starting point. Seventy ACPA-positive patients (22.7%) presented <12 weeks (median after 8 weeks of symptoms) and 239 ACPA-positive patients presented after ≥12 weeks of symptoms (median symptom duration at first presentation at 27 weeks). The RA patients studied were included in the Leiden Early Arthritis Clinic between 1993 and 2006. ACPA, anti-citrullinated protein antibodies; RA, rheumatoid arthritis; SHS, Sharp/van der Heijde score.

Table 1

ACPA characteristics at inclusion of ACPA-positive RA patients with symptoms for <12 or ≥12 weeks

To our knowledge, this is the first study investigating ACPA characteristics in relation to the so-called 'window of opportunity'. Recently published data showed a trend for less joint destruction in ACPA-positive RA patients presenting with symptoms <12 weeks.3 In the present study the radiographic data were extended. No clear differences were observed with respect to ACPA characteristics in relation to symptom duration. Although it cannot be excluded that other ACPA characteristics, such as glycosylation patterns or other 'fine specificities', would show differences, our data indicate that the 'window of opportunity' is not reflected in the maturation of the ACPA response.

A longitudinal study design with regular assessments of ACPA characteristics within the same patients would be more appropriate than a cross-sectional study. However, as ACPA-positive RA patients often present relatively late (only 22.7% of the ACPA-positive RA patients visited a rheumatologist <12 weeks of symptom onset), it will be difficult to obtain adequate patient numbers.

In conclusion, ACPA-positive RA patients with symptoms <12 weeks have less progressive disease than patients with a longer symptom duration. However, the broadness of the ACPA response is not different between these groups, indicating that maturation of the autoantibody response occurs even earlier.10



  • Funding This study was supported by grants from the Centre for Medical Systems Biology (CMSB) and Netherlands proteomics platform within the framework of the Netherlands Genomics Initiative (NGI); by the European Union (Sixth Framework Programme integrated project Autocure and Seventh Framework Programme integrated project Masterswitch). The work of AHMvdHvM is supported by a grant of the Netherlands Organisation of Health Research and Development. The work of AW is supported by the Dutch Organization for Scientific Research (AGIKO grant). LAT work is supported by an NWO-ZonMW VENI grant. REMT's work is supported by a NWO-ZonMW VIDI and VICI grant from the Dutch Organization for Scientific Research.

  • Ethics approval This study was conducted with the approval of the Ethics committee of the Leiden University Medical Center.

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