Background Four TNF-inhibiting biologicals (TNFi) have been approved by European regulatory authorities for active non-radiographic (nr) and radiographic (r; also termed ankylosing spondylitis) axial (ax) SpA.1–4 To be eligible to receive TNFi treatment, nr-axSpA patients (pts) must have either a positive MRI showing inflammation of the sacroiliac joints or a positive CRP assessment (CRP >upper limit of normal [ULN]). CRP is also considered a predictor of treatment response in axSpA.5 However, many axSpA pts are classed as CRP-negative despite levels close to the ULN.
Objectives These analyses investigated the reproducibility of negative CRP test results in pts with active axSpA who were intolerant to or had insufficient response to NSAID treatment.
Methods The 204-week (wk) phase 3 RAPID-axSpA trial (NCT01087762) evaluated the efficacy and safety of certolizumab pegol (CZP) in axSpA pts, and was double-blind and placebo (PBO)-controlled for the initial 24 wks. At screening, pts were either MRI or CRP (>ULN [7.9mg/L]) positive. PBO-treated pts continued on stable conventional medication and were re-randomized to CZP at Wk16 (ASAS20 non-responders) or Wk24 (ASAS20 responders). These analyses considered CRP data for all PBO-randomized (n=107) pts up until re-randomization to CZP (Wk16 or Wk24). CRP was assessed at screening, baseline and at 9 time points to Wk24. Descriptive methods and linear mixed models (LMM) were used to investigate time trends and variability of CRP, and empirical best linear unbiased prediction (EBLUP) to estimate prediction limits of CRP. Log(CRP+1) transformation was used for modelling.
Results Of 106 pts with baseline CRP assessments, 26 (25%) had negative CRP tests at baseline, of whom 13 (50%) had ≥1 positive CRP test to Wk16 (Table). Of the 80/106 (75%) pts with positive CRP at baseline, 25 (31%) had ≥1 negative CRP test to Wk16.
LMM did not reveal statistically significant changes in mean CRP to Wk24 in pts randomized to PBO. EBLUP analysis showed that even for a pt with a CRP score of 2mg/L at a single evaluation, the 80% prediction interval for the next assessment (4 wks apart from the first) included 7.9mg/L, indicating that there was >10% chance of a positive CRP test upon re-evaluation. The 4-wk interval prior to re-evaluation was selected because residual autocorrelation was observed between assessments at shorter intervals.
The EBLUP result was supported by descriptive evaluations, with 10.8% of CRP assessments ≤3mg/L testing positive (>7.9mg/L) at their subsequent assessment (4 wks apart from the first). This increased to 53.1% when the original CRP assessment was between ≥6 and ≤7.9mg/L.
Conclusions In axSpA pts with a clinical indication to initiate TNFi treatment, but with a negative CRP test (<ULN), the CRP test should be repeated at least once after a number of weeks, since there is a substantial chance of finding a positive result at subsequent testing.
EMA. Summary of Product Characteristics [SmPC] (Humira) 2012;
EMA. SmPC (Cimzia) 2013;
EMA. SmPC (Enbrel) 2014;
EMA. SmPC (Simponi) 2015;
Sieper J. Nat Rev Rheumatol 2012;8:280–7
Disclosure of Interest R. Landewé Grant/research support from: Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB Pharma and Wyeth, Consultant for: Abbott, Ablynx, Amgen, Astra-Zeneca, Bristol Myers Squibb, Centocor, Glaxo-Smith-Kline, Novartis, Merck, Pfizer, Roche, Schering-Plough, UCB Pharma and Wyeth, Speakers bureau: Abbott, Amgen, Bristol Myers Squibb, Centocor, Merck, Pfizer, Roche, Schering-Plough, UCB Pharma and Wyeth, T. Nurminen Employee of: UCB Pharma, O. Davies Shareholder of: UCB Pharma, Employee of: UCB Pharma, M. Turina: None declared, D. Baeten Grant/research support from: AbbVie, Pfizer, UCB, MSD, Roche, BMS, Boehringer Ingelheim, Eli Lilly, Novartis and Janssen, Consultant for: AbbVie, Pfizer, UCB, MSD, Roche, BMS, Boehringer Ingelheim, Eli Lilly, Novartis and Janssen