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The timing of serum infliximab loss, or the appearance of antibodies to infliximab (ATI), is related with the clinical activity in ATI-positive patients with rheumatoid arthritis treated with infliximab
  1. Ch Plasencia1,
  2. D Pascual-Salcedo2,
  3. P Alcocer1,
  4. M G Bonilla1,
  5. A Villalba1,
  6. D Peiteado1,
  7. F Arribas2,
  8. J Díez3,
  9. M T Lopez-Casla2,
  10. E Martín-Mola1,
  11. A Balsa1
  1. 1 Rheumatology Department, La Paz University Hospital-Idipaz, Madrid, Spain
  2. 2 Immunology Unit, La Paz University Hospital-Idipaz, Madrid, Spain
  3. 3 Statistics Department, La Paz University Hospital-Idipaz, Madrid, Spain
  1. Correspondence to Dr Chamaida Plasencia, Rheumatology Department, La Paz University Hospital-Idipaz, Paseo la Castellana 261, Madrid PC 28046, Spain; chamiplasencia{at}hotmail.com

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In patients with rheumatoid arthritis (RA), the development of antibodies to infliximab (ATI) is associated with poor clinical response.1 ,2–7 Nevertheless, there is no plausible explanation for why not all patients with ATI experience high disease activity. To investigate whether the timing of ATI appearance and/or drug disappearance is correlated with clinical activity, we measured the infliximab (Ifx) and ATI levels in patients 4 weeks after infusion (n+4).

Eleven ATI-positive patients with RA receiving Ifx every 8 weeks were included. Disease activity was assessed by DAS28 and European League Against Rheumatism (EULAR) criteria at baseline, and during weeks n and n+8. The serum drug and ATI levels were determined using a capture and bridging ELISA, as previously described,1 ,6 ,8–10 at weeks n, n+4 and n+8.

Patients were divided according to the findings from week n+4: Group 1 (ATI-positive=without Ifx and ATI-positive, ATI-negative=with or without Ifx and ATI-negative); Group 2 (with Ifx=ATI-negative and with Ifx, without Ifx=ATI-positive or ATI-negative and without Ifx). Table 1 shows the patients’ demographic and clinical characteristics. At week n+8, four patients were moderate responders and seven patients were non-responders. In week n+4, four patients had ATI but did not have Ifx, two patients had no ATI but did have Ifx, and five patients had neither ATI nor Ifx.

Table 1

Demographic characteristics of 11 patients with rheumatoid arthritis (RA)

ATI status in week n+4 and clinical activity in week n+8 was as follows. Four patients were ATI-positive (36.3%) in week n+4, and were non-responders in week n+8. ATI-positive patients had higher DAS28 (6.56±0.69 ATI-positive vs 4.56±0.93 ATI-negative, p=0.012) and lower clinical improvement in week n+8 (−1.22±0.72 ATI-positive vs 0.94±0.93 ATI-negative, p=0.012) (figure 1). DAS28 and ATI levels were statistically correlated (r=0.662, p=0.026 using Pearson's correlation coefficient (PCC)). ATI levels in week n+8 were higher in ATI-positive patients in week n+4 (Mdn, IQR 8037.5, 2640.0–12 062.5 AU in ATI-positive vs 260.0, 131.0–342.0 AU in ATI-negative in week n+4, p=0.024). ATI levels in week n+4 were lower than ATI levels in week n+8 (Mdn, IQR 0.0, 0.0–1306.0 AU in week n+4 vs 342.0, 186.0–5000.0 AU in n+8, p=0.045).

Figure 1

(A) Association between clinical activity (DAS28) in week n+8 and antibodies to infliximab (ATI) status (positive/negative) in week n+4. The clinical activity was measured by DAS28 (mean±SD) between ATI positive or negative patients in the middle of the infusion cycle. (B) Association between clinical improvement (δ-DAS28) in week n+8 and ATI status in week n+4. The clinical improvement was measured by delta-DAS28 (mean±SD) between ATI positive or negative patients in the middle of the infusion cycle. (C) Association between clinical activity (DAS28) in week n+8 and infliximab (Ifx) status (with/without) in week n+4. The clinical activity was measured by DAS28 (mean±SD) between the patients with or without detectable Ifx levels in the middle of the infusion cycle. (D) Association between clinical improvement (delta-DAS28) in week n+8 and Ifx status in week n+4. The clinical improvement was measured by delta-DAS28 (mean±SD) between the patients with or without detectable Ifx levels in the middle of the infusion cycle.

Ifx serum levels in week n+4 and clinical activity in week n+8. Two patients (18.1%) had Ifx in week n+4 and were classified as moderate responders. These patients had lower DAS28 than patients without Ifx (3.54±0.02 with Ifx vs 5.68±1.08 without Ifx, p=0.036) (figure 1). The clinical improvement was lower in patients without Ifx in week n+4, although these data were not statistically significant (1.23±1.15 with Ifx vs −0.09±1.41 without Ifx, p=0.232) (figure 1). DAS28 and Ifx levels were statistically correlated (r=−0.661, p=0.027, by PCC).

We demonstrated that the disease activity and ATI levels before the Ifx infusion were correlated with the moment of drug disappearance or ATI appearance. At week n+4, ATI levels were observed in most clinically active patients. These findings reflect that clinical efficacy is related to the persistence of circulating Ifx levels. Logically, patients with higher ATI levels neutralised Ifx earlier, thereby preventing the effect of Ifx. Higher ATI levels detected just before the infusion may have resulted from an earlier ATI development after drug infusion or a faster drug clearance.

Five patients with RA had no ATI or Ifx levels in week n+4, most likely because Ifx is in complex with ATI, as suggested by Wolbink et al.10

In conclusion, this study shows that the effect of Ifx in ATI-positive patients is correlated with the timing of the drug disappearance and ATI appearance between infusions, each resulting in different clinical consequences. Another finding is that higher ATI levels are found in patients with earlier drug clearances. Further studies with larger patient groups are needed to confirm the clinical relevance of these findings.

References

Footnotes

  • Contributors ChP, DP-S, EM-M and AB have written this article. DP-S, PA, MTL-C and ChP have carried out the data collection and databases. AV, DP, MGB, PA, AB and ChP have done the clinical evaluation of patients. JD and ChP have done the statistical analysis. DP-S and FA have performed the laboratory assays.

  • Funding This study was supported by unrestricted grants from Pfizer, and the RETICS Program, RD08/0075 (RIER) from ‘Instituto de Salud Carlos III’ (ISCIII).

  • Competing interests AB has received fees from Roche, Schering-Plough, Wyeth, Abbott, BMS and USB. E.M-M. is a consultant and a member of the Pfizer speakers’ bureaus, MSD, UCB and Abbott. ChP, DP-S, MGB and DP have received speaker honoraria from Pfizer. All other authors have declared no conflicts of interest.

  • Patient consent Obtained.

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