Background/Purpose: To determine if RA patients (pts) who had an inadequate response to etanercept(ETN) or adalimumab(ADA) and developed antibodies (Abs) to ETN or ADA responded clinically in the RESTART Trial after switching without a washout to infliximab(IFX) and if the presence of Abs to ETN or ADA correlated with differences in the levels of IFX or Abs to infliximab(ATI) compared to pts who had not developed Abs to ETN or ADA.

Methods: RESTART is a Phase 4, multicenter, open-label, assessor-blinded, active switch study of IFX+MTX (methotrexate) in pts with active RA who had an inadequate response (DAS28 score ≥3.6 and ≥6 SJC and TJC) to ETN or ADA+MTX.  EULAR response was evaluated at wk 10 post-induction (1۫ endpoint).  Pts adequately responding by EULAR criteria remained on IFX 3 mg/kg; incremental increases in IFX dose in pts not achieving/maintaining EULAR response occurred at wks 14 and/or 22, with a final efficacy assessment at wk 26.  Assays were developed to measure Abs against ADA, ETN and IFX.  Antibodies to anti-TNFs were measured at wks 0, 14 and 26 for ADA and wks 0, 6, 14 and 26 for ETN and IFX. IFX levels were measured at wks 0, 6, 14 and 26.

Results: Among the evaluated patients, 40.3% (50/124) of previously treated ETN pts and 46.8% (37/79) of the previously treated ADA pts of ADA pts demonstrated measureable Abs before exposure to IFX.  No cross-reactivity was observed between anti-ADA Abs and IFX.  By Week 26, 71% (88/124) of ETN inadequate responders demonstrated Abs to ETN (median titer = 1280) and 50.6% (40/79) of ADA inadequate responders had demonstrated Abs to ADA (median titer = 320). Of these pts, 195 pts had samples available for ATI testing, of which 24 pts (12.3%) had detectable ATI.  Of these 24 pts, 23 had evidence of prior Abs to ETN (12/12) or ADA (11/12).  Interestingly, the median wk26 serum conc of IFX was significantly lower in those pts who had developed Abs to ADA vs those who had not (2.1 mg/mL vs 11.9 ug/mL; p<0.0001) and contrasted with pts with or without Abs to ETN (8.8 ug/ml vs 11.7 ug/ml, respectively; p = 0.4768). Also, in pts who received IFX dose escalation to 5 or 7 mg/kg, the anti-ADA⁺ pts who were ATI^–   had a median wk26 IFX serum conc (1.8ug/ml) lower than that observed  for the dose escalated pts who were anti-ADA^–  (13.9ug/ml).  Overall, the combined EULAR responses at wks 10 and 26 were 49.7% and 51.8%, resp.  Pts with Abs to ADA showed lower EULAR responses to IFX early on, but following incremental dose increases of IFX, these pts reached responses by wk26 (55.3%) similar to pts who were anti-ADA^– (59%).

Conclusion: Although Abs develop in 6% and 5% of adult pts treated with ETN and ADA (ETN PI 2011, ADA PI 2012, resp), in this pt population of refractory RA pts who had an inadequate response to either ADA or ETN, the majority of pts had developed moderate to high titer Abs to either ETN or ADA. In these pts, 12.3% developed ATI through 26wks after switching to IFX. Since no cross-reactivity was observed between anti-ADA Abs and IFX, the data suggest that some pts who developed Abs to ADA cleared IFX more rapidly than those pts who were anti-ADA^– and did so independent of ATI.  Overall, a majority of IFX-treated pts demonstrated a EULAR response by wk26 regardless of the presence of Abs to ETN, ADA or IFX.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/antibodies-to-etanercept-and-adalimumab-in-rheumatoid-arthritis-inadequate-responders-and-clinical-outcomes-after-an-active-switch-to-infliximab/