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FRI0188 The impact of immunogenicity on drug safety profile
  1. S. Garcês1,2,
  2. J. Freitas3,
  3. J. Canas-Silva1,
  4. L. Aarden4,
  5. J. Demengeot2
  1. 1Rheumatology, Hospital Garcia De Orta, Almada
  2. 2Immunology, Instituto Gulbenkian Ciência, Oeiras
  3. 3Gastrenterology, Hospital Garcia De Orta, Almada, Portugal
  4. 4Immunology, Sanquin Research Institute, Amsterdam, Netherlands

Abstract

Background Over the last years, an increasing body of evidence has highlighted the clinical significance of drug immunogenicity1. Anti-drug antibodies (ADA), by forming immune complexes with the drug, promote its faster clearance from circulation, reducing therapeutic effectiveness2. However, ADA have also been associated with increased incidence of drug-related adverse events (AE), particularly infusion-related AE during infliximab therapy, despite severe thromboembolic phenomena associated with antibodies against adalimumab have also been reported in the literature3,4,5.

Objectives We assessed the association between ADA and infusion-related AE in patients with Rheumatoid Arthritis (RA), Ankylosing Spondylitis (AS), Psoriatic Arthritis (PsA) and Inflammatory Bowel Disease (IBD), receiving infliximab therapy.

Methods We conducted a prospective cohort study over 2-years evolving 84 consecutive patients (22 AR, 33 AS, 9 PsA and 30 IBD) receiving infliximab at 3-5 mg/Kg every 6 or 8 wks, at day care unit of Hospital Garcia de Orta, Almada. Therapeutic response and low disease activity were defined according to the EULAR guidelines (RA and RA-like PsA), ASAS group guidelines (AS and AS-like PsA) and by an expert clinician (IBD patients). ADA were detected by an optimized Bridging ELISA, just prior to next infliximab infusion. Clinicians were blind for the tests results.

Results Seventy-six percent of patients were female, with mean (SD) age of 48 (10.2) years, disease duration of 8 (6.4) years, receiving biologic therapy by 2.9 (2.0) years. All RA patients and 89% of PsA were receiving concomitant MTX. IBD patients were receiving concomitant azathioprine and also hydrocortisone plus anti-histaminic prior to each infliximab infusion. During the follow-up period, a total of 25 patients (30%) had detectable ADA (41% of RA, 33% of PsA, 18% of AS and 23% of IBD patients). Of those, 44% developed an infusion-related AE (4 RA patients, 2 PsA, 2 AS and 4 IBD patients). In all of those cases, ADA detection occurred prior to the AE. All patients with RA, PsA and AS who developed infusion-related AE were unable to maintain therapeutic response over time, while 2 out of 4 patients with IBD were still considered responders during the follow-up period. All the reactions were mild-moderate requiring hydrocortisone and anti-histaminic administration.

Conclusions A significant porpotion of ADA-positives patients develop an infusion-related AE and cannot sustain therapeutic response. The maintenance of therapy in such cases may have serious deleterious effects with no additional therapeutic benefits. Further robust studies are warranted to better evaluate safety aspects related with immunogenicity.

References

  1. Garcês, S et al. Ann Rheum Dis. 2012 Dec 6. [Epub ahead of print]

  2. van Schouwenburg, PA et al. Ann Rheum Dis. 2013 Jan;72(1):104-9

  3. Wolbink, GJ et al. Arthritis Rheum. 2006 Mar;54(3):711-5

  4. Maggi, E et al. Expert Rev Clin Immunol. 2011 Jan;7(1):55-63

  5. Korswagen, LA et al. Arthritis Rheum. 2011 Apr;63(4):877-83

Disclosure of Interest None Declared

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