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Association of female sex and positive rheumatoid factor with low serum infliximab and anti-drug antibodies, related to treatment failure in early rheumatoid arthritis : results from the SWEFOT trial population

Hambardzumyan, K. ; Hermanrud, C. ; Marits, P. ; Vivar, N. ; Ernestam, S. ; Wallman, J. K. LU ; van Vollenhoven, R. F. ; Fogdell-Hahn, A. and Saevarsdottir, S. (2019) In Scandinavian Journal of Rheumatology
Abstract

Objective: Infliximab-treated patients with rheumatoid arthritis (RA) may respond insufficiently due to low serum infliximab (sIFX) levels, caused by anti-drug antibodies (ADAs). However, monitoring of sIFX and ADAs is not routinely implemented, and levels for optimal outcome have not been validated. We searched for predictors for sIFX < 0.2 μg/mL and ADA development in a randomized setting. Methods: In the SWEFOT trial, of 128 patients randomized to methotrexate + IFX therapy, 101 had serum samples at 3, 9, and 21 months that were analysed for sIFX [enzyme-linked immunosorbent assay (ELISA)] and ADAs [ELISA, and precipitation and acid dissociation (PandA) when sIFX > 0.2 μg/mL]. The primary and secondary outcome measures were low... (More)

Objective: Infliximab-treated patients with rheumatoid arthritis (RA) may respond insufficiently due to low serum infliximab (sIFX) levels, caused by anti-drug antibodies (ADAs). However, monitoring of sIFX and ADAs is not routinely implemented, and levels for optimal outcome have not been validated. We searched for predictors for sIFX < 0.2 μg/mL and ADA development in a randomized setting. Methods: In the SWEFOT trial, of 128 patients randomized to methotrexate + IFX therapy, 101 had serum samples at 3, 9, and 21 months that were analysed for sIFX [enzyme-linked immunosorbent assay (ELISA)] and ADAs [ELISA, and precipitation and acid dissociation (PandA) when sIFX > 0.2 μg/mL]. The primary and secondary outcome measures were low disease activity [LDA = 28-joint Disease Activity Score (DAS28) ≤ 3.2] and remission (DAS28 < 2.6). Baseline characteristics were assessed as potential predictors of sIFX < 0.2 μg/mL or ADA positivity, using logistic regression. Results: Categorization of sIFX levels into < 0.2, 0.2–2.9, 3.0–7.0, and > 7.0 μg/mL showed a dose–response association with LDA (30%, 64%, 67%, and 79%, respectively, p = 0.008) and remission (10%, 45%, 39%, and 66%, p = 0.004) at trial cessation (21 months). Female patients had sIFX < 0.2 μg/mL more often than males (35% vs 7%, p = 0.006), with a similar trend for rheumatoid factor (RF)-positive vs RF-negative patients (34% vs 16%, p = 0.059). ADA positivity showed similar patterns, also after adjustment for potential confounders (female sex: p = 0.050; RF positivity: p = 0.067). PandA captured four highly ADA-reactive patients with sIFX > 0.2 μg/mL, of whom three were ADA positive at other time-points, all with high DAS28 at follow-up. Conclusion: In early RA patients receiving IFX as a second-line agent, sIFX < 0.2 μg/mL and ADA development were associated with treatment failure and were more common in females, with a similar trend for RF positivity. Our findings support the use of therapeutic drug monitoring, and PandA in ADA-negative non-responders. Trial registration: SWEFOT NCT00764725 (https://clinicaltrials.gov/ct2/show/NCT00764725).

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publication status
epub
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Scandinavian Journal of Rheumatology
publisher
Taylor & Francis
external identifiers
  • scopus:85068238413
ISSN
0300-9742
DOI
10.1080/03009742.2019.1602670
language
English
LU publication?
yes
id
a391e2b4-0e71-4c40-9590-a176d08b94f4
date added to LUP
2019-07-09 14:35:33
date last changed
2019-11-25 09:32:58
@article{a391e2b4-0e71-4c40-9590-a176d08b94f4,
  abstract     = {<p>Objective: Infliximab-treated patients with rheumatoid arthritis (RA) may respond insufficiently due to low serum infliximab (sIFX) levels, caused by anti-drug antibodies (ADAs). However, monitoring of sIFX and ADAs is not routinely implemented, and levels for optimal outcome have not been validated. We searched for predictors for sIFX &lt; 0.2 μg/mL and ADA development in a randomized setting. Methods: In the SWEFOT trial, of 128 patients randomized to methotrexate + IFX therapy, 101 had serum samples at 3, 9, and 21 months that were analysed for sIFX [enzyme-linked immunosorbent assay (ELISA)] and ADAs [ELISA, and precipitation and acid dissociation (PandA) when sIFX &gt; 0.2 μg/mL]. The primary and secondary outcome measures were low disease activity [LDA = 28-joint Disease Activity Score (DAS28) ≤ 3.2] and remission (DAS28 &lt; 2.6). Baseline characteristics were assessed as potential predictors of sIFX &lt; 0.2 μg/mL or ADA positivity, using logistic regression. Results: Categorization of sIFX levels into &lt; 0.2, 0.2–2.9, 3.0–7.0, and &gt; 7.0 μg/mL showed a dose–response association with LDA (30%, 64%, 67%, and 79%, respectively, p = 0.008) and remission (10%, 45%, 39%, and 66%, p = 0.004) at trial cessation (21 months). Female patients had sIFX &lt; 0.2 μg/mL more often than males (35% vs 7%, p = 0.006), with a similar trend for rheumatoid factor (RF)-positive vs RF-negative patients (34% vs 16%, p = 0.059). ADA positivity showed similar patterns, also after adjustment for potential confounders (female sex: p = 0.050; RF positivity: p = 0.067). PandA captured four highly ADA-reactive patients with sIFX &gt; 0.2 μg/mL, of whom three were ADA positive at other time-points, all with high DAS28 at follow-up. Conclusion: In early RA patients receiving IFX as a second-line agent, sIFX &lt; 0.2 μg/mL and ADA development were associated with treatment failure and were more common in females, with a similar trend for RF positivity. Our findings support the use of therapeutic drug monitoring, and PandA in ADA-negative non-responders. Trial registration: SWEFOT NCT00764725 (https://clinicaltrials.gov/ct2/show/NCT00764725).</p>},
  author       = {Hambardzumyan, K. and Hermanrud, C. and Marits, P. and Vivar, N. and Ernestam, S. and Wallman, J. K. and van Vollenhoven, R. F. and Fogdell-Hahn, A. and Saevarsdottir, S.},
  issn         = {0300-9742},
  language     = {eng},
  month        = {06},
  publisher    = {Taylor & Francis},
  series       = {Scandinavian Journal of Rheumatology},
  title        = {Association of female sex and positive rheumatoid factor with low serum infliximab and anti-drug antibodies, related to treatment failure in early rheumatoid arthritis : results from the SWEFOT trial population},
  url          = {http://dx.doi.org/10.1080/03009742.2019.1602670},
  doi          = {10.1080/03009742.2019.1602670},
  year         = {2019},
}