6 research outputs found
Mechanisms and management of loss of response to anti-TNF therapy for patients with Crohn's disease: 3-year data from the prospective, multicentre PANTS cohort study
This is the final version. Available from Elsevier via the DOI in this record. Background We sought to report the effectiveness of infliximab and adalimumab over the first 3 years of treatment
and to define the factors that predict anti-TNF treatment failure and the strategies that prevent or mitigate loss of
response.
Methods Personalised Anti-TNF therapy in Crohn’s disease (PANTS) is a UK-wide, multicentre, prospective
observational cohort study reporting the rates of effectiveness of infliximab and adalimumab in anti-TNF-naive patients
with active luminal Crohn’s disease aged 6 years and older. At the end of the first year, sites were invited to enrol
participants still receiving study drug into the 2-year PANTS-extension study. We estimated rates of remission across
the whole cohort at the end of years 1, 2, and 3 of the study using a modified survival technique with permutation
testing. Multivariable regression and survival analyses were used to identify factors associated with loss of response
in patients who had initially responded to anti-TNF therapy and with immunogenicity. Loss of response was defined
in patients who initially responded to anti-TNF therapy at the end of induction and who subsequently developed
symptomatic activity that warranted an escalation of steroid, immunomodulatory, or anti-TNF therapy, resectional
surgery, or exit from study due to treatment failure. This study was registered with ClinicalTrials.gov, NCT03088449,
and is now complete.
Findings Between March 19, 2014, and Sept 21, 2017, 389 (41%) of 955 patients treated with infliximab and
209 (32%) of 655 treated with adalimumab in the PANTS study entered the PANTS-extension study (median age
32·5 years [IQR 22·1–46·8], 307 [51%] of 598 were female, and 291 [49%] were male). The estimated proportion of
patients in remission at the end of years 1, 2, and 3 were, for infliximab 40·2% (95% CI 36·7–43·7),
34·4% (29·9–39·0), and 34·7% (29·8–39·5), and for adalimumab 35·9% (95% CI 31·2–40·5), 32·9% (26·8–39·2),
and 28·9% (21·9–36·3), respectively. Optimal drug concentrations at week 14 to predict remission at any later
timepoints were 6·1–10·0 mg/L for infliximab and 10·1–12·0 mg/L for adalimumab. After excluding patients who
had primary non-response, the estimated proportions of patients who had loss of response by years 1, 2, and 3
were, for infliximab 34·4% (95% CI 30·4–38·2), 54·5% (49·4–59·0), and 60·0% (54·1–65·2), and for adalimumab
32·1% (26·7–37·1), 47·2% (40·2–53·4), and 68·4% (50·9–79·7), respectively. In multivariable analysis, loss of
response at year 2 and 3 for patients treated with infliximab and adalimumab was predicted by low anti-TNF drug
concentrations at week 14 (infliximab: hazard ratio [HR] for each ten-fold increase in drug concentration 0·45
[95% CI 0·30–0·67], adalimumab: 0·39 [0·22–0·70]). For patients treated with infliximab, loss of response was
also associated with female sex (vs male sex; HR 1·47 [95% CI 1·11–1·95]), obesity (vs not obese 1·62 [1·08–2·42]),
baseline white cell count (1·06 [1·02–1·11) per 1 × 10⁹ increase in cells per L), and thiopurine dose quartile. Among
patients treated with adalimumab, carriage of the HLA-DQA1*05 risk variant was associated with loss of response
(HR 1·95 [95% CI 1·17–3·25]). By the end of year 3, the estimated proportion of patients who developed anti-drug
antibodies associated with undetectable drug concentrations was 44·0% (95% CI 38·1–49·4) among patients
treated with infliximab and 20·3% (13·8–26·2) among those treated with adalimumab. The development of antidrug antibodies associated with undetectable drug concentrations was significantly associated with treatment
without concomitant immunomodulator use for both groups (HR for immunomodulator use: infliximab 0·40
[95% CI 0·31–0·52], adalimumab 0·42 [95% CI 0·24–0·75]), and with carriage of HLA-DQA1*05 risk variant for
infliximab (HR for carriage of risk variant: infliximab 1·46 [1·13–1·88]) but not for adalimumab (HR 1·60
[0·92–2·77]). Concomitant use of an immunomodulator before or on the day of starting infliximab was associated
with increased time without the development of anti-drug antibodies associated with undetectable drug
concentrations compared with use of infliximab alone (HR 2·87 [95% CI 2·20–3·74]) or introduction of an
immunomodulator after anti-TNF initiation (1·70 [1·11–2·59]). In years 2 and 3, 16 (4%) of 389 patients treated
with infliximab and 11 (5%) of 209 treated with adalimumab had adverse events leading to treatment withdrawal.
Nine (2%) patients treated with infliximab and two (1%) of those treated with adalimumab had serious infections
in years 2 and 3.
Interpretation Only around a third of patients with active luminal Crohn’s disease treated with an anti-TNF drug were
in remission at the end of 3 years of treatment. Low drug concentrations at the end of the induction period predict
loss of response by year 3 of treatment, suggesting higher drug concentrations during the first year of treatment,
particularly during induction, might lead to better long-term outcomes. Anti-drug antibodies associated with
undetectable drug concentrations of infliximab, but not adalimumab, can be predicted by carriage of HLA-DQA1*05
and mitigated by concomitant immunomodulator use for both drugs.Guts UKCrohn’s and Colitis UKCure Crohn’s ColitisAbbVieMerck Sharp and DohmeNapp PharmaceuticalsPfizerCelltrion Healthcar