On meta-analysis of 9 RCTs (8 RCTs in adults, and focusing on maintenance phase), there was no significant difference in the risk of failing to maintain clinical remission in patients who underwent proactive TDM (267/709; 38%) vs conventional management (292/696; 42%) (relative risk [RR], 0.96)
The discussion in this paper makes some important points, as there are some populations in which proactive TDM is more likely to be beneficial.
“The impact of proactive TDM in pediatric patients also merits further consideration. This concept may be particularly important in pediatrics due to the variability in size of patients, which may not be adequately addressed by weight-based dosing.33 This is especially important in younger children, where it has been shown that standard TNFα antagonist regimens and trough levels may not be applicable in this age group, and may require more frequent escalation of therapy.34,35 In the PAILOT trial, proactive TDM in children with clinical response to adalimumab was associated with higher rates of maintaining sustained corticosteroid-free clinical remission at all visits from week 8–72, compared with reactive TDM in which physicians were informed of trough concentration only after loss of response.”
Induction Dosing (Adults and Children):
“It is possible that the early measurement of biologic drug concentrations, to identify patients who may have accelerated clearance, and optimization of a subset of these patients early in the course of therapy may offer benefit.1,30 …Ongoing trials such as OPTIMIZE (NCT04835506) and TITRATE (NCT03937609) in which infliximab is optimized during the induction phase through a pharmacokinetic dashboard in patients with Crohn’s disease and acute severe ulcerative colitis will shed further light on this.”
My take: So far, studies in adults have not shown that proactive therapeutic drug monitoring has been effective in improving clinical outcomes. This may change particularly if studies focus on patients on monotherapy who are at increased risk of subtherapeutic levels. No matter what happens in adults, there is sufficient data showing that proactive therapeutic drug monitoring is essential in children. This is especially important as ‘routine” dosing of infliximab in children may be subtherapeutic in nearly 80%.
Design: This was a multicenter, randomized, double-blind, placebo-controlled withdrawal study of infliximab in patients (n=115) with Crohn’s disease who were in clinical, biochemical, and endoscopic remission after standard infliximab maintenance therapy for at least 1 year. Patients were randomly assigned 1:1 to continue infliximab therapy or to receive matching placebo for 48 weeks.
At the end of the trial at week 48, relapse-free survival was 100% in the infliximab-continuation group and 51% in the infliximab-discontinuation group
My take (borrowed from authors): Discontinuation of infliximab for patients with Crohn’s disease receiving long-term infliximab therapy and in clinical, biochemical, and endoscopic remission leads to a considerable risk of relapse
Using a post hoc analysis of 2 large Crohn’s disease (CD) trial with 420 biologic-naive adult patients, the authors found the following Key Findings:
At week 6, a comparable number of patients achieved clinical remission with infliximab compared with patients treated with ustekinumab (44.9% vs 37.9%; adjusted odds ratio [aOR], 1.22)
At week 6 the clinical response rates were not significantly different (58.4% infliximab vs 54.9% ustekinumab; aOR, 1.25)
At week 6, 42.3% infliximab vs 34.7% ustekinumab had fecal calprotectin level less than 250 mcg/L in those with increased values at baseline
My take: A true head-to-head trial, rather than a post-hoc analysis, would more definitively determine relative efficacy and relative time to response. This study indicates that both agents have similar efficacy by week 6.
Anti-TNF durability was 90% at 1 year, 75% at 3 years, and 55% at 5 years
Patients with Crohn’s disease had better durability than those with UC/IBD-U (Hazard ratio 0.17)
The most common reason for discontinuation of anti-TNF were loss of response in 24 (57%) children
67 (66%) received combined therapy with an immunomodulator and this was associated with improved anti-TNF durability (Hazard ratio 0.30). However, authors note this was in era preceding widespread therapeutic drug monitoring.
The majority of children in the current study did not undergo testing for monogenic mutations
My take: Data for use of anti-TNF agents in this age group (< 6 yrs) has been limited. This study suggests similar effectiveness of anti-TNF agents in VEO-IBD compared to older groups. Given this groups increased risk for monogenic mutations, it is still a good idea, if feasible, to test for these disorders.
Biosimilar utilization initiation increased from a baseline of 1% in June 2019 to 96% by February 2021 among eligible patients; 20% of all patients (n-98) had insurance which preferred originator product
Estimated cost savings over the project duration were nearly $381,000 (average sales price) over the 20 month study
My take: The introduction of biosimilars have resulted in huge cost savings. In addition, for infliximab, the originator product price has also dropped substantially (more than 60% in some locations)
Methods: This was a prospective multicenter cohort study of adult IBD patients (n=176) who underwent 2 switches from the originator IFX to CT-P13 to SB2 (group 1), 1 switch from CT-P13 to SB2 (group 2), and 1 switch from the originator IFX to CT-P13 (group 3).
At 12 months after the most recent switch 76.9% (40 of 52, group 1), 65.7% (46 of 70, group 2) and 76.9% (20 of 26, group 3) of patients were in clinical remission. Treatment persistence at 12 months was 85.0%, 87.0%, and 70.1%, respectively.
There were no significant differences in the rate of clinical, CRP, FC remission, or treatment persistence at 12 months between the 3 groups.
My take: This study did not identify detrimental effects from multiple successive switching and switching between biosimilars of IFX. Longer followup and more clinical experience will be needed to confirm these findings.
Background: Whether proactive therapeutic drug monitoring (pTDM) is superior to reactive TDM (rTDM) is not entirely clear, though some studies have shown better outcomes with pTDM. Additionally, Colombel et al (Clin Gastroenterol Hepatol 2019; 17: 1525-32) showed that antidrug antibodies during combination therapy were detected only in those with the lowest quartile of infliximab trough levels; this suggests that optimized monotherapy should be similarly effective to combination therapy.
Methods: The authors retrospectively analyzed a commercial laboratory database (Prometheus) with 3970 patients and paired 6-thioguanine (6-TGN) levels with infliximab (IFX) and antibodies to infliximab (ATIs)
“Those with higher levels of IFX had negligible benefit from concomitant thiopurine treatment in preventing ATIs.”
ATIs were detected in 9.9% of all patients. IFX level of >5 mcg/mL were associated with a very low risk of ATI (OR 0.05). “Immunogenicity was negligible (<3%) in the presence of IFX concentrations greater than 5 mcg/mL.”
6-TGN levels (>125) were associated with lower risk of ATI, OR 0.42; though, this effect had a significant impact, only for those with with IFX <5 mcg/mL.
The authors note the prospective OPTIMIZE study (NCT04835506) should help determine the effectiveness of pTDM.
My take: In patients with IFX levels >5 mcg/mL, there does not appear to be much benefit for most patients from the addition of a thiopurine; this may not be true for those who are switching to a 2nd anti-TNF agent due to antidrug antibodies. This study supports pTDM to assure adequate IFX levels.
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition
In this retrospective study, among those who developed skin reactions to anti-TNF agents, 71 (64%) continued anti-TNF and 40 (36%) switched to ustekinumab (UST). Key findings:
Switching to UST had a higher rate and odds of resolution of skin findings (29/40 (73%) vs. 24/71 (34%); p <0.0001) and combined remission (21 (52%) vs. 22 (31%); p=0.03) vs. continuing anti-TNF at 6 months
Patients (n=181) on established maintenance IV infliximab who switched to SC CT-P13 were included in this retrospective multi-centre cohort study. Key findings:
Treatment persistence rate was high (N=167, 92.3%) and only 14 patients (7.7%) stopped treatment during the follow-up period. There were low rates of immunogenicity with no change in clinical disease activity indices or biomarkers
The panel agreed that reactive TDM should be used for all biologics for both primary nonresponse and secondary loss of response
It was recommended that treatment discontinuation should not be considered for infliximab or adalimumab until a drug concentration of at least 10–15 mg/mL was achieved
Consensus was also achieved regarding the utility of proactive TDM for anti–tumor necrosis factor therapy. It was recommended to perform proactive TDM after induction and at least once during maintenance.
More data are needed with regard to proactive TDM for biologics other than anti-TNF agents
There are no differences in interpreting TDM between originator biologics and biosimilars
When considering switching within drug class in case of secondary loss of response to a first anti-TNF drug because of the development of antidrug antibodies, an immunomodulator should be added to a subsequent anti-TNF therapy
Low-titer antidrug antibodies can be overcome by treatment optimization (dose escalation, dose interval shortening, and/or addition of an immunomodulator)
My take: This article should help support the practice of proactive TDM and discourage stopping anti-TNF agents until an adequate therapeutic level is achieved.
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
Citation: Gorelik Y, Freilich S, Gerassy-Vainberg S, et al Antibiotic use differentially affects the risk of anti-drug antibody formation during anti-TNFα therapy in inflammatory bowel disease patients: a report from the epi-IIRNGut Published Online First: 03 August 2021. doi: 10.1136/gutjnl-2021-325185
This study reviewed data from 1946 patients with 363 who developed anti-drug antibodies (ADA). Then, specific pathogen and germ-free C57BL mice were treated with respective antibiotics and challenged with infliximab. ADA were assessed after 14 days.
Cox proportional hazard model demonstrated an increased risk of ADA development in patients who used cephalosporins (HR=1.97, 95% CI 1.58 to 2.44), or penicillins with β-lactamase inhibitors (penicillin-BLI, HR=1.4, 95% CI 1.13 to 1.74), whereas a reduced risk was noted in patients treated with macrolides (HR=0.38, 95% CI 0.16 to 0.86) or fluoroquinolones (HR=0.20, 95% CI 0.12 to 0.35).
In mice exposed to infliximab, significantly increased ADA production was observed in cephalosporin as compared with macrolide pretreated mice. Germ-free mice produced no ADA.
My take: The combination of retrospective data and mouse studies suggests that taking some antibiotics (mainly penicillins and cephalosporins) could increase the risk of immunogenicity to infliximab and increase the risk of anti-drug antibodies.