Therapeutic Drug Monitoring of Anti-Tumor Necrosis Factor Blocking Agents

Number: 1091

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses therapeutic drug monitoring of anti-tumor necrosis factor blocking agents. 

1. Medical Necessity

   Aetna considers measurement of antidrug antibodies and/or serum drug levels to adalimumab (e.g., Humira), certolizumab (Cimzia), golimumab (Simponi), or infliximab (e.g., Remicade) medically necessary for members with inflammatory bowel disease (IBD) (i.e., Crohn’s disease or ulcerative colitis) who meet either of the following scenarios:

   1. When there is documentation of a loss of response to one of these medications; or
   2. For proactive monitoring in members 21 years of age or younger with confirmed diagnosis of IBD.

   The following list includes examples of protein‑based immunoassays used for serum level and antibody testing (not an all-inclusive list):

   1. ADALX (Adalimumab Quantitative with Reflex to Antibody, Serum) test
   2. Anser ADA or IFX test (Prometheus Lab)
   3. InformTX (Miraca Life Sciences)
   4. PredictrPK IFX (Prometheus Lab)
   5. Procise ADL or IFX (ProciseDX, Inc).

2. Experimental, Investigational, or Unproven

   Aetna considers the following assays experimental, investigational or unproven because the effectiveness of these approaches has not been established:

   1. Measurements of anti-histone antibodies for monitoring infliximab therapy
   2. Measurements of DNA or mRNA biomarkers for predicting therapeutic response in IBD
   3. Measurement of serum levels of antibodies to adalimumab, certolizumab, golimumab, infliximab, or other tumor necrosis factor (TNF) blocking agents (e.g., guselkumab, mirikizumab, ustekinumab, and vedolizumab), either alone or as a combination test that includes serum drug levels, for anti-TNF therapies for all other indications (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, and uveitis).

3. Related Policies 

   • CPB 0249 - Inflammatory Bowel Disease: Biomarker and Thiopurine Pharmacogenomic Testing
   • CPB 0314 - Rituximab
   • CPB 0315 - Etanercept
   • CPB 0341 - Infliximab
   • CPB 0655 - Adalimumab
   • CPB 0715 - Pharmacogenetic and Pharmacodynamic Testing
   • CPB 0720 - Abatacept (Orencia)
   • CPB 0761 - Certolizumab Pegol (Cimzia)
   • CPB 0790 - Golimumab (Simponi and Simponi Aria)
   • CPB 0885 - Vedolizumab (Entyvio)
   • CPB 0905 - Secukinumab (Cosentyx)
   • CPB 0912 - Ustekinumab

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
Measurement of serum levels of antibodies to adalimumab, certolizumab, golimumab and infliximab,,Measurement of anti-drug antibodies to adalimumab (Humira), certolizumab (Cimzia), golimumab (Simponi) and infliximab (Remicade), serum drug levels to certolizumab and golimumab - no specific code
0514U	Gastroenterology (irritable bowel disease [IBD]), immunoassay for quantitative determination of adalimumab (ADL) levels in venous serum in patients undergoing adalimumab therapy, results reported as a numerical value as micrograms per milliliter (μg/mL)
0515U	Gastroenterology (irritable bowel disease [IBD]), immunoassay for quantitative determination of infliximab (IFX) levels in venous serum in patients undergoing infliximab therapy, results reported as a numerical value as micrograms per milliliter (μg/mL)
80145	Adalimumab
80230	Infliximab
CPT codes not covered for indications listed in the CPB:
Measurements of anti-histone antibodies for monitoring infliximab therapy, measurements of DNA or mRNA biomarkers -no specific code
83520	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified
HCPCS codes not covered for indications listed in the CPB (not all inclusive):
J1628	Injection, guselkumab, 1 mg
J2267	Injection, mirikizumab-mrkz, 1 mg
J3357	Ustekinumab, for subcutaneous injection, 1 mg
J3358	Ustekinumab, for intravenous injection, 1 mg
J3380	Injection, vedolizumab, 1 mg
Q5098	Injection, ustekinumab-srlf (imuldosa), biosimilar, 1 mg
Q5099	Injection, ustekinumab-stba (steqeyma), biosimilar, 1 mg
Q5100	Injection, ustekinumab-kfce (yesintek), biosimilar, 1 mg
Q5137	Injection, ustekinumab-auub (wezlana), biosimilar, subcutaneous, 1 mg
Q5138	Injection, ustekinumab-auub (wezlana), biosimilar, intravenous, 1 mg
Q9996	Injection, ustekinumab-ttwe (pyzchiva), subcutaneous, 1 m
Q9997	Injection, ustekinumab-ttwe (pyzchiva), intravenous, 1 mg
Q9998	Injection, ustekinumab-aekn (selarsdi), 1 mg
Q9999	Injection, ustekinumab-aauz (otulfi), biosimilar, 1 mg
Other HCPCS codes related to the CPB:
J0139	Injection, adalimumab, 1 mg
J0717	Injection, certolizumab pegol, 1 mg (code may be used for medicare when drug administered under the direct supervision of a physician, not for use when drug is self administered)
J1602	Injection, golimumab, 1 mg, for intravenous use
J1745	Injection, infliximab, excludes biosimilar, 10 mg
ICD-10 codes covered if selection criteria are met:
K50.00 - K50.919	Crohn's disease [regional enteritis]
K51.00 - K51.919	Ulcerative colitis
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
H20.00 - H20.049	Iridocyclitis
H30.891 - H30.899	Other chorioretinal inflammations
H44.111 - H44.119	Panuveitis
H44.131 - H44.139	Sympathetic uveitis
L40.0 - L40.9	Psoriasis
M05.00 - M05.A	Rheumatoid arthritis with rheumatoid factor
M06.00 - M06.9	Other rheumatoid arthritis
M08.00 - M08.0A	Unspecified juvenile rheumatoid arthritis
M08.20 - M08.2A	Juvenile rheumatoid arthritis with systemic onset
M08.3	Juvenile rheumatoid polyarthritis (seronegative)
M08.40 - M08.4A	Pauciarticular juvenile rheumatoid arthritis
M45.0 - M45.9	Ankylosing spondylitis
M45.A0 - M45.AB	Non-radiographic axial spondyloarthritis

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Background

Measurement of Serum Levels of Anti-Tumor Necrosis Factor (TNF) Inhibitors and Antibodies 

Therapeutic drug monitoring (TDM) usually refers to the measurement of drugs at designated time-points to maintain a constant concentration in an individual's blood-stream (plasma or serum); thus, optimizing dosing regimens. In general, TDM is not needed for the majority of drugs, and it is primarily employed for monitoring drugs with narrow therapeutic ranges, drugs with marked pharmacokinetic variability, drugs for which target concentrations are difficult to monitor, as well as drugs known to cause adverse events.

Gehin and colleagues (2019) identified a therapeutic target interval for certolizumab pegol drug levels and examined the influence of anti-drug antibodies (ADAs) in patients with inflammatory joint diseases (IJDs). Certolizumab pegol and ADA levels were measured in serum samples collected after 3 months of certolizumab pegol treatment in 268 patients with IJDs (116 axSpA, 91 RA, and 61 PsA) in the NOR-DMARD study. Therapeutic response was defined by ASDAS clinically important improvement in axSpA, European League Against Rheumatism (EULAR) good/moderate response in RA, and improvement in 28-joint DAS of greater than or equal to 0.6 in PsA. Serum drug levels and ADAs were analyzed using automated in-house assays. Certolizumab pegol serum levels varied considerably between individuals (median inter-quartile range [IQR] 32.9 (17.3 to 43.9) mg/L). Certolizumab pegol level of greater than or equal to 20 mg/L was associated with therapeutic response for the total IJD population, with odds ratio (OR) 2.3 (95% CI: 1.2 to 4.5, p = 0.01) and OR 1.9 (95% CI: 1.0 to 3.5, p = 0.05) after 3 and 6 months of treatment, respectively. For individual diagnoses, this association was most consistent for axSpA, with OR 3.4 (95% CI: 1.0 to 11.1, p < 0.05) and OR 3.3 (95% CI: 1.0 to 10.8, p < 0.05), respectively. Certolizumab pegol level of greater than 40 mg/L was not associated with any additional benefit for any of the diagnoses; ADAs were detected in 6.1% (19/310) of samples and were associated with low certolizumab pegol levels (p < 0.01). The authors concluded that serum certolizumab pegol levels of 20 to 40 mg/L were associated with therapeutic response in IJDs. These researchers stated that this study was the 1st to show this association in axSpA and PsA patients. They stated that these findings suggested a possible benefit of therapeutic drug monitoring (TDM) in patients with IJD on certolizumab pegol treatment; however, the clinical significance of tailoring TNF inhibitor (TNFi) treatment in IJDs by TDM should be further examined in randomized controlled trials (RCTs). Moreover, these researchers stated that the lack of data on body weight and of more extensive joint counts in PsA patients was a drawback of this study.

Fumery, et al. (2023) noted that loss of response (LOR) to golimumab (GLM) occurs in nearly 40% of patients with ulcerative colitis (UC). Unlike other anti-tumor necrosis factor (TNF) inhibitors, no study has reported a correlation between serum GLM level and response to drug intensification. In a prospective, multi-center study, these researchers examined the safety and effectiveness of GLM intensification and identified the best threshold of serum GLM before drug intensification predictive of response. Patients with loss of response at 50-mg q4 weeks (W) and 100-mg q4W underwent therapeutic intensification at 100-mg q4W and 100-mg q2W, respectively. Safety and effectiveness were assessed between Weeks 2 and 4 (visit 2) and between Weeks 4 and 8 (visit 3) after intensification. Serum level and anti-GLM antibodies were evaluated at each medical visit. A total of 47 UC patients (50% women; median age of 39 years (inter-quartile range [IQR], 27 to 52)) treated with GLM for a median of 20.4 weeks (IQR, 10.7 to 38.3) were included. The median partial Mayo score was 6 (IQR, 5 to 7), and the median endoscopic Mayo score was 3 (IQR, 2 to 3). The median serum GLM level before intensification was 2.23 μg/ml (IQR, 1.02 to 3.96) and only 1 patient (2.1%) had anti-drug antibodies. At Visit 2 (Week 2 to 4), 40% of patients experienced clinical response, 10% clinical remission, 33% endoscopic response, and 23% endoscopic remission. At Visit 3 (Week 4 to 8), 44% of patients had clinical response, 22% of patients had clinical remission, 45% of patients had endoscopic response, and 41% of patients had endoscopic remission. The median GLM levels before intensification did not differ between responders and non-responders (2.13 μg/ml (0.76 to 2.76) and 3.37 μg/ml (IQR, 1.08 to 4.67), respectively; p = 0.14) assessed at Visit 3. Golimumab intensification to 100-mg q4W (versus q2W) (OR 1.98, 95% CI: 1.06 to 3.70]; p = 0.032) was significantly associated with clinical remission at Visit 3. Serum drug level at baseline or the presence of anti-drug antibodies were not associated with clinical or endoscopic remission/response. Two serious adverse events (AEs; 1 infection and 1 UC flare) were reported during the 24-week follow-up. The authors concluded that in this prospective, multi-center study, 50% of patients recaptured response after GLM intensification in UC; TDM did not predict response after optimization of GLM.

In an editorial commentary on the aforementioned study by Fumery, et al. (2023), Hanzel and Drobne (2023) noted that this trial offered valuable data on GLM dosing intensification with reasonably good clinical outcomes and a clear message that dosing intensification should be offered to all patients losing response as neither drug concentrations nor the presence of anti-drug antibodies had any impact on the outcome of dosing intensification. The editorialists stated that with a larger sample size, the numeric differences in drug concentrations may reach statistical significance; however, their clinical significance would be questionable. In addition, long-term clinical and endoscopic data beyond 8 weeks would have been a valuable addition to further inform clinical practice, which may see a rekindled interest in GLM contingent upon the results of ongoing trials of dual biologic therapy with guselkumab and GLM.

In a systematic review and meta-analysis, Sethi, et al. (2023) examined if the use of TDM in inflammatory bowel disease (IBD) patients on anti-TNF therapy would result in improved rates of clinical and endoscopic remission, surgery, corticosteroid-free remission, and hospitalization. Medline, Embase, Embase Classic, PubMed, Cochrane central databases register of controlled trials, and Cochrane Specialized Trials Register were searched between January 1, 1946, and April 8, 2022. Randomized controlled trials (RCTs) and prospective and retrospective observational studies were included, comparing TDM to standard of care (SOC) or reactive versus proactive TDM. Results were reported as pooled relative risks (RR) with 95% confidence intervals (95% CI). A total of 26 studies, including 9 RCTs, were included. Compared to SOC, proactive TDM was associated with a significantly decreased risk of treatment failure (RR 0.64, 95% CI: 0.48 to 0.85 p < 0.01), and a non-significant decrease in the need for surgery (RR 0.51, 95% CI: 0.25 to 1.02) and hospitalization (RR 0.64, 95% CI: 0.40 to 1.00). In addition, compared to SOC, proactive TDM was associated with higher rates of endoscopic remission (RR 1.19, 95% CI: 0.93 to 1.53) and clinical remission (RR 1.07, 95% CI: 0.97 to 1.18). Compared to reactive TDM, proactive TDM was associated with a significant decreased risk of treatment failure (RR 0.46, 95% CI: 0.21 to 0.98, p = 0.04) and significant reduction in hospitalization (RR 0.33, 95% CI: 0.21 to 0.54, p < 0.01). The authors concluded that compared to SOC, proactive TDM was associated with significant benefit in reducing treatment failure. Compared to reactive TDM, proactive TDM resulted in a significant reduction in hospitalization and treatment failure. Moreover, these researchers stated although these results suggested that TDM may have some benefits, further large, high-quality RCTs and standardized assays are needed to confirm these findings and validate the cost-effectiveness of TDM. These researchers stated future studies are also needed to compare different proactive TDM protocols with one another to examine if an optimal protocol exists. While currently the evidence base is strongest for IFX in terms of exposure-response relationship, future TDM studies should focus on the newer biologics such as ustekinumab, vedolizumab, and tofacitinib, which are now being used more routinely in clinical practice.

The authors stated that this meta-analysis had several drawbacks. First, the included studies varied in study design, resulting in significant heterogeneity. Second, the conclusions were limited by the quality of the studies, many of which had a small sample size. More importantly, assays used in TDM were varied and not yet standardized; thus, may account for differences in the results. Standardizing assays may be an important step to aid in improving the accuracy and generalizability of TDM. Third, these findings, as with most RCTs, were based on a largely Western population meaning they would be difficult to generalize globally. Therefore, the results from this meta-analysis should be interpreted with caution.

Roblin, et al. (2024) stated that TDM has an important role in the management of IBD patients on infliximab (IFX) or adalimumab (ADA); and is recommended in IBD patients presenting a loss of response under anti-TNF agent; however, TDM was not recommended for other biotherapies. These researchers examined all publications regarding TDM and biologics in IBD patients and reported the major results for each biotherapy. Expert opinion: Emerging data suggested that TDM will probably be similarly useful for subcutaneous IFX (IFX SC). In contrast, there is no demonstrated clinical benefit to the use of TDM with GLM. For vedolizumab (VDZ): Results for the use of both reactive and proactive TDM were discordant. For ustekinumab (UST): Data supported the existence of an exposure-response relationship, albeit of a lesser magnitude than with anti-TNF agents. Lastly, recent data from small case series suggested that TDM could be valuable in optimizing anti-IL23 agents, especially risankizumab; however, this requires further clarification. Consistent with the new concept of "proactive" strategy, recent data supported the use of dashboard-driven model-informed precision dosing (MIDP) of anti-TNF agents, in particular IFX. Dashboards are software systems using Bayesian population pharmacokinetic modeling to individualize recommendations for target drug levels. These investigators stated that the use of reactive TDM with anti-TNFs is recommended by most learned societies in the management of LOR to anti-TNFs in IBD. Whether proactive TDM with anti-TNFs should be used routinely in all IBD patients on anti-TNF agents remains to be determined.

In a retrospective study, Song, et al. (2024) examined the role of TDM-guided optimization of IFX dosage in patients with pediatric Crohn’s disease (CD). Medical records of patients with pediatric CD who were treated with IFX and had proactive TDM from June 2020 to June 2022 at the Children's Hospital of Chongqing Medical University were included. Baseline influencing factors for IFX trough concentration (TC) and clinical outcomes before and after the treatment change were analyzed to examine the value of adjusting treatment in the patients. A total of 46 patients (male-to-female ratio = 1.55:1, age of less than 18 years) were included. Uni-variate and multi-variate analyses demonstrated that hormone exposure (OR: 0.042, 95% CI: 0.002 to 0.924, p = 0.044), peri-anal lesions (5.813, 0.984 to 34.349, p = 0.052), simplified endoscopic score for CD (1.656, 1.065 to 2.577, p = 0.025), and total protein (TP) (0.851, 0.749 to 0.967, p = 0.014) were correlated with IFX TC. Shortening the treatment interval increased the IFX TC (pre versus post = 1.69 ± 0.8 versus 12.03 ± 6.64, p = 0.001, n = 12) after 93.9 ± 37.47 days, lowered the pediatric CD activity index and simplified endoscopic score for CD, and increased the biochemical remission, clinical remission, endoscopic remission, as well as endoscopic response rates; however, there was no statistical significance. The authors concluded that hormone exposure, simplified endoscopic score‐CD, peri-anal lesions, and TP levels during the 1st IFX use were factors that affected TC. The shortened interval adjustment guided by proactive TDM could improve IFX concentration and biochemical remission, creatine, as well as endoscopic remission rates after 3 months; however, the long‐term maintenance effect of the concentration may require further investigations with long‐term follow‐up, as well as evaluation of health and economic value.

These researchers stated that the small sample size (n = 46) and retrospective design were the principal drawbacks of this trial. Moreover, inter‐group comparison between different optimization protocols could not be carried out. Furthermore, data retrieval under the set inclusion criteria did not reflect the real situation of all patients. In addition, short follow‐up time and the lack of a control cohort were other weaknesses. These researchers stated that future investigations with a larger sample size and long‐term follow‐up are needed. In particular, prospective, large‐scale, clinical trials implementing natural outcome control, superposition of different optimization schemes, and switching biological drugs, would provide a more comprehensive approach and better guidance for clinical practice.

Gonzalez-Lama, et al. (2024) stated that despite research, there are still controversial areas in the management of CD. These researchers noted that while TDM has emerged as a principal element to optimize the use of biological therapies in managing patients with CD (dose escalation, dose interval shortening, and adding an immunomodulator), the role of proactive TDM remains controversial. Low drug levels and the subsequent loss of response are usually related to immunogenicity, which has been linked, among others, to HLA-DQA1*0526; nevertheless, the impact of HLA determination in clinical practice is still debatable.

Kawano-Dourado, et al. (2024) noted that standard care for immune-mediated inflammatory diseases includes prescribing biologic drugs at pre-determined doses. Dosing may be adjusted reactively; namely, with increased disease activity. In proactive TDM, serum drug levels and anti-drug antibodies are measured irrespective of disease activity, and the drug dosing is adjusted to achieve target serum drug levels, usually within pre-specified therapeutic ranges. The role of proactive TDM in clinical practice remains unclear, with conflicting guideline recommendations and emerging evidence from randomized controlled trials (RCTs). These researchers examined if proactive TDM, as compared with standard care, would improve outcomes in adult patients with IBD, inflammatory arthritis (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis), or psoriasis taking biologic drugs. They carried out a systematic review and pair-wise meta-analysis that identified 10 studies including 2,383 subjects. Inflammatory bowel disease, inflammatory arthritis, and psoriasis were grouped together as best current research evidence on proactive TDM did not suggest heterogeneity of effects on outcomes of interest. Proactive TDM of intravenous IFX during maintenance treatment may increase the proportion of patients who experience sustained disease control or sustained remission without considerable additional harm. For ADA, it remains unclear if proactive TDM during maintenance treatment has an effect on sustained disease control or sustained remission. At induction of treatment, proactive TDM of intravenous IFX may have little or no effect on achieving remission. No eligible trial evidence was available for proactive TDM of ADA at induction of treatment. No eligible trial evidence was available for proactive TDM of other biologic drugs in maintenance or at induction of treatment. The authors stated that the guideline panel issued the following recommendations for patients with IBD, inflammatory arthritis, or psoriasis: First, a weak recommendation in favor of proactive TDM for intravenous IFX during maintenance treatment. Second, a weak recommendation against proactive TDM for ADA and other biologic drugs during maintenance treatment. Third, a weak recommendation against proactive TDM for intravenous IFX, ADA, and other biologic agents during induction of treatment. Moreover, these researchers stated that further investigations are needed and may alter recommendations in the future.

In a systematic review and meta-analysis, Zeraatkar, et al. (2024) examined the safety and effectiveness of proactive TDM of biologic drugs for patients with IBD, inflammatory arthritis, and psoriasis. Data sources included Medline, Embase, Central, and CINAHL from database inception to May 23, 2024. Selected studies included patients with IBD, inflammatory arthritis, and psoriasis; selected trials also randomly assigned participants to either proactive TDM of TNF-alpha inhibitors or other biologic drugs in the intervention group, and to either no TDR or standard care in the control group. Reviewers worked independently and in duplicate to screen search records and collect data from eligible studies. For each outcome, a frequentist, pair-wise, random effects meta-analysis was carried out; and the certainty of evidence was assessed using GRADE (grading of recommendations, assessment, development, and evaluations). Of 10 eligible studies identified, reporting on 2,383 patients, 2 examined induction with IFX (533 patients), 4 examined maintenance with IFX (901 patients), and 3 examined maintenance with ADA (710 patients). One trial was of maintenance with IFX, ADA, and etanercept (239 patients). For patients who had induction with IFX, the effects of proactive TDM on remission and AEs were uncertain. Low certainty evidence suggested that proactive TDM may have little or no effect on disease activity, physical function, mental health, and quality of life (QOL). For patients who had maintenance with IFX, low certainty evidence suggested that proactive TDM may increase the proportion of patients who had sustained disease control or remission (relative risk [RR] 1.26 (95% confidence interval [CI]:1.14 to 1.40), absolute risk difference of 146 more per 1,000 patients treated for 1 year (95% CI: 78 to 224). Furthermore, this treatment and monitoring may reduce disease worsening, and may have little or no effect on disease activity, physical function, mental health, and QOL. The effects of proactive TDM of IFX on AEs and formation of anti-drug antibodies were uncertain. For patients who had maintenance with ADA, the effects of proactive TDM were uncertain. The authors concluded that this systematic review and meta-analysis examined the safety and effectiveness of proactive TDM in patients with IBD, inflammatory arthritis, and psoriasis. For patients undergoing induction, these investigators found low certainty evidence that TDM of IFX may have little or no effect on sustained remission, disease activity, QOL, physical function, and mental health. Conversely, for patients undergoing maintenance, low certainty evidence suggested that proactive TDM of IFX may increase the proportion of patients who experience sustained disease control or remission, may reduce disease worsening, and may have little or no effect on disease activity, physical function, mental health, and QOL. Moreover, these researchers were very uncertain of the effects of proactive TDM of ADA during maintenance.

The authors stated that despite their rigorous search of the literature, it was possible that they missed eligible trials. These researchers mitigated this limitation by also reviewing the references of similar systematic reviews and soliciting experts regarding eligible studies that might not have come up in their search. These investigators examined the certainty of evidence using the GRADE approach. While the GRADE approach presents a comprehensive framework for considering all factors that might bear on the certainty of evidence, its use is ultimately subjective, and other readers might come to different conclusions regarding the certainty of evidence. While these researchers attempted to focus on all outcomes that would be important to patients, none of the studies examined participation in work or education. These investigators restricted eligibility to randomized trials, which are more likely than non-randomized studies to provide credible estimates on effectiveness. Trials, however, could include patients who were less representative of those encountered in clinical practice (e.g., punctual and meticulous in attending appointments). In addition, only 2 studies examined the effects of proactive TDM in children and adolescents. Lastly, this review focused on patient-important outcomes and the authors did not review outcomes such as endoscopic remission, because such outcomes might not reflect patients' subjective experience.

In a systematic review and meta-analysis, Mancenido Marcos, et al. (2024) examined the safety and effectiveness of proactive TDM versus conventional management during maintenance treatment with anti-TNFα in patients with IBD. These investigators carried out a search up to January 2022 (Medline, Embase, and the Cochrane Library). The primary outcome was the ability to maintain clinical remission at 12 months. The certainty of evidence was determined using the GRADE approach. A total of 9 studies were identified: 1 systematic review, 6 randomized clinical trials, and 2 cohort studies. No superior effectiveness of proactive TDM (RR 1.16; 95% CI: 0.98 to 1.37, n = 528; I2 = 55%) was shown. Proactive TDM could improve the durability of anti-TNFα treatment (odds ratio [OR] 0.12; 95% CI: 0.05 to 0.27; n = 390; I2 = 45%), prevent acute infusion reactions (OR 0.21; 95% CI: 0.05 to 0.82; n = 390; I2 = 0%), decrease AEs (OR 0.38; 95% CI: 0.15 to 0.98; n = 390; I2 = 14%), and reduce the probability of surgery, at lower economical expenditure. The authors concluded that available evidence did not confirm the superiority of proactive TDM of anti-TNFα treatment over conventional management in patients with IBD; therefore, proactive TDM should not currently be recommended.

Chen, et al. (2024) noted that anti-TNF monoclonal antibodies, especially IFX and ADA, are considered the 1st-line treatment for active CD; however, the predictive role of TDM of serum anti-TNF in monitoring the treatment of IBD remains controversial. In a retrospective, cross-sectional study, these investigators examined the correlation between serum anti-TNF levels and early endoscopic response in active CD using a TDM-based nomogram. They evaluated the simplified endoscopic activity score for CD (SES-CD), Crohn's disease activity index (CDAI), laboratory parameters, as well as the serum trough levels of IFX and ADA. The trough levels of IFX or ADA were significantly higher in patients with endoscopic response compared to non-responders in the development cohort (p < 0.001). The IFX and ADA levels showed a weak but significantly negative correlation with SES-CD (p < 0.001), CDAI (p < 0.001), and C-reactive protein (CRP) (p < 0.001) at week 14 post-IFX therapy in the development cohort. In addition, the receiver operating characteristic (ROC) curve showed that an optimal level of IFX (4.80 μg/ml) and ADA (8.80 μg/ml) demonstrated the best performance in predicting endoscopic response. Concomitantly, these researchers developed a novel nomogram prediction model based on the results of multi-variate logistic regression analysis, which consisted of CRP, albumin (Alb), and anti-TNF trough levels at week 14. The nomogram revealed significant discrimination and calibration for both IFX and ADA in the development cohort and performed well in the external validation cohort. The authors concluded that the findings of this study showed a robust association between serum concentrations of IFX, ADA, Alb, and CRP and primary endoscopic response in active CD patients. More importantly, the TDM- and laboratory marker-based nomogram may be used to assess the primary endoscopic response to anti-TNF therapy, especially for optimizing treatment strategies and switching therapy in CD patients.

The authors stated that this study had several drawbacks. First, although the relationships between the serum concentrations of IFX and ADA, Alb, CRP, and the efficacy outcomes were both robust and consistent, these data were retrospective and may have been influenced by other factors in addition to both clinical outcomes and drug concentrations. Second, as a retrospective study, the grading of SES-CD was based solely on previous colonoscopy images in the developmental cohort. Third, only 416 patients were included in this trial, including 237 for IFX and 179 for ADA; more prospective, multi-center studies are needed to examine the predictive value of the TDM-based nomogram.

Durham, et al. (2025) stated that IBDs comprise a group of chronic GI disorders characterized by periods of relapse and remission. The mainstay of treatment is medical, involving medications such as steroids, immune modulators, monoclonal antibodies (categorized as biologics), and small molecules. These medications can provide therapeutic benefits; however, they can also cause severe and irreversible toxicities. Clinicians may employ laboratory tests in the diagnosis and management of IBD including assessment of disease activity, monitoring medication response or toxicity, surveillance of infectious complications, as well as detection of nutritional deficiencies. Routine use of laboratory tests may aid clinicians in avoiding re-activation of life-threatening infections such as tuberculosis or hepatitis B virus upon initiation of immune-suppressive therapy. They can also be used to detect vitamin deficiencies such as B12 deficiency, which has the potential to cause irreversible neurologic damage. While some laboratory tests constitute established practices, the use of newer tests such as TDM in the era of biologics is an evolving topic. Although clinical assessment with imaging, endoscopic, and histopathological examination is standard practice, laboratory tests serve as valuable adjuncts. These investigators examined the broad range of laboratory tests available to clinicians; and summarized their use in the current management of IBD in daily clinical practice, with special attention to updates in TDM. The authors noted that several prospective and retrospective studies have been published on the topic of TDM in IBD, and limited evidence indicated that proactive TDM offers reproducible benefit to patient management; and TDM for biologics is mostly limited to anti-TNF drugs in settings of treatment failure.

Lim, et al. (2025) noted that recent studies showed that proactive TDM could improve clinical outcomes in patients with IBD treated with IFX. Repetitive IFX trough level (IFX TL) measurements for proactive TDM may increase patient inconvenience and medical costs. In a prospective study, these investigators examined the optimal interval for TDM during IFX maintenance therapy in patients with IBD. This trial was carried out on the patients with IBD who were in clinical remission on IFX maintenance therapy and had IFX TL of 3 μg/ml or higher after 1-time dose optimization. IFX TL were measured before each IFX infusion to identify the pharmacokinetic (PK) relapse (2 consecutive IFX TL of less than 3 μg/ml). Kaplan-Meier method was used to calculate the time to PK relapse. A total of 103 patients were enrolled and followed for a median of 18.5 months. PK relapse occurred in 19 patients (18.5%), with a higher rate of PK relapse in patients with IFX TL of 3 to 5 μg/ml (16/60, 26.7%) compared to those with IFX TL of 5 μg/ml or higher (3/43, 7.0%). Kaplan-Meier survival time to maintain 95%, 90%, 85%, 80%, and 75% therapeutic IFX TL persistence rate without PK relapse was 4.1, 10.3, 13.3, 14.3, and 19.8 months, respectively. Log-rank test showed that therapeutic IFX TL persistence rates were significantly lower in patients with IFX TL of 3 to 5 μg/ml group compared to those with IFX TL of 5 μg/ml or higher group (p = 0.010). Kaplan-Meier retention time to maintain 85% therapeutic IFX TL persistence rate without PK relapse was 10.3 months in IFX TL 3 to 5 μg/ml group and 20.2 months in IFX TL 5 μg/ml or higher group, respectively. The authors concluded that the findings of this study suggested that annual measurement of IFX TL was beneficial for proactive TDM in patients with IBD and stable IFX maintenance therapy. This approach may aid in reducing repetitive and unnecessary IFX TL measurements, which can reduce patient inconvenience and the medical costs consumed in proactive TDM. Moreover, these researchers stated that further prospective, large-scale studies are needed to ascertain the optimal interval of proactive TDM in patients with IBD.

The authors stated that this trial had several drawbacks. First, the majority of subjects in this study were patients with CD. Previous studies reported that PK relapse appeared common in UC, whereas pharmacodynamic failure appeared common in CD. Strict reimbursement policy of the Korean government did not allow dose intensification in patients with UC, not in patients with CD. As a result, many UC patients with sub-therapeutic IFX TL were changed to SC IFX during the dose optimization period in Korea. Second, the cut-off value for therapeutic IFX TL was set at 3 µg/ml or higher. According to recent expert consensus from the BRIDGe group, the minimal IFX TL for patients in remission during maintenance should be greater than 3 mg/ml; thus, in this study, these investigators set the cut-off value aiming to achieve and maintain TL of 3 µg/ml or higher. Third, the findings of this study should be applied to stable IBD patients with clinical remission and scheduled IFX maintenance therapy. Proactive TDM may be especially important for patients with more severe disease activity and higher drug clearance, including patients with induction therapy, acute severe UC, and more severe CD. These patients exhibited a high inflammatory burden and an increased drug clearance, which increased their risk of inadequate drug exposure, immunogenicity, as well as treatment failure. Therefore, more frequent measurement of IFX TL should be carried out in these patients. Fourth, the median follow-up period of 18.5 months, while reasonable, might not capture longer-term outcomes and the potential for delayed relapses. These investigators stated that longer follow-up could provide additional insights into the durability of the proposed TDM intervals.

Ishida and Sugimoto (2025) stated that IFX remains a key treatment for IBD despite the emergence of new therapies. However, treatment failure due to primary non-response or loss of response is common and often linked to low IFX TLs or anti-drug antibodies; hence, TDM has become a tool in optimizing IFX therapy. Frequent TDM, while beneficial, is not always practical due to cost and burden, making appropriate interval determination essential. Lim et al. (2025) conducted a longitudinal study of 228 IBD patients receiving IFX, performing TDM approximately every 2 months. They found that 85% of patients with TLs of greater than 3 µg/ml at week 14 maintained therapeutic levels for over 13 months without PK relapse. Annual TDM may be sufficient for stable patients. Notably, drug antibodies were mostly detected after a drop in IFX levels, emphasizing the importance of preventing TL decline. Ishida and Sugimoto noted that while several limitations of the study by Lim et al. (2025) were discussed by the authors, other limitations were present. The study did not provide detailed stratified analysis data regarding the use of immunomodulators. Since the concomitant use of immunomodulators may affect the immunogenicity of IFX, it was unclear how this concomitant therapy affected IFX pharmacokinetics. Additionally, many of the patients in this study had CD; the authors included a subgroup analysis of the CD-only subgroup even though an analysis of only patients with UC is desirable. Since the trial was carried out at a Korean facility, there was a provision for increasing the dose of IFX regardless of clinical effectiveness, a practice that is not followed in many countries in which an increase in the dose is permitted only when the effect is insufficient, limiting global generalization of the results. Ishida and Sugimoto concluded that combining IFX TDM with clinical, endoscopic, and biomarker monitoring may enhance patient outcomes. Genetic and serologic markers, such as HLA-DQA1*05 and PR3-ANCA, may aid in predicting treatment response. These researchers stated that despite newer options, IFX remains central in the treatment of patients with IBD, and individualized TDM strategies could support more effective and patient-centered care.

Chen, et al. (2025) noted that ADA taken every other week is an effective treatment in patients with chronic refractory uveitis. Patients who have a sub-optimal response to this treatment may suffer from recurrent inflammation and vision loss. In a retrospective, observational study, these investigators examined the use of TDM and neutralizing anti-drug antibody detection as a strategy to optimize TNF-alpha inhibitor treatment in patients who have a sub-optimal response to the initial dosing of ADA. This trial was carried out in 2 tertiary referral uveitis services in the U.S. between 2015 and 2023. Patients with non-infectious uveitis who had a sub-optimal response to every 2-week dosing of ADA and underwent serum ADA level with reflex to anti-drug antibody testing were followed. Subjects were considered to have neutralizing drug antibodies when serum drug levels were low (less than or equal to 6 ug/ml) and anti-ADA antibodies were present on reflex testing. Treatment adjustment was made by clinicians with the knowledge of serum ADA level and the presence or absence of neutralizing drug antibodies. Every 2-week dosing of ADA was either escalated to weekly dosing or switched to IFX based on these findings. The primary outcome was success or failure at 12 months, as determined by disease inactivity on steroid-sparing therapy. A total of 32 patients with suboptimal response to the initial dosing of ADA were included; 31.2% (n = 10) of patients were found to have neutralizing drug antibodies. All subjects with neutralizing drug antibodies underwent a medication switch to IFX with a remission rate of 40% at 12 months. Subjects without neutralizing drug antibodies (n = 22) underwent dose escalation (77.3%; n = 17) or medication switch (22.7%; n = 5) and achieved a remission rate of 68.2% at 12 months. Altogether, treatment adjustment based on TDM and neutralizing drug antibody detection, in this cohort, resulted in a remission rate of 62.5%. The authors concluded that for patients with uveitis experiencing sub-optimal therapeutic response to ADA dosed every 2 weeks, TDM and neutralizing drug antibody detection may aid clinicians in optimizing TNF-alpha inhibitor treatment. Moreover, these researchers stated that TDM and neutralizing ADA detection is a promising strategy to guide treatment modifications in patients who have a sub-optimal response to the initial every 2-week dosing of ADA; a prospective, larger, randomized trial is needed.

The authors stated that this trial was limited by its retrospective and observational design. It was also limited by a smaller sample size (n = 32), which may limit validity and generalizability. Furthermore, repeat serum level testing may provide more insight as to whether dose escalation would result in higher serum levels and improve clinical response. In patients who were switched to IFX, measuring serum IFX levels and detection of neutralizing ANA to IFX will also aid in determining if patients who developed neutralizing ANA to one biologic agent are more likely to develop neutralizing ANA to another.

An American College of Rheumatology (ACR) guideline on "The treatment of rheumatoid arthritis" (Fraenkel et al., 2021) did not mention TDM. Furthermore, an ACR guideline on "The treatment of juvenile idiopathic arthritis" (Onel et al., 2022) provided the following info regarding medication monitoring:

TNF inhibitor (TNFi): Monitoring via complete blood cell (CBC) counts and liver function tests (LFTs) annually is conditionally recommended. (Very Low Certainty of Evidence)

This guideline did not mention monitoring of serum antibodies to TNFi, either alone or as a combination test that includes serum drug levels.

An UpToDate review on "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors" (Lichtenstein, 2025) states that "Therapeutic drug monitoring involves measuring serum drug trough concentrations and anti-drug antibodies to optimize the use of anti-TNF agents for patients with inflammatory bowel disease. Some patients who initially achieve remission will develop secondary loss of response. Reactive drug monitoring in this setting can help the clinician decide whether dose escalation is needed or if switching to a different drug is preferred. For patients in clinical remission, we reserve therapeutic drug monitoring for patients at higher risk of complications from a disease flare, rather than performing it routinely in all patients."

The American College of Gastroenterology (ACG)’s updated clinical guideline on "Management of Crohn’s Disease in Adults" (Lichtenstein et al., 2025) stated that CD is an idiopathic inflammatory disorder of unknown etiology with genetic, immunologic, and environmental influences. The incidence of CD has steadily increased over the past several decades. The diagnosis and treatment of patients with CD has evolved since the last practice guideline was published. These guidelines represent the official practice recommendations of the ACG and were developed under the auspices of the Practice Parameters Committee for the management of adult patients with CD. The updated guideline recommended the following:

• Biologic therapy (including anti-IL-12/23 therapy, anti-TNF therapy, and anti-integrin therapy) dose optimization may be considered for patients with inadequate or loss of response to that specific biologic agent's induction and maintenance.

The ACG’s updated clinical guideline on "Ulcerative Colitis in Adults" (Rubin et al., 2025) stated that UC is an idiopathic inflammatory disorder of unknown etiology that appears to be rising in incidence and prevalence globally. These updated guidelines were developed to indicate the preferred approach to the management of adult patients with UC as established by valid scientific research and represent the official practice recommendations of the ACG under the auspices of the Practice Parameters Committee. The scientific evidence for the recommendations made in these guidelines was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, assessing the quality of the evidence (high, moderate, low, or very low) and assigning a strength of recommendation based on its apparent clinical benefit (strong or conditional). In instances where the available evidence was not appropriate for a formal GRADE recommendation, but there was consensus of significant clinical merit, statements were developed using expert consensus (termed key concept statements). The updated guideline recommended the following:

• There is insufficient evidence supporting a benefit for proactive TDM in all unselected patients with UC in remission.
• There is insufficient evidence to recommend assessment of serum concentrations of vedolizumab, ustekinumab, guselkumab, mirikizumab, or risankizumab.

Proactive Monitoring in Children and Adolescence with Inflammatory Bowel Disease

Assa et al. (2019) investigated the impact of proactive monitoring of drug trough concentrations and antibodies on treatment response and efficacy in pediatric patients with Crohn's disease (CD). In their nonblinded, randomized controlled trial involving 78 children aged 6 to 18 years who had not previously received biologic treatment but responded to adalimumab induction therapy, participants were assigned to either proactive monitoring (with trough concentrations measured at weeks 4 and 8, then every 8 weeks until week 72) or reactive monitoring (where trough concentrations were assessed only after a loss of response). The study found that 82% of children in the proactive group achieved sustained corticosteroid-free clinical remission compared to 48% in the reactive group (P = .002). Additionally, 42% of the proactive group met a composite outcome of sustained remission and normal inflammatory markers, versus 12% in the reactive group (P = .003). By week 72, a higher percentage of patients in the proactive group had their adalimumab intensified (87% vs. 60%, P = .001). The results indicate that proactive monitoring significantly enhances the likelihood of achieving corticosteroid-free clinical remission compared to reactive monitoring. Clinicaltrials.gov no.: NCT02256462.

Pinto Pais et al. (2020) highlight that biological agents have transformed the treatment of inflammatory bowel disease; however, issues such as primary nonresponse and secondary loss of response remain prevalent, leading to negative outcomes. Clinical trials have shown a correlation between serum drug concentrations and the presence of antidrug antibodies with loss of response, suggesting that therapeutic drug monitoring (TDM)—which involves assessing drug levels and antidrug antibodies—could be an effective strategy to optimize treatment and maximize the benefits of these medications. TDM is particularly promising in clinical practice for pediatric patients, who often experience significant variations in drug pharmacokinetics. The authors provide a literature review focused on optimizing antitumor necrosis factor therapy through personalized treatment strategies based on TDM, along with potential approaches to address loss of response, including a practical management algorithm.

Lyles et al. (2021) highlight that there is a lack of reports on the feasibility and effectiveness of implementing proactive therapeutic drug monitoring (TDM) for anti-tumor necrosis factor (TNF) therapy in inflammatory bowel disease as part of practice-wide quality improvement (QI) initiatives. This study aimed to evaluate whether a TDM QI program could enhance outcomes in a large academic pediatric gastroenterology practice. The researchers established local anti-TNF TDM guidelines to proactively monitor and optimize drug levels, targeting levels greater than 5 μg/mL. They conducted a retrospective cohort analysis of patient outcomes before (pre-TDM) and after (post-TDM) the implementation of these guidelines, using multivariable regression to assess the independent effects. The primary outcome measured was sustained clinical remission (SCR22-52), defined as a physician global assessment (PGA) of inactive disease from 22 to 52 weeks while off corticosteroids at 52 weeks. The analysis included 108 pre-TDM and 206 post-TDM patients, revealing that SCR22-52 was achieved in 42% of pre-TDM patients compared to 59% of post-TDM patients (risk difference, 17.6%; 95% CI, 5.4-29%; P = 0.004). The post-TDM group demonstrated increased adjusted odds of achieving SCR22-52 (odds ratio, 2.03; 95% CI, 1.27-3.26; P = 0.003) and a lower adjusted risk of developing high titer antidrug antibodies (ADAs) (hazard ratio, 0.18; 95% CI, 0.09-0.35; P < 0.001). While the overall risk of anti-TNF cessation was not significantly different, the post-TDM group had a lower adjusted risk of cessation due to any detectable ADA (hazard ratio, 0.45; 95% CI, 0.26-0.77; P = 0.003). The authors concluded that the implementation of a proactive anti-TNF TDM QI program significantly improved key clinical outcomes at the institution, including sustained clinical remission, the incidence of high titer ADAs, and anti-TNF cessation related to ADAs.

Cheifetz et al. (2021) highlighted that TDM of biologics is a rapidly advancing area in the management of IBD. Their objective was to create a consensus statement on the clinical relevance of TDM for biologics in IBD, utilizing a modified Delphi method to develop these statements. After conducting a comprehensive literature review on TDM in IBD, they formulated 45 statements regarding its potential applications. These statements were presented to a panel of 10 gastroenterologists with expertise in IBD and TDM, who rated them anonymously on a scale from 1 to 10. A virtual expert consensus meeting was held to discuss, refine, and reformulate any statements that lacked clarity or did not meet agreement criteria. During this meeting, additional statements were proposed, and panelists re-evaluated the statements, with those receiving a score of 7 or higher from at least 80% of participants being accepted. Ultimately, consensus was reached on 48 out of 49 statements, with the panel agreeing that reactive TDM should be utilized for all biologics in cases of primary nonresponse and secondary loss of response. The authors recommended that treatment discontinuation for infliximab or adalimumab should not occur until drug concentrations of at least 10-15 μg/mL are achieved. The authors acknowledged that randomized controlled trials (RCTs) to test proactive TDM are limited, showing inconsistent results, likely due to variations in study design and dose optimization algorithms. However, consensus was reached on the importance of proactive TDM for anti-tumor necrosis factor therapy, suggesting it be performed after induction and at least once during maintenance. Overall, the panel largely agreed on the utility of TDM for biologics in IBD, particularly for both reactive and proactive TDM of anti-tumor necrosis factors.

In a systematic review and meta-analysis, Nguyen et al. (2022) compared proactive TDM with conventional management in patients with inflammatory bowel disease (IBD). The authors assessed randomized controlled trials (RCTs) involving patients with IBD treated with TNFα antagonists, comparing proactive TDM—which included routine trough concentration assessments and dose adjustments regardless of disease activity—to conventional management, which relied on clinically driven dose adjustments. The primary outcome was the failure to maintain clinical remission, with evidence certainty evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. The meta-analysis included nine RCTs (eight focused on adults in the maintenance phase). The authors found no significant difference in the risk of failing to maintain clinical remission between the proactive TDM group (267 out of 709 patients, or 38%) and the conventional management group (292 out of 696 patients, or 42%) (relative risk [RR], 0.96; 95% confidence interval [CI], 0.81-1.13), with moderate heterogeneity (inconsistency index = 36%) and low certainty evidence according to GRADE. Additionally, there were no differences in outcomes for patients with Crohn's disease (RR, 0.87; 95% CI, 0.66-1.15) or ulcerative colitis (RR, 0.88; 95% CI, 0.72-1.07). Factors such as disease duration, use of concomitant immunomodulators, baseline disease activity, and therapy optimization prior to randomization did not modify this association. Furthermore, no differences were observed in the risk of developing antidrug antibodies or serious adverse events, although patients in the proactive TDM group were more likely to require dose escalation (RR, 1.56; 95% CI, 1.25-1.94). The authors concluded that routine proactive TDM aimed at achieving specific biologic concentration thresholds, regardless of disease activity, did not show a clinical benefit for IBD patients treated with TNFα antagonists in the reviewed RCTs. However, potential benefits in specific disease subtypes and treatment phases, such as induction, not represented in these studies cannot be excluded.

In a systematic review and meta-analysis, Sethi et al. (2023) investigated whether therapeutic drug monitoring (TDM) in patients with inflammatory bowel disease (IBD) receiving anti-tumor necrosis factor (anti-TNF) therapy improves rates of clinical and endoscopic remission, surgery, corticosteroid-free remission, and hospitalization. The researchers searched multiple databases, including MEDLINE, EMBASE, PubMed, and Cochrane, for studies published between January 1, 1946, and April 8, 2022. They included randomized controlled trials (RCTs) and both prospective and retrospective observational studies that compared TDM to standard of care (SOC) or evaluated reactive versus proactive TDM, reporting results as pooled relative risks (RR) with 95% confidence intervals (95% CI). The analysis included 26 studies, comprising 9 RCTs. The findings indicated that proactive TDM, compared to SOC, significantly reduced the risk of treatment failure (RR 0.64, 95% CI 0.48-0.85, p<0.01) and showed a non-significant decrease in the need for surgery (RR 0.51, 95% CI 0.25-1.02) and hospitalization (RR 0.64, 95% CI 0.40-1.00). Additionally, proactive TDM was associated with higher rates of endoscopic remission (RR 1.19, 95% CI 0.93-1.53) and clinical remission (RR 1.07, 95% CI 0.97-1.18). When compared to reactive TDM, proactive TDM significantly decreased the risk of treatment failure (RR 0.46, 95% CI 0.21-0.98, p=0.04) and reduced hospitalization (RR 0.33, 95% CI 0.21-0.54, p<0.01). The authors concluded that proactive TDM demonstrated significant benefits in reducing treatment failure compared to SOC and led to notable reductions in hospitalization and treatment failure compared to reactive TDM. However, further studies with larger RCTs and standardized assays are necessary to confirm these findings and assess the cost-effectiveness of TDM.

The position paper by Felipez et al. (2025) from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition emphasizes the critical role of therapeutic drug monitoring (TDM) in optimizing treatment for pediatric inflammatory bowel disease (IBD). With the rapid evolution of biologic therapies, particularly anti-TNF agents, TDM is essential for personalizing treatment and ensuring effective disease management. The paper recommends specific target trough levels for various medications at different time points during induction and maintenance therapy, highlighting the importance of proactive TDM to enhance clinical outcomes and reduce the risk of immunogenicity. It advocates for higher dosing strategies based on individual patient characteristics, particularly in younger patients and those with severe disease, and underscores the need for ongoing research to refine TDM guidelines and improve pediatric IBD care. Overall, the authors conclude that TDM should be a standard practice in managing pediatric IBD to achieve optimal therapeutic results.

The American College of Gastroenterology (ACG) has a 2025 guideline in progress on Inflammatory Bowel Disease: Diagnosis and Management of Pediatric Crohn’s Disease (Kappelman, 2025) and Pediatric UC (Dubinsky, 2025).

Measurements of Anti-Histone Antibodies for Monitoring Infliximab Therapy

Measurement of anti-histone antibodies has been employed for monitoring of infliximab therapy. However, its clinical value has yet to be established. Allanore, et al. (2004) examined autoantibody induction in rheumatoid arthritis (RA) patients treated with infliximab. These investigators included 59 refractory RA patients treated with infliximab in combination with low-dose prednisone and methotrexate or leflunomide. They tested the sera of the patients for anti-nuclear antibodies (ANA), rheumatoid factor (RF), anti double-stranded DNA antibodies (anti dsDNA), anti-histone and anti-extractable nuclear antigen antibodies (aENA) at baseline and before infusion at weeks 6 and 30. Infliximab, initiated at a dose of 3 mg/kg, was increased to 5 mg/kg if insufficient improvement was observed after 3 infusions. At week 6, only the frequency of anti-histone IgM antibody-positive patients had significantly increased (19% versus 42%, p = 0.009). At week 30, the frequency of patients with ANA had increased from 29% to 69% (p < 0.001), that of patients with anti-dsDNA antibodies had increased from 0% to 3% for IgG (NS) and from 0% to 32% for IgM (p < 0.001); the frequency of anti-histone IgG detection had increased from 22% to 32% (p = 0.04) and that of IgM detection, from 18% to 79% (p < 0.001). No lupus-like syndrome was observed. RF decreased significantly (87 IU to 52.5 IU, from baseline to week 30; p < 0.001). No significant difference was observed between the 16 non-responders and the responders, in terms of autoantibody status at baseline and changes with infliximab therapy. The authors concluded that infliximab therapy led to the selective and delayed induction of autoantibodies. This induction was not associated with clinical symptoms until week 30 and did not differ between responders and non-responders.

Lora, et al. (2014) examined the prevalence of anti-nuclear antibodies (ANA) in patients with psoriasis after treatment with infliximab and correlated the development of antibodies with both response to treatment and adipokines levels. Serum levels of ANA, anti-dsDNA, anti-histone, anti-nucleosome, and anti-ENA antibodies at baseline after 2 and 12 months of treatment with infliximab were measured in 27 patients with psoriasis, as well as in 27 matched controls. Serum C-reactive protein (CRP), chemerin, visfatin, and resistin were also assessed. The prevalence of ANA increased from 22% to 37% and 63% (p < 0.01) during treatment with infliximab, with a gradual progressive increase both in ANA titer and in percentage of ANA pattern. The prevalence of other antibodies also increased from 7% to 30% and 48% (p < 0.01) for anti-ds-DNA and from 7% to 26% and 37% for anti-nucleosome antibodies (p < 0.05), whereas the prevalence of anti-histone and anti-ENA antibodies was unchanged throughout the study period. Basal chemerin, resistin, and CRP levels were higher in patients than in controls, and their levels progressively normalized during treatment (p < 0.01). Conversely, visfatin levels gradually increased (p < 0.01). ANA+ patients tended to show a faster decrease in PASI score, CRP, and chemerin levels after 2 months; however, the PASI score did not differ between ANA+ and ANA- patients at 12 months. A higher increase of visfatin was also observed in ANA+ patients at 2 and 12 months. The authors stated that the ANA response induced by infliximab was restricted to ANA, anti-dsDNA, and anti-nucleosome antibodies. Patients who developed ANA positivity demonstrated a faster clinical, inflammatory, and immunological response to infliximab therapy.

Measurements of DNA or mRNA Biomarkers for Predicting Therapeutic Response in Inflammatory Bowel Disease

Stevens and colleagues (2018) noted that IBD is characterized by substantial heterogeneity in treatment response. With an expanding number of therapeutic agents, identifying optimal treatment at the patient level remains a major challenge. These investigators systematically reviewed available literature on predictive biomarkers of therapeutic response in IBD. An electronic literature search was carried out on 30 January 30, 2018 using Medline, Embase and the Cochrane Library. Retrospective, prospective, uncontrolled and controlled studies reporting on biomarkers predicting therapeutic response in pediatric and adult IBD populations were eligible for inclusion. The methodological quality of the included studies was assessed using the QUIPS tool.  Due to anticipated heterogeneity and limited data, a qualitative, rather than quantitative, assessment was planned. Of the 10,638 citations identified, 92 articles met the inclusion criteria.  Several potential DNA, mRNA and protein markers were evaluated as predictive biomarkers. Most studies focused on predicting response to anti-TNF agents. Substantial between-study heterogeneity was identified with respect to both the biomarkers studied and the definition of response. None of the included studies received a low risk of bias rating for all 6 domains. Currently, none of the biomarkers was sufficiently predictive for clinical use. The authors concluded that the search for predictive biomarkers is still in its infancy and current evidence is limited. They stated that future research efforts should consider the high patient heterogeneity within prospective trials with objective response assessment; and predictive models will most likely comprise a combination of several molecular markers from integrated omics-levels and clinical characteristics.

Antidrug Antibodies and Response to Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis

Mehta and Manson (2020) noted that TNFis have revolutionized the management of RA, however despite considerable progress, only a small proportion of patients maintain long-term clinical response. Selection of, and switching between, biologics is mainly empirical, experiential, and not evidence-based. Most biopharmaceutical proteins (BP) could induce an immune response against the foreign protein component. Immunogenicity and the development of anti-drug antibodies (ADAs) is considered one of the main reasons for loss of therapeutic efficacy (secondary failure). ADAs may neutralize and/or promote clearance of circulating BP with resultant low serum drug levels, loss of clinical response, poor drug survival and adverse events (AEs), such as infusion reactions. ADA identification is technically difficult and not standardized, making interpretation of immunogenicity data from published clinical studies challenging. Trough TNFi drug levels correlate with clinical outcomes, exhibiting a "concentration-response" relationship. Measurement of ADA and drug levels may improve patient care and improve cost-effectiveness of BP use. However, in the absence of clinically-validated, reliable assays and consensus guidelines, TDM and immunogenicity testing have not been widely adopted in routine clinical practice in rheumatology. These researchers stated that prospective, longitudinal studies of BP-naïve patients may provide mechanistic information and address a critical unanswered question -- why BPs are immunogenic in some patients, but tolerogenic in others. Prediction of immunogenicity may allow mitigation and management strategies to be implemented to prevent or minimize the generation of ADAs. Other strategies to personalize biologic selection, include pharmacogenetic testing to identify genetic factors that may predict lack of response to, or toxicities from, TNFi. These investigators stated that further research is needed to develop standardized, clinically-validated assays for both drug and ADA testing. These tests could then be incorporated into evidence-based guidelines to optimize treatment-decisions along the patient pathway: for patients with active disease about to start treatment, not responding to treatment (primary or secondary failure) or for those in remission, to permit drug tapering strategies. Taken together this may help to improve the safety profile, long-term efficacy, and cost-effectiveness of BPs.

Bitoun and colleagues (2023) state that findings from a prospective cohort study of 230 patients with rheumatoid arthritis (RA) suggests that antidrug antibodies are associated with a diminished response to biologic disease–modifying antirheumatic drugs (bDMARDs). The authors analyzed data from the ABI-RA (Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk of Immunization in Rheumatoid Arthritis Patients) multicentric, open, prospective study of adult patients with RA who were initiated on a new bDMARD (adalimumab, infliximab (grouped as anti–tumor necrosis factor [TNF] monoclonal antibodies [mAbs]), etanercept, tocilizumab, and rituximab according to the choice of the treating physician). Patients were recruited between March 2014 to June 2016, with study completion in 2018 and data analysis completed June 2022. "The primary outcome was the association of antidrug antibody positivity with EULAR (European Alliance of Associations for Rheumatology; formerly, European League Against Rheumatism) response to treatment at month 12 assessed through univariate logistic regression. The secondary end points were the EULAR response at month 6 and at visits from month 6 to months 15 to 18 using generalized estimating equation models. Detection of antidrug antibody serum levels was performed at months 1, 3, 6, 12, and 15 to 18 using electrochemiluminescence (Meso Scale Discovery [MSD]) and drug concentration for anti-TNF mAbs, and etanercept in the serum was measured using enzyme-linked immunosorbent assay." "Patients who withdrew from the study before month 12 were considered to be nonresponders at month 12 in the logistic regression models except if they had 2 previous responding visits before dropout and their withdrawal was not due to adverse effects or treatment failure, in which case they were imputed as responders at month 12. Patients who changed their drugs were considered as nonresponders. Univariate and multivariable models were performed on complete cases." The authors found that at month 12, antidrug antibody positivity was 38.2% in patients who were treated with anti-TNF mAbs, 6.1% with etanercept, 50% with rituximab, and 20% with tocilizumab. There was an inverse association between antidrug antibody positivity (odds ratio [OR], 0.19; 95% CI, 0.09-0.38; P < .001) directed against all biologic drugs and EULAR response at month 12. Analyzing all the visits starting at month 6 using generalized estimating equation models confirmed the inverse association between antidrug antibody positivity and EULAR response (P < .001). A similar association was found for tocilizumab alone (P = .03). In the multivariable analysis, antidrug antibodies, body mass index (BMI), and rheumatoid factor (RF) were independently inversely associated with response to treatment. There was a significantly higher drug concentration of anti-TNF mAbs in patients with antidrug antibody–negative vs antidrug antibody–positive status (mean difference, −9.6 [95% CI, −12.4 to −6.9] mg/L; P < .001). Drug concentrations of etanercept (mean difference, 0.70 [95% CI, 0.2-1.2] mg/L; P = .005) and adalimumab (mean difference, 1.8 [95% CI, 0.4-3.2] mg/L; P = .01) were lower in nonresponders vs responders. Methotrexate comedication at baseline was inversely associated with antidrug antibodies (OR, 0.50; 95% CI, 0.25-1.00; P = .05). The authors concluded that of patients with RA, response to biologic drugs was inversely associated with antidrug antibody positivity, and that monitoring of antidrug antibodies could be considered in the management of patients with RA, specifically nonresponses.

Bitoun, et al. acknowledged the following limitations to their prospective cohort study:

• The study demonstrated an association when all biologic drugs were analyzed together; however, the study was not powered to demonstrate an association for each drug class;
• There was a substantial proportion of patients in the unclassified category, as those patients were defined as strictly missing 1 or more antidrug antibody measurements for the analysis of response at month 12;
• The antidrug antibodies were not the only factors that were independently inversely associated with response to treatment in the generalized estimating equation (GEE) analysis;
• The MSD technique is not widely available to clinicians; however, the authors state the percentage of immunized patients in this study is within the same range observed in other studies using the available "classical sandwich ELISA technique"; and
• Secondary end points were not corrected for multiple tests and should be considered exploratory.

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References