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EDITORIAL

Is Proactive Therapeutic Drug Monitoring Ready for the Spotlight in Inflammatory Bowel Disease? Follow the Data

Battat, Robert MD1; Long, Millie D. MD, MPH, FACG2

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The American Journal of Gastroenterology: October 2021 - Volume 116 - Issue 10 - p 2029-2031
doi: 10.14309/ajg.0000000000001500
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Abstract

In this issue of The American Journal of Gastroenterology, Cheifetz et al (1) provides consensus statements on therapeutic drug monitoring (TDM) of biologics in inflammatory bowel disease (IBD). Given the plethora of emerging data, a comprehensive review and consensus is timely and needed.

The authors recommend using reactive TDM for all biologics, summarize concentration targets, and provide guidance on TDM in various scenarios. Proactive TDM is recommended for tumor necrosis factor (TNF)-antagonists, and proactive TDM with TNF-antagonist monotherapy is recommended as an alternative to the combination of TNF-antagonists with immunomodulators.

Although many observational studies support proactive TDM (2–6), 5 randomized controlled trials (RCTs) did not (7–11). The only RCT-demonstrating benefit did not show proactive TDM to affect moderately severe or long-term outcomes. The Trough Concentration Adapted Infliximab Treatment trial compared proactively targeting infliximab concentrations of 3–7 μg/mL with not using TDM in patients who had initially been dose-optimized (7). No between-group differences existed in clinical, biomarker, endoscopic, or durable remission, and insufficient immunogenicity data existed. Although proactive TDM yielded a 10% lower 1-year relapse rate, no differences existed in long-term hospitalization, corticosteroid use, or surgery (12). Similarly, the NORDRUM RCT compared proactive TDM with not using TDM in patients with immune-mediated inflammatory diseases initiating infliximab (8). In 137 patients with IBD, no differences existed between groups for symptom-based remission, fecal calprotectin, or IBD questionnaire scores. In a recent study, proactive point-of-care TDM was compared with reactive-TDM targeting infliximab concentrations of 3–8 μg/mL (13). In 187 patients with IBD, no differences existed for infliximab failure, drug discontinuation, or sustained clinical remission. Endoscopic remission rates were lower with proactive TDM. Similar conclusions exist in proactive TDM analyses of the SERENE trials (10). Finally, the PRECISION RCT enrolled 40 patients per group and compared dashboard-guided dosing (target infliximab concentration >3 μg/mL) with nonadjusted conventional dosing (11). Intention-to-treat analysis, the recommended method in superiority trials to avoid bias, demonstrated no differences in the primary outcome.

Supporting proactive-TDM, the Pediatric Crohn's Disease Adalimumab Level-based Optimization Treatment trial randomized adalimumab-treated pediatric patients to receive either proactive or reactive-TDM (14). Rates of corticosteroid-free clinical remission were greater with proactive TDM, and biomarker data were consistent. However, no differences existed in drug discontinuation or moderately severe exacerbations. These data are consistent with Trough Concentration Adapted Infliximab Treatment trial; proactive TDM yielded fewer mild exacerbations but no differences in severe or long-term outcomes. RCT's on TDM have targeted infliximab concentrations >3 μg/mL. As higher concentrations are associated with improved outcomes (15), TDM trials targeting higher concentrations may demonstrate benefit.

Combination therapy is the most effective strategy to optimize outcomes in IBD. The SONIC and UC-SUCCESS trials were large RCTs demonstrating that combination therapy was superior to either infliximab or azathioprine monotherapy in IBD (16,17). In addition, RCT's have demonstrated that early combination therapy in Crohn's disease yields fewer surgeries, hospitalizations, or serious complications (18).

Rationale for using proactive TDM with TNF-antagonist (“optimized”) monotherapy as an alternative to combination therapy is based on post hoc analyses of the SONIC trial (19). It is hypothesized that improved outcomes with combination therapy are attributable to the higher drug concentrations and lower immunogenicity immunomodulators confer. While plausible, caution is needed when using post hoc data to answer questions that trials are not designed to address. For example, before the gold standard SONIC trial, post hoc analyses of the ACCENT and ACT trials demonstrated no improved efficacy with concomitant immunomodulators (20). Large, well-designed RCTs provide a superior level of evidence to post hoc analyses or observational data.

Thus, it is intriguing that a recommendation is made to use optimized monotherapy in patients with severe disease, but statements regarding use of combination therapy to improve outcomes and drug pharmacokinetics in those without previous immunogenicity were not created for voting. Supportive text clarifies that monotherapy is not recommended over combination therapy and that unoptimized monotherapy without early and aggressive proactive TDM is not as effective as combination therapy. Instead, it should be noted that combination therapy is superior to all forms of TNF-antagonist monotherapy, including with proactive TDM. This will be the case until high-level comparative evidence exists.

Importantly, the consensus statements outlined that optimized monotherapy with proactive TDM could be considered in those at risk of adverse events. This is a common rationale for selecting monotherapy over combination therapy. However, a nationwide cohort study found, for an individual on combination therapy compared with TNF-antagonist monotherapy, absolute increases of 0.05% and 0.35% in annual lymphoma and serious infection risk existed, respectively. Although the relative risk was approximately 2-fold higher, the absolute risk increase was low (21,22). In both Crohn's Therapy, Resource, Evaluation, and Assessment Tool and European National Crohn's Observational REgistry registries, neither increased lymphoproliferative malignancies nor serious infections existed when comparing combination therapy with TNF-antagonist monotherapy (23,24). Meta-analyses also demonstrate that <12 months of thiopurine exposure did not increase lymphoma risk (25).

Data favor combination therapy, demonstrate minimal risk with short-term therapy and a small absolute risk beyond this. Early in treatment, patients suffer from significant inflammation and risk for immunogenicity. In this phase, benefits of combination therapy are most appreciable. In most patients, the benefit of this strategy likely outweighs risks. There is strong rationale for proactive TDM, and a reasonable possibility that future studies find benefit with this approach. However, current data do not support this approach as an equivalent alternative to combination therapy. Importantly, using combination therapy does not preclude use of TDM.

The authors should be commended for providing an important roadmap to using TDM based on available evidence. There is much left unanswered, and important research is yet to be performed before we can universally embrace proactive TDM. In patients without previous immunogenicity, combination therapy is the preferred treatment for those with moderately severe disease or risk factors for high drug clearance, but can we demonstrate that optimized monotherapy is an equivalent alternative? Who will require indefinite combination therapy? HLA-DQ*A105 carriage is associated with immunogenicity, and combination therapy was associated with lower immunogenicity in these patients (26), but will this or other biomarkers predict success with optimized monotherapy? Can we demonstrate benefit to performing proactive TDM after removing an immunomodulator? Will proactive TDM show benefit when targeting higher TNF-antagonist concentrations or for other medication classes? We do not yet have high-level evidence to answer these questions, but this consensus statement is an important starting point.

CONFLICTS OF INTEREST

Guarantor of the article: Robert Battat, MD

Specific author contributions: R.B., M.D.L.: manuscript drafting.

Financial support: None to report.

Potential competing interests: R.B.: None. M.D.L.: consulting for AbbVie, Janssen, Takeda, Pfizer, Prometheus, Salix, Valeant, Target Pharmasolutions, BMS, Genentech, Roche, Lilly, Calibr, Theravance.

Research support: Research support is provided by Takeda, Pfizer.

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