Higher anti-TNF serum levels are associated with perianal fistula closure in Crohn’s disease patients

Abstract

Objectives: Anti-TNF agents are effective to treat perianal Crohn's disease (CD). Evidence suggests that Crohn's disease patients with perianal fistulas need higher infliximab (IFX) serum concentrations compared to patients without perianal CD to achieve complete disease control. Our aim was to compare anti-TNF serum concentrations between patients with actively draining and closed perianal fistulas. Methods: A retrospective survey was performed in CD patients with perianal disease treated with IFX or adalimumab (ADL). Fistula closure was defined as absence of active drainage at gentle finger compression and/or fistula healing on magnetic resonance imaging. Results: We identified 66 CD patients with a history of perianal fistulas treated with IFX (n ¼ 47) and ADL (n ¼ 19). Median IFX serum trough concentrations ([interquartile range]) were higher in patients with closed fistulas (n ¼ 32) compared to patients with actively draining fistulas (n ¼ 15): 6.0 mg/ml [5.4-6.9] versus 2.3 mg/ml [1.1-4.0], respectively (p < .001)). A similar difference was seen in patients treated with ADL: median serum concentrations were 7.4 mg/ml [6.5-10.8] in 13 patients with closed fistulas versus 4.8 mg/ml [1.7-6.2] in 6 patients with producing fistulas (p ¼ .003). Serum concentrations of 5.0 mg/ml for IFX (area under the curve of 0.92; 95% CI: 0.82-1.00)) and 5.9 mg/ml for ADL (area under the curve of 0.89; 95% CI 0.71-1.00) were associated with fistula closure. Conclusion: Cut-off serum concentrations 5.0 mg/ml for IFX and 5.9 mg/ml for ADL were associated with perianal fistula closure. Hence, patients with producing perianal fistulas may benefit from anti-TNF dose intensification to achieve fistula closure.

Correlation of serum levels of anti-tumor necrosis factor agents with perianal fistula healing in Crohn’s disease: a narrative review

“…The modified Van Assche score correlates well with clinical response, but further studies with larger sample of patients are still required for a broader validation of this method. 52 The studies by Strik et al 21 and Plevris et al 24 demonstrated similar findings with the intravenous (IFX) and the subcutaneous agent (ADA). The association of higher serum levels of ADA with better clinical outcomes in the Dutch study was clear (7.4 μg/mL in healed vs. 4.8 μg/mL in active fistulas; P = 0.003).…”

“…This was demonstrated in some cohort studies with IFX and ADA, in induction and maintenance, in adults and children with CD. [19][20][21][22][23][24] The studies published to date are associated with some limitations, such as different outcome measurements, time periods of analysis and lack of objective markers of fistula healing. In general, patients with healed fistulas had higher serum levels of IFX (at trough) and ADA (measured between doses) as compared to those with active perianal disease.…”

Stopping anti‐tumour necrosis factor therapy in patients with perianal Crohn’s disease

“…High infliximab trough levels during induction were associated with a favourable fistula response to infliximab . A cut‐off serum concentration of ≥5.0 µg/mL for infliximab or ≥5.9 µg/mL for adalimumab was associated with closure of perianal Crohn's fistula . Lastly, since financial constraints affect drug usage in certain countries, one‐fourth of the PCD patients stopped anti‐TNF because of financial difficulties and only about one‐third ceased therapy due to achievement of clinical remission.…”

“…We also demonstrated that perianal CD patients who stopped One of the strengths of our study is that to our knowledge it is the first and largest series to report the outcome of discontinuation serum concentration of ≥5.0 µg/mL for infliximab or ≥5.9 µg/mL for adalimumab was associated with closure of perianal Crohn's fistula. 29 Lastly, since financial constraints affect drug usage in certain countries, one-fourth of the PCD patients stopped anti-TNF because of financial difficulties and only about one-third ceased therapy due to achievement of clinical remission. Utilisation of biological therapy is low in Asia due to its high cost and lack of insurance coverage [30,31] This leads to a higher chance of perianal CD relapse after discontinuation of biological agents.…”

Subcutaneous rather than intravenous ustekinumab induction is associated with comparable circulating drug levels and early clinical response: a pilot study

“…8 Recent studies suggest that higher IFX concentrations may be beneficial, particularly in patients with fistulising disease. 11,12 Threshold adalimumab (ADA) concentrations are not as well defined as those for IFX but higher trough concentrations are associated with increased likelihood of clinical remission. 13,14 Despite the progress made in the treatment of inflammatory bowel disease (IBD), there remain a substantial number of patients who do not respond to anti-TNF agents, either through primary nonresponse or secondary loss of response.…”