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. 2022 Sep;56(5):783-793.
doi: 10.1111/apt.17089. Epub 2022 Jun 29.

Understanding anti-TNF treatment failure: does serum triiodothyronine-to-thyroxine (T3/T4) ratio predict therapeutic outcome to anti-TNF therapies in biologic-naïve patients with active luminal Crohn's disease?

Simeng Lin  1   2 , Neil Chanchlani  1   2 , Isabel Carbery  3   4 , Malik Janjua  1   2 , Rachel Nice  5 , Timothy J McDonald  5 , Claire Bewshea  2 , Nicholas A Kennedy  1   2 , Tariq Ahmad  1   2 , Christian P Selinger  3   4 , James R Goodhand  1   2 ; PANTS consortium
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Understanding anti-TNF treatment failure: does serum triiodothyronine-to-thyroxine (T3/T4) ratio predict therapeutic outcome to anti-TNF therapies in biologic-naïve patients with active luminal Crohn's disease?

Simeng Lin et al. Aliment Pharmacol Ther. 2022 Sep.

Abstract

Background: During illness, adaptations of the hypothalamic-pituitary-thyroid axis reduce energy expenditure, protein catabolism and modulate immune responses to promote survival. Lower serum free triiodothyronine-to-thyroxine (fT3/fT4) ratio has been linked to non-response to treatment in a range of diseases, including in biologic-treated patients with inflammatory bowel disease.

Aim: To assess whether baseline serum fT3/fT4 ratio predicted primary non-response (PNR) and non-remission to infliximab and adalimumab in patients with Crohn's disease METHODS: Thyroid function tests were undertaken in stored serum from biologic-naïve adult patients with active luminal Crohn's disease immediately prior to treatment with infliximab (427 originator; 122 biosimilar) or adalimumab (448) in the Personalised Anti-TNF Therapy in Crohn's Disease study (PANTS).

Results: Baseline median [IQR] fT3/fT4 ratios were lower in women than men (0.30 [0.27-0.34] vs 0.32 [0.28-0.36], p < 0.001), in patients with more severe inflammatory disease, and in patients receiving corticosteroids (0.28 [0.25-0.33] vs. 0.32 [0.29-0.36], p < 0.001). Multivariable logistic regression analysis demonstrated that fT3/fT4 ratio was independently associated with PNR at week 14 (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.31-0.85, p = 0.009), but not non-remission or changes in faecal calprotectin concentrations at week 54. The optimal threshold to determine PNR was 0.31 (area under the curve 0.57 [95% CI 0.54-0.61], sensitivity 0.62 [95% CI 0.41-0.74], and specificity 0.53 [95% CI 0.42-0.73]).

Conclusions: Lower baseline serum fT3/fT4 ratio was associated with female sex, corticosteroid use and disease activity. It predicted PNR to anti-TNF treatment at week 14, but not non-remission at week 54.

Keywords: Crohn’s disease; IBD; PANTS; T3; T4; TSH; low T3 syndrome; low T3/T4 ratio; non-thyroidal illness syndrome; sick euthyroid syndrome.

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Conflict of interest statement

Dr. Lin reports non‐financial support from Pfizer, non‐financial support from Ferring, outside the submitted work. Dr. Kennedy reports grants from F. Hoffmann‐La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non‐financial support from Immundiagnostik, grants and non‐financial support from AbbVie, grants and personal fees from Celltrion, personal fees and non‐financial support from Janssen, personal fees from Takeda, personal fees and non‐financial support from Dr Falk, outside the submitted work.

Prof. Ahmad reports grants and non‐financial support from F. Hoffmann‐La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non‐financial support from Immundiagnostik, personal fees from Biogen inc, grants and personal fees from Celltrion Healthcare, personal fees and non‐financial support from Immundiagnostik, personal fees from Takeda, personal fees from ARENA, personal fees from Gilead, personal fees from Adcock Ingram Healthcare, personal fees from Pfizer, personal fees from Genentech, non‐financial support from Tillotts, outside the submitted work. Dr Selinger has received unrestricted research grants from Warner Chilcott, Janssen and AbbVie, has provided consultancy to Warner Chilcott, Dr Falk, AbbVie, Takeda, Fresenius Kabi, Arena, Galapagos, Celltrion, Norgine and Janssen, and had speaker arrangements with Warner Chilcott, Norgine, Galapagos, Fresenius Kabi, Celtrion, Dr Falk, AbbVie, MSD, Pfizer and Takeda. Dr. Goodhand reports grants from F. Hoffmann‐La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non‐financial support from Immundiagnostik, outside the submitted work. The following authors have nothing to declare: Neil Chanchlani, Isabel Carbery, Malik Janjua, Rachel Nice, Timothy J McDonald and Claire Bewshea.

Figures

FIGURE 1
FIGURE 1
Study profile. Patients were not assessable when one of more key data items were missing. Abbreviations: TSH: thyroid‐stimulating hormone, fT3: free triiodothyronine, fT4: free thyroxine.
FIGURE 2
FIGURE 2
Forest plot showing the coefficients from a multivariable linear regression model of associations with fT3/fT4 ratio. The resultant values represent the change of fT3/fT4 ratio associated with each variable. Abbreviations: CRP = C‐reactive protein.
FIGURE 3
FIGURE 3
Beeswarm plot of fT3/fT4 ratio at baseline and primary non‐response at week 14, (A) combined cohort (B) infliximab‐treated patients, (C) adalimumab‐treated patients. The number of individuals tested for each group are shown in black at the top of each panel.
FIGURE 4
FIGURE 4
Beeswarm plot of fT3/fT4 ratio at baseline, stratified by outcome at week 14. The number of individuals tested for each group are shown in black at the top of each panel.
FIGURE 5
FIGURE 5
Forest plot showing the coefficients from a multivariable logistic regression model of associations with primary non‐response.
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