Intest Res.  2023 Oct;21(4):460-470. 10.5217/ir.2022.00128.

Serum albumin is the strongest predictor of anti-tumor necrosis factor nonresponse in inflammatory bowel disease in resource-constrained regions lacking therapeutic drug monitoring

• Kumar P
• Vuyyuru SK
• Das P
• Kante B
• Ranjan MK
• Thomas DM
• Mundhra S
• Sahu P
• Venigalla PM
• Jain S
• Goyal S
• Golla R
• Virmani S
• Singh MK
• Sachdeva K
• Sharma R
• Dash NR
• Makharia G
• Kedia S
• Ahuja V

• KMID: 2547196
• DOI: http://doi.org/10.5217/ir.2022.00128

Abstract

Background/Aims
Evidence on predictors of primary nonresponse (PNR), and secondary loss of response (SLR) to anti-tumor necrosis factor (anti-TNF) agents in inflammatory bowel disease is scarce from Asia. We evaluated clinical/biochemical/molecular markers of PNR/SLR in ulcerative colitis (UC) and Crohn’s disease (CD).
Methods
Inflammatory bowel disease patients treated with anti-TNF agents (January 2005–October 2020) were ambispectively included. Data concerning clinical and biochemical predictors was retrieved from a prospectively maintained database. Immunohistochemistry for expression of oncostatin M (OSM), OSM receptor (OSM-R), and interleukin-7 receptor (IL-7R) were done on pre anti-TNF initiation mucosal biopsies.
Results
One-hundred eighty-six patients (118 CD, 68 UC: mean age, 34.1±13.7 years; median disease duration at anti-TNF initiation, 60 months; interquartile range, 28–100.5 months) were included. PNR was seen in 17% and 26.5% and SLR in 47% and 28% CD and UC patients, respectively. In CD, predictors of PNR were low albumin (P<0.001), postoperative recurrence (P=0.001) and high IL-7R expression (P<0.027) on univariate; and low albumin alone (hazard ratio [HR], 0.09; 95% confidence interval [CI], 0.03–0.28; P<0.001) on multivariate analysis respectively. Low albumin (HR, 0.31; 95% CI, 0.15–0.62; P=0.001) also predicted SLR. In UC, predictors of PNR were low albumin (P<0.001), and high C-reactive protein (P<0.001), OSM (P<0.04) and OSM-R (P=0.07) stromal expression on univariate; and low albumin alone (HR, 0.11; 95% CI, 0.03–0.39; P=0.001) on multivariate analysis respectively.
Conclusions
Low serum albumin at baseline significantly predicted PNR in UC and PNR/SLR in CD patients. Mucosal markers of PNR were high stromal OSM/OSM-R in UC and high IL-7R in CD patients.

Keyword

Colitis, ulcerative; Crohn disease; Albumins; Nonresponse; Anti-tumor necrosis factor

Figure

• 

  Fig. 1. Histopathological finding (immunohistochemical staining). (A-D) Interleukin-7 receptor expression on the stromal lymphocytes and macrophages (arrows) in biopsies from treatment naïve patients with Crohn’s disease, then in disease control, with lesser expression (A: ×100, B: ×200, C: ×200, D: ×40). (E-H) Oncostatin expression in lympho-mononuclear cells, stromal cells as well as in mucosal epithelium (arrows) in colonic biopsies from treatment naïve patients with ulcerative colitis, in comparison to biopsy from disease control, with lesser expression (arrows) (E: ×40, F: ×200, G: ×200, H: ×100). (I-L) Oncostatin-Rß expression in lympho-mononuclear cells, stromal cells as well as in mucosal epithelium (arrows) in colonic biopsies from treatment naïve patients with ulcerative colitis, in comparison to biopsy from disease control, with lesser expression (arrows) (I: ×40, J: ×200, K: ×200; L: ×40).

• 

  Fig. 2. Receiver operating characteristic (ROC) curves for baseline albumin levels as predictor of nonresponse to anti-tumor necrosis factor therapy at week 14 in ulcerative colitis (UC) and Crohn’s disease (CD) patients.

Reference

1. Allez M, Karmiris K, Louis E, et al. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects. J Crohns Colitis. 2010; 4:355–366.

2. Gisbert JP, Panés J. Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am J Gastroenterol. 2009; 104:760–767.

3. Arias MT, Vande Casteele N, Vermeire S, et al. A panel to predict long-term outcome of infliximab therapy for patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2015; 13:531–538.

4. Gisbert JP, Chaparro M. Predictors of primary response to biologic treatment [anti-TNF, vedolizumab, and ustekinumab] in patients with inflammatory bowel disease: from basic science to clinical practice. J Crohns Colitis. 2020; 14:694–709.

5. West NR, Hegazy AN, Owens BM, et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med. 2017; 23:579–589.

6. Belarif L, Danger R, Kermarrec L, et al. IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease. J Clin Invest. 2019; 129:1910–1925.

7. Ahuja V, Tandon RK. Inflammatory bowel disease in the AsiaPacific area: a comparison with developed countries and regional differences. J Dig Dis. 2010; 11:134–147.

8. Kedia S, Ahuja V. Epidemiology of inflammatory bowel disease in India: the great shift East. Inflamm Intest Dis. 2017; 2:102–115.

9. Kumar P, Vuyyuru SK, Kante B, et al. Stringent screening strategy significantly reduces reactivation rates of tuberculosis in patients with inflammatory bowel disease on anti-TNF therapy in tuberculosis endemic region. Aliment Pharmacol Ther. 2022; 55:1431–1440.

10. Dignass A, Eliakim R, Magro F, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. J Crohns Colitis. 2012; 6:965–990.

11. Van Assche G, Dignass A, Panes J, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: definitions and diagnosis. J Crohns Colitis. 2010; 4:7–27.

12. Sandborn WJ, Feagan BG, Hanauer SB, et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn’s disease. Gastroenterology. 2002; 122:512–530.

13. Kennedy NA, Heap GA, Green HD, et al. Predictors of antiTNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol. 2019; 4:341–353.

14. Roda G, Jharap B, Neeraj N, Colombel JF. Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol. 2016; 7:e135.

15. Papamichael K, Rivals-Lerebours O, Billiet T, et al. Long-term outcome of patients with ulcerative colitis and primary nonresponse to infliximab. J Crohns Colitis. 2016; 10:1015–1023.

16. Magro F, Rodrigues-Pinto E, Santos-Antunes J, et al. High C-reactive protein in Crohn’s disease patients predicts nonresponse to infliximab treatment. J Crohns Colitis. 2014; 8:129–136.

17. Peters CP, Eshuis EJ, Toxopeüs FM, et al. Adalimumab for Crohn’s disease: long-term sustained benefit in a population-based cohort of 438 patients. J Crohns Colitis. 2014; 8:866–875.

18. Kathiresan S, Larson MG, Vasan RS, et al. Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level. Circulation. 2006; 113:1415–1423.

19. Adams A, Gupta V, Mohsen W, et al. Early management of acute severe UC in the biologics era: development and international validation of a prognostic clinical index to predict steroid response. Gut. 2023; 72:433–442.

20. Yang F, Bian C, Zhu L, Zhao G, Huang Z, Huang M. Effect of human serum albumin on drug metabolism: structural evidence of esterase activity of human serum albumin. J Struct Biol. 2007; 157:348–355.

21. Soeters PB, Wolfe RR, Shenkin A. Hypoalbuminemia: pathogenesis and clinical significance. JPEN J Parenter Enteral Nutr. 2019; 43:181–193.

22. Fasanmade AA, Adedokun OJ, Olson A, Strauss R, Davis HM. Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis. Int J Clin Pharmacol Ther. 2010; 48:297–308.

23. Kopylov U, Seidman E. Predicting durable response or resistance to antitumor necrosis factor therapy in inflammatory bowel disease. Therap Adv Gastroenterol. 2016; 9:513–526.

24. Morita Y, Bamba S, Takahashi K, et al. Prediction of clinical and endoscopic responses to anti-tumor necrosis factor-α antibodies in ulcerative colitis. Scand J Gastroenterol. 2016; 51:934–941.

25. Hirai F, Takeda T, Takada Y, et al. Efficacy of enteral nutrition in patients with Crohn’s disease on maintenance anti-TNF-alpha antibody therapy: a meta-analysis. J Gastroenterol. 2020; 55:133–141.

26. Atreya R, Neurath MF. Mechanisms of molecular resistance and predictors of response to biological therapy in inflammatory bowel disease. Lancet Gastroenterol Hepatol. 2018; 3:790–802.

27. Arora U, Ananthakrishnan AN, Kedia S, et al. Effect of oral tobacco use and smoking on outcomes of Crohn’s disease in India. J Gastroenterol Hepatol. 2018; 33:134–140.

28. Gupta A, Pratap Mouli V, Mohta S, et al. Antitubercular therapy given to differentiate Crohn’s disease from intestinal tuberculosis predisposes to stricture formation. J Crohns Colitis. 2020; 14:1611–1618.

29. Carrette F, Surh CD. IL-7 signaling and CD127 receptor regulation in the control of T cell homeostasis. Semin Immunol. 2012; 24:209–217.