What literature exists that looks at efficacy of infliximab for the treatment of acute severe ulcerative colitis and Crohn's disease in patients with low albumin?

Available tertiary literature consistently supports hypoalbuminemia as a clinically relevant marker of increased infliximab clearance and reduced drug exposure in acute severe ulcerative colitis (ASUC). Hindryckx et al. describe enhanced infliximab clearance in ASUC driven by inflammatory burden, fecal drug loss, and impaired Fc receptor recycling, with low serum albumin functioning as a surrogate of protein-losing enteropathy and high-clearance states. Fiske et al. further emphasize that albumin <35 g/L, particularly when accompanied by CRP > 50 mg/L, identifies patients at risk for underexposure, and that the 2019 British Society of Gastroenterology (BSG) guideline similarly recognizes CRP > 50 mg/L and albumin <35 g/L as high-risk features in which accelerated induction (e.g., 5 mg/kg at weeks 0, 1, and 3 rather than 0, 2, and 6) may be considered. Gordon and Battat provide the most quantitative synthesis, reporting that low albumin is independently associated with increased infliximab clearance in pharmacokinetic (PK) models and that modeled clearance > 0.627 L/day was associated with substantially higher 6-month colectomy risk (61.5% vs 7.7%). Observational exposure-response data summarized across these reviews show that detectable or higher early infliximab trough concentrations correlate with improved remission (clinical remission 69% vs 15%) and lower colectomy rates (24-week colectomy 7% vs 55%; 90-day colectomy 29% vs 67% compared with placebo in steroid-refractory ASUC). Collectively, these tertiary sources support a mechanistic and observational link between low serum albumin, accelerated infliximab clearance, reduced serum drug concentrations, and higher risk of treatment failure; however, all emphasize that evidence derives primarily from retrospective cohorts and pharmacokinetic modeling, and no randomized trial has prospectively validated albumin-guided dosing strategies in ASUC. [1], [2], [3], [4]

Primary Studies Evaluating the Association Between Serum Albumin and Infliximab Pharmacokinetics and Clinical Outcomes in Ulcerative Colitis and IBD Cohorts
Reference	Design and objective	Population (Total N)	Albumin variable	Key PK findings tied to albumin	Key efficacy outcomes tied to albumin	Notes
Brandse 2015	Prospective mechanistic study; assess fecal IFX loss and association with response in severe UC	N = 30 severe UC receiving IFX	Baseline albumin reported; subgroup cut point ≤37 g/L vs >37 g/L shown	Day 1 fecal IFX higher in week 2 nonresponders vs responders, median 5.01 mg/mL (IQR 1.91 to 20.14) vs 0.54 mg/mL (IQR 0.0 to 4.40); P = 0.0047. Albumin subgroup: fecal IFX Day 1 higher with albumin ≤37 g/L vs >37 g/L, 3.43 (0.03 to 12.48) vs 0.89 (0.0 to 7.78) ug/mL; P = 0.04. Week 2 serum IFX lower with albumin ≤37 g/L vs >37 g/L, 14.5 (4.50 to 18.85) vs 19.5 (13.65 to 26.35) ug/mL; P = 0.03.	Fecal IFX on Day 1 was significantly higher in non-responders (5.01 vs 0.54 ug/mL; $P=0.0047$ ).	Albumin findings are subgroup comparisons, not a primary multivariable predictor
Brandse 2016	Prospective PK and exposure response; identify drivers of IFX exposure and link to outcomes	N = 19 moderate to severe UC	Baseline albumin as continuous PK covariate; subgroup <35 g/L described	Albumin and clearance negatively correlated, P < 0.01. Clearance estimates: 0.87, 0.54, 0.40 L/d at albumin 25, 38, 50 g/L. CRP exposure: AUC lower with baseline CRP >50 mg/L vs <50 mg/L, 587 vs 1361 mg/L/d; P = 0.001. Albumin exposure: with baseline albumin <35 g/L there was a trend toward lower AUC vs higher albumin, 636 vs 1354 mg/L/d; P = 0.07. Week 6 trough higher in endoscopic responders vs nonresponders, 8.1 (IQR 3.0 to 13.7) vs 2.9 (IQR 0.01 to 5.8) mg/mL; P = 0.03	Week 6 serum IFX >6.6 mg/mL identified as cutoff for endoscopic response, OR 18.7 (95% CI 1.6 to 223); P = 0.02. ROC AUC 0.80; sensitivity 88%; specificity 73%	The albumin AUC result is explicitly a trend, so it should not be framed as definitive
Ungar 2016	Retrospective; compare induction IFX levels in ASUC vs moderately severe UC	N = 32 total, ASUC n = 16; MSUC n = 16	Day 14 albumin; correlation analysis	Day 14 IFX trough lower in ASUC vs MSUC, 7.15 ± 5.3 vs 14.4 ± 11.2 µg/mL; P = 0.007. Day 14 albumin lower in ASUC vs MSUC, 3.1 vs 4.05 g/dL; P = 0.0001. Correlation between Day 14 trough and albumin reported as r = 0.5; P = 0.06.	Not an albumin outcomes study; primarily PK phenotype	Albumin correlation is a trend, not statistically significant
Choy 2018	Retrospective multicenter; predictors after IFX salvage in ASUC	N = 54 ASUC receiving IFX rescue	CRP/Alb ratio evaluated; baseline albumin described	Not a PK study	Discharge CRP/Alb ratio >0.37 predicted colectomy within 12 months; AUROC 0.73; sensitivity 80%; specificity 62%; PPV 42%; NPV 90%. Pretreatment albumin and pretreatment CRP/Alb ratio reported as not predictive	Albumin signal is embedded in the ratio at discharge, not pretreatment
Govani 2020	Retrospective; accelerated induction strategy and predictors in hospitalized ASUC	N = 66 IFX naive ASUC	Albumin nadir; CRP/Alb ratio used in protocol	Not a PK study; protocol used CRP/Alb ratio >1 to select 10 mg/kg.	90 day colectomy accelerated vs single dose, 30.3% vs 24.2%; P = 0.58. Multivariable predictors included CRP at IFX initiation OR 1.25; P < 0.01 and albumin nadir OR 0.20; P = 0.02	Albumin is an independent predictor of colectomy risk in this cohort
Syal 2021	Retrospective; predictors of IFX rescue failure in ASUC	N = 63 ASUC receiving IFX rescue; 5 mg/kg n = 29; 10 mg/kg n = 34	Admission albumin threshold and modeling	Not a PK study	Admission albumin independently predicted 90 day colectomy, OR 0.10; P = 0.04. Bands at IFX administration also predictive, OR 1.21; P = 0.02. Rule: albumin ≤2.5 g/dL plus bands ≥13% had PPV 100% for 90 day colectomy	Strongest explicit albumin threshold signal for failure risk
Fasanmade 2010	Post hoc PK and response analyses from ACT 1 and ACT 2 in UC	N = 728 UC	Baseline albumin stratification, <3.5 g/dL vs ≥3.5 g/dL reported	Example PK values reported: 5 mg/kg median serum IFX 18.9 µg/mL (<3.5) vs 33.4 µg/mL (≥3.5). 10 mg/kg median serum IFX 25.5 µg/mL (<3.5) vs 77.5 µg/mL (≥3.5).	Clinical response trend described as lower exposure and lower response with lower albumin strata	Large dataset for albumin as PK driver; not ASUC specific
Dotan 2014	Population PK in IBD; identify factors increasing clearance and shortening half life	N = 54 IBD; 169 concentrations	Albumin covariate; range 2.1 to 5.0 g/dL	Typical clearance 0.381 L/d. Factors associated with higher clearance included low albumin, high body weight, ATI; P < 0.001. ATI associated with 259% increase in clearance. Median effective half-life 5.6 ± 2.4 days.	No clinical outcomes	Mechanistic PK support for why low albumin states have higher clearance
ECCO P473 2015 abstract only	Population PK covariate analysis in IBD	N = 324 IBD	Low albumin listed as clearance covariate	Abstract reports increased clearance with ATI 6.04 fold and body weight 2.76 fold; albumin inversely associated with clearance in the model.	No clinical outcomes	Abstract only
ASUC = acute severe ulcerative colitis; ATI = antibodies to infliximab; AUC = area under the concentration–time curve; AUROC = area under the receiver operating characteristic curve; CI = confidence interval; CRP = C-reactive protein; CRP/Alb ratio = C-reactive protein to albumin ratio; IFX = infliximab; IBD = inflammatory bowel disease; IQR = interquartile range; MSUC = moderately severe ulcerative colitis; NPV = negative predictive value; OR = odds ratio; PK = pharmacokinetics; PPV = positive predictive value; ROC = receiver operating characteristic; UC = ulcerative colitis.

References:
[1] [1] Brandse JF, van den Brink GR, Wildenberg ME, et al. Loss of Infliximab Into Feces Is Associated With Lack of Response to Therapy in Patients With Severe Ulcerative Colitis. Gastroenterology. 2015;149(2):350-5.e2. doi:10.1053/j.gastro.2015.04.016
[2] [2] Brandse JF, Matht RA, van der Kleij D, et al. Pharmacokinetic Features and Presence of Antidrug Antibodies Associate With Response to Infliximab Induction Therapy in Patients With Moderate to Severe Ulcerative Colitis. Clin Gastroenterol Hepatol. 2016;14(2):251-8.e82. doi:10.1016/j.cgh.2015.10.029
[3] [3] Ungar B, Mazor Y, Weisshof R, et al. Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis. Aliment Pharmacol Ther. 2016;43(12):1293-1299. doi:10.1111/apt.13631
[4] [4] Choy MC, Seah D, Gorelik A, et al. Predicting response after infliximab salvage in acute severe ulcerative colitis. J Gastroenterol Hepatol. 2018;33(7):1347-1352. doi:10.1111/jgh.14072
[5] [5] Govani SM, Berinstein JA, Waljee AK, Stidham RW, Higgins PDR, Hardiman KM. Use of Accelerated Induction Strategy of Infliximab for Ulcerative Colitis in Hospitalized Patients at a Tertiary Care Center. Dig Dis Sci. 2020;65(6):1800-1805. doi:10.1007/s10620-019-05957-0
[6] [6] Syal G, Robbins L, Kashani A, et al. Hypoalbuminemia and Bandemia Predict Failure of Infliximab Rescue Therapy in Acute Severe Ulcerative Colitis. Dig Dis Sci. 2021;66(1):199-205. doi:10.1007/s10620-020-06177-7
[7] [7] 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(5):297-308. doi:10.5414/cpp48297
[8] [8] Dotan I, Ron Y, Yanai H, et al. Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study. Inflamm Bowel Dis. 2014;20(12):2247-2259. doi:10.1097/MIB.0000000000000212
[9] [9] Brandse JF, et al. Antibodies to infliximab, body weight and low serum albumin levels increase clearance of infliximab: a population pharmacokinetic study in 324 IBD patients. J Crohns Colitis. 2015;9(suppl 1):S315-S316. doi:10.1093/ecco-jcc/jju027.591