B0385 - Patients With High Visceral Adipose Tissue Burden Have a Higher Target Therapeutic Infliximab Concentrations: Should We Be Filling the VAT?

Monday, October 24, 2022

10:00 AM – 12:00 PM ET

Location: Crown Ballroom

Presenting Author(s)

Andres Yarur, MD

Cedars-Sinai Medical Center
Los Angeles, CA

Andres Yarur, MD¹, Shaina Sekhri, MD², Parakkal Deepak, MBBS, MS³, Maria T. Abreu, MD⁴, Adam Cheifetz, MD⁵, Konstantinos Papamichail, MD, PhD⁵, Marla C. Dubinsky, MD⁶, Poonam Beniwal-Patel, MD⁷, Phillip Gu, MD⁸, Dermot McGovern, MD, PhD⁸, Gil Y. Melmed, MD¹
¹Cedars-Sinai Medical Center, Los Angeles, CA; ²Medical College of Wisconsin, Milwaukee, WI; ³Washington University in St. Louis, St. Louis, MO; ⁴The University of Miami Health System, Miami, FL; ⁵Beth Israel Deaconess Medical Center, Boston, MA; ⁶Susan and Leonard Feinstein IBD Center, Icahn School of Medicine, Mount Sinai, New York, NY; ⁷Medical College of Wisconsin Affiliated Hospitals, Wauwatosa, WI; ⁸Cedars Sinai Medical Center, Los Angeles, CA

Introduction: In patients with Crohn’s disease (CD) or ulcerative colitis (UC), body composition (BC) and specifically visceral adipose tissue (VAT) has been associated with worse response to infliximab (IFX), potentially playing a role in clearance and volume distribution. VAT may also explain heterogenicity in target trough levels of IFX (TLI) associated with favorable outcomes. The aim of this study was to assess whether TLI cutoffs linked to efficacy in patients with CD/UC receiving IFX vary based on VAT.

Methods: We conducted a prospective cross-sectional study including patients with CD or UC receiving maintenance IFX therapy (≥ 22 weeks). Variables collected at enrollment included disease phenotype, inflammation biomarkers (c-reactive protein [CRP] and fecal calprotectin [FCal]), Harvey Bradshaw Index (HBI) and simple endoscopic score (SES-CD) in CD, partial and endoscopic Mayo score (PMS and EMS) in UC. TLI and anti-drug antibodies (ADA) were measured using a drug-tolerant assay. BC parameters were measured using a GE Lunar iDXA scan (body mass, total fat and lean mass, VAT mass). Primary outcome was steroid-free deep remission (SFDR) defined as HBI < 5 in CD and PMS< 2 in UC and a normal CRP and FCal while off corticosteroids. Secondary outcome was endoscopic remission (EMS≤1 in UC or SES-CD≤2) when colonoscopy was done within 12 weeks of index visit. Optimal ITL cutoffs for SFDR by VAT% (VAT/total body mass) were determined using the Youden J statistics (J).

Results: Overall, 142 patients were enrolled and 110 had endoscopic assessment done. Differences between patients by SFDR status are shown in Table 1. An exposure-response association was identified across all VAT%, with higher ITL thresholds associated with higher VAT% (Figure 1). The optimal ITL cutoffs associated with SFDR and endoscopic remission were 3.9 mcg/mL (J: 0.52) and 4.9 mcg/mL (J: 0.56) for patients in the lowest two VAT% quartiles (< 1.2%) while optimal ITL cutoffs associated with SFDR and endoscopic remission for those patients in the highest two VAT% quartiles were 15.3 mcg/mL (J: 0.63) and 13.6 mcg/mL (J: 0.57), respectively.

Discussion: ITL cutoffs associated with favorable outcomes were higher in patients with high VAT%. This suggests that patients with higher VAT burden may require higher ITL vs. those with lower VAT. Clinicians should therefore consider VAT burden when interpreting ITL and performing therapeutic drug monitoring.

Figure: Infliximab trough levels associated with treatment efficacy were higher on those patients with a higher visceral adipose tissue burden

	Active Disease	Steroid-Free Deep Remission	P value
Female gender [n (%)]	40 (55.6)	39 (55.7)	0.99
Age [mean in years [SD])	43 (17)	39 (17)	0.10
Hispanic ethnicity [n (%)]	3 (4.2)	3 (4.3)	0.97
Race [n (%)] Caucasian African-American Asian Other	64 (90.1) 5 (7.0) 1 (1.4) 1 (1.4)	62 (92.5) 5 (7.5) None None	0.59
Disease Type [n (%)] Crohn’s disease Ulcerative colitis	42 (58.3) 30 (41.7)	45 (64.3) 25 (25.7)	0.47
Active smoker at baseline [n (%)]	5 (6.9)	9 (12.86)	0.24
Years with IBD [Median in years (IQR)]	2 (1-8)	1 (1-5)	0.10
Crohn’s Disease Phenotype
Location¹ [n (%)] L1: Ileal L2: Colonic L3: Ileocolonic	10 (13.4) 7 (9.7) 24 (33.3)	9 (12.9) 9 (12.9) 26 (37.1)	0.86 0.56 0.64
L4: Upper Gastrointestinal tract involvement [n (%)]	2 (2.8)	2 (2.9)	0.98
B1: Not stricturing, non-penetrating [n (%)]	16 (22.2)	23 (32.9)	0.16
B2: Stricturing [n (%)]	22 (30.6)	12 (17.1)	0.06
B3: Penetrating [n (%)]	9 (12.5)	9 (12.9)	0.95
Ulcerative Colitis Phenotype
Ulcerative Colitis Extension² [n (%)] Proctitis Left-sided Colitis Pan-colitis	3 (4.2) 10 (13.9) 17 (23.6)	1 (1.4) 4 (5.7) 20 (54.1)	0.32 0.10 0.50

Total Mass [Mean in Kg (SD)]	84.0 (21.3)	78.0 (19.2)	0.081
Body Mass Index [Mean in Kg/m² (SD)]	28.8 (6.3)	26.8 (6.3)	0.07
Percentage of Body Fat [Mean in % (SD)]	48.9 (11.0)	48.0 (10.6)	0.62
Total VAT³ Mass [Mean in gr (SD)]	1417.8 (1116.0)	893.1 (769.0)	0.0014*
VAT³ percentage of total body mass [Mean in % (SD)]	1.54 (0.96)	1.04 (0.75)	0.0007*
VAT³ percentage of total fat mass [Mean in % (SD)]	29.3 (15.3)	20.9 (14.2)	< 0.001*
Percentage of lean mass [Mean in Kg (SD)]	59.3 (9.1)	62.8 (1.3)	0.04*
Lean mass [Mean in Kg (SD)]	48.9 (11.0)	48.0 (10.6)	0.62
Previous Use of Biologic [n (%)]	16 (22.2)	8 (11.4)	0.086
Number of previous biologics⁴ [n (%)] 1 2 3 4 5	19 (42.2) 12 (26.7) 9 (20.0) None 1 (2.2)	17 (39.5) 9 (20.9) 7 (16.3) 1 (2.3) None	0.45
Use 5-aminosalicilates [n (%)]	7 (9.7)	5 (7.1)	0.58
On combination therapy with immunomodulator [n (%)]	30 (41.7)	43 (61.4)	0.019*
Combination therapy with immunomodulator [n (%)] None Methotrexate Azathioprine Mercaptopurine	42 (58.3) 6 (8.3) 23 (31.9) 1 (1.4)	28 (40.0) 11 (15.7) 28 (40.0) 3 (4.3)	0.013*
Simple Endoscopic Score-CD^1,5 [Median (IQR)]	8 (4-10)	0 (0-1)	< 0.0001*
Endoscopic Mayo Score^2,5[n (%)] 0 1 2 3	None 1 (3.6) 14 (50.0) 13 (46.4)	7 (38.9) 2 (11.1) 4 (22.2) 5 (27.9)	0.001*
SIBDQ⁴[Mean (SD)]	50 (12.4)	53 (12.5)	0.271
Infliximab trough concentration [Median in μg/mL (IQR]	5.7 (2.6-10.7)	14.4 (6.3-20.6)	< 0.0001*
Detectable anti-infliximab antibodies [n (%)]	4 (5.6)	2 (2.7)	0.42

(1) Only patients with Crohn’s disease.

(2) Only patients with ulcerative colitis

(3) VAT: Visceral Adipose Tissue Mass.

(4) Applies to patients with previous exposure to biologic

(5) Patients with endoscopic assessment

(6) SIBDQ: Simple Inflammatory Bowel Disease Questionnaire

(*) Statistically significant

Table: Table 1: Differences in study variables between those patients that did and did not achieve steroid-free remission

Disclosures:

Andres Yarur: Arena Pharmaceuticals – Consultant. Bristol Myers Squibb – Consultant. Prometheus Laboratories – Consultant. Takeda – Advisory Committee/Board Member.

Shaina Sekhri indicated no relevant financial relationships.

Parakkal Deepak indicated no relevant financial relationships.

Maria Abreu: AbbVie – Advisory Committee/Board Member, Consultant. Alimentiv – Speakers Bureau. Arena Pharmaceuticals – Advisory Committee/Board Member, Consultant. Bristol Myers Squibb – Advisory Committee/Board Member, Consultant. Eli Lilly – Advisory Committee/Board Member, Consultant. Gilead – Advisory Committee/Board Member, Consultant. Intellisphere (HCP Live Institutional Perspectives in GI) – Speakers Bureau. Janssen – Speakers Bureau. Janssen Biotech (nonbranded) – Consultant. Janssen Biotech (Women in GI Advisory Board) – Advisory Committee/Board Member, Consultant. Janssen Biotech NART – Consultant. Janssen Global Services – Consultant. Janssen Ortho – Advisory Committee/Board Member, Consultant. Microba – Advisory Committee/Board Member, Consultant. Pfizer – Grant/Research Support. Prime CME – Speakers Bureau. Prometheus Biosciences – Advisory Committee/Board Member, Consultant, Grant/Research Support. Takeda – Grant/Research Support, Speakers Bureau. UCB Biopharma – Advisory Committee/Board Member, Consultant. WebMD Global – Advisory Committee/Board Member, Consultant.

Adam Cheifetz indicated no relevant financial relationships.

Konstantinos Papamichail indicated no relevant financial relationships.

Marla Dubinsky: AbbVie – Consultant. Arena Pharmaceuticals – Consultant. Bristol Myers Squibb – Consultant. Celgene – Consultant. Eli Lilly – Consultant. Galapagos – Consultant. Genetech – Consultant. Gilead Sciences – Consultant. Janssen Pharmaceuticals – Consultant. Pfizer Inc – Consultant. Prometheus Laboratories – Consultant. Takeda – Consultant. Trellus Health – Shareholder. UCB – Consultant.

Poonam Beniwal-Patel: Takeda – Speakers Bureau.

Phillip Gu indicated no relevant financial relationships.

Dermot McGovern: Boehringer-Ingelheim – Consultant. Bridge Therapeutics – Consultant. Gilead – Consultant. Merck – Consultant. Palatin – Consultant. pfizer – Consultant. Prometheus Biosciences – Consultant, Stock-publicly held company(excluding mutual/index funds). Prometheus Laboratories – Consultant.

Gil Melmed: AbbVie – Consultant. Arena – Consultant. Boehringer Ingelheim – Consultant. Bristol Meyers Squibb – Advisor or Review Panel Member, Consultant. Entasis – Consultant. Janssen – Consultant. Medtronic – Consultant. Pfizer – Consultant, Grant/Research Support. Samsung Bioepis – Consultant. Shionogi – Advisor or Review Panel Member. Takeda – Consultant. TechLab – Consultant.