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JAMA Surg. 2017 Aug; 152(eight): e171538.

Association of Preoperative Anti–Tumor Necrosis Gene Therapy With Adverse Postoperative Outcomes in Patients Undergoing Abdominal Surgery for Ulcerative Colitis

Audrey S. Kulaylat, MD,¹ Afif N. Kulaylat, MD,ⁱ Eric W. Schaefer, MS,² Andrew Tinsley, Dr.,^three Emmanuelle Williams, MD,³ Walter Koltun, Doc,^one Christopher S. Hollenbeak, PhD,^{1, 2} and Evangelos Messaris, Dr., PhD ¹

Audrey South. Kulaylat

^oneDepartment of Surgery, College of Medicine, The Pennsylvania State University, Hershey

Afif N. Kulaylat

¹Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey

Eric Westward. Schaefer

ⁱⁱSection of Public Wellness Sciences, Higher of Medicine, The Pennsylvania State Academy, Hershey

Andrew Tinsley

ⁱⁱⁱDivision of Gastroenterology, Department of Internal Medicine, College of Medicine, The Pennsylvania State Academy, Hershey

Emmanuelle Williams

³Sectionalisation of Gastroenterology, Department of Internal Medicine, College of Medicine, The Pennsylvania State University, Hershey

Walter Koltun

¹Section of Surgery, College of Medicine, The Pennsylvania State Academy, Hershey

Christopher Due south. Hollenbeak

¹Section of Surgery, College of Medicine, The Pennsylvania State University, Hershey

ⁱⁱDepartment of Public Health Sciences, College of Medicine, The Pennsylvania Land University, Hershey

Evangelos Messaris

¹Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey

Received 2016 Dec 30; Accustomed 2017 Mar 12.

Key Points

Question

Are adverse postoperative events higher among patients with ulcerative colitis who require anti–tumor necrosis factor (TNF) therapy?

Findings

In this analysis involving the insurance claims records of 2476 patients who underwent colectomy or total proctocolectomy for ulcerative colitis, preoperative anti-TNF agent utilise was not associated with a pregnant increase in postoperative complications. However, anti-TNF agent utilize within 90 days of surgery among patients who underwent ileal pouch-anal anastomosis was associated with higher complication rates.

Meaning

For patients using anti-TNF therapy for ulcerative colitis, avoidance of ileal pouch-anal anastomosis during the initial ulcerative colitis–associated process may be warranted.

Abstract

Importance

Despite the increasing apply of anti–tumor necrosis factor (TNF) therapy in ulcerative colitis, its effects on postoperative outcomes remain unclear, with many patients requiring surgical intervention despite optimal medical direction.

Objective

To assess the association of preoperative use of anti-TNF agents with adverse postoperative outcomes.

Pattern, Setting, and Participants

This analysis used insurance claims data from a big national database to identify patients 18 years or older with ulcerative colitis. These insured patients had inpatient and/or outpatient claims betwixt Jan i, 2005, and Dec 31, 2013, with Current Procedural Terminology codes for a subtotal colectomy or total abdominal colectomy, a total proctocolectomy with end ileostomy, or a combined full proctocolectomy and ileal pouch-anal anastomosis. Only data regarding the start or index surgical admission within the time frame were bathetic. Apply of anti-TNF agents, corticosteroids, and immunomodulators within 90 days of surgery was identified using Healthcare Common Process Coding System codes. Inclusion in the written report required the patient to have an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-ix-CM) diagnosis code for ulcerative colitis. Exclusion occurred if the patient had a secondary ICD-nine-CM diagnosis code for Crohn disease or if the patient was not continuously enrolled in an insurance plan for at to the lowest degree 180 days before and after the index surgery. Data were collected and analyzed from February one, 2015, to June 2, 2016.

Chief Outcomes and Measures

Outcomes included xc-twenty-four hours complications, emergency department visits, and readmissions. Multivariable logistic regression was used to model covariates, including anti-TNF agent use, on the occurrence of outcomes.

Results

Of the 2476 patients identified, 1379 (55.7%) were men, and the mean (SD) age was 42.1 (12.9) years. Among these, 950 (38.4%) underwent subtotal colectomy or total abdominal colectomy, 354 (xiv.3%) underwent total proctocolectomy with end ileostomy, and 1172 (47.3%) received ileal pouch-anal anastomoses. In univariate analyses, increased postoperative complications were observed among patients in the ileal pouch accomplice who received anti-TNF agents preoperatively vs those who did not (137 [45.ii%] vs 327 [37.vi%]; P = .02) but not amidst those in the colectomy or proctocolectomy cohorts. An increase in complications was also observed on multivariable analyses amid patients in the ileal pouch cohort (odds ratio, 1.38; 95% CI, 1.05-1.82).

Conclusions and Relevance

Unlike preoperative anti-TNF agent use amongst patients who underwent colectomy or full proctocolectomy and experienced no significant increment in postoperative complications, anti-TNF agent use within xc days of surgery among patients who underwent ileal pouch-anal anastomosis was associated with higher 90-twenty-four hour period postoperative complication rates.

Introduction

Medical therapies for inflammatory bowel diseases go along to evolve, but surgical interventions maintain a significant role, specially in ulcerative colitis (UC). The clinical grade of UC exhibits a highly variable spectrum of severity amidst patients. Approximately 50% of patients with chronic disease will relapse each year, and up to 90% of these patients will experience at least 1 relapse in 25 years. Even with optimal medical direction, approximately one-3rd of patients with UC requiring hospitalization for their disease will ultimately undergo surgery. About of these patients feel either bereft responses to medical therapy or intolerable adverse effects from medications.

The first class of biologic agents used in the treatment of inflammatory bowel diseases comprised antibodies targeting tumor necrosis factor (TNF), a pro-inflammatory cytokine. Infliximab first gained US Food and Drug Administration approving for the treatment of UC in 2005 and was followed several years later past adalimumab. Past interfering with the inflammatory cascade, anti-TNF agents have demonstrated improved mucosal healing, reductions in corticosteroid requirements, and induction or maintenance of remission. Yet, because these underlying inflammatory mechanisms are also implicated in wound healing and infection defence, impairing these mechanisms in a surgical patient is justly met with some caution.

Initially, blessing of infliximab for UC was limited to patients with moderate to severe disease. Although described more thoroughly within the Crohn affliction literature, a "pinnacle-down" arroyo, which employs early use of biologic agents to induce remission and is followed by maintenance with immunomodulators, has received increased emphasis. This approach has too been used in patients with UC, and it has been suggested that a subgroup of patients with UC may benefit from this strategy. Furthermore, the indications for anti-TNF therapy have expanded to include salvage therapy for corticosteroid-resistant cases, decreasing the emergency colectomy rate to 29%. Although improved, the colectomy population withal represents a substantial proportion of patients undergoing surgery after a recent anti-TNF assistants. The once-singled-out indications for surgical and medical therapy are increasingly converging, and the patients who are now candidates for anti-TNF agents are the same ones who remain at high risk for surgery. Understanding the potential effect of administering anti-TNF agents on the surgical patient is therefore critical. In this study, we used a large national claims database to explore the effects of anti-TNF agents on surgical patients with UC.

Methods

Data

Between Feb 1, 2015, and June 2, 2016, we used the MarketScan Commercial Claims and Encounters (CCAE) database (Truven Wellness Analytics) to identify the patient cohort for this study. The CCAE database captures both inpatient and outpatient claims, including outpatient pharmaceutical claims, for patients (also as their spouses and dependents) with employer-based private insurance in the U.s.. Because it is based on insurance enrollment, the database contains information that has a strong longitudinal integrity throughout inpatient and outpatient encounters. The inclusion of both inpatient and outpatient pharmaceutical data, including prescription fills, provides an authentic reflection of patient medication utilization patterns and is a large reward of this database. This study was approved past the institutional review board of the Penn State Milton S. Hershey Medical Eye, Hershey, Pennsylvania. The demand for patient informed consent was waived for this study by the institutional review board of the Penn State Milton Due south. Hershey Medical Center because of the minimal adventure of this study.

Patient Selection

A total of 2476 patients 18 years or older were identified through the CCAE database. These patients had inpatient and/or outpatient claims from January i, 2005, through December 31, 2013, with Current Procedural Terminology (CPT) codes indicating a subtotal colectomy without primary anastomosis or total abdominal colectomy (STC/TAC) (CPT codes 44141, 44143, 44144, 44146, 44147, 44150, 44151, 44206, 44208, and 44210), a full proctocolectomy with finish ileostomy (TPC/EI; CPT codes 44155, 44156, and 44212), or a combined total proctocolectomy and ileal pouch-anal anastomosis (IPAA; CPT codes 44152, 44153, 44157, 44158, and 44211). Patients who underwent an IPAA with CPT code 44152 or 44153 or a stoma reversal (CPT codes 44227, 44620, 44625, and 44626) within half-dozen months after their alphabetize procedure were designated as receiving a diverting loop ileostomy. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-nine-CM) diagnosis codes for UC (556.0-556.six, 556.8, and 556.nine) were used to isolate patients with a UC diagnosis for inclusion in this study. If multiple admissions involving a surgical procedure were identified, then only data regarding the beginning surgical admission within the time frame were abstracted to identify the index UC-related procedure for each patient. Patients were excluded if they had a secondary ICD-9-CM diagnosis lawmaking for Crohn disease or if they were not continuously enrolled in an insurance plan for at least 180 days before and afterward the alphabetize surgery.

Covariates

Preoperative comorbidities were identified with claims within 180 days prior to surgery using the Quan modification of the Charlson Comorbidity Index, which is based on 17 comorbidities. Additional comorbidities were identified using ICD-9-CM diagnosis codes for various types of protein-calorie malnutrition (260.Ten, 261.X, 262.10, and 263.X) and for failure to thrive (783.2 and 783.7). Use of anti-TNF agents, corticosteroids, and immunomodulators within 90 days of surgery was identified using Healthcare Mutual Procedure Coding Organisation codes for inpatient and outpatient claims and using generic names for outpatient pharmaceutical claims. Anti-TNF agents were adalimumab (J0135), certolizumab pegol (J0717), and infliximab (J1745). Corticosteroids were prednisone (J7506); hydrocortisone acetate, hydrocortisone sodium phosphate, and hydrocortisone sodium succinate (J1700, J1710, and J1720); and methylprednisolone, methylprednisolone acetate, and methylprednisolone sodium succinate (J1020, J1030, J1040, J2920, J2930, and J7509). Immunomodulators were azathioprine sodium (J7500, J7501), half-dozen-mercaptopurine (S0108), and cyclosporine (J7502, J7515, and J7516). For patients with anti-TNF agent use, the most contempo solar day prior to surgery when there was a claim for a biologic agent was collected. Emergency cases were defined as those with a merits for an emergency department (ED) visit within 2 days of the surgical procedure.

Outcomes

Primary outcomes of interest inside each surgical group included complications, postoperative ED visits, and readmissions. Complications were defined according to the description by Loftus and colleagues of postoperative complications relevant to patients with UC undergoing colorectal resections. These complications were identified from inpatient and outpatient claims with CPT or ICD-nine-CM codes within 90 days of belch; they included fistula, abscess, stricture, sepsis-pneumonia-bacteremia, wound debridement or dehiscence, anal/rectal repair or manipulation, lysis of adhesions, and revision of ileostomy. Postoperative ED visits were defined as a service subcategory code of 20 for inpatient and outpatient claims. Readmissions were defined every bit any inpatient claim inside 90 days of discharge. Among patients receiving biologic agents, we examined whether receiving an infusion closer to the date of the index surgery afflicted postsurgical outcomes.

Statistical Analysis

Wilcoxon and χⁱⁱ tests, equally advisable, were used to compare preoperative variables and postoperative outcomes between patients receiving and patients not receiving anti-TNF agents in each surgical group. Multivariable logistic regression was used to model the occurrence of each effect within 90 days by the following covariates: anti-TNF agent use, age, sex, comorbidity alphabetize, malnutrition, failure to thrive, corticosteroid apply, immunomodulator utilise, emergency case, and presence of diverting stoma (among the IPAA cohort only). A linear association for comorbidity alphabetize was assumed. Nonlinear associations (on the log-odds calibration) for age were examined in these models using B-splines, but linear associations were found to exist advisable in all cases and were used in the final models. Odds ratios (ORs) and 95% CIs were reported for all factors in the models. P < .05 was considered statistically significant, and 2-sided P values were used.

Among the subset of patients who received anti-TNF therapy, we examined whether outcomes differed according to fourth dimension betwixt anti-TNF agent use and surgery. Univariable logistic regression was used to model the occurrence of each effect equally a function of time since infusion. Nonlinear curves for day were tested using B-splines, but all nonlinear curves were nonsignificant, and thus linear curves were fit. The estimated probabilities of each outcome as a office of time were reported for these models. Multivariable analyses could not be performed because the upshot rates of each outcome were besides small.

In improver, sensitivity assay that excluded patients undergoing emergency surgery was performed given the inherent heterogeneity in disease severity and operative complexity in this population. All logistic models were refit after these exclusions.

Statistical analyses were conducted using SAS software, version nine.4 (SAS Institute Inc) and R software, version 3.1.2 (http://www.r-projection.org).

Results

Of the 2476 patients identified, 1379 (55.seven%) were men and 1097 (44.3%) were women. The hateful (SD) age of all patients was 42.1 (12.ix) years.

Subtotal Colectomy or Total Abdominal Colectomy

A total of 950 patients (38.iv%) who underwent an STC/TAC procedure were identified (Tabular array one), of whom 254 (26.7%) had claims for an anti-TNF agent—primarily infliximab (Table 2)—within 90 days of surgery, given at a mean (SD) of 39.one (22.3) days prior to surgery. Patients receiving anti-TNF agents compared with those with no anti-TNF agent use were significantly younger (mean [SD] age, 37.six [thirteen.42] years vs 42.4 [xiii.36] years; P < .001) and underwent fewer emergency surgical procedures (33 [thirteen%] vs 191 [27.4%]; P < .001) just did not differ regarding sex, comorbidity index, or malnutrition status (Table 1). Significantly more patients receiving anti-TNF therapy compared with those with no anti-TNF agent use had corticosteroid use (170 [66.ix%] vs 361 [51.9%]; P < .001) and immunomodulator apply (69 [27.2%] vs 145 [20.eight%]; P = .04).

Table 1.

Patient Demographics Among 3 Surgical Cohorts

Characteristic	STC/TAC, No. (%) (n = 950)			TPC/EI, No. (%) (north = 354)			IPAA, No. (%) (n = 1172)
	No Anti-TNF Amanuensis Use (n = 696)	Anti-TNF Agent Utilize (north = 254)	P Value	No Anti-TNF Agent Use (north = 261)	Anti-TNF Amanuensis Utilise (n = 93)	P Value	No Anti-TNF Agent Apply (n = 869)	Anti-TNF Amanuensis Use (n = 303)	P Value
Age, mean (SD), y	42.4 (13.36)	37.6 (13.42)	<.001	50.5 (10.81)	47.four (11.65)	.01	41.2 (12.00)	38.vi (12.66)	.002
Sex
Male	368 (52.9)	151 (59.iv)	.07	139 (53.3)	57 (61.3)	.18	498 (57.3)	166 (54.8)	.45
Female	328 (47.1)	103 (40.6)		122 (46.7)	36 (38.seven)		371 (42.seven)	137 (45.ii)
Comorbidity index (CCI)
0	531 (76.iii)	196 (77.2)	.58	181 (69.iii)	72 (77.4)	.29	704 (81)	261 (86.1)	.07
one	60 (viii.6)	27 (10.6)		30 (11.5)	11 (11.8)		56 (six.iv)	21 (6.ix)
ii	72 (10.3)	22 (8.7)		35 (thirteen.4)	eight (eight.half-dozen)		84 (9.7)	16 (5.3)
≥iii	33 (four.7)	9 (three.five)		15 (5.7)	ii (2.two)		25 (2.9)	5 (ane.seven)
Malnutrition	49 (vii)	26 (10.2)	.11	14 (v.4)	x (10.8)	.08	18 (2.1)	13 (4.3)	.04
Failure to thrive	37 (5.three)	27 (10.vi)	.004	20 (7.seven)	9 (nine.7)	.54	24 (2.viii)	13 (four.three)	.19
Emergent procedure	191 (27.4)	33 (xiii)	<.001	24 (9.2)	14 (15.i)	.12	35 (iv)	sixteen (5.iii)	.36

Abbreviations: CCI, Charlson Comorbidity Index; IPAA, ileal pouch-anal anastomosis; STC/TAC, subtotal colectomy or full abdominal colectomy; TNF, tumor necrosis gene; TPC/EI, total proctocolectomy with end ileostomy.

Tabular array 2.

Medication Utilise Within 90 Days of Surgery Amongst iii Cohorts

Medication	No. (%)
	STC/TAC (due north = 950)	TPC/EI (n = 354)	IPAA (n = 1172)
Corticosteroids	531 (55.9)	182 (51.4)	557 (47.5)
Immunomodulator	214 (22.five)	79 (22.iii)	298 (25.4)
Azathioprine sodium	138 (xiv.5)	47 (xiii.three)	175 (14.ix)
half-dozen-Mercaptopurine	76 (8)	31 (viii.viii)	125 (10.vii)
Cyclosporine	3 (0.iii)	1 (0.3)	v (0.iv)
Anti-TNF agent	254 (26.seven)	93 (26.three)	303 (25.9)
Infliximab	198 (20.8)	68 (19.two)	237 (twenty.2)
Adalimumab	53 (5.vi)	25 (7.ane)	63 (5.4)
Certolizumab pegol	8 (0.8)	4 (1.1)	3 (0.3)

Abbreviations: IPAA, ileal pouch-anal anastomosis; STC/TAC, subtotal colectomy or total abdominal colectomy; TNF, tumor necrosis gene; TPC/EI, total proctocolectomy with end ileostomy.

In univariate analyses, patients receiving anti-TNF agents compared with those with no anti-TNF agent apply had fewer ED visits within 90 days of surgery (79 [31.1%] vs 270 [38.8%]; P = .03), but there were no differences in readmissions or complications. On multivariable analyses, however, the receipt of therapy was not significantly associated with these outcomes (Table 3). Among patients who received a biologic agent, the timing of its well-nigh recent administration did not influence the occurrence of any agin outcomes within 90 days (Figure, A).

Tabular array three.

Logistic Regression Analyses for 90-Day Postoperative Outcome Variables

Variable	OR (95% CI)
	Any Complication	P Value	Emergency Department Visit	P Value	Readmission	P Value
Subtotal Colectomy or Total Abdominal Colectomy
Anti-TNF agent utilize	0.86 (0.62-i.18)	.35	0.73 (0.53-ane.00)	.052	0.82 (0.60-i.xi)	.20
Historic period, 10-y increment	0.96 (0.87-1.06)	.40	0.89 (0.81-0.98)	.02	0.80 (0.72-0.88)	<.001
Female person	1.31 (1.01-1.71)	.045	1.xviii (0.91-ane.52)	.22	1.02 (0.79-1.32)	.87
CCI, i-point increment	0.99 (0.87-1.11)	.83	1.11 (0.99-i.25)	.07	1.17 (1.04-1.31)	.007
Malnutrition	1.12 (0.68-1.83)	.65	1.03 (0.63-1.67)	.91	0.96 (0.58-1.56)	.87
Failure to thrive	one.xiv (0.66-1.92)	.64	1.05 (0.62-1.76)	.85	1.37 (0.82-ii.28)	.23
Corticosteroid use	0.94 (0.72-one.25)	.69	ane.26 (0.96-i.66)	.09	1.28 (0.98-1.68)	.07
Immunomodulator use	ane.xiv (0.82-1.58)	.43	i.xiii (0.82-ane.55)	.47	1.22 (0.89-1.68)	.22
Emergency procedure	1.19 (0.87-1.62)	.27	one.34 (0.99-one.80)	.06	one.22 (0.90-1.65)	.twenty
Total Proctocolectomy With End Ileostomy
Anti-TNF amanuensis use	1.01 (0.59-1.lxx)	.98	0.95 (0.55-1.59)	.83	1.83 (one.08-3.10)	.02
Age, x-y increase	1.06 (0.87-1.31)	.56	0.84 (0.69-1.03)	.x	0.94 (0.76-ane.16)	.54
Female	1.17 (0.75-1.84)	.49	0.66 (0.41-1.04)	.07	1.22 (0.75-1.96)	.42
CCI, i-betoken increment	ane.05 (0.84-1.31)	.67	ane.eleven (0.89-one.39)	.36	0.95 (0.73-i.21)	.67
Malnutrition	0.95 (0.34-2.42)	.91	one.05 (0.39-two.67)	.92	1.65 (0.63-4.19)	.29
Failure to thrive	0.60 (0.22-1.43)	.27	0.41 (0.14-1.02)	.07	0.55 (0.xix-1.37)	.23
Corticosteroid utilise	0.67 (0.42-1.05)	.08	0.88 (0.56-one.40)	.60	1.08 (0.66-1.75)	.76
Immunomodulator use	one.xiii (0.65-one.93)	.66	ane.07 (0.62-i.83)	.lxxx	0.96 (0.54-1.68)	.89
Emergency procedure	0.92 (0.43-1.90)	.83	1.31 (0.63-ii.66)	.46	0.78 (0.34-1.67)	.54
Ileal Pouch-Anal Anastomosis
Anti-TNF agent use	1.38 (one.05-ane.82)	.02	0.85 (0.65-1.11)	.24	0.96 (0.lxx-1.35)	.83
Age, 10-y increase	1.07 (0.96-1.18)	.21	0.96 (0.87-1.06)	.38	0.99 (0.88-i.11)	.82
Female	1.xxx (i.02-1.65)	.03	1.35 (ane.07-1.71)	.01	one.37 (1.03-1.84)	.03
CCI, 1-betoken increase	1.05 (0.91-one.21)	.50	i.04 (0.91-1.20)	.55	ane.00 (0.85-i.nineteen)	.97
Malnutrition	1.25 (0.59-ii.61)	.56	0.75 (0.35-1.57)	.45	0.73 (0.31-1.93)	.50
Failure to thrive	0.68 (0.32-1.36)	.29	i.03 (0.52-2.03)	.92	2.26 (0.91-6.87)	.11
Corticosteroid apply	1.03 (0.81-i.32)	.fourscore	1.26 (0.99-1.61)	.06	ane.25 (0.93-ane.68)	.xiv
Immunomodulator use	1.02 (0.77-1.34)	.90	1.11 (0.84-one.46)	.45	0.92 (0.66-ane.28)	.61
Emergency procedure	i.47 (0.83-2.62)	.eighteen	2.68 (one.48-5.07)	.002	1.05 (0.54-2.sixteen)	.88
Diverting stoma	0.89 (0.66-1.22)	.47	1.x (0.81-1.50)	.55	4.eighteen (3.02-v.78)	<.001

Abbreviations: CCI, Charlson Comorbidity Index; OR, odds ratio; TNF, tumor necrosis factor.

Logistic Regression Models of Complications, Emergency Department (ED) Visits, and Readmissions Within ninety Days

Each consequence is shown on a separate row for each surgical group. Blackness lines indicate probabilities; grayness regions, 95% CIs.

Total Proctocolectomy With Cease Ileostomy

For TPC/EI procedures, a total of 354 patients (14.3%) were identified (Table 1). Approximately 93 patients (26.3%) received an anti-TNF agent within 90 days of surgery (Table ii). Over again, infliximab was the most usually used agent, given at a mean (SD) of 41.5 (xx.9) days earlier surgery. Patients receiving anti-TNF agents compared with those with no anti-TNF agent use were younger (mean [SD] age, 47.4 [11.65] years vs 50.5 [10.81] years; P = .01) and more than likely to be receiving corticosteroids (62 [66.seven%] vs 120 [46.0%]; P = .001) or immunomodulators (thirty [32.3%] vs 49 [18.viii%]; P = .007), but they did non significantly differ in sex, comorbidity index, or emergency surgical process (Table 1).

Compared with those with no anti-TNF agent use, patients receiving anti-TNF therapy did not have more than complications or ED visits but did have higher readmission rates within 90 days (66 [25.3%] vs 36 [38.7%]; P = .01). This association was also observed on multivariable analyses (Tabular array iii). No associations were institute between the timing of preoperative anti-TNF assistants prior to the index surgery and occurrence of agin postoperative outcomes within 90 days (Figure, B).

Ileal Pouch-Anal Anastomosis

A total of 1172 patients (47.3%) who underwent IPAA as their index UC-related procedure were identified (Table 1). Every bit in the other two cohorts, 303 patients (25.9%) in the IPAA cohort received anti-TNF agents, most of which was infliximab (Table 2) given at a hateful (SD) of 46.6 (21.1) days before surgery. Patients receiving anti-TNF agents compared with those with no anti-TNF agent use were younger (mean [SD] historic period, 38.6 [12.66] years vs 41.ii [12] years; P = .002) and had a higher proportion of malnutrition (thirteen [4.3%] vs xviii [2.1%]; P = .04), corticosteroid employ (191 [63.0%] vs 366 [42.1%]; P < .001), and immunomodulator employ (96 [31.vii%] vs 202 [23.2%]; P = .004) merely similar proportions of emergency surgical procedures (Table 1).

Among patients in the IPAA cohort, no significant associations were noted betwixt anti-TNF therapy and either ED visits or 90-day readmissions on either univariate analyses or multivariable analyses. Still, different the STC/TAC and TPC/EI cohorts, the IPAA accomplice had a significantly higher incidence of complications within xc days of surgery (137 [45.2%] vs 327 [37.half-dozen%]; P = .02). This upshot was likewise observed on multivariable logistic regression; use of a biologic agent was associated with 38% higher odds of complications (OR, 1.38; 95% CI, i.05-1.82). Because of this significant association, further analysis was performed to identify the specific complications responsible for this clan (Table 4). Timing of anti-TNF therapy upward to 90 days prior to the alphabetize surgery did not appear to influence the complication rate (Effigy, C).

Table iv.

Reported xc-Day Postoperative Complications in the IPAA Cohort

Complexity	No. (%)		P Value
	No Anti-TNF Amanuensis Apply (n = 869)	Anti-TNF Agent Utilise (due north = 303)
Fistula	96 (eleven)	42 (thirteen.9)	.19
Abscess	154 (17.seven)	56 (18.five)	.77
Stricture	18 (2.1)	9 (three)	.37
Sepsis-pneumonia-bacteremia	86 (9.ix)	xl (thirteen.two)	.xi
Wound debridement and dehiscence	39 (4.5)	22 (7.3)	.06
Anal/rectal repair or manipulation	43 (4.9)	20 (half-dozen.6)	.27
Lysis of adhesions	15 (ane.7)	14 (4.half dozen)	.005
Revision of ileostomy	x (1.2)	iv (i.three)	.82

Abbreviations: IPAA, ileal pouch-anal anastomosis; TNF, tumor necrosis gene.

Sensitivity Analysis

To exam the robustness of these findings, a sensitivity analysis was performed that excluded all emergency cases in all logistic models. The estimated ORs from these models were similar to the estimates when using all patients for the iii surgical groups and the 3 adverse postoperative outcomes.

Discussion

In the current literature, significant heterogeneity has been reported regarding the effects of anti-TNF agents on surgical patients with UC. Existing data are primarily based on retrospective studies, which vary by the types of surgery included (resections vs IPAA-related procedures) and the biologic agents studied (infliximab alone vs with adalimumab and certolizumab) and are oft limited by small sample sizes. Most have shown no departure in outcomes, just several have suggested either increased infectious or total postoperative complications amongst patients who received anti-TNF agents preoperatively. Multiple meta-analyses accept also yielded contradictory results, and the literature is similarly conflicted regarding postoperative complications associated with anti-TNF amanuensis use in Crohn disease.

In this written report, merely patients in the IPAA accomplice demonstrated an increase in 90-day complications after preoperative use of anti-TNF agents. A sensitivity analysis removing any patients who had an ED visit inside ii days of admission corroborated this finding. This finding has been observed in several other studies, all of which included only patients undergoing IPAA-related procedures. Of the 3 studies that too exclusively examined patients who underwent IPAA procedures but did not identify increases in complications, the anti-TNF arms had relatively small sample sizes of fewer than thirty patients and may not have been powered fairly to detect differences in complication rates.

In this report, every bit opposed to having an event on restorative procedures, anti-TNF agents had no detrimental effect on postoperative complications in patients who underwent resection (STC/TAC or TPC/EI) equally their initial UC-related surgery. Previous studies that examined patients undergoing only resection are thin, with only a few studies examining patients undergoing only colectomy. Rather, many studies include mixed cohorts of patients undergoing both resection only and resection with IPAA. Of these studies, none identified an increased run a risk of postoperative complications in patients on preoperative anti-TNF therapy. A retrospective report by Gu and colleagues, which stratified patients into those undergoing full proctocolectomy with IPAA vs subtotal colectomy, found increased rates of pelvic sepsis among patients who underwent IPAA and were receiving biologic therapy but no increased complications among patients who underwent colectomy and were receiving biologic therapy, which are consistent with our current findings. Considering mixed groups of surgical patients may, therefore, be diluting a detrimental result of biologic agents on patients who underwent IPAA and was an observation suggested in a meta-assay past Selvaggi and colleagues.

Given the complexity of IPAA procedures, it is not surprising that this accomplice appears more vulnerable to alterations in the inflammatory cascade induced by anti-TNF agents. The complications that either met or approached statistical significance between the groups included those associated with wound debridement or dehiscence or adhesion germination. This profile of complications suggests that these alterations in the inflammatory process may bear on wound healing, although further studies focusing on this clan are warranted.

Although data on infliximab use in surgical patients with UC are conflicted, data on other anti-TNF agents in this population are largely absent. Of those that do include adalimumab and certolizumab, a variable effect of anti-TNF agents on postoperative complications was noted, similar to studies examining infliximab lone. One written report performed a subgroup analysis direct comparing complications between infliximab and adalimumab users and found no differences betwixt the agents. As the oldest biologic agent, infliximab offers the largest clinical experience and body of supporting literature but requires in-office intravenous infusion, different the subcutaneous self-administration permitted by adalimumab and certolizumab. Furthermore, because diverse clinical considerations and emerging resistance patterns are used to guide the pick of biologic agents, an improved understanding of whatsoever differences between these 3 agents in a surgical population is an important area for future research.

Several other pregnant associations identified in this written report are consistent with previous findings in the literature. Female person sex was associated with increased odds of all 3 agin outcomes among patients in the IPAA group and with increased postoperative complications amidst patients in the STC/TAC group. A large retrospective study past Riegler and colleagues noted an association of female sexual practice and increased disease activeness with greater colitis extent. Conversely, increasing age was associated with reduced disease severity in that report; in our study, older patients in the STC/TAC cohort were found to accept decreased odds of ED visits and readmissions. Interestingly, corticosteroid employ was not constitute to exist associated with postoperative complications subsequently controlling for other patient covariates. The employ of certain medications (eg, corticosteroids and immunomodulators) in this study was considered binary because dosages could not always be identified inside the CCAE database. This limitation may have biased our results either toward the null hypothesis (past overestimating the consequence of corticosteroids in patients who received only 1 dose) or toward showing a significant departure if the corticosteroid dosages used among anti-TNF patients were substantially higher than amidst patients not receiving anti-TNF therapy.

Limitations

Several limitations are present in this study. Kickoff, using the CCAE database, we were unable to determine whether patients had received inpatient infusions of anti-TNF agents preoperatively, thus potentially misclassifying some of the patients receiving anti-TNF agents and biasing the results toward the null hypothesis. 2nd, the CCAE database contains only privately insured patients and thus does not include the Medicare population (all patients 65 years or older), the Medicaid population, or individuals without wellness insurance. Although this proportion still represents near patients with UC, this subset is still not generalizable to the entire UC population because a previous report estimated that only 58% of patients with UC have continuous enrollment in a private health insurance plan for at least 1 yr. Third, although anastomotic leaks lack a specific ICD-9-CM code, they are commonly associated with intra-intestinal abscesses, which are captured by the definition of complications by Loftus and colleagues. Finally, because only the initial procedure that patients underwent was captured in this analysis, nosotros were unable to compare patients undergoing delayed completion proctectomy with IPAA with patients undergoing TPC with primary IPAA.

Conclusions

Postoperative complications were not increased among patients with UC receiving preoperative anti-TNF agents who underwent resection lone (STC/TAC or TPC/EI). Amid patients undergoing a restorative process every bit their index UC-related procedure, all the same, the utilize of anti-TNF therapy inside ninety days of surgery was associated with increased complications. Therefore, in a patient who is a candidate for a restorative procedure, our data suggest that performing a TPC with concurrent IPAA as the initial UC-related procedure should be avoided or at least delayed for more than than ninety days after anti-TNF agent utilize. Information technology remains unclear whether a 3-stage or a modified 2-stage arroyo (initial subtotal colectomy with end ileostomy followed by completion proctectomy with IPAA and no proximal diversion) is a safer culling. A previous written report suggested that patients receiving biologic agents who undergo delayed IPAA exercise not experience the complications observed in patients undergoing primary IPAA; yet, further studies using larger cohorts are warranted to directly compare these 2 cohorts of patients.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831468/

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