Systematic Reviews
Copyright ©The Author(s) 2021.
World J Gastroenterol. Mar 7, 2021; 27(9): 886-907
Published online Mar 7, 2021. doi: 10.3748/wjg.v27.i9.886
Table 1 Disease phenotype of study cohort
Ref.
CD, Location, n (%)
CD, Behavior, n (%)
UC, Location, n (%)
Ileal
Colonic
Ileocolonic
UGT
Inflammatory
Stricturing
Fistulizing
Perianal
Penetrating
Extensive
Left-side
Pancolitis
Proctitis
Chaparro et al[12], 201849 (38.6)25 (19.7)52 (40.9)4 (3.1)67 (52.8)34 (26.8)26 (20.5)85 (66.9)39 (30.7)16 (12.6)
Ungar et al[28], 201631 (27.9)26 (23.4)54 (48.6)49 (44.1)28 (25.2)34 (30.6)16 (14.4)17 (15.3)
Yarur et al[29], 201616 (27.9)9 (15.6)14 (24.1)3 (5.2)29 (50.0)20 (34.4)11 (19.0)1 (14.3)6 (86.7)0
Roblin et al[26], 201413 (59.1)4 (18.2)5 (22.7)4 (18.2)4 (18.2)14 (77.8)4 (18.2)
Morita et al[18], 201619 (29.7)45 (70.3)
Morita et al[19], 201614 (33.3)4 (9.5)24 (57.1)50.06 (14.3)
Strik et al[27], 20199 (13.6)
Plevris et al[24], 202011 (17.2)26 (40.6)27 (42.2)11 (17.2)16 (25.0)
Zittan et al[30], 201612 (20.0)14 (23.3)34 (56.7)18 (30.0)
Juncadella et al[16], 201820 (27.8)13 (18.1)39 (54.2)3 (4.2)10 (13.9)32 (44.4)29 (40.3)10 (38.5)16 (61.5)
Papamichael et al[23], 201663 (62.4)
Papamichael et al[20], 201720 (46.5)
Papamichael et al[22], 201829 (51.8)
Feng et al[14], 201915 (10.6)6 (4.3)120 (85.1)29 (20.6)15 (10.6)
Papamichael et al[21], 201820 (18.3)25 (22.9)59 (54.1)5 (4.6)18 (16.4)38 (34.5)
Dreesen et al[31], 2020
Imaeda et al[15], 201414 (31.1)4 (8.9)27 (60.0)16 (35.6)4 (8.9)
EI-Matary et al[32], 20195 (8.5)17 (28.8)27 (45.8)10 (16.9)
Kang et al[17], 20198 (7.6)6 (5.7)91 (86.7)70 (66.7)18 (17.1)3 (2.9)
Hanzel et al[33], 201904 (14.3)24 (8.6)6 (2.1)4 (14.3)16 (69.6)7 (30.4)
Dreesen et al[13], 2018
Pouillon et al[25], 201913 (41.9)15 (48.4)3 (9.7)
Yacoub et al[34], 201814(35.9)6 (15.4)19 (48.7)11 (28.2)6 (15.4)27 (62.8)15 (34.9)1 (2.3)
UGT: Upper gastroenterological tract; CD: Crohn’s disease; UC: Ulcerative colitis.
Table 2 Demographics of study cohorts in inflammatory bowel disease
Ref.DiagnosticBiologicalNumberFemale, n (%)Smoking, n (%)Previous surgery, n (%)Previous biological therapy, n (%)Concomitant medications
CS, n (%)
IMMs, n (%)
5-ASA, n (%)
Surgical intervention, n (%)
Enteral nutrition, n (%)
Chaparro et al[12], 2018IBDADA/IFX18290 (49.5)50 (27.5)49 (26.9)48 (26.4)63 (34.6)
Ungar et al[28], 2016IBDADA/IFX14564 (44.1)19 (13.1)33 (22.8)37 (25.5)27 (18.6)79 (54.5)
Yarur et al[29], 2016IBDADA6627 (40.9)6 (9.1)42 (63.6)14 (21.2)21 (31.2
Roblin et al[26], 2014IBDADA4022 (55)5 (12.5)
Morita et al[18], 2016UCADA/IFX6425 (39.1)4 (6.3)50 (78.1)34 (53.1)48 (75.0)
Morita et al[19], 2016CDADA4215 (35.7)18 (42.9)15 (35.7)5 (11.9)24 (57.1)30 (71.4)
Strik et al[27], 2019PfCDADA199 (47.4)5 (26.3)9 (47.4)4 (21.1)
Plevris et al[24], 2020PfCDADA3517 (48.6)3 (8.6)21 (60.0)15 (42.9)
Zittan et al[30], 2016CDADA6031 (51.7)9 (15.0)36 (60.0)Total of concomitant therapy: 18 (30.0)
Papamichael et al[20], 2017UC ADA4320 (46.5)4/35 (11.4)38 (88.4)12 (27.9)7 (16.3)
Juncadella et al[16], 2018IBD ADA9860 (61.2)34 (34.7)28/72 (38.9)26 (26.5)
Feng et al[14], 2019CDIFX14151 (36.2)5 (3.5)22 (15.6)8 (5.7)20 (14.2)
Papamichael et al[22], 2018UCIFX5624 (42.9)11 (19.6)18 (32.1)
Papamichael et al[21], 2018CDIFX11051 (46.4)19 (17.3)20 (18.2)8 (7.3)28 (25.5)
Strik et al[27], 2019PfCDIFX4729 (61.7)7 (14.9)15 (31.9)13 (27.7)
Plevris et al[24], 2020PfCDIFX2911 (37.9)4 (13.8)1 (3.4)17 (58.6)
Papamichael et al[23], 2016UCIFX10137 (36.6)12 (12.0)5 (4.9)36 (35.6)49 (48.5)
Dreesen et al[31], 2020CDIFX11668 (58.6)
Imaeda et al[15], 2014CDIFX4512 (26.7)8 (17.8)15 (33.3)33 (73.3)
EI-Matary et al[32], 2019PCDIFX5221 (40.4)33 (63.5)AZA 17 (32.7);MTX 30 (57.7)7 (13.5)15 (28.8)10 (19.2)
Kang et al[17], 2019PCDIFX10531 (29.5)6 (5.7)6 (5.7)95 (90.5)
Dreesen et al[13], 2018IBDVDZ179106 (59.2)32 (17.9)153 (85.5)73 (40.8)20 (11.2)
Yacoub et al[34], 2018IBDVDZ8244 (53.7)18 (22.0)67 (78.0)6 (7.3)13 (15.9)14 (17.1)
Hanzel et al[33], 2019IBDVDZ5119 (37.3)10 (19.6)43 (84.3)20 (39.2)6 (11.8)
Pouillon et al[25], 2019UCVDZ3113 (41.9)7 (22.6)28 (90.3)12 (38.7)7 (22.6)14 (45.2)
IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis; IFX: Infliximab; ADA: Adalimumab; VDZ: Vedolizumab; PFCD: Perianal fistula Crohn’s disease; CS: Corticosteroid; IMM: Immunosuppressor; 5-ASA: 5-amino salicylic acid.
Table 3 Quality of articles
Ref.
Item 1
Item 2
Item 3
Item 4
Item 5
Item 6
Chaparro et al[12], 2018★★
Ungar et al[28], 2016★★
Yarur et al[29], 2016★★★
Roblin et al[26], 2014★★
Morita et al[18], 2016★★★
Morita et al[19], 2016★★★
Strik et al[27], 2019★★★
Plevris et al[24], 2020★★★
Zittan et al[30], 2016★★★
Juncadella et al[16], 2018★★★
Papamichael et al[23], 2016★★★★
Papamichael et al[20], 2017★★★★
Papamichael et al[22], 2018★★★
Feng et al[14], 2019★★★★
Papamichael et al[21], 2018★★★
Dreesen et al[31], 2020★★★★★★
Imaeda et al[15], 2014★★★
EI-Matary et al[32], 2019★★★★★★
Kang et al[17], 2019★★
Hanzel et al[33], 2019★★★★★★
Dreesen et al[13], 2018★★★
Pouillon et al[25], 2019★★★
Yacoub et al[34], 2018★★★★★★
Item 1: The representativeness of the exposed cohorts; Item 2: Identification of exposure; Item 3: The verification of concerned results absent in the start of study; Item 4: The sufficient evaluation of study results; Item 5: Follow-up is long enough after study results take place; and Item 6: Follow-up of cohorts is long enough. ★: Contents of the literature in line with the item.
Table 4 Biologic management in inflammatory bowel disease patients
Ref.
Biology
Diagnosis, n
Therapeutic stage
Therapeutic course
Injection dose
Injection frequency
Chaparro et al[12], 2018ADAIBD 94MaintenanceAt least 6 mo//
Ungar et al[28], 2016IFXIBD 88MaintenanceAt least 6 mo//
Yarur et al[29], 2016ADAIBD 67InductionLess than 1 mo//
Roblin et al[26], 2014IFXIBD 78InductionLess than 2 mo//
Chaparro et al[12], 2018ADAIBD 66MaintenanceAt least 12 wk160 mg, 80 mg, 40 mgInduction: 160 mg at week 0 and 80 mg at week 2; Maintenance: 2 weekly (47 patients), weekly (19 patients)
Ungar et al[28], 2016ADAIBD 40Maintenance//2 weekly or weekly
Morita et al[18], 2016ADAUC 33Induction and Maintenance/160 mg, 80 mg, 40 mg160 mg at week 0, 80 mg at week 2, and 40 mg 2 weekly
IFXUC 31Induction and maintenance/5 mg/kgAt weeks 0, 2, 6 and 8 weekly later
Morita et al[19], 2016ADACD 42MaintenanceAt least 6 mo40 mg2 weekly
Strik et al[27], 2019ADAPfCD 19Maintenance/40 mg2 weekly (11 patients), Weekly (8 patients)
IFXPfCD 47Maintenance/5 mg/kg, 10 mg/kg5 mg/kg 8 weekly (27 patients), 5 mg/kg 6 weekly (10 patients)5 mg/kg 4 weekly (3 patients), 10 mg/kg 8 weekly (4 patients); 10 mg/kg 6 weekly (2 patients), 10 mg/kg 4 weekly (1 patients)
Plevris et al[24], 2020ADAPfCD 35MaintenanceAt least 24 wk40 mgWeekly (17 patients), Fortnightly (18 patients)
IFXPfCD 29MaintenanceAt least 24 wk5 mg/kg, 10 mg/kg5 mg/kg 8 weekly (16 patients), 5 mg/kg 6 weekly (7 patients); 10 mg/kg 8 weekly (3 patients), 10 mg/kg 6 weekly (3 patients)
Zittan et al[30], 2016ADACD 60Maintenance/40 mg or not40 mg (53 patients), other than 40 mg (7 patients); 2 weekly (35 patients), other than 2 weekly (25 patients)
Juncadella et al[16], 2018ADAIBD 98Maintenance/40 mg or not40 mg 2 weekly (59 patients), other than 40 mg 2 weekly (36 patients)
Papamichael et al[20], 2017ADAUC 43Induction14 wk160 mg, 80 mg, 40 mg160 mg at week 0, 80 mg at week 2, 40 mg 2 weekly or weekly from week 4, or 80 mg 2 weekly or weekly from week 4
Feng et al[14], 2019IFXCD 141MaintenanceAt least 14 wk5 mg/kg5 mg/kg at weeks 0, 2, 6 and thereafter every 8 wk during the study period (week 30)
Papamichael et al[22], 2018IFXUC 56Maintenance///
Papamichael et al[21], 2018IFXCD 110Maintenance/5 mg/kg or not5 mg/kg 8 weekly (63 patients), other than 5 mg/kg 8 weekly (47 patients)
Papamichael et al[23], 2016IFXUC 101Induction14 wk//
Dreesen et al[31], 2020IFXCD 116Induction and maintenance54 wk5 mg/kgInduction: 5 mg/kg at week 0, 2, 6; Maintenance: 5 mg/kg, 7.5 mg/kg, or 10 mg/kg at week 14 and later
Imaeda et al[15], 2014IFXCD 45MaintenanceAt least 6 mo5 mg/kg, 10 mg/kg5 mg/kg 8 weekly (37 patients), 10 mg/kg 8 weekly (8 patients)
EI-Matary et al[32], 2019IFXPfCD 52//5 mg/kg or more5 mg/kg/dose, often rounded up to the nearest 100 mg at weeks 0, 2, 6; Dose 4 was received at a median time interval following the third dose
Kang et al[17], 2019IFXPCD 105Maintenance///
Hanzel et al[33], 2019VDZIBD 51Induction and maintenance54 wk300 mgInduction: At weeks 0, 2, 6, 10; Maintenance: 4 weekly or 8 weekly from week 14 onwards
Dreesen et al[13], 2018VDZUC 66; CD 113Induction and maintenance22 wk300 mgInduction: At weeks 0, 2, 6 (179 IBD patients), At week 10 (102 CD patients); Maintenance: 8 weekly (162 IBD patients), 4 weekly (4 UC and 13 CD patients)
Pouillon et al[25], 2019VDZUC 31Maintenance/300 mg8 weekly (19 samples) or 4 weekly (16 samples)
Yacoub et al[34], 2018VDZCD 39; UC43Induction and maintenance52 wk300 mgInduction: At weeks 0, 2, 6; Maintenance: 4 weekly or 8 weekly from week 14 onwards
IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis; IFX: Infliximab; ADA: Adalimumab; VDZ: Vedolizumab; PFCD: Perianal fistula Crohn’s disease.
Table 5 Correlation between endoscopic outcome and biologic blood concentration
Ref.
Patients
Definition of primary endpoint
Biology
Cut-off value
Clinical outcome (Yes/Not)
SE
SP
PPV
NPV
AUC
Chaparro et al[12], 2018IBDMucosal healing: (1) CD: SES-CD < 3; (2) UC: MES ≤ 1; and (3) CD in Postoperative setting: Rutgeerts < 2ADA7.2 μg/mL (TL)Mucosal healing (35/59)0.650.560.460.720.60
IFX3.4 μg/mL (TL)Mucosal healing (58/30)0.600.600.730.420.63
Ungar et al[28], 2016IBDMucosal healing: (1) CD: SES-CD < 3; (2) UC: MES ≤ 1ADA7.1 μg/mL (SL)Mucosal healing 0.320.850.510.720.70
IFX6 μg/mL (SL)Mucosal healing0.390.850.700.620.75
Yarur et al[29], 2016IBDMucosal healing: Lack of any inflammatory findings in the intestinal mucosaADA7.8 μg/mL (SL)Mucosal healing (19/47)0.610.950.76
Histological healing: Lack of histologic inflammation on biopsies obtained during colonoscopyADA7.5 μg/mL (SL)Histological healing (20/46)0.620.830.73
Roblin et al[26], 2014IBDMucosal healing: (1) CD: Disappearance of all ulcerations; (2) UC: MES < 2ADA4.9 μg/mL (TL)Absence of mucosal healing (16/24)0.660.850.880.510.77
Morita et al[18], 2016UCMucosal healing: UCEIS: The bleeding descriptor and the erosions and ulcers descriptor were both 0, and the vascular pattern descriptor was 0 or 1ADA10.3 μg/mL (TL)Mucosal healing (Absence)0.820.800.87
IFX2.7 μg/mL (TL)Mucosal healing (11/20)0.830.890.93
Morita et al[19], 2016CDMucosal healing: Endoscopic score based on the modified Rutgeerts’ scoring system: 0 (No lesions or scar) or 1 (≤ 5 apthous lesions)ADA7.90 μg/mL (TL)Mucosal healing (14/28)0.690.860.79
Strik et al[27], 2019PfCDFistula closure: Absence of active drainage at gentle finger compression and/or fistula healing on magnetic resonance imagingADA5.9 μg/mL (SL)Fistula closure (13/6)0.89
IFX5.0 μg/mL (TL)Fistula closure (32/15)0.92
Plevris et al[24], 2020PfCDPerianal fistula healing: No spontaneous discharge or no discharge on palpation in the absence of seton drainage; Perianal fistula closure: Absence of an external skin openingADA9.8 μg/mL (TL)Fistula closure (15/20)0.930.750.86
ADA6.8 μg/mL (TL)Fistula healing (21/14)1.000.790.90
IFX7.1 μg/mL (TL)Fistula healing (18/11)0.781.000.93
IFX7.1 μg/mL (TL)Fistula closure (13/16)0.641.000.97
Zittan et al[30], 2016CDMucosal healing: Absence of any ulceration in all ileocolonic segmentsADA8.14 μg/mL (TL)Mucosal healing (35/25)0.910.760.840.86
Juncadella et al[16], 2018CDEndoscopic remission: Absence of a mucosal break for CD, a Rutgeerts score of ≤ 1 for CD with ileocolonic resection, a Mayo endoscopic score of ≤ 1 for UC. Histological healing: Absence of any sign of active inflammation including erosions, abscesses, or neutrophil infiltrationADA12 μg/mL (SL)Endoscopic remission (20/25)0.800.68
ADA12.2 μg/mL (SL)Histological healing (13/28)0.570.85
UCADA16.2 μg/mL (SL)Endoscopic remission (7/20)0.850.61
ADA16.2 μg/ mL (SL)Histological healing (3/23)1.000.83
Papamichael et al[23], 2016UCShort term mucosal healing: (1) MES ≤ 1 at weeks 10-14; (2) MES ≥ 2 at baselineIFX15 μg/mL week 6 (SL)STMH at weeks 10-14 (54/47)0.600.740.730.620.64
IFX2.1 μg/mL week 14 (SL)0.840.620.780.710.64
Papamichael et al[20], 2017UCShort term mucosal healing: (1) MES ≤ 1 at weeks 8-14; (2) MES ≥ 2 at baselineADA9.4 μg/ mL week 4 (SL)STMH at weeks 8-14 (12/31)0.670.770.500.87
ADA7.5 μg/mL week 4 (SL)STMH at weeks 8-140.890.590.470.93
Papamichael et al[22], 2018UCEndoscopic healing: a Mayo endoscopic sub-score of ≤ 1. Histological healing: No or only focal mild active inflammationIFX7.5 μg/mL (TL)Endoscopic healing (31/39)0.770.620.620.77
IFX10.5 μg/mL (TL)Histological healing (28/41)0.540.780.630.71
Papamichael et al[21], 2018CDEndoscopic remission: Absence of any mucosal break, a Rutgeerts score of ≤ 1 for CD with ileocolonic resection. Histologic remission: Absence of active inflammationIFX9.7 μg/mL (SL)Endoscopic remission (62/34)0.570.730.800.48
IFX9.8 μg/ mL (SL)Histological remission (43/44)0.630.660.640.64
Feng et al[14], 2019CDMucosal healing: Complete absence of any sign of ulcerationIFX4.85 μg/mL week 14 (SL)Mucosal healing (82/59)0.670.800.80
IFX2.85 μg/mL week 30 (SL)Mucosal healing (59/50)0.730.840.78
Dreesen et al[31], 2020CDEndoscopic remission: (1) CDEIS < 3 at weeks 12 and 54; (2) Absence of ulceration at weeks 12 and 54IFX23.1 mg/L week 2 (TL)Endoscopic remission at week 12 (54/42)0.560.800.720.650.67
IFX10.0 mg/L week 6 (TL)Endoscopic Remission at week 12 (37/65)0.370.890.760.590.64
IFX10.6 mg/L week 54 (TL)Absence of ulceration at week 54 (59/24)0.940.420.490.920.71
Imaeda et al[15], 2014CDMucosal healing: Endoscopic score based on the modified Rutgeerts’ scoring system: 0 (No lesions or scar) or 1 (≤ 5 apthous lesions)IFX4.0 μg/mL (TL)Mucosal healing (20/58)0.710.700.63
EI-Matary et al[32], 2019PfCD Healing perianal fistula: Decrease or cessation of fistula drainage, as reported by patients and confirmed by treating physicians; Healed fistula: Closure of a previously identified fistula opening, as reported by treating physiciansIFX12.7 μg/mL (TL)Fistula healing (14/13)0.620.650.80
Kang et al[17], 2019PCDMucosal healing: SES-CD 0IFX4.2 μg/mL (TL)Mucosal healing0.650.700.670.680.68
Partial mucosal healing: SES-CD < 3IFX3.7 μg/mL (TL)Partial mucosal healing0.700.710.790.610.73
Hanzel et al[33], 2019IBDEndoscopic remission: (1) CD: SES-CD ≤ 4; (2) UC: MES ≤ 1; Clinical remission: (1) CD: mean daily stool frequency of ≤ 1.5, abdominal pain ≤ 1; (2) UC: a rectal bleeding score of 0, a stool frequency score of ≤ 1VDZ22.0 μg/ mL week 6 (TL)Combined Remission (Endoscopic Remission AND Clinical Remission) within the first year of treatment (16/35)0.770.730.720.880.73
VDZ8.0 μg/ mL week 22 (TL)0.790.750.650.860.82
Dreesen et al[13], 2018UCMucosal healing: MES ≤ 1VDZ28.9 μg/ mL week 2 (TL)Mucosal healing at week 14 (32/22)0.730.620.590.750.70
VDZ13.9 μg/mL week 14 (TL)Mucosal Healing at week 14 (32/22)0.850.540.480.880.72
CDMucosal healing: Complete absence of ulcerationsVDZ13.6 μg/mL week 22 (TL)Mucosal healing at week 22 (10/33)0.690.710.830.520.70
Pouillon et al[25], 2019UCHistological healing: Nancy Histological Index ≤ 1VDZ25.0 μg/mL (TL)Histological healing (18/17)0.770.710.740.750.75
Yacoub et al[34], 2018CDMucosal healing: (1) Absence of any ulcerations during endoscopy; (2) The absence of significant intestinal inflammation on MRIVDZ18.0 μg/mL week 6 (TL)Mucosal healing within the first year of treatment (18/21)0.800.630.730.710.70
UCMucosal healing: (1) MES ≤ 1; (2) The absence of significant intestinal inflammation on MRIVDZ18.0 μg/mL week 6 (TL)Mucosal healing within the first year of treatment (24/19)1.000.750.881.000.75
IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis; PCD: pediatric Crohn’s disease; IFX: Infliximab; ADA: Adalimumab; VDZ: Vedolizumab; SE: Sensitivity; SP: Specificity; PPV: Positive prospective value; NPV: Negative prospective value; AUC: Area under the curve; SL: Serum level; TL: Trough level.