. 2022 Dec 19;15:17562848221142673. doi: 10.1177/17562848221142673

Table 1.

Evidence regarding therapeutic intervention on early CD.

Authors	Study type	Patients’ characteristics	Follow-up	Early disease/therapy definition	Intervention/exposure	Outcomes	Main results
D’Haens et al.⁷	Open-label randomized trial	Newly diagnosed and treatment-naïve CD patients	24 months	⩽4 years since diagnosis	Infliximab (episodic treatment with 5 mg/kg) + azathioprine (2–2.5 mg/kg) (n = 67); azathioprine (n = 66)	CFR (CDAI < 150 + absence of CCT + no intestinal resection)	Absolute difference of 19.4% (95% CI: 2.4–36.43) in CFR between early combined immunosuppression versus azathioprine. Longer time to relapse and lower CCT exposure in patients assigned to early combined immunosuppression
Baert et al.³⁰	Extension study (follow-up of an RCT)	Newly diagnosed and treatment-naïve CD patients	24 months	⩽4 years since diagnosis	Infliximab 5 mg/kg (weeks 0, 2, and 6) in combination with azathioprine 2–2.5 mg/kg (n = 26) versus CCT (n = 23)	Stable remission (CDAI < 150 or HBI < 3) and no use of CCT; complete mucosal healing (SES-CD = 0)	In patients with early-stage CD, CFR was more frequent in those with complete mucosal healing [70.8% versus 27.3% (patients with endoscopic activity)]; this supports that a top-down approach in early CD may alter disease course
Sandborn et al.¹²	Open-label induction; RCT maintenance	Moderate to severe CD (CDAI 220–450), with secondary failure to infliximab	26 weeks	⩽2 years since diagnosis	Induction – certolizumab pegol 400 mg weeks 0, 2, and 4; maintenance – if clinical response at week 6, certolizumab 400 mg every 2 (n = 161) or 4 weeks (n = 168)	Clinical response (⩾100-point reduction in CDAI) and remission (CDAI score ⩽150 points)	Clinical response after induction was not superior in patients with early disease (60.0% versus 64.1%), nor for patients receiving maintenance certolizumab, every 2 weeks. Maintenance certolizumab every 4 weeks was associated with higher clinical response in those with longer disease (42.2% for > 5 years, 31.6 for 2–5 years from diagnosis)
Schreiber et al.¹³	RCT – posthoc analysis	Moderate-to-severe CD (CDAI 220–450) + clinical response (⩾100-point reduction in CDAI) after certolizumab induction	26 weeks	Very early disease defined as <12 months after diagnosis; early as 12–24 months after diagnosis	Certolizumab pegol 400 mg every 4 weeks (n = 151) versus placebo (n = 109)	Clinical response (⩾100-point reduction in CDAI) and remission (CDAI score ⩽150 points)	Response during maintenance inversely related to disease duration [89.5% (up to 12 months of disease duration), 75.0% (between 12 and 24 months), 62.2% (24–60 months)]
Ramadas et al.²⁸	Observational	CD incident cases	Median follow-up 92 months (range 41–261)	⩽1 year since diagnosis	Azathioprine (~2 mg/kg; n = 117) or 6-mercaptopurine (~1 mg/kg; n = 12)	Need for intestinal surgery (resection of bowel, stricturoplasty, stoma formation)	Early thiopurines start was independently associated with a significant reduction in the cumulative probability of intestinal surgery (HR: 0.47, 95% CI 0.27–0.79)
Kato et al.³¹	Observational	CD patients admitted for induction therapy with infliximab	14 weeks	⩽19 months since diagnosis	Infliximab 5 mg/kg (weeks 0, 2, and 6) (n = 22)	Effect of infliximab on patients’ immune profiles (Treg, serum cytokines and chemokines)	Modulation of the peripheral immune system of CD patient in very early stage induced a differentiation toward Th17, alleviating the inflammatory drive
Rubin et al.³²	Observational	CD patients	24 months	Early-TNF treatment (initiated anti-TNF within 30 days of the first prescription for CD)	‘Step-up’ (5-ASA, CCT and/or IS prior to anti-TNF; n = 1396); ‘IS-to TNF’ (IS prior to anti-TNF; n = 1031); ‘Early-TNF’ (n = 1321)	Concomitant CCT use, CD surgery, anti-TNF dose escalation, and anti-TNF discontinuation/switch	Earlier use of anti-TNF is associated with a lower risk of concomitant CCT use, anti-TNF dose escalation, discontinuation/switch of anti-TNF therapy, and CD-related surgery compared to conventional models of step-up or IS to anti-TNF strategies
Lakatos et al.³³	Observational	CD incident cases	At least 52 weeks	Very early disease defined as < 18 months after diagnosis; early as < 36 months + at least 6 months before the first surgery	Azathioprine (⩾1.5 mg/kg) (n = 224)	Need for surgery	Early azathioprine use was significantly associated with a reduction in the CD-related surgical rates (HR: 0.43, 95% CI: 0.28–0.65)
Schreiber et al.¹⁴	RCT and open-label extension	Moderate-to-severe CD (CDAI 220–450 points) + clinical response (⩾100-point reduction in CDAI) after adalimumab induction	56 weeks	⩽2 years since diagnosis	Adalimumab 40 mg (eow or weekly) (n = 517); placebo (n = 260)	Clinical response (⩾100-point reduction in CDAI) and remission (CDAI score ⩽150 points), hospitalizations	Shorter disease duration was identified as a significant predictor for higher remission rate, lower hospitalization, and less adalimumab-related serious adverse events
Feagan et al.³⁴	RCT	CD patients who had initiated prednisone induction therapy (15–40 mg/day) within the preceding 6 weeks	50 weeks	⩽2 years since diagnosis	Infliximab (5 mg/kg at weeks 1, 3, 7, 14, 22, 30, 38, and 46) + methotrexate (gradual increase up to 25 mg/week) (n = 63) versus infliximab + placebo (n = 63)	Time to treatment failure [lack of CFR (CDAI < 150) at week 14 or failure to maintain remission through week 50]	Although patients who had been diagnosed within 2 years had a lower rate of treatment failure in both treatment groups, the between-group differences were not significant
Peters et al.³⁵	Observational	CD patients	Median follow-up of 2.0 years (IQR: 1.1–2.7)	No definition	Adalimumab [160 mg (week 0) and 80 mg (week 2) for induction, maintenance with 40 mg eow] (n = 438)	Clinical response (ongoing adalimumab or intended discontinuation), CFR, clinical remission (no diarrhea, abdominal pain, or draining fistulae)	Longer duration of disease before adalimumab start increased the risk to failure to induction therapy (OR: 1.05; 95% CI: 1.02–1.09, p = 0.01)
Colombel et al.¹⁵	RCT	Moderate-to-severe CD (CDAI of 220–450), with secondary failure to infliximab	52 weeks	⩽2 years since diagnosis	Adalimumab 40 mg (eow) (n = 64); adalimumab induction + placebo maintenance (n = 65)	Deep remission: CDAI < 150 + absence of mucosal ulceration)	Attainment of deep remission was superior in patients with disease diagnosed up to 2 years prior starting (33.0%) than in those with longer disease duration (20.0% if 2–5 years, 16.0% if >5 years)
Juillerat et al.³⁶	Observational	CD patients exposed at least once to infliximab	Median follow-up 13 months (range 2–43)	No definition	Infliximab exposure (n = 1014)	Predictive clinical characteristics for the successful ‘long-term use’ (5 years) of infliximab	Initiation of infliximab earlier in the disease course influenced short-term but not long-term response
Nuij et al.³⁷	Observational	413 IBD patients were included, (201 CD, 188 UC, and 24 IBDU)	Median follow-up 39 months (range: 0.2–47.9)	Early treatment defined as starting anti-TNF at most 16 months diagnosis; very early (12 months)	Anti-TNF therapy (n = 66; infliximab n = 51, adalimumab n = 10, certolizumab n = 5)	Mucosal healing, complications, surgery	Starting anti-TNF early was not associated with higher achievement of mucosal healing, lower occurrence of disease complications or surgery
Colombel et al.³⁸	RCT and open-label extension	Moderate-to-severe CD (CDAI of 150–450) + ulcerations on endoscopy + no previous biologics or immunomodulators	26 weeks	⩽18 months after diagnosis, no previous use of IS or biologics, and no fistulas	Infliximab (5 mg/kg, n = 62), azathioprine (2.5 mg/kg, n = 51), or combination (infliximab + azathioprine, n = 72)	Clinical remission (CDAI < 150), mucosal healing (no ulcerations), composite endpoints (clinical remission ± mucosal healing ± normal CRP)	Early disease was associated with higher rates of clinical remission (81.0% versus 80.0%, p = 0.036) and clinical remission plus mucosal healing (63.0% versus 53.3%, p = 0.004), when compared with non-early disease
Safroneeva et al.¹⁷	Observational	CD patients	Up to 96 months	⩽2 years since diagnosis	Immunomodulators (n = 188), TNF antagonist (n = 55), or combination of both (n = 49)	Occurrence of bowel strictures, perianal fistulas, internal fistulas, intestinal surgery, perianal surgery	Early use of immunomodulators or anti-TNF was associated with a reduced risk of bowel strictures (HR: 0.496, p = 0.004), reduced risk of intestinal surgery (HR: 0.322, p = 0.005), perianal surgery (HR: 0.361, p = 0.042), and of developing any complication (HR 0.567, p = 0.006)
Khanna et al.³⁹ (REACT trial)	Open-label cluster RCT	CD patients	Up to 24 months	No definition	Combined immunosuppression (adalimumab + antimetabolite; n = 1084) or conventional therapy (n = 898)	Proportion of patients in CFR (HBI ⩽ 4)	Patients treated with early combination therapy had a significant reduction in serious adverse events such as surgery, hospital admission, or serious disease-related complications
Kotze et al.¹⁶	Observational	Anti-TNF naïve patients	17.3 (±12.4) months	⩽2 years since diagnosis	Infliximab (5 mg/kg, n = 175) or adalimumab (160 mg, 80 mg and then 40 mg eow, n = 58)	Loss of efficacy (need for CCT, surgery, dose increase, interval shortening or switching to other anti- TNF)	The rates of loss of efficacy were similar among patients with early and non-early disease
Ogata et al.¹⁹	Observational	Moderate-to-severe active CD	24 weeks	⩽2 years since diagnosis	Adalimumab (160 mg at week 0, 80 mg at week 2, and 40 mg eow thereafter, n = 1693)	Clinical remission (CDAI < 150), adverse events	Clinical remission rates were significantly higher in patients with shorter disease duration compared with those with longer duration, at weeks 4 and 24
Ma et al.¹⁸	Observational	CD patients with primary response to anti-TNF therapy	Median follow-up 154 weeks (IQR: 106.4–227.8)	⩽2 years since diagnosis	Infliximab (5 mg/kg, n = 100) or adalimumab (160 mg, 80 mg and then 40 mg, n = 90)	Occurrence of surgical resection or clinical secondary loss of response	Less patients in the early initiation group required surgery (5.7% versus 30.7%, p = 0.001) or experienced secondary loss of response (45.3% versus 67.2%, p = 0.006)
Oh et al.²¹	Observational	CD patients naïve to both intestinal surgery and intestinal complications	Mean follow-up 103 months (±53.92)	⩽2 years since diagnosis	Early anti-TNF group (n = 79); early IS group (n = 286); late therapy group (n = 305)	Intestinal surgery, stricturing complications, penetrating complications, colorectal cancer, and mortality	Late anti-TNF/IS treatment was independently associated with higher risks of intestinal surgery (HR: 2.32, p < 0.001), behavioral progression (HR: 2.00, p < 0.001), strictures (HR: 1.73, p = 0.003), and penetrating complications (HR: 3.31, p < 0.001) than early treatment
Colombel et al.²⁰ (CALM trial)	RCT	Moderate-to-severe CD (CDAI of 150–450) + active endoscopic disease (CDEIS > 6) + CRP 5 mg/L or more, FC of 250 μg/g or more, or both	48 weeks	⩽2 years since diagnosis	Tight control (n = 122) versus conventional management (n = 122) (adalimumab 160 mg at week 0, 80 mg at week 2 and 40 mg eow thereafter)	Mucosal healing (CDEIS < 4 and no deep ulcers); deep remission (CDAI < 150, CDEIS < 4 and no deep ulcers, no draining fistula, no CCT for ⩾ 8 weeks); biological remission (FC < 250 μg/g, CRP < 5 mg/L, CDEIS < 4)	Patients with recent disease onset benefit from early biological treatment (higher mucosal healing and CFR)
Faleck et al.²²	Observational	CD diagnosis + active symptoms attributed to CD	6 months	⩽2 years since diagnosis	Vedolizumab (n = 650)	Clinical remission, CFR, or endoscopic remission	Early treatment is associated with higher rates of clinical, CFR and endoscopic remission than later treatment
Frei et al.²³	Observational	CD patients	10 years	⩽2 years since diagnosis	Early anti-TNF group (infliximab, adalimumab, or certolizumab pegol; n = 246); late anti-TNF group (n = 696)	Stenosis, perianal fistula, any fistula, perianal surgery, intestinal surgery, extraintestinal manifestations	Early anti-TNF treatment was associated with reduced risks of bowel stenosis, osteoporosis, and anemia
Panaccione et al.²⁹	RCT – post-hoc analysis	Moderate-to-severe CD (CDAI 220–450 or HBI ⩾ 7	52/56 weeks	Four different subgroups of disease duration: <1 year; ⩾1–<2 years; ⩾2–⩽5 years; and > 5 years	Placebo (n = 263), or adalimumab (160 mg, followed by 80 mg and then 40 mg eow, n = 377), followed by maintenance therapy with adalimumab	Clinical remission defined as CDAI < 150; clinical response defined: CR-70 and CR-100	Induction – highest remission rates in patients with shortest disease duration (45.8% if disease duration < 12 months, 31.0% for 12–24 months, 23.1% for 24–60 months); similarly, response rates were highest in the < 1 year subgroup. Maintenance – patients with < 1 year disease duration had the highest remission rates (p = 0.002)
Loftus et al.²⁴	Observational	Moderately to severely active CD with or without prior adalimumab experience	6 years	⩽2 years since diagnosis	Adalimumab (160 mg, 80 mg and then 40 mg eow) (n = 2057)	Physician’s Global Assessment, clinical remission (HBI < 5), SIBDQ	Patients with early disease achieved numerically higher HBI remission rates than patients with longer disease duration (84% versus 68%)
Zhu et al.⁴⁰	Observational	CD patients	Median follow-up 17 months	⩽18 months since diagnosis, no previous treatment with disease-modifying agents	Infliximab (5 mg/kg) + azathioprine (1.5 or 2.0 mg/kg/d) (n = 154)	Lémann index, based on MRE; predictors of short-term bowel resection	‘Early therapy’ group had higher decrease in the Lémann Index (61.4% versus 42.9%) as well as lower increase (20% versus 35.7%); drug therapy reversed bowel damage to a greater extent in early CD patients
Jung et al.⁴¹	Observational	CD patients	5–7 years	⩽1 year since diagnosis	Infliximab (n = 410) or adalimumab (n = 199) for at least 6 months	Abdominal surgery, CD-related ER visit or hospitalization, new CCT use	Late anti-TNF initiation associated with an increased risk of surgery (HR: 1.64; 95% CI: 1.05–2.55) and was associated with increased risk of ER visit (HR: 1.38, 95% CI: 0.99–1.94)
Ungaro et al.²⁵	Observational	Moderate to severe CD (CDAI of 150–450)	3 years	⩽2 years since diagnosis	Tight control (n = 61) versus conventional management (n = 61) (adalimumab 160 mg at week 0, 80 mg at week 2 and then 40 mg eow)	Deep remission (CD endoscopic index of severity scores below 4, with no deep ulcerations or CCT treatment, for 8 or more weeks)	Induction of deep remission in early CD with decreased risk of disease progression over a median time of 3 years, regardless of tight control or conventional management strategy

5-ASA, 5-aminosalicylic acid; 95% CI, 95% confidence interval; CCT, corticosteroid; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; CDEIS, Crohn’s Disease Endoscopic Index of Severity; CFR, corticosteroid-free remission; CRP, C-reactive protein; eow, every other week; ER, emergency room; FC, fecal calprotectin; HBI, Harvey Bradshaw Index; HR, hazard ratio; IQR, interquartile range; IS, immunosuppressants; MRE, magnetic resonance enterography; N, number; RCT, randomized controlled trials; SES-CD, Simple Endoscopic Score for CD; SIBDQ, Short Inflammatory Bowel Disease Questionnaire; TNF, tumor necrosis factor; Treg, regulatory T-cells.