| Remission |
|---|
| Khanna 201517 | Primary outcome at 12 months was remission rate (adjusted for cluster size, practice size, country, baseline remission rate) | At 12 months, crude remission rate was 66.0% for early combined intervention versus 61.9% for conventional Adjusted difference was 2.5% (95% CI −5.2 to 10.2) At 24 months, crude remission rate was 73.1% for early combined intervention and 65.1% for conventional Adjusted difference was 6.4% (95% CI −0.9% to 13.6%) | Early combined intervention was not more effective than conventional management at controlling symptoms; there was a modest and non-significant benefit in clinical remission17 |
| D’Haens 200816 | Proportion of patients in remission at 26 and 52 weeks Secondary outcome: proportion of patients in remission at week 78 and 104 | 26 weeks: 60.0% of patients in early combined group in remission versus 35.9% in conventional treatment (absolute difference 24.1%, 95% CI 7.3 to 40.8) 52 weeks: 61.5% of patients in combined group versus 42.2% in conventional (absolute difference 19.4%, 95% CI 2.4 to 36.3) No significant difference in proportion in remission at week 78 and 104 (individual proportions not reported) | Early combined therapy was more effective at inducing remission and resulted in remission faster than conventional treatment16 |
| Hoekman 201818 | Proportion of semesters (6 months) in clinical remission per patient over 8 years in patients from D’Haens 2008 | Proportion of semesters in clinical remission was 73% for early combined and 70% for conventional (P = 0.85) | There was no difference in rate of remission long-term (authors also noted that the possible benefits of early combined immunosuppression may not alter long-term course of Crohn’s if regimen not maintained)18 |
| Relapse |
|---|
| D’Haens 200816 | Time to relapse after successful induction at week 14 | Median time to relapse longer in early combined group compared to conventional therapy (329 days versus 175 days, P = 0.031) | Time to relapse was longer in patients receiving early combined therapy16 |
| Hoekman 201818 | Time to flare over 8 year follow up from D’Haens 2008 Proportion who experienced at least one flare during 8-year follow-up | Median time to flare was shorter for step-up versus early combined (5 semesters versus 9 semesters, P = 0.02) Proportion who experienced at least one flare was higher in step-up versus early combined (78% versus 58%, P = 0.02) | Top-down treatment was associated with a lower relapse rate compared to conventional treatment18 |
| Disease severity score |
|---|
| Khanna 201517 | HBI score at 6, 18, 24 months | No difference between groups at any time point (individual mean differences not provided) | There was no difference in clinical symptoms between groups17 |
| D’Haens 200816 | CDAI at 10 weeks | CDAI: mean reduction was 231 points in early combined group versus 178 in conventional (mean difference 53.3, 95% CI 9.2 to 97.4) No differences were observed beyond 10 weeks (no data provided) | There was a more rapid drop in symptom scores up until week 10, then the scores in both groups were similar16 |
| Adverse outcome of Crohn’s disease |
|---|
| Khanna 201517 | Time to adverse outcome Adverse outcome defined as composite of surgery or hospital admission for Crohn’s disease, disease complication | Reduced rate of adverse outcomes in early combined intervention group compared to conventional therapy (HR 0.73%, 95% CI 0.62 to 0.86; NNT at 24 months 14) | There was a reduction in adverse outcomes for early combined therapy suggesting that it may alter the natural history of Crohn’s disease; this difference should be interpreted cautiously since it was a secondary endpoint17 |
| Corticosteroid use |
|---|
| Khanna 201517 | Time to treatment with corticosteroids | No difference between early combined intervention and conventional over 24 months (HR 0.97, 95% CI 0.77 to 1.21) | There was no difference in corticosteroid use17 |
| D’Haens 200816 | Exposure to methylprednisolone in 4-week windows over 104 weeks | Lower exposure to methylprednisolone in early combined group (no quantitative measure provided) | Patients with early combined therapy were exposed to substantially less corticosteroid than the conventional treatment group16 |
| Hoekman 201818 | Ever-treated with corticosteroid during 8-year follow-up from D’Haens 2008 Proportion of semesters in corticosteroid-free remission | 41% of early combined versus 62% of conventional were treated with corticosteroids (p=0.02) No difference in proportion of semesters in corticosteroid-free remission (69% in early combined versus 63% in conventional, P = 0.71) | Conventional treatment patients were treated with corticosteroids more frequently than early combined18 |
| Quality of life |
|---|
| Khanna 201517 | SF-36 physical and mental, at baseline, 6, 12, 18 and 24 months EQ-5D at baseline, 6, 12, 18 and 24 months | No difference at any time point for mental or physical quality of life No difference at any time point | There was no difference in quality of life between treatments17 |
| D’Haens 200816 | IBDQ scores at 10 weeks | Mean increase of 59.2 in early combined group versus 37.4 in conventional (mean difference 21.8, 95% CI 8.7 to 34.9) No difference between groups beyond 10 weeks | There was a more rapid improvement in quality of life scores for early combined therapy versus conventional16 |
| Mortality |
|---|
| Khanna 201517 | Mortality over 24 months | No difference between groups; for early combined intervention compared to conventional HR 0.62 (95% CI 0.24 to 1.63) | There was no difference in mortality17 |
| Surgery for Crohn’s disease |
|---|
| Hoekman 201818 | Proportion undergoing Crohn’s disease related surgery during follow-up (8 years) | 12% in early combined versus 20% in conventional (P = 0.32) | There was no difference in the rate of surgery18 |
| Khanna 201517 | Time to surgery | Reduced rate of surgery in early combined intervention group versus conventional therapy (HR 0.69, 95% CI 0.50 to 0.97; NNT at 24 months 35) | There was a reduction in need for surgery for early combined treatment17 |
| Hospitalization for Crohn’s disease |
|---|
| Hoekman 201818 | Proportion of Crohn’s disease-related hospitalizations during follow-up | Hospitalization occurred in 25% of early combined and 35% of conventional (P = 0.32) | There was no difference in the rate of hospitalization18 |
| Khanna 201517 | Time to hospitalization | No difference for early combined intervention compared to conventional (HR 0.84, 95% CI 0.65 to 1.08) | There was no difference in hospitalization rates between groups17 |
| Serious complication |
|---|
| Hoekman 2018 | Proportion with fistula during follow-up (8 years) | 10% of early combined versus 18% of conventional (P = 0.20) | There was no difference in the rate of new fistulas |
| Khanna 201517 | Time to serious complication; complication defined as new abscess, fistula or stricture, serious worsening of disease activity or extra-intestinal manifestations | Reduced rate of complications for early combined intervention compared to conventional treatment (HR 0.73, 95% CI 0.61 to 0.87; NNT at 24 months 16) | There was a reduction in serious complications with early combined treatment17 |
| Endoscopic findings |
|---|
| D’Haens 200816 | Proportion of patients with no ulcers at week 104 Endoscopy score at 104 weeks | No ulcers for 73.1% of patients in early combined versus 30.4% in conventional (P = 0.0028) Endoscopy scores 0.7 in early combined versus 3.1 in conventional (P < 0.001) | “Patients with early combined therapy were less likely to have ulcerations after 2 years of treatment”16 |
| Hoekman 201818 | Proportion with absence of ulcers over follow up (8 years) | Absence of ulcers in 44% of early combined versus 33% of conventional therapy (P = 0.55) | There was no difference in absence of ulcers18 |
| Safety |
|---|
| Khanna 201517 | Proportion of patients with serious drug-related adverse events | 10/1084 for early combined versus 10/898 for conventional | The proportion of serious drug related adverse events was not different between groups17 |
| D’Haens 200816 | Proportion of patients with adverse events | 30.8% in early combined versus 25.3% in conventional management group | There were no important differences in adverse effects but authors noted that study was inadequate to address safety differences16 |
| Hoekman 201818 | Proportion of patients with adverse events (over 8 years) | Infusion reactions occurred in 14% of early combined patients and 10% of conventional patients; serious infections occurred in 22% of early combined patients and 10% of conventional therapy | Was not commented on specifically18 |
