Table 1.

Focused clinical questions on the pharmacological management of moderate to severe Crohn’s disease, and corresponding questions in PICO format addressed in this technical review

S#	Focused Question	PICO Question
		Patients	Intervention	Comparator	Critical Outcomes
OUTPATIENTS with MODERATE TO SEVERE LUMINAL CROHN’S DISEASE
1A.	In adult outpatients with moderate to severe CD, what is the overall efficacy of TNF-α antagonists (infliximab, adalimumab, certolizumab pegol), vedolizumab and ustekinumab for induction and maintenance of remission?	Adult outpatients with moderate to severe CD	TNF-α antagonists (infliximab, adalimumab, certolizumab pegol) Vedolizumab Ustekinumab	Placebo	Induction of clinical remission Maintenance of clinical remission
1B.	In adult outpatients with moderate to severe CD, what is the efficacy and safety of natalizumab?	Adult outpatients with moderate to severe CD	Natalizumab	Placebo	Induction of clinical remission Maintenance of clinical remission Serious infection
2.	In adult outpatients with moderate to severe CD, what is the comparative efficacy of different biologic agents (infliximab, adalimumab, certolizumab pegol, vedolizumab, ustekinumab), in biologic-naïve and in patients with prior TNF-α antagonist exposure, for induction and maintenance of remission?	Adult outpatients with moderate to severe CD, (A) biologic-naïve and (B) prior exposure to TNF-α antagonist	Infliximab Adalimumab Certolizumab pegol Vedolizumab Ustekinumab	Placebo or another active comparator	Induction of clinical remission Maintenance of clinical remission
3.	In adult outpatients with moderate to severe CD, what is the efficacy of immunomodulator monotherapy (thiopurines, methotrexate) for induction and maintenance of remission?	Adult outpatients with moderate to severe CD	Thiopurines (azathioprine, mercaptopurine) Methotrexate (oral or subcutaneous)	Placebo (or 5-aminosalicylates)	Achieving remission Prevention of relapse (≈maintenance of remission)
4.	In adult outpatients with moderate to severe CD, is biologic monotherapy (infliximab, adalimumab, certolizumab pegol, vedolizumab, ustekinumab superior to immunomodulator monotherapy (thiopurines, methotrexate) for induction and maintenance of remission?	Adult outpatients with moderate to severe CD	Monotherapy with TNF-α antagonists (infliximab, adalimumab, certolizumab pegol) Vedolizumab Ustekinumab	Immunomodulators (thiopurines or methotrexate)	Induction of clinical remission Maintenance of clinical remission
5.	In adult outpatients with moderate to severe CD, is combination therapy of a biologic agent (infliximab, adalimumab, certolizumab pegol, vedolizumab, ustekinumab) with an immunomodulator (thiopurines or methotrexate) superior to biologic monotherapy for induction and maintenance of remission?	Adult outpatients with moderate to severe CD	Combination therapy with of a biologic agent (infliximab, adalimumab, certolizumab pegol, vedolizumab, ustekinumab) + immunomodulator (thiopurines or methotrexate)	Biologic monotherapy (infliximab, adalimumab, certolizumab pegol, vedolizumab, ustekiumab)	Induction of clinical remission Maintenance of clinical remission
6.	In patients with quiescent CD on combination therapy with biologic and immunomodulators, is ongoing combination therapy superior to withdrawal of immunomodulators in maintaining remission?	Adult outpatients who achieve remission on combination therapy with biologic and immunomodulators	Discontinuation of immunomodulators	Continuing combination therapy	Maintenance of clinical remission
7.	In adult outpatients with moderate to severe CD, is top-down therapy superior to step therapy for achieving remission, and preventing disease complications?	Adult outpatients with moderate to severe CD	Top-down therapy Upfront use of biologic-based combination therapy	Step therapy Acceleration to biologic-based combination therapy only after failure of 5-aminosalicylates or immunomodulators	Achieving remission Prevention of disease-related complications
8.	In adult outpatients with moderate to severe CD, what is the overall efficacy of corticosteroids (systemic prednisone or budesonide) for induction and maintenance of remission?	Adult outpatients with moderate to severe CD	Prednisone (or equivalent) Budesonide	Placebo	Induction of clinical remission Maintenance of clinical remission
9.	In adult outpatients with moderate to severe CD, what is the overall efficacy of sulfasalazine or 5-aminosalicylates for induction and maintenance of remission?	Adult outpatients with moderate to severe CD	Sulfasalazine Diazo-bonded 5-aminosalicylates (balsalazide, olsalazine) Mesalamine	Placebo	Induction of clinical remission Maintenance of clinical remission
OUTPATIENTS with MODERATE TO SEVERE FISTULIZING CROHN’S DISEASE
10.	In adult outpatients with fistulizing CD, what is the efficacy and safety of the following drugs: TNF-α antagonists (infliximab, adalimumab, certolizumab pegol), vedolizumab, and ustekinumab, immunomodulator monotherapy (thiopurines, methotrexate), antibiotics?	Adults with fistulizing CD	TNF-α antagonists (infliximab, adalimumab, certolizumab pegol) Vedolizumab Ustekinumab Thiopurines (azathioprine, mercaptopurine) Methotrexate Antibiotics	Placebo/No treatment	Induction and maintenance of fistula closure
11.	In adult patients with fistulizing CD (without abscess), is adding antibiotics to TNF-α antagonists superior to TNF-α antagonists alone?	Adults with fistulizing CD (without abscess) receiving TNF-α antagonists	Antibiotics	Placebo	Induction and maintenance of fistula closure