The Ideal Management of Crohn’s Disease: Top Down Versus Step Up Strategies. A Prospective Controlled Trial in the Benelux.

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Newly diagnosed Crohn's disease patients will benifit more from a 'top-down' approach where they receive the most potent therapy available, than from the current 'step-up' strategy where they start with the least potent treatment and build up to the most potent therapy if necessary.

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Randomization strategy 1:

TOP-DOWN Start infliximab 5 mg/kg three infusions at week 0, 2 and 6 + azathioprine 2 to 2.5 mg/kg day from day 0 onwards.

If patients improve and tolerate both drugs:
Conintue azathioprine, repeat infliximab 1 infusion 5 mg/kg if relapse.

If patients respond (decrease of CDAI >50 if CDAI 200-250 at start, or > 75 if CDAI 250-350 at start, or >100 if CDAI at start >350)but do not tolerate azathioprine, even when given as split dose, with meals or as an evening dose, or in case of pancreatitis: stop azathioprine, start MTX IM 25 mg/week for 12 weeks, then tapered to 15 mg/week IM together with folic acid 2 mg/day PO.
If symptoms flare (see section 8.1.4) in spite of MTX/azathioprine, repeat infliximab 1 infusion 5 mg/kg.


If patients do not improve on the above mentioned strategy:

Cross over to prednisone 40 mg/day or methylprednisolone 32 mg/day at least 4 weeks after the last infliximab infusion.
Continue azathioprine (or MTX)

Taper as outlined below.





Randomization strategy 2:

STEP-UP
First line treatment:

1. Entocort CIR/Budenofalk 9 mg per day OM for ileal or ileocolonic involvement OR Medrol 32 mg/Prednisone 40 mg per day for colonic involvement alone or in case of severe EIM, poor general well-being or fever.

2. Antibiotics (Flagyl or quinolones) to be added at the discretion of the investigator.

3. Initial therapy with IV methylprednisolone for up to 14 days allowed. TPN/enteral nutrition allowed as adjunctive therapy.

If improvement: tapering following guidelines.


Second line treatment:

1. if symptoms flare (increase of CDAI >50 and CDAI > 200) during
corticosteroid tapering, go back to starting dose and try to taper again. Exclude complications such as abscesses or strictures.

2. if relapse during second attempt to taper, add azathioprine 2-2.5 mg/kg/day PO

3. if relapse within 4 months after steroid withdrawal, start steroids again, this time in combination with azathioprine.

4. if refractory to corticosteroids after 4 weeks, increase the dose to 80 mg of prednisone (64 mg methylprednisolone) and add azathioprine


Adding azathiopine: start 2 to 2.5 mg/kg/day, together full dose of corticosteroids. Try to taper the steroids again according to guidelines.


Third line treatment:

1. pts with severe adverse events on azathioprine:

Stop azathioprine, start MTX 25 mg/week. After three injections, start tapering corticosteroids again.


2. pts who cannot be withdrawn from steroids in spite of azathioprine for at least 4 months in optimal dose: Continue azathioprine, start Infliximab 5 mg/kg at weeks 0, 2 and 6 without increasing the steroids ! Continue to taper steroids after 3 infliximab infusions.


Fourth line treatment:
pts with severe relapse in spite of MTX or intolerant to azathioprine and MTX.
Start Infliximab 5 mg/kg at weeks 0, 2 and 6. One single 5 mg/kg infusion to be
repeated upon relapse of symptoms. Continue MTX if tolerated.