2014 was the last year for the E-series van. Starting in 2015 and continuing, because of the naturally lower production numbers of the remaining E-Series fleet production, Ford has made more things common between the E350 and E450 than in years past. I recall one of significance is the rear axle gear ratio now being the same. The E350 used to get 10% better fuel economy in years past until recently. Now it's the same as the E450. There are a some heavy duty upgrades in the E450 that is more than smaller motor homes need, but even so......
If I had a choice, I would get the E450, even for a 21 foot motor home. The ride would be exceptionally rough so I would address that problem by swapping to E350 chassis 10,000 or 11,500 front coil springs, and remove a leaf or two in back to better match your actual trip loads. Invest a little more to get things matched up properly and you will have the best of both worlds of heavy duty and a comfortable ride.
