4x4 bed rails sit higher than 4x2, so it often forces you to flip the axels to get the trailer high enough. If the truck is lifted, it may not be practicle to get the trailer high enough.
On rough roads, the issue I see is if your right truck tires drop into a pothole at the same time your left trailer tires drop into a pothole, the overhang can hit the bed rails. Depending on the clearance, you have maybe 10 degrees of side to side angle before it becomes a problem with a 5th wheel. With a TT, you can probably get upwards of 30 degrees before it would try to lever the hitch off the ball. Just driving down a washboard road, it shouldn't make much difference.