The main thing that can be annoying is figuring out module exports from a js library that you want to use (which is probably easy enough if you have a modern javascript background). I haven't found a library that's stumped me yet, but some are more annoying than others. Jetbrains have a tool called Dukat which will supposedly one day automate this, but for now it's not there.

Distribution size can be an issue, but it's not terrible. My current (moderately complex) app is floating at around 2MB. I haven't tried splitting it up, though that is possible.