To a home game? No, probably no difference at all. But to anyone looking to get published Dungeon, or wanting to buy or produce sourcebooks related to Lolth or Driders? Huge difference. As soon as you enshrine setting specific flavour in the core books, you cannot contradict it in later material.
I mean, good grief, look at the hue and cry when they did a few experiments to try to rebuild things like slaad or modrons. And that stuff wasn't even in the bloody core.
I gotta say, if you're running "official" material, you're running it because you think WOTC made a good thing and you like it. That's it. There is no other reason to run official material at home. If you're playing in some kind of sanctioned play, then you're not
really the DM, WOTC is. They decide what the game does or does not include, and you play it because you will earn something from doing so (and it is also, hopefully fun).
At home, with no WOTC oversight and you being the be-all, end-all decider of what is or isn't in your game, get to choose how you include Lolth, if at all. I run numerous games where Drow don't exist and many others where they are simply "dark elves" and even then they may not be evil at all, but simply another variety of elf who happen to be dark blue/gray/black instead of pale/golden/silvery.
No matter how much we don't like it, there is going to be some "baggage" in Core. It's unavoidable. Short of making "Core" a dictionary of rules with no fluff, flavor or attempting to re-create everything from the past as though it were something unique and new (which will just come across as forced and will seem to have baggage anyway), and I don't think anyone wants either of those things. D&D is some 40 years old. Think of
anything that's 40 or more years old. Car manufacturers have baggage, people have baggage, after 40 years, it's unavoidable.
At the end of the day, you're going to have to retool
something out of the box. I doubt anyone is going to like
everything. One of those "can't please everyone" sorts of situations. And as long as your game is not being run by WOTC, then you as the DM have the freedom to do so, and you should, because someone will at some point, in some game, and eventually it will be you.