Multiple monitors sure are a drag. This weekend I downgraded my primary monitor from a 32" 4k display to a 27" 1440p display, for the purpose of gaming at 165Hz instead of 60Hz (and wow, what a difference).
This has caused several annoying side effects. I used to run my 4k 32" monitor at 125% scaling, and my ancillary 24" 4k monitor at 225%. Everything looked fine, or so I thought. Now my 27" monitor runs at 100%, and this causes some internal Windows flag to change somewhere, making many apps on the secondary monitor look horrible. It just nearest-neighbors apps up to 200% instead of scaling them correctly. If you make the second monitor the primary monitor, then everything looks good again -- except you can't use Nvidia GSync on a secondary monitor, the whole reason I downgraded my main monitor. Amazingly, the mere existence of the 100ppi montior is what seems to break things. If you run it at 200%, apps on the other monitor at 200% still look terrible.
My theory is that things looked bad before, but the 125->225 scaling didn't look quite as egregiously bad as 100->200 does. But I'm picky about these things and think I would have noticed. So I don't know.
Some apps, notably Chrome, work just fine. (But Discord is an offender, and it's just Chrome, isn't it? That makes it all the more annoying.)
As an aside, everything looks pretty crappy at 100ppi. Fonts are blurry again. You can see the pixels in every photo or illustration you view. Upgrading to 4k a few years ago didn't make much of a difference to me, but downgrading is a huge difference. That said, Overwatch is soooo smooth. I can't wait until technology allows us to run games at 4k@120/144/165/240, however. I also miss the wider-than-sRGB color gamut.