I just went through the setup wizard for 4 accounts, and I noticed that my mouse clicks don't line up well with the interface windows in LOTRO. I seem to recall this problem when I first used ISBoxer for LOTRO many years ago, but I can't remember what the fix was.
I will note that ISBoxer detected that my old .ini files were set for 1600x1200 resolution (instead of the 1680x1050 that I'm using now) and prompted me to fix them (which I agreed to), so I don't know if that's related to the problem.
I would probably go into the in-game video options and make sure that the windowed mode, resolution and DirectX API version settings are the same in all windows. If you use fullscreen mode in all windows, they should all be correctly forced to 1680x1050; in DirectX 11 with Fullscreen mode, that should be the only option they have.
Also, I have 3 displays connected to my machine, but the Window Layout Wizard in ISBoxer only wants to use 2 of them. Is this a limitation in the software, or is it something that I have setup wrong on my system that is preventing the ISBoxer Toolkit from detecting the 3rd display?
Neither.

I see that ISBoxer has detected the 3rd display, by looking at your layouts. However, It's only
using two of them because by default the Window Layout Wizard (or Window Layout page of the Quick Setup Wizard, same deal) only generates layouts for 1 or 2 monitors (or if you have the same number of Characters as monitors, it will also generate 1 full screen per monitor).
To get the wizard to use more monitors, adjust the "Swap Groups" option under the "Multiple monitors" heading. You can choose how many instances go on each display, and then the wizard will use that information when generating multi-monitor layouts.
Or you can always manually adjust the Window Layout afterward by selecting it in the top left pane under Window Layouts, and then selecting "Regions" in the bottom left pane.
If your 3 displays are plugged into different video cards, be aware of the limitations of moving 3D-accelerated windows from a monitor powered by one card, to a monitor powered by the other (a massive performance hit). --
http://isboxer.com/wiki/GPU_Management