Set the system wide DPI to a comfortable level for your highest resolution screen, using X Resources. There is a DPI calculator here.
With the DPI set in step 1, work out what scaling is comfortable on your secondary screen. You can do this by adjusting the
layout.css.devPixelsPerPxFirefox setting or with
xrandr --output HDMI1 --scale 1.3x1.3
Calculate the total screen size for the
xrandr --fbparameter. To do this multiply the x and y resolution values of your secondary screen by the scaling factor, and then add the primary value, depending on whether you have your screens left/right or above/below. In my case both my monitors are 1920x1080, my secondary monitor is scaled at 1.3 and I have my primary monitor below my secondary monitor, so my total screen size is 1920 * 1.3 x 1080 * 1.3 + 1080, or 2496x2484.
Calculate the position of your two monitors. My primary monitor is centred below my secondary monitor. So my secondary monitor is at 0x0 and my primary monitor is at (1920 * 1.3 - 1920) / 2 x 1080 * 1.3 or 285x1404.
Put the above values into xrandr:
xrandr --output HDMI1 --scale 1.3x1.3 --mode 1920x1080 --fb 2496x2484 --pos 0x0
xrandr --output eDP1 --scale 1x1 --pos 285x1404
With thanks to this SE post.