1
It's harder to pitch when you know you're only going to get 3 runs at most of support (major bonus points to Greinke and King Felix).
It's harder to pitch when you are in 1-run games a lot (extension of point 1)
It's harder to pitch if your defense sucks (this helps out Halladay and Verlander in particular)
It's harder to pitch if you pitch more innings (this isn't entirely captured by doing rate * playing time math...the longer you throw, the harder it is to maintain your production levels and it's non-linear...it's not 20% harder to throw 240 innings compared to 200...it's probably more like 50% harder)