I've seen neglected pitching staffs give up a ton of runs due to to bringing in the same relievers at extremely high fatigue. In that case, I look at it like everyone in that league is feasting on them so not really an unfair skewed stat.
Also noticed I'm a chronic "victim" of underperforming my Pythag, as much as 100 points, but at least by 5-10 games. So I don't put much creedence in it.
And should probably start a thread trying to figure out why.