I haven't cleared all zones yet, but the impression I got was that base game quests were more cohesive. Like there was a linear storyline, you had to follow a trail on the map for the main quest, and many side quests were somehow tying into the main quest. Like some of them added backstory to the main quest and made you understand some chars/villains better. So it was worth clearing side quests alongside the main quest while slowly making your way through a zone.
In newer zones there is no linearity, the main quest makes you run in circles all around the map and the side quests are completely unrelated. In DLC zones I clear the side quests first and then tackle the main quest and it has no impact on my understanding of the game.
Athan Atticus Imperial Templar of Shezarr