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The first 2 loops are pretty difficult if you don't get the right cards/relics. If you can survive to the 3rd loop, things start getting easy. By that time, your deck should be fully fleshed out and the relics you need should be obtained.
While the game forces Blights on you (special relics that hurt you and buff enemies), most of them are a non-issue to deal with. Enemy health and damage get buffed every loop, but not fast enough. The only Blight to avoid is one where enemies get 1 Intangible. Since that Blight isn't forced upon you, it's easy to avoid.
The biggest problem I've found is that Mind Blast trivializes every fight in the game. In case you haven't run into it, Mind Blast is a colorless card (available to all classes) that costs 0 and deals damage based on how many cards are in your draw pile. Upgrading it makes the card Innate (guaranteed to be in your hand on turn 1).
Once obtained and upgraded, simply fill your deck with junk cards to keep adding to the damage it deals. If you can get your hands on more Mind Blast cards, the build gets even more broken. The sweet spot is about 3 copies. On the last Endless run I abandoned (at floor 388), I had 363 cards and 121 curses for my Du-Vu doll. My starting hand contained 3 Mind Blast+ cards and a Bottled Limit Break. On turn 1 I was dealing about 600dmg per Mind Blast.
In my experience, the Blight that usually leads to my death is Haunted(enemies gain Intangible at the start of each combat).
Is the Custom section fun?