I'd expect any non trivial (like changing color/size) interaction involves custom coding of a wholly new, invisible item as in "if player has item 300 and item 278, make them inactive and give him secret item 1200".

Based on a link somebody else posted, that may be right. The number of combinations is so large though. It must have been exhausting

As Binding of Isaac is a money printing machine, it was definitely worth it.

This dev-blog article from 2015 pretty-much admits that it's all done manually: https://web.archive.org/web/20151108110741/http://bindingofi...

> now as some of you know, item combos have to be hard coded at this point due to how nutty some of the tears are in rebirth. the most requested update you guys wanted in afterbirth was item combos, so the team has been hard at work the past few weeks mostly focusing on said combos.

Oh my goodness that must have been exhausting by the time the game was done

Entity component system is popular for this