It would be unusual to require more than one or two sets of creepage/clearance rules on a single project, so I wouldn't stress too much about doing anything complicated. Just define a net class to contain the nets that need special handling, use directives (with or without blankets) in the schematic to assign the class to the nets that need to be in it, and create PCB rules against that class.
Make sure to set your rule priorities appropriately so that the most strict requirements are the highest priority.
For example, if you have a mains-powered device, then you could simply set up a "Mains" net class and assign it to the required nets. Then in PCB you might need to have a set of rules for creepage/clearance between nets that are both in Mains, and maybe more strict rules for when only one of the two nets is in Mains. Simple as that.
You can also assign net classes in PCB, but it's generally better to do it in the schematic so that it's visible, and is less prone to getting lost when pushing changes back and forth between Sch and Pcb.