Ways that diseases can simply inherently be difficult without any house rules:
1) Obviously, is the ritual is unavailable. Only likely to be an issue for a low level group or a group without a ritual caster, both of whom would need to 'return to town' to get diseases magically cleansed.
2) For a group with an average skill check that is low on health resources or when dealing with a disease that involves damage or reduced hp to begin with. While it takes a really abysmal skill check to outright kill someone, it is more possible to roll poorly enough to simply deal damage to the patient - which, in the wrong conditions, could be problematic as well.
3) When in a time crunch. If the group are moving from one encounter to the next in rapid succession (either due to the plot, threat of discovery, or any other reason), they have to at least deal with the initial effects of the disease.
Diseases have definitely made their presence known to my group, and we've had several PCs suffering from them for extended periods - but because of that, as we're getting into Paragon, we've invested a bit more in ways to deal with that. (These days, more relying on our Bard's ability to freely cast Song of Sustenance, giving everyone a free +5 on Endurance checks for 48 hours).
But I can definitely see how, for many groups, diseases are rarely an issue. There are some excellent house rule suggestions in the thread already - here is one of mine:
Disease Specific Ritual Components.
"Mindfire! A wicked disease, spread by ill contact with terrible things from... beyond. It is said that nature's tears can cleanse it... but only the purest of waters will do. I've heard of a spring, deep in the Still Forest, said to have such healing powers... you could seek it out yourself, or see if you can find the shifter trader that roams outside of town, who often sells vials of it to those in need..."
Basically, instead of using normal ritual components for the Cure Disease ritual, each disease would require a specific component unique to it. The more powerful the disease, the rarer the component. This could turn into a hunt to acquire such a thing, making a disease a quest in and of itself... or it could simply mean the PCs need to find the right contact or merchant who can sell them what they need.
The key is, even if the PCs can easily acquire the component, they have to actually expend the effort to do so - returning to town, seeking someone out, etc. When they are out in the wild, they will have to deal with the disease normally or figure out a nearby place to find the component they need. A smart group might go and acquire some of these components for common diseases before they go adventuring - but unlike generic components, these purchases can't be turned to other uses, and so it becomes costly to stock up on a lot of them. So you might end up having the entire party getting diseased, and only have the resources to magically cure half of them.
I like it mainly because I think it both removes how trivial a disease is to remove, while also adding a level of flavor that I think will make each disease stand out as more memorable. Not a perfect solution, but it might work for some.
