One Word.
Susano'o.
Normally that would be enough to protect him from most attacks, but Itachi wields the Totsuka no Tsurugi. If it were to hit any of the Paths or Nagato, they would be sealed away forever. (For the record, sealing doesn't destroy the sword.)
He also wields the Yata no Kagami (Eight Span Mirror.) Which is absolutely incapable of being pierced or destroyed.
Yata no Kagami and Susano'o make the ultimate defense while the Totsuka no Tsurugi would be capable of killing each Path with a single hit.
Note: Itachi is capable of performing other techniques, such as Amaterasu and Genjutsus while inside of the Susano'o.