He called her John, once, and at the time she was hurt that he couldn't even remember her when she was standing two feet away from him. How many times had they been standing there together, before he met John, and yet it's his name that comes out of Sherlock's mouth most readily.
"I've replaced the skull," John told her early on, but that doesn't make it much better, because it just gives an empty skull priority of place over her.
She was hurt, but she had gotten used to that dull ache from her interactions with Sherlock, and she found that it got easier to deal with as time went on. Some part of her, sometimes, was close to laughing, because their relationship would be almost farce if it weren't tragic, and there are days, even if he doesn't look at her, even in the weeks in which he doesn't come by at all, when it isn't tragic.
She confronts him with deductions of her own, and he starts to try to care, and she lets him know it's okay. That he can't remember she's there, that he can't think of any reason he might need her, even that he calls her John…it's all okay.
After he—afterwards, she thinks of that moment again and it doesn't seem so hurtful, after all, being interchangeable with his best friend in the world.