Lupus is the recurring diagnosis House M.D. often considers before ruling it out.
The show became famous for repeatedly raising lupus during its diagnostic discussions. House and his team frequently consider systemic lupus erythematosus because it can affect multiple organs and produce a wide range of symptoms, making it a plausible explanation for unusual cases.
The phrase became a running joke because lupus was so often suggested and then rejected. In the series, however, lupus is not always wrong: it is eventually the correct diagnosis in at least one prominent case.
Lupus is a real autoimmune disease, not a fictional medical term. The recurring reference should not be confused with the show’s separate catchphrase “It’s not lupus,” which summarizes the joke rather than naming a different diagnosis.