House M.D. repeatedly jokes that lupus is rarely the final diagnosis.
The running gag comes from the series' focus on unusual diseases. House and his colleagues frequently consider lupus when a patient has several unexplained symptoms, but the diagnosis usually turns out to be something else. The line became one of the show's best-known medical catchphrases because it reflects the team's habit of listing many possible explanations before finding the correct one.
Lupus is not fictional: systemic lupus erythematosus is a real autoimmune disease. It can affect multiple organs and produce varied symptoms, which makes it medically plausible as a differential diagnosis. The joke concerns its frequency in the show's plots, not whether lupus exists.
The recurring phrase is often remembered as “It’s never lupus.” The series eventually did feature lupus diagnoses, making the gag a deliberate exaggeration rather than a literal medical rule.