One of the most important advantages of mass spectrometry is the ability to quantify proteins and their modifications in parallel to obtain a holistic picture of the protein of interest. Here, we present a hybrid immunoaffinity targeted mass spectrometry (MS) approach that combines efficient pan-antibody enrichment of a specific protein from plasma with the selectivity of targeted MS analysis to quantitate specific protein modifications. In this study, we used this approach to quantify plasma levels of the chemokine CXCL10 that has been associated with many immunological disorders such as systemic lupus erythematosus and primary Sjögren's Syndrome. The hybrid approach enabled sensitive, specific and simultaneous quantification of total, full-length (active) CXCL101-77 and DPP4 truncated (inactive) CXCL103-77 in human plasma. Samples from 30 healthy individuals and 34 primary Sjögren's Syndrome patients were analyzed. The ratio of CXCL101-77 to truncated CXCL103-77 was significantly increased and demonstrated an improved classification of the primary Sjögren's syndrome patients (ROC AUC = 0.74) when compared to total CXCL10 (ROC AUC = 0.66). Furthermore, the ratio of CXCL101-77 to truncated CXCL103-77 correlated best with Sjögren's syndrome disease activity. As this strategy can be readily adapted to other proteins and modifications of interest, we are convinced that it will lead to a more detailed understanding of different proteoforms in physiology and pathology yielding more relevant biomarkers and drug targets.