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The prevalence and burden of autoimmune and autoantibody mediated disease is increasing worldwide, yet most disease etiologies remain unclear. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leverage advances in programmable-phage immunoprecipitation (PhIP-Seq) methodology to explore the modulation, or lack thereof, of proteome-wide autoantibody profiles in both health and disease. We demonstrate that each individual, regardless of disease state, possesses a distinct set of autoreactivities constituting a unique immunological fingerprint, or "autoreactome", that is remarkably stable over years. In addition to uncovering important new biology, the autoreactome can be used to better evaluate the relative effectiveness of various therapies in altering autoantibody repertoires. We find that therapies targeting B-Cell Maturation Antigen (BCMA) profoundly alter an individual's autoreactome, while anti-CD19 and CD-20 therapies have minimal effects, strongly suggesting a rationale for BCMA or other plasma cell targeted therapies in autoantibody mediated diseases., Competing Interests: Competing Interest Declaration Potential Conflicts J.D.R. reports being a founder and paid consultant for Delve Bio, Inc., and a paid consultant for the Public Health Company and Allen & Co. M.A.S. receives unrelated research funding from the NIH, the CDC, Cepheid and Merck and unrelated Honoria from UpToDate, Inc. M.R.W. reports being a founder and paid consultant for Delve Bio, Inc. and receives unrelated research grant funding from Roche/Genentech and Novartis, and received speaking honoraria from Genentech, Takeda, WebMD, and Novartis. C.J.T. reports being on the Scientific Advisory Boards for Caribou Biosciences, T-CURX, Myeloid Therapeutics, ArsenalBio, Cargo Therapeutics, Celgene/BMS Cell Therapy; is a member a DSMB member of Kyverna; is on Ad hoc advisory boards/consulting (last 12 months) for Nektar Therapeutics, Legend Biotech, Prescient Therapeutics, Century Therapeutics, IGM Biosciences, Abbvie; has Stock options in Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, ArsenalBio, Cargo Therapeutics; and reports the right to receive payment from Fred Hutch as an inventor on patents related to CAR T-cell therapy. J.A.H. reports research funding from Merck and Takeda and consulting fees from Takeda, Gilead, SentiBio, and Century Therapeutics. J.G. reports research funding from Sobi, Juno Therapeutics (a BMS company), Celgene (a BMS company), Angiocrine Bioscience; is an Ad hoc consultant for Sobi, Legend Biotech, Janssen, Kite Pharma, MorphoSys. D.J.G. has received research funding, has served as an advisor and has received royalties from Juno Therapeutics, a Bristol-Myers Squibb company; has served as an advisor and received research funding from Seattle Genetics; has served as an advisor for GlaxoSmithKline, Celgene, Janssen Biotech, Ensoma and Legend Biotech; and has received research funding from SpringWorks Therapeutics, Sanofi, and Cellectar Biosciences. K.C.O. received unrelated research funding from, and is an equity shareholder of Cabaletta Bio, and receives unrelated research funding from Seismic, argenx, and Viela Bio/Horizon (now Amgen). R.J.N. reports unrelated research support from the National Institutes of Health, Genentech, Inc., Alexion Pharmaceuticals, Inc., argenx, Annexon Biosciences, Inc., Ra Pharmaceuticals, Inc. (now UCB S.A.), the Myasthenia Gravis Foundation of America, Inc., Momenta Pharmaceuticals, Inc. (now Janssen), Immunovant, Inc., Grifols, S.A., and Viela Bio, Inc. (now Horizon Therapeutics plc). R.J.N. has also served as a consultant/advisor unrelated to research in this manuscript for Alexion Pharmaceuticals, Inc., argenx, Cabaletta Bio, Inc., Cour Pharmaceuticals, CSL Behring, Grifols, S.A., Ra Pharmaceuticals, Inc. (now UCB S.A.), Immunovant, Inc., Momenta Pharmaceuticals, Inc. (now Janssen), and Viela Bio, Inc. (now Horizon Therapeutics plc). J.L.D., C.M.B. and M.R.W. receive licensing fees from CDI Labs.