Hosono Y, Sie B, Pinal-Fernandez I, Pak K, Mecoli CA, Casal-Dominguez M, Warner BM, Kaplan MJ, Albayda J, Danoff S, Lloyd TE, Paik JJ, Tiniakou E, Aggarwal R, Oddis CV, Moghadam-Kia S, Carmona-Rivera C, Milisenda JC, Grau-Junyent JM, Selva-O'Callaghan A, Christopher-Stine L, Larman HB, Mammen AL. *Annals of the Rheumatic Diseases* · February 2023 · DOI: [10.1136/ard-2022-222441](https://doi.org/10.1136/ard-2022-222441) How to cite ### AMA Hosono Y, Sie B, Pinal-Fernandez I, et al. Coexisting autoantibodies against transcription factor Sp4 are associated with decreased cancer risk in patients with dermatomyositis with anti-TIF1γ autoantibodies. Ann Rheum Dis. 2023;82(2):246-252. doi:10.1136/ard-2022-222441 ### APA ``` Hosono, Y., Sie, B., Pinal-Fernandez, I., Pak, K., Mecoli, C. A., Casal-Dominguez, M., … Mammen, A. L. (2023). Coexisting autoantibodies against transcription factor Sp4 are associated with decreased cancer risk in patients with dermatomyositis with anti-TIF1γ autoantibodies. Annals of the Rheumatic Diseases, 82(2), 246–252. https://doi.org/10.1136/ard-2022-222441 ``` ### BibTeX ``` @article{Hosono2023Sp4, author = {Hosono, Yuji and Sie, Brandon and Pinal-Fernandez, Iago and Pak, Katherine and Mecoli, Christopher A. and Casal-Dominguez, Maria and Warner, Blake M. and Kaplan, Mariana J. and Albayda, Jemima and Danoff, Sonye and Lloyd, Thomas E. and Paik, Julie J. and Tiniakou, Eleni and Aggarwal, Rohit and Oddis, Chester V. and Moghadam-Kia, Siamak and Carmona-Rivera, Carmelo and Milisenda, Jose C{\'e}sar and Grau-Junyent, Josep Maria and Selva-O'Callaghan, Albert and Christopher-Stine, Lisa and Larman, H. Benjamin and Mammen, Andrew L.}, title = {Coexisting autoantibodies against transcription factor {Sp4} are associated with decreased cancer risk in patients with dermatomyositis with anti-{TIF1}$\gamma$ autoantibodies}, journal = {Annals of the Rheumatic Diseases}, year = {2023}, volume = {82}, number = {2}, pages = {246--252}, doi = {10.1136/ard-2022-222441}, pmid = {36008132} } ``` Phage ImmunoPrecipitation Sequencing (PhIP-Seq) on MSA-negative dermatomyositis sera surfaced a previously undescribed autoantibody — against transcription factor Sp4 — that almost exclusively coexists with the cancer-associated anti-TIF1γ autoantibody. Among dual-positive patients in two independent cohorts, cancer prevalence dropped sharply, reframing TIF1γ-positive dermatomyositis as a serologically heterogeneous risk group rather than a uniformly high-risk one. [ Read publication at Annals of the Rheumatic Diseases ](https://doi.org/10.1136/ard-2022-222441) In this publication: - In the University of Pittsburgh validation cohort, anti-TIF1γ/anti-Sp4 dual-positive patients had 13.3% cancer prevalence versus 67.7% in the TIF1γ-only arm (n=46, p<0.001). - In the Johns Hopkins discovery cohort, 0 of 26 dual-positive patients had cancer compared with 5 of 35 (14%) TIF1γ-only patients (p=0.04). - Across 371 Hopkins myositis sera screened by ELISA, 96.3% of anti-Sp4-positive dermatomyositis patients were also anti-TIF1γ-positive — a near-exclusive coexistence pattern. - Sp4 was discovered by PhIP-Seq screening of 43 MSA-negative DM sera and orthogonally validated by full-length protein immunoprecipitation before ELISA cohort screening. Patients with anti-TIF1γ autoantibodies have a substantially elevated risk of an underlying or imminent malignancy — a clinical association strong enough that anti-TIF1γ positivity routinely prompts intensive cancer screening. Yet not every anti-TIF1γ-positive patient develops cancer, and there is no validated way to predict which ones will. The investigators used Phage ImmunoPrecipitation Sequencing (PhIP-Seq) on serum from 43 dermatomyositis patients in whom standard line-blot testing had not detected any of the known DM-specific autoantibodies. The screen surfaced reactivity against **Sp4**, a transcription factor not previously implicated in DM autoimmunity. The team confirmed Sp4 as a true autoantigen by immunoprecipitating full-length Sp4 protein with patient sera, then built an ELISA and screened large clinical cohorts. What emerged was a striking pattern. Anti-Sp4 autoantibodies appeared almost exclusively in DM patients who were *also* anti-TIF1γ-positive. And among those dual-positive patients, cancer was conspicuously absent. In the Johns Hopkins discovery cohort, none of the 26 anti-TIF1γ/anti-Sp4 dual-positive patients had cancer, compared with 14% of TIF1γ-positive patients lacking anti-Sp4. An independent University of Pittsburgh validation cohort reproduced the effect: 13.3% cancer in the dual-positive arm versus 67.7% in the TIF1γ-only arm. For rheumatologists and oncologists co-managing TIF1γ-positive DM patients, anti-Sp4 testing offers a route to right-size cancer surveillance — though the biological mechanism is not yet established and prospective studies are needed before clinical adoption. The Sp4/TIF1γ result also illustrates how the joint distribution of autoantibody specificities can re-stratify risk inside an otherwise homogeneous serological group — the kind of unbiased, proteome-scale autoantibody discovery that programmable phage-display platforms were built to enable. 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