OBJECTIVE: Previous studies have shown a familial component in RA and in some other rheumatic autoimmune diseases (RAIDs), but because of the different study designs the risk estimates for familial risks differ extensively. The objective of this study is to identify familial components for RAIDs. METHODS: We collected data on patients diagnosed in Swedish hospitals with RA, AS, PM/DM, SS, SLE and SSc (and scleroderma) and calculated familial standardized incidence ratios (SIRs) for each of these (concordant) and between them (discordant). RESULTS: The combined number of RAID patients in the offspring population (for whom SIRs were calculated) was 71 544, and in the whole population the number was 152 714, accounting for 19.8% of all autoimmune diseases in Sweden. AS showed the highest concordant familial risk of 18.42, followed by SLE (14.04), SS (8.63), SSc (4.50), PM/DM (4.03) and RA (3.03). There was no sex difference in SIRs. Risks for AS and SLE were 80.28 and 19.53 for persons whose parents and siblings were affected. Discordant risks were far lower than concordant risks, but they were significant for RA with all the other five RAIDs, for SLE and SSc with four RAIDs, for AS and SS with three RAIDs and for PM/DM with two RAIDs, attesting to extensive polyautoimmunity between RAIDs. CONCLUSION: The derived familial risks in this nationwide family study on medically diagnosed RAID are compatible with emerging evidence on the polygenic background of these complex diseases. Novel genetic pathways offer new therapeutic targets that alleviate disease onset optimally in high-risk familial patients and others.

Bioinformatics and Biostatistics Working Section GeneWerk GmbH Heidelberg Germany

Center for Primary Health Care Research Lund University Malmö Sweden

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Molecular Genetic Epidemiology German Cancer Research Center Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Consortium

Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague Pilsen Czech Republic

Hopp Children's Cancer Center

Stanford Prevention Research Center Stanford University School of Medicine Stanford CA USA

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Sundquist K, Martinéus J, Li X, Hemminki K, Sundquist J.  Concordant and discordant associations between rheumatoid arthritis, systemic lupus erythematosus and ankylosing spondylitis based on all hospitalizations in Sweden between 1973 and 2004. Rheumatology (Oxford)  2008;47:1199–202. PubMed PMC

Hemminki K, Li X, Sundquist J, Sundquist K.  Familial associations of rheumatoid arthritis with autoimmune disorders and related conditions. Arthritis Rheum  2009;60:661–8. PubMed

Hayter SM, Cook MC.  Updated assessment of the prevalence, spectrum and case definition of autoimmune disease. Autoimmun Rev  2012;11:754–65. PubMed

Roberts MH, Erdei E.  Comparative United States autoimmune disease rates for 2010–2016 by sex, geographic region, and race. Autoimmun Rev  2020;19:102423. PubMed PMC

Worthington J.  Investigating the genetic basis of susceptibility to rheumatoid arthritis. J Autoimmun  2005;25 Suppl:16–20. PubMed

Goldblatt F, O'Neill SG.  Clinical aspects of autoimmune rheumatic diseases. Lancet  2013;382:797–808. PubMed

Noaiseh G, Baer AN.  Toward better outcomes in Sjögren's syndrome: the promise of a stratified medicine approach. Best Pract Res Clin Rheumatol  2020;34:101475. PubMed

Denton CP, Khanna D.  Systemic sclerosis. Lancet  2017;390:1685–99. PubMed

Burmester GR, Pope JE.  Novel treatment strategies in rheumatoid arthritis. Lancet  2017;389:2338–48. PubMed

Barnas JL, Looney RJ, Anolik JH.  B cell targeted therapies in autoimmune disease. Curr Opin Immunol  2019;61:92–9. PubMed PMC

Durcan L, O'Dwyer T, Petri M.  Management strategies and future directions for systemic lupus erythematosus in adults. Lancet  2019;393:2332–43. PubMed

The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature  2007;447:661–83. PubMed PMC

Cárdenas-Roldán J, Rojas-Villarraga A, Anaya JM.  How do autoimmune diseases cluster in families? A systematic review and meta-analysis. BMC Med  2013;11:73. PubMed PMC

Kuo C-F, Grainge MJ, Valdes AM.  et al.  Familial aggregation of systemic lupus erythematosus and coaggregation of autoimmune diseases in affected families. JAMA Intern Med  2015;175:1518–26. PubMed

Kuo C-F, Grainge MJ, Valdes AM.  et al.  Familial risk of Sjögren's syndrome and co-aggregation of autoimmune diseases in affected families: a nationwide population study. Arthritis Rheumatol  2015;67:1904–12. PubMed PMC

Kuo C-F, Luo S-F, Yu K-H.  et al.  Familial risk of systemic sclerosis and co-aggregation of autoimmune diseases in affected families. Arthritis Res Ther  2016;18:231. PubMed PMC

Kuo C-F, Grainge MJ, Valdes AM.  et al.  Familial aggregation of rheumatoid arthritis and co-aggregation of autoimmune diseases in affected families: a nationwide population-based study. Rheumatology (Oxford)  2017;56:928–33. PubMed PMC

Hemminki K, Forsti A, Sundquist K, Sundquist J, Li X.  Familial associations of monoclonal gammopathy of unknown significance with autoimmune diseases. Leukemia  2016;30:1766–9. PubMed

Hemminki K, Ji J, Brandt A, Mousavi SM, Sundquist J.  The Swedish family-cancer database 2009: prospects for histology-specific and immigrant studies. Int J Cancer  2010;126:2259–67. PubMed

Brandt A, Bermejo JL, Sundquist J, Hemminki K.  Familial risks of breast and prostate cancers: does the definition of the at risk period matter?  Eur J Cancer  2010;46:752–7. PubMed

Ludvigsson JF, Andersson E, Ekbom A.  et al.  External review and validation of the Swedish national inpatient register. BMC Public Health  2011;11:450. PubMed PMC

Fiederling J, Shams AZ, Haug U.  Validity of self-reported family history of cancer: a systematic literature review on selected cancers. Int J Cancer  2016;139:1449–60. PubMed

Murff HJ, Spigel DR, Syngal S.  Does this patient have a family history of cancer? An evidence-based analysis of the accuracy of family cancer history. JAMA  2004;292:1480–9. PubMed

Mai PL, Garceau AO, Graubard BI.  et al.  Confirmation of family cancer history reported in a population-based survey. J Natl Cancer Inst  2011;103:788–97. PubMed PMC

Askling J, Fored CM, Geborek P.  et al.  Swedish registers to examine drug safety and clinical issues in RA. Ann Rheum Dis  2006;65:707–12. PubMed PMC

Kirino Y, Remmers EF.  Genetic architectures of seropositive and seronegative rheumatic diseases. Nat Rev Rheumatol  2015;11:401–14. PubMed

Kerminen S, Martin AR, Koskela J.  et al.  Geographic variation and bias in the polygenic scores of complex diseases and traits in Finland. Am J Human Genet  2019;104:1169–81. PubMed PMC

Simone D, Al Mossawi MH, Bowness P.  Progress in our understanding of the pathogenesis of ankylosing spondylitis. Rheumatology (Oxford)  2018;57:vi4–vi9. PubMed PMC

Kwon Y-C, Chun S, Kim K, Mak A.  Update on the genetics of systemic lupus erythematosus: genome-wide association studies and beyond. Cells  2019;8, 1180–1197 PubMed PMC

Bliddal S, Nielsen CH, Feldt-Rasmussen U.  Recent advances in understanding autoimmune thyroid disease: the tallest tree in the forest of polyautoimmunity. F1000Res  2017;6:1776. PubMed PMC

Fallahi P, Elia G, Ragusa F.  et al.  The aggregation between AITD with rheumatologic, or dermatologic, autoimmune diseases. Best Pract Res Clin Endocrinol Metab  2019;33:101372. PubMed

Cho JH, Gregersen PK.  Genomics and the multifactorial nature of human autoimmune disease. N Engl J Med  2011;365:1612–23. PubMed

Ramos PS, Criswell LA, Moser KL.  et al.  A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap. PLoS Genet  2011;7:e1002406. PubMed PMC

Li YR, Li J, Zhao SD.  et al.  Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nat Med  2015;21:1018–27. PubMed PMC

Tajuddin SM, Schick UM, Eicher JD.  et al.  Large-scale exome-wide association analysis identifies loci for white blood cell traits and pleiotropy with immune-mediated diseases. Am J Human Genet  2016;99:22–39. PubMed PMC

Hwangbo Y, Park YJ.  Genome-wide association studies of autoimmune thyroid diseases, thyroid function, and thyroid cancer. Endocrinol Metab (Seoul)  2018;33:175–84. PubMed PMC

Acosta-Herrera M, Kerick M, González-Serna D.  et al.  Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases. Ann Rheum Dis  2019;78:311–9. PubMed PMC

David T, Ling SF, Barton A.  Genetics of immune-mediated inflammatory diseases. Clin Exp Immunol  2018;193:3–12. PubMed PMC

Discovery of new myositis genetic associations through leveraging other immune-mediated diseases