Defining Biological Subsets in Systemic Lupus Erythematosus: Progress Toward Personalized Therapy
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Systemic lupus erythematosus (SLE) is a heterogeneous disease with respect to disease severity, response to treatment, and organ damage, the pathogenesis of which includes immunological mechanisms that are driven by both genetic and environmental factors. There are clear differences in the pathogenesis of SLE between patients of different ancestral backgrounds, including differences in genetic risk factors, immunological parameters, and clinical manifestations. Patients with high and low levels of type I interferon (IFN) in circulation represent one major biological subset within SLE, and these two groups of patients are present in all ancestral backgrounds. Genetic factors, autoantibodies, and levels of other cytokines all differ between high and low IFN patients. This distinction has also been important in predicting response to treatment with anti-type I IFN therapies, providing a precedent in SLE for biological subsets predicting treatment response. This review highlights some recent developments in defining biological subsets of SLE based on disease pathophysiology, and we speculate how this improved knowledge of disease heterogeneity will inform our efforts to personalize therapy in this disease.
KeywordsSystemic Lupus Erythematosus Systemic Lupus Erythematosus Patient Lupus Nephritis African American Belimumab
Compliance with Ethical Standards
No sources of funding were used to support the writing of this article.
Conflict of interest
Dr Sinicato, Dr Postal, and Dr Appenzeller have no conflicts to declare. Dr Niewold received research grants from EMD Serono and Janssen, Inc. These companies had no role in the preparation of this manuscript.
S. Appenzeller: Fundação Apoio À Pesquisa Estado São Paulo-Brasil (FAPESP 2008/02917-0, 2009/06049-6, and 2009/15286-1), Conselho Nacional Pesquisa Desenvolvimento-Brasil CNPq (300447/2009-4, 471343/2011-0, 302205/2012-8, and 473328/2013-5).
T.B. Niewold: National Institutes of Health (NIH) Grants (AR060861, AR057781, AR065964, and AI071651), Alliance for Lupus Research, Rheumatology Research Foundation, Cure JM Foundation, The Myositis Foundation, the Mayo Clinic Foundation, the Lupus Research Institute, and the Lupus Foundation of Minnesota.
- 3.Gonzalez LA, Toloza SM, Alarcon GS. Impact of race and ethnicity in the course and outcome of systemic lupus erythematosus. Rheum Dis Clin N Am. 2014;40:433–54, vii–viii.Google Scholar
- 33.Ritterhouse LL, Crowe SR, Niewold TB, Merrill JT, Roberts VC, Dedeke AB, et al. B lymphocyte stimulator levels in systemic lupus erythematosus: higher circulating levels in African American patients and increased production after influenza vaccination in patients with low baseline levels. Arthritis Rheum. 2011;63:3931–41.CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Freedman BI, Langefeld CD, Andringa KK, Croker JA, Williams AH, Garner NE, Lupus Nephritis–End-Stage Renal Disease Consortium, et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol. 2014;66:390–6.CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Sigurdsson S, Nordmark G, Garnier S, Grundberg E, Kwan T, Nilsson O, et al. A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5. Hum Mol Genet. 2008;17:2868–76.CrossRefPubMedPubMedCentralGoogle Scholar
- 48.Niewold TB, Kelly JA, Kariuki SN, Franek BS, Kumar AA, Kaufman KM, et al. IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Ann Rheum Dis. 2012;71:463–8.CrossRefPubMedGoogle Scholar
- 51.Cherian TS, Kariuki SN, Franek BS, Buyon JP, Clancy RM, Niewold TB. Brief Report: IRF5 systemic lupus erythematosus risk haplotype is associated with asymptomatic serologic autoimmunity and progression to clinical autoimmunity in mothers of children with neonatal lupus. Arthritis Rheum. 2012;64:3383–7.CrossRefPubMedPubMedCentralGoogle Scholar
- 55.Grondal G, Kristjansdottir H, Gunnlaugsdottir B, Arnason A, Lundberg I, Klareskog L, et al. Increased number of interleukin-10-producing cells in systemic lupus erythematosus patients and their first-degree relatives and spouses in Icelandic multicase families. Arthritis Rheum. 1999;42:1649–54.CrossRefPubMedGoogle Scholar
- 64.Kariuki SN, Franek BS, Kumar AA, Arrington J, Mikolaitis RA, Utset TO, et al. Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus. Arthritis Res Ther. 2010;12:R151.CrossRefPubMedPubMedCentralGoogle Scholar
- 67.Sasaki Y, Iseki M, Yamaguchi S, Kurosawa Y, Yamamoto T, Moriwaki Y, et al. Direct evidence of autosomal recessive inheritance of Arg24 to termination codon in purine nucleoside phosphorylase gene in a family with a severe combined immunodeficiency patient. Hum Genet. 1998;103:81–5.CrossRefPubMedGoogle Scholar
- 69.Vigna-Perez M, Hernandez-Castro B, Paredes-Saharopulos O, Portales-Perez D, Baranda L, Abud-Mendoza C, et al. Clinical and immunological effects of rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther. 2006;8:R83.CrossRefPubMedPubMedCentralGoogle Scholar