Biomarkers in connective tissue diseases
2017; Elsevier BV; Volume: 140; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2017.10.003
ISSN1097-6825
AutoresNeelakshi R. Jog, Judith A. James,
Tópico(s)Autoimmune Bullous Skin Diseases
ResumoAutoimmune connective tissue diseases are clinically variable, making biomarkers desirable for assessing future disease risk, supporting early and accurate diagnosis, monitoring disease activity and progression, selecting therapeutics, and assessing treatment response. Because of their correlations with specific clinical characteristics and often with disease progression, autoantibodies and other soluble mediators are considered potential biomarkers. Additional biomarkers might reflect downstream pathologic processes or appear because of ongoing inflammation and damage. Because of overlap between diseases, some biomarkers have limited specificity for a single autoimmune connective tissue disease. This review describes select current biomarkers that aid in the diagnosis and treatment of several major systemic autoimmune connective tissue disorders: systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and anti-neutrophil cytoplasmic antibody–associated vasculitides. Newly proposed biomarkers that target various stages in disease onset or progression are also discussed. Newer approaches to overcome the diversity observed in patients with these diseases and to facilitate personalized disease monitoring and treatment are also addressed. Autoimmune connective tissue diseases are clinically variable, making biomarkers desirable for assessing future disease risk, supporting early and accurate diagnosis, monitoring disease activity and progression, selecting therapeutics, and assessing treatment response. Because of their correlations with specific clinical characteristics and often with disease progression, autoantibodies and other soluble mediators are considered potential biomarkers. Additional biomarkers might reflect downstream pathologic processes or appear because of ongoing inflammation and damage. Because of overlap between diseases, some biomarkers have limited specificity for a single autoimmune connective tissue disease. This review describes select current biomarkers that aid in the diagnosis and treatment of several major systemic autoimmune connective tissue disorders: systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and anti-neutrophil cytoplasmic antibody–associated vasculitides. Newly proposed biomarkers that target various stages in disease onset or progression are also discussed. Newer approaches to overcome the diversity observed in patients with these diseases and to facilitate personalized disease monitoring and treatment are also addressed. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: December 2017. Credit may be obtained for these courses until November 30, 2018.Copyright Statement: Copyright © 2017-2018. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Neelakshi R. Jog, PhD, and Judith A. James, MD, PhD (authors); Cezmi A. Akdis, MD (editor)Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: J. A. James has received grants from the NIH (U54GM104938, U01AI101934, U19AI082714, P30GM103510, and P30AR053483) and did work on a patent for biomarkers for systemic lupus erythematosus disease activity, and intensity and flare held by Oklahoma Medical Research Foundation. N. R. Jog declares no relevant conflicts of interest. C. A. Akdis (editor) disclosed no relevant financial relationships.Activity Objectives:1.To understand the utility of autoantibodies in managing connective tissue disease.2.To identify statistical measures of commonly ordered autoantibody tests.3.To recognize important associations between particular biomarkers and clinical manifestations of disease.Recognition of Commercial Support: This CME activity has not received external commercial support.List of CME Exam Authors: Keerthi Karamched, MD, Vivian Nanagas, MD, MSc, and Alan Baptist, MD, MPHDisclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: The exam authors disclosed no relevant financial relationships.Autoimmune connective tissue disorders are a heterogeneous group of diseases that affect connective tissue in various organs resulting from poorly controlled autoimmune responses, complement activation, interferon dysregulation, and associated inflammation. Although their clinical presentations vary, these diseases share significant genetic risk factors, as demonstrated by cross-analysis of genome-wide association studies1Farh K.K. Marson A. Zhu J. Kleinewietfeld M. Housley W.J. Beik S. et al.Genetic and epigenetic fine mapping of causal autoimmune disease variants.Nature. 2015; 518: 337-343Crossref PubMed Scopus (474) Google Scholar and common regulatory mechanisms of autoimmune diseases.2Shooshtari P. Huang H. Cotsapas C. Integrative genetic and epigenetic analysis uncovers regulatory mechanisms of autoimmune disease.Am J Hum Genet. 2017; 101: 75-86Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Environmental and female-associated factors also play critical roles in development of autoimmune diseases.3Deane K.D. El-Gabalawy H. Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE.Nat Rev Rheumatol. 2014; 10: 212-228Crossref PubMed Scopus (53) Google Scholar, 4Niklas K. Niklas A.A. Majewski D. Puszczewicz M. Rheumatic diseases induced by drugs and environmental factors: the state-of-the-art—part one.Reumatologia. 2016; 54: 122-127Crossref PubMed Scopus (0) Google Scholar, 5Niklas K. Niklas A.A. Majewski D. Puszczewicz M.J. Rheumatic diseases induced by drugs and environmental factors: the state-of-the-art—part two.Reumatologia. 2016; 54: 165-169Crossref PubMed Scopus (0) Google Scholar, 6Sharma R. Harris V.M. Cavett J. Kurien B.T. Liu K. Koelsch K.A. et al.Rare X chromosome abnormalities in systemic lupus erythematosus and Sjogren's syndrome.Arthritis Rheumatol. 2017; ([Epub ahead of print])Crossref Scopus (3) Google Scholar, 7Oliver J.E. Silman A.J. Why are women predisposed to autoimmune rheumatic diseases?.Arthritis Res Ther. 2009; 11: 252Crossref PubMed Scopus (0) Google Scholar In nearly all systemic autoimmune rheumatic diseases evaluated to date, autoantibody production and immune dysregulation precede clinical onset,8Arbuckle M.R. McClain M.T. Rubertone M.V. Scofield R.H. Dennis G.J. James J.A. et al.Development of autoantibodies before the clinical onset of systemic lupus erythematosus.N Engl J Med. 2003; 349: 1526-1533Crossref PubMed Scopus (1416) Google Scholar, 9Eriksson C. Kokkonen H. Johansson M. Hallmans G. Wadell G. Rantapaa-Dahlqvist S. Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden.Arthritis Res Ther. 2011; 13: R30Crossref PubMed Scopus (0) Google Scholar, 10McClain M.T. Arbuckle M.R. Heinlen L.D. Dennis G.J. Roebuck J. Rubertone M.V. et al.The prevalence, onset, and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus.Arthritis Rheum. 2004; 50: 1226-1232Crossref PubMed Scopus (0) Google Scholar, 11Lu R. Munroe M.E. Guthridge J.M. Bean K.M. Fife D.A. Chen H. et al.Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies.J Autoimmun. 2016; 74: 182-193Crossref PubMed Scopus (27) Google Scholar, 12Munroe M.E. Lu R. Zhao Y.D. Fife D.A. Robertson J.M. Guthridge J.M. et al.Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification.Ann Rheum Dis. 2016; 75: 2014-2021Crossref PubMed Scopus (28) Google Scholar, 13Munroe M.E. Young K.A. Kamen D.L. Guthridge J.M. Niewold T.B. Costenbader K.H. et al.Discerning risk of disease transition in relatives of systemic lupus erythematosus patients utilizing soluble mediators and clinical features.Arthritis Rheumatol. 2017; 69: 630-642Crossref PubMed Scopus (2) Google Scholar, 14Ma W.T. Chang C. Gershwin M.E. Lian Z.X. Development of autoantibodies precedes clinical manifestations of autoimmune diseases: a comprehensive review.J Autoimmun. 2017; 83: 95-112Crossref PubMed Scopus (0) Google Scholar, 15Paul B.J. Kandy H.I. Krishnan V. Pre-rheumatoid arthritis and its prevention.Eur J Rheumatol. 2017; 4: 161-165Crossref PubMed Google Scholar although a significant amount of this information is not yet integrated to standard clinical care. Ongoing research is focused on improving biomarkers for diagnosis, prognosis, treatment selection, and optimized therapy. This review describes current and new emerging biomarkers for major connective tissue diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), and anti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitides. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: December 2017. Credit may be obtained for these courses until November 30, 2018. Copyright Statement: Copyright © 2017-2018. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Neelakshi R. Jog, PhD, and Judith A. James, MD, PhD (authors); Cezmi A. Akdis, MD (editor) Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: J. A. James has received grants from the NIH (U54GM104938, U01AI101934, U19AI082714, P30GM103510, and P30AR053483) and did work on a patent for biomarkers for systemic lupus erythematosus disease activity, and intensity and flare held by Oklahoma Medical Research Foundation. N. R. Jog declares no relevant conflicts of interest. C. A. Akdis (editor) disclosed no relevant financial relationships. Activity Objectives:1.To understand the utility of autoantibodies in managing connective tissue disease.2.To identify statistical measures of commonly ordered autoantibody tests.3.To recognize important associations between particular biomarkers and clinical manifestations of disease. Recognition of Commercial Support: This CME activity has not received external commercial support. List of CME Exam Authors: Keerthi Karamched, MD, Vivian Nanagas, MD, MSc, and Alan Baptist, MD, MPH Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The exam authors disclosed no relevant financial relationships. SLE is a systemic autoimmune disease characterized by production of anti-nuclear autoantibodies (ANAs). Early and accurate diagnosis and disease monitoring are hindered by its heterogeneous presentation and clinical course. Serologic and urinary biomarkers are either in use or are emerging as potential biomarkers for SLE. These autoantibodies (Table I), complement products, and cytokines/chemokines/soluble mediators have the potential to facilitate diagnosis, identify subjects at greater risk for SLE, and monitor disease activity or specific organ involvement (Fig 1).Table IAutoantibody specificities in patients with connective tissue diseases and their association with disease phenotypeAntibodyAssociated disease phenotypeOther associated diseasesReferenceSLE Anti-dsDNALNNeuropsychiatric lupus erythematosus21Cozzani E. Drosera M. Gasparini G. Parodi A. Serology of lupus erythematosus: correlation between immunopathological features and clinical aspects.Autoimmune Dis. 2014; 2014: 321359PubMed Google Scholar Anti-SmLN31Migliorini P. Baldini C. Rocchi V. Bombardieri S. Anti-Sm and anti-RNP antibodies.Autoimmunity. 2005; 38: 47-54Crossref PubMed Scopus (0) Google Scholar Anti-Ro/SSA (Ro60)LNNeonatal lupus erythematosusSubacute cutaneous lupus erythematosusSjögren syndrome32Yoshimi R. Ueda A. Ozato K. Ishigatsubo Y. Clinical and pathological roles of Ro/SSA autoantibody system.Clin Dev Immunol. 2012; 2012: 606195Crossref PubMed Scopus (0) Google Scholar Anti-La/SSBLNNeonatal lupus erythematosusSubacute cutaneous lupus erythematosusSjögren syndrome32Yoshimi R. Ueda A. Ozato K. Ishigatsubo Y. Clinical and pathological roles of Ro/SSA autoantibody system.Clin Dev Immunol. 2012; 2012: 606195Crossref PubMed Scopus (0) Google Scholar Anti–ribosomal PLNNeuropsychiatric lupus erythematosusPediatric-onset SLE33Briani C. Lucchetta M. Ghirardello A. Toffanin E. Zampieri S. Ruggero S. et al.Neurolupus is associated with anti-ribosomal P protein antibodies: an inception cohort study.J Autoimmun. 2009; 32: 79-84Crossref PubMed Scopus (0) Google Scholar, 34Valoes C.C. Molinari B.C. Pitta A.C. Gormezano N.W. Farhat S.C. Kozu K. et al.Anti-ribosomal P antibody: a multicenter study in childhood-onset systemic lupus erythematosus patients.Lupus. 2017; 26: 484-489Crossref PubMed Scopus (0) Google Scholar Anti-RNPSLESystemic sclerosis21Cozzani E. Drosera M. Gasparini G. Parodi A. Serology of lupus erythematosus: correlation between immunopathological features and clinical aspects.Autoimmune Dis. 2014; 2014: 321359PubMed Google Scholar, 31Migliorini P. Baldini C. Rocchi V. Bombardieri S. Anti-Sm and anti-RNP antibodies.Autoimmunity. 2005; 38: 47-54Crossref PubMed Scopus (0) Google Scholar Anti-cardiolipinSLE, antiphospholipid syndrome10McClain M.T. Arbuckle M.R. Heinlen L.D. Dennis G.J. Roebuck J. Rubertone M.V. et al.The prevalence, onset, and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus.Arthritis Rheum. 2004; 50: 1226-1232Crossref PubMed Scopus (0) Google ScholarRA RFRASLE, Sjögren syndrome60Steiner G. Smolen J. Autoantibodies in rheumatoid arthritis and their clinical significance.Arthritis Res. 2002; 4: S1-S5Crossref PubMed Google Scholar, 61Nishimura K. Sugiyama D. Kogata Y. Tsuji G. Nakazawa T. Kawano S. et al.Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis.Ann Intern Med. 2007; 146: 797-808Crossref PubMed Google Scholar ACPARA61Nishimura K. Sugiyama D. Kogata Y. Tsuji G. Nakazawa T. Kawano S. et al.Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis.Ann Intern Med. 2007; 146: 797-808Crossref PubMed Google Scholar, 65England B.R. Thiele G.M. Mikuls T.R. Anticitrullinated protein antibodies: origin and role in the pathogenesis of rheumatoid arthritis.Curr Opin Rheumatol. 2017; 29: 57-64Crossref PubMed Scopus (10) Google Scholar Anti-CarPRA73Gan R.W. Trouw L.A. Shi J. Toes R.E. Huizinga T.W. Demoruelle M.K. et al.Anti-carbamylated protein antibodies are present prior to rheumatoid arthritis and are associated with its future diagnosis.J Rheumatol. 2015; 42: 572-579Crossref PubMed Scopus (48) Google Scholar, 74Vidal-Bralo L. Perez-Pampin E. Regueiro C. Montes A. Varela R. Boveda M.D. et al.Anti-carbamylated protein autoantibodies associated with mortality in Spanish rheumatoid arthritis patients.PLoS One. 2017; 12: e0180144Crossref PubMed Scopus (0) Google Scholar RA33RA60Steiner G. Smolen J. Autoantibodies in rheumatoid arthritis and their clinical significance.Arthritis Res. 2002; 4: S1-S5Crossref PubMed Google ScholarSystemic sclerosis Anti-centromereLimited cutaneous systemic sclerosisPAH83Denton C.P. Khanna D. Systemic sclerosis.Lancet. 2017; ([Epub ahead of print])Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 84Steen V.D. Autoantibodies in systemic sclerosis.Semin Arthritis Rheum. 2005; 35: 35-42Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 85Koenig M. Dieude M. Senecal J.L. Predictive value of antinuclear autoantibodies: the lessons of the systemic sclerosis autoantibodies.Autoimmun Rev. 2008; 7: 588-593Crossref PubMed Scopus (0) Google Scholar Scl70Diffuse cutaneous systemic sclerosisPulmonary fibrosisRenal crisis83Denton C.P. Khanna D. Systemic sclerosis.Lancet. 2017; ([Epub ahead of print])Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 84Steen V.D. Autoantibodies in systemic sclerosis.Semin Arthritis Rheum. 2005; 35: 35-42Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 85Koenig M. Dieude M. Senecal J.L. Predictive value of antinuclear autoantibodies: the lessons of the systemic sclerosis autoantibodies.Autoimmun Rev. 2008; 7: 588-593Crossref PubMed Scopus (0) Google Scholar Anti–RNAP IIIDiffuse cutaneous systemic sclerosisRenal crisis83Denton C.P. Khanna D. Systemic sclerosis.Lancet. 2017; ([Epub ahead of print])Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 86Moinzadeh P. Fonseca C. Hellmich M. Shah A.A. Chighizola C. Denton C.P. et al.Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma.Arthritis Res Ther. 2014; 16: R53Crossref PubMed Scopus (0) Google Scholar Anti-Th/ToLimited cutaneous systemic sclerosisPAHPulmonary fibrosis87Okano Y. Medsger Jr., T.A. Autoantibody to Th ribonucleoprotein (nucleolar 7-2 RNA protein particle) in patients with systemic sclerosis.Arthritis Rheum. 1990; 33: 1822-1828Crossref PubMed Scopus (0) Google ScholarANCA-associated vasculitis Anti-PR3 ANCAGPAMPA, EGPA109Kallenberg C.G. Key advances in the clinical approach to ANCA-associated vasculitis.Nat Rev Rheumatol. 2014; 10: 484-493Crossref PubMed Scopus (57) Google Scholar, 110Franssen C.F. Stegeman C.A. Kallenberg C.G. Gans R.O. De Jong P.E. Hoorntje S.J. et al.Antiproteinase 3- and antimyeloperoxidase-associated vasculitis.Kidney Int. 2000; 57: 2195-2206Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar Anti-MPO ANCAMicroscopic polyangiitisEGPAGPA109Kallenberg C.G. Key advances in the clinical approach to ANCA-associated vasculitis.Nat Rev Rheumatol. 2014; 10: 484-493Crossref PubMed Scopus (57) Google Scholar, 110Franssen C.F. Stegeman C.A. Kallenberg C.G. Gans R.O. De Jong P.E. Hoorntje S.J. et al.Antiproteinase 3- and antimyeloperoxidase-associated vasculitis.Kidney Int. 2000; 57: 2195-2206Abstract Full Text Full Text PDF PubMed Scopus (157) Google ScholarAnti-CarP, Anti-carbamylated protein antibodies; PR3, proteinase 3; RNP, ribonuclear protein. Open table in a new tab Anti-CarP, Anti-carbamylated protein antibodies; PR3, proteinase 3; RNP, ribonuclear protein. ANAs are a hallmark of SLE. Nearly all patients with SLE exhibit ANAs at diagnosis, with a 1:80 immunofluorescent titer showing up to 98% sensitivity but 75% specificity for SLE classification.16Leuchten N. Hoyer A. Brinks R. Schoels M. Schneider M. Smolen J. et al.Performance of anti-nuclear antibodies for classifying systemic lupus erythematosus: a systematic literature review and meta-regression of diagnostic data.Arthritis Care Res (Hoboken). 2017; ([Epub ahead of print])PubMed Google Scholar ANAs are also found in patients with many other autoimmune diseases, malignancies, or hepatic diseases; unaffected family members of patients with lupus; and even up to 14% of healthy subjects,17Satoh M. Chan E.K. Ho L.A. Rose K.M. Parks C.G. Cohn R.D. et al.Prevalence and sociodemographic correlates of antinuclear antibodies in the United States.Arthritis Rheum. 2012; 64: 2319-2327Crossref PubMed Scopus (120) Google Scholar especially with increasing age. Therefore a positive ANA value serves as a necessary but insufficient criterion for SLE classification or diagnosis but not as a definitive test.18Tedeschi S.K. Johnson S.R. Boumpas D. Daikh D. Dorner T. Jayne D. et al.Developing and refining new candidate criteria for SLE classification: an international collaboration.Arthritis Care Res (Hoboken). 2017; ([Epub ahead of print])Crossref Google Scholar Patients with a negative ANA test result are extremely unlikely to have any lupus-specific autoantibodies. Therefore through the Choosing Wisely campaign, the American College of Rheumatology (ACR) recommends testing for specific autoantibodies only when a positive ANA level and clinical suspicion are present.19Yazdany J. Schmajuk G. Robbins M. Daikh D. Beall A. Yelin E. et al.Choosing wisely: the American College of Rheumatology's Top 5 list of things physicians and patients should question.Arthritis Care Res (Hoboken). 2013; 65: 329-339Crossref PubMed Scopus (0) Google Scholar Repeat testing is not indicated in subjects with positive ANA results because changes in ANA titers alone show no clinical correlation with increased disease activity or worsening prognosis. Testing of ANAs and other autoantibodies in preclinical disease states or to identify subjects for potential preventive interventions will require additional studies and guidelines.20Fritzler M.J. Choosing wisely: Review and commentary on anti-nuclear antibody (ANA) testing.Autoimmun Rev. 2016; 15: 272-280Crossref PubMed Scopus (12) Google Scholar Anti–double-stranded DNA (anti-dsDNA) antibody responses have high specificity (92% to 96%) and moderate sensitivity (57% to 67%) for SLE.21Cozzani E. Drosera M. Gasparini G. Parodi A. Serology of lupus erythematosus: correlation between immunopathological features and clinical aspects.Autoimmune Dis. 2014; 2014: 321359PubMed Google Scholar They constitute a criterion for SLE classification by ACR criteria (requiring 4/11 criteria for classification) and by the Systemic Lupus International Collaborating Clinics criteria (requiring 4/17 criteria or dsDNA plus biopsy-proven lupus nephritis [LN]).22Tan E.M. Cohen A.S. Fries J.F. Masi A.T. McShane D.J. Rothfield N.F. et al.The 1982 revised criteria for the classification of systemic lupus erythematosus.Arthritis Rheum. 1982; 25: 1271-1277Crossref PubMed Scopus (11272) Google Scholar, 23Hochberg M.C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.Arthritis Rheum. 1997; 40: 1725Crossref PubMed Google Scholar, 24Petri M. Orbai A.M. Alarcon G.S. Gordon C. Merrill J.T. Fortin P.R. et al.Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.Arthritis Rheum. 2012; 64: 2677-2686Crossref PubMed Scopus (959) Google Scholar Anti-dsDNA forms immune complexes with nucleosomes observed in patients with SLE, leading to immune complex deposition in the kidney.25Bardana Jr., E.J. Harbeck R.J. Hoffman A.A. Pirofsky B. Carr R.I. The prognostic and therapeutic implications of DNA:anti-DNA immune complexes in systemic lupus erythematosus (SLE).Am J Med. 1975; 59: 515-522Abstract Full Text PDF PubMed Google Scholar Furthermore, anti-dsDNA antibodies show cross-reactivity to α-actinin and can bind to mesangial cells in the kidney.26Zhao Z. Weinstein E. Tuzova M. Davidson A. Mundel P. Marambio P. et al.Cross-reactivity of human lupus anti-DNA antibodies with alpha-actinin and nephritogenic potential.Arthritis Rheum. 2005; 52: 522-530Crossref PubMed Scopus (0) Google Scholar Immune complexes formed by anti-dsDNA antibodies in the kidney can activate the complement cascade, leading to damage in patients with glomerulonephritis.27Hahn B.H. Antibodies to DNA.N Engl J Med. 1998; 338: 1359-1368Crossref PubMed Scopus (518) Google Scholar Patients with proliferative LN have increased anti-dsDNA as early as 4 years before diagnosis, and an increase of greater than 1 IU/mL/y was specific for LN.28Olson S.W. Lee J.J. Prince L.K. Baker T.P. Papadopoulos P. Edison J. et al.Elevated subclinical double-stranded DNA antibodies and future proliferative lupus nephritis.Clin J Am Soc Nephrol. 2013; 8: 1702-1708Crossref PubMed Scopus (11) Google Scholar Anti-dsDNA with low complement levels also associates with mucocutaneous, renal, and hematologic flare within 1 year.29Petri M. Singh S. Tesfasyone H. Malik A. Prevalence of flare and influence of demographic and serologic factors on flare risk in systemic lupus erythematosus: a prospective study.J Rheumatol. 2009; 36: 2476-2480Crossref PubMed Scopus (25) Google Scholar In patients with clinically stable SLE and increasing levels of anti-dsDNA (≥25%) and C3a (≥50%), the free released product of complement activation, treatment with moderate prednisone can avert severe clinical flares.30Tseng C.E. Buyon J.P. Kim M. Belmont H.M. Mackay M. Diamond B. et al.The effect of moderate-dose corticosteroids in preventing severe flares in patients with serologically active, but clinically stable, systemic lupus erythematosus: findings of a prospective, randomized, double-blind, placebo-controlled trial.Arthritis Rheum. 2006; 54: 3623-3632Crossref PubMed Scopus (0) Google Scholar Although less common (sensitivity, 26% to 31%) antibodies against the Sm antigen are highly specific (95% to 99%) for SLE and can associate with early mortality.31Migliorini P. Baldini C. Rocchi V. Bombardieri S. Anti-Sm and anti-RNP antibodies.Autoimmunity. 2005; 38: 47-54Crossref PubMed Scopus (0) Google Scholar About 30% to 70% of patients with SLE have anti-Ro/Sjögren syndrome type A antigen (SSA), and Ro/SSA is associated with subacute lupus erythematosus, sicca symptoms, and secondary Sjögren syndrome. Anti-Ro/SSA antibodies can bind to either of 2 antigenic proteins: 52-kDa and 60-kDa Ro. Antibodies to 60-kDa Ro/SSA are more frequently observed in patients with SLE and correlate with photosensitivity, cutaneous vasculitis, and hematologic disorders.32Yoshimi R. Ueda A. Ozato K. Ishigatsubo Y. Clinical and pathological roles of Ro/SSA autoantibody system.Clin Dev Immunol. 2012; 2012: 606195Crossref PubMed Scopus (0) Google Scholar Antibodies to a related antigen, La/SSB, are present in approximately 10% of patients with SLE and associated with lower prevalence of renal disease.32Yoshimi R. Ueda A. Ozato K. Ishigatsubo Y. Clinical and pathological roles of Ro/SSA autoantibody system.Clin Dev Immunol. 2012; 2012: 606195Crossref PubMed Scopus (0) Google Scholar Anti-ribosomal P antibodies, similar to anti-Sm antibodies, are very specific for SLE but occur in only approximately 20% of white patients with SLE. Anti-ribosomal P is enriched in neuropsychiatric33Briani C. Lucchetta M. Ghirardello A. Toffanin E. Zampieri S. Ruggero S. et al.Neurolupus is associated with anti-ribosomal P protein antibodies: an inception cohort study.J Autoimmun. 2009; 32: 79-84Crossref PubMed Scopus (0) Google Scholar and pediatric-onset disease.34Valoes C.C. Molinari B.C. Pitta A.C. Gormezano N.W. Farhat S.C. Kozu K. et al.Anti-ribosomal P antibody: a multicenter study in childhood-onset systemic lupus erythematosus patients.Lupus. 2017; 26: 484-489Crossref PubMed Scopus (0) Google Scholar A number of other autoreactivities have been reported in patients with SLE.21Cozzani E. Drosera M. Gasparini G. Parodi A. Serology of lupus erythematosus: correlation between immunopathological features and clinical aspects.Autoimmune Dis. 2014; 2014: 321359PubMed Google Scholar Of interest are anti-nucleosome responses, which correlate with disease activity in clinically quiescent patients,35Ng K.P. Manson J.J. Rahman A. Isenberg D.A. Association of antinucleosome antibodies with disease flare in serologically active clinically quiescent patients with systemic lupus erythematosus.Arthritis Rheum. 2006; 55: 900-904Crossref PubMed Scopus (70) Google Scholar and anti-cardiolipin responses, which are implicated in thrombosis and recurrent fetal loss and are associated with a complex clinical outcome, with patients meeting a higher number of ACR criteria.10McClain M.T. Arbuckle M.R. Heinlen L.D. Dennis G.J. Roebuck J. Rubertone M.V. et al.The prevalence, onset, and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus.Arthritis Rheum. 2004; 50: 1226-1232Crossref PubMed Scopus (0) Google Scholar Because no single autospecificity is sufficient for SLE diagnosis, recent efforts have focused on detecting autoantibody signatures encompassing combinations of autoreactivities. One autoantigen array covers antigens related to 8 distinct autoimmune diseases.36Robinson W.H. DiGennaro C. Hueber W. Haab B.B. Kamachi M. Dean E.J. et
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