Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects

This completely updated and expanded 2nd edition of Systemic Lupus Erythematosus, A Manual includes topics not covered previously with contributors who are at the forefront of each specific topic and with a global appeal. Each chapter is short and is presented critically with selected references, which should be valuable to a wider audience. This book combines basic with clinical science to help internists and specialists in the diagnosis and management of patients with SLE. It is a quick referral for people in the pharmaceutical industry in their efforts to bring much-needed drugs. It provides all the needed information to basic researchers old and new alike, who wish to enter the field of lupus and systemic autoimmunity in general.

• Focused state-of-the-art chapters prepared by top-notch experts in the field
• Latest understanding of cellular, molecular, biochemical aspects of disease pathogenesis
• Advanced aspects of genetic, microbiome, environmental, hormonal, and immunological contribution to the expression of the disease
• Current understanding of clinical features of the disease
• Recent efforts to develop new treatments

• Language: English
• Publisher: Academic Press
• Release date: Apr 7, 2020
• ISBN: 9780128145524

Book preview

Systemic Lupus Erythematosus

Basic, Applied and Clinical Aspects

Second Edition

Edited by

George C. Tsokos

Professor of Medicine, Harvard Medical School, and Chief, Rheumatology Division, Beth Israel Deaconess Medical Center, Boston, MA, United States

Contents

Cover

Title page

Copyright

Dedication

Contributors

Introduction

Introduction to the second edition

Part I: Epidemiology and diagnosis

Chapter 1: History of systemic lupus erythematosus with an emphasis on certain recent major issues

Abstract

History of clinical observations

History of laboratory investigations

History of genetics of SLE

History of therapy in SLE with an emphasis on the use of steroids

History of classification criteria for SLE

Chapter 2: The patient

Abstract

Improve the interactions with your patients

Improving adherence

Disability

Patient education

The lupus secrets

Chapter 3: A plea of a young patient to the lupus experts

Chapter 4: Epidemiology

Abstract

Introduction

Incidence and prevalence

Factors that affect the course of SLE

Chapter 5: Measuring disease activity

Abstract

Chapter 6: Disease development and outcome

Abstract

Historical perspective

Clinical manifestations

Assessment of disease activity

Disease damage

Patient reported outcomes

Mortality

Causes of death

Treatment guidelines and quality indicators

Conclusions

Chapter 7: Socioeconomic aspects of SLE

Abstract

Introduction

Sociodemographic determinants of health in SLE

Healthcare access and utilization

The economic burden of SLE

Conclusion

Chapter 8: Biomarkers in systemic lupus erythematosus

Abstract

Introduction

Biomarkers for diagnosis of SLE

Biomarkers for measuring SLE disease activity

Biomarkers to detect specific organ involvement

Conclusions

Part II: Pathogenesis

Chapter 9: Overview of the pathogenesis of systemic lupus erythematosus

Abstract

Genetics

Epigenetics

Gender

Environment

Immune dysregulation

Tissue damage

Conclusions

Chapter 10: System lupus erythematosus and the environment

Abstract

Introduction

Infectious agents, dysbiosis the microbiome, and SLE

Cigarette smoking, alcohol and SLE

Cosmetics, chemicals, and risk of SLE

Ultraviolet radiation, vitamin D, and SLE

Drugs, vaccines, and SLE

Geography, socioeconomics, and SLE

Conclusion

Chapter 11: Genes and genetics in human SLE

Abstract

Introduction

Transcription factors

Clearance of apoptotic cells and immune complexes

Autophagy

Type I IFN pathway

NFκB pathway

Neutrophils and NETosis

T cell signaling

B cell signaling

Genes and phenotypes

SLE risk genes as therapeutic targets

Drug repositioning and predicting clinical outcomes

Conclusions

Chapter 12: Monogenic lupus

Abstract

Introduction

Complement deficiency

Deficiencies in DNA damage repair and clearance

Abnormalities of DNA sensing

Other interferonopathies

Apoptosis

Cell signaling

Implications for SLE as a whole

Conclusion

Chapter 13: Hormones

Abstract

Sex hormones

Estrogen-estrogen receptor signaling

Innate immune response

Adaptive immune response

Estrogen and SLE

Other hormones

Hormone therapy

Conclusions

Chapter 14: Clinical aspects of the complement system in systemic lupus erythematosus

Abstract

Introduction

Complement testing and its interpretation

New connections for lupus and complement

Conclusions

Chapter 15: T cells

Abstract

Mechanisms through which T Cells promote SLE

Chapter 16: B cells in SLE

Abstract

Introduction

B lineage cell abnormalities in SLE indicating disturbances of B cell differentiation

Functional abnormalities of SLE B lineage cells

B cell signaling in post-activated B cells in SLE

Conclusions

Chapter 17: Neutrophils in systemic lupus erythematosus

Abstract

Introduction

Neutrophil dysfunction in SLE

NETosis in the pathogenesis of SLE

Low-density granulocytes (LDGs) in SLE

DNA methylation changes in SLE neutrophils and LDGs

Conclusion

Chapter 18: The role of dendritic cells in systemic lupus erythematosus

Abstract

Dendritic cell origins, subsets, and functions

DCs and SLE

Amplifying mechanisms promoting IFN-α secretion in SLE and activation of DCs

Overall picture of DC implication in SLE pathogenesis

Chapter 19: Cytokines

Abstract

Cytokines in SLE

Conclusions

Chapter 20: RNA/DNA sensing in SLE—Toll-like receptors and beyond

Abstract

Introduction

Toll-like receptor family (TLRs)

Toll-like receptor 7 (TLR7)

Toll-like receptor 8 (TLR8)

Toll-like receptor 9 (TLR9)

Cytosolic RNA and DNA sensors

Conclusions

Chapter 21: The role of interferons in systemic lupus erythematosus

Abstract

Introduction

The interferon families

Regulation of interferon production

Interferons and the immune system

Interferons in systemic lupus erythematosus

Conclusion

Chapter 22: Fcγ receptors in autoimmunity and end-organ damage

Abstract

Introduction

FcγRs structure

IgG and FcγR interactions

FcγRs and complement

Activating and inhibitory FcγR signaling

Regulation of FcγR affinity for ligand

Roles of FcγR in SLE

FcγR-mediated leukocyte recruitment

Activation of immune cell effector functions

Roles of FcγRs in lupus nephritis pathogenesis

FcγR polymorphisms and copy number variation in lupus

Future directions

Chapter 23: Apoptosis, autophagy, and necrosis

Abstract

Definition

Apoptosis

Autophagy

Necrosis

Chapter 24: Infections in early systemic lupus erythematosus pathogenesis

Abstract

Introduction

Pathogens associated with lupus autoimmunity and clinical disease

Epstein–Barr virus as a model infection in the etiology of SLE

Pathogen exposures that may protect against lupus autoimmunity

Conclusion

Acknowledgements

Chapter 25: Microbiota influences on systemic lupus erythematosus and Sjögren’s syndrome

Abstract

Introduction

Microbiota in mouse models of SLE and pSS

Human host-microbiome studies in SLE and pSS

Conclusions/Outlook

Chapter 26: Origin of autoantibodies

Abstract

B cell tolerance in SLE

Altered BCR signaling in lupus

Properties of lupus autoantibodies

GC versus extrafollicular origin of autoantibodies

Role of TLR signaling

Intracellular accumulation nucleic acids promotes autoantibody production

How does IFN-I promote autoantibody production?

Association of autoantibodies with abnormal clearance of apoptotic cells

Chapter 27: Anti-DNA antibodies

Abstract

Introduction

Cellular source of anti-DNA antibodies

Contribution of antigen selection

Triggers: chromatin and environmental exposures

Mechanisms of injury in the kidney and brain

Immune complexes and myeloid cell activation

Summary

Chapter 28: Antihistone and antispliceosome antibodies

Abstract

Histones are key protein components of chromatin

Anti-histone antibodies

Assays for anti-histone antibodies

Solid phase assays for anti-histone antibodies

Problems and discrepancies in measuring anti-histone antibodies

Prevalence and disease association of anti-histone and anti-nucleosome antibodies

Anti-histone in SLE

Anti-histone in drug-induced lupus

Anti-snRNP antibodies

Cellular localization and function of snRNP

Reactivity of anti-snRNPs autoantibodies

History of detection of autoantibodies to snRNPs and potential problems

Detection of antibodies to snRNPs in clinical practice

Clinical significance of antibodies to snRNPs

Other anti-snRNPs antibodies

Mechanism of production

Chapter 29: Immune complexes in systemic lupus erythematosus

Abstract

Introduction

Basic immunochemistry of ICs

Generation of autoantibodies and ICs in SLE

IFN-α production from pDCs induced by ICs through TLRs

Vicious cycle between NETs and ICs

FcγRs and clearance of ICs

Role of FcγRs and ICs in each hematopoietic cell in SLE

Complement activation by ICs

Clearance of ICs by complement

Depositions of ICs in lupus nephritis

Detection of ICs in the tissue and serum

Treatment for SLE based on ICs

Summary

Chapter 30: MicroRNA in systemic lupus erythematosus

Abstract

Introduction

The biology of miRNAs

Role of miRNAs in SLE

MiRNAs in target tissues of SLE

Conclusion

Chapter 31: Metabolic control of lupus pathogenesis: central role for activation of the mechanistic target of rapamycin

Abstract

Introduction

Accumulation of dysfunctional mitochondria is the source of oxidative stress in T cells

Extramitochondrial generation of oxidative stress

Oxidative stress emanates from the liver in SLE

Oxidative stress due to diminished reducing power

Biomarkers of oxidative stress reflect disease activity in SLE

Oxidative stress is a target for treatment in SLE

NAC-responsive accumulation of kynurenine is a trigger of mTOR pathway activation in SLE

Acknowledgments

Chapter 32: Epigenetics

Abstract

Introduction

DNA methylation in T Cells from SLE patients

DNA hydroxymethylation

Histone modifications

MicroRNAs in SLE

Molecular mechanisms of pathological epigenetic pemodeling in SLE

Epigenetic modification as promising targets for future treatment

Conclusions

Chapter 33: What do mouse models teach us about human SLE?

Abstract

Commonly used murine lupus models

Conditional knockout system of lupus models helps delineate the cell-intrinsic mechanisms of autoimmunity and lupus development

Murine lupus strains constitute excellent models for defining the genetic architecture of SLE

Mouse models help validate GWAS-identified lupus risk alleles

The contribution of antiDNA autoantibodies

The pathogenic role of leukocytes in lupus

Multiple cytokines and chemokines also contribute to lupus pathogenesis

Lessons from therapeutic studies in murine lupus models

Concluding thoughts

Chapter 34: Genes and genetics of murine systemic lupus erythematosus

Abstract

Introduction

Mouse models of lupus used in genetic studies

Predisposing loci and genes in natural-occurring lupus models

Lupus predisposing variants that promote lupus in nonautoimmune mice

Genes affecting susceptibility to end-organ pathology

Susceptibility genes affect several key stages in lupus pathogenesis

Comparison with human SLE genes

Conclusion

Acknowledgment

Part III: Mechanisms of tissue damage

Chapter 35: Mechanisms of renal damage in systemic lupus erythematosus

Abstract

Introduction

Kidney disease in lupus is not always lupus nephritis

Regeneration and fibrosis are keys to recovery from LN.

Concluding remarks

Acknowledgements

Chapter 36: Mechanisms of vascular damage in systemic lupus erythematosus

Abstract

Epidemiology of vascular damage in systemic lupus erythematosus

Risk of vascular damage: traditional versus nontraditional factors

Role of cytokines in vascular damage in SLE

Autoantibodies and immune complexes

Cellular mediators

Chapter 37: The mechanism of skin damage

Abstract

Introduction

Clinical aspects

Pathogenesis of skin damage

Chapter 38: Pathogenesis of tissue injury in the brain in patients with systemic lupus erythematosus

Abstract

The challenge of neurolupus

Models of neurolupus

Genetics of brain disease

The pathological substrates of lupus brain disease

Mechanisms of accelerated cerebrovascular disease

Antibody-mediated brain disease in lupus: antineuronal antibodies

Antibody-mediated brain disease in lupus: anti glial antibodies

Cytokine pathways: Type I interferon

Other cytokines pathways

Inflammatory cells

Part IV: Clinical aspects of the disease

Chapter 39: Constitutional symptoms and fatigue in systemic lupus erythematosus

Abstract

Introduction

Fatigue

Fever

Lymphadenopathy

Splenomegaly

Weight loss

Conclusion

Chapter 40: The musculoskeletal system in SLE

Abstract

Arthritis

Myalgia/myopathy/myositis

Osteonecrosis

Osteoporosis

Chapter 41: Cutaneous lupus erythematosus

Abstract

Epidemiology

Classification criteria for SLE

Photosensitivity

Cutaneous manifestations

Scores in cutaneous lupus erythematosus

Subtypes of cutaneous lupus erythematosus

Conclusion

Acknowledgment

Chapter 42: The clinical evaluation of kidney disease in systemic lupus erythematosus

Abstract

Introduction

The scope of lupus nephritis

The diagnosis of lupus nephritis

Evaluation of kidney function

Evaluation of the urine

Evaluation of proteinuria

The kidney biopsy

Antiphospholipid syndrome and the kidney

Pregnancy and lupus nephritis

Childhood lupus nephritis

Conclusion

Chapter 43: The pathology of lupus nephritis

Abstract

Introduction

Introduction to nephropathology

Introduction to the nephropathology of SLE

Renal biopsy and SLE

The lesions of lupus nephritis

Classification of lupus nephritis

Selected topics in classification

Selected clinco-pathologic topics

Chapter 44: Cardiovascular disease in systemic lupus erythematosus: an update

Abstract

Burden of cardiovascular disease in lupus

Traditional risk factors for cardiovascular disease in SLE

SLE-specific risk factors for cardiovascular disease

Atherogenesis

Biomarkers for atherosclerosis

Imaging strategies for early detection of cardiovascular disease

Treatment of cardiovascular disease in SLE

Summary

Chapter 45: The lung in systemic lupus erythematosus

Abstract

Introduction

Role of inflammation in SLE lung

Clinical presentations of lung involvement in SLE

Parenchymal disease

Pulmonary vascular disease

Overlap syndromes

COPA syndrome and SAVI: Interferonopathies with lung involvement

A case for screening for Lung Disease In SLE

Summary

Acknowledgment

Chapter 46: Gastrointestinal, hepatic, and pancreatic disorders in systemic lupus erythematosus

Abstract

Introduction

The gastrointestinal tract in SLE

The liver in SLE

Biliary tract disease in SLE

The pancreas in SLE

Acute abdominal pain in SLE

Intestinal microbiome in SLE

Conclusions

Chapter 47: Systemic lupus erythematosus and infections

Abstract

Introduction

Epidemiology of SLE infections

Immunologic pathogenesis of infections in systemic lupus erythematosus

Treatment-associated immunosuppression and infection risk

Types of infections

Preventative strategies

Chapter 48: Malignancies in systemic lupus erythematosus

Abstract

Introduction

Hematologic cancers

Lung cancers

Cervical cancer

Breast, ovarian, and endometrial cancers

Conclusions

Chapter 49: The nervous system in systemic lupus erythematosus

Abstract

Introduction

Classification of neurolupus

Mechanisms of neurolupus

Clinical approach

Investigations

Central nervous system disease in people with lupus

Peripheral nervous system disease in people with lupus

Questionable clinical syndromes

Treatment of neurolupus

Conclusion

Chapter 50: Overlap syndromes

Abstract

Introduction

Clinical and laboratory manifestations of overlap syndromes

Immunology of overlap syndromes

Genetics

Animal models

Treatment

Chapter 51: Systemic lupus erythematosus and the eye

Abstract

Introduction

The role of ophthalmic features in the criteria for classification and disease activity

Clinical presentation

Investigations

Treatment

Conclusion

Chapter 52: Fertility and pregnancy in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus—A manual

Fertility and SLE

Pregnancy in SLE patients

Management of SLE during pregnancy

Conclusions

Chapter 53: Neonatal lupus: Clinical spectrum, biomarkers, pathogenesis, and approach to treatment

Abstract

Introduction

Risk of cardiac NL and population prevalence

Transient clinical manifestations of NL: cutaneous, hepatic, hematologic, and neurologic

Immutable manifestations of NL: cardiac

Factors contributing to mortality

Seeking biomarkers: the candidate autoantibodies

Linking antibody to tissue damage and fibrosis: accounting for antigen target accessibility

Guidelines for monitoring antiSSA/ Ro-exposed pregnancies and approach to cardiac NL

Translating pathogenesis to prevention

Chapter 54: Incomplete lupus syndromes

Abstract

Definition

Significance

Epidemiology

Clinical manifestations

Transition to SLE

Treatment

Chapter 55: Lupus in children

Abstract

Epidemiology

Clinical manifestations

Familial SLE

Morbidity and mortality

Therapeutic considerations in children

Chapter 56: Drug-induced lupus

Abstract

Introduction and historical perspective

Diagnosis of drug-induced lupus

Lupus-inducing drugs with specific clinical features

Distinguishing DIL from idiopathic SLE

Treatment and management of DIL

Lupus-inducing drugs

The expanding breadth of lupus-inducing drugs

Epidemiology of DIL

Genetic factors in DIL

Drug metabolism in the etiology of DIL

Pathogenesis of DIL

Proposed mechanisms underlying DIL

Conclusions

Chapter 57: Vasculitis in lupus

Abstract

Prevalence and associated features of vasculitis in lupus

Cutaneous vasculitis

Lupus mesenteric vasculitis

Large vessel vasculitis

Other forms of vasculitis

Part V: Antiphospholipid Syndrome

Chapter 58: Pathogenesis of antiphospholipid syndrome

Abstract

Introduction

Pathogenic mechanisms of aPL

Cell receptors for aPL interaction

Signaling pathways of aPL-mediated cell activation

aPL and atherothrombosis

aPL and oxidative stress

aPL and complement activation

Conclusion

Acknowledgment

Chapter 59: Antibodies and diagnostic tests in antiphosholipid syndrome

Abstract

Antiphospholipid syndrome as an autoantibody–mediated disease

Classification laboratory assays

Nonclassification laboratory assays

Other autoantibodies in antiphospholipid syndrome

3-Anti-endothelial cell antibodies

Complement activation

Chapter 60: Clinical manifestations

Abstract

Introduction

Features associated with aPL

Part VI: Treatment of the disease

Chapter 61: Nonsteroidal antiinflammatory drugs in systemic lupus erythematosus

Abstract

Introduction

Inhibitory role of NSAIDs

Effects on the kidneys

Gastrointestinal side effects

Increased cardiovascular risk: What is the Verdict?

Central nervous system (aseptic meningitis) side effects

Effects on reproduction

Conclusion

Chapter 62: Value of antimalarial drugs in the treatment of lupus

Abstract

Introduction

Pharmacokinetics and pharmacodynamics of antimalarials

Mechanisms of action

The beneficial effects of antimalarials in SLE

Practical aspects related to the use of antimalarials

Screening for glucose-6-phosphate dehydrogenase deficiency

Nonophthalmologic adverse effects of antimalarial agents

Ophthalmologic adverse effects of antimalarial agents

Use of antimalarials in pregnancy and lactation

Chapter 63: Systemic glucocorticoids

Abstract

Introduction

Nomenclature

Rationale and mechanism of action of glucocorticoids in SLE

Forms and mode of administration of systemic corticosteroids

Approach for the use of glucocorticoids based on organ system involvement

Tapering and withdrawal of glucocorticoids

Side effects of glucocorticoids

Future direction

Chapter 64: Cytotoxic drug treatment

Abstract

Introduction

Alkylating agents

Nucleotide synthesis inhibitors

Calcineurin inhibitors

General issues in lupus patients on cytotoxic- immunosuppressive drug treatment

Chapter 65: Treatment of antiphospholipid syndrome

Abstract

Introduction

Primary thromboprophylaxis

Prevention of recurrent thrombosis

Alternative therapies for refractory and difficult cases

Other therapies

Pregnancy

Recurrent early miscarriage

Fetal death

Management of pregnancy in patients with APS and previous thrombosis

Management of refractory obstetric APS

Postpartum period

Chapter 66: New treatments of systemic lupus erythematosus

Abstract

Cytokines

Complement

Costimulatory pathways

Cell surface molecules

Intracellular molecules

Conclusion

Chapter 67: Repositioning drugs for systemic lupus erythematosus

Abstract

Why try to repurpose/reposition drugs for SLE patients?

Strategies for drug repurposing/repositioning in SLE

Current and future repurposing/repositioning efforts

Summary

Index

Copyright

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Dedication

To patients, physicians, and researchers who fight lupus from dawn to dusk.

Contributors

Nancy Agmon-Levin

Clinical Immunology, Angioedema and Allergy Unit, The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Tel Aviv

The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel

Graciela S. Alarcón

Department of Medicine, Division of Clinical Immunology and Rheumatology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States

Department of Medicina, School of Medicine, Cayetano Heredia Peruvian University, Lima, Peru

Olga Amengual,     Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

Stacy P. Ardoin,     Ohio State University, Columbus, OH, United States

Swati Arora,     Division of Nephrology, Allegheny Health Network, Pittsburgh, PA, United States

Yemil Atisha-Fregoso,     Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States

John P. Atkinson,     Washington University School of Medicine, Department of Medicine, Division of Rheumatology, St. Louis, MO, United States

Tatsuya Atsumi,     Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

Isabelle Ayoub,     Division of Nephrology, Ohio State University Wexner Medical Center, Columbus, OH, United States

Maria-Louise Barilla-LaBarca,     Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States

Bonnie L. Bermas,     UTSouthwestern Medical Center, Dallas, TX, United States

Sasha Bernatsky,     Divisions of Rheumatology and Clinical Epidemiology, Department of Medicine, McGill University, Montreal, QC, Canada

George Bertsias,     Rheumatology, Clinical Immunology and Allergy, Medical School, University of Crete, Heraklion, Greece

Tanmayee Bichile,     Department of Medicine, Medicine and Autoimmunity Institute, Allegheny Health Network, Pittsburgh, PA, United States

Patrick Blanco,     Laboratoire d’Immunologie et Immunogénétique, FHU ACRONIM, Hôpital Pellegrin, Centre Hospitalier Universitaire, CNRS-UMR 5164, ImmunoConcEpt, Université de Bordeaux, Bordeaux, France

Miyuki Bohgaki

NTT Sapporo Medical Center, Sapporo Hokkaido

Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo Hokkaido, Japan

Gisela Bonsmann,     Department of Dermatology, University of Muenster, Muenster, Germany

Maria Orietta Borghi

Immunology Research Laboratory, IRCCS Istituto Auxologico Italiano, Milan

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

Dimitrios T. Boumpas,     Rheumatology and Clinical Immunology, 4th Department of Medicine, Medical School, University of Athens and Biomedical Research Foundation of the Academy of Athens, Athens, Greece

Rebecka Bourn,     Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States

Jill P. Buyon,     Division of Rheumatology, New York University School of Medicine, New York City, NY, United States

Roberto Caricchio,     Department of Medicine, Section of Rheumatology; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States

Edward K.L. Chan,     Department of Oral Biology, University of Florida, Gainesville, FL, United States

Christopher Chang,     Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, United States

Manon Charrier,     Service de néphrologie, Hôpital Pellegrin, Centre Hospitalier Universitaire, Université de Bordeaux, Bordeaux, France

Cecilia Beatrice Chighizola,     Immunology Research Laboratory, IRCCS Istituto Auxologico Italiano, Milan, Italy

Ann E. Clarke,     Division of Rheumatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

José C. Crispín,     Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

Bettina Cuneo,     Department of Pediatrics and Obstetrics, University of Colorado School of Medicine, Aurora, CO, United States

Thomas Dörner

Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany

German Rheumatism Research Center Berlin, Leibniz Institute, Berlin, Germany

Erika M. Damato,     Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom

Alastair K.O. Denniston

Academic Unit of Ophthalmology, University of Birmingham, Birmingham

Department of Ophthalmology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom

Amy Devlin,     Tufts Medical Center & Beth Israel Deaconess Medical Center, Division of Rheumatology, Boston, MA, United States

Betty Diamond,     Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States

T. Ernandez,     Service of Nephrology, University Hospital of Geneva, Switzerland

Titilola Falasinnu,     Department of Epidemiology and Population Health, Stanford Medicine, Stanford, CA, United States

Ruth Fernandez-Ruiz,     Colton Center for Autoimmunity and Division of Rheumatology, NYU School of Medicine, New York, NY, United States

Brianna Fitzpatrick,     Lupus Research Alliance Young Leaders Board

Lindsy Forbess,     Division of Rheumatology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, United States

Eleni A. Frangou,     Department of Nephrology, Limassol General Hospital, Limassol Cyprus; Medical School, University of Cyprus, Nicosia, Cyprus; Biomedical Research Foundation of the Academy of Athens, Athens, Greece

Marvin J. Fritzler,     Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

Shu Man Fu

Division of Rheumatology, Department of Medicine, University of Virginia, Charlottesville VA

Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, Charlottesville, VA

Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, United States

Richard Furie,     Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States

Felicia Gaskin,     Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, United States

Dafna Gladman,     University of Toronto, Toronto, ON, Canada

Caroline Gordon,     Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom

Amrie C. Grammer,     AMPEL BioSolutions and RILITE Research Institute, Charlottesville, VA, United States

Eric L. Greidinger,     Division of Rheumatology, Miami VAMC, University of Miami Miller School of Medicine, Miami, FL, United States

Teri M. Greiling,     Oregon Health & Science University, Portland, OR, United States

Shuhong Han,     Division of Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL, United States

James E. Hansen,     Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, United States

Sarfaraz A. Hasni,     National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States

Fadi Hassan,     Department of Internal Medicine E, Galilee Medical Center, Nahariya, Israel

Christian M. Hedrich,     Department of Women’s and Children’s Health, Institute of Translational Medicine, University of Liverpool, Liverpool; Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust Hospital, Liverpool; Institute in the Park, Alder Hey Children’s NHS Foundation Trust Hospital, Liverpool, United Kingdom

Keiju Hiromura,     Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

Diane Horowitz,     Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States

Xin Huang,     Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China

David Hunt,     Anne Rowling Neuroinflammation Clinic, University of Edinburgh, Edinburgh, United Kingdom

Peter M. Izmirly,     Division of Rheumatology, New York University School of Medicine, New York City, NY, United States

Judith A. James

Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK

Departments of Medicine and Pathology, Oklahoma Clinical and Translational Science Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

Wael N. Jarjour,     Ohio State University, Columbus, OH, United States

Caroline A. Jefferies,     Division of Rheumatology, Department of Medicine, Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, United States

Caroline Jefferies

Division of Rheumatology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA

Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, United States

Xiaoyue Jiang,     Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Mariana J. Kaplan,     National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States

Takayuki Katsuyama,     Division of Rheumatology and Clinical Immunology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Munther Khamashta,     Consultant Physician, London Lupus Centre, London Bridge Hospital, London, United Kingdom

Kathryn M. Kingsmore,     AMPEL BioSolutions and RILITE Research Institute, Charlottesville, VA, United States

Takao Koike

Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo Hokkaido

Hokkaido Medical Center for Rheumatic Diseases, Sapporo Hokkaido, Japan

Dwight H. Kono,     Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States

Martin A. Kriegel,     Yale School of Medicine, New Haven, CT, United States

Annegret Kuhn

Interdisciplinary Center for Clinical Trials (IZKS), University Medical Center Mainz, Mainz

Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany

Vasileios C Kyttaris,     Beth Israel Deaconess Medical Center, Division of Rheumatology, Harvard Medical School, Boston, MA, United States

Antonio La Cava,     Department of Medicine, University of California Los Angeles, Los Angeles, CA, United States

Alexandra Ladouceur,     Centre hospitalier de l’Université de Montréal (CHUM), Montréal, QC, Canada

Robert G. Lahita,     New York Medical College, University Hospital, Paterson, NJ, United States

Aysche Landmann,     Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany

Estibaliz Lazaro,     Service de Médecine interne, FHU ACRONIM, Hôpital Haut-Lévêque, Centre Hospitalier Universitaire, CNRS-UMR 5164, ImmunoConcEpt, Université de Bordeaux, Bordeaux, France

Mara L. Lennard Richard,     Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, United States

Andreia C. Lino

Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany

German Rheumatism Research Center Berlin, Leibniz Institute, Berlin, Germany

Peter E. Lipsky,     AMPEL BioSolutions and RILITE Research Institute, Charlottesville, VA, United States

M. Kathryn Liszewski,     Washington University School of Medicine, Department of Medicine, Division of Rheumatology, St. Louis, MO, United States

Mindy S. Lo,     Instructor, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States

Qianjin Lu,     Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China

Mary Mahieu,     Northwestern University Feinberg School of Medicine, Chicago, IL, United States

Susan Malkiel,     Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States

Susan Manzi,     Department of Medicine, Medicine and Autoimmunity Institute, Allegheny Health Network, Pittsburgh, PA, United States

Galina Marder,     Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States

T.N. Mayadas,     Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States

Pier Luigi Meroni,     Immunology Research Laboratory, IRCCS Istituto Auxologico Italiano, Milan, Italy

Joan T. Merrill,     Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, University of Oklahoma, Norman, OK, United States

Chandra Mohan,     Department of Biomedical Engineering, University of Houston, Houston, TX, United States

Chi Chiu Mok,     Department of Medicine, Tuen Mun Hospital, New Territories, Hong Kong

Vaishali R. Moulton,     Division of Rheumatology and Clinical Immunology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Philip I. Murray,     Academic Unit of Ophthalmology, University of Birmingham, Birmingham, United Kingdom

Mohammad E. Naffaa,     Division of Rheumatology, Galilee Medical Center, Nahariya, Israel

Masaomi Nangaku,     Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Tokyo, Japan

Timothy Niewold,     Colton Center for Autoimmunity and Division of Rheumatology, NYU School of Medicine, New York, NY, United States

K. Okubo,     Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States

Nancy J. Olsen,     Penn State MS Hershey Medical Center, Hershey, PA, United States

Trina Pal,     New York Medical College, University Hospital, Paterson, NJ, United States

Ziv Paz,     Division of Rheumatology, Galilee Medical Center, Nahariya, Israel

Andras Perl,     Division of Rheumatology, Departments of Medicine and Microbiology and Immunology, State University of New York, Upstate Medical University, College of Medicine, Syracuse, NY, United States

Guillermo J. Pons-Estel

Department of Medicine, Regional Center for Rheumatic and Autoimmune Diseases (GO-CREAR), Rosario

Rheumatology Service, Rosario Provincial Hospital, Rosario, Argentina

Bo Qu,     Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Anisur Rahman,     Division of Medicine, University College London, London, UK

Ziaur S.M. Raman,     Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, United States

Rosalind Ramsey-Goldman

Northwestern University Feinberg School of Medicine, Chicago, IL, United States

Department of Medicine/Division of Rheumatology Northwestern University Feinberg School of Medicine, Chicago, IL, United States

Westley H. Reeves,     Division of Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL, United States

Christophe Richez,     Service de Rhumatologie, FHU ACRONIM, Hôpital Pellegrin, Centre Hospitalier Universitaire, CNRS-UMR 5164, ImmunoConcEpt, Université de Bordeaux, Bordeaux, France

Florencia Rosetti,     Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

Brad H. Rovin,     Division of Nephrology, Ohio State University Wexner Medical Center, Columbus, OH, United States

Robert L. Rubin,     Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 1 University of New Mexico, Albuquerque, NM, United States

Stephanie Saeli,     Department of Medicine, Medicine and Autoimmunity Institute, Allegheny Health Network, Pittsburgh, PA, United States

G. Saggu,     Cue Biopharma, Boston, MA. United States

Lisa R. Sammaritano,     Hospital for Special Surgery, New York, NY, United States

Minoru Satoh,     Department of Clinical Nursing, University of Occupational and Environmental Health Japan, Kitakyushu, Fukuoka, Japan

Amr H. Sawalha,     Division of Rheumatology, Department Pediatrics; Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States

Amit Saxena,     Division of Rheumatology, New York University School of Medicine, New York City, NY, United States

Savino Sciascia,     Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases (CMID), Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Hospital and University of Turin, Turin, Italy

Syahrul Sazliyana Shaharir,     Rheumatology Unit, Department of Internal Medicine, National University of Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia

Amir Sharabi,     Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv; Rheumatology Institute, Rabin Medical Center, Petach-Tikva, Israel

Nan Shen

Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States

Robert H. Shmerling,     Tufts Medical Center & Beth Israel Deaconess Medical Center, Division of Rheumatology, Boston, MA, United States

Julia F. Simard

Department of Epidemiology and Population Health, Stanford Medicine, Stanford, CA

Division of Immunology and Rheumatology, Department of Medicine, Stanford Medicine, Stanford, CA, United States

Vanja Sisirak,     CNRS-UMR 5164, ImmunoConcEpt, Université de Bordeaux, Bordeaux, France

Samantha Slight-Webb,     Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States

Isaac Ely Stillman,     Director, Renal Pathology Service – Beth Israel Deaconess Medical Center, Associate Professor of Pathology – Harvard Medical School, Boston, MA, United States

Sun-Sang J. Sung

Division of Rheumatology, Department of Medicine, University of Virginia, Charlottesville, VA

Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, United States

Payal Thakkar,     Allegheny Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, United States

Argyrios N. Theofilopoulos,     Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States

Donald E. Thomas, Jr

Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD

Arthritis and Pain Associates of Prince Georges County, Greenbelt, MD, United States

Hiromi Tissera,     McGill University Health Centre, Montreal, QC, Canada

Zahi Touma,     University of Toronto Lupus Clinic, Toronto Western Hospital, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto, ON; University of Toronto, Toronto Western Research Institute, University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, Toronto, ON, Canada

Betty P. Tsao,     Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, United States

Manuel F. Ugarte-Gil

Rheumatology Service, Guillermo Almenara Irigoyen National Hospital, Lima

Southern Scientific University, Lima, Peru

Murray B. Urowitz,     University of Toronto, Toronto Western Research Institute, University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, Toronto, ON, Canada

Silvio Manfredo Vieira,     Yale School of Medicine, New Haven, CT, United States

Benjamin Wainwright,     Division of Rheumatology, New York University School of Medicine, New York City, NY, United States

Daniel J. Wallace,     Division of Rheumatology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, United States

Hongyang Wang

Division of Rheumatology, Department of Medicine, University of Virginia, Charlottesville, VA

Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, United States

Haijing Wu,     Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China

Soad Haj Yahia

Clinical Immunology, Angioedema and Allergy Unit, The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Tel Aviv

The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel

C. Yung Yu,     Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University, Columbus, OH, United States

Zhenhuan Zhao

Division of Rheumatology, Department of Medicine, University of Virginia, Charlottesville, VA

Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, United States

Haoyang Zhuang,     Division of Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL, United States

Introduction

As long as we consider systemic lupus erythematosus one disease and we see one clinical trial after another fail, we can offer the people who suffer only qualified hope and encouragement. There is no doubt that we understand the disease better now than we did 50 years ago but we still use the same immunosuppressive and cytotoxic drugs albeit more wisely.

We have enlisted to the processes that lead to the expression of the disease additional players as we have followed new advances in the fields of immunology, inflammation, cell and molecular biology, and genomics. Yet we have not made much-needed advances in delineating the relative contribution of each mechanism to the expression of disease in each individual. It has become increasingly clear that cellular and molecular pathways may contribute to immunopathology at different degrees in each patient. There is no doubt that the biologics that have been tested in each trial do exactly what they were designed to do (deplete a cell, neutralize a cytokine or block a receptor, and so on) but if given indiscriminately to every lupus patient, the statistically recorded benefit may not rise to significant levels. There is no doubt that lupus cries out for individualized medicine and that herding everybody under the eleven American College of Rheumatology criteria misses the fact that each person with lupus employs individual pathways to express the same set of clinical manifestations.

We have also been slow in identifying the molecular and cellular mechanisms, which are involved in the expression of injury in each affected organ. Even if the autoimmune response is responsible for instigating tissue injury it is now better understood that autoimmunity and organ damage do not go hand-in-hand. Attempts to reverse injurious processes in organs should prove of clinical value. We understand that molecules (cell surface receptors, kinases, phosphatases and others) that are found to be abnormally expressed in lupus and claimed to contribute to disease pathology, are usually expressed by additional cells in the body and if inhibited across the board will invariably bring about unwanted side effects. This argument mandates the consideration of targeted delivery of drugs and biologics to maximize clinical efficacy and minimize side effects.

This book has taken a different approach in presenting the readers with state-of-the-art authoritative information on current topics of lupus. In order to minimize the load to the contributors we have presented a rather large (66) number of chapters after parsing out topics. Each contributor was asked to present available information in a critical, authoritative manner in shorter text and a limited (around 50) number of references selected critically. There is no doubt that readers will recognize shortcomings. I invite all possible feedback to improve the next edition.

While planning the book, we had in mind the increasing number of scientists, care givers, disease activists, clinical trial planners and industry officers who enter the battle against lupus. I believe that organization of the book will facilitate information retrieval and useful synthesis.

The 66 chapters are organized in six sections. The first introduces the history, epidemiology, diagnosis, and the efforts to develop biomarkers for the disease. In the second section (pathogenesis) 24 players are presented including various cells, antibodies, inflammation mediators, and processes. In the third section (mechanisms of tissue injury) elements and processes involved in the development of organ injury are presented synthetically. In the fourth section the clinical manifestations of the disease are presented in 19 chapters. Special space was allotted to the 41st chapter, which presents the pathology of lupus nephritis. My friend Isaac (Dr. Stillman) understands the pathology of lupus nephritis in a way that very few do and I believe we should have a clear understanding of the pathology before we commit our patients to intense treatment with cytotoxic drugs. The fifth section is dedicated to the antiphospholipid syndrome and the sixth to the treatment of the disease. Besides the required chapters on the used drugs, a chapter on the lessons we have learned from clinical trials is included along with a chapter on the efforts to repurpose existing drugs to treat lupus.

This book exists because of the encouragement and excitement of Linda Versteeg-Buschman of Elsevier whom I thank warmly through these lines. Halima Williams has provided unwavering support of the highest quality through the chapter solicitation, collection and editing phases of the chapters. She made my job easy and joyful.

George C. Tsokos

Introduction to the second edition

The success of the first edition has encouraged me to prepare the second edition of this book. In addition, many advances have been reported during the last five years, which had to be presented. Although we lament the slow pace of appearance of drugs for lupus there is light at the end of the tunnel. Benlysta has claimed official success whereas a few more biologics hold high promise and they may soon make to the clinic.

While planning the second edition of the book, I had in mind the increasing number of scientists, care givers, disease activists, clinical trial planners, and industry officers who enter the battle against lupus. I believe that organization of the book will facilitate information retrieval and useful synthesis. While the majority of the chapters have been updated by the same contributors, several are new to reflect recent advances. I have included a chapter by Brianna Fitzpatrick a young lady with lupus who presents in a most convincing manner what she expects from all of us.

The second edition is again organized in six sections. The first introduces the history, epidemiology, diagnosis, and the efforts to develop biomarkers for the disease. In the second section (pathogenesis) all players and contributors of the expression of the disease are presented including v cells, antibodies, inflammation mediators, and processes. In the third section (mechanisms of tissue injury) elements and processes involved in the development of organ injury are presented synthetically. In the fourth the clinical manifestations of the disease are presented. The fifth section is dedicated to the anti-phospholipid syndrome and the sixth to the treatment of the disease.

This book exists because of the encouragement and excitement of Linda Versteeg-Buschman of Elsevier whom I thank warmly through these lines. Leticia Lima has provided unwavering support of the highest quality though the chapter solicitation, collection, and editing phases of the chapters. She made my job easy and joyful. Lastly, I want to thank in the most cordial way all my friends who updated their chapters or contributed new ones. My real contribution to the outstanding quality of the second edition is minimal, if any.

George C. Tsokos

Part I

Epidemiology and diagnosis

Chapter 1: History of systemic lupus erythematosus with an emphasis on certain recent major issues

Chapter 2: The patient

Chapter 3: A plea of a young patient to the lupus experts

Chapter 4: Epidemiology

Chapter 5: Measuring disease activity

Chapter 6: Disease development and outcome

Chapter 7: Socioeconomic aspects of SLE

Chapter 8: Biomarkers in systemic lupus erythematosus

Chapter 1

History of systemic lupus erythematosus with an emphasis on certain recent major issues

Shu Man Fua,b,c

Felicia Gaskind

a    Division of Rheumatology, Department of Medicine, University of Virginia, Charlottesville VA, United States

b    Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, Charlottesville, VA, United States

c    Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, United States

d    Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, United States

Abstract

The clinical history of SLE is interesting and torturous. It can be divided into two periods: the age of dermatology with emphasis on skin manifestation and the period of transition to systemic lupus erythematosus (SLE). The history of laboratory investigation with emphasis of the development of clinical laboratory tests is presented. Certain other interesting aspects of the history of SLE are presented. These include the histories of genetic, therapeutic interventions, and the clarification criteria of SLE.

Keywords

cutaneous lupus

SLE

serological tests

genetics

therapy

clarification criteria

History of clinical observations

The clinical history of systemic lupus erythematosus (SLE) is interesting and torturous. It took more than 150 years for clinicians to describe the characteristics of all involved organs. The detailed histories of SLE from Hippocrates to Osler and from 600 AD to the mid-1970s have been described by Smith and Cyr¹ and by Benedek, respectfully.² Here only the highlights of clinical history will be presented without specific references. Most of the hallmarks in the Age of Dermatology are from Smith and Cyr.¹

The age of dermatology

The Latin word lupus, meaning wolf, was in the medical literature prior to the 1200s to describe skin lesions that devour flesh. Because of the inability to distinguish herpes, leprosy, and cancer as the cause of the skin lesions devouring the flesh, the term lupus was then applied to skin lesions nonspecifically. Rogerius (1230) has been credited to dissociate the skin lesions of lupus from that of herpes. The term was applied mostly to lesions on the lower extremities and on the face. Robert Willan, a British physician published his Manual on Skin Diseases with color illustrations based on his astute clinical observations. He was able to identify distinct clinical presentations of lupus skin diseases. Most of the early description of lupus skin diseases were lupus vulgaris.

Lupus erythematosus was first described as Erythema centrifugum by Laurent T Biett (1781–1840), a prominent French dermatologist. This was reported in 1833 by his pupil Cazenave (1802–77) ….a remarkable variety of this disease under the name of Erythema centrifugum. It is often of very rare occurrence, and appears most frequently in young people, especially in females, whose health is otherwise excellent…. Cazenave in his article published in 1851 renamed Erythema centrifugum as lupus erthemteux (LE). Prior to this, Ferdinand von Hebra (1816–80), a Viennese physician used the term of butterfly rash in 1848 to describe one of the two types of lupus erythematosus.

Regarding the etiology of lupus skin disease, it was remarkable that Jonathan Hutchinson (1828–1913), a British surgeon with multiple talents described photosensitivity in 1879 may be a cause of lupus by stating … Erythematous lupus is very rarely seen in those parts of the surface which is constantly protected by clothes. It is always made worse by exposure to the wind and cold… Sunburn of the nose is a common exciting cause. In 1880, he described the lesion of lupus marginatus that resembles subacute lupus erythematosus described by Sontheimer et al.³ in 1979.

During the 19th century there was much debate about the pathogenesis of lupus skin diseases. It was assumed to be due to infections because most lupus patients came from poor neighborhoods with crowded living arrangements. With the discovery of tubercle bacillus by Robert Koch in 1882, several reports of growing tubercle bacillus from lupus lesions were published leading to popularity of the theory.⁴ Despite the finding by Walther Pick in 1901 that only 15 out of 29 patients with LE were positive for a tuberculin skin test with positive TB history, the tuberculous etiology of LE remained a favorite theory of LE pathogenesis. Most investigators argued for or against this theory based on clinical statistics,² a practice still used by contemporary investigators in lupus research. The tuberculous etiology of LE led to the use of gold and other heavy metals such as bismuth as therapeutic agents for decades.

Transition of lupus erythematosus to systemic lupus erythematosus

Moriz Kaposi (1837–1920) was credited as the first physician in 1872 to describe internal organ involvement in LE and coined the term of SLE in distinction to LE, a limited skin disease.¹ He classified LE with internal organ involvement as Lupus erythematosus disseminates et aggregatus (SLE). He described these patients with fever, weight loss, anemia, amenorrhea, dysmenorrhea, adenitis, arthralgia/arthritis, increased mental disturbance, and coma, realizing many major clinical features of SLE. Sir William Osler (1849–1919) is credited for the implication of lupus nephritis as the cause of early demise in SLE due to his 1895 description of two cases of fatal nephritis that developed shortly after the appearance of the skin disease. Prior to the description of fatal nephritis, the causes of death in LE were assumed to be due to infections. Regarding his contribution to the study of SLE, it has been over-emphasized. In his description of 29 cases of SLE from 1895 to 1904, only two were clearly SLE with the majority of the cases being Henoch-Schonlein purpura.⁵ In 1902, JH Sequeira and H Balean both being British dermatologists published their series of 71 lupus patients (60 being discoid lupus and 11 being SLE). They described acroasphyxia (Raynaud’s phenomenon) as a common feature. They gave detailed clinical features and autopsy findings of an 18 year old female with malaise, malar rash, headache, abdominal pain, and peripheral edema with hematuria and casts and pulmonary embolism. They should share equal recognition for their contribution to the early study of SLE. To complete the transition to SLE from discoid lupus was the recognition of the occurrence of SLE without skin disease as reported in 1936 by Freidberg, Gross, and Wallach.⁶

There were other landmarks for the studies on SLE and they have been summarized by Benedek.² The familial study by Arnett and Shulman in 1976 emphasized the importance of genetic factors and their interaction with environmental factors in the pathogenesis of SLE.⁷ The discovery of drug induced lupus further supports the role of environmental factors in this disorder. These studies provide the basis for the recent efforts on the elucidation of the genetics of SLE.

History of laboratory investigations

Development of clinical tests

The first laboratory test that was found to be helpful in the diagnosis SLE is the biological false positive test for syphilis that was first described to be associated with lupus by A Reinhart in 1909.⁸ In 1952, Haserick and Long described 5 cases of SLE with a biological false positive test that preceded the onset of SLE by as much as 8 years.⁹ This lag time between serological positivity and clinical manifestation is similar to that reported more recently by Arbuckle et al.¹⁰ with other lupus-related auto-antibodies (Auto-Abs).

Hargraves, Richmond, and Morton described the LE cells in the bone marrow of SLE patients in 1948.¹¹ Because the LE cell test is positive in 50%–70% of the patients and seen in other diseases, it is no longer used as a laboratory test for SLE. However, the LE cell test led Holman and Kunkel¹² to identify the LE factor as antibodies (Abs) against complexes formed by nuclear nucleoprotein and DNA. These anti-DNA/nucleoprotein complex Abs were shown to differ from those reactive with ds-DNA.¹³,¹⁴ It is of special interest that Deicher et al.¹³ demonstrated the presence of at least two types of anti-dsDNA Abs by immunoprecipitation in SLE patients. Thus far it remains to be determined whether these two types of anti-dsDNA Abs have clinical significance. It is revealing to revisit the 1974 paper published by Gershwin and Steinberg¹⁵ stating that Patients with lupus nephritis had either precipitating antibodies to DNA, or a mixture of precipitating and nonprecipitating, whereas those patients without nephritis had only nonprecipitating, antibodies to DNA. Furthermore the avidity for DNA was greatest in sera from patients with nephritis. The antigen-binding capacity of sera from patients with and without lupus nephritis was similar, suggesting that qualitative differences in anti-DNA activity may be as important as quantitative ones. Thus, it appears that the heterogeneity of anti-dsDNA Abs measured by the current binding assays render them to be one of the many lupus-related autoantibodies.¹⁶

Friou et al.¹⁷ reported the development of the indirect immunofluorescence technique to detect antinuclear antibodies (FANA) in 1958. For historical reasons, he recalled that their experiments reported in Friou et al. were completed in February 1957.¹⁸ Although positive FANA tests were not specific for SLE, it was accepted as a better screening test because of its less technical demand in comparison with the LE cell test. These Abs are also found in approximately 15% of the normal population irrespective of their ages.¹⁹ Despite the use human Hep2 cells as the substrate and the improvement of optics in immunofluorescence microscopy, a small percentage of SLE patients remain ANA negative. Thus, the specificity and sensitivity issue remains, rendering the use of positive ANA as an entry criterion for patient selection in the new EULAR/ACR classification criteria for SLE²⁰ problematic.

HR Holman pioneered the method for the preparation of extractable nuclear antigens (ENA) to study auto-Abs in SLE.²¹ Anti-Sm Abs were the first auto-Abs shown to be reactive with ENA by Tan and Kunkel²² by immunoprecipitant analysis with the serum from a young woman, Ms. Smith, who succumbed to lupus nephritis at the age of 21 years.²³ It is specific for SLE and remains one of the 11 criteria in the 1982/1997 modified-ACR criteria for the classification of SLE.²⁴,²⁵ Sm is one of the components of snRNP.²² RNP was the second component of snRNP to be recognized as an autoantigen. With an agglutination assay using red cells coated with ENA, Sharp et al.²⁶ showed that a population of patients with overlapping features of SLE, progressive systemic sclerosis, and polymyositis, had high titers of anti-RNP Abs with a distinct clinical course. These patients have mixed-connective tissue disease (MCTD). It is important to emphasize the presence of high titers for anti-RNP Abs to be diagnostic of MCTD. Anti-Ro/SSA Abs were first identified by Clark, Reichlin, and Tomasi²⁷ with the serum from patient Ro by immunodiffusion analysis. The Ro Ag was later identified to be a 60 KD nucleoprotein binding to RNA.²⁸ Anti-Ro Abs are the most common lupus-related auto-Abs in healthy individuals.¹⁹ The presence of these Abs in normal young females may result in fetal heart block or neonatal lupus.

It should be stressed that the earlier described auto-Abs were detected initially by immunodiffusion analyses. Their usefulness in diagnosing SLE was based on clinical correlation with these auto-Abs detected by this technique. The recent developed ELISA assay and the BioRad Multiplex Assays do not correlate exactly with the results by immunodiffusion. Thus interpretation of the current clinical serological assay results in the diagnosis of SLE should be done with caution. Clinically patients with isolated Abs to the auto-Ag panel in the BioRad Multiplex system without positive ANA are often encountered.

As of 2015, more than 180 auto-Abs have been described in SLE to diverse organ and cell constituents.²⁹ Those chosen to be included in the classification criteria for SLE are those available in clinical laboratories. These small groups of auto-Abs are employed to measure autoimmune activity in SLE patients. Their absence does not indicate the absence of autoimmunity and does not exclude the diagnosis of SLE.

History of genetics of SLE

As stated earlier, the familial occurrence of multiple SLE cases suggests that genetics plays a significant role in the pathogenesis of SLE. The HLA complex was the first genetic locus identified to be linked to SLE susceptibility in 1970.³⁰ With the genome-wide association studies (GWAS), more than 100 genetic loci have been confirmed to be associated with SLE.³¹ With few exceptions most identified alleles have OR between 1.2 and 16. To achieve the threshold for clinical SLE many combinations of these genes are plausible in any given individual patient. The complexity of lupus genetics contributes significantly to the heterogeneity of the disease clinical presentation and responses to therapies.

History of therapy in SLE with an emphasis on the use of steroids

The history of therapies for SLE is also a torturous one. The most controversial tissues are how much steroid and for how long steroid should be used in the treatment of SLE. Shortly after the demonstration of remarkable steroid effects on rheumatoid arthritis by Hench et al.,³² ACTH was demonstrated to be effective in treating some cases of SLE.³³,³⁴ The choice of ACTH was due to the limited availability of synthetic cortisone. With the availability of prednisone, this medication was used by Pollack et al. in the early 1960s to treat lupus nephritis.³⁵ 40–60 mg prednisone for 6 months was effective to treat patients with active proliferative LN. In many patients this high dose could be tapered to 15–20 mg daily with controlling the disease activity. In comparison those treated with 15–20 mg daily doses of prednisone were not effective. This finding might have been the basis for treating lupus patients with moderate to severe symptoms with high doses of prednisone initially and then taper the prednisone to 15–20 mg daily. Today daily doses of prednisone below 10 mg remain acceptable.

The effectiveness of using immunosuppressive agents in the treatment of SLE were demonstrated to be effective in the early 1970s. It was initially shown in 1970 that a short-term use of cyclophosphamide as a single agent was not effective.³⁶ One year later, Steinberg et al.³⁷ concluded from a control clinical trial that with concurrent corticosteroid therapy, up to 30 mg/day of prednisone, was permitted. Patients receiving cyclophosphamide had greater improvement than did placebo-treated patients in five indexes: anti-DNA antibodies, serum complement, urine sediment, proteinuria, and extra-renal disease. There was no difference in creatinine clearance. There was a strong positive correlation between cyclophosphamide dosage and number of indexes improved. Toxic side effects of cyclophosphamide were noted. In 1986, Austin et al.³⁸ published the results of a long-term therapeutic trial of LN patients treated with high doses of oral prednisone alone versus those treated with an intravenous high-dose of cyclophosphamide plus low-doses of prednisone. Those receiving a high dose of intravenous cyclophosphamide have reduced risk of progressing to end stage of renal disease. Because of the ethical concern of toxicity,³⁹ immunosuppressives have remained steroid-sparing agents and are not used as the primary agents.⁴⁰

During the last two decades, the long-term detrimental effects of moderate/low doses of prednisone⁴¹ have been recognized. This prompted observational trials without the use of oral prednisone in LN.⁴²,⁴³ Recently, a multi-target therapy with tacrolimus and mycophenolate mofetil (MMF) plus pulse methylprednisolone with tapering a course of oral prednisone to from 1 mg/kg to 10 mg/day as induction therapy was superior to pulse methylprednisolone with intravenous cyclophosphamide.⁴⁴ Tacrolimus, MMF plus 10 mg/day oral prednisone was also shown to be superior in the maintenance therapy phase of LN.⁴⁵ Unfortunately in these studies, prednisone was used at a moderately high dose. It remains to be determined whether oral steroid can be eliminated completely in the multitarget therapy in the maintenance phase with more rapid tapering in the induction phase. The latter multitarget approach may receive acceptance when biomarkers are developed to guide the use of prednisone such as circulating inflammatory cytokine levels after steroid pulses.

It is apparent that more than 60 years after the demonstration of usefulness of glucocorticoid in the treatment of lupus, how much steroid and for how long steroid should be used in the treatment of SLE remains controversial. However, it is clear that most patients would chose immunosuppressive agents with lower/no doses of prednisone after experiencing the side effects of moderate doses of prednisone.

History of classification criteria for SLE

It is not surprising that committees were needed and were formed to determine the classification criteria of SLE because of its marked protean clinical presentations and clinical courses with highly varied serological laboratory findings. The 1982/1997 Revised ACR Criteria for the Classification of SLE²⁴,²⁵ have been proven to be moderately useful. The 1982/1997 ACR criteria separate the nine criteria for end organ damage from autoimmunity manifestation such as ANA and anti-dsDNA Abs. This separation represents a foresight of the committee realizing that autoimmunity alone needs not to progress to autoimmune disease and that these are two genetically determined and interactive pathways in the pathogenesis of SLE.⁴⁶ Although it is clearly stated that the classification criteria were for the use of recruiting patients for clinical research and not for clinical use, they have been often used for clinical classification. The misuse of these criteria in clinical practice creates a significant obstacle in providing quality care to our patients, especially in the case that a significant proportion of primary care physicians consider the presence of anti-dsDNA to be diagnostic of lupus.

With the failure of many clinical trials for therapeutic agents in SLE, the pressure to recruit patients for clinical trial mounts. This leads to the pressure to revise the 1982/1997 revised ACR criteria for the classification of SLE and the result of the formation of a new committee in 2017 jointly appointed by EULAR and ACR. The proposed EULAR/ACR classification criteria incorporated most of the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. The criteria are more cumbersome. With adult SLE populations in both Europe and in the Americas, the EULAR/ACR classification criteria for SLE do not appear to be superior to the 1982/1997 revised ACR classification.⁴⁷,⁴⁸ It appears that the new criterion is more sensitive but less specific. This preliminary conclusion is disappointing in that the proposed EULAR/ACR criteria classification for SLE did not achieve the initial goal to have a more sensitive and specific classification system for SLE.

As I reviewed the literature for this chapter, I came across an article by H. Holman⁴⁹ that recorded his reflection on the discovery of anti-dsDNA Abs. He lamented the long failure of recognition of autoimmunity by citing a plausible explanation in the 1962 book The Structure of Scientific Revolution by Thomas Kuhn. H Holman wrote "Exploring the histories of astronomy and physics, Kuhn argued that dominant concepts in a scientific field (e.g., Earth-centered vs. Sun-centered astronomy, mechanical vs. relativistic physics) did not change as a result of steady, longitudinal growth of knowledge. Rather, they changed when the powerful authority figures in the field, who adhered to the prevailing theoretical view, departed. This allowed younger people with contrary evidence and views to be recognized. The Kuhnian analysis was applied to many fields of science and provoked much controversy. However, the Kuhnian notions of theoretical concepts as paradigms, and paradigm replacement as a consequence of changing of the guards, persist. Whether that explains the dominance of horror autotoxicus for a half century despite contrary evidence is a matter of conjecture." His reflection on autoimmunity may be applicable here.

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