Systemic lupus erythematosus : basic, applied and clinical aspects

572 Pages·2016·41.018 MB·English

by  George Tsokos

Dedication
To Cathy, Donna, Alice, Thomas, Luz, Betty, Leosha
and all who fight lupus from dawn to dusk.
We promise to do better.
Systemic Lupus
Erythematosus
Basic, Applied and Clinical Aspects
Edited by
George C. Tsokos
Harvard Medical School, Boston, MA, USA
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Cover Figures
The figures were kindly provided by the Photographic Laboratory (with thanks to J. Bueckmann and P. Wissel), Department of
Dermatology, University of Muenster, Germany.
Figure Legends
Top Left: Discoid lupus erythematosus (DLE): Confluent discoid lesions with central scarring, slight residual erythema and
hyperpigmented border at the forehead in a patient with dark skin type.
Top Middle: Subacute cutaneous lupus erythematosus (SCLE): Polycyclic confluence of annular lesions in different stages of
development (fully developed lesions with typical collarette scaling at the inner border and central clearing) at the back.
Top Right: Discoid lupus erythematosus (DLE): Residual activity with erythema and hyperkeratosis in an area of scarring alopecia
(occipital).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes
in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information,
methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own
safety and the safety of others, including parties for whom they have a professional responsibility.
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products, instructions, or ideas contained in the material herein.
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ISBN: 978-0-12-801917-7
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List of Contributors
Nancy Agmon-Levin The Zabludowicz Center for Dimitrios T. Boumpas Rheumatology and Clinical
Autoimmune Diseases Sheba Medical Center, Sackler Immunology, 4th Department of Medicine, Medical
Faculty of Medicine, Tel-Aviv University, Tel Aviv, School, University of Athens and Biomedical Research
Israel Foundation of the Academy of Athens, Athens, Greece
Graciela S. Alarcón Department of Medicine, Division Rebecka Bourn Arthritis and Clinical Immunology,
of Clinical Immunology and Rheumatology, School of Oklahoma Medical Research Foundation, Oklahoma
Medicine, The University of Alabama at Birmingham, City, OK, USA
Birmingham, AL, USA
Jill P. Buyon Division of Rheumatology, New York
Olga Amengual Division of Rheumatology, Endocrinology University School of Medicine, New York City, NY,
and Nephrology, Hokkaido University Graduate School USA
of Medicine, Sapporo, Japan
Roberto Caricchio Department of Medicine, Section of
Stacy P. Ardoin Ohio State University, Columbus, OH, Rheumatology and Department of Microbiology and
USA Immunology, Temple University School of Medicine,
Philadelphia, PA, USA
John P. Atkinson Division of Rheumatology, Department
of Medicine, Washington University School of Medicine, Michelle D. Catalina AMPEL BioSolutions, University of
Saint Louis, MO, USA Virginia Research Park, Charlottesville, VA, USA
Tatsuya Atsumi Division of Rheumatology, Endocrinology Edward K.L. Chan Department of Oral Biology,
and Nephrology, Hokkaido University Graduate School University of Florida, Gainesville, FL, USA
of Medicine, Sapporo, Japan
Christopher Chang Division of Rheumatology, Allergy
Isabelle Ayoub Division of Nephrology, Ohio State and Clinical Immunology, University of California at
University Wexner Medical Center, Columbus, OH, USA Davis, Davis, CA, USA
Bonnie L. Bermas Brigham and Women’s Hospital, Sandra Chartrand Hôpital Maisonneuve-Rosemont affil-
Boston, MA, USA iated to Université de Montréal, Montréal, QC, Canada
Sasha Bernatsky McGill University Health Centre, Cecilia Beatrice Chighizola Immunology Research
Montreal, QC, Canada Laboratory, IRCCS Istituto Auxologico Italiano, Milan,
Italy; Department of Clinical Sciences and Community
George Bertsias Rheumatology, Clinical Immunology and
Health, University of Milan, Milan, Italy
Allergy Medical School, University of Crete Heraklion,
Heraklion, Greece Ann E. Clarke Division of Rheumatology, Department of
Medicine, University of Calgary, Calgary, AB, Canada
Patrick Blanco University of Bordeaux, CIRID, UMR/
CNRS, Bordeaux, France; CHU de Bordeaux, Bordeaux, José C. Crispín Department of Immunology and
France Rheumatology, Instituto Nacional de Ciencias Médicas
y Nutrición Salvador Zubirán, Mexico City, Mexico
Miyuki Bohgaki NTT Sapporo Medical Center, Sapporo
Hokkaido, Japan Chao Dai Division of Rheumatology, Department of
Medicine, University of Virginia, Charlottesville,
Gisela Bonsmann Department of Dermatology, University
VA, USA; Center for Immunity, Inflammation, and
of Muenster, Muenster, Germany
Regenerative Medicine, Department of Medicine,
Maria Orietta Borghi Immunology Research Laboratory,
University of Virginia, Charlottesville, VA, USA
IRCCS Istituto Auxologico Italiano, Milan, Italy;
Erika M. Damato Birmingham Midland Eye Centre, City
Department of Clinical Sciences and Community
Hospital, Birmingham, UK
Health, University of Milan, Milan, Italy
xix
xx List of Contributors
Yun Deng Division of Rheumatology, Department of Gary S. Gilkeson Medical Research Service, Ralph H.
Medicine, David Geffen School of Medicine, University Johnson VA Medical Center, Charleston, SC, USA;
of California, Los Angeles, Los Angeles, CA, USA Department of Medicine, Division of Rheumatology,
Medical University of South Carolina, Charleston, SC,
Alastair K.O. Denniston Department of Ophthalmology,
USA
University Hospitals Birmingham NHS Foundation Trust,
Birmingham, UK; Academic Unit of Ophthalmology, Dafna Gladman University of Toronto, Toronto, ON,
University of Birmingham, Birmingham, UK Canada
Amy Devlin Beth Israel Deaconess Medical Center, Rosalind Ramsey Goldman North-western University
Division of Rheumatology, Boston, MA, USA Feinberg School of Medicine, Chicago, IL, USA
Betty Diamond Autoimmune & Musculoskeletal Disease Luis A. González-Naranjo Division of Rheumatology,
Center, Feinstein Institute for Medical Research, North Department of Internal Medicine, School of Medicine,
Shore LIJ Health System, Manhasset, NY, USA Universidad de Antioquia, Medellín, Colombia
Mary Anne Dooley Dooley Rheumatology, Chapel Hill, Caroline Gordon Department of Rheumatology, City
NC, USA Hospital, Sandwell and West Birmingham Hospitals
NHS Trust, Birmingham, UK; Rheumatology Research
Jefte M. Drijvers Ragon Institute of MGH, MIT and
Group, College of Medical and Dental Sciences,
Harvard, Cambridge, MA, USA
University of Birmingham, Edgbaston, Birmingham,
Roland M. du Bois Imperial College, London, UK
UK
Yong Du Department of Biomedical Engineering,
Amrie C. Grammer AMPEL BioSolutions, University of
University of Houston, Houston, TX, USA
Virginia Research Park, Charlottesville, VA, USA
T. Ernandez Service of Nephrology, University Hospital
Eric L. Greidinger Division of Rheumatology, Miami
of Geneva, Switzerland
VAMC, University of Miami Miller School of Medicine,
Concetta Ferretti Department of Medicine, University of Miami, FL, USA
California Los Angeles, Los Angeles, CA, USA
Niklas Hagberg Section of Rheumatology, Department of
Aryeh Fischer University of Colorado School of Medicine, Medical Sciences, Uppsala University, Uppsala, Sweden
Aurora, CO, USA
John G. Hanly Dalhousie University, Halifax, Nova
Samantha Fisher Department of Dermatology, University Scotia, Canada; Nova Scotia Health Authority, Halifax,
of Florida, Gainesville, FL, USA Nova Scotia, Canada
Eleni A. Frangou Biomedical Research Foundation of the James E. Hansen Department of Therapeutic Radiology,
Academy of Athens, Athens, Greece Yale School of Medicine, New Haven, CT, USA
Marvin J. Fritzler Department of Biochemistry and Shuhong Han Division of Rheumatology & Clinical
Molecular Biology, Cumming School of Medicine, Immunology, University of Florida, Gainesville, FL,
University of Calgary, Calgary, AB, Canada USA
Richard Furie North Shore LIJ Division of Rheumatology, Sarfaraz A. Hasni National Institute of Arthritis and
Great Neck, NY, USA; Hofstra North Shore LIJ Musculoskeletal and Skin Diseases, National Institutes
School of Medicine, Hofstra University, Hempstead, of Health, Bethesda, MD, USA
NY, USA
Christian M. Hedrich Children’s Hospital Dresden,
Shu Man Fu Division of Rheumatology, Department Pediatric Rheumatology and Immunology Section,
of Medicine, University of Virginia, Charlottesville, University Medical Center Carl Gustav Carus, TU
VA, USA; Center for Immunity, Inflammation, and Dresden, Dresden, Germany
Regenerative Medicine, Department of Medicine,
Diane Horowitz North Shore LIJ Division of
University of Virginia, Charlottesville, VA, USA;
Rheumatology, Great Neck, NY, USA; Hofstra North
Department of Microbiology, Immunology, and Cancer
Shore LIJ School of Medicine, Hofstra University,
Biology, School of Medicine, University of Virginia,
Hempstead, NY, USA
Charlottesville, VA, USA
Xin Huang Department of Dermatology, Hunan Key
Felicia Gaskin Department of Psychiatry and
Laboratory of Medical Epigenomics, Second Xiangya
Neurobehavioral Sciences, School of Medicine,
Hospital, Central South University, Changsha, Hunan,
University of Virginia, Charlottesville, VA, USA
China
List of Contributors xxi
Peter M. Izmirly Division of Rheumatology, New York Peter E. Lipsky AMPEL BioSolutions, University of
University School of Medicine, New York City, NY, Virginia Research Park, Charlottesville, VA, USA
USA
Mindy S. Lo Boston Children’s Hospital, Harvard Medical
Clément Jacquemin University of Bordeaux, CIRID, School, Boston, MA, USA
UMR/CNRS, Bordeaux, France; CHU de Bordeaux,
Qianjin Lu Department of Dermatology, Hunan Key
Bordeaux, France
Laboratory of Medical Epigenomics, Second Xiangya
Judith James Arthritis and Clinical Immunology, Hospital, Central South University, Changsha, Hunan,
Oklahoma Medical Research Foundation, Oklahoma China
City, OK, USA; Departments of Medicine and Pathology,
Mary Mahieu Northwestern University Feinberg School
Oklahoma Clinical and Translational Science Institute,
of Medicine, Chicago, IL, USA
University of Oklahoma Health Sciences Center,
Susan Malkiel Autoimmune & Musculoskeletal Disease
Oklahoma City, OK, USA
Center, Feinstein Institute for Medical Research, North
Wael N. Jarjour Ohio State University, Columbus, OH, USA
Shore LIJ Health System, Manhasset, NY, USA
Mariana J. Kaplan National Institute of Arthritis and
Susan Manzi Department of Medicine, Lupus Center of
Musculoskeletal and Skin Diseases, National Institutes
Excellence, Allegheny Health Network, Pittsburgh,
of Health, Bethesda, MD, USA
PA,USA
Munther Khamashta Division of Women’s Health,
Galina Marder North Shore LIJ Division of Rheumatology,
Graham Hughes Lupus Research Laboratory, Lupus
Great Neck, NY, USA; Hofstra North Shore LIJ School
Research Unit, The Rayne Institute, King’s College,
of Medicine, Hofstra University, Hempstead, NY, USA
London, UK; Louise Coote Lupus Unit, Guy’s and St
T.N. Mayadas Department of Pathology, Brigham and
Thomas’ NHS Foundation Trust, St Thomas’ Hospital,
Women’s Hospital and Harvard Medical School,
London, UK
Boston, USA
Takao Koike NTT Sapporo Medical Center, Sapporo
Terry K. Means Center for Immunology and Inflammatory
Hokkaido, Japan; Department of Medicine II, Hokkaido
Diseases and Division of Rheumatology, Allergy, and
University Graduate School of Medicine, Sapporo
Immunology, Massachusetts General Hospital and
Hokkaido, Japan
Harvard Medical School, Charlestown, MA, USA
Dwight H. Kono Department of Immunology and
Pier Luigi Meroni Immunology Research Laboratory, IRCCS
Microbial Science, The Scripps Research Institute, La
Istituto Auxologico Italiano, Milan, Italy; Department of
Jolla, CA, USA
Clinical Sciences and Community Health, University of
Christine Konya Division of Rheumatology & Lupus Milan, Milan, Italy; Division of Rheumatology, Istituto
Center, BIDMC, Harvard Medical School, Boston, MA, Ortopedico Gaetano Pini, Milan, Italy
USA
Joan T. Merrill Clinical Pharmacology Research Program,
Annegret Kuhn Interdisciplinary Center for Clinical Oklahoma Medical Research Foundation, University of
Trials (IZKS), University Medical Center Mainz, Oklahoma, OK, USA
Mainz, Germany; Division of Immunogenetics, Tumor
Chandra Mohan Department of Biomedical Engineering,
Immunology Program, German Cancer Research Center
University of Houston, Houston, TX, USA
(DKFZ), Heidelberg, Germany
Chi Chiu Mok Department of Medicine, Tuen Mun
Vasileios C. Kyttaris Division of Rheumatology, Beth
Hospital, New Territories, Hong Kong
Israel Deaconess Medical Center, Harvard Medical
Vaishali R. Moulton Division of Rheumatology, Depart-
School, Boston, MA, USA
ment of Medicine, Beth Israel Deaconess Medical Center,
Antonio La Cava Department of Medicine, University of Harvard Medical School, Boston, MA, USA
California Los Angeles, Los Angeles, CA, USA
Philip I. Murray Academic Unit of Ophthalmology,
Robert G. Lahita Newark Beth Israel Medical Center, University of Birmingham, City Hospital, Birmingham,
Newark, NJ, USA; Rutgers New Jersey Medical School, UK
Newark, NJ, USA
Jim C. Oates Medical Research Service, Ralph H. Johnson
Aysche Landmann Division of Immunogenetics, Tumor VA Medical Center, Charleston, SC, USA; Department
Immunology Program, German Cancer Research Center of Medicine, Division of Rheumatology, Medical
(DKFZ), Heidelberg, Germany University of South Carolina, Charleston, SC, USA
xxii List of Contributors
Ziv Paz Division of Rheumatology & Lupus Center, Amr H. Sawalha Division of Rheumatology, Department
BIDMC, Harvard Medical School, Boston, MA, USA of Internal Medicine, University of Michigan, Ann
Arbor, MI, USA; Center for Computational Medicine
William F. Pendergraft III University of North Carolina
and Bioinformatics, University of Michigan, Ann Arbor,
Kidney Center, Chapel Hill, NC, USA
MI, USA
Andras Perl Division of Rheumatology, Department
Amit Saxena Division of Rheumatology, New York
of Medicine, College of Medicine, Upstate Medical
University School of Medicine, New York City, NY, USA
University, State University of New York, Syracuse, NY,
USA; Department of Microbiology and Immunology, Savino Sciascia Division of Women’s Health, Graham
College of Medicine, Upstate Medical University, State Hughes Lupus Research Laboratory, Lupus Research
University of New York, Syracuse, NY, USA Unit, The Rayne Institute, King’s College, London,
UK; Centro di Ricerche di Immunologia Clinica ed
Shiv Pillai Ragon Institute of MGH, MIT and Harvard,
Immunopatologia e Documentazione su Malattie
Cambridge, MA, USA
Rare (CMID), Università di Torino, Torino, Italy;
Guillermo J. Pons-Estel Department of Autoimmune
Louise Coote Lupus Unit, Guy’s and St Thomas’ NHS
Diseases, Institut Clinic de Medicina I Dermatologia,
Foundation Trust, St Thomas’ Hospital, London, UK
Hospital Clinic, Barcelona, Catalonia, Spain
Syahrul Shaharir Department of Rheumatology, City
Bo Qu Shanghai Institute of Rheumatology, Renji Hospital,
Hospital, Sandwell and West Birmingham Hospitals
Shanghai Jiao Tong University School of Medicine,
NHS Trust, Birmingham, UK; Department of Internal
Shanghai, China
Medicine, National University of Malaysia Medical
Anisur Rahman Division of Medicine, University College Centre, Cheras, Kuala Lumpur, Malaysia
London, London, UK
Chengqun Shao Newark Beth Israel Medical Center,
Rosalind Ramsey-Goldman Northwestern University Newark, NJ, USA
Feinberg School of Medicine, Chicago, IL, USA Nan Shen Shanghai Institute of Rheumatology, Renji
Westley H. Reeves Division of Rheumatology & Clinical Hospital, Shanghai Jiao Tong University School
Immunology, University of Florida, Gainesville, FL, of Medicine, Shanghai, China; Institute of Health
USA Sciences, Shanghai Institutes for Biological Sciences
(SIBS) & Shanghai Jiao Tong University School of
Noé Rodríguez-Rodríguez Department of Medicine,
Medicine (SJTUSM), Chinese Academy of Sciences
Division of Rheumatology, Beth Israel Deaconess
(CAS), Shanghai, China; Division of Rheumatology,
Medical Center, Harvard Medical School, Boston,
The Center for Autoimmune Genomics and Etiology
MA, USA; Department of Immunology, Universidad
(CAGE), Cincinnati Children’s Hospital Medical
Complutense de Madrid, Madrid, Spain
Center, Cincinnati, OH, USA
Lars Rönnblom Section of Rheumatology, Department of
Robert Shmerling Beth Israel Deaconess Medical Center,
Medical Sciences, Uppsala University, Uppsala, Sweden
Division of Rheumatology, Boston, MA, USA
Florencia Rosetti Department of Immunology and
Yehuda Shoenfeld The Zabludowicz Center for Auto-
Rheumatology, Instituto Nacional de Ciencias Médicas
immune Diseases Sheba Medical Center, Sackler
y Nutrición Salvador Zubirán, Mexico City, Mexico
Faculty of Medicine, Tel-Aviv University, Tel Aviv,
Brad H. Rovin Division of Nephrology, Ohio State University Israel; Incumbent of the Laura Schwarz-Kipp Chair for
Wexner Medical Center, Columbus, OH, USA Research of Autoimmune Diseases, Sackler Faculty of
Medicine, Tel-Aviv University, Tel Aviv, Israel
Matthew M. Ryals AMPEL BioSolutions, University of
Virginia Research Park, Charlottesville, VA, USA Stepan Shumyak Division of Rheumatology & Clinical
Immunology, University of Florida, Gainesville, FL,
G. Saggu Department of Pathology, Brigham and Women’s
USA
Hospital and Harvard Medical School, Boston, USA
Samantha Slight-Webb Arthritis and Clinical Immuno-
Lisa R. Sammaritano Hospital for Special Surgery,
logy, Oklahoma Medical Research Foundation,
New York, NY, USA
Oklahoma City, OK, USA
Minoru Satoh Department of Clinical Nursing, University
Isaac Ely Stillman Beth Israel Deaconess Medical Center,
of Occupational and Environmental Health, Japan,
Boston, MA, USA
Kitakyushu, Fukuoka, Japan; Department of Medicine,
University of Florida, Gainesville, FL, USA; Department George Stojan Harvard Medical School, Division of
of Pathology, Immunology, and Laboratory Medicine, Rheumatology, Beth Israel Deaconess Medical Center,
University of Florida, Gainesville, FL, USA Boston, MA, USA
List of Contributors xxiii
Sun-Sang J. Sung Division of Rheumatology, Department Bruce T. Volpe Biomedical Sciences, Feinstein Institute
of Medicine, University of Virginia, Charlottesville, for Medical Research, Hofstra North Shore LIJ School
VA, USA; Center for Immunity, Inflammation, and of Medicine, Manhasset, NY, USA
Regenerative Medicine, Department of Medicine,
Hongyang Wang Division of Rheumatology, Department
University of Virginia, Charlottesville, VA, USA
of Medicine, University of Virginia, Charlottesville,
Argyrios N. Theofilopoulos Department of Immunology VA, USA; Department of Microbiology, Immunology,
and Microbial Science, The Scripps Research Institute, and Cancer Biology, School of Medicine, University of
La Jolla, CA, USA Virginia, Charlottesville, VA, USA
Donald E. Thomas Jr. Department of Medicine, Mark H. Wener Departments of Laboratory Medicine &
Uniformed Services University of the Health Sciences, Medicine, University of Washington, Seattle, WA, USA
Bethesda, MD, USA; Arthritis and Pain Associates of
Haijing Wu Department of Dermatology, Hunan Key
Prince Georges County, Greenbelt, MD, USA
Laboratory of Medical Epigenomics, Second Xiangya
Hiromi Tissera McGill University Health Centre, Hospital, Central South University, Changsha, Hunan,
Montreal, QC, Canada China
Zahi Touma University of Toronto Lupus Clinic, Toronto Yuan Xu Division of Rheumatology & Clinical Immunology,
Western Hospital, Centre for Prognosis Studies in the University of Florida, Gainesville, FL, USA
Rheumatic Diseases, Toronto, ON, Canada; Department
Lijun Yang Department of Pathology, Immunology, &
of Internal Medicine, Division of Rheumatology,
Laboratory Medicine, University of Florida, Gainesville,
University of Toronto, Toronto, ON, Canada
FL, USA
Betty P. Tsao Division of Rheumatology, Department of
C. Yung Yu Center for Molecular and Human Genetics,
Medicine, David Geffen School of Medicine, University
The Research Institute at Nationwide Children’s
of California, Los Angeles, Los Angeles, CA, USA
Hospital and Department of Pediatrics, The Ohio State
Manuel F. Ugarte-Gil Servicio de Reumatología, Hospital University, Columbus, OH, USA
Nacional Guillermo Almenara Irigoyen, EsSalud, Lima,
Haoyang Zhuang Division of Rheumatology & Clinical
Peru; Universidad Científica del Sur, Lima, Peru
Immunology, University of Florida, Gainesville, FL,
Murray B. Urowitz University of Toronto Lupus Clinic, USA
Toronto Western Hospital, Centre for Prognosis
Studies in the Rheumatic Diseases, Toronto, ON,
Canada; Department of Internal Medicine, Division of
Rheumatology, University of Toronto, Toronto, ON,
Canada; Toronto Western Research Institute, Toronto,
ON, Canada
Introduction
As long as we consider systemic lupus erythematosus one on current topics of lupus. In order to minimize the load
disease and we see one clinical trial after another fail, we to the contributors we have presented a rather large (66)
can offer the people who suffer only qualified hope and number of chapters, after parsing out topics. Each contribu-
encouragement. There is no doubt that we understand the tor was asked to present available information in a critical,
disease better now than we did 50 years ago but we still use authoritative manner in shorter text and a limited (around
the same immunosuppressive and cytotoxic drugs, albeit 50) number of references selected critically. There is no
more wisely. doubt that readers will recognize shortcomings. I invite all
We have enlisted additional players to the processes that possible feedback to improve the next edition.
lead to the expression of the disease as we have followed While planning the book, we had in mind the increas-
new advances in the fields of immunology, inflammation, ing number of scientists, care givers, disease activists,
cell and molecular biology, and genomics. Yet we have not clinical trial planners, and industry officers who enter
made much-needed advances in delineating the relative the battle against lupus. I believe that the organization of
contribution of each mechanism to the expression of disease the book will facilitate information retrieval and useful
in each individual. It has become increasingly clear that cel- synthesis.
lular and molecular pathways may contribute to immuno- The 66 chapters are organized in six sections. The first
pathology at different degrees in each patient. There is no introduces the history, epidemiology, diagnosis, and the
doubt that the biologics that have been tested in each trial do efforts to develop biomarkers for the disease. In the second
exactly what they were designed to do (deplete a cell, neu- section (pathogenesis) 24 players are presented including
tralize a cytokine or block a receptor, and so on) but if given various cells, antibodies, inflammation mediators, and pro-
indiscriminately to every lupus patient, the statistically cesses. In the third section (mechanisms of tissue damage)
recorded benefit may not rise to significant levels. There elements and processes involved in the development of organ
is no doubt that lupus cries out for individualized medicine injury are presented synthetically. In the fourth the clinical
and that herding everybody under the 11 American College manifestations of the disease are presented in 19 chapters.
of Rheumatology criteria misses the fact that each person Special space was allotted to chapter 41, which presents
with lupus “employs” individual pathways to express the the pathology of lupus nephritis. My friend Isaac Stillman
same set of clinical manifestations. understands the pathology of lupus nephritis in a way that
We have also been slow in identifying the molecular very few do and I believe we should have a clear under-
and cellular mechanisms that are involved in the expres- standing of the pathology before we commit our patients to
sion of injury in each affected organ. Even if the autoim- intense treatment with cytotoxic drugs. The fifth section is
mune response is responsible for instigating tissue injury dedicated to the antiphospholipid syndrome and the sixth to
it is now better understood that autoimmunity and organ the treatment of the disease. Besides the required chapters
damage do not go hand-in-hand. Attempts to reverse injuri- on the drugs used, a chapter on the lessons we have learned
ous processes in organs should prove of clinical value. We from clinical trials is included, along with a chapter on the
understand that molecules (cell surface receptors, kinases, efforts to repurpose existing drugs to treat lupus.
phosphatases, and others) that are found to be abnormally This book exists because of the encouragement and
expressed in lupus and claimed to contribute to disease excitement of Linda Versteeg-Buschman of Elsevier whom
pathology are usually expressed by additional cells in the I thank warmly through these lines. Halima Williams
body and if inhibited across the board will invariably bring has provided unwavering support of the highest quality
about unwanted side effects. This argument mandates the throughout the solicitation, collection, and editing phases
consideration of targeted delivery of drugs and biologics to of the chapters. She made my job easy and joyful.
maximize clinical efficacy and minimize side effects.
This book has taken a different approach in presenting George C. Tsokos
the readers with state-of-the-art authoritative information Harvard Medical School
xxv
Chapter 1
History of Systemic Lupus Erythematosus
Christine Konya, Ziv Paz
Division of Rheumatology & Lupus Center, BIDMC, Harvard Medical School, Boston, MA, USA
suggested the use of caprifolin to treat the conditions of
Declare the past, diagnose the present, foretell the future.
cancer and wolf, or as quoted (translated from German): “for
Hippocrates
the wolf and for cancer, caprifolin (honeysuckle).” Rudolf
Virchow quoted even an older text dating back to the end of
the thirteenth century and referred to Roger de Palma, from
When we interview and treat patients who were diagnosed the school of Salerno: “ Sometimes lupus arises in the thighs
with systemic lupus erythematosus (SLE), read their and the lower legs (and is) distinguished from cancer from
posts in social networks, follow their support groups and the symptoms mentioned above.”4 In the middle ages, the
forums, we see how their hope brings them together. They term “lupus” was used to describe ulcerative or necrotiz-
find comfort in sharing their stories. The story of each ing skin diseases as it reminded the describers of the bite of
SLE patient is different, but not only because the patients a wolf. Superstitious people at that time related these skin
are different. The disease affects every single patient in conditions to the bite of a werewolf given the grotesque
distinct ways and changes its nature over time. The many appearance of the ulcerative skin disease.5,6
faces of this disease make its history so unique and fasci- Robert Willan (1757–1808) and his student Thomas
nating. Systemic lupus erythematosus is one of the most Bateman were British dermatologists who used the term
complex autoimmune systemic diseases. Its cause remains “lupus” to describe a destructive skin disease preferentially
unknown and our treatment options are still limited, affecting the face and the nose.7 In the mid-nineteenth century,
despite the fact that SLE has been recognized as a defined the French dermatologist Laurent Theodore Biett used the term
clinical entity for more than 100 years. “erythema centrifugum” to describe these skin lesions.2,8 The
Hippocrates was thought to be the first to describe the current name of the disease, lupus e rythematosus, was given in
cutaneous manifestations of SLE, calling it herpes esthiome- 1833 by Biett’s student Pierre Louis Cazenave, who called it
nos (gnawing dermatosis).1,2 It is not completely clear when “lupus érythèmateux or lupus erythematosus.” Cazenave was
the word lupus became synonyms with the disease. However, also the first to describe other aspects of the disease. He appre-
records indicate that it may have been Hebernus, the archbishop ciated the predilection to young females, the painless nature of
of Tours, France, in 855 AD, who was the first to use the word the facial lesions, and other features of the disease. His exact
“lupus” to describe the disease in his writing: “The Miracles of words are still relevant today and many times used by rheuma-
Saint Martin.” He mentions the bishop of Liège who was suf- tologists to describe examination findings:
fering from a severely consuming disease called lupus in the “In some circumstances (lupus) manifests itself at first
common tongue, and was miraculously cured after spending as a violet rubefaction on part of the face, and mainly on the
time in the shrine of Saint Martin in Tours.3 Later, Paracelsus, nose, which at the same time is rather swollen: over many
a fifteenth century Swiss German renaissance physician who months the color rises little by little; the surface becomes
was known for his astute observations, considered SLE to be animated; a small ulcer forms and on top of it, a scab, which
a skin disease with “greater blood supply” and recommended then thickens and covers the ulcer, which becomes progres-
treatment with bloodletting, which was the treatment of most sively deeper. Lastly, the skin may get thinner in imper-
conditions in those days. He used the term “lupus” to define ceptible stages and adopt the appearance of a scar, without
the cutaneous manifestations of the disease or, by his own there being tubercles or ulcers, and without displaying
words, “a hungry wolf eating flesh.”3 worse injuries than a livid color and, from time to time, a
Rudolph Virchow (1821–1902) was the first to review light and barely perceptible peeling.”9
systematically the history of SLE. In his writings, Virchow Ferdinand von Hebra used the phrase “butterfly rash” to
mentioned a reference from the old German book Margerita describe Cazenave’s skin findings of lupus erythematosus.10
Medicine, published in 1502 by the German physician Johann In 1872 at the Vienna School of Medicine, Moritz Kaposi,
Trollat von Vochenberg. In this reference, von Vochenberg Hebra’s son-in-law, was the first one who appreciated
Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-801917-7.00001-2
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