Introduction
OVERVIEW clinical presentation and then a focus on organ systems
Lupus is a chronic disease of unknown etiology that is
very difficult to diagnose and treat, sometimes over-
diagnosed and more often than not diagnosed with
great delay. Since the last edition of this book, major
advances have been noted in the treatment of many
autoimmune illnesses using biological therapy, but
nothing exists that is able to completely reverse the
ravages of an autoimmune disease like lupus. Although
there are some promising drugs on the horizon, the
absence of significant progress in understanding and
treating this disease over a 40-year period is not due to
modest research funding or lack of attention, but may
be the result of the complexity of the disease and
a misunderstanding of the criteria for diagnosis,
biomarkers of severity, and instruments to measure clin-
ical activity. The establishment of clear indices that allow
regulatory agencies to see some consistency of response
is critical to the development of new agents to treat
lupus. More important, however, both pharmaceutical
and government regulatory agencies have to have
a clearer understanding of the disease, its multisystem
nature and the nuances of the immune system. This is
not a one-cause one-cure illness.
The question of whether lupus is one illness or many
may be one of the difficulties. This protean illness pres-
ents in a variety of ways and its clinical manifestations
depend on the organs chosen by the immune system
for attack. Three simple things can be said about SLE;
the disease favors women, has a genetic association,
and has an elusive trigger. In this 5th edition, these simple
facts are explored in lucid detail. In this edition we have
revised every chapter, eliminated some and have added
many new chapters. The book is organized in sections:
the pathogenesis of disease, the clinical aspects of the
illness with a special section on the antiphospholipid
syndrome, and finally a section on treatment.
The section on the pathogenesis of disease deals with
genetics, cellular, humoral, and environmental aspects.
We have also included a subsection on tissue injury
because all of these aspects of pathogenesis have such
importance to a basic understanding of disease. All of
the chapters in this section are new with many new
authors and provide a view into the scientific thinking
of this disease which is not available anywhere else.
Clinical aspects of the disease are divided into the
xvii
that might be affected by lupus. In this section we have
paid special attention to research and clinical trials and
have added chapters on design of trials and measure-
ment of disease activity. An additional section entitled
“antiphospholipid syndrome” parallels the clinical SLE
section and is divided into basic pathogenesis and clin-
ical aspects of the disease as well. At the end of the book
is the treatment section which relates the latest drugs
approved and development for the disease.
Over 90% of the authors for this edition are new and
contributing new topics. The book is enhanced in all
areas to provide the reader with the latest information
about SLE, its science, presentation and treatment.
Lupus gives us a handle on molecular biology, insight
into common ailments like atherosclerosis and diseases
like multiple sclerosis and Sjögren syndrome.
THE HISTORY OF SYSTEMIC LUPUS
ERYTHEMATOSUS
The history of SLE is long and interesting. Lupus is
the Latin word for wolf and the Romans used the term
loosely to mean “eating and devouring diseases”,
much as the Greeks referred to the term Herpes which
means “to creep.” Many terms including leprosy, which
means “to scale” in Greek, have come down through the
centuries and are used today for specific syndromes.
Hippocrates had names for several ulcerating diseases
which he called herpes esthiomenos. Most historians
believe that he included lupus in that group. In antiquity
a variety of illnesses, many relevant to the face and dis-
figuring, were called “nole me tangere” (touch me not)
and were different than boils of the lower extremities
that were called lupus lesions [1]. After 1500 AD, physi-
cians tried to use lupus for lesions of the face, but it was
not until the early part of the 19th century when Robert
Willon (1757e1812) and his students presented a classifi-
cation scheme for diseases and lesions of the skin. Vesic-
ular skin lesions were under the heading of Herpes, and
destructive or ulcerative skin lesions of the face and nose
were called lupus. These classifications were further
defined by a student of Willon’s, Thomas Bateman.
One of Bateman’s students, Laurent Biett (1781e1840)
(the Parisian school), pursued and enlarged the classifi-
cation of skin lesions and his student, Cazenave
xviii INTRODUCTION
(1802e1877), was the first physician to use the term
lupus erythematosus [2, 3]. This new name evolved
over many years. Biett divided Willon’s skin lesions
called lupus into three categories as it appeared in the
fourth edition of their famous dermatology textbook
entitled Abrege Practique Des Maladies de la Peau [2]. There
were the first, lupus qui detruit en surface (lupus which
destroys on the surface); the second, lupus qui detruit en
profondeur (lupus which destroys at a depth); and third,
lupus avec hypertrophic (lupus with hypertrophy). Caze-
nave was responsible for producing the fourth edition
of the Abrege textbook in 1851 and in that edition he
identified a fourth category of the skin classification
noting atrophy, telangiectasias, fixed erythema,
adherent scaling and follicular plugging. He called this
fourth category lupus erythemateux. In 1846, Ferdinand
von Hebra (1816e1880), an accomplished Viennese
physician, used “butterfly rash” or “bat wing rash” to
describe the familiar malar rash of the disease. The
butterfly rash was more accepted and is a term used
today. In his 1856 book, Von Hebra published the first
illustrations of the disease in the Atlas of Skin Diseases.
In 1872, Moretz Kaposi described the visceral forms of
the illness and physicians began to suspect that this
illness was more generalized than the skin and used
the term acute disseminated in their descriptions [4].
Kaposi proposed two types of lupus: disseminated and
discoid. In his writings, he supposed that the dissemi-
nated form consisted of subcutaneous nodules, arthritis,
lymphadenopathy, fever, weight loss, anemia, and
central nervous system involvement. In 1894, Payne at
Saint Thomas Hospital in London suggested that there
was “a vascular disturbance causing hyperemia” that
could be influenced by quinine. In 1904, William Osler
described two women who developed renal failure
within ten months of developing facial erythema, which
in retrospect was the facial rash described by Von Hebra
[5]. Osler described a number of other illnesses at the
time, among them Henoch Schoenlein purpura and
disseminated gonococcemia which could be confused
with the lesions in the two women with lupus. In
Vienna, at the same time, Jadassohn [6] described similar
syndromes in a few patients. Both he and Osler estab-
lished SLE as a distinct entity by the turn of the century,
even though many general practitioners still thought of
SLE as a form of skin tuberculosis.
In 1902, Sequira and Balean of the London Hospital
published 71 cases of lupus erythematosus: 60 had
discoid and 11 had disseminated disease. The new
description of acroasphyxia (Raynaud phenomenon)
was a common feature.
Typical cases of SLE were reported under a variety of
names during this period and not until the 1920s and
1930s were the cases well defined [7]. This was mainly
because the pathologists who studied morbid anatomic
pathology prior to the 1930s concerned themselves
only with the pathologic changes and not the clinical
condition of the patients. The atypical bacterial endocar-
ditis of Emmanuel Libman and Benjamin Sacks,
reported in 1924, were carefully described and were
explained some 60 years later as a consequence of phos-
pholipid antibodies [8]. Following that description,
George Baehr published a series of 23 autopsied cases
of the renal wire loop lesions of lupus nephritis and
described the solar sensitivity so well known in this
disease. Knowledge of lupus pathology was evolving
in the early twentieth century. In 1936 Freiberg, Gross
and Wallach autopsied a young woman with lupus
and no skin lesions showing that the disease was not
restricted to include skin lesions and not associated or
caused by tuberculosis. Klempner Pollack and
Baehr, in 1941, suggested that collagen was a part of
the disease because of the many instances of fibrinoid
necrosis that they found with the disease. Thus evolved
the name collagen disease which was used for many years
to describe all of the diseases involving connective
tissue.
Hack and Reinhart were the first to describe the false-
positive syphilis test in SLE and, in 1940, Keil similarly
reported ten cases of SLE with false-positive syphilis
tests. Haserick and Lang wrote about an additional
series of cases where the presence of the false-positive
serology predated the clinical lupus by up to 8 years.
In all of these cases, the false-positive syphilis tests prob-
ably resulted from the presence of antiphospholipid
antibodies, the discovery of which was to take an addi-
tional 30 years. In 1955, Moore studied another
148 patients who were positive for syphilis and found
that some 7% developed lupus over time, whereas 30%
had symptoms relegated to collagen vascular disease [9].
In 1949, Phillip Hench discovered cortisone and the
future of the connective tissue diseases changed forever
e rheumatoid arthritis (RA) patients and those with
lupus were manageable and “cures” were reported [10].
In 1948, Hargraves, Richmond, and Morton described
the LE cell in the bone marrow of SLE patients [11]. This
test was later adapted to peripheral blood. This discovery
laid the foundation for our confirmation of the disease
lupus as an autoimmune disease. These were phagocytes
eating cells coated with autoantibody. Until it was
described in other illnesses like RA, it was thought to
be pathognomonic of lupus. Dubois, in 1953, and Harvey,
in 1954 [12], sought to set the record straight by stressing
the chronicity of SLE and recognized the diagnostic
importance of the LE test. The presence of this finding
in only 50e70% of lupus patients and the rapid develop-
ment of more specific tests of autoimmune disease
made its use limited. Other serum abnormalities like
hypergammaglobulinemia detected in newer techniques
like immunoelectrophoresis suggested that gamma
 INTRODUCTION
globulins were abundant in the sera of lupus patients and
these were in reality the antibodies that reacted with
normal tissues. These were later called autoantibodies.
George Friou, in 1957 [13], applied the indirect immuno-
fluorescent test of Coons to the study of these autoanti-
bodies. The fluorescent antinuclear antibody test
(FANA) is positive in some 95e98% of SLE cases. At
about the time of the Friou discovery, Deicher, Holman,
and Kunkel at Rockefeller University [14], along with
three other groups, described the antibodies to DNA,
both double and single stranded. Thus, began one of
the most influential and prolific laboratories for the study
of lupus in the entire world. In 1956, Eng Tan and Kunkel
described an antibody to a glycoprotein called SM after
the first initials of one of the many patients followed in
the research clinic [15]. The patient’s name was Smith
and she was one of many patients from whom new auto-
antibodies were described. Following that autoantibody
came the discovery of antibodies to ribonucleoprotein
and other cellular components which later helped to
dissect cell function and open the doors to molecular
biology.
As more and more antibodies were described, clinical
conditions like the overlap syndrome of mixed connec-
tive tissue disease of Gordon Sharp followed.
Dixon and colleagues [16] assisted with the develop-
ment of many murine strains of the disease driven by
genetics of the mouse strain and sharing many of the
features of the human disease. In 1954, Leonhardt
described the familial nature of lupus, later studied by
Schulman and Arnett at Hopkins [17] and subsequently
by Hahn, Harley, and Behrens [18]. Studies provided
discussions of multiplex families and twins as well as
gender-specific inheritance and the presence of constitu-
tive MHC II and MHC III relationships. All the while,
our understanding of the cellular components of the
innate and adaptive immune system as well as the fine
nuances of the various antibodies in understanding
cell functions led to today’s revolution in our knowledge
of this important illness.
Finally, the work of Hughes [19] and others opened
the door to our understanding of antiphospholipid anti-
body syndrome as an important aspect of lupus. The
frequency of this syndrome within the disease lupus is
a great curiosity and we have given an entire section
to this syndrome within the book.
No history of lupus gives credit to the countless
investigators who have provided data to enhance our
knowledge of the disease. The history of lupus is not
static and there will be many more years of clinical
xix
and scientific advances until we find the cause of
this disease.
Robert G. Lahita
Newark, NJ 2010
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