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リウマチ Vol.41 No.2 indexに戻る
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リウマチ Vol.41 No.2 |
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「SLE―A Prospect for the 21st Century：Lessons
from the Past」 |
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| Daniel J Wallace M. D |
| UCLA School of Medicine, Los Angels, CA, USA |
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| 招請講演 |
Lupology, the study of lupus patients, underwent
many iterations during the 20th century. 1900-1948 representing
the period of empiric
observation, mostly by pathologists with an interest in collagen-vascular
diseases. The description of the LE cell phenomenon in 1948 and
the clinical introduction of corticosteroids the same year greatly
increased the numbers of known lupus patients and allowed meaningful
clinical interventions. The years between 1948 and 1965 were characterized
by a handful of lupus experts describing the prevalence of symptoms,
signs and laboratory findings associated with the disorder and
the influence of interventions with corticosteroids. Antinuclear
antibodies, anti-DNA and the role of complement was first described.
Drug induced lupus was defined, and chronic cutaneous（discoid）lupus
became distinguishable from SLE. The availability of azathioprine
and cyclophosphamide in the early 1960s increased the options lupologists
had in managing their patients.
The explosive growth of immunology between 1965 and 1980 saw investigators
differentiate lymphocytes into T and B components and demonstrated
the basic principles of cellular immunity taken for granted. Over
20 autoantibodies potentially relevant to autoimmunity were described
and characterized. Clinicians formed a committee for the first
time and devised criteria for defining systemic lupus. With an
agreed upon definition, meaningful epidemiologic and mortality
surveys could be published. During the 1980s, antiphospholipid
antibodies and their related syndromes became delineated. These
insights improved the management of lupus pregnancies as well.
Much to our surprise, phospholipid mediated central nervous system
events and cognitive dysfunction associated with SLE turned out
to be rarely part of a vasculitic process but dependent on blood
flow, cytokines and coagulation disturbances. The mechanisms by
which drugs cause lupus was unraveled：antihistone antibodies, the
role of oxidized metabolites of aromatic amines and DNA hypomethylation
among others.
Since 1990, there has been an explosion of new published information
germane to SLE. Basic science and cellular immunology insights
relate macrophage dysfunction, cell signaling defects, co-stimulatory
molecules, T cell subsets, pro-inflammatory mediators（adhesion
molecules, nitric oxide, cyclooxygenase), apoptosis, aberrant cytokine
production, and tolerance defects to the disorder. Linkage studies,
genome scans and association studies led investigators to describe
20-30 lupus susceptibility genes. Ultraviolet light can damage
lupus skin by autoantigen formation, direct cytotoxicity and promoting
an inflammatory reaction. Humeral research has explored idiotypic
networks, the phylogenetically important antibodies to the nucleosome,
the ability of autoantibodies to penetrate living cells, nerve
tissue antibodies, and the pathogenecity of cationic IgG anti-DNAantibodies.
The end of the millennium witnessed lupologists forming consortiums
to better define lupus related disorders（e. g., undifferentiated
connective tissue disease and update the ACR criteria), evolve
clinical indices to assess damage and response to therapy（e. g.,
BILAG, SLEDAI, SLAM, damage indices), look into hormonal interventions（SELENA),
and evolve quality of life measures. Though newer antibiotics,
antihypertensives and antihyperlipidemic agents have increased
the lupus patient's lifespan, the morbidity of long term corticosteroid
use is still significant.
In 1994, the first entirely new lupus drug in a generation, DHEA,
began multicentered clinical trials. The dawning of the 21st century
has witnessed an array of exciting interventions being studied
by industry and lupus investigator initiated cooperative efforts.
These include cox-2 selective antagonists, inhibitors of lipooxygenase
and adhesion molecules, newer generation immune suppressives（mycophenolate
mofetil, leflunomide, immunophylls）and hormonal interventions.
At least 6 biologics targeting specific immune interactions have
been studied or are being studied, and the next decade will adapt
peptide vaccinations, gene transfer therapy, stem cell transplantation
and modalities which influence apoptosis to help the suffering
of lupus patients. We have come a long way and these is a lot to
look forward to. |
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