review
Optimising management of
systemic lupus erythematosus
There is now a better understanding of autoimmunity in systemic lupus erythematosus, which has
led to improved therapeutic strategies, but revolutionary treatments have yet to be discovered
Ioannis Parodis MD PhD
Division of Rheumatology,
Department of Medicine,
Karolinska Institutet;
Rheumatology Unit,
Karolinska University
Hospital, Stockholm,
Sweden
Systemic lupus erythematosus (SLE) is a chronic
inflammatory autoimmune disorder that
predominantly affects women of child-bearing age with
a ~9:1 female-to-male ratio. Patients with SLE suffer an
impaired health-related quality of life (HRQoL), and
experience fatigue and pain as major problems.
The pathogenesis of SLE is multifactorial and its
aetiology is largely unknown. 1 Genes, hormones
and environmental factors have been implicated
among the causes of the disease. Multiple organs
may be involved, including the skin, joints, kidneys
and the central nervous system, with renal and
neuropsychiatric SLE probably constituting the
most severe manifestations. Considerable variations
in severity can be observed during the course of
the disease, with periods of remission and flares,
the intensity of the latter ranging from mild to
severe, to sometimes organ- or life-threatening.
Mortality during the early course of the disease is
associated with activity grade and infections, but
comorbidities, especially cardiovascular disease,
are considerable causes of death at later stages. 2
In SLE, both the innate and the adaptive
immunity may be aberrant, and defective
apoptotic cell clearance is hypothesised to be
a central phenomenon underlying the initiation
of autoreactive responses. The type I interferon
pathway has a central role in the pathogenesis of
SLE, 3 and the hyperactivity of the B cell lineage also
has pivotal significance. The disease is characterised
by a prominent production of autoantibodies
to nuclear components and immune complex
depositions, resulting in inflammation and damage
in organs and/or tissues. There is now a better
understanding of autoimmunity in SLE, which
has led to improved therapeutic strategies, but
revolutionary treatments have yet to be discovered.
Management of SLE
The management of SLE and the development of
new therapies have been challenging because of the
prominent heterogeneity of the disease in clinical
presentation and underlying immunopathology,
as well as its unpredictable course. For these
reasons, the treatment of SLE varies and is
highly individualised. Commonly used therapies
include corticosteroids, antimalarial agents,
immunosuppressive agents and non-steroidal anti-
inflammatory drugs (NSAIDs). 4,5 Several immune
components have been identified as potential targets
of novel treatments. Unfortunately, the majority of
trials have failed. In 2011, drug agencies in several
countries approved belimumab, an anti-BAFF (B
cell-activating factor belonging to the TNF family)
monoclonal antibody, for the treatment of SLE. 6,7
The introduction of belimumab has contributed to
improved management; however, it is still unclear
which patient groups are expected to benefit most
from this drug. Considering the cost and potential
toxicity of biologic therapies, further survey towards
identification of predictors of treatment response is
of utmost importance.
Therapeutic strategies in SLE
The management of SLE has traditionally been non-
specific, with symptomatic therapeutic approaches.
As mentioned above, the reasons for this can be
traced to: (i) the lack of therapies targeting specific
immune components, with the possible exceptions
of belimumab, rituximab and cyclosporine; and
(ii), the wide spectrum of clinical manifestations.
The treatment strategies are therefore individual,
depending on the organ involvement, the severity
of the disease and the complications. Non-major
organ involvement may be treated with for example,
glucocorticoids, antimalarial agents, and NSAIDs. In
more severe or non-responsive cases, azathioprine,
mycophenolate mofetil and methotrexate are
commonly used. Despite their widespread use, not
all of these drugs have been approved for SLE.
The use of antimalarial agents in SLE is coupled
to a wide variety of beneficial effects, making
this drug class the cornerstone of SLE therapy. 8,9
The modulatory effects of antimalarial agents
on immune responses are mediated by several
mechanisms, for example, through interference
with antigen processing. The use of antimalarial
agents in SLE has been associated with remission
maintenance effects, 8 as well as prevention of flares
and decreased corticosteroid use during pregnancy. 10
Hydroxychloroquine has been shown to improve
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