Lupus

PRIMER
Box 6 | Proposed remission grades in SLE*
Grade A: complete remission
• Systemic Lupus Erythematosus (SLE) Disease Activity
Index‐2000 score of 0
• No serological disease activity
• No clinical disease activity
• Glucocorticoid and immunosuppressant free
Grade B: clinical remission off glucocorticoids
• Serologically active disease activity
• Clinically quiescent disease
• Glucocorticoid free
• Use of immunosuppressants is allowed
Grade C: clinical remission on glucocorticoids
• Serologically active disease activity
• Clinically quiescent disease
• Use of glucocorticoids is allowed (<5 mg daily)
• Use of immunosuppressants is allowed
*See REF. 176.
damage are important predictors of worse QOL 148,152 .
Fatigue affects QOL profoundly 148,153 and is present in up
to 80% of patients with SLE 153 . Fatigue, often perceived
as a feature of active lupus, is a multifactorial symptom
with a questionable relationship with disease activity 154 .
Other factors that potentially contribute to fatigue are
obesity, low physical activity, poor sleep quality, mood
disorders, cognitive dysfunction, anxiety and vitamin D
deficiency 154 . Although fatigue is often recalcitrant, studies
suggest that treatment with calcifediol (a vitamin D
precursor) results in a small but significant reduction
in fatigue in patients with vitamin D‐deficient SLE 155 .
In addition, post hoc analysis of randomized controlled
trials of belimumab have shown a decreased degree of
fatigue among responders 156 , although this drug cannot
be recommended exclusively for the treatment of SLEassociated
fatigue. Recently, a study of 1,827 patients
from the SLICC cohort confirmed the effect of mood
disorders on the QOL of patients with SLE 157 .
It is important to remember that many drugs
used to treat SLE can cause serious adverse effects,
particularly glucocorticoids. Moreover, the marked
changes in phys ical appearance caused by steroid therapy
can be devastat ing, particularly in young female
patients 158 . Thus, it is not surprising that glucocorticoids
are consistently identified as one of the major
predictors of decreased QOL 148,153 . While lowering
gluco corticoid doses is strongly recommended, treating
fatigue and depression while still ensuring sufficient
immunosuppression can be challenging.
Outlook
Prevention
SLE comes at a physical, social and economic cost. Up to
30% of patients with SLE receive disability benefits and
perhaps 20% of patients cease employment 10 years
after diagnosis 159 . Several parts of the immune system
can be dysfunctional. Although the focus in recent
years has been on developing new-targeted therapies,
simpler, more cost-effective strategies might already
exist. Moreover, although prevention infers reducing the
chance of getting the disease, it must also be aimed at
reducing the chance of damage accrual once the disease
is identified.
Specific autoantibodies can be detected in patients
9 years before the diagnosis of SLE (mean: 3.3 years) 160 .
In addition, ANA positivity is found in 78% and
dsDNA- specific antibodies in 55% of future patients
with SLE, which presents an opportunity for primary
prevention. One study found that patients treated with
hydroxychloro quine or glucocorticoids early in disease
development had a delayed onset of a formal SLE diagnosis,
which required four or more ACR criteria 161 (BOX 4).
Early identification of symptoms is paramount if this
strategy is to work.
Identificaton of damage
Although overall SLE-associated mortality has improved
with 10‐year survival of 63% in the 1950s to 91% in 2000,
this disguises a slowdown in mortality improvement
after the 1980s 10 . To overcome this slowdown, there is
a need to improve identification and management of
both renal and neuropsychiatric lupus in particular. As a
result, long-term survival in SLE remains poor 162 .
Future strategies should include the early detection of
damage. Potential biomarkers include urinary levels
of VCAM1, which correlates with proliferative and
membranous glomerulonephritis, proteinuria and renal
damage 163 as well as disease activity 91 . Other urinary biomarkers
including TNF-like weak inducer of apoptosis
(TWEAK, also known as TNFSF12) are also increased
in mouse models of SLE as well as in patients. TWEAK,
part of the TNF superfamily, acts proximally in the
induction of several nephritis-related cytokines, such as
CC-chemokine ligand 5 (CCL5) and CXC-chemokine
ligand 10 (CXCL10). Higher urinary levels of TWEAK
reflect renal flares of SLE and are found at lower levels in
non-renal flares and stable lupus nephritis 164 .
Diagnosing neuropsychiatric SLE remains a challenge.
Functional MRI can detect certain phenotypes
including stroke. A subset of dsDNA-specific antibodies
cross-react with the extracellular ligand-binding
domain, comprising the NR2A and NR2B subunits of
the N‐methyl-d‐aspartate receptor. Although there is
no clear correlation between anti‐NR2 antibodies and
neuropsychiatric SLE, anti‐NR2 antibodies purified
from patients with neuropsychiatric SLE can induce
cognitive changes, memory deficit, neurotoxicity and
compromised blood–brain barrier in mice 165,166 .
The challenge is to translate these research tools to
bedside tests that can rapidly identify ‘at-risk’ patients
with SLE to prevent organ damage and prolong lifespan
and QOL.
Management of cardiovascular complications
An increased risk of CVD and early mortality is associated
with SLE and especially longer SLE duration 167 .
The overall risk of CVD is estimated to be between 2.6
(REF. 168) and 10‐times higher 169 in patients with SLE than
16 | 2016 | VOLUME 2 www.nature.com/nrdp
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