Lateef and Petri Arthritis Research & Therapy 2012, 14(Suppl 4):S4

http://arthritis-research.com/content/14/S4/S4

REVIEW

Unmet medical needs in systemic lupus

erythematosus
Aisha Lateef1 and Michelle Petri*2

Introduction
Abstract Systemic lupus erythematosus (SLE) is a complex auto-
Systemic lupus erythematosus (SLE) is an autoimmune immune disease, predominantly affecting young women
disease of diverse manifestations, with onset usually during the prime years of their life. The chronic nature of
in young women in the third to fourth decade of life. the disease, its relapsing remitting course and organ
The chronic nature of this relapsing remitting disease damage accrual over time frustrate both the physician
leads to organ damage accrual over time. Mortality and and the patient. Clinical and translational research has
morbidity are increased in patients with SLE compared advanced the available therapeutic options, translating
with the general population. Therapeutic advances into better patient outcomes. Five-year survival in
over the last few decades have led to significant patients with SLE has improved from 50% in the 1950s to
improvements in patient outcomes. Five-year survival over 90% currently. However, the mortality still remains
has improved to over 90% from a low of 50% in the high compared with the general population.
1950s. However, multiple aspects of the management Multiple aspects of SLE remain challenging. The
of SLE patients are still far from optimal. Early diagnosis diverse and nonspecific presentations can lead to delay in
remains a challenge; diagnostic delays leading to diagnosis. Disease monitoring remains difficult due to
delay in definitive treatment are common. Monitoring the low sensitivity of current disease activity markers.
treatment remains problematic due to the paucity of Management of refractory disease, especially nephritis,
sensitive biomarkers. Current treatment regimens rely cutaneous and neuropsychiatric manifestations, remains
heavily on corticosteroids, even though corticosteroids unsatisfactory. End-stage renal failure, scarring cuta-
are well known to cause organ damage. Treatment neous lesions and neurological damage remain fearsome
of refractory disease manifestations such as nephritis, complications of the disease. Cardiovascular disease
recalcitrant cutaneous lesions and neurological secondary to accelerated atherosclerosis has emerged as
involvement require new approaches with greater an important contributor to the higher morbidity and
efficacy. Cognitive dysfunction is common in SLE mortality in longstanding disease. Damage due to both
patients, but early recognition and adequate treatment disease and treatment, especially corticosteroid-associated
are yet to be established. Premature accelerated damage, tends to accumulate over time. Fatigue, fibro-
atherosclerosis remains a leading cause of morbidity myalgia and depression negatively impact the quality of
and mortality. Fatigue is one of the most disabling life (QoL). Clinical research in the field of SLE thera-
symptoms, and contributes to the poor quality of life in peutics has met with limited success in recent years.
patients with SLE. Ongoing research in SLE faces many Heterogeneous patient populations, limitations of out-
challenges, including enrollment of homogeneous come measures and the lack of a uniform control group
patient populations, use of reliable outcome measures are mostly responsible for the suboptimal responses.
and a standard control arm. The current review will Although there are numerous unmet medical needs in
highlight some of the outstanding unmet challenges in SLE, this review will focus on some of the major out-
the management of this complex disease. standing issues – including early diagnosis, biomarkers in
SLE, management of refractory disease, atherosclerosis
in SLE, corticosteroid-associated damage, QoL in SLE,
*Correspondence: mpetri@jhmi.edu and clinical research in SLE.
2
Division of Rheumatology, Johns Hopkins University, School of Medicine, Johns
Hopkins Lupus Center, 1830 E. Monument Street, Suite 7500, Baltimore, MD 21205,
USA Early diagnosis
Full list of author information is available at the end of the article SLE is a multi-system heterogeneous disease with protean
manifestations. Initial nonspecific presentations can lead
© 2010 BioMed Central Ltd © 2012 BioMed Central Ltd to diagnostic delays. The revised American College of
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Rheumatology (ACR) classification criteria, although not tool and not a single biomarker has been validated for
designed for diagnostic purposes, have been used by clinical use to date. As SLE is a heterogeneous disease, a
rheumatologists for almost three decades [1]. The single biomarker is unlikely to be sufficient. Rather,
Systemic Lupus International Collaborating Clinics different markers may provide information about specific
(SLICC) group recently developed another set of revised disease aspects, as summarized in Table 1.
criteria. These new criteria include 17 variables derived
by expert consensus (SLICC committee members) and Management of refractory disease
statistical analysis, using real-life patient scenarios. The There is no clear definition of refractory disease in SLE,
final set of new criteria was then validated in another but it generally refers to patients who fail to respond to
group of SLE patients and controls. The control group conventional treatments. In a heterogeneous disease such
comprised other autoimmune diseases, which may have as SLE, the clinical situation may vary, depending on the
overlapping features with SLE. disease manifestations and organ involvement. Although
SLICC criteria require that at least one clinical criterion any clinical feature may become persistent and non-
and one immunologic criterion be present, with a total of responsive to therapy, the most concerning features are
four criteria, to have a classification of SLE. Under this refractory lupus nephritis, scarring cutaneous disease
new classification, lupus nephritis by biopsy (in the and neuropsychiatric lupus (NPSLE).
presence of SLE autoantibodies) is sufficient for classifi-
cation [2]. Using expert consensus as the gold standard, Lupus nephritis
the revised criteria demonstrated greater sensitivity (97% Renal involvement is a major cause of mortality and
vs. 83%, P  <0.0001) but less specificity (84% vs. 96%, morbidity in SLE. A large proportion of patients, up to
P <0.0001) than the current ACR criteria in the validation 60%, develop immune complex-mediated lupus nephritis
group [2]. These criteria are clinically more relevant and during the course of their disease. The treatment of lupus
will probably identify more patients with clinically nephritis has rapidly advanced over the last few decades.
defined lupus than using the current ACR criteria. How- Glucocorticoids and cyclophosphamide were once
ever, one should stress that these criteria are primarily considered the standard of care. Although effective in the
meant for classification of patient cohorts for research majority of patients, cyclophosphamide was associated
and their use for diagnostic purposes has to be carried with serious adverse effects including infections, malig-
out with caution. Some patients may initially present nancy and infertility. Lower doses of cyclophosphamide
with insufficient features to fulfill the classification and mycophenolate emerged as effective options for
criteria, termed ‘incomplete lupus’ or ‘lupus-like disease’ induction therapy, with better safety profiles [14,15].
by some groups. Patients with different ethnic backgrounds might have
differential responses to cyclophosphamide versus myco-
Biomarkers in systemic lupus erythematosus phenolate [16]. Azathioprine and mycophenolate have
SLE is the most diverse autoimmune disease, clinically been shown to be effective options for maintenance
and serologically. Genetic influences as well as epigenetic therapy in randomized trials [17,18]. Mycophenolate was
and environmental interactions probably play a role, superior to azathioprine in the ALMS trial, but not in a
perhaps dependent on the ethnic background of the MAINTAIN trial [17,18].
individual. Classification criteria may help but currently, Alternate approaches have been tried for patients
there is no single parameter that is sensitive or specific failing to respond to these conventional treatments.
enough to correctly identify or subtype all SLE patients. Calcineurin inhibitors, cyclosporine and recently tacro-
Similarly, the disease course can be variable with either limus have shown promising results in patients unres-
intermittent flares or chronic activity. Levels of auto- ponsive to first-line therapies, but need further evaluation
antibodies (anti-double-stranded (DNA) antibody) and in larger controlled trials [19-21]. B cells play a central
complement components represent serologic disease role in the pathogenesis of lupus nephritis, making them
activity. They are routinely used to monitor disease activity a logical therapeutic target. Rituximab, a chimeric anti-
in most clinical settings, but their association with CD20 antibody, efficiently and reliably depletes CD20-
clinical activity has not been consistent in longitudinal positive B cells. A large number of open-label studies
studies [3]. documented the efficacy of rituximab in refractory lupus
There is an unmet need for more sensitive and reliable nephritis [22]. Unfortunately, a large randomized con-
biomarkers that can predict susceptibility, activity, trolled trial (LUNAR) did not show any significant differ-
severity and disease subtype in SLE. Multiple candidate ences in outcomes with rituximab compared with
markers have been proposed, including the type 1 placebo [23]. However, this trial excluded patients with
interferon signature, B-lymphocyte stimulator and many refractory disease, the very subset in which evidence of
others [4-13]. These markers are currently only a research benefit was shown in open-label studies. Additionally,
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Table 1. Potential biomarkers and their proposed applications in SLE

Category Biomarker Associations Comments
Susceptibility IRF-5
STAT-4 Specific haplotypes confer increased susceptibility
to SLE. Genome-wide association studies have Genetic epistasis between different loci has
HLA-DRB1
identified many loci, mostly related to immune been described
PTPN22 regulatory genes
Fcγ receptors

Complement proteins Deficiency in early components of the classical Partial C4 deficiency due to gene copy number
complement pathway is a strong risk factor for SLE variations increases the risk of SLE

Disease activity IFNα High levels of IFNα or IFN inducible genes Despite the association with activity, the
(IFN signature) and chemokines correlated with IFN signature was not predictive of flare in
disease activity longitudinal studies

B-cell subsets CD27high plasma cells correlated with disease activity

Data are limited and almost all proposed
Serum cytokines, receptors Multiple cytokines (for example, IL-6, IL-10, IL-16,
candidates are still far from being established as
and adhesion molecules IL-18), soluble receptors (sIL-2 R) and adhesion
a reliable marker in SLE
molecules (for example, sICAM and sVCAM) have
been suggested to correlate with disease activity

Disease severity IFNα High IFN signature group has more severe disease Holds the potential to identify high-risk patients
manifestations

Disease subtype IFNα High versus low IFN groups have distinct clinical
features, autoantibody associations and genetic
profiles IFN signature and BLyS levels may potentially
define subgroups of patients
BLyS High BLyS levels are associated with specific
autoantibodies

Flares BLyS Higher and rising BLyS levels were predictive of The association has not been consistent across
increase in disease activity at subsequent visit the studies

Organ specific Anti-C1-q antibodies Correlate with the presence and severity of lupus Potential robust marker for lupus nephritis
nephritis

Anti-NR2 antibodies Associated with neuropsychiatric manifestations in Human results have been largely negative
a murine model
Anti NR2 antibodies, anti-N-methyl-D-asparate (NMDA) receptor antibodies; BLyS, B-lymphocyte stimulator; HLA, human leukocyte antigen; IFN, interferon; IRF,
interferon regulatory factor; PTPN22, protein tyrosine phosphatase N22; sICAM, soluble intracellular adhesion molecule; SLE, systemic lupus erythematosus; STAT,
signal transduction and activator of transcription; sVCAM, soluble vascular adhesion molecule.

heavy background immunosuppression may have masked relapses remain common and progression to renal damage
any beneficial effect of rituximab [24]. Open-label data may occur. The incidence of end-stage renal disease
continue to be positive and a recent systematic review attributable to lupus nephritis has not declined over the
concluded that evidence for rituximab efficacy in decades [31,32]. About 10 to 30% of SLE patients still
refractory lupus nephritis is strong, and another well- progress to end-stage renal disease with associated
conducted trial may provide more answers [25,26]. morbidity and mortality. Multiple variables affect renal
Hydroxychloroquine deserves special mention in the prognosis, including the disease severity, antibody asso-
treatment of SLE, including lupus nephritis. Hydroxy- ciations, ethnicity, genetic background, socioeconomic
chloroquine has been shown to improve response rates, status and concomitant co-morbidities [33,34].
decrease flares and improve survival [27,28]. Every SLE
patient should receive hydroxychloroquine, unless in- Cutaneous lupus
tolerant or contraindicated. Renal protective therapies Skin involvement occurs in 70 to 85% of SLE patients and
such as angiotensin-converting enzyme inhibitors and includes acute, subacute and chronic cutaneous lesions.
angiotensin receptor blockers, strict control of blood Discoid lupus is the most common form of chronic
pressure and serum lipids, are important adjuncts to lesion, and may be the initial presentation of SLE in up to
therapeutic regimens for lupus nephritis [29,30]. 10% of cases. Resistant discoid lesions may cause scarring
Despite aggressive immunosuppressive and supportive of the affected skin areas and permanent scarring
therapies, induction of remission may be slow or partial, alopecia. This can lead to significant disfigurement,
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emotional distress, physical limitations and disability in a cognitive dysfunction, no treatment of proven benefit
large number of patients. Although generally believed to exists for cognitive dysfunction in SLE [45,47].
be associated with less severe systemic disease, discoid NPSLE management remains problematic due to the
lupus has also been associated with more damage accrual lack of specific tools for diagnosis and attribution. Treat-
[35]. In addition, the risk of squamous cell carcinoma is ment options are limited to glucocorticoids and a few
increased in scarred areas. immunosuppressants (cyclophosphamide, azathioprine,
The conventional approaches include photoprotection, mycophenolate, rituximab), with efficacy mostly suggested
corticosteroids (topical, intralesional and systemic) and by case reports and open-label studies. A European League
antimalarial agents [36]. Other topical agents such as Against Rheumatism task force recently published
calcineurin inhibitors and retinoids can benefit some recommendations on the management of NPSLE; it was
patients with refractory lesions. Multiple immunosup- felt that ‘there is currently no good quality evidence to
pressants including methotrexate, azathioprine, myco- guide several diagnostic, primary prevention, therapeutic
phenolate, cyclophosphamide, dapsone, gold and thalido- and monitoring decisions in NPSLE, emphasizing the
namide have been tried for refractory disease [36]. need for further research’ [48].
Biologic agents including TNF inhibitors, efazulimab
(anti-CD11 antibody) rituximab (anti-CD20 antibody) Atherosclerosis and systemic lupus erythematosus
and tocilizumab (anti-IL-6) have been used in some SLE is associated with premature and accelerated athero-
refractory cases [37]. Data are limited to anecdotal sclerosis, contributing significantly to the increased
reports, case series and open studies. A recent Cochrane mortality and morbidity associated with the disease [49].
review concluded that the evidence about therapies for An increased frequency of conventional risk factors, such
discoid lupus, other than topical corticosteroids and anti- as hypertension, dyslipidemia and diabetes, has been
malarials, was not conclusive [38]. The need for additional noted in patients with SLE. Yet the excess risk cannot be
therapies for such a disfiguring manifestation of young fully explained by the traditional Framingham risk factors
people with SLE cannot be overemphasized. [50,51].
Multiple putative mechanisms have been proposed but
Neuropsychiatric lupus the exact pathogenesis of atherosclerosis in the setting of
NPSLE remains one of the most challenging issues in the SLE is yet to be fully elucidated. High-density lipoprotein
management of SLE patients. Affecting up to 30 to 40% of was reported to be significantly dysfunctional and pro-
the patients, NPSLE includes diverse neurologic and inflammatory in SLE patients, and correlated with
psychiatric manifestations, from subtle cognitive deficits measures of subclinical atherosclerosis [52]. Endothelial
to severe psychosis, seizures and strokes. The attribution cell dysfunction in SLE leads to abnormal vascular
of neuropsychiatric events to SLE is often challenging in reactivity and repair, contributing to the accelerated
the clinical setting. The ACR committee has described atherogenesis [53]. Interferon activity was independently
case definitions for 19 NPSLE syndromes, but the speci- associated with subclinical measures of atherosclerosis in
ficity remains low [39,40]. Anti-ribosomal P antibodies a cohort study [54]. Specific subtypes of peripheral blood
have been associated with NPSLE, especially psychosis mononuclear cells, the low-density granulocytes, and
[41]. Measurement of cerebral spinal fluid cytokine and increased Toll-like receptor signaling have been proposed
chemokine levels remains a research tool [42]. Neuro- to contribute to higher interferon production and
imaging can be helpful but the sensitivity and specificity vascular dysfunction in patients with SLE [55,56].
remain quite low [43]. Autoantibodies including antiphospholipid and antilipo-
The management of NPSLE depends on the manifesta- protein antibodies have been associated with abnormal
tion and the likely predominant mechanism. Current vascular function and atherosclerosis in SLE [57].
strategies include the use of immunosuppressive thera- Despite the evidence of a link between inflammation
pies when the underlying mechanisms are predominantly and atherosclerosis in SLE, multiple studies have failed to
inflammatory. Anticoagulation and/or antiplatelet show any consistent association of coronary calcium
therapy should be considered when antiphospholipid scores or carotid plaques with markers of disease activity
antibodies are persistently positive in moderate to high [51,58,59]. In patients with SLE, the proportion of
titers. Non-SLE precipitation and aggravating factors noncalcified vulnerable plaque was shown to be increased
should be addressed. Cognitive dysfunction merits special compared with the calcified stable plaque, and correlated
mention. It is present in a majority of SLE patients, even with measures of disease activity [60]. Elevated homo-
newly diagnosed patients [44,45], and has also been cysteine, asymmetric dimethylarginine, leptin and high-
associated with psychosocial factors such as depression, sensitivity C-reactive protein levels have been proposed
fatigue, anxiety and pain [45,46]. Although antidepres- as markers of accelerated atherosclerosis in SLE in some
sants may benefit some patients with depression and studies [61-64].
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The management of atherosclerosis in SLE is currently with 50% rating it as the most disabling symptom [73].
limited to the control of traditional risk factors. Statins Fatigue can significantly contribute to the poor QoL in
are believed to have anti-inflammatory properties, in SLE patients [72]. The pathophysiological mechanisms of
addition to their lipid-lowering effects. However, two SLE-related fatigue are probably multifactorial, with a
large randomized controlled trials failed to show any predominant role being played by the psychological
beneficial effects of 20 mg atorvastatin versus placebo in domains. Psychosocial factors such as mood disorders,
adult and pediatric SLE patients without clinical anxiety, poor sleep quality and chronic pain syndrome
cardiovascular disease [65,66]. The use of statins in SLE have shown consistent associations with fatigue in SLE
patients should thus be limited to treat hyperlipidemia. [74,75]. Exercise programs have been shown to have a
Hydroxychloroquine was noted to have weak protective positive impact on fatigue among SLE patients [76].
effects on cardiovascular risk in SLE [28]. Mycophenolate However, fatigue remains an unmet need, reflected by the
reduced the atherosclerotic burden in mice models but finding that 81% of SLE patients feel that the healthcare
failed to reduce progression of subclinical atherosclerosis service did not support them enough in the management
in a large cohort study [67,68]. Several trials evaluating of SLE-related fatigue [77].
anti-interferon therapy in SLE are currently ongoing, and Fibromyalgia is a chronic pain disorder characterized
beneficial effects on atherosclerosis might become by widespread generalized pain, often associated with
evident. However, no SLE treatment is currently of fatigue, anxiety and sleep disturbances. The prevalence of
proven benefit to reduce the risk of or halt the fibromyalgia is much higher in SLE patients, compared
progression of atherosclerosis in SLE. with the general population [78]. Fibromyalgia in SLE
contributes to the lower QoL and correlates with psycho-
Corticosteroid-associated damage in systemic somatic and affective variables but not with disease
lupus erythematosus activity or damage [78-80]. The widespread pain of con-
Corticosteroids are the mainstay of therapy for SLE, with comitant fibromyalgia can lead to diagnostic confusions
proven efficacy. The harm they cause in the short term and potential overtreatment if symptoms are mistaken
and the long term, however, is one of the major issues in for SLE disease activity.
SLE management. Corticosteroids increase the traditional Mood disturbances are very common in patients with
cardiovascular risk factors, including serum lipids, blood SLE, with depression being the most prevalent affective
pressure, weight and glucose. Fifteen years after the diag- symptom [81,82]. Depression contributes to the fatigue
nosis of SLE, the majority of permanent organ damage and cognitive dysfunction, and significantly correlates
can be attributed to the corticosteroids. Although the with lower QoL in patients with SLE [45,71,83]. Although
risk of damage is higher with high doses, there is no safe psychological effects of dealing with a chronic disease
dose for chronic use. Even small doses, if continued long may contribute to the high prevalence of depression,
enough, will significantly increase the morbidity [69]. The disease-specific mechanisms probably play a role. Asso-
cumulative dose of corticosteroids has significant asso- ciations with specific antibodies and alterations in
ciation with cataracts and osteoporotic fractures. Both cerebral blood flow have been reported in depressed SLE
the current dose and the cumulative dose are associated patients [84,85]. However, the data are not conclusive
with cardiovascular events [70]. When adjusted for con- and depression in patients with SLE should be treated
founding by indication due to SLE disease activity, the with conventional measures similar to the general
hazard ratio for organ damage increases dramatically population.
with prednisone doses of 6 to 12 mg/day (hazard ratio =
1.5), 12 to 18 mg/day (hazard ratio = 1.64) and >18 mg/day Perspective on future therapeutics and clinical
(hazard ratio = 2.51) [69]. Every attempt should be made to research in SLE
minimize the dose and duration of corticosteroid exposure. Despite advances in therapies, the control of disease
activity in SLE remains suboptimal. Flares are common
Quality of life in systemic lupus erythematosus and sustained disease control is generally limited to a
The QoL in patients with SLE is significantly lower than small fraction of patients [86]. These findings suggest
in healthy controls and patients with other chronic that, despite significant improvements in SLE treatment,
diseases [71,72]. Disease activity and organ damage did conventional approaches have probably reached their
not consistently correlate with lower QoL in SLE. Instead, maximal benefit and alternate options have to be con-
the major predictors of poor QoL in SLE are nondisease- sidered. Multiple new agents with immunomodulatory
specific variables including fatigue, chronic pain and effects have been investigated in recent years but limited
mood disturbances [71,72]. success has been achieved. Two large randomized
Fatigue is a common and often crippling symptom controlled trials evaluating rituximab for treatment of
experienced by about 85 to 92% of patients with SLE, SLE failed to meet their primary endpoints, despite good
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efficacy data in open-label studies [23,87]. Only overall condition [93]. The SLE Responder Index has
belimumab showed efficacy in randomized controlled been used successfully in the belimumab phase 3 trials
trials and received US Food and Drug Administration and has the potential to serve as an outcome measure in
approval for treatment of SLE [88,89]. These studies have the future SLE therapeutic trials.
raised important issues that should be addressed in The background immunosuppression used as the
future SLE research. standard of care in SLE trials adds another confounder to
The heterogeneous nature of the disease makes it the picture. Most studies have employed diverse back-
difficult to design clinical studies in SLE. In the absence ground treatments in both the treatment and placebo
of specific biomarkers, classification criteria are generally groups, to which the candidate agent is added. In
used to define study populations. Although these criteria addition, treatment adjustments have been either man-
encompass the breadth of the disease spectrum, patients dated or at least allowed during the studies. However,
with diverse manifestations and probably different patho- these concomitant therapies may have their own effects,
genic mechanisms will be grouped together. This masking the efficacy of the target intervention. Examples
limitation can be avoided by defining specific disease include the failed LUNAR and EXPLORER trials, in
subgroups based on organ manifestations, such as renal which rituximab or placebo were added to background
disease. However, this would seriously limit the eligible therapy including high-dose corticosteroids and immuno-
patient population, however, stressing the need for suppressive drugs such as mycophenolate [23,87].
multicenter collaborative projects. Limiting the inclusion Efficacy of rituximab over placebo was not found in these
in this manner may not be even a viable option if trials, despite a large body of evidence favoring rituximab
uncommon manifestations are considered. Currently, in observational and cohort studies. In contrast, the
some degree of heterogeneity in study populations has to belimumab trial design permitted early tapering of
be accepted. corticosteroids and may have contributed, at least
Another major issue in SLE research has been the partially, to the positive results [88,89]. However, design-
choice of outcome measures. The US Food and Drug ing a trial in SLE where the active arm receives only the
Administration draft guidance statement on SLE clinical experimental agent will be difficult and unethical. There
trials suggested the use of disease activity indices to is a need to develop a clearly defined standard of care
measure the efficacy of the intended intervention [90]. control arm, against which the newer agents can be
Several such indices have been developed and validated tested.
for use in clinical trials. Some disease activity indices  – The field of SLE clinical and therapeutic research is
such as the SLE Disease Activity Index (SLEDAI) and its advancing rapidly. Large international collaborations
variants (SLEDAI-2K, SELENA-SLEDAI)  – measure have resulted in development of new criteria, composite
overall disease activity, while others – such as the British outcome indices and insights into disease pathogenesis.
Isles Lupus Assessment Group Index (BILAG) – measure Multiple newer biologic agents targeting specific immune
organ-specific activity. Physician’s global assessment uses system pathways and effectors are undergoing evaluation
the treating physician’s overall assessment to assign a [94]. Hopefully, these efforts will lead to development of
numerical value to the disease activity on a visual analog newer therapeutic agents in SLE, a dire need.
scale of 0 to 3 [91]. This assessment has been used to
define flares (>1  point rise) in clinical trials [91]. Conclusions
Physician visual analog scale rating was found to have The management of SLE remains a challenge despite
high variability in a comparative study of outcome significant advances in the treatment. The new SLICC
measures by the SLICC study group [92], but it has been classification criteria with better sensitivity will probably
successfully incorporated as part of the SLE Responder help in better identification of patients, but we have not
Index (SRI) [93]. The SLE Responder Index is a composite yet reached the stage where early diagnosis can be
index developed to incorporate the strengths of different universally achieved. The field of disease biomarkers is
disease activity indices. This index provides a rapidly evolving with many putative candidates. However,
comprehensive definition of meaningful clinical response no biomarker has been successfully validated for use in
and has been used to define the primary end point in the routine clinical setting. Instead of a single measure, a
clinical trials [93]. The SLE Responder Index utilizes the battery of markers may perhaps be developed in the
SELENA-SLEDAI score to determine global improve- future to predict different disease aspects in a hetero-
ment, British Isles Lupus Assessment Group Index geneous disease such as SLE. Refractory disease
domain scores to ensure no significant worsening in manifestations and development of damage associated
previously unaffected organ systems, and physician’s with disease and therapies remain outstanding issues.
global assessment to ensure that improvements in disease Premature mortality and higher morbidity from
activity are not achieved at the expense of the patient’s atherosclerosis in this predominantly young group of
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patients are a major concern. Fatigue is one of the most SA, Stevens AM, Reveille JD, Sanchez E, Martin J, Niewold TB, Vila LM, Scofield
prevalent and disabling symptom in SLE, significantly RH, Gilkeson GS, Gaffney PM, Criswell LA, Moser KL, Merrill JT, Jacob CO, Taso
BP, James JA, Vyse TJ, Alarcon-Riquelme ME, BIOLUPUS Network, Harley JB,
contributing to the poor QoL. The quest for newer Richardson BC, Sawalha AH: Evidence for gene-gene epistatic interactions
targeted therapies has met with limited success despite among susceptibility loci for systemic lupus erythematosus. Arthritis
many clinical trials. Whether there is a true lack of Rheum 2012, 64:485-492.
7. Seyhan A, Toole MA, Zhang Y, Immermann FW, Hill A, Reddy P, Masferrer J,
efficacy or whether the trial designs in SLE are partly to Zhou T, Mounts W, Whitley M: Impact of baseline Interferon pathway
blame is open to discussion. However, advances have activation on widespread gene expression changes with disease flare in
been made in developing reliable outcome measures for lupus patients: interim report from the BOLD (Biomarkers of lupus
disease) study. Ann Rheum Dis 2012, 71(Suppl 3):74.
clinical research. Future research will focus on the goals 8. Fernando MM, Freudenberg J, Lee A, Morris DL, Boteva L, Rhodes B, Gonzalez-
of increasing survival, limiting organ damage and Escribano MF, Lopez-Nevot MA, Navarra SV, Gregersen PK, Martin J, IMAGEN,
improving QoL for patients with SLE. Vyse TJ: Transancestral mapping of the MHC region in systemic lupus
erythematosus identifies new independent and interacting loci at MSH5,
HLA-DPB1 and HLA-G. Ann Rheum Dis 2012, 71:777-784.
Abbreviations
9. Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK: Activation of the
ACR, American College of Rheumatology; IL, interleukin; NPSLE,
interferon-alpha pathway identifies a subgroup of systemic lupus
neuropsychiatric lupus; QoL, quality of life; SLE, systemic lupus erythematosus;
erythematosus patients with distinct serologic features and active
SLEDAI, SLE Disease Activity Index; SLICC, Systemic Lupus International
disease. Arthritis Rheum 2005, 52:1491-1503.
Collaborating Clinics; TNF, tumor necrosis factor.
10. Petri M, Singh S, Tesfasyone H, Dedrick R, Fry K, Lal P, Williams G, Bauer J,
Gregersen P, Behrens T, Baechler E: Longitudinal expression of type I
Competing interests interferon responsive genes in systemic lupus erythematosus. Lupus 2009,
The authors declare that they have no competing interests. 18:980-989.
11. Landolt-Marticorena C, Bonventi G, Lubovich A, Ferguson C, Unnithan T, Su J,
Declarations Gladman DD, Urowitz M, Fortin PR, Wither J: Lack of association between
This article has been published as part of Arthritis Research & Therapy Volume the interferon-alpha signature and longitudinal changes in disease
14 Suppl 4, 2012: New therapeutic targets in systemic lupus erythematosus. activity in systemic lupus erythematosus. Ann Rheum Dis 2009,
The supplement was proposed and developed by the journal. Articles were 68:1440-1446.
commissioned by the journal, were independently prepared by the authors 12. Petri M, Stohl W, Chatham W, McCune WJ, Chevrier M, Ryel J, Recta V, Zhong J,
and have undergone the journal’s standard peer review process. Publication Freimuth W: Association of plasma B lymphocyte stimulator levels and
of the supplement has been supported by an unrestricted educational grant disease activity in systemic lupus erythematosus. Arthritis Rheum 2008,
from UCB. Completed articles underwent a data quality check by Darwin 58:2453-2459.
Healthcare Communications, funded by UCB 13. Akhter E, Burlingame RW, Seaman AL, Magder L, Petri M: Anti-C1q
antibodies have higher correlation with flares of lupus nephritis than
Author details other serum markers. Lupus 2011, 20:1267-1274.
1
Division of Rheumatology, University Medicine Cluster, National University 14. Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS,
Health System, 1E Kent Ridge Road, Singapore 119074, Singapore. 2Division of Mysler E, Sanchez-Guerrero J, Solomons N, Wofsy D, Aspreva Lupus
Rheumatology, Johns Hopkins University, School of Medicine, Johns Hopkins Management Study Group: Mycophenolate mofetil versus
Lupus Center, 1830 E. Monument Street, Suite 7500, Baltimore, MD 21205, cyclophosphamide for induction treatment of lupus nephritis. J Am Soc
USA. Nephrol 2009, 20:1103-1112.
15. Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, de Ramon Garrido E,
Published: 18 December 2012 Danieli MG, Abramovicz D, Blockmans D, Cauli A, Direskeneli HGaleazzi M, Gül
A, Levy Y, Petera P, Popovic R, Sinico RA, Cattaneo R, Font J, Depresseux G,
References Cosyns JP, Carvera R: The 10-year follow-up data of the Euro-Lupus
1. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Nephritis Trial comparing low-dose and high-dose intravenous
Talal N, Winchester RJ: The 1982 revised criteria for the classification of cyclophosphamide. Ann Rheum Dis 2010, 69:61-64.
systemic lupus erythematosus. Arthritis Rheum 1982, 25:1271-1277. 16. Isenberg D, Appel GB, Contreras G, Dooley MA, Ginzler EM, Jayne D, Sanchez-
2. Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR, Bruce IN, Guerrero J, Wofsy D, Yu X, Solomons N: Influence of race/ethnicity on
Isenberg D, Wallace DJ, Nived O, Sturfelt G, Ramsey-Goldman R, Bae SC, Hanly response to lupus nephritis treatment: the ALMS study. Rheumatology
JG, Sanchez-Guerro J, Clarke A, Aranow C, Manzi S, Urowitz M, Gladman D, (Oxford) 2010, 49:128-140.
Kalunian K, Costner M, Werth VP, Zoma A, Bernatsky S, Ruiz-Irastorza G, 17. Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, Eitner F, Appel
Khasmashta MA, Jacobsen S, Buyon JP, et al.: Derivation and validation of GB, Contreras G, Lisk L, Solomons N, ALMS Group: Mycophenolate versus
the Systemic Lupus International Collaborating Clinics classification azathioprine as maintenance therapy for lupus nephritis. N Engl J Med
criteria for systemic lupus erythematosus. Arthritis Rheum 2012, 2011, 365:1886-1895.
64:2677-2686. 18. Houssiau FA, D’Cruz D, Sangle S, Remy P, Vasconcelos C, Petrovic R, Fiehn C,
3. Ho A, Magder LS, Barr SG, Petri M: Decreases in anti-double-stranded DNA de Ramon Garrido E, Gilboe IM, Tektonidou M, Blockmans D, Ravelinigien I, le
levels are associated with concurrent flares in patients with systemic lupus Guern V, Depresseux G, Guillevin L, Cervera R, MAINTAIN Nephritis Trial Group:
erythematosus. Arthritis Rheum 2001, 44:2342-2349. Azathioprine versus mycophenolate mofetil for long-term
4. Liu CC, Ahearn JM: The search for lupus biomarkers. Best Pract Res Clin immunosuppression in lupus nephritis: results from the MAINTAIN
Rheumatol 2009, 23:507-523. Nephritis Trial. Ann Rheum Dis 2010, 69:2083-2089.
5. Niewold TB, Kelly JA, Kariuki SN, Franek BS, Kumar AA, Kaufman KM, Thomas 19. Chen W, Liu Q, Tang X, Fu P, Liu F, Liao Y, Yang Z, Zhang J, Chen J, Lou T, Fu J,
K, Walker D, Kamp S, Frost JM, Wong AK, Merrill JT, Alarcon-Riquelme NE, Tikly Kong Y, Liu Z, Li Z Yu X: Outcomes of maintenance therapy with tacrolimus
M, Ramsey-Goldman R, Reveille JD, Petri MA, Edberg JC, Kimberly RP, Alarcon versus azathioprine for active lupus nephritis: a multicenter randomized
GS, Kamen DL, Gilkeson GS, Vyse TJ, James JA, Gaffney PM, Moser KL, Crow clinical trial. Lupus 2012, 21:944-952.
MK, Harley JB: IRF5 haplotypes demonstrate diverse serological 20. Wang S, Li X, Qu L, Wang R, Chen Y, Li Q, He X, Zhang X, Wang H, Wu J, Xu Y,
associations which predict serum interferon alpha activity and explain the Chen J: Tacrolimus versus cyclophosphamide as treatment for diffuse
majority of the genetic association with systemic lupus erythematosus. proliferative or membranous lupus nephritis: a non-randomized
Ann Rheum Dis 2012, 71:463-468. prospective cohort study. Lupus 2012, 21:1025-1035.
6. Hughes T, Adler A, Kelly JA, Kaufman KM, Williams AH, Langefeld CD, Brown 21. Zavada J, Pesickova S, Rysava R, Olejarova M, Horak P, Hrncir Z, Rychlik I,
EE, Alarcon GS, Kimberly RP, Edberg JC, Ramsey-Goldman R, Petri M, Boackle Havrda M, Vitova J, Lukac J, Rovensky J, Tegzova D, Böhmova J, Zadrazil J,
Lateef and Petri Arthritis Research & Therapy 2012, 14(Suppl 4):S4 Page 8 of 9
http://arthritis-research.com/content/14/S4/S4

Hána J, Dostál C, Tesar V: Cyclosporine A or intravenous cyclophosphamide 42. Okamoto H, Kobayashi A, Yamanaka H: Cytokines and chemokines in
for lupus nephritis: the Cyclofa-Lune study. Lupus 2010, 19:1281-1289. neuropsychiatric syndromes of systemic lupus erythematosus. J Biomed
22. Ramos-Casals M, Soto MJ, Cuadrado MJ, Khamashta MA: Rituximab in Biotechnol 2010, 2010:268436.
systemic lupus erythematosus: a systematic review of off-label use in 188 43. Luyendijk J, Steens SC, Ouwendijk WJ, Steup-Beekman GM, Bollen EL, van der
cases. Lupus 2009, 18:767-776. Grond J, Huizinga TW, Emmer BJ, van Buchem MA: Neuropsychiatric
23. Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, systemic lupus erythematosus: lessons learned from magnetic resonance
Maciuca R, Zhang D, Garg JP, Brunetta P, Appel G, LUNAE Investigator Group: imaging. Arthritis Rheum 2011, 63:722-732.
Efficacy and safety of rituximab in patients with active proliferative lupus 44. Petri M, Naqibuddin M, Carson KA, Sampedro M, Wallace DJ, Weisman MH,
nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Holliday SL, Padilla PA, Brey RL: Cognitive function in a systemic lupus
Rheum 2012, 64:1215-1226. erythematosus inception cohort. J Rheumatol 2008, 35:1776-1781.
24. Lateef A, Petri M: Biologics in the treatment of systemic lupus 45. Petri M, Naqibuddin M, Carson KA, Wallace DJ, Weisman MH, Holliday SL,
erythematosus. Curr Opin Rheumatol 2010, 22:504-509. Sampedro M, Padilla PA, Brey RL: Depression and cognitive impairment in
25. Weidenbusch M, Rommele C, Schrottle A, Anders HJ: Beyond the LUNAR newly diagnosed systemic lupus erythematosus. J Rheumatol 2010,
trial. Efficacy of rituximab in refractory lupus nephritis. Nephrol Dial 37:2032-2038.
Transplant 2012. [Epub ahead of print] 46. Kozora E, Ellison MC, West S: Depression, fatigue, and pain in systemic lupus
26. Diaz-Lagares C, Croca S, Sangle S, Vital EM, Catapano F, Martinez-Berriotxoa A, erythematosus (SLE): relationship to the American College of
Garcia-Hernandez F, Callejas-Rubio JL, Rascon J, D’Cruz D, Jayne D, Rheumatology SLE neuropsychological battery. Arthritis Rheum 2006,
Ruiz-Irastorza G, Emery P, Isenberg D, Ramos-Casals M, Khamashta MA, 55:628-635.
UK-BIOGEAS Registry: Efficacy of rituximab in 164 patients with biopsy- 47. Petri M, Naqibuddin M, Sampedro M, Omdal R, Carson KA: Memantine in
proven lupus nephritis: pooled data from European cohorts. Autoimmun systemic lupus erythematosus: a randomized, double-blind placebo-
Rev 2012, 11:357-364. controlled trial. Semin Arthritis Rheum 2011, 41:194-202.
27. Kasitanon N, Fine DM, Haas M, Magder LS, Petri M: Hydroxychloroquine use 48. Bertsias GK, Ioannidis JP, Aringer M, Bollen E, Bombardieri S, Bruce IN, Cervera
predicts complete renal remission within 12 months among patients R, Dalakas M, Doria A, Hanly JG, Huizinga TW, Isenberg D, Kallenberg C, Piette
treated with mycophenolate mofetil therapy for membranous lupus JC, Schneider M, Scolding N, Smolen J, Stara A, Tassiulas I, Tektonidou M,
nephritis. Lupus 2006, 15:366-370. Tincani A, van Buchem MA, van Vollenhoven R, Ward M, Gordon C, Boumpas
28. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA: Clinical DT: EULAR recommendations for the management of systemic lupus
efficacy and side effects of antimalarials in systemic lupus erythematosus: erythematosus with neuropsychiatric manifestations: report of a task
a systematic review. Ann Rheum Dis 2010, 69:20-28. force of the EULAR standing committee for clinical affairs. Ann Rheum Dis
29. Kitamura N, Matsukawa Y, Takei M, Sawada S: Antiproteinuric effect of 2010, 69:2074-2082.
angiotensin-converting enzyme inhibitors and an angiotensin II receptor 49. Nossent J, Cikes N, Kiss E, Marchesoni A, Nassonova V, Mosca M, Olesinska M,
blocker in patients with lupus nephritis. J Int Med Res 2009, 37:892-898. Pokorny G, Rozman B, Schneider M, Vlachioyiannopoulos PG, Swaak A:
30. Duran-Barragan S, McGwin G, Jr, Vila LM, Reveille JD, Alarcon GS: Current causes of death in systemic lupus erythematosus in Europe,
Angiotensin-converting enzyme inhibitors delay the occurrence of renal 2000–2004: relation to disease activity and damage accrual. Lupus 2007,
involvement and are associated with a decreased risk of disease activity in 16:309-317.
patients with systemic lupus erythematosus--results from LUMINA (LIX): 50. Esdaile JM, Abrahamowicz M, Grodzicky T, Li Y, Panaritis C, du Berger R, Cote R,
amultiethnic US cohort. Rheumatology (Oxford) 2008, 47:1093-1096. Grover SA, Fortin PR, Clarke AE, Senécal JL: Traditional Framingham risk
31. Croca SC, Rodrigues T, Isenberg DA: Assessment of a lupus nephritis cohort factors fail to fully account for accelerated atherosclerosis in systemic
over a 30-year period. Rheumatology (Oxford) 2011, 50:1424-1430. lupus erythematosus. Arthritis Rheum 2001, 44:2331-2337.
32. Ward MM: Changes in the incidence of endstage renal disease due to 51. Roman MJ, Shanker BA, Davis A, Lockshin MD, Sammaritano L, Simantov R,
lupus nephritis in the United States, 1996–2004. J Rheumatol 2009, Crow MK, Schwartz JE, Paget SA, Devereux RB, Salmon JE: Prevalence and
36:63-67. correlates of accelerated atherosclerosis in systemic lupus erythematosus.
33. Barr RG, Seliger S, Appel GB, Zuniga R, D’Agati V, Salmon J, Radhakrishnan J: N Engl J Med 2003, 349:2399-2406.
Prognosis in proliferative lupus nephritis: the role of socio-economic 52. McMahon M, Grossman J, Skaggs B, Fitzgerald J, Sahakian L, Ragavendra N,
status and race/ethnicity. Nephrol Dial Transplant 2003, 18:2039-2046. Charles-Schoeman C, Watson K, Wong WK, Volkmann E, Chen W, Gorn A,
34. Costenbader KH, Desai A, Alarcon GS, Hiraki LT, Shaykevich T, Brookhart MA, Karpouzas G, Weisman M, Wallace DJ, Hahn BH: Dysfunctional
Massarotti E, Lu B, Solomon DH, Winkelmayer WC: Trends in the incidence, proinflammatory high-density lipoproteins confer increased risk of
demographics, and outcomes of end-stage renal disease due to lupus atherosclerosis in women with systemic lupus erythematosus. Arthritis
nephritis in the US from 1995 to 2006. Arthritis Rheum 2011, 63:1681-1688. Rheum 2009, 60:2428-2437.
35. Santiago-Casas Y, Vila LM, McGwin G, Jr, Cantor RS, Petri M, Ramsey-Goldman 53. Wright SA, O’Prey FM, Rea DJ, Plumb RD, Gamble AJ, Leahey WJ, Devine AB,
R, Reveille JD, Kimberly RP, Alarcon GS, Brown EE: Association of discoid McGivern RC, Johnston DG, Finch MB, Bell AL, McVeigh GE: Microcirculatory
lupus erythematosus with clinical manifestations and damage accrual in a hemodynamics and endothelial dysfunction in systemic lupus
multiethnic lupus cohort. Arthritis Care Res (Hoboken) 2012, 64:704-712. erythematosus. Arterioscler Thromb Vasc Biol 2006, 26:2281-2287.
36. Kuhn A, Ruland V, Bonsmann G: Cutaneous lupus erythematosus: update of 54. Somers EC, Zhao W, Lewis EE, Wang L, Wing JJ, Sundaram B, Kazerooni EA,
therapeutic options part I. J Am Acad Dermatol 2011, 65:e179-e193. McCune WJ, Kaplan MJ: Type I interferons are associated with subclinical
37. Kuhn A, Ruland V, Bonsmann G: Cutaneous lupus erythematosus: update of markers of cardiovascular disease in a cohort of systemic lupus
therapeutic options part II. J Am Acad Dermatol 2011, 65:e195-e213. erythematosus patients. PLoS One 2012, 7:e37000.
38. Jessop S, Whitelaw DA, Delamere FM: Drugs for discoid lupus 55. Denny MF, Yalavarthi S, Zhao W, Thacker SG, Anderson M, Sandy AR, McCune
erythematosus. Cochrane Database Syst Rev 2009, 4:CD002954. WJ, Kaplan MJ: A distinct subset of proinflammatory neutrophils isolated
39. ACR adhoc Committee on Neuropsychiatric Lupus Nomenclature: The from patients with systemic lupus erythematosus induces vascular
American College of Rheumatology nomenclature and case definitions for damage and synthesizes type I IFNs. J Immunol 2010, 184:3284-3297.
neuropsychiatric lupus syndromes. Arthritis Rheum 1999, 42:599-608. 56. Huang Q, Pope RM: Toll-like receptor signaling: a potential link among
40. Ainiala H, Hietaharju A, Loukkola J, Peltola J, Korpela M, Metsanoja R, Auvinen rheumatoid arthritis, systemic lupus, and atherosclerosis. J Leukoc Biol
A: Validity of the new American College of Rheumatology criteria for 2010, 88:253-262.
neuropsychiatric lupus syndromes: a population-based evaluation. 57. Matsuura E, Lopez LR, Shoenfeld Y, Ames PR: β2-glycoprotein I and oxidative
Arthritis Rheum 2001, 45:419-423. inflammation in early atherogenesis: a progression from innate to
41. Karassa FB, Afeltra A, Ambrozic A, Chang DM, De Keyser F, Doria A, Galeazzi M, adaptive immunity? Autoimmun Rev 2012, 12:241-249.
Hirohata S, Hoffman IE, Inanc M, Massardo L, Mathieu A, Mok CC, Morozzi G, 58. Kiani AN, Magder L, Petri M: Coronary calcium in systemic lupus
Sanna G, Spindler AJ, Tzioufas AG, Yoshio T, Ioannidis JP: Accuracy of anti- erythematosus is associated with traditional cardiovascular risk factors,
ribosomal P protein antibody testing for the diagnosis of neuropsychiatric but not with disease activity. J Rheumatol 2008, 35:1300-1306.
systemic lupus erythematosus: an international meta-analysis. Arthritis 59. Maksimowicz-McKinnon K, Magder LS, Petri M: Predictors of carotid
Rheum 2006, 54:312-324. atherosclerosis in systemic lupus erythematosus. J Rheumatol 2006,
Lateef and Petri Arthritis Research & Therapy 2012, 14(Suppl 4):S4 Page 9 of 9
http://arthritis-research.com/content/14/S4/S4

33:2458-2463. erythematosus: prevalence and clinical implications. Clin Rev Allergy

60. Kiani AN, Vogel-Claussen J, Magder LS, Petri M: Noncalcified coronary Immunol 2003, 25:25-28.
plaque in systemic lupus erythematosus. J Rheumatol 2010, 37:579-584. 79. Torrente-Segarra V, Carbonell-Abello J, Castro-Oreiro S, Manresa Dominguez
61. Kiani AN, Mahoney JA, Petri M: Asymmetric dimethylarginine is a marker of JM: Association between fibromyalgia and psychiatric disorders in
poor prognosis and coronary calcium in systemic lupus erythematosus. systemic lupus erythematosus. Clin Exp Rheumatol 2010, 28(6 Suppl
J Rheumatol 2007, 34:1502-1505. 63):S22-S26.
62. McMahon M, Skaggs BJ, Sahakian L, Grossman J, FitzGerald J, Ragavendra N, 80. Friedman AW, Tewi MB, Ahn C, McGwin G, Jr, Fessler BJ, Bastian HM, Baethge
Charles-Schoeman C, Chernishof M, Gorn A, Witztum JL, Wong WK, Weisman BA, Reveille JD, Alarcon GS: Systemic lupus erythematosus in three ethnic
M, Wallace DJ, La Cava A, Hahn BH: High plasma leptin levels confer groups: XV. Prevalence and correlates of fibromyalgia. Lupus 2003,
increased risk of atherosclerosis in women with systemic lupus 12:274-279.
erythematosus, and are associated with inflammatory oxidised lipids. Ann 81. Bachen EA, Chesney MA, Criswell LA: Prevalence of mood and anxiety
Rheum Dis 2011, 70:1619-1624. disorders in women with systemic lupus erythematosus. Arthritis Rheum
63. Roman MJ, Crow MK, Lockshin MD, Devereux RB, Paget SA, Sammaritano L, 2009, 61:822-829.
Levine DM, Davis A, Salmon JE: Rate and determinants of progression of 82. Meszaros ZS, Perl A, Faraone SV: Psychiatric symptoms in systemic lupus
atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 2007, erythematosus: a systematic review. J Clin Psychiatry 2012, 73:993-1001.
56:3412-3419. 83. Moldovan I, Katsaros E, Carr FN, Cooray D, Torralba K, Shinada S, Ishimori ML,
64. Gustafsson J, Simard JF, Gunnarsson I, Elvin K, Lundberg IE, Hansson LO, Jolly M, Wallace DJ, Weisman MH, Nicassio PM: The Patient Reported
Larsson A, Svenungsson E: Risk factors for cardiovascular mortality in Outcomes in Lupus (PATROL) study: role of depression in health-related
patients with systemic lupus erythematosus, a prospective cohort study. quality of life in a Southern California lupus cohort. Lupus 2011,
Arthritis Res Ther 2012, 14:R46. 20:1285-1292.
65. Petri MA, Kiani AN, Post W, Christopher-Stine L, Magder LS: Lupus 84. Giovacchini G, Mosca M, Manca G, Della Porta M, Neri C, Bombardieri S,
Atherosclerosis Prevention Study (LAPS). Ann Rheum Dis 2011, 70:760-765. Ciarmiello A, Strauss HW, Mariani G, Volterrani D: Cerebral blood flow in
66. Schanberg LE, Sandborg C, Barnhart HX, Ardoin SP, Yow E, Evans GW, depressed patients with systemic lupus erythematosus. J Rheumatol 2010,
Mieszkalski KL, Ilowite NT, Eberhard A, Imundo LF, Kirmua Y, von Scheven E, 37:1844-1851.
Silverman E, Bowyer SL, Punaro M, Singer NG, Sherry DD, McCurdy D, Klein- 85. Lapteva L, Nowak M, Yarboro CH, Takada K, Roebuck-Spencer T, Weickert T,
Gitelman M, Wallace C, Silver R, Wagner-Weiner L, Higgins GC, Brunnger HI, Bleiberg J, Rosenstein D, Pao M, Patronas N, Steele S, Manzano M, van der
Jung L, Soep JB, Reed AM, Provenzale J, Thompson SD, Athesrosclerosis Veen JW, Lipsky PE, Marneco S, Wesley R, Volpe B, Diamond B, Illei GG: Anti-N-
Prevention in Pediatric Lupus Erythematosus Investigators: Use of methyl-D-aspartate receptor antibodies, cognitive dysfunction, and
atorvastatin in systemic lupus erythematosus in children and adolescents. depression in systemic lupus erythematosus. Arthritis Rheum 2006,
Arthritis Rheum 2012, 64:285-296. 54:2505-2514.
67. Kiani AN, Magder LS, Petri M: Mycophenolate mofetil (MMF) does not slow 86. Nikpour M, Urowitz MB, Ibanez D, Gladman DD: Frequency and
the progression of subclinical atherosclerosis in SLE over 2 years. determinants of flare and persistently active disease in systemic lupus
Rheumatol Int 2012, 32:2701-2705. erythematosus. Arthritis Rheum 2009, 61:1152-1158.
68. van Leuven SI, Mendez-Fernandez YV, Wilhelm AJ, Wade NS, Gabriel CL, 87. Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, Utset
Kastelein JJ, Stroes ES, Tak PP, Major AS: Mycophenolate mofetil but not TO, Gordon C, Isenberg DA, Hsieh HJ, Zhang D, Brunetta PG: Efficacy and
atorvastatin attenuates atherosclerosis in lupus-prone LDLr(–/–) mice. safety of rituximab in moderately-to-severely active systemic lupus
Ann Rheum Dis 2012, 71:408-414. erythematosus: the randomized, double-blind, phase ii/iii systemic lupus
69. Thamer M, Hernan MA, Zhang Y, Cotter D, Petri M: Prednisone, lupus activity, erythematosus evaluation of rituximab trial. Arthritis Rheum 2010,
and permanent organ damage. J Rheumatol 2009, 36:560-564. 62:222-233.
70. Magder L, Petri M: Incidence of and risk factors for adverse cardiovascular 88. Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, Sanchez-
events among patients with systemic lupus erythamatosus. Am J Epidemiol Guerrero J, Schwarting A, Merrill JT, Chatham WW, Stohl W, Ginzler EM,
2012, 176:708-719. Hough DR, Zhong ZJ, Freimuth W, van Vollenhoven RF, BLISS-76 Study Group:
71. Choi ST, Kang JI, Park IH, Lee YW, Song JS, Park YB, Lee SK: Subscale analysis A phase III, randomized, placebo-controlled study of belimumab, a
of quality of life in patients with systemic lupus erythematosus: monoclonal antibody that inhibits B lymphocyte stimulator, in patients
association with depression, fatigue, disease activity and damage. Clin Exp with systemic lupus erythematosus. Arthritis Rheum 2011, 63:3918-3930.
Rheumatol 2012, 30:664-672. 89. Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, Li EK,
72. Pettersson S, Lovgren M, Eriksson L, Moberg C, Svenungsson E, Gunnarsson I, Thomas M, Kim HY, Leon MG, Tanasescu C, Nasanov E, Lan JL, Pineda L,
Welin Henriksson E: An exploration of patient-reported symptoms in Zhong ZJ, Freimuth W, Petri MA, BLISS-52 Study Group: Efficacy and safety of
systemic lupus erythematosus and the relationship to health-related belimumab in patients with active systemic lupus erythematosus: a
quality of life. Scand J Rheumatol 2012, 41:383-390. randomised, placebo-controlled, phase 3 trial. Lancet 2011, 377:721-731.
73. Zonana-Nacach A, Roseman JM, McGwin G, Jr, Friedman AW, Baethge BA, 90. Guidance for Industry, Systemic Lupus Erythematosus – Developing
Reveille JD, Alarcon GS: Systemic lupus erythematosus in three ethnic Medical Products for Treatment [http://www.fda.gov/downloads/Drugs/
groups. VI: factors associated with fatigue within 5 years of criteria GuidanceComplianceRegulatoryInformation/Guidances/ucm072063.pdf ]
diagnosis. LUMINA Study Group. LUpus in MInority populations: NAture vs 91. Petri M, Buyon J, Kim M: Classification and definition of major flares in SLE
Nurture. Lupus 2000, 9:101-109. clinical trials. Lupus 1999, 8:685-691.
74. Burgos PI, Alarcon GS, McGwin G, Jr, Crews KQ, Reveille JD, Vila LM: Disease 92. Wollaston SJ, Farewell VT, Isenberg DA, Gordon C, Merrill JT, Petri MA,
activity and damage are not associated with increased levels of fatigue in Kalunian KC: Defining response in systemic lupus erythematosus: a study
systemic lupus erythematosus patients from a multiethnic cohort: LXVII. by the Systemic Lupus International Collaborating Clinics group.
Arthritis Rheum 2009, 61:1179-1186. J Rheumatol 2004, 31:2390-2394.
75. Jump RL, Robinson ME, Armstrong AE, Barnes EV, Kilbourn KM, Richards HB: 93. Furie RA, Petri MA, Wallace DJ, Ginzler EM, Merrill JT, Stohl W, Chatham WW,
Fatigue in systemic lupus erythematosus: contributions of disease activity, Strand V, Weinstein A, Chevrier MR, Zhong ZJ, Freimuth WW: Novel evidence-
pain, depression, and perceived social support. J Rheumatol 2005, based systemic lupus erythematosus responder index. Arthritis Rheum
32:1699-1705. 2009, 61:1143-1151.
76. Tench CM, McCarthy J, McCurdie I, White PD, D’Cruz DP: Fatigue in systemic 94. Hahn BH: Targeted therapies in systemic lupus erythematosus: successes,
lupus erythematosus: a randomized controlled trial of exercise. failures and future. Ann Rheum Dis 2011, 70(Suppl 1):i64-i66.
Rheumatology (Oxford) 2003, 42:1050-1054.
77. Moses N, Wiggers J, Nicholas C, Cockburn J: Prevalence and correlates of
doi:10.1186/ar3919
perceived unmet needs of people with systemic lupus erythematosus.
Cite this article as: Lateef A, Petri M: Unmet medical needs in systemic
Patient Educ Couns 2005, 57:30-38. lupus erythematosus. Arthritis Research & Therapy 2012, 14(Suppl 4):S4.
78. Buskila D, Press J, Abu-Shakra M: Fibromyalgia in systemic lupus