Symposium-Rheumatology

Advances in management of systemic lupus

erythematosus
Subramanian Shankar, Vineet Behera

Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organ systems. In the past
40 years, prognosis for patients with SLE has improved significantly because of advances in the understanding
of molecular mechanisms involved in the pathogenesis of disease, which has translated into early diagnosis and
novel therapeutic strategies. This article will focus on three aspects that have shaped this transformation, namely;
a revisit to diagnostic criteria, development of newer biomarkers, and incorporation of newer targeted therapies.

Keywords: Advances, connective tissue disorder, systemic lupus erythromatosus

Introduction
Systemic lupus erythematosus (SLE) is a chronic
autoimmune disease affecting multiple organ systems.
In the past 40 years, prognosis for patients with SLE
has improved significantly because of advances in the
understanding of molecular mechanisms involved in
the pathogenesis of disease, which has translated into
early diagnosis and novel therapeutic strategies. This
article will focus on three aspects that have shaped
this transformation, namely; a revisit to diagnostic
criteria, development of newer biomarkers, and
incorporation of newer targeted therapies.

Classification Criteria of SLE

Pitfalls in existing criteria for SLE

Criteria for SLE classification was developed by the

American College of Rheumatology (ACR) in 1971,
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DOI:
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and revised in 1982 and 1997.[1] These criteria were not

weighted for specificity, sensitivity or disease severity,
and often excluded patients with early or limited
disease. In fact, data from tertiary centres suggested
that only 60% of patients referred for SLE fulfilled
the ACR criteria, whereas another 15% of patients had
SLE features but did not fulfill the criteria.[2] The major
pitfalls with ACR criteria, which created the need for
newer criteria,[3] included the following.
The 1982 criteria were biased and weighted toward
cutaneous lupus, with four cutaneous criteria.
However, the newer therapies for SLE were
largely directed against renal or other major organ
involvement.
Hypocomplementemia (omitted in the 1982 criteria)
has been shown to be strongly associated with SLE,
and its exclusion from SLE criteria often missed
patients with SLE.
Advances have been made in autoantibody assays,
such as the anti-phospholipid, anti-dsDNA, and antiSm antibodies. The criterion for anti-phospholipid
antibodies has not been subjected to validation,
and its inclusion may lead to confusion between
SLE and primary APS. The appropriateness of new
commercial enzyme-linked immunosorbent assay
(ELISA) for anti-DNA has not been evaluated.

Department of Internal Medicine, Armed Forces Medical College, Pune, Maharashtra, India
Address for correspondence:
Gp Capt (Dr) S Shankar, Department of Internal Medicine, Armed Forces Medical College, Pune, Maharashtra, India.
E-mail: shankarsid@gmail.com

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Shankar and Behera: Advances in SLE

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Many of the existing criteria require redefinition

and refinement based on current practice. This is
especially relevant for the renal and neurologic
criteria (only psychosis and seizure are included)
to reflect the breadth of neurologic lupus, as noted
by the ACR neurologic classification criteria.[4]
Future criteria must be generalizable to multiple
ethnic groups and be internationally valid. Different
frequencies of individual criteria for different
ethnicities have already been shown for AfricanAmericans and for Japanese.
Future criteria need to include input from nonrheumatology specialists who frequently care for
and diagnose lupus, including dermatologists,
neurologists, and nephrologists.

like myelitis and mononeuritis multiplex have been

included. The new SLICC criteria has a sensitivity and
specificity of 94% and 92% compared to ACR criteria
having 86% and 93%, respectively.

SLE is likely a disease with multiple subsets. Accurate

classification criteria would allow future clinical trials
to look at treatment variability by subset, including
chronic cutaneous lupus and APS.

Biomarkers are very useful in diagnosis, evaluation, and

management of SLE and can be of help in early detection
of a disease flare and monitoring disease activity. An
ideal biomarker should accurately detect disease activity
and guide therapy at every stage of SLE.

SLICC criteria

This created the way for the Systemic Lupus

International
Collaborating
Clinics
(SLICC)
Classification 2012 Criteria. SLICC group is an
international group of investigators dedicated to SLE
clinical research. The SLICC classification criteria
for SLE represent an 8-year effort of clinical review,
consensus, and statistical analyses. The new criteria
are simple, include most SLE patients, and retain
specificity while being more sensitive.
The final criteria were derived using recursive
partitioning[5] (tree-based approach) (using the CART
software package), in which patients were categorized
into two groups based on all candidate variables, and
the resulting partitions were evaluated. A simple rule
was applied the patient must satisfy at least four
criteria, including at least one clinical criterion and one
immunologic criterion or the patient must have biopsyproven lupus nephritis in the presence of antinuclear
antibodies or anti-dsDNA antibodies. The SLICC
classification criteria were subjected to rigorous testing.
The new patient sample used for validation consisted of
690 patients and included patients from multiple centers
with multiple diagnoses that have clinical features,
which overlap with the clinical features of lupus.
The key features in SLICC criteria are that lupus
nephritis alone with ANA positivity can be classified
as SLE. Hypocomplementemia becomes an important
component and multiple neurological syndromes
March 2014 | Vol 19 | Issue 1

*Classify a patient as having SLE if

The patient satisfies four of the criteria (listed

in Table 1) including at least one clinical
criterion and one immunologic criterion; or
The patient has biopsy-proven nephritis
compatible with SLE and with ANA or antidsDNA antibodies.

Biomarkers In SLE

Need for novel biomarkers

Autoantibodies like ANA and dsDNA have been the

traditional agents used in the diagnosis of SLE. But
ANA has a low specificity for SLE, and its sensitivity
may be as low as 70%, especially early in the
disease.[6] Anti-dsDNA is better with 95% specificity
but has a low sensitivity.[7] This created the need for
novel biomarkers for SLE. Decades of extensive
work has led to discovery of a number of candidate
biomarkers, the precise clinical utility of which-outside
of the research setting-awaits determination.[8]

New biomarkers in SLE

The newer biomarkers developed for use in SLE are

given in Table 2.[9] Anti-nucleosome antibodies are
associated with organic damage and are useful in
diagnosis of SLE, drug-induced lupus, disease flares,
and early detection of lupus nephritis.[10] Anti-C-1q
antibodies, NMDA receptor antibody, and anti-alpha
actinin antibody have also shown promise in early
diagnosis of SLE and diagnosis of flares. Numerous
biomarkers have been investigated in lupus nephritis
and have shown a role in early detection of renal
pathology, predicting flares, and predicting chronic
kidney disease as given in Tables2 and 3.

Alternative biomarkers

New high-throughput technologies, such as

transcriptomics and proteomics, have been applied
in search for biomarkers. Interferon-signature gene
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Shankar and Behera: Advances in SLE

30
Table 1: Clinical and immunological criteria used In SLICC criteria*
CLINICAL CRITERIA
Acute cutaneous lupus

Chronic Cutaneous Lupus

Oral Ulcers OR Nasal Ulcers
Non-scarring alopecia
Synovitis involving 2 or more
joints
Serositis
Renal
Neurologic
Hemolytic anemia
Leukopenia (<4000/mm3) OR
Lymphopenia (<1000/mm3)
Thrombocytopenia
(<100,000/mm3)
IMMUNOLOGIC CRITERIA
ANA
Anti-dsDNA
Anti-Sm
Anti-phospholipid antibody

Low complement
Direct Coombs test

Lupus malar rash, bullous lupus, toxic epidermal necrolysis variant of SLE, maculopapular lupus rash, photosensitive lupus
rash (in the absence of dermatomyositis)
Classic discoid rash localized (above the neck) or generalized (above and below the neck), hypertrophic (verrucous) lupus,
lupus panniculitis (profundus), mucosal lupus, chillblains lupus, discoid lupus/lichen planus overlap
Oral: palate, buccal, tongue, nasal ulcers. In the absence of other causes, such as vasculitis, Behcets disease,
infection,inflammatory bowel disease, reactive arthritis, and acidic foods
Diffuse thinning or hair fragility with visible broken hairs, in the absence of other causes such asalopecia areata, drugs,
iron deficiency, andandrogenic alopecia
Characterized by swelling or effusion OR tenderness in 2 or more joints and at least 30 minutes of morning stiffness
Typical pleurisy for more than 1 day OR pleural effusions ORpleural rub. Typical pericardial pain (pain with recumbency
improved by sitting forward) for more than 1 day ORpericardial effusionOR pericardial rub OR pericarditis by
electrocardiography.
Urine proteinto-creatinine ratio (or 24-hour urine protein) representing 500 mg protein/24 hours OR redblood cellcasts
Seizures, psychosis, mononeuritis multiplex (in the absence of other known causes such as primary vasculitis), myelitis,
peripheral orcranial neuropathy(in the absence of other known causes such as primary vasculitis, infection, anddiabetes
mellitus), acute confusional state (in the absence of other causes, including toxic/metabolic, uremia, drugs)
Leucopenia at least once: In the absence of other known causes such as Feltys syndrome, drugs, and portal
hypertension.Lymphopenia at least once: In the absence of other known causes such as corticosteroids, drugs, and infection
At least once in the absence of other known causes such as drugs, portal hypertension, and thrombotic thrombocytopenic
purpura
Level above laboratory reference range
Antibody level above laboratory reference range (or 2-fold if tested by ELISA)
Presence of antibody to Sm nuclear antigen
Positivity, as determined by
Positive test for lupus anticoagulant
False-positive test result for rapid plasma reagin
Medium- or high-titer anticardiolipin antibody level (IgA, IgG, or IgM)
Positive test result for anti2-glycoprotein I (IgA, IgG, or IgM)
(C3,C4, orCH50)
(In the absence of hemolytic anemia)

expression correlates with autoantibody profiles in SLE

and may be useful in cutaneous lupus, discoid lupus,
and neuromyelitis optica.[29] Micro RNAs (MiRNAs)
play a crucial role in maintaining immune system
development and function, and are implicated in SLE.
Unique miRNA expression signatures in SLE have the
potential to not only act as biomarkers for the diagnosis
and assessment of SLE but may be the future therapeutic
potential in management of SLE. RNA microarray
analyses of peripheral blood leukocytes can distinguish
between SLE flare and infection and might be useful in
the diagnosis and monitoring of the disease.

strategies so that the therapeutic efficacy can be enhanced

while treatment-related side effects can be minimized.

Future insights SLE biomarkers[30]

Treatment of SLE

Next-generation SLE biomarkers

The focus today is shifting towards discovering
biomarkers that predict onset of SLE in susceptible indi
viduals, development of flares in patients with established
SLE, predicting disease outcomes, and assessing the
effectiveness of therapeutic interventions. These will allow
proactive institution of therapeutic and even preventive
Journal of Mahatma Gandhi Institute of Medical Sciences

Pharmacodynamic biomarkers[31]
New biomarkers are being searched to aid identification
of patients who might respond favorably to a particular
biologic, selection of the type and dose of biologics used, and
evaluation of therapeutic efficacy. An illustrative example
is sifalimumab and rontalizumab, anti-IFN monoclonal
antibodies under evaluation for the treatment of SLE,
which were developed based on the seminal discovery of
the interferon signature and related biomarkers.

Conventional therapies

Early diagnosis and better treatment options of SLE

and its complications have markedly improved the
5-year survival of patients with SLE. However,
morbidity, especially renal failure, and mortality from
cardiovascular events after long-term follow up are
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Table 2: Novel biomarkers in diagnosis of SLE[11]

Biomarker
New antibodies
Anti-nucleosome
antibodies[12]
Anti-C-1q
antibodies[13]

Used As marker of

Role in SLE

Disease activity and

organ involvement

Drug-induced lupus
Lupus nephritis
Lupus flares
Nephritic flares
Negative predictive value
of 100%
Thrombocytopenia with
lupus.
Neuropsychiatric disease

Disease activity and

organ involvement

Anti-platelet
Platelets
antibodies
NMDA receptor
Neuronal damage
antibody[14]
Anti-Alpha actinin Disease activity
antibody[15]
Renal involvement
cellular markers/new molecules
CD27 plasma
Disease activity
cells[16]
CD44v3/CD44v6 - T Disease activity
cells[17]
CD4-CD8- (double Disease activity
negative) T cells[18]
Plasma MBL[19]
Disease activity

Lupus nephritis

Distinguish a lupus flare-up

from infection
Lupus nephritis
Lupus nephritis

Lupus nephritis (high levels)

Cutaneous lupus (low levels)
Diagnosis or disease Diagnosis of SLE
activity

Complement
Activation
products[20]
[C4d-bound RBCs,
anti-MCV, EC4d,
and BC4d]
Cytokines[21]
Disease activity/
IFN-, IFN
flares
-gamma
MCP-1[22]
IL-2, IL-6, IL-10,
TNF , IFN-, IL17, IL-23, TGF-B
TWEAK[23]
Genomic markers
Fc receptor gene
polymorphisms[24]
DNA Methylation
markers
(CD70, CD154,
Perforin)[25]
Micro RNAs[26]

Disease activity/
flares
Disease activity
Disease activity

Marker and potential

predictive Marker for antitype I IFN therapy

Diagnosis and prognosis

of SLE
Lupus nephritis

Disease susceptibility Diagnosis of SLE

Disease activity

Diagnosis and monitoring

Table 3: Novel Biomarkers in Lupus Nephritis[27,28]

BIOMARKER
Predict Renal pathology
Glycoprotein pathology
CXCL 10
CD 29
Anti-nucleosome antibody
Complement C4d
Predict CKD
LFABP
M EPCR
FOXP3
Predict Impending Nephritis Flare
MCP-1
NGAL
Transferrin
Hepcidin
AntiC1Q
1-acid glycoprotein (AGP)
Mannose binding lectin

TYPE

Urine protein
Urine m RNA
T cell surface markers
Serum marker
Urine protein
Urine protein
Endothelial surface marker
Urine mRNA
Urine protein/ mRNA
Urine protein
Urine protein
Urine protein
Urine protein
Urine protein
Serum protein

MCP-1 = Monocyte chemoattractant protein-1, NGAL = Neutrophil gelatinaseassociated lipocalin

which has led to promising new leads in SLE therapy.

Hydoxychloquine acts by reducing the formation of
peptide-MHC protein complexes required to stimulate
CD4+ T cells, processing and transport of the peptideMHC complex to the cell membrane and results in downregulation of the immune response against autoantigenic
peptides.33 Studies have shown that hydroxychloroquine
is an essential medication in lupus nephritis, neuro lupus
and has got a role in alleviating cutaneous, articular and
other manifestations of SLE.34 The benefits also include
a favorable effect on lipid profile, lower side effects and a
protection against the occurrence of thrombotic events.35
Its efficiency has also been demonstrated in the reduction
of the risk of flares and to have a protective effect on
survival in people with SLE.36

Targeted Therapy In SLE

Disease activity and
effects of treatment

Monitoring of SLE
New gene therapy strategies

MBL = Mannose binding lectin, anti-MCV = Anti-mutated citrullinated

vimentin antibody, EC4d = C4d levels on erythrocytes, PC4d = Platelets,
and BC4d = B cells, TWEAK = Tumor necrosis factor-like weak inducer of
apoptosis, MCP-1 = Monocyte chemoattractant protein-1

still an important issue. With the use of conventional

therapies like corticosteroids, anti-malarials, aspirin,
and hydroxychloroquine, half of patients with organthreatening disease do not survive 20 years after
diagnosis, and the quality of life for those individuals with
all forms of SLE is usually seriously compromised.[32]
Thus, there is a need for improved therapies for SLE,
March 2014 | Vol 19 | Issue 1

Principle of targeted therapy

B lymphocytes play a central role in the pathogenesis

of SLE. Pathogenic autoantibodies produced by B cells
leads to tissue damage via immune complex formation,
complement activation, and direct effects on cells. They
also contribute to immune dysregulation by producing
cytokines, presenting antigens, and regulating T-cell
functions.[37] The regulatory and effector functions
of T cells are also abnormal in patients with SLE.
Elevated levels of certain cytokines / chemokines /
growth factors made by monocytes / macrophages and
endothelial cells also drive lupus disease activity and
organ damage. These include B-cell activating factor
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Shankar and Behera: Advances in SLE

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Table 4: Targeted Therapies in SLE[51]

Target
B Cell targeted therapies
B Cell depletion
Anti-CD 20

Anti-CD 22
Anti-CD 11
B Cell activation
Anti-B Lys Antibody
Figure 1: Possible targets in treatment of SLE

(BAFF)/B lymphocyte stimulator, tumor necrosis

factor (TNF) alpha, INF-a, IFN-, interleukin (IL)12, IL-6, IL-10, and MCP-1.[38] Over the last few
years, multiple studies have targeted these and other
appropriate pathways in the therapy of SLE as given
in Figure 1. Newer molecules have been developed
targeting these pathways as given in Table 4.

Rituximab

Rituximab (RTX) is a chimeric monoclonal antibody

that binds CD20, a protein expressed on B cells at all
stages of development. Multiple open-label studies have
reported the efficacy of RTX in patients with severe
refractory SLE and catastrophic anti-phospholipid
syndrome with maximal clinical benefit to be evident
even after 18 months.[39] Case series clearly suggest that
RTX ameliorates hemolytic anemia, thrombocytopenia,
arthritis, and probably central nervous system vasculitis
associated with SLE.[40]
Two initial randomized, double-blind, placebocontrolled trials namely EXPLORER and LUNAR[41,42]
to objectively assess the efficacy and safety of RTX in
generalized lupus or nephritis-specific lupus were not
successful where all patients were given high doses of
corticosteroids and immune-suppressives as well. But
EXPLORER study showed significant improvement
in anti-dsDNA and complement levels. But a recent
review evaluated the use of RTX in 188 SLE patients
from 35 studies, reporting efficacy rates approaching
90 percent.[43]
In a recently published RITUXILUP study by Lightstone
et al., the efficacy of treating lupus nephritis without
maintenance steroids was tried using two doses of 1g
Journal of Mahatma Gandhi Institute of Medical Sciences

Anti-B Lys + APRIL

(a proliferation-inducing
ligand) antibody
B Cell tolerogens
B cell Tolerogen

Agent

Role in SLE

Rituximab

a. Effective in treating
refractory SLE
b. Improvements in disease
activity
c. No benefit in proliferative
lupus nephritis
Epratuzumab a. Reduction in
corticosteroid doses in SLE
Efalizumab Improvement in cutaneous
SLE
Belimumab a. Reduction in SLE activity
b. Reduced flares
Atacicept Decrease in SLE auto
antibodies

Abetimus

No long-term benefit in
lupus nephritis
No results released

B cell Tolerogen
Edratide
T-Cell target and costimulatory blockers
Anti-CD40 ligand
IDEC-131 Unproven role
antibodies
(Toralizumab)
CTLA4-Ig Fusion protein
Abatacept Improvements in non-lifethreatening
SLE manifestations
Cell surface receptor
Sirolimus Role in Refractory SLE
activation inhibition
Cytokine inhibition
Infliximab Doubtful efficacy in lupus
Anti-TNF-
nephritis
Sifalimumab No results released
Anti-IFN-/-
Rontalizumab
Anti-IL-1
Anakinra Improvements in SLE
arthritis
Anti-IL-6
Tocilizumab Clinical and serologic
improvements in SLE
Anti-IL-10
B-N10
Improvements in disease
activity
Other potential targets
AntiC5 monoclonal
Eculizumab Improvements in SLE
antibody
Soluble recombinant
sCR1 (TP10, Improvements in disease
complement C3 inhibitor
BRL 55736) activity
Chemokine (MCP)
Bindarit
Improvements in disease
Inhibition
activity

rituximab with methyl prednisolone (500 mg) on days

1 and 15 and maintenance treatment of mycophenolate
mofetil. The study showed that about 90% of patients
achieved complete remission in this regimen creating a
ray of hope that oral steroids can be safely avoided in
lupus nephritis with the use of rituximab.[44]
The dosage of RTX may vary from low doses (100mg
weekly) used in thrombocytopenia of lupus to high
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Shankar and Behera: Advances in SLE

doses (375 mg/m2 IV weekly) used in severe or

refractory cases. To summarize, although RTX cannot
be considered first-line therapy for mild-to-moderate
SLE, it is of benefit in severe refractory disease.

Belimumab
The B-lymphocyte stimulator (BLyS) is important for the
survival of B cells, and studies have shown overexpression
of BLyS in SLE[45] with higher BLyS levels correlating
with SLE disease activity. Belimumab is a fully human
monoclonal antibody that selectively targets and inhibits
BLyS resulting in autoreactive B cell apoptosis.[46]
In serologically active SLE patients, Belimumab led
to a significantly better response over placebo and
led to a significant reduction in B-cell counts, rise in
complement levels, and reduction in immunoglobulin
levels and anti-dsDNA levels.[47] Belimumab was
further evaluated in two large randomized, double-blind,
placebo-controlled, multicenter phase 3 trials, BLISS-52
and BLISS-76 including 865 and 826 seropositive
SLE patients, respectively.[48,49] Belimumab was well
tolerated, achieved significantly better results, delayed
time to first SLE disease flare, and led to significant
reduction in steroid doses than placebo.
It is the first and the only biologic agent approved for
the treatment of refractory SLE.[50] It is used in doses
of 10 mg/kg IV q 2 Weeks x 3 doses, then q 4 Weeks
thereafter.

Other agents used

Epratuzumab

Epratuzumab has been used to treat patients with SLE

with neuropsychiatric and cardio-respiratory symptoms
of SLE, which are resistant to conventional therapies.
[52]
The dosage is 360 mg/m2, IV, every 2 weeks, for 4
doses.
Atacicept

Atacicept is a recombinant fusion protein, which

inhibits B cell stimulation. It was tried in SLE patients,
in which reductions up to 60% of mature and total
B-cell populations was seen.[53]
Abatacept

Abatacept has shown benefit in SLE patients with non-life-

threatening manifestations and is found to be superior

to placebo in reducing symptoms and improving
quality of life and reducing flares.[54] Animal data
suggest a beneficial role of T-cell co-stimulation
blockade (Abatacept) SLE models.
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33

TNF a inhibitors
Two large randomized trials evaluated the efficacy and
safety of TNF inhibitors (infliximab, etanercept) in SLE,
but both were terminated prematurely and, therefore, they
are not used for SLE.[55] The use of these is commonly
associated with the induction of lupus autoantibodies and
anti-TNF-induced lupus (ATIL) which can have different
levels of cutaneous, renal and neurological involvement. It
can be prevented by concomitant immunosuppression and
is treated by withdrawal of TNF inhibitors and steroids
and/or immunosuppressive therapy( in severe cases).56
Tocilizumab (IL-6)
Interleukin-6 (IL-6) is a key proinflammatory cytokine.
Tocilizumab used in doses of 2-8 mg/kg twice weekly
for 12 weeks led to reduction in inflammatory markers
and auto-antibody levels in SLE.[57]
Abetimus
It is an intravenously administered tetrameric
oligonucleotide conjugate that safely reduces antidsDNA antibodies. Its use was associated with
reductions in circulating anti-dsDNA antibodies.
However, two pivotal trials in lupus nephritis failed to
demonstrate statistically significant improvement.[58]
Eculizumab
Furie et al. reported the safety, tolerability,
pharmacokinetics, and pharmacodynamics of a single
administration of eculizumab (0.1, 0.75, 2, 4, and 8
mg/kg) in 24 patients with SLE.[59]

Other therapies in SLE

Various non-biological agents and drugs that are

under study for SLE. None of the above agents are
significantly ameliorative of SLE, and none have
been shown to significantly influence its morbidity or
mortality. The salient ones are summarized below:
1. Fish oil is ameliorative in patients with mild
activity.[60]
2. A large trial evaluating the efficacy of vitamin D is
in progress.
4.
Mycophenolate mofetil is equivalent to
cyclophosphamide as induction therapy for SLE
nephritis and is superior to azathioprine for
maintenance.[61]
5. Topical pinecrolimus and tacrolimus are effective
for chronic cutaneous SLE.[62]
6. Leflunomide improves SLE arthritis.[63]
7. N-acetyl cysteine improves outcome in murine
lupus, and a phase 1/2 trial is underway to assess the
safety and efficacy of NAC treatment in SLE.[64]
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34

Haemopetic stem cell transplant (HSCT)

In patients with severe SLE refractory to conventional
immunosuppressive treatments, allogenic HSCT can
achieve sustained clinical remissions (ranging from
50% to 70% disease-free survival at 5 years) associated
with qualitative immunological changes.[65]

Conclusion
In recent years, advances in our understanding of the
mechanisms of SLE have offered newer diagnostic
modalities and better drug targets for treatment. Over the
next years, we will test the efficacy of many new therapeutic
agents. The coming years promise to be an exciting time
for the development and trial of new pharmacological
treatments and immunotherapies for patients with SLE
as we benefit from improved understanding of disease
pathogenesis and molecular mechanisms.

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How to cite this article: Shankar S, Behera V. Advances in
management of systemic lupus erythematosus. J Mahatma Gandhi
Inst Med Sci 2014;19:28-36.
Source of Support: Nil, Conflict of Interest: None declared.

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