An overview of
current research and
Topical
Reviews
Reports on the Rheumatic Diseases | Series 7 | Spring 2013 | Topical Reviews No 2
Overview of the management of
systemic lupus erythematosus
John A Reynolds
Ian N Bruce
Arthritis Research UK Epidemiology Unit, Institute of
Inflammation and Repair, University of Manchester/
NIHR Manchester Musculoskeletal Biomedical Research
Unit, Central Manchester University Hospitals NHS
Foundation Trust
Systemic lupus erythematosus (SLE) is a
heterogeneous autoimmune disease with
a broad clinical presentation
When assessing a patient with SLE it is
important to differentiate active disease
from irreversible organ damage, adverse
effects of treatment and other co-morbid
conditions
Patients with SLE have increased co-
morbidities including osteoporosis,
cardiovascular disease, infection risk and
depression, which need to be identified
and managed appropriately
Corticosteroids and immunosuppressant
therapies are the treatments of choice for
active disease, but newer biological
therapies may offer improved disease
control and fewer adverse effects
1
practice in rheumatic
disease
Introduction
Systemic lupus erythematosus (SLE) is a systemic
inflammatory autoimmune disease predominantly
affecting women. The prevalence of lupus is estimated
at 12.578.5 cases per 100,000 population in Europe
and the USA with a female:male ratio of around 9:1.1,2
In the UK SLE is approximately 2.5 times more common
in South Asian and 56 times more common in Afro-
Caribbean individuals.3 Due to the rarity of SLE it is
difficult to accurately determine the incidence, but it
has been estimated to be between 2.0 and 7.6 cases
per 100,000 population/year.1 The aetiology and im-
munopathogenesis of SLE have been extensively re-
viewed elsewhere.4,5 This review will focus on advances
in the management of SLE in terms of both the disease
itself and its associated co-morbidities.
Clinical features of SLE
SLE is one of a small number of truly multisystem
disorders. The heterogeneous nature of the disease
can result in delayed diagnosis and cause considerable
difficulty in the design of robust clinical trials. There
is no diagnostic test specific for SLE and as such the
diagnosis remains a clinical one, relying on a com-
bination of clinical and laboratory features. The 1992
Revised American College of Rheumatology (ACR)
Classification Criteria, while developed to aid trial
design, offer a useful aide-mmoire to the rheuma-
tologist of some of the more common features of SLE
(Table 1).6,7 Newer criteria have only recently been
published but are likely to be more widely used in
the future (Table 2).8
 TABLE 1. 1997 Updated American College of Rheumatology criteria for classification of systemic lupus
erythematosus. (Adapted with permission of John Wiley & Sons, Inc from: Tan EM et al. The 1982 revised criteria for the
classification of systemic lupus erythematosus. Arthritis Rheum 1982 Nov;25(11):1271-7 and Hochberg MC. Updating the
American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum
1997 Sep;40(9):1725.)

Criteria Brief definition notes

1 Malar rash
2 Discoid rash
3 Photosensitivity Patient history or physician observation
4 Oral ulcers Oral
or nasopharyngeal
5 Non-erosive arthritis Tenderness, swelling or effusion in 2 peripheral joints
6 Pleurisy or pericarditis Pleurisy: convincing history of pleuritic pain, pleural rub, or effusion
or pericarditis: ECG evidence, rub, or effusion
7 Renal Persistent proteinuria (>0.5 g/day or >3+ by dipstick)
or cellular casts on microscopy (red, granular, tubular or mixed)
8 Neurological Seizures or psychosis in the absence of drugs or metabolic derangements
9 Haematological At least 1 of:
Haemolytic anaemia with reticulocytosis
Leucopenia (<4000/mm3) on 2 occasions
Lymphopenia (<1500/mm3) on 2 occasions
Thrombocytopenia (<100,000/mm3) without drug cause
10 Immunological At least 1 of:
Anti-DNA antibody
Anti-Smith antibody
Positive antiphospholipid antibodies identified by:
abnormal serum level of IgM or IgG anticardiolipin antibodies
positive lupus anticoagulant
11 Positive ANA

At least 4 criteria are needed for the classification of SLE.

ANA antinuclear antibodies; DNA deoxyribonucleic acid; ECG electrocardiogram; Ig immunoglobulin

It is interesting to note that, in addition to differences
in disease prevalence, marked ethnic variation in organ
involvement has also been reported; for example,
when compared to Caucasian lupus patients Afro-
Caribbean patients have an increased risk of renal
disease while antiphospholipid syndrome (APS) is
less common.2,9
A wide spectrum of autoantibodies can be found
in patients with SLE and are often associated with
specific clinical features. Antinuclear antibodies
(ANA) are found in 98% of SLE patients but are non-
specific. The presence of anti-double-stranded DNA
(dsDNA) is highly specific for SLE but they are only
present in around 70% of cases.10 Other autoanti-
bodies reported in patients with SLE include anti-
Smith, anti-ribosomal P and anti-proliferating cell
nuclear antigen (PCNA).11 Of all these antibodies, it is
only dsDNA that has been shown to be pathogenic
(for lupus nephritis)12 the others appear to be bio-
markers for the presence of an autoimmune state.
Mortality in SLE
There has been a significant reduction in mortality
among lupus patients over the last 5060 years; the
5-year survival is now estimated at around 95%.2 This
does of course still mean there is an unacceptably
high mortality in this condition affecting younger
women. In the largest observational study to date (of
c.9500 lupus patients) increased mortality was seen
in female patients, particularly within the first year
following diagnosis.13 This early peak in mortality,
which is commonly due to lupus disease activity and
infection, is followed by a second later peak chiefly
due to cardiovascular disease (CVD).14

2
TABLE 2. Clinical and immunological criteria used in the Systemic Lupus International Collaborating Clinics
(SLICC) classification system. (Adapted with permission of John Wiley & Sons, Inc from: Petri M et al. Derivation and
validation of Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.
Arthritis Rheum 2012 Aug;64(8):2677-86.)

Clinical criteria Brief definition notes

Acute cutaneous lupus Lupus malar rash (do not count if malar discoid), bullous lupus, toxic epidermal
necrolysis variant of SLE, maculopapular lupus rash, photosensitive lupus rash
or subacute cutaneous lupus (nonindurated psoriaform and/or annular polycyclic
lesions that resolve without scarring, although occasionally with postinflam-
matory dyspigmentation or telangiectasias)
Chronic cutaneous lupus Classical discoid rash [localised above the neck; generalised above and
below the neck], hypertrophic (verrucous) lupus, lupus panniculitis (profundus),
mucosal lupus, lupus erythematosus tumidus, chilblains lupus, discoid lupus/
lichen planus overlap
Oral ulcers Palate [buccal, tongue]
or nasal ulcers (in the absence of other causes)
Nonscarring alopecia
Synovitis 2 joints, characterised by swelling or effusion
or tenderness in 2 joints and 30 minutes of morning stiffness
Serositis Typical pleurisy for >1 day, or pleural effusions, or pleural rub
or typical pericardial pain for >1 day, or pericardial effusion, or pericardial rub, or
pericarditis by ECG
Renal Urine protein:creatinine ratio (or 24-hr urine protein) representing 500 mg
protein/24 hr
or red blood cell casts
Neurological Seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial
neuropathy, acute confusional state (in the absence of other causes)
Haemolytic anaemia
Leucopenia Leucopenia (<4000/mm3 at least once)
or lymphopenia (<1000/mm3 at least once)
Thrombocytopenia Platelet (<100,000/mm3) at least once
Immunological criteria

ANA Above reference range

Anti-dsDNA x2 above if ELISA
Anti-Smith
Antiphospholipid Lupus anticoagulant, false-positive RPR, medium- or high-titre anticardiolipin
(IgA, IgG or IgM), anti-b2 -glycoprotein I (IgA, IgG or IgM)
Low complement Low C3, C4 or CH50
Positive direct Coombs In the absence of haemolytic anaemia
test

Classify a patient as having SLE if:

the patient satisfies 4 of the criteria listed in the table including at least 1 clinical criterion
and 1 immunological criterion, OR
the patient has biopsy-proven nephritis compatible with SLE and with ANA or anti-dsDNA
antibodies.
Note: criteria are cumulative and need not be present concurrently.

ANA antinuclear antibodies; dsDNA double-stranded deoxyribonucleic acid; ECG electrocardiogram; ELISA enzyme-linked immunosorbent assay;
Ig immunoglobulin; RPR rapid plasma reagin; SLE systemic lupus erythematosus

3
Identification of high-risk patients
No universal prognostic factor has been identified,
but some clinical features of SLE are associated with a
worse prognosis. In a study by Lopez et al of 350 lupus
patients, older age, higher disease activity and pre-
existing organ damage were all independently as-
sociated with premature death.15 In addition, renal
disease (identified either at biopsy or by measure-
ment of serum creatinine) and thrombocytopenia
are associated with increased mortality.16-18 Perhaps
most importantly, it is increased lupus disease activity
overall that should alert the rheumatologist to the
fact that the patient is at risk of a poor outcome.17
Morbidity in SLE
The clinical course in SLE can vary markedly from
relatively mild symptoms through to life-threatening
multi-organ disease. A thorough assessment of lupus
patients is important to clearly identify active disease
and the presence of organ involvement. Disease activity
scoring systems have been developed primarily for
use in research studies in order to try to capture activity
in this heterogeneous disease (reviewed in Griffiths et
al19). Although developed for use in research studies,
these scoring systems offer a useful framework for
the treating physician.
Global scoring systems such as the Systemic Lupus
Erythematosus Disease Activity Index (SLEDAI) pro-
vide a single total activity score, with serious manifes-
tations (e.g. neurological disease) weighted more
heavily.20 Recent updates to SLEDAI include SELENA-
SLEDAI (Safety of Estrogens in Lupus Erythematosus:
National Assessment-SLEDAI)21 and SLEDAI-2K, both
of which aim to capture ongoing rather than just new
or recurrent activity.22
The British Isles Lupus Assessment Group (BILAG)
index offers a more comprehensive approach to the
assessment of lupus disease activity. Rather than gen-
erating a global activity score, the BILAG-2004 index
classifies activity, over a 4-week period, according to
9 different organ systems.23 Furthermore, rather than
using an arbitrary definition of disease activity the
benchmark is set against whether or not the signs or
symptoms would prompt an escalation of therapy. It
is important when using indices such as BILAG that
only features due to SLE activity per se (and not dam-
age or other conditions) are recorded.
Against a background of a cluster of negative random-
ised trials (see below) new scoring systems to capture
therapeutic response in SLE are being developed.
These response indices, analogous to an ACR or Euro-
pean League Against Rheumatism (EULAR) response
in rheumatoid arthritis, aim to quantify changes in
disease activity in clinical trials. The SLE Responder
4
Index (SRI) comprises a reduction in SELENA-SLEDAI
score of 4 points, no new BILAG A or more than
1 new B score, and no significant worsening in
Physicians Global Assessment (PGA) score.24 This
composite scoring system has thus far only been
used in the clinical trials of belimumab.25,26 The
development of sensitive and reproducible scoring
systems will be essential for the conduct of more
robust clinical trials.
Clinical assessment of the lupus
patient
In the assessment of symptomatic patients consider-
ation should be given as to whether the clinical features
are due to:
Lupus disease activity (i.e. a lupus flare)
Other lupus-related pathology, e.g. thrombosis or
vasospasm
Irreversible organ damage
Non-lupus causes, e.g. infection, atherosclerosis,
other autoimmune diseases or drug-related
adverse events.
It is important to remember that other diseases (e.g.
infection) can co-exist in the SLE patient and can be
worsened by a lupus flare, resulting in dual-pathology.
An accurate diagnosis therefore relies on interpretation
of symptoms against a background of probability.
For example, haematuria and proteinuria are more
likely to be due to a urinary tract infection rather
than lupus nephritis. Indeed, concomitant infections
are one of many co-morbidities common in SLE and
are discussed in detail below. The Systemic Lupus
International Collaborating Clinics Damage Index
(SLICC-DI) allows damage to be recorded and quanti-
fied as a score between 0 and 46.27 Unlike the meas-
ures of disease activity all damage is scored from the
time of diagnosis of SLE onwards, regardless of whether
or not it can be attributed to lupus.
Can a lupus flare be predicted?
SLE often follows a relapsing and remitting pattern
of disease. The ability to identify those patients in
whom a flare is likely allows either a proactive in-
crease in therapy or instigation of more stringent
monitoring. No single predictive marker for lupus
flare has yet been identified. Perhaps the most rec-
ognised link is that between raised dsDNA titre and/
or low serum complement (C3, C4 and C1q) and the
development or flare of lupus nephritis.28,29 An increase
in dsDNA titre, or the development of blood dyscrasia
(anaemia, lymphocytopenia or thrombocytopenia)
can also predict flare in lupus cohorts and has been
reviewed by Bertsias et al.30 A combination of clinical
(disease activity) and laboratory features (full blood
 Establish diagnosis
Determine likely prognosis
Assess severity and organ involvement
Lifestyle (sun avoidance etc)
Topical agents
Symptomatic agents
Manage co-morbidities
FIGURE 1. Overview of the management of systemic lupus erythematosus.
count, serum complement) is therefore recommen-
ded for monitoring SLE patients, as reflected for
example in the 2010 EULAR guidelines for the moni-
toring of lupus patients both in clinical practice and
in observational studies.31
Management of lupus: no major
organ involvement
The general principle of management of SLE is anal-
ogous to that of other inflammatory disorders: sup-
pression of inflammation in an attempt to prevent
organ damage. The intensity of therapy is therefore
dictated by the severity and site of organ involvement,
and the overall prognosis for specific organ involve-
ment. The management of SLE is summarised in
Figure 1.
Non-organ-specific symptoms in SLE are common
and include marked fatigue, arthralgia, myalgia,
fever, weight-loss and mood changes (often low
mood and depression). These can be severe enough
to significantly impair a patients quality of life.32
Management of these symptoms, particularly fatigue,
is often challenging as the causes are multifactorial
and no specific therapies exist. These symptoms will
to some extent be improved by increasing overall
control of the disease. Fatigue and chronic pain are
therefore common in SLE, although there is evidence
that the prevalence of fibromyalgia itself is lower
than would be expected.33
In mildmoderate lupus, musculoskeletal and muco-
cutaneous features are likely to dominate the clinical
picture. Common manifestations include mucosal
ulceration (typically oral and nasal), scarring alopecia,
5
No major organ involvement
Antimalarials
Low-dose steroids
Azathioprine/methotrexate
Major organ involvement
Cyclophosphamide (intravenous)
Mycophenolate mofetil
Calcineurin inhibitors (ciclosporin A or
tacrolimus
Biologics (rituximab or belimumab) or
Enrol in a clinical trial
non-erosive arthropathy (Jaccouds arthropathy) and
skin rashes (malar rash, discoid lesions and other
photosensitive rashes). Oral corticosteroids at low
moderate doses and antimalarial therapy are the
mainstay of management of mildmoderate disease,
using the lowest dose of steroids to adequately con-
trol the symptoms. Higher-dose steroids and steroid-
sparing agents are used when this approach is in-
sufficient to control the disease. In addition, steroid
and antimalarial agents can be important adjuvant
therapy to reduce the risk of flare in patients with
more severe disease.
UV protection
Exposure to sunlight is a recognised precipitant of a
lupus flare. Patients often have photosensitive rashes,
or may experience a worsening of systemic symptoms
in response to ultraviolet (UV) radiation. Lupus patients
should be advised to avoid sitting in direct sunlight
and to use physical protection from the sun (e.g. long
sleeves, hats and sun-protective clothing) where
appropriate. Diffusers on low-energy light bulbs and
fluorescent light sources may also be of help. High-
factor sunblock (ideally sun protection factor (SPF)
50) is also recommended and should be applied
regularly. Sunlight avoidance may, however, partly
contribute to the increased prevalence of vitamin D
deficiency in patients with SLE.34 Although the clini-
cal relevance of low vitamin D in SLE with regard to
immunological function is currently under investi-
gation, vitamin D deficiency is of course an estab-
lished risk factor for poor bone health, including the
development of osteomalacia and osteoporosis (the
latter is discussed below).
Antimalarial therapy
Hydroxychloroquine (HCQ) (up to 6.5 mg/kg daily)
has been shown to be very effective in the man-
agement of mucocutaneous disease, serositis and
fatigue.35,36 It should be noted that prolonged use of
chloroquine phosphate (but to a lesser extent HCQ)
can lead to the development of retinopathy.37 In
2009 the Royal College of Ophthalmologists issued
good practice guidelines for the use of antimalarial
therapy by rheumatologists and dermatologists.38
In the absence of pre-existing retinal disease routine
ophthalmological review is not recommended. In
more refractory cases, or if ocular toxicity is a concern,
mepacrine has also been used with good effect,
although it can result in a dose-dependent yellow
discoloration of the skin. HCQ and mepacrine can
also be efficacious in combination. The therapeutic
options for treatment of cutaneous lupus have been
extensively reviewed by Kuhn et al.39 Importantly,
HCQ use has also been associated with a reduction
in overall mortality in lupus patients.40
Corticosteroids
Systemic corticosteroids remain a keystone in the
management of SLE, particularly when a rapid
response is desirable. The response of moderately
active lupus to steroid therapy is such that if effec-
tiveness alone were the only consideration then
other agents would rarely be needed. Low doses (e.g.
510 mg daily) are often sufficient for mild disease,
but can be increased to 0.5 mg/kg where the disease
is moderately active. Corticosteroid therapy is, how-
ever, associated with significant unwanted effects
and hence long-term high or moderate doses are
undesirable.41 The therapeutic aim should therefore
be to maximise benefit while minimising steroid-
related harms. Steroid-sparing therapies such as
azathioprine (AZA) can therefore be used in order to
reduce the cumulative exposure to steroids. EULAR
guidelines for the management of steroid therapy in
rheumatic diseases were published in 2007 and cover
issues such as risk stratification, monitoring and
management of complications of glucocorticoids.42
Immunosuppressant agents
Azathioprine (AZA) (13 mg/kg) is the most com-
monly used steroid-sparing agent for the manage-
ment of patients with SLE.43 The effective metabolism
of AZA is dependent on normal thiopurine methyl-
transferase (TPMT) activity. Patients should therefore
be screened for a homozygous deficiency of TPMT
(present in 1 in 300 of the population) which results in
an extremely high risk of bone marrow suppression.44
In homozygous-deficient patients AZA should be
avoided. Patients with heterozygous deficiency
should have their target AZA dose adjusted down-
wards by approximately 50% and any further dose
6
adjustments should be carefully monitored. In patients
with inflammatory arthritis methotrexate (MTX) is
often beneficial in controlling synovitis and may
also reduce cutaneous disease.45 The effect of MTX
on disease activity appears to be rather modest, but
there is clinical trial evidence that MTX can allow
more rapid and greater steroid withdrawal.46 Sulfa-
salazine is usually avoided in SLE due to its association
with drug-induced lupus. The evidence for this associ-
ation is, however, limited to case reports and has not
been clearly demonstrated in larger cohorts.47
Management of lupus: major organ
involvement
In patients with significant major organ involvement
rapid resolution of inflammation is needed in order
to prevent the development of irreversible damage.
The therapeutic options include high-dose intravenous
(IV) methylprednisolone, immunosuppressant ther-
apies (including cyclophosphamide (CYC) and myco-
phenolate mofetil (MMF)) and biological therapies.
It should however be noted that there is no clear evi-
dence for any additional benefit of IV methylpred-
nisolone over high-dose oral prednisolone.48 The
treatment choice is dictated primarily by the site and
extent of organ involvement, although other issues
(e.g. gonadal function, CYC) need to be considered.
Much of the evidence for the effectiveness of these
therapies in SLE, particularly CYC, is derived from
studies of lupus nephritis. However, CYC is also used
widely for systemic features where rapid disease
control is needed (e.g. vasculitis, transverse myelitis,
pulmonary haemorrhage). Although a comprehen-
sive review of the management of lupus nephritis is
beyond the scope of this review an excellent sum-
mary was recently published by Houssiau.49
Mycophenolate mofetil
MMF is the pro-drug of mycophenolic acid which
targets lymphocyte activation and survival by inhibi-
ting de novo purine synthesis. As with CYC, much
of the evidence base for the use of MMF in lupus is
in the context of renal disease. A meta-analysis of
4 randomised controlled trials (RCTs) shows that MMF
is as effective as CYC for induction of remission and is
associated with fewer adverse events (gonadal failure
and alopecia).50 MMF is therefore increasingly being
used in preference to CYC in lupus nephritis and other
major organ disease. Also MMF was superior to AZA
for maintenance therapy for nephritis in the ALMS
(Aspreva Lupus Management Study) trial,51 but not in
the MAINTAIN (Mycophenolate Mofetil Versus Azathio-
prine for Maintenance Therapy of Lupus Nephritis)
trial.52 These two trials differed significantly in terms
of size and the racial composition of the study group.
Although the positive results from these studies has
led to the use of MMF for non-renal manifestations of
lupus with much anecdotal success, there is relatively
limited published data on its use.53
Calcineurin inhibitors
Ciclosporin A and tacrolimus have both made the
transition from transplant medicine to management
of lupus although they are less commonly used than
the agents described above. Both ciclosporin and
tacrolimus offer an adjunct therapy to MMF in systemic
disease and a potential alternative for induction/
maintenance therapy in lupus nephritis.54,55 Ciclosporin
may be particularly attractive in lupus nephritis as it
may be safer than MMF in pregnancy.56 Topical tacro-
limus can also be particularly useful for the manage-
ment of both subacute cutaneous lupus and discoid
lupus.57
Rituximab
Abnormalities in B-cell activation in lupus prompted
the off-licence use of B-cell-depleting therapies, most
notably rituximab (RTX). RTX is a chimeric monoclonal
antibody directed against CD20 which is expressed
on the surface of B-cells. Treatment results in a rapid
and prolonged depletion of B-cells. A recent meta-
analysis of all the available open-label studies suggests
that B-cell depletion occurs in around 95% of patients,
with an associated improvement in disease activity.58
It was disappointing, therefore, that two RCTs failed to
show any benefit. The EXPLORER (Exploratory Phase
II/III SLE Evaluation of Rituximab) and the LUNAR
(Lupus Nephritis Assessment with Rituximab) trials
both showed no improvement with RTX when com-
pared to the placebo arm.59,60 In both of these studies
RTX was used as an adjunct to existing therapy (high
doses of corticosteroids or MMF) which likely blunted
any true benefit of RTX. Despite these trials RTX re-
mains an attractive option to treat patients who have
failed conventional immunosuppression, and in the
UK an open-label prospective register is being estab-
lished to assess safety and patterns of use of this and
other biologic agents in SLE (http://www.bilagbr.org).
Belimumab
In 2011 belimumab (Benlysta) became the first drug
for 50 years to be licensed for treatment of SLE.
Belimumab is a fully-humanised monoclonal anti-
body which blocks the binding of the activating
factor, B-lymphocyte stimulator (BLyS), to its receptor
on the surface of B-cells. Two large RCTs (BLISS
(Belimumab in Subjects with Systemic Lupus Eryth-
ematosus)-52 and BLISS-76) with over 1600 patients
demonstrated that belimumab resulted in a modest
but significant improvement in lupus disease activity
when compared to adjustments of standard of care
alone (as assessed using the SRI discussed above).25,26
7
These positive findings are encouraging, and the
investigators recognised a subpopulation of patients
who particularly responded to treatment (i.e. patients
with increased dsDNA and low complement). Further
studies are needed in order to identify those patients
who are most likely to benefit, and to confirm the
current safety data over a longer time period.
Management of co-morbidities in
patients with SLE
The assessment and management of disease activity
constitutes only part of the care of lupus patients. It
is equally important to address co-morbid conditions
which arise either from the lupus disease itself or as
adverse effects of treatment. The 2010 EULAR guide-
lines for the monitoring of lupus focus on the identi-
fication of co-morbidities.31
Osteoporosis
Patients with SLE have an increased risk of osteopo-
rosis compared to the general population. Risk factors
for reduced bone mineral density (BMD) include age,
low body weight, inflammatory markers (erythrocyte
sedimentation rate (ESR) and C-reactive protein (CRP))
and pre-existing organ damage.61 In addition, cortico-
steroid doses of >7.5 mg in particular are associated
with a greater risk of osteoporosis.62 Management of
bone health in these patients should follow estab-
lished practice for osteoporosis in other patient groups:
conservative measures (including smoking cessation
and exercise), optimisation of vitamin D levels (which
are frequently deficient), calcium supplementation,
and use of bisphosphonates.63 It is also worth noting
that the FRAX tool (http://www.shef.ac.uk/FRAX) which
is commonly used to assess future risk of fracture is
validated for patients between 40 and 90 years, and so
caution should be exercised when using such a tool
in younger female lupus patients.
Infection
Severe infection remains the primary cause of mor-
tality in approximately 25% patients with SLE. Bacterial
infections, particularly pneumonia, are the most
common cause of hospitalisation due to infection.64
The risk of infection is increased by both disease-
related factors (lung involvement, renal disease, lym-
phopenia, complement consumption and functional
hyposplenism) and drug-related effects (cumulative
steroid exposure and immunosuppressant use).64,65
The most frequently seen viral infection is herpes
zoster, while S. pneumoniae, E. coli and S. aureus are
the most common bacterial pathogens in this group.
Hyposplenism secondary to excessive immune com-
plex deposition results in an increased risk of infection
with encapsulated organisms (e.g. S. pneumoniae,
H. influenzae, S. typhi). Opportunistic infections
(especially atypical tuberculosis (TB), cytomegalo-
virus (CMV) reactivation and Pneumocystis jirovecii)
need to be considered, particularly in the lympho-
penic patients.66 Infection risk can be minimised by
aiming for disease remission using minimal steroid
and immunosuppressive therapy. Vaccination against
influenza and pneumococcal infection should also be
recommended to all patients. It should be remem-
bered, however, that live vaccines are contraindicated
in patients on immunosuppressive therapy (including
steroids at doses of >20 mg/day).67
Cardiovascular disease
Patients with SLE have a significantly increased risk
of cardiovascular disease, around 56 times higher,
compared to healthy controls.68 This increased risk
is at least in part due to an increased prevalence of
traditional cardiovascular risk factors, including
smoking, hypertension, type 2 diabetes and dys-
lipidaemia.69,70 Guidelines for the management of
these risk factors were proposed by Wajed et al.71
These offer a pragmatic target-based approach to
cardiovascular risk factor management for the clin-
ician. It should be noted, however, that the evidence
for these risk-reduction strategies is derived from
their benefit in the general population; more studies
are needed to demonstrate that these are beneficial
in SLE.
In addition, there are lupus-specific factors that pre-
dispose these patients to premature atherosclerosis,
including disease activity, renal disease and cortico-
steroid use.72 It is proposed, therefore, that control of
inflammation, while minimising steroid exposure,
may also reduce cardiovascular mortality in lupus.
Mental health
SLE has been shown to have a greater negative impact
on health-related quality of life than other chronic
diseases.73 The reason for this is unclear, but may be
due to the systemic nature of the condition. Clear
neuropsychiatric involvement is common, with a
cumulative incidence of 3040%. In 2010 EULAR
guidelines for the management of neuropsychiatric
lupus were published, covering the broad spectrum
of disease manifestations.74 Of the quality of life assess-
ment tools available, the LupusQoL is the most exten-
sively validated.75 Despite the availability of these
measures, there is little known about how quality of
life can be improved for lupus patients. Management
should therefore focus on the specific manifestations
(e.g. depression, anxiety, fatigue) following conven-
tional approaches.
Risk of thrombosis
In addition to traditional risk factors, patients with
lupus have an increased risk of thromboembolic
disease. Higher disease activity, lupus nephritis and
8
hypertension may all contribute to this increased
risk.76 APS is common in SLE, with clinical conse-
quences in 1015% of all patients.76 APS antibodies
and lupus anticoagulant should be determined in all
patients at baseline and following the emergence of
any new risk factors for thrombosis.77 In non-pregnant
patients with lupus and APS, long-term anticoagulation
is required for secondary prevention of thrombosis.
Assessment of thrombotic risk is also a key part of
pregnancy assessment and management in SLE (see
below).77,78
Premature gonadal failure
Early menopause is a common feature of SLE and
other autoimmune diseases.79 Exposure to CYC may
be a contributing factor in up to a half of cases.80
Distressing symptoms, including mood changes and
severe flushing, are more difficult to treat in SLE due
to concerns that hormone replacement therapy (HRT)
may precipitate a disease flare.81 In patients with mild
moderate disease HRT increases the risk of mild
moderate flares and may also increase thrombotic
risk. The effect on patients with more severe disease
has not been studied. Alternative agents such as selec-
tive serotonin reuptake inhibitors (SSRIs), clonidine
and topical oestrogens may be beneficial in symptom
control.
Pregnancy
Many lupus patients are women of childbearing age,
which has implications for the planning and monitor-
ing of pregnancy, disease management during preg-
nancy and lactation, and risk of additional compli-
cations (e.g. thrombosis, pre-eclampsia, neonatal
lupus/congenital heart block). Although a comprehen-
sive review of immunosuppressant agents in preg-
nancy is beyond the scope of this article it should
be remembered that only corticosteroids, HCQ and
AZA are considered safe to use in pregnancy. Other
agents have potential effects on fertility (e.g. CYC) or
teratogenesis (e.g. CYC, MTX, MMF) and the likely
risk:benefit ratio of these treatments needs to be
thoroughly discussed with the patient. The manage-
ment of the pregnant lupus patient has recently been
reviewed in detail by Baer et al.78
Summary and future research
Despite recent advances in the treatment of SLE,
morbidity and mortality remain unacceptably high.
The disease is poorly understood, leading to a
paucity of proven targeted therapies. Furthermore,
the significant disease heterogeneity can cloud the
apparent benefits of new agents in clinical trials.
More research is needed into the pathogenesis of
SLE in order to identify new drug targets. Trials of
these new drugs will, however, only be successful if
combined with more stringent and comprehensive
disease outcome measures. It is highly likely that
the disease that we understand as SLE comprises
multiple related, but different, conditions. Identify-
ing the exact clinical and pathological phenotype
of these patients is essential in order to develop per-
sonalised treatment strategies. Until such a time,
management of these patients is likely to remain as
challenging as it is interesting.
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Do you want to update your MSK core skills?

Arthritis Research UK and the Royal College of General Practitioners
launch new core skills training for GPs and GPSTs

Each year 20% of the population will consult their GP with a musculoskeletal problem
such as arthritis and it is estimated that every day there are over 100,000 musculo-
skeletal GP consultations in England alone.
It is essential that GPs feel confident in their ability to treat common musculoskeletal
conditions. However they often dont fit neatly into the typical diagnosis, treatment
and cure model.
Working with the Royal College of General Practitioners, Arthritis Research UK has
funded and jointly developed a new training programme to improve GPs and GPSTs
core skills in diagnosing and managing musculoskeletal conditions.
The Core Skills in Musculoskeletal Care Project has been developed by GPs for
GPs and draws on the latest evidence and consensus thinking.
The training project consists of e-learning modules, face-to-face workshops focused
on clinical skills, and an impact toolkit which contains practical resources for GPs.
You can access the free e-learning modules at www.elearning.rcgp.org.uk/msk.
Go to www.arthritisresearchuk.org/gpresources to download GP resources and
self-management information for your patients.

11
 Do you want to update your MSK core skills?
Arthritis Research UK and the Royal College of General Practitioners
launch new core skills training for GPs and GPSTs

Please see overleaf for full details, including a link to the free e-learning modules.

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