An overview of

current research and

practice in rheumatic
disease

Topical
Reviews

Reports on the Rheumatic Diseases | Series 7 | Spring 2013 | Topical Reviews No 2

Overview of the management of

systemic lupus erythematosus
Introduction

John A Reynolds
Ian N Bruce

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 AfroCaribbean 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 immunopathogenesis of SLE have been extensively reviewed 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.

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

Clinical features of SLE

Patients with SLE have increased comorbidities including osteoporosis,

cardiovascular disease, infection risk and
depression, which need to be identified
and managed appropriately

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 combination 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 rheumatologist 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

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

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

Malar rash

Discoid rash

Photosensitivity

Patient history or physician observation

Oral ulcers

Oral
or nasopharyngeal

Non-erosive arthritis

Tenderness, swelling or effusion in 2 peripheral joints

Pleurisy or pericarditis

Pleurisy: convincing history of pleuritic pain, pleural rub, or effusion

or pericarditis: ECG evidence, rub, or effusion

Renal

Persistent proteinuria (>0.5 g/day or >3+ by dipstick)

or cellular casts on microscopy (red, granular, tubular or mixed)

Neurological

Seizures or psychosis in the absence of drugs or metabolic derangements

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 AfroCaribbean patients have an increased risk of renal
disease while antiphospholipid syndrome (APS) is
less common.2,9

only dsDNA that has been shown to be pathogenic

(for lupus nephritis)12 the others appear to be biomarkers 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

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 nonspecific. 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 autoantibodies reported in patients with SLE include antiSmith, anti-ribosomal P and anti-proliferating cell
nuclear antigen (PCNA).11 Of all these antibodies, it is

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 postinflammatory 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

test

In the absence of haemolytic anaemia

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

Identification of high-risk patients

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.

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 preexisting organ damage were all independently associated with premature death.15 In addition, renal
disease (identified either at biopsy or by measurement 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

Clinical assessment of the lupus

patient
In the assessment of symptomatic patients consideration 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.

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.

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 quantified as a score between 0 and 46.27 Unlike the measures 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.

Global scoring systems such as the Systemic Lupus

Erythematosus Disease Activity Index (SLEDAI) provide a single total activity score, with serious manifestations (e.g. neurological disease) weighted more
heavily.20 Recent updates to SLEDAI include SELENASLEDAI (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 generating 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 damage or other conditions) are recorded.

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 increase in therapy or instigation of more stringent
monitoring. No single predictive marker for lupus
flare has yet been identified. Perhaps the most recognised 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

Against a background of a cluster of negative randomised trials (see below) new scoring systems to capture
therapeutic response in SLE are being developed.
These response indices, analogous to an ACR or European League Against Rheumatism (EULAR) response
in rheumatoid arthritis, aim to quantify changes in
disease activity in clinical trials. The SLE Responder

Establish diagnosis

No major organ involvement

Determine likely prognosis

Antimalarials
Low-dose steroids
Azathioprine/methotrexate

Assess severity and organ involvement

Major organ involvement

Cyclophosphamide (intravenous)
Mycophenolate mofetil
Calcineurin inhibitors (ciclosporin A or
tacrolimus
Biologics (rituximab or belimumab) or
Enrol in a clinical trial

Lifestyle (sun avoidance etc)

Topical agents
Symptomatic agents
Manage co-morbidities

FIGURE 1. Overview of the management of systemic lupus erythematosus.

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 control the symptoms. Higher-dose steroids and steroidsparing agents are used when this approach is insufficient 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.

count, serum complement) is therefore recommended for monitoring SLE patients, as reflected for
example in the 2010 EULAR guidelines for the monitoring 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 analogous to that of other inflammatory disorders: suppression 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 involvement. The management of SLE is summarised in
Figure 1.

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. Highfactor 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 clinical relevance of low vitamin D in SLE with regard to
immunological function is currently under investigation, vitamin D deficiency is of course an established risk factor for poor bone health, including the
development of osteomalacia and osteoporosis (the
latter is discussed below).

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 mucocutaneous features are likely to dominate the clinical
picture. Common manifestations include mucosal
ulceration (typically oral and nasal), scarring alopecia,

Antimalarial therapy

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 Sulfasalazine is usually avoided in SLE due to its association
with drug-induced lupus. The evidence for this association is, however, limited to case reports and has not
been clearly demonstrated in larger cohorts.47

Hydroxychloroquine (HCQ) (up to 6.5 mg/kg daily)

has been shown to be very effective in the management 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

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 therapies (including cyclophosphamide (CYC) and mycophenolate mofetil (MMF)) and biological therapies.
It should however be noted that there is no clear evidence for any additional benefit of IV methylprednisolone 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 comprehensive review of the management of lupus nephritis is
beyond the scope of this review an excellent summary was recently published by Houssiau.49

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 effectiveness 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, however, 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 steroidrelated 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

Mycophenolate mofetil
MMF is the pro-drug of mycophenolic acid which
targets lymphocyte activation and survival by inhibiting 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 Azathioprine 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

Immunosuppressant agents
Azathioprine (AZA) (13 mg/kg) is the most commonly used steroid-sparing agent for the management of patients with SLE.43 The effective metabolism
of AZA is dependent on normal thiopurine methyltransferase (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 downwards by approximately 50% and any further dose

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.

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 tacrolimus can also be particularly useful for the management of both subacute cutaneous lupus and discoid
lupus.57

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 guidelines for the monitoring of lupus focus on the identification of co-morbidities.31

Rituximab

Osteoporosis

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 metaanalysis 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 compared 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 remains an attractive option to treat patients who have
failed conventional immunosuppression, and in the
UK an open-label prospective register is being established to assess safety and patterns of use of this and
other biologic agents in SLE (http://www.bilagbr.org).

Patients with SLE have an increased risk of osteoporosis 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, corticosteroid 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 established 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 mortality 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 diseaserelated factors (lung involvement, renal disease, lymphopenia, 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 complex deposition results in an increased risk of infection
with encapsulated organisms (e.g. S. pneumoniae,
H. influenzae, S. typhi). Opportunistic infections

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 antibody 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 Erythematosus)-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

(especially atypical tuberculosis (TB), cytomegalovirus (CMV) reactivation and Pneumocystis jirovecii)
need to be considered, particularly in the lymphopenic 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 remembered, however, that live vaccines are contraindicated
in patients on immunosuppressive therapy (including
steroids at doses of >20 mg/day).67

hypertension may all contribute to this increased

risk.76 APS is common in SLE, with clinical consequences 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

Cardiovascular disease

Premature gonadal failure

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 dyslipidaemia.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 clinician. 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.

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 selective serotonin reuptake inhibitors (SSRIs), clonidine
and topical oestrogens may be beneficial in symptom
control.

In addition, there are lupus-specific factors that predispose these patients to premature atherosclerosis,
including disease activity, renal disease and corticosteroid use.72 It is proposed, therefore, that control of
inflammation, while minimising steroid exposure,
may also reduce cardiovascular mortality in lupus.

Pregnancy
Many lupus patients are women of childbearing age,
which has implications for the planning and monitoring of pregnancy, disease management during pregnancy and lactation, and risk of additional complications (e.g. thrombosis, pre-eclampsia, neonatal
lupus/congenital heart block). Although a comprehensive review of immunosuppressant agents in pregnancy 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 management of the pregnant lupus patient has recently been
reviewed in detail by Baer et al.78

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 assessment tools available, the LupusQoL is the most extensively 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 conventional approaches.

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

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

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. Identifying the exact clinical and pathological phenotype
of these patients is essential in order to develop personalised treatment strategies. Until such a time,
management of these patients is likely to remain as
challenging as it is interesting.

16. Yap DY, Tang CS, Ma MK, Lam MF, Chan TM. Survival analysis
and causes of mortality in patients with lupus nephritis. Nephrol
Dial Transplant 2012 Aug;27(8):3248-54.
17. Alarcn GS, McGwin G Jr, Bastian HM et al; LUMINA Study Group.
Systemic lupus erythematosus in three ethnic groups. VII [correction of VIII]. Predictors of early mortality in the LUMINA cohort
[erratum in Arthritis Rheum 2001 Jun;45(3):306]. Arthritis Rheum
2001 Apr;45(2):191-202.
18. Kiss E, Regczy N, Szegedi G. Systemic lupus erythematosus
survival in Hungary: results from a single centre. Clin Exp Rheumatol 1999 Mar-Apr;17(2):171-7.
19. Griffiths B, Mosca M, Gordon C. Assessment of patients with
systemic lupus erythematosus and the use of lupus disease activity indices. Best Pract Res Clin Rheumatol 2005 Oct;19(5):685708.
20. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH;
The Committee on Prognosis Studies in SLE. Derivation of the
SLEDAI: a disease activity index for lupus patients. Arthritis Rheum
1992 Jun;35(6):630-40.

References
1. ONeill S, Cervera R. Systemic lupus erythematosus. Best Pract
Res Clin Rheumatol 2010 Dec;24(6):841-55.

21. Buyon JP, Petri MA, Kim MY et al. The effect of combined
estrogen and progesterone hormone replacement therapy on
disease activity in systemic lupus erythematosus: a randomized
trial. Ann Intern Med 2005 Jun;142(12 Pt 1):953-62.

2. Petri M. Epidemiology of systemic lupus erythematosus. Best

Pract Res Clin Rheumatol 2002 Dec;16(5):847-58.
3. Johnson AE, Gordon C, Palmer RG, Bacon PA. The prevalence
and incidence of systemic lupus erythematosus in Birmingham,
England: relationship to ethnicity and country of birth. Arthritis
Rheum 1995 Apr;38(4):551-8.

22. Gladman DD, Ibaez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002 Feb;29(2):28891.
23. Yee C-S, Farewell V, Isenberg DA et al. British Isles Lupus Assessment Group 2004 index is valid for assessment of disease activity
in systemic lupus erythematosus. Arthritis Rheum 2007 Dec;56
(12):4113-9.

4. Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus.

J Clin Pathol 2003 Jul;56(7):481-90.
5. Gualtierotti R, Biggioggero M, Penatti AE, Meroni PL. Updating
on the pathogenesis of systemic lupus erythematosus. Autoimmun
Rev 2010 Nov;10(1):3-7.

24. Furie RA, Petri MA, Wallace DJ et al. Novel evidence-based

systemic lupus erythematosus responder index. Arthritis Rheum
2009 Sep;61(9):1143-51.

6. Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the
classification of systemic lupus erythematosus. Arthritis Rheum
1982 Nov;25(11):1271-7.
7. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus
erythematosus. Arthritis Rheum 1997 Sep;40(9):1725.

25. Furie R, Petri M, Zamani O et al; BLISS-76 Study Group. A phase

III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients
with systemic lupus erythematosus. Arthritis Rheum 2011 Dec;
63(12):3918-30.

8. Petri M, Orbai AM, Alarcn GS 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.

26. Navarra SV, Guzmn RM, Gallacher AE et al; BLISS-52 Study

Group. Efficacy and safety of belimumab in patients with active
systemic lupus erythematosus: a randomised, placebo-controlled,
phase 3 trial. Lancet 2011 Feb;377(9767):721-31.

9. Molina JF, Molina J, Garcia C, Gharavi AE, Wilson WA, Espinoza

LR. Ethnic differences in the clinical expression of systemic lupus
erythematosus: a comparative study between African-Americans
and Latin Americans. Lupus 1997 Jan;6(1):63-7.

27. Gladman DD, Goldsmith CH, Urowitz MB et al. The Systemic

Lupus International Collaborating Clinics/American College of
Rheumatology (SLICC/ACR) Damage Index for Systemic Lupus
Erythematosus International Comparison. J Rheumatol 2000 Feb;
27(2):373-6.

10. Isenberg DA, Shoenfeld Y, Walport M et al. Detection of crossreactive anti-DNA antibody idiotypes in the serum of systemic
lupus erythematosus patients and of their relatives. Arthritis
Rheum 1985 Sep;28(9):999-1007.

28. Birmingham DJ, Irshaid F, Nagaraja HN et al. The complex

nature of serum C3 and C4 as biomarkers of lupus renal flare.
Lupus 2010 Oct;19(11):1272-80.
29. Akhter E, Burlingame RW, Seaman AL, Magder L, Petri M. AntiC1q antibodies have higher correlation with flares of lupus nephritis
than other serum markers. Lupus 2011 Oct;20(12):1267-74.

11. Lyons R, Narain S, Nichols C, Satoh M, Reeves WH. Effective

use of autoantibody tests in the diagnosis of systemic autoimmune
disease. Ann N Y Acad Sci 2005 Jun;1050:217-28.

30. Bertsias G, Ioannidis JPA, Boletis J et al. EULAR recommendations for the management of systemic lupus erythematosus:
report of a Task Force of the EULAR Standing Committee for
International Clinical Studies Including Therapeutics. Ann Rheum
Dis 2008 Feb;67(2):195-205.

12. Waldman M, Madaio MP. Pathogenic autoantibodies in lupus

nephritis. Lupus 2005 Jan;14(1):19-24.
13. Bernatsky S, Boivin JF, Joseph L et al. Mortality in systemic
lupus erythematosus. Arthritis Rheum 2006 Aug;54(8):2550-7.
14. Urowitz MB, Bookman AA, Koehler BE, Gordon DA, Smythe
HA, Ogryzlo MA. The bimodal mortality pattern of systemic
lupus erythematosus. Am J Med 1976 Feb;60(2):221-5.

31. Mosca M, Tani C, Aringer M et al. European League Against

Rheumatism recommendations for monitoring patients with
systemic lupus erythematosus in clinical practice and in observational studies. Ann Rheum Dis 2010 Jul;69(7):1269-74.

15. Lopez R, Davidson JE, Beeby MD, Egger PJ, Isenberg DA.
Lupus disease activity and the risk of subsequent organ damage
and mortality in a large lupus cohort. Rheumatology (Oxford)
2012 Mar;51(3):491-8.

32. Mok CC, Ho LY, Cheung MY, Yu KL, To CH. Effect of disease
activity and damage on quality of life in patients with systemic
lupus erythematosus: a 2-year prospective study. Scand J Rheumatol 2009 Mar-Apr;38(2):121-7.

33. Taylor J, Skan J, Erb N et al. Lupus patients with fatigue: is

there a link with fibromyalgia syndrome? Rheumatology (Oxford)
2000 Jun;39(6):620-3.

53. Mok CC. Mycophenolate mofetil for non-renal manifestations

of systemic lupus erythematosus: a systematic review. Scand J
Rheumatol 2007 Sep-Oct;36(5):329-37.

34. Kamen DL, Cooper GS, Bouali H, Shaftman SR, Hollis BW,
Gilkeson GS. Vitamin D deficiency in systemic lupus erythematosus. Autoimmun Rev 2006 Feb;5(2):114-7.

54. Rihova Z, Vankova Z, Maixnerova D et al. Treatment of lupus

nephritis with cyclosporine: an outcome analysis. Kidney Blood
Press Res 2007 Apr;30(2):124-8.

35. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta

MA. Clinical efficacy and side effects of antimalarials in systemic
lupus erythematosus: a systematic review. Ann Rheum Dis 2010
Jan;69(1):20-8.

55. Lee YH, Lee HS, Choi SJ, Dai Ji J, Song GG. Efficacy and safety
of tacrolimus therapy for lupus nephritis: a systematic review of
clinical trials. Lupus 2011 May;20(6):636-40.

36. Wallace DJ. Antimalarial agents and lupus. Rheum Dis Clin
North Am 1994 Feb;20(1):243-63.

56. Lamarque V, Leleu MF, Monka C, Krupp P. Analysis of 629 pregnancy outcomes in transplant recipients treated with Sandimmun.
Transplant Proc 1997 Aug;29(5):2480.

37. Jover JA, Leon L, Pato E et al. Long-term use of antimalarial

drugs in rheumatic diseases. Clin Exp Rheumatol 2012 May-Jun;
30(3):380-7.

57. Srdy M, Ruzicka T, Kuhn A. Topical calcineurin inhibitors in

cutaneous lupus erythematosus. Arch Dermatol Res 2009 Jan;
301(1):93-8.

38. Royal College of Ophthalmologists. Hydroxychloroquine

and ocular toxicity: recommendations on screening. 2009 Oct.
Available via: http://www.rcophth.ac.uk/page.asp?section=451
&sectionTitle=Clinical+Guidelines.

58. Murray E, Perry M. Off-label use of rituximab in systemic lupus

erythematosus: a systematic review. Clin Rheumatol 2010 Jul;29
(7):707-16.
59. Merrill JT, Neuwelt CM, Wallace DJ et al. Efficacy and safety
of rituximab in moderately-to-severely active systemic lupus
erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis
Rheum 2010 Jan;62(1):222-33.

39. Kuhn A, Ruland V, Bonsmann G. Cutaneous lupus erythematosus: update of therapeutic options. Part I. J Am Acad Dermatol
2011 Dec;65(6):e179-e193.
40. Alarcn GS, McGwin G, Bertoli AM et al; LUMINA Study Group.
Effect of hydroxychloroquine on the survival of patients with
systemic lupus erythematosus: data from LUMINA, a multiethnic
US cohort (LUMINA L). Ann Rheum Dis 2007 Sep;66(9):1168-72.

60. Rovin BH, Furie R, Latinis K et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus
Nephritis Assessment with Rituximab study. Arthritis Rheum
2012 Apr;64(4):1215-26.

41. Saag KG, Koehnke R, Caldwell JR et al. Low dose long-term

corticosteroid therapy in rheumatoid arthritis: an analysis of
serious adverse events. Am J Med 1994 Feb;96(2):115-23.

61. Sinigaglia L, Varenna M, Binelli L et al. Determinants of bone

mass in systemic lupus erythematosus: a cross sectional study
on premenopausal women. J Rheumatol 1999 Jun;26(6):1280-4.

42. Hoes JN, Jacobs JW, Boers M et al. EULAR evidence-based

recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 2007 Dec;
66(12):1560-7.

62. Bhattoa HP, Bettembuk P, Balogh A, Szegedi G, Kiss E. Bone

mineral density in women with systemic lupus erythematosus.
Clin Rheumatol 2002 May;21(2):135-41.

43. Abu-Shakra M, Shoenfeld Y. Azathioprine therapy for patients

with systemic lupus erythematosus. Lupus 2001 Mar;10(3):152-3.

63. Sandhu SK, Hampson G. The pathogenesis, diagnosis, investigation and management of osteoporosis. J Clin Pathol 2011 Dec;
64(12):1042-50.

44. Newman WG, Payne K, Tricker K et al; TARGET study recruitment team. A pragmatic randomized controlled trial of thiopurine
methyltransferase genotyping prior to azathioprine treatment:
the TARGET study. Pharmacogenomics 2011 Jun;12(6):815-26.

64. Goldblatt F, Chambers S, Rahman A, Isenberg DA. Serious

infections in British patients with systemic lupus erythematosus:
hospitalisations and mortality. Lupus 2009 Jul;18(8):682-9.

45. Sato EI. Methotrexate therapy in systemic lupus erythematosus. Lupus 2001 Mar;10(3):162-4.

65. Ruiz-Irastorza G, Olivares N, Ruiz-Arruza I, Martinez-Berriotxoa

A, Egurbide MV, Aguirre C. Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther 2009;11(4):R109.

46. Wong JM, Esdaile JM. Methotrexate in systemic lupus

erythematosus. Lupus 2005 Feb;14(2):101-5.

66. Barber C, Gold WL, Fortin PR. Infections in the lupus patient:
perspectives on prevention. Curr Opin Rheumatol 2011 Jul;23(4):
358-65.

47. Gordon MM, Porter DR, Capell HA. Does sulphasalazine cause
drug induced systemic lupus erythematosus? No effect evident
in a prospective randomised trial of 200 rheumatoid patients
treated with sulphasalazine or auranofin over five years. Ann
Rheum Dis 1999 May;58(5):288-90.

67. Millet A, Decaux O, Perlat A, Grosbois B, Jego P. Systemic lupus

erythematosus and vaccination. Eur J Intern Med 2009 May;20(3):
236-41.

48. Parker BJ, Bruce IN. High dose methylprednisolone therapy

for the treatment of severe systemic lupus erythematosus. Lupus
2007 Jun;16(6):387-93.

68. Manzi S, Meilahn EN, Rairie JE et al. Age-specific incidence

rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham
Study. Am J Epidemiol 1997 Mar;145(5):408-15.

49. Houssiau FA. Therapy of lupus nephritis: lessons learned

from clinical research and daily care of patients. Arthritis Res
Ther 2012 Jan;14(1):202.

69. Symmons DP, Gabriel SE. Epidemiology of CVD in rheumatic

disease, with a focus on RA and SLE. Nat Rev Rheumatol 2011 Jul;
7(7):399-408.

50. Touma Z, Gladman DD, Urowitz MB, Beyene J, Uleryk EM,

Shah PS. Mycophenolate mofetil for induction treatment of
lupus nephritis: a systematic review and metaanalysis. J Rheumatol 2011 Jan;38(1):69-78.

70. Bruce IN, Urowitz MB, Gladman DD, Ibaez D, Steiner G. Risk
factors for coronary heart disease in women with systemic lupus
erythematosus: the Toronto Risk Factor Study. Arthritis Rheum
2003 Nov;48(11):3159-67.

51. Dooley MA, Jayne D, Ginzler EM et al; ALMS Group. Mycophenolate versus azathioprine as maintenance therapy for lupus
nephritis. N Engl J Med 2011 Nov;365(20):1886-95.

71. Wajed J, Ahmad Y, Durrington PN, Bruce IN. Prevention of

cardiovascular disease in systemic lupus erythematous: proposed
guidelines for risk factor management. Rheumatology (Oxford)
2004 Jan;43(1):7-12.

52. Houssiau FA, DCruz D, Sangle S et al; MAINTAIN Nephritis

Trial Group. Azathioprine versus mycophenolate mofetil for
long-term immunosuppression in lupus nephritis: results from
the MAINTAIN Nephritis Trial. Ann Rheum Dis 2010 Dec;69(12):
2083-9.

72. Sherer Y, Zinger H, Shoenfeld Y. Atherosclerosis in systemic

lupus erythematosus. Autoimmunity 2010 Feb;43(1):98-102.
10

73. Jolly M. How does quality of life of patients with systemic

lupus erythematosus compare with that of other common chronic
illnesses? J Rheumatol 2005 Sep;32(9):1706-8.

77. Cohen D, Berger SP, Steup-Beekman GM, Bloemenkamp KW,

Bajema IM. Diagnosis and management of the antiphospholipid
syndrome. BMJ 2010 May;340:c2541.

74. Bertsias GK, Ioannidis JP, Aringer M et al. EULAR recommendations for the management of systemic lupus erythematosus
with neuropsychiatric manifestations: report of a task force of
the EULAR standing committee for clinical affairs. Ann Rheum
Dis 2010 Dec;69(12):2074-82.

78. Baer AN, Witter FR, Petri M. Lupus and pregnancy. Obstet
Gynecol Surv 2011 Oct;66(10):639-53.

75. Yazdany J. Health-related quality of life measurement in

adult systemic lupus erythematosus: Lupus Quality of Life (LupusQoL), Systemic Lupus Erythematosus-Specific Quality of Life Questionnaire (SLEQOL), and Systemic Lupus Erythematosus Quality
of Life Questionnaire (L-QoL). Arthritis Care Res (Hoboken) 2011
Nov;63 Suppl 11:S413-S419.

80. Gonzlez LA, Pons-Estel GJ, Zhang JS et al; LUMINA Study

Group. Effect of age, menopause and cyclophosphamide use on
damage accrual in systemic lupus erythematosus patients from
LUMINA, a multiethnic US cohort (LUMINA LXIII). Lupus 2009
Feb;18(2):184-6.

79. Sammaritano LR. Menopause in patients with autoimmune

diseases. Autoimmun Rev 2012 May;11(6-7):A430-A436.

81. Lateef A, Petri M. Hormone replacement and contraceptive

therapy in autoimmune diseases. J Autoimmun 2012 May;38(2-3):
J170-J176.

76. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002 Mar;346(10):752-63.

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 musculoskeletal 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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Registered Charity England and Wales no. 207711,

Scotland no. SC041156

ISSN 1759-7846. Published 3 times

a year by Arthritis Research UK.