Sample Chapter20 - Mod 17

Systemic Lupus
20 Erythematosus: Pathogenesis
and Clinical Features
George Bertsias, Ricard Cervera, Dimitrios T Boumpas
A previous version was coauthored by Ricard Cervera, Gerard Espinosa and
David D’Cruz
Learning objectives:
• Use the epidemiology and natural history of nervous, gastrointestinal, and haematological
systemic lupus erythematosus (SLE) to inform systems
diagnostic and therapeutic decisions • Evaluate the challenges in the diagnosis and
• Describe and explain the key events in the differential diagnosis of lupus and the pitfalls
pathogenesis of SLE and critically analyse the in the tests used to diagnose and monitor
contribution of genetics, epigenetics, hormonal, lupus activity
and environmental factors to the immune • Identify important aspects of the disease such
aberrancies found in the disease as women’s health issues (ie, contraception and
• Explain the key symptoms and signs of the pregnancy) and critical illness
diseases and the tissue damage associated • Outline the patterns of SLE expression in
with SLE specific subsets of patients depending on age,
• State the classification criteria of lupus and their gender, ethnicity, and social class
limitations when used for diagnostic purposes • Classify and assess patients according to
• Describe and explain the clinical manifestations the severity of system involvement and use
of SLE in the musculoskeletal, dermatological, appropriate clinical criteria to stratify patients in
renal, respiratory, cardiovascular, central terms of the risk of morbidity and mortality
‘wolf ’s bite’. In 1846 the Viennese physician Ferdinand von

1 Introduction Hebra (1816–1880) introduced the butterfly metaphor to
Systemic lupus erythematosus (SLE) is the describe the malar rash. He also used the term ‘lupus
prototypic multisystem autoimmune disorder with a erythematosus’ and published the first illustrations in his
broad spectrum of clinical presentations Atlas of Skin Diseases in 1856. Lupus was first recognised as
encompassing almost all organs and tissues. The a systemic disease with visceral manifestations by Moriz
extreme heterogeneity of the disease has led some Kaposi (1837–1902). The systemic form was further
investigators to propose that SLE represents a established by Osler in Baltimore and Jadassohn in Vienna.
syndrome rather than a single disease. Other important milestones include the description of the
false positive test for syphilis in SLE by Reinhart and Hauck
2 Major milestones in the history of from Germany (1909); the description of the endocarditis
lesions in SLE by Libman and Sacks in New York (1923);
lupus the description of the glomerular changes by Baehr (1935),
The term ‘lupus’ (Latin for ‘wolf ’) was first used during the and the use of the term
Middle Ages to describe erosive skin lesions evocative of a
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Systemic Lupus Erythematosus: Pathogenesis and Clinical Features
‘ iffuse connective tissue disease’ by Klemperer, Pollack

d disease starts with a preclinical phase characterised by
and Baehr (1941). The beginning of the modern era in autoantibodies common to other systemic
SLE was the discovery of the ‘LE’ cell by Hargraves, autoimmune diseases and proceeds with a more
Richmond and Morton at the Mayo Clinic in 1948. disease-specific clinically overt autoimmune phase
(Bertsias et al 2010a). During its course periods of
flares intercept periods of remission culminating in
3 Epidemiology disease- and therapy-related damage, such as
Prevalence rates in lupus are estimated to be as high as 51 alopecia, fixed erythema, cognitive dysfunction,
per 100 000 people in the USA. The incidence of lupus valvular heart disease, avascular necrosis, tendon
has nearly tripled in the last 40 years, mainly due to rupture, Jaccoud’s arthropathy, and osteoporosis. Early
improved diagnosis of mild disease. Estimated incidence damage is mostly related to disease whereas late
rates in North America, South America, and Europe range damage—namely infections, atherosclerosis, and
from 2 to 8 per 100 000 per year. Women are affected malignancies—is usually related to complications of
nine times more frequently than men and African longstanding disease and immunosuppressive therapy.
American and Latin American mestizos are affected
much more frequently than Caucasians, and have higher
disease morbidity. The disease appears to be more 5 Aetiology and pathogenesis
common in urban than rural areas. Sixty-five per cent of The aetiology of SLE includes both genetic and
patients with SLE have disease onset between the ages of environmental components with female sex strongly
16 and 55 years, 20% present before age 16, and 15% after influencing pathogenesis. These factors lead to an
the age of 55. Men with lupus tend to have less irreversible break in immunological tolerance manifested
photosensitivity, more serositis, an older age at diagnosis, by immune responses against endogenous nuclear
and a higher 1 year mortality compared to women. SLE antigens.
tends to be milder in the elderly with lower incidence of
malar rash, photosensitivity, purpura, alopecia, Raynaud’s
phenomenon, renal and central nervous system 5.1 Genetic factors
involvement, but greater prevalence of serositis, Siblings of SLE patients are approximately 30 times
pulmonary involvement, sicca symptoms, and more likely to develop SLE compared with individuals
musculoskeletal manifestations. without an affected sibling. The rate of gene discovery
in SLE has increased during the past few years thanks
to large genome-wide association studies (GWAS)
4 Natural history and course using hundreds of thousands of single nucleotide
SLE is a chronic disease of variable severity with a polymorphism (SNP) markers (figure 2).
waxing and waning course, with significant morbidity GWAS in lupus have confirmed the importance of
that can be fatal—if not treated early—in some patients genes associated with immune response and
(figure 1). The inflammation
Figure 1 Natural history of systemic lupus erythematosus. SLICC, Systemic Lupus International Collaborating Clinics/American College of
Rheumatology damage index. Reprinted with permission from Bertsias GK, Salmon JE, Boumpas DT. Therapeutic opportunities in
systemic lupus erythematosus: state of the art and prospects for the new decade. Ann Rheum Dis 2010;69:1603–11.
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EULAR Textbook on Rheumatic Diseases
Figure 2 Manhattan plot of a genome-wide association study (GWAS) in systemic lupus erythematosus (SLE) involving 1311 cases
and 3340 controls of European ancestry. Each dot in this figure (known as a Manhattan plot) corresponds to a genetic marker that,
in this particular study, included ~550 000 single nucleotide polymorphisms (SNPs). Dots are colour coded and arranged along the
x-axis according to position with each colour representing a different chromosome. The y-axis represents the significance level (–log
P value) for the association of each SNP with SLE (ie, comparison between SLE cases and controls). Because of the multiple testing
the level of significance for definitive genetic associations is quite high in the range of approximately 5×10–8 while results
between –log P values of approximately 5–7 are considered as associations of borderline significance. Reprinted with permission from
Criswell LA. Genome-wide association studies of SLE. What do these studies tell us about disease mechanisms in lupus? The
Rheumatologist 2011.
(HLA-DR, PTPN22, STAT4, IRF5, BLK, OX40L, FCGR2A, 5.3 Environmental factors
BANK1, SPP1, IRAK1, TNFAIP3, C2, C4, CIq, PXK),
Candidate environmental triggers of SLE include
DNA
ultraviolet light, demethylating drugs, and infectious or
repairs (TREX1), adherence of inflammatory cells to the endogenous viruses or viral-like elements. Sunlight is
endothelium (ITGAM), and tissue response to injury the most obvious environmental factor that may
(KLK1, KLK3). These findings highlight the importance exacerbate SLE. Epstein– Barr virus (EBV) has been
of Toll-like receptor (TLR) and type 1 interferon (IFN) identified as a possible factor in the development of
signalling pathways. Some of the genetic loci may explain lupus. EBV may reside in and interact with B cells and
not only the susceptibility to disease but also its severity. promotes interferon α (IFNα) production by
For instance, STAT4, a genetic risk factor for rheumatoid plasmacytoid dendritic cells (pDCs), suggesting that
arthritis and SLE, is associated with severe SLE. One of elevated IFNα in lupus may be—at least in part—due to
the key components of these pathways is TNFAIP3, which aberrantly controlled chronic viral infection.
has been implicated in at least six autoimmune disorders, It is well established that certain drugs induce
including SLE. autoantibodies in a significant number of patients,
most of whom do not develop signs of an autoantibody
5.2 Epigenetic effects associated disease. Over 100 drugs have been
reported to cause
The risk for SLE may be influenced by epigenetic drug-induced lupus (DIL), including a number of the
effects such as DNA methylation and post- newer biologics and antiviral agents. Although the
translational modifications of histones, which can be pathogenesis of DIL is not well understood, a genetic
either inherited or environmentally modified. predisposition may play a role in the case of certain
Epigenetics refers to inherited changes in gene drugs, particularly those agents that are metabolised by
expression caused by mechanisms other than DNA acetylation such as procainamide and hydralazine, with
base sequence changes. The most well understood disease more likely to develop in patients who are slow
type of epigenetic factor is DNA methylation, which acetylators. These drugs may alter gene expression in
plays a role in a variety of human processes, such as X CD4+ T cells by inhibiting DNA methylation and induce
chromosome inactivation and certain cancers. over-expression of LFA-1 antigen, thus promoting
Previous research has also implicated the importance autoreactivity.
of DNA methylation in SLE. Differences in the
methylation status of genes may explain, at least in
part, the discordance observed in some identical 5.4 Hormonal factors
twins that are discordant for SLE. Epigenetic In murine models, addition of oestrogen or prolactin
mechanisms may represent the missing link between can lead to an autoimmune phenotype with an
genetic and environmental risk factors. increase in
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mature high-affinity autoreactive B cells. Oral apoptotic cells are presented by dendritic cells to T
contraceptive use in the Nurses’ Health Study was cells leading to their activation. Activated T cells in
associated with a slightly increased risk of developing turn help B cells to produce antibodies to these self-
SLE (relative risk 1.9 compared to never users). This constituents by secreting cytokines such as interleukin
poses important questions pertaining to the use of 10 (IL10) and IL23 and by cell surface molecules such
oestrogens for oral contraception or as hormone as CD40L and CTLA-4. In addition to this antigen-
replacement therapy in postmenopausal women. driven T cell-dependent production of autoantibodies,
While it is clear that hormones can influence recent data support T
autoimmune development in murine models, the use cell-independent mechanisms of B cell stimulation via
of oral contraceptives does not increase disease combined B cell antigen receptor (BCR) and TLR
flares in women with stable disease (Sanchez- signalling. The pathogenesis of SLE involves a
Guerrero et al 2005). Pregnancy may cause in some multitude of cells and molecules that participate in
cases a lupus flare, but this is not due to an increase apoptosis, innate and adaptive immune responses
in oestradiol or progesterone; in fact, the levels of (table 1).
these hormones are lower in the second and third
trimester for SLE patients in comparison with
healthy pregnant women. 6.1 Pathogenesis: key events
Increased amounts of apoptosis-related endogenous
nucleic acids stimulate the production of IFNα and
6 Pathogenesis and pathophysiology promote autoimmunity by breaking self-tolerance
Immune responses against endogenous nuclear through activation of antigen-presenting cells (figure
antigens are characteristic of SLE. Autoantigens 3). Once initiated, immune reactants such as immune
released by complexes amplify and sustain the inflammatory
response.
Figure 3 In systemic lupus erythematosus all pathways lead to endogenous nucleic acids-mediated production of interferon α (IFNα).
Increased production of autoantigens during apoptosis (UV-related and/or spontaneous), decreased disposal, deregulated handling and
presentation are all important for the initiation of the autoimmune response. Nucleosomes containing endogenous danger ligands that
can bind to pathogen-associated molecular pattern receptors are incorporated in apoptotic blebs that promote the activation of DCs and
B cells and the production of IFN and autoaantibodies, respectively. Cell surface receptors such as the BCR and FcRIIa facilitate the
endocytosis of nucleic acid containing material or immune complexes and the binding to endosomal receptors of the innate immunity
such as TLRs. At the early stages of disease, when autoantibodies and immune complexes may not have been formed, antimicrobial
peptides released by damaged tissues such as LL37 and neutrophil extracellular traps, may bind with nucleic acids inhibiting their
degradation and thus facilitating their endocytosis and stimulation of TLR-7/9 in plasmacytoid DCs. Increased amounts of apoptosis-
related endogenous nucleic acids stimulate the production of IFN and promote autoimmunity by breaking self-tolerance through
activation and promotion of maturation of conventional (myeloid) DCs. Immature DCs promote tolerance while activated mature DCs
promote autoreactivity. Production of autoantibodies by B cells in lupus is driven by the availability of endogenous antigens and is
largely dependent upon T cell help, mediated by cell surface interactions (CD40L/CD40) and cytokines (IL21). Chromatin-containing
immune complexes vigorously stimulate B cells due to combined BCR/TLR crosslinking. DC, dendritic cell, BCR, B cell receptor, FcR, Fc
receptor, UV, ultraviolet; TLR, toll-like receptor. Reprinted with permission from Bertsias GK, Salmon JE, Boumpas DT. Therapeutic
opportunities in systemic lupus erythematosus: state of the art and prospects for the new decade. Ann Rheum Dis 2010;69:1603–11.
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• Apoptosis: a source of autoantigens and molecules with adjuvant/cytokine (interferon α (IFNα)) inducer activity.
Apoptotic cell blebs are rich in lupus autoantigens. Increased spontaneous apoptosis, increased rates of ultraviolet -
induced apoptosis in skin cells, or impaired clearance of apoptotic peripheral blood cells have been found in some
lupus patients.
• Nucleic acids (DNA and RNA): a unique target in lupus linked to apoptosis. Their recognition in healthy
individuals is prohibited by a variety of barriers which are circumvented in lupus whereby alarmins released by
from stressed tissues (HMGB1), antimicrobial peptides, neutrophil extracellular traps (NETs), and immune
complexes facilitate their recognition and transfer to endosomal sensors (see below TLRs, NLRs).
Innate immunity
• Toll-like receptors (TLRs): conserved innate immune system receptors strategically located on cell membranes,
cytosol and in endosomal compartments where they survey the extracellular and intracellular space. TLRs
recognising nucleic acids (TLRs-3,-7,-8 and -9) are endosomal. Autoreactive B or T lymphocytes peacefully
coexisting with tissues expressing the relevant antigens may become pathogenic after engagement of TLRs. TLRs
also activate APCs (dendritic, MO, B cells) enhancing autoantigen presentation. B cells from active lupus patients
have increased TLR9 expression. Compared to other antigens, chromatin containing immune complexes are 100-fold
more efficacious in stimulating lupus B cells because of the presence of nucleic acids and the resultant combined
BCR and TLR stimulation.
• Dendritic cells: Two types: plasmacytoid dendritic cells (pDCs) and myeloid (CD11c+) DC (mDCs).
• pDCs: represent genuine ‘IFNα’ factories. In lupus, exogenous factors/antigens (ie, viruses) or autoantigens recognised by
the innate immune system receptors activate DCs and produce IFNα. mDCs: involved in antigen presentation with
immature conventional mDCs promoting tolerance while mature autoreactivity. In lupus, several factors (IFNα,
immune complexes, TLRs) promote mDC maturation and thus autoreactivity.
• Interferon α: a pluripotent cytokine produced mainly by pDCs via both TLR-dependent and TLR-independent
mechanisms with potent biologic effects on DCs, B and T cells, endothelial cells, neuronal cells, renal resident cells,
and other tissues. Several lupus-related genes encode proteins that mediate or regulate TLR signals and are
associated with increased plasma IFNα among patients with specific autoantibodies which may deliver stimulatory
nucleic acids to TLR7 or TLR9 in their intracellular compartments. Activation of the IFN pathway has been
associated with the presence of autoantibodies specific for RNA-associated proteins. RNA-mediated activation
of TLR is an important mechanism contributing to production of IFNα and other proinflammatory cytokines.
Activation of the IFN pathway is associated with renal disease and many measures of disease activity.
• Complement: Activation of complement shapes the immune inflammatory response and facilitates clearance of
apoptotic
material.
• Neutrophils: In lupus a distinct subset of proinflammatory neutrophils (low density granulocytes) induces vascular
damage
and produces IFNα. Pathogenic variants of ITAM increase the binding to ICAM and the adhesion leucocytes to
activated endothelial cells.
• Endothelial cells: In lupus, impaired DNA degradation as a result of a defect in repair endonucleases (TREX1)
increases
the accumulation of ssDNA derived from endogenous retro-elements in endothelial cells and may activate production
of IFNα by them. IFNα in turn propagates endothelial damage and impairs its repair.
Adaptive immunity
• T and B cells: Interactions between co-stimulatory ligands and receptors on T and B cells, including CD80 and CD86
with CD28, inducible costimulator (ICOS) ligand with ICOS, and CD40 ligand with CD40, contribute to B cell
differentiation to antibody producing plasma cells. Autoantibodies also facilitate the delivery of stimulatory nucleic
acids to TLRs. Cytokines and chemokines produced by T and B cells also shape the immune response and promote
tissue damage.
• B lymphocyte stimulator (Blys): The soluble TNF family member BlyS is a B cell survival and differentiation. Blys is
increased in serum of many lupus patients; inhibition of Blys prevents lupus flares.
• Immune complexes: In healthy individuals, immune complexes are cleared by FcR and complement receptors. In
lupus,
genetic variations in FcR genes and the C3bi receptor gene (ITGAM) may impair the clearing of immune complexes
which
Table 1 Keythen deposit
pathogenic and cause
processes, tissue
cells injury at in
and molecules sites such lupus
systemic as theerythematosus
skin and kidney.
complement receptors; failure to clear immune

6.2 Disease mechanisms and tissue damage complexes results in tissue deposition and tissue injury
Immune complexes and complement activation at sites. Tissue damage is mediated by recruitment of
pathways mediate effector function and tissue injury. inflammatory cells, reactive oxygen intermediates,
production of inflammatory cytokines, and modulation
In healthy
of the coagulation cascade.
individuals, immune complexes are cleared by Fc and
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Autoantibody-mediated tissue injury has been manifestations, SLE runs an unpredictable course.
implicated in neuropsychiatric SLE (NPSLE), The dynamic nature of the disease often makes its
where antibodies reacting with both DNA and diagnosis challenging.
glutamate receptors on neuronal cells can mediate Although the ACR classification criteria may also be
excitotoxic neuronal cell death or dysfunction. used as a diagnostic aid, there are several caveats in
Locally produced cytokines, such as IFNα and their use for diagnostic purposes. These criteria were
tumour necrosis factor (TNF), contribute to affected developed and validated for the classification of
tissue injury and inflammation. These mediators, patients with a longstanding established disease and
together with the cells producing them (macrophages, may exclude patients with early disease or disease
leucocytes, dendritic cells and lymphocytes), are the limited to a few organs. Thus, in spite of their excellent
subject of investigation as potential therapeutic targets sensitivity (>85%) and specificity (>95%) for patients
in lupus. Recent studies have also highlighted the role with established disease, their sensitivity for patients
of locally expressed factors for the protection of early in the disease may be significantly lower. Some
tissues under immune attack. For example, defects in systems are overrepresented; the mucocutaneous
kallikreins may jeopardise the ability of lupus kidneys manifestations, for example, are represented with four
to protect themselves from injury, criteria (photosensitivity, malar rash, discoid lesions,
PD-1-ligand down-regulates the activity of the and oral ulcers). All features included in the
infiltrating lymphocytes, and impaired regulation of classification criteria are contributing equally without
complement amplifies vascular injury. any weight based upon sensitivity and specificity for
Vascular damage in SLE has received increased each individual criterion. Thus, studies have shown and
attention in view of its relationship with accelerated experience supports that criteria such as objective
atherosclerosis. Homocysteine and proinflammatory evidence of renal disease (significant proteinuria, active
cytokines, such as IFNα, impair endothelial function urine sediment or renal biopsy with evidence of lupus
and decrease the availability of endothelial precursor nephritis), discoid rash, and cytopenias are more useful
cells to repair endothelial injury. Pro-inflammatory in establishing the diagnosis of lupus than the other
high density lipoproteins (HDL) and a dysfunction of criteria. Because SLE is a disease whose course is
HDL mediated by antibodies have also been typified by periodic involvement of one organ system
implicated in defective repair of endothelium. after another, it is apparent that patients must have the
Moreover, pathogenic variants of ITAM (immuno- disease for years before they fulfil the classification
tyrosine activation motif) alter its binding to ICAM-1 criteria. Among patients referred for lupus to tertiary
(intercellular adhesion molecule 1) and may increase care centres, two thirds of patients fulfil ACR criteria,
the adherence of leucocytes to activated endothelial approximately 10% have clinical lupus but do not fulfil
cells. Impaired DNA degradation as a result of criteria, and 25% have fibromyalgia-like symptoms and
mutations of the 3’ repair exonuclease 1 (TREX1), and positive antinuclear antibody (ANA) but never develop
increased accumulation of single stranded DNA lupus.
derived from endogenous retro-elements in endothelial
cells, may activate the IFN-stimulatory DNA response
and direct immune-mediated injury to the vasculature. 8 Activity indices
Assessing disease activity in SLE is crucial to the
physician as it forms the basis for treatment decisions.
7 Classification criteria Disease activity needs to be distinguished from
Criteria for SLE classification were developed in 1971, damage as this has important implications for the long
revised in 1982, and revised again in 1997 (table 2) term prognosis and the appropriate treatment. Several
(Hochberg 1997). These criteria distinguish patients validated global and organ-specific activity indices are
with the disease in question from those without the widely used in the evaluation of SLE patients (Urowitz
disease. The American College of Rheumatology and Gladman 1998). These include the European
(ACR) classification criteria were developed for Consensus Lupus Activity Measure (ECLAM), the
clinical studies of lupus to ensure that cases reported in British Isles Lupus Assessment Group Scale (BILAG),
the literature do in fact have the disease. In addition to the Lupus Activity Index (LAI), the National Institutes
the wide variety of of Health SLE Index Score (SIS), the Systemic Lupus
Activity Measure (SLAM), and the SLE
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Criteria Definition
Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial
folds
Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging;
atrophic scarring occurs in older lesions
Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician
observation
Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician

Arthritis Non-erosive arthritis involving two or more peripheral joints, characterised by tenderness,
swelling or effusion
Serositis a. Pleuritis: convincing history of pleuritic pain or rub heard by a physician or
evidence of pleural effusion or
b. Pericarditis: documented by ECG or rub or evidence of pericardial effusion
Renal disorder a. Persistent proteinuria >0.5 g per day or >3+ if quantitation is not performed or
b. Cellular casts: may be red cell, haemoglobin, granular tubular, or mixed
Neurological disorder a. Seizures: in the absence of offending drugs or known metabolic derangements (eg,
uraemia, acidosis, or electrolyte imbalance) or
b. Psychosis: in the absence of offending drugs or known metabolic
derangements (eg, uraemia, acidosis, or electrolyte imbalance)
Haematologic disorder a. Haemolytic anaemia with reticulocytosis, or

b. Leucopenia: <4000/mm3, or
c. Lymphopenia: <1500/mm3, or
d. Thrombocytopenia: <100 000/mm3 in the absence of offending drugs
Immunologic disorder a. Anti-DNA: antibody to native DNA in abnormal titre, or
b. Anti-Sm: presence of antibody to Sm nuclear antigen, or
c. Positive finding of antiphospholipid antibodies based on: (1) an abnormal
serum concentration of IgG or IgM anticardiolipin antibodies, (2) a positive test
result for lupus anticoagulant using a standard method, or (3) a false positive
serologic test for syphilis known to be positive for at least 6 months and
confirmed by Treponema pallidum immobilisation or fluorescent treponemal
antibody absorption test
Antinuclear antibody An abnormal titre of antinuclear antibody by immunofluorescence or an equivalent
assay at any point in time and in the absence of drugs known to be associated with
‘drug-induced lupus’ syndrome
Adapted from Hochberg 1997.
Table 2 The American College of Rheumatology revised classification criteria for systemic lupus erythematosus
Disease Activity Index (SLEDAI). These indices have For clinical trials, composite end points and
been developed in the context of long term responder indices may be more useful, especially for
observational studies and have been shown to be strong studies in general lupus, as compared to studies for
predictors of damage and mortality, and reflect change lupus affecting single organs (eg, nephritis). To this
in disease activity. Moreover, they have been validated end, using composite index (SLE responder index,
against each other. We recommend the use of at least SRI) investigators in the Belimumab trial were able
one of these indices for monitoring of disease activity. to show efficacy. The SRI includes improvement in
In our experience the ECLAM and the SLEDAI (table SLEDAI by at least 4 without worsening in BILAG
3) are more convenient for use in daily practice. and PGA. The SRI could be adjusted to look for
Computerised clinical charts that compute several larger treatment effects (for instance, more than 7 or
disease activity indices simultaneously have been 12 points difference in SLEDAI) similar to what is
developed. being used in rheumatoid arthritis (ACR 20, and 50,
Existing disease activity indices have important or EULAR moderate and good response).
limitations when used in the context of clinical
trials.
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Descriptor Definition Score

Seizure Recent onset. Exclude metabolic, infectious or drug-related causes 8
Psychosis Altered ability to function in normal activity due to severe disturbance 8
in the perception of reality. Includes hallucinations; incoherence;
marked loose associations; impoverished thought content; marked
illogical thinking; bizarre disorganised or catatonic behaviour. Exclude
the presence of uraemia and offending drugs
Organic brain syndrome Altered mental function with impaired orientation or impaired 8
memory or other intellectual function, with rapid onset and fluctuating
clinical features. Includes a clouding of consciousness with a reduced
capacity to focus and an inability to sustain attention on environment
and at least two of the following: perceptual disturbance, incoherent
speech, insomnia or daytime drowsiness, increased or decreased
psychomotor activity. Exclude metabolic infectious and drug-related
causes
Visual Retinal changes from systemic lupus erythematosus cytoid bodies, 8
retinal haemorrhages, serous exudate or haemorrhage in the choroid,
optic neuritis (not due to hypertension, drugs or infection)
Cranial nerve New onset of a sensory or motor neuropathy involving a cranial 8

nerve
Lupus headache Severe, persistent headache; may be migrainous 8
Cerebrovascular New syndrome. Exclude arteriosclerosis 8
Vasculitis Ulceration, gangrene, tender finger nodules, periungal infarction, 8
splinter haemorrhages. Vasculitis confirmed by biopsy or angiogram
Arthritis More than two joints with pain and signs of inflammation 4
Myositis Proximal muscle aching or weakness associated with elevated 4
creatine phosphokinase/aldolase levels, electromyographic
changes, or a biopsy showing myositis
Casts Heme, granular or erythrocyte 4

Haematuria More than 5 erythrocytes per high power field. Exclude other causes 4
Proteinuria More than 0.5 g of urinary protein excreted per 24 h. New onset or 4
recent increase of more than 0.5 g per 24 h
Pyuria More than 5 leucocytes per high power field. Exclude infection 4
New malar rash New onset or recurrence of an inflammatory type of rash 4
Alopecia New or recurrent. A patch of abnormal, diffuse hair loss 4
Mucous membrane New onset or recurrence of oral or nasal ulceration 4
Pleurisy Pleuritic chest pain with pleural rub or effusion, or pleural 4
thickening
Pericarditis Pericardial pain with at least one of rub or effusion. Confirmation by 4
ECG or echocardiography
Low complement A decrease in CH50, C3 or C4 levels (to less than the lower limit of the 2
laboratory determined normal range)
Increased DNA binding More than 25% binding by Farr assay (to more than the upper limit of 2
the laboratory determined normal range, eg, 25%)
Fever More than 38oC after the exclusion of infection 1
Thrombocytopenia Fewer than 100 000 platelets 1
Table 3 The Systemic Lupus Erythematosus Disease Activity Index3(SLEDAI)
Leucopenia Leucocyte count <3000/mm (not due to drugs) 1
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Item Score Item Score

Ocular (either eye by clinical assessment) Peripheral vascular
Any cataract ever 0, 1 Claudication for 6 months 0, 1
Retinal change or optic atrophy 0, 1 Minor tissue loss (pulp space) 0, 1
Neuropsychiatric Significant tissue loss ever (eg, loss of digit or 0, 1, 2
limb) (score 2 if >1 site)
Cognitive impairment (eg, memory 0, 1
deficit, difficulty with calculation, Venous thrombosis with swelling, ulceration 0, 1
poor concentration, difficulty in
spoken or written language, impaired or
performance level) or major psychosis venous stasis
Gastrointestinal
Seizures requiring therapy for 6 months 0, 1 Infarction or resection of bowel below
Cerebrovascular accident ever (score 2 if 0, 1, 2 duodenum, spleen, liver or gallbladder ever, 0, 1, 2
for any cause (score 2 if >1 site)
>1)
Cranial or peripheral neuropathy 0, 1 Mesenteric insufficiency 0, 1
(excluding optic)
Chronic peritonitis 0, 1
Transverse myelitis 0, 1 Stricture or upper gastrointestinal tract 0, 1
Renal surgery ever
Estimated or measured glomerular 0, 1 Chronic pancreatitis 0, 1
filtration rate <50%
Musculoskeletal
Proteinuria >3.5 g/24 h 0, 1 Muscle atrophy or weakness 0, 1
or end-stage renal disease (regardless of or 3 Deforming or erosive arthritis (including 0, 1
dialysis or transplantation) reversible deformities, excluding avascular
necrosis)
Pulmonary
Pulmonary hypertension (right 0, 1 Osteoporosis with fracture or vertebral 0, 1
ventricular prominence, or loud P2) collapse (excluding avascular necrosis)
Pulmonary fibrosis (physical 0, 1 Avascular necrosis (score 2 if >1) 0, 1, 2
and radiographical)
Osteomyelitis 0, 1
Shrinking lung (radiograph) 0, 1 Tendon rupture 0, 1
Pleural fibrosis (radiograph) 0, 1 Skin
Pulmonary infarction (radiograph) 0, 1 Scarring chronic alopecia 0, 1
Cardiovascular Extensive scarring of panniculum other 0, 1
than scalp and pulp space
Angina or coronary artery bypass 0, 1
Myocardial infarction ever (score 2 if >1) 0, 1, 2 Skin ulceration (excluding thrombosis for 0, 1
>6 months)
Cardiomyopathy (ventricular dysfunction) 0, 1
Premature gonadal failure 0, 1
Valvular disease (diastolic murmur, or 0, 1
systolic murmur >3/6) Diabetes (regardless of treatment) 0, 1
Pericarditis for 6 months or pericardiectomy 0, 1 Malignancy (exclude dysplasia) (score 2 if >1 0, 1
Table 4 The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for
site)
systemic lupus erythematosus
9 Chronicity and damage index index records damage in 12 organs or systems (table 4).
There is no index to measure harms caused by drugs in
The Systemic Lupus International Collaborating
lupus at present. The change must have been present for
Clinics/ American College of Rheumatology
at least 6 months and is ascertained clinically or by
(SLICC/ACR) damage index is a validated instrument
simple investigations. Studies have shown that the early
specifically designed to ascertain damage in SLE
acquisition of damage is a sign of a poor prognosis.
(Gladman et al 1996). Damage in SLE may be due to the
disease itself or to drug therapy. The
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LE specific skin lesions LE non-specific skin lesions

Acute cutaneous LE Cutaneous vascular
Localised disease Vasculitis
Generalised Leucocytoclastic
Subacute cutaneous LE Palpable purpura
Urticarial
vasculitis
Annular Polyarteritis nodosa-like
Papulosquamous (psoriasiform) Papulonodular mucinosis
Dego’s disease-like
Chronic cutaneous LE Atrophy blanche-
‘Classical’ LE (DLE) like Livedo
Localised reticularis
Thrombophlebitis
Generalised Raynaud’s
Hypertrophic (verrucous) phenomenon
DLE Lupus panniculitis Erythromelalgia
(profundus) LE non-specific bullous lesions
Mucosal LE Epidermolysis bullosa acquisita
Lupus tumidus Dermatitis herpetiformis-like bullous
Chilblains LE Pemphigus erythematosus
lupus
Porphyria cutanea
tarda Urticaria
Vasculopathy
Anetoderma/cutis laxa
Acanthosis nigricans (type B insulin resistance)
Periungal telangiectasia
Erythema
multiforme Leg
ulcers
Lichen planus
Alopecia (non-scarring)
‘Lupus hair’
Telogen effluvium
Alopecia areata
Sclerodactyly
Rheumatoid nodules
Calcinosis
Table 5 Classification of lupus erythematosus cutisskin lesions
(LE) associated
disease. The acute butterfly rash should be

10 Clinical features differentiated from other causes of facial erythema
10.1 Mucocutaneous features such as rosacea, seborrhoeic, atopic, and contact
dermatitis, and glucocorticoid-induced dermal
Mucocutaneous involvement is almost universal in atrophy and flushing.
SLE with both lupus-specific and non-specific lesions Other acute cutaneous lesions include generalised
(table 5). Lupus-specific lesions can be further erythema and bullous lesions. The rash of acute
classified as acute, subacute, and chronic lesions. cutaneous lupus erythematosus can be transient and
Acute rashes-malar rash. The classic lupus ‘butterfly’ heal without scarring, although persistently active
rash presents acutely as an erythematous, elevated rashes may result in permanent telangiectasias.
lesion, pruritic or painful, in a malar distribution, Subacute rashes. Subacute cutaneous lupus
commonly precipitated by exposure to sunlight (figure erythematosus (SCLE) is not uniformly associated with
4). The rash may last from days to weeks and is SLE. Approximately 50% of affected patients have SLE
commonly accompanied by other inflammatory and about 10% of patients with SLE have this type of
manifestations of the skin
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Other rashes (figure 7). Lupus profundus presents as

a firm nodular lesion with or without an overlying
cutaneous lesion. The nodules are often painful and
consist of perivascular infiltrates of mononuclear cells
plus panniculitis, manifested as hyaline fat necrosis
with mononuclear cell infiltration and lymphocytic
vasculitis. They usually appear on the scalp, face, arms,
chest, back, thighs, and buttocks; ulcerations are
uncommon and they usually resolve leaving a depressed
area. Lupus tumidus, a rare variant, is characterised by
photodistributed lesions with chronic pink indurated
plaques or broad lesions that are slow to heal.
Alopecia. Alopecia—defined as exaggerated hair
loss—occurs in most SLE patients. It may involve the
scalp, eyebrows, eyelashes, beard, and body hair.
Scarring alopecia is a complication of discoid lupus that
Figure 4 Acute cutaneous lupus erythematosus. These lesions are
typically affects the scalp. ‘Lupus hair’ is characterised by
abrupt in onset, frequently appear after exposure to the sun, and thin hair that easily fractures. It usually occurs along
are characterised by erythema and oedema. the frontal hairline, is associated with disease activity,
and grows back normally as the disease subsides.
Photosensitivity. Photosensitivity is defined as the
development of a rash after exposure to ultraviolet (UV)
lesion. Patients with SCLE may present with annular B radiation coming from sunlight or fluorescent lights. It
or psoriasiform skin lesions, and this is strongly occurs in 60–100% of SLE patients. Some patients are
associated with anti-Ro (SS-A) and anti-La (SS-B) also sensitive to UVA radiation (emitted from
antibodies. Patients with SCLE have a high incidence of photocopiers or some light bulbs), and may even be
photosensitivity and in rare instances can present with sensitive to the visible light spectrum. Not all
erythema multiforme-like lesions (Rowell’s syndrome). photosensitive individuals have lupus, nor are the two
SCLE lesions begin as small, erythematous, slightly disorders causally linked in all SLE patients.
scaly papules that evolve into either a psoriasiform Pathology and the ‘lupus band test’. Biopsy specimens
(papulosquamous) or annular form. The latter often of skin lesions from patients with DLE and SLE contain
coalesce to form polycyclic or figurative patterns the membrane attack complex (C5b through C9) as well as
(figure 5). The lesions typically have erythematous, immune complexes at the dermal–epidermal junction. The
and sometimes crusted, margins. search for immunoreactant deposition in non-lesional skin
Commonly affected areas are the shoulders, forearms, of lupus patients has been referred to as the ‘lupus band
neck, and upper torso. The face is usually spared. test’ (LBT). The diagnostic and prognostic significance
Chronic rashes. Discoid lupus erythematosus of the non-lesional LBT is controversial.
(DLE) lesions develop in up to 25% of SLE patients. Differential diagnosis. Several dermatologic entities
Patients with DLE have approximately a 5–10% risk of can mimic LE-specific lesions and should be
developing SLE which tends to be mild. Risk is even considered in patients with atypical features and/or
higher with numerous and widespread skin lesions. refractoriness to standard therapy. Acne rosacea can
Discoid lesions are characterised by discrete, result in a red face and is often confused with acute
erythematous, slightly infiltrated plaques covered by a cutaneous LE. Photosensitive psoriasis can simulate
well-formed adherent scale that extends into dilated papulosquamous SCLE, while occasionally erythema
hair follicles (follicular plugging) (figure 6). They are multiforme may be confused with annular SCLE.
often seen on the face, neck, and scalp, but also occur Other common dermatoses may co-exist in SLE
on the ears, and infrequently on the upper torso. They patients such as contact dermatitis, eczema, and
slowly expand with active inflammation at the seborrhoeic dermatitis.
periphery, and then heal, leaving depressed central Mucous membranes. Involvement of the mucous
scars, atrophy, telangiectasias, and dyspigmentation membranes occur in 25–45% of SLE patients. The
(hyper- or hypopigmentation). The differential most common manifestations include irregularly
diagnosis includes hypertrophic lichen planus, shaped raised
eczema, and actinic keratosis; some early and scaly
discoid lesions must also be differentiated from
psoriasis.
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Figure 5 Subacute cutaneous lupus

lesions. Typical features include
symmetric, widespread, superficial,
and non-scarring lesions.
Involvement of the neck, shoulders,
upper chest, upper back, and
extensor surface of the hand is
common. These lesions begin as
small photosensitive, erythematous,
scaly papules or plaques that evolve
into a papulosquamous
(psoriasiform) or annular polycyclic
form as in this patient. Subacute
cutaneous lupus erythematosus has
been associated with the presence of
anti-Ro/SS-A antibodies, genetic
deficiencies of complement C2 and
C4, and certain medications, such as
hydrochlorothiazide.
depigmentation can occur on the lips. Nasal ulcers

have been noted in patients with SLE. Involvement of
the upper airway mucosa can also occur and cause
hoarseness.
10.2 Musculoskeletal features

The musculoskeletal system is affected in 53–95% of
SLE patients.
Arthritis/arthropathy. Joint involvement is classically
described as non-erosive, non-deforming arthralgias/
arthritis in a distribution similar to that of rheumatoid
arthritis, primarily affecting the small joints of the hands,
wrists, and knees (figure 8). Arthritis may be the
presenting symptom or accompany other lupus
manifestations during a flare. The patient’s symptoms
(pain and stiffness) are usually out of proportion to the
Figure 6 Facial discoid lupus rash with a malar distribution. Note
degree of synovitis present on physical examination, and
the erythema (indicating disease activity), keratin plugged
follicles, and dermal atrophy. The characteristic pattern of
synovitis may be transient (resolving within a few days in
hyperpigmentation at the active border and hypopigmentation at
some patients), migratory, and reversible. At the other
the inactive centre is especially evident in black patients. Discoid extreme are a few patients with an impressive synovitis
lesions are usually found on the face, scalp, ears or neck. Patient indistinguishable from rheumatoid arthritis for which the
consent: obtained. term ‘rhupus’ has been used. Tenosynovitis is an early
manifestation of SLE and tendon rupture syndromes have
white plaques, areas of erythema, silvery white scarred been reported in a number of different sites in the body
lesions, and ulcers with surrounding erythema on the including the patellar tendons, the Achilles tendon, the
soft or hard palate or buccal mucosa. These lesions long head of the biceps, the triceps, and the extensor
should be distinguished clinically from those of lichen tendons of the hands. Subcutaneous nodules along the
planus, candidiasis, aphthous stomatitis, intraoral flexor tendons of the hand can be found in SLE. Chest
herpes, Adamantiades-Behçet’s disease, bite marks, pain or discomfort secondary to costochondritis has been
leukoplakia, and malignancy. Oral ulcers in SLE are reported and other conditions such as angina pectoris,
usually painless and there is not always temporal
association with systemic disease activity. Oral lesions
may be the first signs of lupus. Typical discoid lesions
with erythema atrophy and
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Figure 8 Jacoud-type arthropathy. Deformities in the hands such

as ulnar drift at the metacarpophalangeal joints, swan neck and
boutonniere deformities, and hyperextension at the
interphalangeal joint of the thumb closely resemble those seen in
rheumatoid arthritis. The absence of erosions on radiographs and
their reducibility distinguish this condition from the deforming
arthritis of rheumatoid arthritis. Courtesy of Dr D Vassilopoulos.
CPK value in the presence of symptoms and signs

of myositis should not dissuade the physician
from its diagnosis. The skin lesions of
dermatomyositis can also appear in patients with
SLE.
Avascular bone necrosis. Avascular necrosis (AVN)
of bone is a major cause of morbidity and disability in
SLE. Symptomatic AVN occurs in 5–12%. Higher
prevalence has been reported when magnetic
resonance imaging (MRI) is used for its detection.
Acute joint pain presenting late in the course of SLE
and localised to a very few areas, especially shoulders,
hips, and knees, may indicate AVN. Factors that can
induce bone ischaemia and necrosis include
Raynaud’s phenomenon, vasculitis, fat emboli,
corticosteroids, and the antiphospholipid syndrome.
Osteonecrosis often develops shortly after the onset
of high-dose corticosteroid therapy.
Figure 7 (A) Livedo reticularis and (B) periungal erythema with 10.3 Renal features (see also in-depth
nailfold vasculitis. discussion)
Renal involvement occurs in 40–70% of all SLE
pericarditis, and oesophageal spasm must be ruled patients and is a major cause of morbidity and
out. Relapsing polychondritis can also occur and it hospital admissions. Immune complex
usually responds to low-dose corticosteroid formation/deposition in the kidney results in intra-
treatment. glomerular inflammation with recruitment of
Myositis. Generalised myalgia and muscle leucocytes and activation and proliferation of
tenderness are common during disease exacerbations. resident renal cells (figure 9).
Inflammatory myositis involving the proximal muscles Proteinuria of various levels is the dominant feature
has been reported in 5–11% of cases and may develop of lupus nephritis (LN) and is usually accompanied
at any time during the course of the disease. A low by glomerular haematuria. Urinalysis is the most
serum creatine phosphokinase (CPK) value can be important and effective method to detect and
found in patients with connective tissue disease monitor disease renal activity. To assure its quality,
including SLE; thus a normal several steps
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have to be taken. These include expeditious

examination of a fresh, early morning, midstream,
clean catch, non-refrigerated urine specimen; and
flagging of specimens from patients at substantial
risk of developing LN to ensure careful examination
at central laboratories. Haematuria (usually
microscopic, rarely macroscopic) indicates
inflammatory glomerular or tubulointerstitial
disease. Erythrocytes are fragmented or misshaped
(dysmorphic). Granular and fatty casts reflect
proteinuric states while red blood cell, white blood
cell, and mixed cellular casts reflect nephritic states.
Broad and waxy casts reflect chronic renal failure. In
severe proliferative disease, urine sediment
containing the full range of cells and casts can be
found (‘telescopic urine sediment’) as a result of severe
Figure 9 Electron microscopy demonstrating subendothelial
glomerular and tubular ongoing disease
deposition of electron dense immune complexes in a patient
superimposed on chronic renal damage. Renal with proliferative lupus nephritis. Electron microscopy helps to
biopsy rarely helps the diagnosis of lupus, but is the define distribution (ie, subendothelial, epithelial, membranous
best way of documenting the renal pathology (figure deposits) of immune complexes and may be useful in the
10). In the absence of renal abnormalities, renal recognition of early proliferative changes when the light
biopsy has nothing to offer and should not be microscopy findings may be more subtle. In such cases the
performed. presence of subendothelial deposits—even if scarce—along with
other features of proliferative nephritis (nephritic sediment, low
C3, anti-DNA antibodies) are strongly suggestive of the diagnosis
of proliferative lupus nephritis.
Figure 10 WHO types of lupus nephritis. (A) Normal glomerulus (class I). (B) Mesangial disease (type II). Note mesangial
hypercellularity and expansion of the mesangial matrix which, however, does not compromise the capillary loops. (C) Proliferative
nephritis. Dramatic diseases in mesangial and endocapillary cellularity produce a lobular appearance of the glomerular tufts and
compromise the patency of most capillary loops. When less than 50% of glomeruli are involved, nephritis is denoted as focal (type III).
When more than 50% glomeruli are involved, it is denoted as diffuse (type IV). (D) Membranous nephropathy (type V). In
membranous lupus nephropathy the capillary walls of the glomerular tuft are prominent and widely patent, resembling ‘stiff’
structures with decreased compliance.
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Figure 11 Severe neuropsychiatric lupus. MRIs showing cerebrovascular disease (A and B); thrombosis in the sagittal sinus in a patient
with antiphospholipid antibodies (C); and acute transverse myelitis (D).
10.4 Nervous system features (see also in rare cases headaches may herald severe pathology
and need to be investigated in the presence of ‘red-flag’
in-depth discussion) symptoms or signs (unusual intensity not subsiding to
SLE affects both the central nervous system (CNS) and analgesics, fever, confusion, meningeal or focal
the peripheral nervous system (PNS) (figure 11). neurologic signs), with imaging and lumbar puncture.
Nervous system involvement in SLE remains one of Cognitive dysfunction has been reported in up to 20–
the major causes of morbidity and mortality; it is the 30% of SLE patients, but it is usually mild. Psychosis is
least understood manifestation of the disease, and reported in up to 3.5% and is characterised by either
remains a complex diagnostic entity as a result of its the presence of delusions or hallucinations. The latter
multiple clinical presentations. The ACR described are most frequently auditory. Generalised and focal
case definitions and classification criteria for 19 seizures are reported in 7–10% of patients and may
CNS and PNS syndromes observed in patients with occur either in the setting of active generalised
SLE, which collectively are referred to as multisystem lupus or as isolated neurologic events.
neuropsychiatric SLE (NPSLE) syndromes (table 6). Seizures are also associated with the presence of
The EULAR task force on SLE has critically antiphospholipid antibodies. Demyelination, transverse
reviewed the literature on NPSLE in an effort to myelopathy, and chorea are rare manifestations
provide an evidence and expert-based response to occurring in <1% of patients. Clinical and
common clinical questions encountered in the disease neuroimaging evidence of demyelination may be
(Bertsias et al 2010b). indistinguishable from multiple sclerosis. Myelitis may
present either with grey matter signs (upper motor
10.4.1 An overview of specific NPSLE neuron signs, spasticity, hyperreflexia) or white matter
manifestations. signs (lower motor neuron syndrome with flaccid
The association between SLE and headache is paralysis and decreased reflexes). The latter associates
controversial. Studies have shown that headaches are with neuromyelitis optica (NMO) and
common (>20–40%), but usually are not related to lupus.
However,
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Central nervous system includes accelerated, premature atherosclerosis and

valvular heart disease. Studies have also demonstrated
Aseptic meningitis an increased risk for myocardial infarction or stroke
Cerebrovascular disease compared to the healthy population, and this risk
Demyelinating syndrome cannot be fully explained by the traditional CVD risk
Headache (including migraine and benign factors.
intracranial hypertension) Valvular heart disease is common in SLE and has
been linked to the presence of antiphospholipid
Movement disorder antibodies. The most common abnormality is diffuse
(chorea) Myelopathy
thickening of the mitral and aortic valves followed by
Seizure disorder
vegetations, valvular regurgitation, and stenosis in
Acute confusional decreasing order of frequency. The combined
state Anxiety disorder incidence of stroke, peripheral embolism, heart
Cognitive dysfunction failure, infective endocarditis, and the need for
valve replacement is approximately threefold higher
Mood disorder
Psychosis in those patients with valvular disease compared to
those without it. Pathologic studies have shown active
Peripheral nervous system and healed valvulitis, as well as active Libman-
Acute inflammatory demyelinating Sacks vegetations with acute thrombus, healed
polyradiculoneuropathy (Guillain-Barré syndrome) vegetations with or without hyalinised thrombus, or
Autonomic disorder both active and healed vegetations, in the same or
different valves.
Mononeuropathy, single/multiplex
Myasthenia gravis
Neuropathy, cranial 10.6 Pleura and lungs
Plexopathy The most common pleuropulmonary manifestation
Adapted from the American College of Rheumatology
Polyneuropath of SLE is pleuritis (table 7). Pleuritic pain is
nomenclature
y and case definitions for neuropsychiatric lupus
syndromes. present in 45–60% of patients and may occur with
Table 6 Neuropsychiatric syndromes in systemic lupus
or without a pleural effusion, with clinically apparent
erythematosus pleural effusions reported in up to 50%. Effusions are
usually bilateral and equally distributed between the
the presence of antibodies to aquaporin. Peripheral left and right hemithoraces. The effusion is
sensorimotor neuropathy has been reported in up to 1% invariably exudative with higher glucose and lower
of SLE patients and may occur independently of other lactate dehydrogenase levels than those found in
disease characteristics. rheumatoid arthritis.
Clinically significant interstitial lung disease (ILD)
complicates SLE in 3–13% of patients, but is rarely
10.5 Cardiovascular features severe. Acute lupus pneumonitis presenting as cough,
Pericarditis may occur in approximately 25% of SLE dyspnoea, pleuritic pain, hypoxaemia, and fever occurs
patients. Pericardial effusions may be asymptomatic in 1–4%.
and are usually mild to moderate. Tamponade is rare. Chest radiographs reveal unilateral or bilateral
Myocardial involvement is rare and typically occurs in infiltrates. Pulmonary haemorrhage is a rare but
the presence of generalised lupus activity. The patient potentially catastrophic complication of SLE. Clinical
may present with fever, dyspnoea, tachycardia, and features are non-specific but diffuse alveolar
congestive heart failure. Clinical features of left infiltrates, hypoxaemia, dyspnoea, and anaemia are
ventricular dysfunction, non-specific ST-T wave characteristic. Alveolar haemorrhage usually occurs
changes, segmental wall motion abnormalities, and in patients with a known history of SLE, high titres
decreased ejection fraction are found in >80% of of anti-DNA antibodies, and active extrapulmonary
patients. MRI has been used to detect both clinical and disease. Fibreoptic bronchoscopy
subclinical myocardial involvement in SLE. with bronchoalveolar lavage (BAL) and transbronchial
SLE patients have substantially increased morbidity lung biopsies are usually needed to substantiate the
and mortality from cardiovascular disease (CVD). This diagnosis.
The ‘shrinking lung syndrome’ is characterised by
progressive dyspnoea and small lung volumes on
chest radiographs, and is thought to be secondary to
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Pleuropulmonary Frequency
manifestation
Pleuritic chest pain or pleurisy Common, with or without effusion or friction rub
Pleural effusion Exudate; unilateral or bilateral
Acute pneumonitis Not common; presentation includes: fever, non-productive cough, infiltrates,
hypoxia; high mortality rates
Interstitial lung disease Insidious onset of dyspnoea on exertion, non-productive cough, pleuritic chest
pain
Bronchiolitis obliterans Can be difficult to diagnose; requires biopsy; responds to corticosteroids
with organising
pneumonia
Pulmonary capillaritis or Rare, associated with antiphospholipid antibodies; poor prognosis
diffuse alveolar haemorrhage
Shrinking lung syndrome Occurs in patients with longstanding SLE; possible cause: diaphragmatic
weakness
Pulmonary embolism Common in patients with antiphospholipid antibodies
or infarction
Pulmonary hypertension Insidious onset of dyspnoea on exertion, chronic fatigue, weakness, palpitations,
oedema
Lymphadenopathy Massive mediastinal lymphadenopathy uncommon in patients with SLE alone.
Cervical and auxiliary common, correlates with disease activity
Infection Typical and atypical pathogens. Due to immune dysfunction and immunosuppressive
medications
Malignant tumour Lung cancer; lymphoma more common
Table 7 Pleuropulmonary manifestations of systemic lupus erythematosus (SLE)
diaphragmatic dysfunction. It can be difficult to 10.8 Haematologic features

differentiate from respiratory muscle weakness, primary
parenchymal disease or pleural causes of low lung Haematologic abnormalities are common and can be
volumes without the use of invasive studies. Pulmonary the presenting symptom or sign in SLE. Major
hypertension (PH) is a rare but potentially life- clinical manifestations include anaemia,
threatening complication. Dyspnoea is the most leucopenia, thrombocytopenia, and the
common presenting symptom while up to 58% of antiphospholipid syndrome.
patients have Raynaud’s phenomenon. Anaemia. Anaemia in SLE is common and
correlates with disease activity. Its pathogenesis
includes anaemia of chronic disease, haemolysis
10.7 Lymphadenopathy and splenomegaly (autoimmune or microangiopathic), blood loss, renal
Lymphadenopathy occurs in approximately 40% of insufficiency, medications, infection, hypersplenism,
patients, usually at the onset of disease or during myelodysplasia, myelofibrosis, and aplastic anaemia.
disease A frequent cause is suppressed erythropoiesis from
flares. Lymph nodes are typically soft, non-tender, chronic inflammation.
discrete, Overt autoimmune haemolytic anaemia has been
and usually detected in the cervical, axillary, and reported in up to 10% of patients; of note, SLE patients
inguinal area. Clinically significant may have a positive Coombs test without overt
lymphadenopathy that raises diagnostic issues is less haemolysis. Blood loss, either from the
common. Patients with lymphadenopathy are more gastrointestinal (GI) tract, usually secondary to
likely to have constitutional symptoms. A lymph node medications (non-steroidal anti-inflammatory drugs
biopsy may be warranted when the degree of (NSAIDs)), or due to excessive menstrual bleeding,
lymphadenopathy is out of proportion to the activity of may cause an iron deficiency anaemia. A rare cause of
the lupus. Splenomegaly occurs in 10–45% of patients, iron deficiency anaemia in SLE may be low grade
particularly during active disease, and is not pulmonary haemorrhage without signs of
necessarily associated with cytopenias. Splenic atrophy haemoptysis.
and functional hyposplenism have also been reported A microangiopathic haemolytic anaemia with or
in SLE and may predispose to severe septic without the other features (fever, thrombocytopenia,
complications. kidney involvement, neurologic symptoms) of
thrombotic
20_Eular_Fpp.indd 492 4/21/2012 7:38:09 PM

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thrombocytopenic purpura (TTP) has been described 10.9 Liver and GI tract features
in SLE. The presence of schistocytes in the peripheral GI tract. GI manifestations are reported in 25–40%
blood smear and increased lactate dehydrogenase
of patients with SLE, and represent either lupus GI
(LDH) levels are the hallmarks of this disorder. When
involvement or effects of medications. Dyspepsia has
this occurs in the setting of generalised lupus activity, been reported in 11–50%, and peptic ulcers (usually
we prefer to call it TTP-like syndrome and use
gastric) in 4–21%.
immunosuppressive therapy. In the absence of
Abdominal pain. Abdominal pain accompanied
generalised lupus activity we view it as a bona fide
by nausea and vomiting occurs in up to 30% of SLE
TTP. A similar syndrome can also occur in the
patients. Special consideration should be given in
presence of antiphospholipid antibodies. Red cell
conditions such as peritonitis, mesenteric vasculitis
aplasia due to antibodies against erythrocyte
with intestinal infarction, pancreatitis, and
progenitors has been rarely reported in SLE patients.
inflammatory bowel disease. Risk factors for the
Leucopenia. Leucopenia is common in SLE; it can be
development of mesenteric vasculitis include
the presenting symptom and is usually associated with
peripheral vasculitis and CNS lupus. The clinical
disease activity. A white blood cell count <4500/mm3
presentation is usually with insidious symptoms that
has been reported in up to 30–40% of cases, especially in
may be intermittent for months before the
the presence of active disease. Severe leucopenia development of an acute abdomen with nausea,
(neutrophil count <500/ mm3) is rare. Lymphocytopenia vomiting, diarrhoea, GI bleeding, and fever. Patients
(lymphocyte count <1500/ mm3) occurs in approximately
with acute presentation may also have mesenteric
20% of SLE patients.
thrombosis and infarction, often in association with
Thrombocytopenia. Mild thrombocytopenia (platelet antiphospholipid antibodies. The diagnosis of
counts 100 000–150 000/mm3) has been reported in mesenteric vasculitis may be difficult to establish.
25–50% of patients; counts <50 000/mm 3 occur in only Plain radiographic studies may reveal segmental bowel
10%. The most common cause of thrombocytopenia in dilatation, air-fluid levels, ‘thumb-printing’ or
SLE is immune-mediated platelet destruction, but narrowing of the lumen, and pseudo-obstruction.
increased platelet consumption may also occur due to
Abdominal computed tomography (CT) scan findings
microangiopathic haemolytic anaemia or
compatible with mesenteric vasculitis include
hypersplenism. Impaired platelet production secondary
prominence of mesenteric vessels with a comb-like
to medications is another contributing factor. Idiopathic
appearance supplying dilated bowel loops, small bowel
thrombocytopenic purpura (ITP) may be the first sign
thickening and ascites. Vasculitis generally involves
of SLE, followed by other symptoms as long as many small arteries, which can lead to a negative arteriogram.
years later. In such cases, presence of high-titre ANAs or Pancreatitis due to lupus may result from vasculitis or
extractable nuclear antigens (ENAs) raise the possibility thrombosis and occurs in as many as 2–8% of patients.
of underlying SLE. Table 8 depicts our approach to Elevated levels of serum amylase have been described
thrombocytopenia in lupus. in patients with SLE without
Lupus related?
• Rule out drug effects. Ask for over-the-counter drugs such as quinine for leg cramps, vitamins, supplements or
herbal
medicines
• Discontinue all but absolutely essential drugs
• Discontinue agents that may interfere with platelet function (aspirin, non-steroidal anti-inflammatory drugs)
Confirm autoimmune aetiology by examining peripheral smear. Rule out platelet clumping that can cause false
thrombocytopenia and abnormalities of the white or the red blood cells
• Consider bone marrow examination especially in older patients to rule out occult myelodysplasia
• Tests for antiplatelet antibodies are not helpful
• Rule out thrombotic thrombocytopenic purpura or antiphospholipid-related microangiopathic haemolytic anaemia
(anaemia with pronounced reticulocytosis and fragmented erythrocytes in the peripheral smear; antiphospholipid
antibodies or syndrome)
Look for evidence of lupus activity in other organs (especially major organs)
• Determine severity: severe: platelets <20×103/μl; moderate-to-severe: platelets 20–50×103/μl
• Treatment goal is not a normal platelet count but a safe platelet count (30–50×103/μl)
Table 8 An approach to thrombocytopenia in systemic lupus erythematosus
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pancreatitis and thus should be interpreted in light of wool spots result from focal ischaemia and are not
the overall clinical examination. pathognomonic for lupus. Retinal vasculitis is usually
Liver disease. Hepatic disease may be more common associated with generalised active systemic disease
in SLE than initially thought. However, clinically and presents early in the disease process. Corneal and
significant hepatic disease is generally unusual. The conjunctiva involvement is usually part of Sjögren’s
incidence of hepatomegaly is 12–25%. Excessive syndrome associated with SLE; uveitis and scleritis
fatty infiltration (steatosis) is a common finding and are extremely rare manifestations in SLE, seen in <1%
may occur as part of the disease process or may be of patients. Optic neuritis is rare and may be
secondary to corticosteroid treatment. Liver associated with transverse myelitis.
chemistries (aspartate aminotransferase (AST),
alanine aminotransferase (ALT), LDH, alkaline 11 Diagnosis
phosphatase) may be abnormal in patients with
active disease or those receiving NSAIDs. The term 11.1 Serologic tests
‘lupoid hepatitis’ was formerly used to describe Antinuclear antibodies. The ANA assay is an ideal
autoimmune hepatitis because of clinical and screening test because of its sensitivity (95% when
serologic similarities to SLE. Autoantibodies may using human cultured cells as the substrate) and
help to distinguish between autoimmune hepatitis simplicity. The entity of ‘ANA-negative lupus’ described
and liver disease associated with lupus. ANAs can in previous years is usually associated with the
be seen in both disorders, but anti- smooth muscle presence of other cytoplasmic autoantibodies such as
and anti-mitochondrial antibodies are not common in anti-Ro (SS-A) and anti-ribosomal P protein. The
SLE (<30%) and usually when found are in low titres. specificity of ANAs for SLE is low, since they are
In lupus-associated hepatitis histology rarely shows found in many other conditions such as scleroderma,
the periportal (interface) hepatitis with piecemeal polymyositis, dermatomyositis, rheumatoid arthritis,
necrosis characteristic of autoimmune hepatitis, and autoimmune thyroiditis, autoimmune hepatitis,
liver-associated chemistries tend to be lower in lupus infections, neoplasms, and in association with many
with drugs. Also, some healthy individuals test positive for
only mild (usually up to three to four times normal) ANAs. The formation of ANAs is age-dependent; it is
elevation. The absence of these antibodies and the estimated that 10–35% of individuals older than 65
presence of anti-ribosomal P protein antibodies could years have ANAs. However, the titres are generally
be suggestive of lupus hepatitis. lower (<1:40) than those in systemic autoimmune
Ascites is uncommon in SLE and, when detected, diseases. In contrast to the low positive predictive
infectious causes and/or perforation must be excluded value of ANA testing, a patient with a negative test has
by paracentesis. Congestive heart failure and less than a 3% chance of having SLE; thus, a negative
hypoalbuminaemia secondary to nephrotic syndrome ANA test is useful for excluding the diagnosis
or protein-losing enteropathy represent other possible of SLE. However, in the presence of typical features of
causes of ascites in patients with lupus. Protein- lupus, a negative ANA test does not exclude the
losing enteropathy has been described in some diagnosis. This is especially true for laboratories that
patients with SLE and can be the first manifestation of employ enzyme immunoassays or other automated
the disease. It usually occurs in young women and is assays which display marked inter-manufacturer
characterised by the onset of profound oedema and variation in performance.
hypoalbuminaemia. In such cases, reported sensitivity against positive
immunofluorescence ANA with titre at 1:160 ranges
from 70–98%.
10.10 Ophthalmic features Antibodies to extractable nuclear antigens (ENAs). The
Up to 8% of SLE patients develop inflammation of nucleosome—a complex of DNA and histones—was
the retinal artery during the course of their disease. the first identified lupus autoantigen. Autoantibodies to
An equal number of patients have infarction of the single stranded DNA (ssDNA) and individual histones
retinal vasculature secondary to antiphospholipid are common in SLE as well as in drug-induced lupus.
antibodies. Antibodies to double stranded (ds) DNA are found in
Both conditions can lead to the presence of ‘cotton up to 70% of SLE patients at some point during the
wool’ spots in the retina visible on ophthalmoscopy course of
or fluorescein angiography (where perivascular
exudates and patches of dye leakage along the vessels
are seen). Cotton
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their disease, and are 95% specific for SLE, making them undifferentiated connective tissue syndromes. These
a valuable disease marker. Anti-Sm (Smith) antibodies patients account for 10–20% of patients referred to
are detected in 10–30% and their presence is tertiary care centres. Among patients presenting with
pathognomonic for SLE. Anti-nRNP antibodies are symptoms suggestive of a connective tissue disease,
associated with only a small fraction (10–15%) fulfil classification
anti-Sm but are not disease specific. Anti- criteria for SLE after 5 years follow-up. Prognostic
ribosomal antibodies are specific for SLE but less factors for SLE are young age, alopecia, serositis,
sensitive than anti-dsDNA or anti-Sm discoid lupus, positive Coombs test, and positive anti-
antibodies. Sm and anti-DNA antibodies. Latent or incomplete
lupus describes patients who present with a
11.2 Prognostic markers and the role of constellation of symptoms suggestive of SLE, but do
autoantibodies not qualify by clinical intuition or classification
criteria as having classical SLE. These patients
Analysis of large cohorts has defined clusters of
usually present with one or two of the ACR criteria
autoantibodies associated with distinct SLE
and other features not included in the classification
features. Serum anti-dsDNA titres have been
criteria. Most of these patients do not develop SLE or
correlated with LN, progression to end-stage renal
when they do it is usually mild and rarely involves
disease, and increased disease severity, damage or
major organs.
poor survival.
Antiphospholipid antibodies are strongly associated Case series suggest that SLE may occasionally present
with features of the antiphospholipid syndrome (APS) with high fever and lymphadenopathy
(arterial/ venous thrombosis, fetal loss, simulating lymphoid or haematological
thrombocytopenia), CNS involvement (especially malignancy, neurological events (chorea,
cerebrovascular disease), severe LN, damage accrual, cerebrovascular accident, myelitis),
and death. Anti-Ro (SS-A) and
anti-La (SS-B) antibodies have been associated with
neonatal lupus, and congenital heart block in the Manifestations Onset Anytime
children of seropositive mothers. Antibodies to other Arthralgia 77% 85%
extractable nuclear antigens (anti-Ro/La/Sm/RNP) Constitutional 53% 77%
have been associated with mucocutaneous involvement
and less severe nephropathy in most studies. Skin 53% 78%
Arthritis 44% 63%
11.3 Diagnosis: typical and atypical Renal 38% 74%
presentations Raynaud’s 33% 60%
The diagnosis of lupus requires integration of patient’s Central nervous system 24% 54%
symptoms, physical examination findings, and the Vasculitis 23% 56%
results of diagnostic tests. Table 9 shows the frequency
of various manifestations both at disease onset and at Mucous membranes 21% 52%
anytime during the disease course. Presence of one or Gastrointestinal 18% 45%
more of these features or the involvement of at least Lymphadenopathy 16% 32%
two different organs in young women should always
Pleurisy 16% 30%
raise the possibility of lupus. However, many of these
features are not unique to lupus but could be seen in Pericarditis 13% 23%
other infectious, metabolic, malignant, and other Lung 7% 14%
systemic rheumatic diseases.
Nephrotic syndrome 5% 11%
11.3.1 Pitfalls and challenges in Azotaemia 3% 8%
diagnosis Myositis 3% 3%
Undifferentiated connective tissue disease. Thrombophlebitis 2% 6%
The recognition that systemic rheumatic diseases Myocarditis 1% 3%
have several common features which makes a Pancreatitis 1% 2%
specific diagnosis difficult has led to the concept
of the Table 9 Frequency of various manifestations of systemic lupus
erythematosus at disease onset and at any time during the disease
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unusual skin rashes (chronic urticarial, paniculitis), Pregnancy may increase lupus activity but flares are
abdominal vasculitis, pneumonitis/pulmonary usually mild. Pregnancy outcome is optimal when
haemorrhage, pulmonary hypertension, isolated the disease is in clinical remission for 6–12 months and
serositis, myocarditis, aplastic anaemia or isolated the patient’s renal function is stable and normal or near-
cytopenias. A careful history for manifestations of normal. Patients with LN and antiphospholipid
lupus in the past and a careful examination together antibodies are at risk of developing pre-eclampsia
with serology may help recognise the disease. and should be monitored closely. Proteinuria may
increase during pregnancy in women with underlying
kidney disease.
11.4 Differential diagnosis Differentiation of pre-eclampsia from lupus renal
Differential diagnosis from other polyarticular activity is not difficult in most cases. Very low serum
diseases affecting young women, such as rheumatoid complement, active urine sediment, and evidence of
arthritis or Still’s disease, may not be easy at the initial generalised lupus activity favour the latter. Other
stages. Other diseases to be considered include features such as hypertension, thrombocytopenia,
undifferentiated connective tissue disease, primary rise in serum uric acid levels, and proteinuria may be
Sjögren’s syndrome, primary antiphospholipid observed in both conditions. Low grade activation of
syndrome, fibromyalgia with positive ANA, the classic complement pathway may be attributable to
idiopathic thrombocytopenic purpura, drug induced pregnancy alone. Ovarian induction and fertilisation
lupus, and autoimmune thyroid disease. can be successful in SLE patients, but rates of fetal
Patients presenting with fever or splenomegaly/ and maternal complication may be higher.
lymphadenopathy must be differentiated from Fetus. SLE may affect the fetus in several ways,
infectious diseases or lymphoma. In febrile patients especially if the mother has a history of LN,
with known SLE, leucocytosis, neutrophilia, shaking antiphospholipid, anti-Ro and/or anti-La antibodies.
chills, and normal levels of anti-DNA antibodies These conditions are associated with increased risk
favour infection. Lupus may present with localised or of miscarriage, stillbirth, premature delivery,
generalised lymphadenopathy or splenomegaly, but intrauterine growth restriction, and fetal heart block.
the size of lymph nodes is rarely >2 cm while Neonatal lupus is a passively transferred autoimmune
splenomegaly is mild-to-moderate. Patients with disease that occurs in some babies born to mothers
known or suspected SLE with prominent with anti-SS-A/Ro and/or anti-SS-B/La antibodies.
lymphadenopathy, massive splenomegaly or The most serious complication in the neonate is
expansion of a monoclonal CD19+/ CD22+ B cell complete heart block, which occurs in up to 2% of
population should raise the suspicion of non-Hodgkin such pregnancies. Isolated skin rash occurs in a
lymphoma. In patients presenting with neurological similar percentage. Once a woman has given birth to
symptoms, infections, cerebrovascular accidents or an infant with congenital heart block, the recurrence
immune mediated neurologic diseases such as rate is about 15%.
multiple sclerosis or Guillain-Barré disease must be Table 10 summarises the key points relevant to the
considered. Finally, in patients presenting with
pulmonary–renal syndrome, the disease must be management of pregnancy in SLE patients.
differentiated from Goodpasture’s syndrome, or
antineutrophil cytoplasmic antibody (ANCA) 13 Lupus in childhood and adolescence
associated vasculitis. The differential diagnosis of
glomerulonephritis includes post-infectious Approximately 15–20% of all SLE cases are diagnosed
glomerulonephritis (streptococcal, staphylococcal, in childhood. Paediatric SLE may differ from adult
subacute bacterial endocarditis, or hepatitis C virus), SLE, in disease expression, physiologic,
membranoproliferative glomerulonephritis, or renal developmental and psychosocial issues. Because of
vasculitis (ANCA or anti-GBM associated). paucity of data in paediatric SLE, little is known about
its epidemiology, long term outcome, and optimal
12 SLE and pregnancy management. In general, the same principles are
applied in the management of paediatric lupus;
Mothers. There is no significant difference in fertility however, the special needs of this population also
between patients with SLE and unaffected individuals. have to be taken into consideration.
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• Planning of pregnancy
– Ensure that lupus is inactive for at least 6 months. Reassure patient (small risk for major flare)
– Discourage pregnancy if creatinine is >2 mg/dl
• Check for antiphospholipid antibodies and other antibodies that may be of relevance during pregnancy (eg,
anti-SSA, anti-SSB)
• Check baseline labs including serology, and serum chemistry including creatinine, albumin, uric acid, anti-dsDNA,
C3, C4
• Be aware of the small risk for congenital heart block (CHB), especially in women with both anti -SSA and anti-
SSB antibodies or with a prior episode of CHB. In such cases, may monitor for CHB between 16 and 24 weeks
of gestation
• Monitor closely blood pressure and proteinuria. Should this develop, differentiate between active nephritis and
pre- eclampsia. The presence of generalised lupus activity and active urine sediment and significantly low serum
complement favours lupus nephritis
Table 10 An approach to the management of pregnancy in systemic lupus erythematosus
14 Drug-induced lupus following causes: (1) exacerbation of pre-existing

manifestations of SLE; (2) development of new life-
A variety of drugs have been identified as being threatening manifestations of SLE; (3) infections
definite, probable or possible causes of lupus (table 11). resulting from immunosuppression; (4) adverse
DIL should be suspected in patients with no diagnosis or effects of drugs used to treat SLE; (5) malignancy
history of SLE, who develop a positive ANA and at least resulting from prolonged use of cytotoxic drugs, and
one clinical feature of lupus after an appropriate duration (6) acute serious illnesses that are unrelated to SLE,
of drug exposure, and whose symptoms resolve after but whose manifestations are altered or exaggerated
discontinuation of the drug. DIL is probably under- by it. Infection is the most common form of
reported since most cases are mild and self-limiting pulmonary involvement in patients with SLE.
once the offending drug is discontinued. Infections in SLE patients can be confused with
Clinical features include fever, myalgias, rash, arthritis, disease exacerbation, and empiric therapy with
and serositis. Haematological abnormalities, kidney broad spectrum antibiotics is warranted until
disease, and CNS lupus are uncommon. Antihistone infection is ruled out. In the case of the lungs, a
antibodies are present in more than 95% of cases, diagnosis of acute lupus pneumonitis can be made
whereas hypocomplementaemia and anti-DNA after rigorously excluding infections in patients
antibodies are rare, with the probable exception of presenting with features resembling infectious
disease associated with use of IFNα and anti-TNF pneumonia. A high index of suspicion should be
therapies. maintained for the young female patient presenting
with unexplained pulmonary infiltrates. Alveolar
15 Emergencies and critical illness haemorrhage is also a serious but rare complication
of lupus with high morbidity and mortality.
Emergency room (ER) visits. SLE patients may visit Respiratory failure may occur, and more than half of
the ER for complications related to lupus itself or its affected patients in most series required mechanical
treatment, or for unrelated reasons. Critical questions ventilation. Patients with alveolar haemorrhage
confronting the clinician are: (1) whether the event is usually have lupus nephritis as a pre-existing
related to lupus; and condition.Vascular events (myocardial or
(2) whether in the presence of lupus the management cerebrovascular) due to premature accelerated
should differ. In general, lupus-related emergencies atherosclerosis are increasingly recognised among
frequently occur when disease is active. For example, SLE patients. Although patients are often concerned
approximately 60% of primary NPSLE events occur in about vasculitis, the majority of coronary occlusive
the presence of generalised lupus activity. Common disease in SLE results from atherosclerosis or
symptoms bringing lupus patients to the ER are fever, thrombosis. Cases of left ventricular free wall
shortness of breath, and chest pain. Poor compliance, rupture, acute mitral regurgitation following rupture
low education level, severity of the underlying disease, of chordae tendinae, and aortic dissection have been
and higher damage scores are risk factors for described. Cerebrovascular accidents presenting
hospitalisation. acutely with hemiplegia, aphasia,
Lupus in the intensive care unit (ICU). Life-
threatening illness can develop in patients with lupus
from any of the
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Agent Risk Agent Risk

Antiarrhythmics Antibiotics
Procainamide High Isoniazid Low
Quinidine Moderate Minocycline Very low
Disopyramide Very low Nitrofurantoin Very low
Propafenone Very low Anti-inflammatories
Antihypertensives D-Penicillamine Low
Hydralazine High Sulfasalazine Low
Methyldopa Low Phenylbutazone Very low
Captopril Low Zafirlukast Very low
Enalapril Low Mesalamine Low
Acebutolol Low Diuretics
Labetalol Very low Chlorthalidone Very low
Pindolol Very low Hydrochlorothiazide Very low
Clonidine Very low Antihyperlipidaemics
Minoxidil Very low Lovastatin Very low
Prazosin Very low Simvastatin Very low
Antipsychotics Miscellaneous
Chlorpromazine Low Propylthiouracil Low
Perphenazine Very low Levodopa Very low
Phenelzine Very low Aminoglutethimide Very low
Lithium carbonate Very low Timolol eye drops Very low
Anticonvulsants Biologic agents
Carbamazepine Low TNFα blockers High
Phenytoin Very low Interferon α Low
Trimethadione Very low
Primidone Very low
Ethosuximide Very low
Table 11 Drugs reported to induce lupus-like disease and associated autoantibodies
cerebral dysfunction, cortical blindness or other hepatic aneurysms, cholecystitis, perforated rectal
deficits of cerebral function can be caused by ulcer, appendix, caecum or colon, and pancreatitis.
intracranial haemorrhage from ruptured aneurysms, Active SLE presenting with acute abdomen and a high
thrombotic strokes from vasculitis or vasculopathy SLEDAI score are more likely to have active intra-
secondary to antiphospholipid antibodies, or embolic abdominal vasculitis than patients with active lupus but
strokes from cardiac emboli. Spinal cord myelopathy low SLEDAI scores, and should be promptly referred
is a devastating manifestation of SLE. Patients for abdominal CT with contrast. In view of the high
present with weakness or paralysis, bilateral sensory mortality in this subgroup, patients with a high index
deficits, and impaired sphincter control. Symptoms of suspicion should undergo early laparotomy.
usually evolve in a matter of hours or days. MRI of
the spinal cord may show characteristic
abnormalities of cord oedema if obtained early. 16 Recommended assessment and
Because of the poor prognosis early diagnosis and monitoring and referral guidelines
aggressive therapy are important.
Due to its low prevalence, most general internists and
Acute abdomen in SLE patients may be secondary to primary care physicians will not have experience in
mesenteric arterial thrombosis, ischaemic bowel, the
ruptured
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management of moderate to severe disease. However, 17.2 Morbidity, comorbidities, and

their role in the early diagnosis, monitoring of mortality
patients with mild, stable diseases, and the referral
for patients with unstable or moderate to severe In lupus, treatment-related morbidity may not be
disease is essential. easily separable from disease-related morbidity. The
Guidelines for the initial assessment and frequency of incidence of hospital admissions for patients with lupus
monitoring for general use are shown in table 12. is 0.69 admissions per patient-year. Infections,
coronary artery disease, and orthopaedic management
of osteonecrosis were prominent reasons for
17 Prognosis, morbidity and hospitalisation. A bimodal mortality pattern was
comorbidities, and mortality first described in 1974 showing that early mortality
in SLE is associated with lupus activity and
17.1 Prognosis infection, whereas late mortality is associated with
Although current treatment of lupus has improved atherosclerotic
survival dramatically, prolonged and complete complications.
remission— defined as 5 years without clinical and Infections. Infections account for 20–55% of all
laboratory evidence of active disease and on no deaths in SLE patients. Susceptibility to infections
treatment—has remained elusive for most patients. may be due to underlying immune dysregulation
The incidence of flare is estimated to 0.65 per patient- and
year of follow-up. Moreover, a significant number of therapeutic factors, particularly high-dose
patients (10–20% in tertiary referral centres) do not glucocorticoids (GC) and immunosuppressive
respond adequately to immunosuppressive therapies. drugs. A broad spectrum of infections have been
reported in SLE, including bacterial, mycobacterial,
viral, fungal,
History: review of systems

Joint pain/swelling, Raynaud’s
phenomenon Photosensitivity, rash, hair
loss,
Shortness of breath, pleuritic chest pain
General symptoms (depression, fatigue, fever, weight change)
Physical examination
Rashes (acute, subacute, chronic, non-specific, others), alopecia, oral or nasal ulcers
Lymphadenopathy, splenomegaly, pericardial or pleural effusions
Fundoscopic examination, oedema
Other features as suggested by history/symptoms
Imaging: laboratory
Haematology*
Chemistry*
PT/PTT, antiphospholipid antibodies
Urinalysis*
Serology (ANA, ENA including anti-dsDNA†, complement†)
Chest x-ray
ECG
Other tests as suggested by history/symptoms
Disease activity index (at each visit or at major changes in therapy)

Side effects of therapy
Damage index (SLICC) (every 1-2 years)
*Every 3–6 months, if stable.
†Every 3–6 months in patients with active renal disease.
ANA, antinuclear antibody; ENA, extractable nuclear antigen; ECG, electrocardiogram; PT, prothrombin
time; PTT, partial thromboplastin time; SLICC, Systemic Lupus International Collaborating Clinics.
Table 12 Recommended initial assessment and monitoring of systemic lupus erythematosus
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and parasitic infections, with the respiratory, urinary Osteoporosis. Uncontrolled disease activity,
tract, and CNS the most commonly involved sites. Risk premature menopause, relative vitamin D deficiency
factors for infections include increased clinical and/or due to avoidance of sun exposure, and the use of
serological lupus activity at baseline, major organ systematic GC all contribute to reduced bone mineral
involvement (especially renal and lung involvement), density in SLE. Vertebral compression fractures are
lymphopenia, persistent neutropenia (<1000/mm 3), common, especially as the age of patients increases.
hypoalbuminaemia (especially for severe CNS Malignancies. Haematological malignancies
infections), high dose of GC (each increase of 10 mg/ (particularly non-Hodgkin’s lymphoma (NHL)),
day prednisone is associated with an 11-fold and cervical and lung cancer occur more
increased risk for serious infection), and prior (within commonly in SLE compared to the general
the last 6 months) use of cytotoxic drugs (especially, population.
azathioprine, and cyclophosphamide). The Immunosuppressive therapy and intrinsic SLE-related
evaluation of a lupus patient who receives mechanisms may account for this risk. NHL is
immunosuppressive therapy and presents with associated with SLE (standardised incidence ratio
symptoms or signs (SIR) 3.6), with the most commonly identified
suggestive of infection possesses diagnostic and histologic subtype being diffuse large B cell
therapeutic challenges. Findings that favour the lymphoma, which usually runs an aggressive course.
diagnosis of infection include the presence of Hodgkin’s lymphoma (HL) is also more frequent in
shaking chills, leucocytosis and/or neutrophilia SLE (SIR 3.2). The risk for haematological
(especially in the absence of steroid therapy), malignancies may increase after exposure to
increased numbers of band forms or immunosuppressive medications,
metamyelocytes on peripheral blood particularly after a period of 5 years following
smear, and concomitant immunosuppressive therapy. cessation of therapy. Since SLE and lymphomas share
The diagnosis of SLE fever is favoured by the clinical manifestations (fever, lymphadenopathy,
presence of leucopenia (not explained by cytotoxic splenomegaly, cytopenias, monoclonal expansion of
therapy), B cells), a high index of suspicion is necessary for
normal or only slightly increased C reactive protein, early detection of the latter. In such cases, an
low C3/C4, and elevated anti-DNA antibodies. Pending aggressive investigation is warranted with appropriate
microbiology results, adequate antimicrobial therapy imaging studies and, potentially, lymph node biopsy.
(including broad spectrum antibiotics in suspected Cervical dysplasia is increased in women with lupus
nosocomial infection) is recommended to reduce as a result of impaired clearance of human papilloma
adverse outcomes. virus (HPV) due to exposure to cytotoxic agents,
Atherosclerosis. SLE patients have 2.3–7.5 particularly cyclophosphamide (increase by 1 g of
increased risk for developing coronary heart disease intravenous cyclophosphamide exposure
compared to age-matched controls, after adjusting for corresponding to 13% increased risk of cervical
traditional carcinoma). Therefore, SLE should be regarded as a
CVD risk factors. Traditional CVD risk factors are risk factor for cervical malignancy and high-risk
reinforced by disease-related risk factors, such as HPV infection. We would recommend cervical
circulating prothrombotic antiphospholipid cytology for cancer screening once (EULAR) or
antibodies, antibodies against HDL cholesterol twice (United States Preventive Services Task Force)
interfering with its function, a typical lupus pattern in the first year and then annually, adding HPV
of dyslipidaemia (low HDL cholesterol, high testing to the first year obtained cervical smears and
triglycerides, normal or slightly elevated low density then modifying subsequent screening based on these
lipoprotein (LDL) cholesterol results (cervical cytology screening every 6 months
(LDL-C), and abnormal serum homocysteine for women with detectable HPV DNA and annually
levels) and the proatherogenic effect of systemic for others). Although the efficacy of HPV vaccine
inflammation. Aggressive treatment of dyslipidaemia has not been investigated in patients with autoimmune
(target LDL-C <100 mg/dl (<2.6 mmol/l) and diseases, the EULAR guidelines concluded that HPV
vaccination should be considered for women with
triglycerides <150 mg/dl (<1.7 mmol/l)) is
SLE until the age of 25 years, similar to the
recommended for patients with multiple risk factors,
general population.
especially those with moderate or severe lupus
particularly in the presence of carotid thickening by
ultrasound imaging techniques.
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General management
Prognosis
In patients with SLE, new clinical signs (rashes (B), arthritis (B), serositis (B), neurological manifestations -seizures/psychosis
(B)), routine laboratory (complete blood count (CBC) (B), serum creatinine (B), proteinuria (B) and urinary sediment (B)),
and immunological tests (serum C3 (B), anti-dsDNA (B), anti-Ro/SSA (B), anti-La/SSB (C), anti-phospholipid (B), anti-RNP
(B)), may provide prognostic information for the outcome in general and involvement of major organs, and thus should be
considered in the evaluation of these patients. Confirmation by imaging (brain MRI (B)), and pathology (renal biopsy (B)) may
add prognostic
information and should be considered in selected patients.
Monitoring
New clinical manifestations such as number and type of skin lesions (C) or arthritis (D), serositis (D), and neurological
manifestations (seizures/psychosis) (D), laboratory tests (CBC) (B), immunological tests (serum C3/C4 (B), anti-C1q (B),
anti- dsDNA (B)), and validated global activity indices (D) have diagnostic ability for monitoring for lupus activity and flares,
and may be
used in the monitoring of lupus patients.
Comorbidities
SLE patients are at increased risk for certain comorbidities, either due to the disease and/or its treatment. These
comorbidities include infections (urinary track infections (B), other infections (C)), atherosclerosis (B), hypertension (B),
dyslipidaemias (B), diabetes (C), osteoporosis (C), avascular necrosis (C), malignancies (especially non-Hodgkin
lymphoma) (B). Minimisation of risk
factors together with a high index of suspicion, prompt evaluation, and diligent follow-up of these patients is
recommended.
Neuropsychiatric lupus
Diagnosis
In SLE patients the diagnostic work-up (clinical (A–C), laboratory (B), neuropsychological (C), and imaging tests (B–C)) of
neuropsychiatric manifestations should be similar to that in the general population presenting with the same neuropsychiatric
manifestations.
Pregnancy in lupus
Pregnancy affects mothers with SLE and their offspring in several ways.
a) Mother. There is no significant difference in fertility in lupus patients (C). Pregnancy may increase lupus disease activity
but these flares are usually mild (B). Patients with lupus nephritis and anti-phospholipid antibodies are more at risk of
developing pre- eclampsia and should be monitored more closely (B).
b) Fetus. SLE may affect the fetus in several ways, especially if the mother has a history of lupus nephritis, anti-phospholipid,
anti-Ro and/or anti-La antibodies. These conditions are associated with an increase of the risk of miscarriage (B), stillbirth
(B), premature delivery (B), intrauterine growth restriction (C), and fetal heart block (B). Prednisolone (D),
azathioprine (D), hydroxychloroquine (A), and low dose aspirin (D) may be used in lupus pregnancies. At present
evidence suggests that
mycophenolate mofetil, cyclophosphamide and methotrexate must be avoided (D).
Anti-phospholipid syndrome
In patients with SLE and anti-phospholipid antibodies, low-dose aspirin may be considered for primary prevention of
thrombosis and pregnancy loss (D). Other risk factors for thrombosis should also be assessed. Oestrogen-containing drugs
increase the risk for thrombosis (D). In non-pregnant patients with SLE and anti-phospholipid syndrome-associated
thrombosis, long term anticoagulation with oral anticoagulants is effective for secondary prevention of thrombosis (A). In
pregnant patients with SLE and anti-phospholipid syndrome, combined unfractionated or low molecular weight heparin and
aspirin reduce pregnancy loss and thrombosis and should be considered (A).
Lupus nephritis
Monitoring
Renal biopsy (B), urine sediment analysis (B), proteinuria (B), and kidney function (B) may have independent predictive ability
for clinical outcome in therapy of lupus nephritis but need to be interpreted in conjunction. Changes in immunological tests (anti-
dsDNA,
* The strength of each statement (A–D) is given in parentheses, in bold. A: evidence from randomised controlled trials (RCTs) or
serum
meta- C3) (B)
analysis have without
of RCTs only limited ability
concerns to validity;
for the predict the response
B: as in A but to treatment
with concerns and may
about the be usedofonly
validity as supplemental
the evidence, or evidence
information.
from meta- analysis of epidemiological studies or prospective controlled studies without concerns about the validity of the evidence;
C: evidence from
non-prospective controlled (retrospective cohort, case–control, or cross-sectional) or uncontrolled studies without concerns about the
validity; D: based on evidence from meta-analysis from epidemiological studies, non-randomised controlled studies (prospective or
non-prospective), or uncontrolled studies with major concerns about the validity of the evidence; or no data (expert opinion).
Adapted from Bertsias G, Ioannidis JP, 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;67:195–205.
Table 13 Summary of the EULAR statements and recommendations on the diagnosis and monitoring of systemic lupus erythematosus
(SLE) based on evidence and expert opinion
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18 Evidence-based recommendations In the Euro-Lupus Cohort, 76 out of the 1000 patients

with SLE (8%) developed the disease before the age of
for the management of SLE 14 years. The female: male ratio (7:1) was lower than
The EULAR Task Force on SLE has developed the general SLE population (10:1). In addition, the
recommendations covering the most important aspects clinical and immunological patterns of SLE in childhood
in the management (Bertsias et al 2008). These onset patients differed slightly from the disease in other
recommendations—developed not only for the SLE patients.
specialists but for all internists—were based on a Childhood onset patients were more likely to have
combined research- based evidence approach and severe organ involvement, especially nephropathy, at
expert opinion consensus. The recommendations for presentation. Other major manifestations, such as
the diagnosis and monitoring of SLE are shown in table neurologic involvement, thrombocytopenia and
13. haemolytic anaemia, were also common initial features
in the childhood onset group. However, during the
disease evolution, the pattern was quite similar in
19 Lupus in Europe: the Euro-Lupus childhood onset and adult patients. Interestingly, the
initial diagnosis in the childhood onset group was
Cohort delayed, presumably because doctors are reluctant to
The Euro-Lupus Cohort is composed of 1000 patients diagnose SLE in childhood patients and because
with SLE that have been followed prospectively since typical signs and symptoms are less common. This is
1991. These patients have been gathered by a reflected in a mean 5 year delay in establishing the
European consortium of more than 40 investigators diagnosis of SLE in the childhood onset group.
from seven European countries. The general clinical Although SLE has traditionally been considered a
and serologic characteristics of this cohort at the disease of young women, several reports have
beginning of the study are shown in tables 14 and 15 described SLE in older populations. In the Euro-
(Cervera et al 1993). Lupus Cohort, 90 patients (9%) developed the
disease after the age of 50. Female predominance
was not so pronounced in the older onset group
SLE manifestation Prevalence (%) (5:1). Of interest, the clinical expression of SLE in
Arthritis 84 older patients differed in several aspects from the
disease in young adults. The clinical picture in
Malar rash 58
older-onset best resembles patients with
Fever 52 drug-induced SLE, primary Sjögren’s syndrome, or
Photosensitivity 45 polymyalgia rheumatica. Thus, in the Euro-Lupus
Nephropathy 39
Cohort, typical SLE manifestations, such as malar
rash,
Serositis 36
Raynaud’s phenomenon 34
Neurologic involvement 27 Serological features Prevalence (%)
Oral ulcers 24 Antinuclear antibodies 96
Thrombocytopenia 22 Anti-DNA antibodies 78
Sicca syndrome 16 Anti-Ro (SSA) antibodies 25
Livedo reticularis 14 Anti-LA (SSB) antibodies 19
Thrombosis 14 Anti-RNP antibodies 13
Lymphadenopathy 12 Anti -Sm antibodies 10
Discoid lesions 10 Rheumatoid factor 18
Myositis 9 IgG anticardiolipin antibodies 24
Haemolytic anaemia 8 IgM anticardiolipin antibodies 13
Lung involvement 7 Lupus anticoagulant 15
Subacute cutaneous lesions 6 Table 15 Prevalence of serological features in a series of 1000
Chorea 2 systemic lupus erythematosus patients
Table 14 Clinical manifestations in a series of 1000 European

systemic lupus erythematosus (SLE) patients
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photosensitivity, arthritis or nephropathy, were less decade. These lower frequencies of SLE clinical
common than in the younger patients. In contrast, sicca manifestations could be due to genetic or
syndrome was common. environmental differences between Europeans and
In terms of the effect of gender in the clinical Americans or Asians but could also reflect the effect
expression of lupus, 92 out of the 1000 (9%) of medical care during the study. Of interest, there
patients with SLE were men. A higher prevalence of was a lower frequency of most SLE manifestations
serositis was found in the male patients at during the last
presentation. In contrast, arthritis tended to occur 5 years of this prospective study (1995–2000)
less commonly in men, although the difference was (Cervera et al 2003), compared with the cumulative
not statistically significant. This atypical clinical manifestations during the initial 5 years of the
presentation is relevant because it can lead to a delay study (1990–1995). For example, the frequency of
in diagnosis. During disease evolution, a lower active lupus nephropathy during the last 5 years was
prevalence of arthritis was found in the males. 6.8% compared to a cumulative prevalence of 22.2%
The prevalence of nephropathy, neurological during the initial 5 years of the study (table 16). The
involvement, thrombocytopenia, vasculitis, and lower frequencies in the last 5 years probably reflect
serositis was similar in both groups. No significant the effect of therapy and of medical care during the
immunological differences were found between men study, but may also reflect natural remissions which
and women. may occur with advancing age and the menopause.
The frequencies of the main lupus manifestations Over the past 50 years, survival has improved
during the initial 10 years of the prospective Euro- dramatically in patients with SLE. In the Euro-Lupus
Lupus Cohort are slightly lower than those reported Cohort, at 10 years from entry into the study survival
in several large series from the USA and Asia in the was 92%. The slightly higher survival in this European
last cohort
SLE manifestations 1990–2000 1990–1995 1995–2000

(n=1000) (n=1000) (n=840)* p Value†
No. (%) No. (%) No. (%)
Malar rash 311 (31.1) 264 (26.4) 144 (17.1) <0.001
Discoid lesions 78 (7.8) 54 (5.4) 50 (5.9)
Subacute cutaneous lesions 67 (6.7) 46 (4.6) 21 (2.5) 0.023
Photosensitivity 229 (22.9) 187 (18.7) 112 (13.3) 0.002
Oral ulcers 125 (12.5) 89 (8.9) 61 (7.3)
Arthritis 481 (48.1) 413 (41.3) 240 (28.6) <0.001
Serositis 160 (16) 129 (12.9) 52 (6.2) <0.001
Nephropathy 279 (27.9) 222 (22.2) 57 (6.8) <0.001
Neurologic involvement 194 (19.4) 136 (13.6) 97 (11.5)
Thrombocytopenia 134 (13.4) 95 (9.5) 76 (9.0)
Haemolytic anaemia 48 (4.8) 33 (3.3) 24 (2.9)
Fever 166 (16.6) 139 (13.9) 62 (7.4) <0.001
Raynaud’s phenomenon 163 (16.3) 132 (13.2) 74 (8.9) 0.003
Livedo reticularis 70 (7.0) 55 (5.5) 30 (3.6)
Thrombosis 92 (9.2) 72 (7.2) 41 (4.9) 0.049
Myositis 43 (4.3) 40 (4) 11 (1.3) <0.001
*Number of patients that continued in the study in 1995.

†All p values are a comparison between the frequencies in the 1990–1995 and in the 1995–2000 periods.
Table 16 Clinical manifestations related to systemic lupus erythematosus (SLE) in the Euro-Lupus Cohort during the 10 year prospective
study (1990–2000)
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when compared with the US series may be due to thromboses (27%), and infections (25%) as the main
the predominance of Caucasian patients in the present causes of death in the 10 year observational period.
cohort (97%). Thus, it is known that race influences However, it is important to stress that when the causes
outcome in SLE, and blacks and Hispanic Americans of death during the initial 5 years were compared with
of mestizo or native Indian origin have a poorer those during the ensuing 5 years, active SLE and
outcome. The improved survival of patients with SLE infections (29% each) appeared to be the most common
has been associated with an alteration in the patterns causes during the initial 5 years, while thromboses
of mortality. The Euro-Lupus Cohort showed a (26%) became the most common cause of death during
similar percentage of active SLE (27%), the last 5 years (table 17).
Causes of death 1990–2000 1990–1995 1995–2000

(total = 68) (total = 45) (total = 23)
No. (%) No. (%) No. (%)
Active systemic lupus erythematosus 18 (26.5) 13 (28.9) 5 (21.7)
(SLE)
Multisystem 5 (7.4) 4 (8.9) 1 (4.3)
Renal 6 (8.8) 4 (8.9) 2 (8.7)
Cardiopulmonary 3 (4.4) 3 (6.7) 0 (0)
Haematologic 1 (1.5) 1 (2.2) 0 (0)
Neurologic 3 (4.4) 1 (2.2) 2 (8.7)
Infections 17 (25) 13 (28.9)* 4 (17.4)‡
Bacterial sepsis 15 (22.1) 11 (24.4) 4 (17.4)
Pulmonary 6 (8.8) 4 (8.9) 2 (8.7)
Abdominal 5 (7.4) 4 (8.9) 1 (4.3)
Urinary 4 (5.9) 3 (6.7) 1 (4.3)
Fungal 1 (1.5) 1 (2.2) 0
Viral 1 (1.5) 1 (2.2) 0
Thromboses 18 (26.5) 12 (26.7) 6 (26.1)
Cerebral 8 (11.8) 5 (11.1) 3 (13)
Pulmonary 4 (5.9) 3 (6.7) 1 (4.3)
Coronary 5 (7.4) 3 (6.7) 2 (8.7)
Other 1 (1.5) 1 (2.2) 0 (0)
Malignancies 4 (5.9) 3 (6.7) 1 (4.3)
Breast 1 (1.5) 1 (2.2) 0 (0)
Lung 2 (2.9) 1 (2.2) 0 (0)
Lymphoma 1 (1.5) 1 (2.2) 0 (0)
Gastric bleeding 2 (2.9) 2 (4.4)† 0 (0)
Obstetric 1 (1.5) 1 (2.2) 0 (0)
Suicide 1 (1.5) 1 (2.2) 0 (0)
Surgical 1 (1.5) 1 (2.2) 0 (0)
Accident 1 (1.5) 0 (0) 1 (4.3)
Unknown 14 (20.6) 7 (15.6) 7 (30.4)
*In 6 patients, the cause of death was attributed to infection plus other factors (active SLE in 5 and thrombosis in 1). †In 2
patients the cause of death was attributed to gastric bleeding plus other factors (active SLE in 1 and infection in 1). ‡In 1
patient the cause of death was attributed to infection plus active SLE.
Table 17 Causes of death in the Euro-Lupus Cohort during the 10 year prospective study (1990–2000)
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Summary points
SLE is a multisystem autoimmune disorder with a broad Currently there are no diagnostic criteria for the
spectrum of clinical presentations. disease. The ACR classification criteria may be used for
There is a peak age of onset among women between the late diagnostic purposes but sensitivity—especially early in the
teens and early 40s and a female to male ratio of 9:1. disease—is low. To date, lupus remains a clinical diagnosis
of exclusion
Ethnicity, age at onset, gender, and clinical and immunological
features, especially antiphospholipid antibodies at onset, can The antiphospholipid syndrome may co-exist with SLE and
all influence the prevalence and clinical disease evolution. contribute to morbidity and mortality.
The pathogenesis of SLE is complex and includes genetic, There have been significant improvements in long term
environmental, ethnic, and immunological factors. survival, but patients with SLE still have higher risks of
premature mortality compared to the general population.
Criteria for classification of SLE as well as for describing
central nervous system disorders and the pathologic Factors contributing to mortality include major organ
description of lupus nephritis have been validated. involvement, especially nephropathy, thrombosis, accelerated
atherosclerosis, and an increased risk of cancer
Several systems have been validated for describing disease
activity and the SLICC/ACR criteria are used to describe damage.
erythematosus with neuropsychiatric manifestations:

report of a task force of the EULAR standing committee for
20 Recommended textbooks clinical affairs. Ann Rheum Dis 2010b;69:2074–82.
Wallace D, Hahn BHH, eds. Dubois lupus erythematosus, Bertsias GK, Salmon JE, Boumpas DT. Therapeutic
7th edn. Lippincott Williams and Wilkins, 2007. opportunities in systemic lupus erythematosus: state of
Lahita G, ed. Systemic lupus erythematosus, 5th edn. the art and prospects for the new decade. Ann Rheum Dis
Amsterdam: Elsevier, 2011. 2010a;69:1603–11.
Cervera R, Khamashta MA, Font J, et al. Morbidity and
mortality in systemic lupus erythematosus during a
10-year period. A comparison of early and late
21 SLE: internet sites manifestations in a cohort of 1000 patients. Medicine
http://www.lupus.org (Baltimore) 2003;82:299-308.
http://www.lupusuk.com Cervera R, Khamashta MA, Font J, et al. Systemic lupus
http://www.mayoclinic.com/health/lupus/DS00115 erythematosus: clinical and immunologic patterns of
http://www.lupus.org.uk disease expression in a cohort of 1,000 patients. The
http://www.lupusresearchinstitute.org European Working Party on Systemic Lupus
Erythematosus. Medicine (Baltimore) 1993;72:113–24.
Gladman D, Ginzler E, Goldsmith C, et al. The development
and initial validation of the Systemic Lupus International
22 Key references Collaborating Clinics/American College of
(complete list of references available at Rheumatology damage index for systemic lupus
http://www.eular.org/edu_textbook.cfm) erythematosus. Arthritis Rheum 1996;39:363–9.
Hochberg MC. Updating the American College of
Anon. The American College of Rheumatology Rheumatology revised criteria for the classification of
nomenclature and case definitions for neuropsychiatric systemic lupus erythematosus. Arthritis Rheum
lupus syndromes. Arthritis Rheum 1999;42:599–608. 1997;40:1725.
Bertsias G, Ioannidis JP, Boletis J, et al. EULAR Sánchez-Guerrero J, Uribe AG, Jiménez-Santana L, et al. A
recommendations for the management of systemic trial of contraceptive methods in women with systemic
lupus erythematosus. Report of a Task Force of the lupus erythematosus. N Engl J Med 2005;353:2539–49.
EULAR Standing Committee for International Clinical Urowitz MB, Gladman DD. Measures of disease activity
Studies Including Therapeutics. Ann Rheum Dis and damage in SLE. Baillieres Clin Rheumatol
2008;67:195–205. 1998;12:405–13.
Bertsias GK, Ioannidis JP, Aringer M, et al. EULAR
recommendations for the management of systemic lupus
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Systemic Lupus

‘wolf ’s bite’. In 1846 the Viennese physician Ferdinand von

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‘ iffuse connective tissue disease’ by Klemperer, Pollack

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complement receptors; failure to clear immune

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Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician

Haematologic disorder a. Haemolytic anaemia with reticulocytosis, or

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Descriptor Definition Score

Cranial nerve New onset of a sensory or motor neuropathy involving a cranial 8

Casts Heme, granular or erythrocyte 4

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Item Score Item Score

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LE specific skin lesions LE non-specific skin lesions

disease. The acute butterfly rash should be

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Other rashes (figure 7). Lupus profundus presents as

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Figure 5 Subacute cutaneous lupus

depigmentation can occur on the lips. Nasal ulcers

10.2 Musculoskeletal features

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Figure 8 Jacoud-type arthropathy. Deformities in the hands such

CPK value in the presence of symptoms and signs

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have to be taken. These include expeditious

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Central nervous system includes accelerated, premature atherosclerosis and

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diaphragmatic dysfunction. It can be difficult to 10.8 Haematologic features

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Table 10 An approach to the management of pregnancy in systemic lupus erythematosus

14 Drug-induced lupus following causes: (1) exacerbation of pre-existing

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Agent Risk Agent Risk

Table 11 Drugs reported to induce lupus-like disease and associated autoantibodies

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management of moderate to severe disease. However, 17.2 Morbidity, comorbidities, and

History: review of systems

Disease activity index (at each visit or at major changes in therapy)

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18 Evidence-based recommendations In the Euro-Lupus Cohort, 76 out of the 1000 patients

Table 14 Clinical manifestations in a series of 1000 European

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