Systemic Lupus Erythematosus: Pathogenesis and Clinical Features

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Systemic Lupus 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
systemic lupus erythematosus (SLE) to inform diagnostic and therapeutic decisions
• Describe and explain the key events in the
pathogenesis of SLE and critically analyse the contribution of genetics, epigenetics, hormonal, and environmental factors to the immune aberrancies found in the disease
• Explain the key symptoms and signs of the
diseases and the tissue damage associated with SLE
• State the classification criteria of lupus and their
limitations when used for diagnostic purposes
• Describe and explain the clinical manifestations
of SLE in the musculoskeletal, dermatological, renal, respiratory, cardiovascular, central

nervous, gastrointestinal, and haematological systems
• Evaluate the challenges in the diagnosis and
differential diagnosis of lupus and the pitfalls in the tests used to diagnose and monitor lupus activity
• Identify important aspects of the disease such
as women’s health issues (ie, contraception and pregnancy) and critical illness
• Outline the patterns of SLE expression in
specific subsets of patients depending on age, gender, ethnicity, and social class
• Classify and assess patients according to
the severity of system involvement and use appropriate clinical criteria to stratify patients in terms of the risk of morbidity and mortality

1 Introduction
Systemic lupus erythematosus (SLE) is the prototypic multisystem autoimmune disorder with a broad spectrum of clinical presentations encompassing almost all organs and tissues. The extreme heterogeneity of the disease has led some investigators to propose that SLE represents a syndrome rather than a single disease.
2 Major milestones in the history of lupus
The term ‘lupus’ (Latin for ‘wolf ’) was first used during the Middle Ages to describe erosive skin lesions evocative of a

‘wolf ’s bite’. In 1846 the Viennese physician Ferdinand von Hebra (1816–1880) introduced the butterfly metaphor to describe the malar rash. He also used the term ‘lupus erythematosus’ and published the first illustrations in his Atlas of Skin Diseases in 1856. Lupus was first recognised as a systemic disease with visceral manifestations by Moriz Kaposi (1837–1902). The systemic form was further established by Osler in Baltimore and Jadassohn in Vienna. Other important milestones include the description of the false positive test for syphilis in SLE by Reinhart and Hauck from Germany (1909); the description of the endocarditis lesions in SLE by Libman and Sacks in New York (1923); the description of the glomerular changes by Baehr (1935), and the use of the term

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‘diffuse connective tissue disease’ by Klemperer, Pollack and Baehr (1941). The beginning of the modern era in SLE was the discovery of the ‘LE’ cell by Hargraves, Richmond and Morton at the Mayo Clinic in 1948.
3 Epidemiology
Prevalence rates in lupus are estimated to be as high as 51 per 100 000 people in the USA. The incidence of lupus has nearly tripled in the last 40 years, mainly due to improved diagnosis of mild disease. Estimated incidence rates in North America, South America, and Europe range from 2 to 8 per 100 000 per year. Women are affected nine times more frequently than men and African American and Latin American mestizos are affected much more frequently than Caucasians, and have higher disease morbidity. The disease appears to be more common in urban than rural areas. Sixty-five per cent of patients with SLE have disease onset between the ages of 16 and 55 years, 20% present before age 16, and 15% after the age of 55. Men with lupus tend to have less photosensitivity, more serositis, an older age at diagnosis, and a higher 1 year mortality compared to women. SLE tends to be milder in the elderly with lower incidence of malar rash, photosensitivity, purpura, alopecia, Raynaud’s phenomenon, renal and central nervous system involvement, but greater prevalence of serositis, pulmonary involvement, sicca symptoms, and musculoskeletal manifestations.
4 Natural history and course
SLE is a chronic disease of variable severity with a waxing and waning course, with significant morbidity that can be fatal—if not treated early—in some patients (figure 1). The

disease starts with a preclinical phase characterised by autoantibodies common to other systemic autoimmune diseases and proceeds with a more disease-specific clinically overt autoimmune phase (Bertsias et al 2010a). During its course periods of flares intercept periods of remission culminating in disease- and therapy-related damage, such as alopecia, fixed erythema, cognitive dysfunction, valvular heart disease, avascular necrosis, tendon rupture, Jaccoud’s arthropathy, and osteoporosis. Early damage is mostly related to disease whereas late damage—namely infections, atherosclerosis, and malignancies—is usually related to complications of longstanding disease and immunosuppressive therapy.
5 Aetiology and pathogenesis
The aetiology of SLE includes both genetic and environmental components with female sex strongly influencing pathogenesis. These factors lead to an irreversible break in immunological tolerance manifested by immune responses against endogenous nuclear antigens.
5.1 Genetic factors
Siblings of SLE patients are approximately 30 times more likely to develop SLE compared with individuals 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) using hundreds of thousands of single nucleotide polymorphism (SNP) markers (figure 2).
GWAS in lupus have confirmed the importance of genes associated with immune response and 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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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, BANK1, SPP1, IRAK1, TNFAIP3, C2, C4, CIq, PXK), DNA repairs (TREX1), adherence of inflammatory cells to the endothelium (ITGAM), and tissue response to injury (KLK1, KLK3). These findings highlight the importance of Toll-like receptor (TLR) and type 1 interferon (IFN) signalling pathways. Some of the genetic loci may explain not only the susceptibility to disease but also its severity. For instance, STAT4, a genetic risk factor for rheumatoid arthritis and SLE, is associated with severe SLE. One of the key components of these pathways is TNFAIP3, which has been implicated in at least six autoimmune disorders, including SLE.
5.2 Epigenetic effects
The risk for SLE may be influenced by epigenetic effects such as DNA methylation and post-translational modifications of histones, which can be either inherited or environmentally modified. Epigenetics refers to inherited changes in gene expression caused by mechanisms other than DNA base sequence changes. The most well understood type of epigenetic factor is DNA methylation, which plays a role in a variety of human processes, such as X chromosome inactivation and certain cancers. Previous research has also implicated the importance of DNA methylation in SLE. Differences in the methylation status of genes may explain, at least in part, the discordance observed in some identical twins that are discordant for SLE. Epigenetic mechanisms may represent the missing link between genetic and environmental risk factors.

5.3 Environmental factors
Candidate environmental triggers of SLE include ultraviolet light, demethylating drugs, and infectious or endogenous viruses or viral-like elements. Sunlight is the most obvious environmental factor that may exacerbate SLE. Epstein– Barr virus (EBV) has been identified as a possible factor in the development of lupus. EBV may reside in and interact with B cells and promotes interferon α (IFNα) production by plasmacytoid dendritic cells (pDCs), suggesting that elevated IFNα in lupus may be—at least in part—due to aberrantly controlled chronic viral infection.
It is well established that certain drugs induce autoantibodies in a significant number of patients, most of whom do not develop signs of an autoantibody associated disease. Over 100 drugs have been reported to cause drug-induced lupus (DIL), including a number of the newer biologics and antiviral agents. Although the pathogenesis of DIL is not well understood, a genetic predisposition may play a role in the case of certain drugs, particularly those agents that are metabolised by acetylation such as procainamide and hydralazine, with disease more likely to develop in patients who are slow acetylators. These drugs may alter gene expression in CD4+ T cells by inhibiting DNA methylation and induce over-expression of LFA-1 antigen, thus promoting autoreactivity.
5.4 Hormonal factors
In murine models, addition of oestrogen or prolactin can lead to an autoimmune phenotype with an increase in


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mature high-affinity autoreactive B cells. Oral contraceptive use in the Nurses’ Health Study was associated with a slightly increased risk of developing SLE (relative risk 1.9 compared to never users). This poses important questions pertaining to the use of oestrogens for oral contraception or as hormone replacement therapy in postmenopausal women. While it is clear that hormones can influence autoimmune development in murine models, the use of oral contraceptives does not increase disease flares in women with stable disease (Sanchez-Guerrero et al 2005). Pregnancy may cause in some cases a lupus flare, but this is not due to an increase in oestradiol or progesterone; in fact, the levels of these hormones are lower in the second and third trimester for SLE patients in comparison with healthy pregnant women.
6 Pathogenesis and pathophysiology
Immune responses against endogenous nuclear antigens are characteristic of SLE. Autoantigens released by

apoptotic cells are presented by dendritic cells to T cells leading to their activation. Activated T cells in turn help B cells to produce antibodies to these self-constituents by secreting cytokines such as interleukin 10 (IL10) and IL23 and by cell surface molecules such as CD40L and CTLA-4. In addition to this antigen-driven T cell-dependent production of autoantibodies, recent data support T cell-independent mechanisms of B cell stimulation via combined B cell antigen receptor (BCR) and TLR signalling. The pathogenesis of SLE involves a multitude of cells and molecules that participate in apoptosis, innate and adaptive immune responses (table 1).
6.1 Pathogenesis: key events
Increased amounts of apoptosis-related endogenous nucleic acids stimulate the production of IFNα and promote autoimmunity by breaking self-tolerance through activation of antigen-presenting cells (figure 3). Once initiated, immune reactants such as immune 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 apoptosisrelated 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
• 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 then deposit and cause tissue injury at sites such as the skin and kidney.
Table 1 Key pathogenic processes, cells and molecules in systemic lupus erythematosus

6.2 Disease mechanisms and tissue damage
Immune complexes and complement activation pathways mediate effector function and tissue injury. In healthy individuals, immune complexes are cleared by Fc and

complement receptors; failure to clear immune complexes results in tissue deposition and tissue injury at sites. Tissue damage is mediated by recruitment of inflammatory cells, reactive oxygen intermediates, production of inflammatory cytokines, and modulation of the coagulation cascade.


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Autoantibody-mediated tissue injury has been implicated in neuropsychiatric SLE (NPSLE), where antibodies reacting with both DNA and glutamate receptors on neuronal cells can mediate excitotoxic neuronal cell death or dysfunction.
Locally produced cytokines, such as IFNα and tumour necrosis factor (TNF), contribute to affected tissue injury and inflammation. These mediators, together with the cells producing them (macrophages, leucocytes, dendritic cells and lymphocytes), are the subject of investigation as potential therapeutic targets in lupus. Recent studies have also highlighted the role of locally expressed factors for the protection of tissues under immune attack. For example, defects in kallikreins may jeopardise the ability of lupus kidneys to protect themselves from injury, PD-1-ligand down-regulates the activity of the infiltrating lymphocytes, and impaired regulation of complement amplifies vascular injury.
Vascular damage in SLE has received increased attention in view of its relationship with accelerated atherosclerosis. Homocysteine and proinflammatory cytokines, such as IFNα, impair endothelial function and decrease the availability of endothelial precursor cells to repair endothelial injury. Pro-inflammatory high density lipoproteins (HDL) and a dysfunction of HDL mediated by antibodies have also been implicated in defective repair of endothelium. Moreover, pathogenic variants of ITAM (immuno-tyrosine activation motif) alter its binding to ICAM-1 (intercellular adhesion molecule 1) and may increase the adherence of leucocytes to activated endothelial cells. Impaired DNA degradation as a result of mutations of the 3’ repair exonuclease 1 (TREX1), and increased accumulation of single stranded DNA derived from endogenous retro-elements in endothelial cells, may activate the IFN-stimulatory DNA response and direct immune-mediated injury to the vasculature.
7 Classification criteria
Criteria for SLE classification were developed in 1971, revised in 1982, and revised again in 1997 (table 2) (Hochberg 1997). These criteria distinguish patients with the disease in question from those without the disease. The American College of Rheumatology (ACR) classification criteria were developed for clinical studies of lupus to ensure that cases reported in the literature do in fact have the disease. In addition to the wide variety of

manifestations, SLE runs an unpredictable course. The dynamic nature of the disease often makes its diagnosis challenging.
Although the ACR classification criteria may also be used as a diagnostic aid, there are several caveats in their use for diagnostic purposes. These criteria were developed and validated for the classification of patients with a longstanding established disease and may exclude patients with early disease or disease limited to a few organs. Thus, in spite of their excellent sensitivity (>85%) and specificity (>95%) for patients with established disease, their sensitivity for patients early in the disease may be significantly lower. Some systems are overrepresented; the mucocutaneous manifestations, for example, are represented with four criteria (photosensitivity, malar rash, discoid lesions, and oral ulcers). All features included in the classification criteria are contributing equally without any weight based upon sensitivity and specificity for each individual criterion. Thus, studies have shown and experience supports that criteria such as objective evidence of renal disease (significant proteinuria, active urine sediment or renal biopsy with evidence of lupus nephritis), discoid rash, and cytopenias are more useful in establishing the diagnosis of lupus than the other criteria. Because SLE is a disease whose course is typified by periodic involvement of one organ system after another, it is apparent that patients must have the disease for years before they fulfil the classification criteria. Among patients referred for lupus to tertiary care centres, two thirds of patients fulfil ACR criteria, approximately 10% have clinical lupus but do not fulfil criteria, and 25% have fibromyalgia-like symptoms and positive antinuclear antibody (ANA) but never develop lupus.
8 Activity indices
Assessing disease activity in SLE is crucial to the physician as it forms the basis for treatment decisions. Disease activity needs to be distinguished from damage as this has important implications for the long term prognosis and the appropriate treatment. Several validated global and organ-specific activity indices are widely used in the evaluation of SLE patients (Urowitz and Gladman 1998). These include the European Consensus Lupus Activity Measure (ECLAM), the British Isles Lupus Assessment Group Scale (BILAG), the Lupus Activity Index (LAI), the National Institutes of Health SLE Index Score (SIS), the Systemic Lupus Activity Measure (SLAM), and the SLE


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Criteria Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurological disorder
Haematologic disorder
Immunologic disorder
Antinuclear antibody

Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring occurs in older lesions
Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
Oral or nasopharyngeal ulceration, usually painless, observed by a physician
Non-erosive arthritis involving two or more peripheral joints, characterised by tenderness, swelling or effusion
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
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
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)
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
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
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 been developed in the context of long term observational studies and have been shown to be strong predictors of damage and mortality, and reflect change in disease activity. Moreover, they have been validated against each other. We recommend the use of at least one of these indices for monitoring of disease activity. In our experience the ECLAM and the SLEDAI (table 3) are more convenient for use in daily practice. Computerised clinical charts that compute several disease activity indices simultaneously have been developed.
Existing disease activity indices have important limitations when used in the context of clinical trials.

For clinical trials, composite end points and responder indices may be more useful, especially for studies in general lupus, as compared to studies for lupus affecting single organs (eg, nephritis). To this end, using composite index (SLE responder index, SRI) investigators in the Belimumab trial were able to show efficacy. The SRI includes improvement in SLEDAI by at least 4 without worsening in BILAG and PGA. The SRI could be adjusted to look for larger treatment effects (for instance, more than 7 or 12 points difference in SLEDAI) similar to what is being used in rheumatoid arthritis (ACR 20, and 50, or EULAR moderate and good response).


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Descriptor Seizure Psychosis
Organic brain syndrome
Cranial nerve Lupus headache Cerebrovascular Vasculitis Arthritis Myositis
Casts Haematuria Proteinuria Pyuria New malar rash Alopecia Mucous membrane Pleurisy Pericarditis Low complement Increased DNA binding Fever Thrombocytopenia Leucopenia

Recent onset. Exclude metabolic, infectious or drug-related causes
Altered ability to function in normal activity due to severe disturbance 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
Altered mental function with impaired orientation or impaired 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
Retinal changes from systemic lupus erythematosus cytoid bodies, retinal haemorrhages, serous exudate or haemorrhage in the choroid, optic neuritis (not due to hypertension, drugs or infection)
New onset of a sensory or motor neuropathy involving a cranial nerve
Severe, persistent headache; may be migrainous
New syndrome. Exclude arteriosclerosis
Ulceration, gangrene, tender finger nodules, periungal infarction, splinter haemorrhages. Vasculitis confirmed by biopsy or angiogram
More than two joints with pain and signs of inflammation
Proximal muscle aching or weakness associated with elevated creatine phosphokinase/aldolase levels, electromyographic changes, or a biopsy showing myositis
Heme, granular or erythrocyte
More than 5 erythrocytes per high power field. Exclude other causes
More than 0.5 g of urinary protein excreted per 24 h. New onset or recent increase of more than 0.5 g per 24 h
More than 5 leucocytes per high power field. Exclude infection
New onset or recurrence of an inflammatory type of rash
New or recurrent. A patch of abnormal, diffuse hair loss
New onset or recurrence of oral or nasal ulceration
Pleuritic chest pain with pleural rub or effusion, or pleural thickening
Pericardial pain with at least one of rub or effusion. Confirmation by ECG or echocardiography
A decrease in CH50, C3 or C4 levels (to less than the lower limit of the laboratory determined normal range)
More than 25% binding by Farr assay (to more than the upper limit of the laboratory determined normal range, eg, 25%) More than 38oC after the exclusion of infection
Fewer than 100 000 platelets Leucocyte count <3000/mm3 (not due to drugs)

Table 3 The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)

Score 8 8
8 8 8 8 4 4
4 4 4 4 4 4 4 4 4 2 2 1 1 1

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Item Ocular (either eye by clinical assessment)
Any cataract ever Retinal change or optic atrophy Neuropsychiatric Cognitive impairment (eg, memory deficit, difficulty with calculation, poor concentration, difficulty in spoken or written language, impaired performance level) or major psychosis Seizures requiring therapy for 6 months Cerebrovascular accident ever (score 2 if >1) Cranial or peripheral neuropathy (excluding optic) Transverse myelitis Renal Estimated or measured glomerular filtration rate <50% Proteinuria >3.5 g/24 h or end-stage renal disease (regardless of dialysis or transplantation)
Pulmonary Pulmonary hypertension (right ventricular prominence, or loud P2) Pulmonary fibrosis (physical and radiographical) Shrinking lung (radiograph) Pleural fibrosis (radiograph) Pulmonary infarction (radiograph)
Cardiovascular Angina or coronary artery bypass Myocardial infarction ever (score 2 if >1) Cardiomyopathy (ventricular dysfunction) Valvular disease (diastolic murmur, or systolic murmur >3/6) Pericarditis for 6 months or pericardiectomy

0, 1 0, 1
0, 1
0, 1 0, 1, 2 0, 1 0, 1
0, 1 0, 1 or 3
0, 1 0, 1 0, 1 0, 1 0, 1
0, 1 0, 1, 2 0, 1 0, 1 0, 1

Item Peripheral vascular Claudication for 6 months Minor tissue loss (pulp space) Significant tissue loss ever (eg, loss of digit or limb) (score 2 if >1 site) Venous thrombosis with swelling, ulceration or venous stasis Gastrointestinal Infarction or resection of bowel below duodenum, spleen, liver or gallbladder ever, for any cause (score 2 if >1 site) Mesenteric insufficiency Chronic peritonitis Stricture or upper gastrointestinal tract surgery ever Chronic pancreatitis Musculoskeletal Muscle atrophy or weakness Deforming or erosive arthritis (including reversible deformities, excluding avascular necrosis) Osteoporosis with fracture or vertebral collapse (excluding avascular necrosis) Avascular necrosis (score 2 if >1) Osteomyelitis Tendon rupture Skin Scarring chronic alopecia Extensive scarring of panniculum other than scalp and pulp space Skin ulceration (excluding thrombosis for >6 months) Premature gonadal failure Diabetes (regardless of treatment) Malignancy (exclude dysplasia) (score 2 if >1 site)

0, 1 0, 1 0, 1, 2 0, 1
0, 1, 2 0, 1 0, 1 0, 1 0, 1
0, 1 0, 1
0, 1 0, 1, 2 0, 1 0, 1
0, 1 0, 1 0, 1 0, 1 0, 1 0, 1

Table 4 The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for systemic lupus erythematosus

9 Chronicity and damage index
The Systemic Lupus International Collaborating Clinics/ American College of Rheumatology (SLICC/ACR) damage index is a validated instrument specifically designed to ascertain damage in SLE (Gladman et al 1996). Damage in SLE may be due to the disease itself or to drug therapy. The

index records damage in 12 organs or systems (table 4). There is no index to measure harms caused by drugs in lupus at present. The change must have been present for at least 6 months and is ascertained clinically or by simple investigations. Studies have shown that the early acquisition of damage is a sign of a poor prognosis.

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LE specific skin lesions Acute cutaneous LE Localised Generalised Subacute cutaneous LE
Annular Papulosquamous (psoriasiform)
Chronic cutaneous LE ‘Classical’ LE (DLE)
Localised Generalised Hypertrophic (verrucous) DLE Lupus panniculitis (profundus) Mucosal LE Lupus tumidus Chilblains lupus

LE non-specific skin lesions
Cutaneous vascular disease Vasculitis
Leucocytoclastic Palpable purpura Urticarial vasculitis
Polyarteritis nodosa-like Papulonodular mucinosis Dego’s disease-like
Atrophy blanche-like Livedo reticularis Thrombophlebitis
Raynaud’s phenomenon Erythromelalgia LE non-specific bullous lesions
Epidermolysis bullosa acquisita Dermatitis herpetiformis-like bullous LE Pemphigus erythematosus
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 cutis

Table 5 Classification of lupus erythematosus (LE) associated skin lesions

10 Clinical features
10.1 Mucocutaneous features
Mucocutaneous involvement is almost universal in SLE with both lupus-specific and non-specific lesions (table 5). Lupus-specific lesions can be further classified as acute, subacute, and chronic lesions.
Acute rashes-malar rash. The classic lupus ‘butterfly’ rash presents acutely as an erythematous, elevated lesion, pruritic or painful, in a malar distribution, commonly precipitated by exposure to sunlight (figure 4). The rash may last from days to weeks and is commonly accompanied by other inflammatory manifestations of the

disease. The acute butterfly rash should be differentiated from other causes of facial erythema such as rosacea, seborrhoeic, atopic, and contact dermatitis, and glucocorticoid-induced dermal atrophy and flushing. Other acute cutaneous lesions include generalised erythema and bullous lesions. The rash of acute cutaneous lupus erythematosus can be transient and heal without scarring, although persistently active rashes may result in permanent telangiectasias.
Subacute rashes. Subacute cutaneous lupus erythematosus (SCLE) is not uniformly associated with SLE. Approximately 50% of affected patients have SLE and about 10% of patients with SLE have this type of skin

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Systemic Lupus Erythematosus: Pathogenesis and Clinical Features