476 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 womens 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 George Bertsias, Ricard Cervera, Dimitrios T Boumpas A previous version was coauthored by Ricard Cervera, Gerard Espinosa and David DCruz Systemic Lupus Erythematosus: Pathogenesis and Clinical Features 20 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. Th e 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 Th e term lupus (Latin for wolf ) was fi

rst used during the Middle Ages to describe erosive skin lesions evocative of a wolf s bite. In 1846 the Viennese physician Ferdinand von Hebra (18161880) introduced the butterfl y metaphor to describe the malar rash. He also used the term lupus erythematosus and published the fi rst illustrations in his Atlas of Skin Diseases in 1856. Lupus was fi rst recognised as a systemic disease with visceral manifestations by Moriz Kaposi (18371902). Th e 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 2 0 _ E u l a r _ F p

p . i n d d 4 7 6 20_Eular_Fpp.indd 476 4 / 2 1 / 2 0 1 2 7 : 3 7 : 5 4 P M 4/21/2012 7:37:54 PM Systemic Lupus Erythematosus: Pathogenesis and Clinical Features 477

disease starts with a preclinical phase characterised by autoantibodies common to other systemic autoimmune diseases and proceeds with a more disease-specifi c clinically overt autoimmune phase (Bertsias et al 2010a). During its course periods of fl ares intercept periods of remission culminating in disease- and therapy-related damage, such as alopecia, fi xed erythema, cognitive dysfunction, valvular heart disease, avascular necrosis, tendon rupture, Jaccouds arthropathy, and osteoporosis. Early damage is mostly related to disease whereas late damagenamely infections, atherosclerosis, and malignanciesis usually related to complications of longstanding disease and immunosuppressive therapy. 5 Aetiology and pathogenesis Th e aetiology of SLE includes both genetic and environmental components with female sex strongly infl uencing pathogenesis. Th ese 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 aff

ected sibling. Th e 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 (fi gure 2). GWAS in lupus have confi rmed the importance of genes associated with immune response and infl ammation diff use connective tissue disease by Klemperer, Pollack and Baehr (1941). Th e 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. Th e 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 aff ected nine times more frequently than men and African American and Latin American mestizos are aff ected much more frequently than Caucasians, and have higher disease morbidity. Th e disease appears to be

more common in urban than rural areas. Sixty-fi ve per cent of patients with SLE have disease onset between the ages of 16 and 55 years, 20% present before age 16, and 15% aft er 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, Raynauds 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 signifi cant morbidity that can be fatalif not treated earlyin some patients (fi gure 1). Th e 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 :160311.

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: 3 7 : 5 5 P M 4/21/2012 7:37:55 PM EULAR Textbook on Rheumatic Diseases 478 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 identifi ed as a possible factor in the development of lupus. EBV may reside in and interact with B cells and promotes interferon (IFN) production by plasmacytoid dendritic cells (pDCs), suggesting that elevated IFN in lupus may beat least in partdue to aberrantly controlled chronic viral infection. It is well established that certain drugs induce autoantibodies in a signifi cant 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. Th ese 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 ( HLA-DR , PTPN22 , STAT4 , IRF5 , BLK , OX40L , FCGR2A , BANK1 , SPP1

, IRAK1 , TNFAIP3 , C2 , C4 , CIq , PXK ), DNA repairs ( TREX1 ), adherence of infl ammatory cells to the endothelium ( ITGAM ), and tissue response to injury ( KLK1 , KLK3 ). Th ese fi ndings 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 Th e risk for SLE may be infl uenced by epigenetic eff ects such as DNA methylation and post-translational modifi cations of histones, which can be either inherited or environmentally modifi ed. Epigenetics refers to inherited changes in gene expression caused by mechanisms other than DNA base sequence changes. Th e 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. Diff erences 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. 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 fi gure (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 th e x-axis according to position with each colour representing a different chromosome. The y-axis represents the signifi cance level (log P value) for the association of each SNP with SLE (ie, comparison between SLE cases and controls). Because of the multiple test ing the level of signifi cance for defi nitive genetic associations is quite high in the range of approximately 510 8 while results between log P values of approximately 57 are considered as associations of borderline signifi cance. 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. 2 0 _ E u l a r _ F

p p . i n d d 4 7 8 20_Eular_Fpp.indd 478 4 / 2 1 / 2 0 1 2 7 : 3 7 : 5 6 P M 4/21/2012 7:37:56 PM