Systemic Lupus Erythematosus: Pathogenesis 20 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 1 Introduction ‘wolf’s bite’. In 1846 the Viennese physician Ferdinand von Hebra (1816–1880) introduced the butterfl y metaphor to Systemic lupus erythematosus (SLE) is the prototypic describe the malar rash. He also used the term ‘lupus multisystem autoimmune disorder with a broad spectrum erythematosus’ and published the fi rst illustrations in his of clinical presentations encompassing almost all organs Atlas of Skin Diseases in 1856. Lupus was fi rst recognised as a and tissues. Th e extreme heterogeneity of the disease has systemic disease with visceral manifestations by Moriz Kaposi led some investigators to propose that SLE represents a (1837–1902). Th e systemic form was further established by syndrome rather than a single disease. Osler in Baltimore and Jadassohn in Vienna. Other important milestones include the description of the false positive test for 2 Major milestones in the history of syphilis in SLE by Reinhart and Hauck from Germany (1909); lupus the description of the endocarditis lesions in SLE by Libman Th e term ‘lupus’ (Latin for ‘wolf’) was fi rst used during the and Sacks in New York (1923); the description of the Middle Ages to describe erosive skin lesions evocative of a glomerular changes by Baehr (1935), and the use of the term 476 220_Eular_Fpp.indd0_Eular_Fpp.indd 447676 44/21/2012/21/2012 77:37:54:37:54 PPMM Systemic Lupus Erythematosus: Pathogenesis and Clinical Features ‘diff use connective tissue disease’ by Klemperer, Pollack and disease starts with a preclinical phase characterised by Baehr (1941). Th e beginning of the modern era in SLE was autoantibodies common to other systemic autoimmune the discovery of the ‘LE’ cell by Hargraves, Richmond and diseases and proceeds with a more disease-specifi c Morton at the Mayo Clinic in 1948. 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 3 Epidemiology damage, such as alopecia, fi xed erythema, cognitive Prevalence rates in lupus are estimated to be as high as 51 per dysfunction, valvular heart disease, avascular necrosis, 100 000 people in the USA. Th e incidence of lupus has nearly tendon rupture, Jaccoud’s arthropathy, and osteoporosis. tripled in the last 40 years, mainly due to improved diagnosis Early damage is mostly related to disease whereas late of mild disease. Estimated incidence rates in North America, damage—namely infections, atherosclerosis, and South America, and Europe range from 2 to 8 per 100 000 malignancies—is usually related to complications of per year. Women are aff ected nine times more frequently longstanding disease and immunosuppressive therapy. 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 5 Aetiology and pathogenesis more common in urban than rural areas. Sixty-fi ve per cent Th e aetiology of SLE includes both genetic and of 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% aft er the infl uencing pathogenesis. Th ese factors lead to an age of 55. Men with lupus tend to have less photosensitivity, irreversible break in immunological tolerance manifested by more serositis, an older age at diagnosis, and a higher 1 year immune responses against endogenous nuclear antigens. 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 5.1 Genetic factors nervous system involvement, but greater prevalence of Siblings of SLE patients are approximately 30 times more serositis, pulmonary involvement, sicca symptoms, and likely to develop SLE compared with individuals without musculoskeletal manifestations. 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 4 Natural history and course of thousands of single nucleotide polymorphism (SNP) SLE is a chronic disease of variable severity with a waxing markers (fi gure 2). and waning course, with signifi cant morbidity that can be GWAS in lupus have confi rmed the importance of genes fatal—if not treated early—in some patients (fi gure 1). Th e associated with immune response and infl ammation 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. 477 220_Eular_Fpp.indd0_Eular_Fpp.indd 447777 44/21/2012/21/2012 77:37:55:37:55 PPMM 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 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 the 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 testing the level of signifi cance for defi nitive 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 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. (HLA-DR, PTPN22, STAT4, IRF5, BLK, OX40L, FCGR2A, 5.3 Environmental factors BANK1, SPP1, IRAK1, TNFAIP3, C2, C4, CIq, PXK), DNA Candidate environmental triggers of SLE include ultraviolet repairs (TREX1), adherence of infl ammatory cells to the light, demethylating drugs, and infectious or endogenous endothelium (ITGAM), and tissue response to injury (KLK1, viruses or viral-like elements. Sunlight is the most obvious KLK3). Th ese fi ndings highlight the importance of Toll-like environmental factor that may exacerbate SLE. Epstein– receptor (TLR) and type 1 interferon (IFN) signalling Barr virus (EBV) has been identifi ed as a possible factor in pathways. Some of the genetic loci may explain not only the the development of lupus. EBV may reside in and interact susceptibility to disease but also its severity. For instance, with B cells and promotes interferon α (IFNα) production STAT4, a genetic risk factor for rheumatoid arthritis and SLE, by plasmacytoid dendritic cells (pDCs), suggesting that is associated with severe SLE. One of the key components of elevated IFNα in lupus may be—at least in part—due to these pathways is TNFAIP3, which has been implicated in at aberrantly controlled chronic viral infection. least six autoimmune disorders, including SLE. It is well established that certain drugs induce autoantibodies in a signifi cant number of patients, most of 5.2 Epigenetic effects whom do not develop signs of an autoantibody associated disease. Over 100 drugs have been reported to cause Th e risk for SLE may be infl uenced by epigenetic eff ects drug-induced lupus (DIL), including a number of the newer such as DNA methylation and post-translational biologics and antiviral agents. Although the pathogenesis of modifi cations of histones, which can be either inherited or DIL is not well understood, a genetic predisposition may environmentally modifi ed. Epigenetics refers to inherited play a role in the case of certain drugs, particularly those changes in gene expression caused by mechanisms other agents that are metabolised by acetylation such as than DNA base sequence changes. Th e most well procainamide and hydralazine, with disease more likely to understood type of epigenetic factor is DNA methylation, develop in patients who are slow acetylators. Th ese drugs which plays a role in a variety of human processes, such as may alter gene expression in CD4+ T cells by inhibiting X chromosome inactivation and certain cancers. Previous DNA methylation and induce over-expression of LFA-1 research has also implicated the importance of DNA antigen, thus promoting autoreactivity.