Systemic lupus erythematosus one disease or many?

Systemic lupus erythematosus one disease or many?

Autoimmunity Reviews 11 (2012) 593–595 Contents lists available at SciVerse ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/lo...

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Autoimmunity Reviews 11 (2012) 593–595

Contents lists available at SciVerse ScienceDirect

Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev

Review

Systemic lupus erythematosus one disease or many? N. Agmon-Levin a, M. Mosca b, M. Petri c, Y. Shoenfeld a, d,⁎ a

The Zabludowicz Center for Autoimmune Diseases Sheba Medical Center, Tel Hashomer, Israel Rheumatology Unit, University of Pisa, Italy c Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA d Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune Diseases, Tel-Aviv University, Tel Aviv, Israel b

a r t i c l e

i n f o

Available online 25 October 2011 Keywords: Systemic lupus erythematosus Genetics Environmental factors Classification criteria Personalized medicine

a b s t r a c t Systemic lupus erythematosus (SLE) characterizes by a variety of clinical manifestations and the presence of a wide profile of autoantibodies. This clinical and serological heterogeneity raised the question: is SLE a single disease with varied phenotypes, or a similar phenotype shared by different diseases with diverse pathogenic mechanisms? Herein we debate the clinical, genetic, hormonal and serological differences typically observed in SLE on the one hand, and the numerous similarities between subtypes of this disease on the other. Leading to the conclusion that SLE may be considered not as a single disease but rather as a single syndrome, which defines by a set of signs, symptoms, or phenomena that occur together and suggest a particular abnormality. Additionally, the accumulated knowledge on gene expression pathways, autoantibodies clusters, hormonal and environmental factors associated with SLE may allow a better classification of this syndrome and updating of SLE criteria. This may further allow targeted biologics and other therapies as well as “personalized medicine” to begin. © 2011 Elsevier B.V. All rights reserved.

Contents 1. Introduction . . . . . . . . . . . . . . . . . . 2. Lupus is a group of diseases because…. . . . . . 3. Lupus is one disease with a wide clinical spectrum 4. Conclusions . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune diseases. It characterizes by heterogeneity of clinical manifestations, degrees of severity as well as alternating phases of remission and flares [1]. In the course of SLE, patients may present with arthritis, rashes, serositis, various cytopenias, kidney disease, psychiatric, neurological and other manifestations [2]. This multi systemic disease can be predicted by the presence of specific autoantibodies years before it is clinically overt [3, 4]. In addition several

⁎ Corresponding author at: The Zabludowicz Center for Autoimmune Diseases, Department of Medicine ‘B’, The Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel. Tel.: + 972 3 5308070; fax: + 972 3 5353673. E-mail address: [email protected] (Y. Shoenfeld). 1568-9972/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2011.10.020

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autoantibodies and cluster of autoantibodies were noticeably associated not only with the occurrence of the disease but also with its specific manifestations [5]. The great heterogeneity of SLE raised the debate is it a single disease with varied phenotypes, or a similar phenotype shared by a variety of different diseases with diverse pathogenic mechanisms? One aspect of this debate is the intimate link between SLE and the antiphospholipid syndrome (APS), primarily described by Graham Hughes in a group of patients with SLE [6]. APS is defined by obstetric morbidity and/or recurrent thromboses in the presence of antiphospholipid (aPL) antibodies [6]. Previously, it was noted that patients may exhibit APS manifestations with no characteristic of SLE, and therefore were classified as primary APS (PAPS) whereas the presence of APS concomitantly with SLE was termed secondary APS (SAPS). For years clinicians and scientist have tried to better discriminate PAPS from SAPS. Unlike SLE, PAPS was primarily not

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considered to be a systemic disease. However, in the course of time PAPS was found to be associated with damage to various organs and systems and to evolve into SLE in up to 10% of patients [7]. Moreover, the expression lupus-like APS was coined to define APS patients displaying systemic “SLE features” although SLE criteria are not fulfilled [7–8]. Certain manifestations of SLE such as the presence of anti-nuclear antibodies, complement activation or immune mediated kidney disease was accepted as markers to distinguish this disease from primary APS. In the last decade the presence of anti-nuclear antibodies, hypocomplementemia, non-thrombotic kidney disease and renal failure were all documented in patients diagnosed with PAPS, and the activation of complement was found to be closely related with APS in experimental models [7]. Hence, the concept of SLE–APS spectrum was suggested to support the many similarities between SAPS and PAPS. In the same manner, one may consider SLE itself to be a single heterogeneous disease with a variety of manifestations or a collection of comparable signs and symptoms among patients with apparently different clinical conditions. Thus, herein we shall discuss the clinical and scientific data supporting each of those opposite points of view. 2. Lupus is a group of diseases because… Lupus is already accepted as many diseases similar to other autoimmune/rheumatic conditions. Rheumatoid arthritis is split into seropositive and seronegative varieties. Juvenile idiopathic arthritis has multiple types. Why should SLE be any different? In fact, lupus is already accepted as different diseases: SLE, chronic cutaneous lupus, sub-acute cutaneous lupus, drug-induced lupus and neonatal lupus. As our knowledge advances, we should expect the term SLE to be further subdivided. Genetics indicate that SLE is multiple different diseases. The explosion of new knowledge of the genetic pathogenesis of SLE has been one of the major success stories in SLE in this decade. Before the advent of genome-wide association studies, it was known that certain HLA DR and DQ alleles predisposed to SLE, and, importantly, to autoantibody formation. Family studies helped to identify the role of deficiencies of early complement components [9]. This then led to work on the role of complement in immune complex processing and in apoptosis [10]. The newly identified SLE genes map into distinct pathogenetic pathways [11]. One of the most interesting has been the Type I interferon pathway (toll-like receptor) [12]. SLE patients with Type I interferon alpha signature are more likely to have active serology (low complement, high anti-dsDNA) and leukopenia [13]. Other gene expression pathways include immune-complex processing and immune signal transduction. SLE varies between male and female affected. In general, SLE patients – both female and male – tend to be hypoandrogenic. In women, this is most commonly identified as low levels of DHEA-S. Male SLE, though, differentiates from female SLE, in that it is a worse disease (more lupus nephritis) with a worse outcome (more renal failure, myocardial infarction, and death). These differences, though, do not suggest that male and female SLE are different diseases; rather, they show the importance of hormonal pathways on disease expression. Autoantibody clusters and different disease patterns are typically observed in SLE. HLA-DR and DQ polymorphisms determine the type of autoantibodies produced [14]. We have shown that autoantibody clusters then predict some SLE phenotypes (Table 1). The three clusters are: anti-Smith and anti-RNP (lupus nephritis), anti-DNA with anti-Ro and La (Sjogren's) and anti-DNA with antiphospholipid antibodies (thrombosis) [15]. Genetics likely even more profoundly affect clinical phenotype. SLE may be like Ehlers–Danlos, with multiple genetic subtypes with different manifestations [16]. Although SLE is known as a disease with a flare pattern — that is only half the story! Half of SLE patients have a pattern of chronic

Table 1 Comparison of clinical features by autoantibody clusters. Sm/RNP

DNA/Ro/La

DNA/LA/aCL

Proteinuria Nephrotic Less hematologic

Sjogrens

Fewer African-Americans Less malar/discoid Thrombosis

activity [17]. In patients with the flare pattern the average patient flares once a year. Those with anti-dsDNA or low complement are twice as likely to flare over the next year (but serologies don't predict who will flare the next month). Are these disease patterns different diseases? In multiple sclerosis, the relapsing remitting pattern and the chronic progressive pattern, require different treatments. In conclusion it is inevitable that SLE will be subtyped into many parts — driven by new knowledge on genetics and gene expression pathways. This will allow targeted biologics and “personalized medicine” to begin. To some extent, the answer to the question “Is SLE one disease or many” is semantic. The correct answer is “Depending on genes, environmental factors and hormones, different phenotypes may arise requiring different treatment approaches.” Last but not the least the Systemic Lupus International Collaborating Clinics have developed and validated a new set of classification criteria, updating the American College of Rheumatology 1983 criteria [10,11]. These new criteria extend the definition of the clinical criteria to reflect new clinical knowledge. Updated criteria are essential in the accurate description of patients in clinical research — how else can we explore the genotype to phenotype connection?

3. Lupus is one disease with a wide clinical spectrum because… Systemic lupus erythematosus (SLE) is characterized by a wide range of clinical manifestations and autoantibodies and virtually any manifestation is considered to be possible in patients with SLE [18,19]. As was once declared in the Greenwald's law of lupus: “anything happening to a patient with SLE which is not immediately otherwise explicable will automatically be blamed on the lupus, regardless of pathophysiologic validity” [20]. As clinicians we all see SLE patients presenting with very different clinical manifestations during their disease course and very often we could say that each patient “has his/her own disease”. Indeed there are patients who never develop kidney or neurological involvement, while others have a disease course characterized mainly by the presence of glomerulonephritis or neurological involvement. However, although there are different disease expressions between patients, during the disease course patients accrue the same clinical manifestations. Data from the Eurolupus cohort, the LUMINA study and other cohorts show that new organ involvement can be observed over time [21]. Up to 90% of SLE patients will develop articular and cutaneous manifestations during their disease course, late onset glomerulonephritis has also been described [22,23]. Therefore, it is possible to identify a set of signs and symptoms that tends to occur together and which reflects the presence of a particular disease. Although antibody clustering is important in identifying subgroups of disease, refining lupus prognosis and guiding the management of the disease, autoantibodies are not mutually exclusive [15,24]. In addition autoantibodies accrue at disease onset and during the disease course [5]. Finally, although certainly genetic differences play a role in determining disease phenotypes, available data do not give yet the fingerprint of different SLE diseases. Risk alleles explain only between 5 and 15% of the whole genetic contribution to the disease [25]. Therefore, it is plausible that the complex interplay of different environmental and genetic factors can determine different clinical expressions not only

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among patients but also in the life of a single patient [26]. As an example, different infectious agents have been related with the development of disease specific autoantibodies and clinical manifestations; in SLE high titers of rubella resulted associated with psychosis or depression, whereas high titers of EBV antibodies have been correlated with skin and joint manifestations [26]. This could be one explanation for the variability of SLE clinical picture over time. In conclusion, although some data suggest that SLE could be depicted as a group of diseases with different genetic background, mechanisms, clinical manifestations, prognosis and therapeutic approach, observations from our patients allow finding commonalities among patients that support the hypothesis of a single disease with a heterogeneous clinical picture. 4. Conclusions Taking it all together, it seems that the “truth” stays in between these opposite points of view, and SLE is not a single disease but rather a single syndrome. A syndrome is defined by a set of signs, symptoms, phenomena or characteristics that are known to occur together and suggest a particular abnormality. So, that the presence of one or more of those features alerts the physician to the possible presence of the others. Syndromes tend to have a range of possible etiologies or diseases that could create such a set of circumstances, usually without a known cause. In other words, on the one hand SLE encompasses diverse clinical presentation that may involve only one organ (i.e. SCLE) or manifest as a multi system disease, it differs between genders and by pattern of relapses and remissions. SLE is a complex genetic condition that cannot be explained by a single mutation or even simple genetic alterations. On the other hand it is a single syndrome with a typical set of symptoms present in up to 90% of patients (i.e. articular and cutaneous manifestations) and although more than 100 autoantibodies have been described in SLE almost 100% of patients will demonstrate anti-nuclear antibodies. Moreover, the presence of one or more serological or clinical characteristics do alert physicians to the possibility of other manifestations associated with this syndrome. Last but not the least, although treatment of dissimilar manifestation poses a challenge to SLE specialists and many times requires an individualized approach, for most SLE patients a very similar and meticulous follow up as well as preventive and therapeutic approaches are needed. Take-home messages • SLE is not a single disease but rather a single syndrome characterized by a variety of clinical manifestations and a wide profile of autoantibodies. • The newly identified SLE genes map shed some light on the different subtypes of SLE although currently risk alleles explain only between 5 and 15% of the whole genetic contribution to this syndrome. • The complex interplay of different environmental, hormonal and genetic factors can determine different clinical expressions of SLE. • The accumulated knowledge on SLE genetics, serology, hormonal and environmental influences may allow better classification of SLE subtypes and updating of SLE criteria, which will enable a “personalized medicine” approach to begin.

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