Eur J Clin Microbiol Infect Dis DOI 10.1007/s10096-014-2098-7
REVIEW
Infections and systemic lupus erythematosus S. Esposito & S. Bosis & M. Semino & D. Rigante
Received: 9 February 2014 / Accepted: 20 March 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that presents a protean spectrum of clinical manifestations, and may affect any organ. The typical course of SLE is insidious, slow, and progressive, with potential exacerbations and remissions, and even dramatically acute and rapidly fatal outcomes. Recently, infections have been shown to be highly associated with the onset and/or exacerbations of SLE, and their possible causative and/or protective role has been largely emphasized in the medical literature. However, the etiopathogenesis of SLE is still obscure and far from being completely elucidated. Among infections, particularly Epstein–Barr virus (EBV), parvovirus B19, retrovirus, and cytomegalovirus (CMV) infections might play a pivotal pathogenetic role. The multifaceted interactions between infections and autoimmunity reveal many possibilities for either causative or protective associations. Indeed, some infections, primarily protozoan infections, might confer protection from autoimmune processes, depending on the unique interaction between the microorganism and host. Further studies are needed in order to demonstrate that infectious agents might, indeed, be causative of SLE, and to address the potential clinical sequelae of infections in the field of autoimmunity.
S. Esposito (*) : S. Bosis : M. Semino Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Commenda n. 9, 20122 Milano, Italy e-mail: [email protected] D. Rigante Institute of Pediatrics, Università Cattolica Sacro Cuore, Rome, Italy
Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that may affect any organ, presenting a protean spectrum of clinical manifestations. The global incidence of SLE is 6–35 new cases per 100,000 per year, with a higher frequency among women than men (90 % of patients are women at reproductive age) [1]. In Northern Europe, the prevalence rates of SLE range from approximately 40 cases per 100,000 white persons to more than 200 per 100,000 among blacks. In the United States, the prevalence rates vary between 3.2 and 250 per 100,000 in different ethnic groups [2–12]. This disease is rare in Africa, though common in African descendants around the world. Specifically, both the incidence and prevalence rates in people of African or Asian background are approximately 2–3 times higher than in the white population; moreover, the disease is more common in Aboriginal Australians and some Native American groups of Canada and the United States. SLE can occur at any age, but it manifests more frequently after 5 years of age, with increased prevalence after the first decade [7, 13, 14]. The incidence and prevalence rates of SLE in adults are considerably higher than in childhood (less than 1 per 100,000 in children under 16 years old in Europe and North America) [2]. At the molecular level, the disease is characterized by a persistent inflammatory state that is detrimental for multiple organs, including skin, joints, vessels, kidneys, serous membranes, central nervous system, and blood. Such chronic damage is due to both immune dysregulation and hyperproduction of different autoantibodies and immune complexes. The clinical manifestation is characterized by ethnicity, gender, age, and socioeconomic factors [1, 15, 16]. The diagnosis of SLE is based on the criteria established from the American College of Rheumatology (ACR), and the more recent Systemic Lupus International Collaborating Clinics classification criteria, drafted in 2012 [17, 18]. These criteria include the
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presence of dermatologic signs, arthritis, and serositis, variably combined with renal, neurologic, and hematologic disorders. Additional diagnostic criteria are SLE-typical immunologic abnormalities, such as antinuclear antibodies (80–90 % of patients), double-stranded DNA-directed autoantibodies (58–70 % of patients), and antibodies directed to other nuclear antigens, such as histones and small nuclear ribonucleoproteins (in a minor group of patients). Four or more criteria (including at least one clinical and one immunological) are necessary for the diagnosis of SLE. Criteria can be satisfied either serially or simultaneously, during any interval of observation, and in the absence of any another explanation in the patient’s clinical picture [17, 18]. The typical course of SLE is insidious, slow, and progressive, and presents cycles of remission and acute phases, which can potentially and rapidly become fatal. The classical symptoms at the onset or during the exacerbation of the disease are fever, fatigue, anorexia, myalgia, and weight loss, all variously intertwined with specific organ-related inflammatory signs [4, 5]. Because of the fact that the overall outcome is highly variable, ranging from remission to death, the long-term prognosis still remains poor. In recent years, the life expectancy for subjects with SLE has greatly improved, nowadays reaching a 15-year survival rate of 80 % [2, 6]. Pediatric SLE (starting at an age less than 16 years) is usually more aggressive than adult SLE, often severely involving major organs, including the kidneys and central nervous system. Moreover, SLE in childhood is associated with increased mortality risk and reduced remission rates. Major causes of death include renal disease, severe disease flares with significant organ damage, and infections [3, 6]. The etiology and pathogenesis of SLE remain still unraveled. It is believed that SLE represents a complex multifactorial disease arising from a combination of genetic susceptibility, hormonal, and environmental factors (including infections, ultraviolet radiation, medications, drugs, and chemicals), which lead to the production and perpetuation of aberrant autoimmune responses. Recently, infections have been shown to be highly associated with the onset and/or exacerbations of SLE, and their causative and/or protective role has been largely emphasized in the medical literature [19–22]. The aim of this review was to screen the medical literature of the last 15 years and investigate the role of infectious agents in the pathogenesis of SLE.
Infections and autoimmunity Host defense against microbial agents are based on the ability of the immune system to distinguish “self” from “non-self” molecules. In patients with SLE, such ability is lost, and autoantibodies (SLE-specific and/or typical of different rheumatologic diseases) are found in the blood. The reason for the
presence of these autoantibodies is still under debate; however, they are useful biomarkers for SLE diagnosis. It has been reported that aberrations of the physiological and protective processes of the immune system may occur during viral, bacterial, parasitic, or fungal infections in genetically prone subjects [20, 21]. In particular, the association between infections and autoimmunity has been a topic of discussion among researchers for a long time, and many theories have been suggested to explain the autoreactivity observed in some individuals. Different etiopathogenetic mechanisms have been associated with the activation of autoreactive T and B cells, and it has been hypothesized that these mechanisms are mediated by diverse infectious agents. For example, molecular mimicry is one of these, and it is based on the activation of autoimmune responses by microbial peptides that possess a structure similar to human self-antigens. A variety of viruses and bacteria can produce superantigens that bind the variable domain of T cell receptors and a wide variety of major histocompatibility complex (MHC) class II molecules. This process activates a large number of T lymphocytes with different antigenic specificity, and also induces autoimmune reactions. The enhanced presentation of autoantigens by antigen-presenting cells at the inflammatory site could be followed by the priming of large numbers of T cells. This process of “epitope spreading” might contribute to the development of autoimmune responses. Another suggested mechanism, known as “bystander activation”, is characterized by the increase of cytokine production, which induces the expansion of previously activated T cells within the inflammatory site. Another possibility is that lymphotropic viruses might activate lymphocytes, causing increased production of antibodies and circulating immune complexes, which might damage tissues and organs of the host. Dysregulation of the apoptotic pathway in host cells might also be a possible mechanism, either by exposing nuclear material to the immune system or by causing the production of autoantibodies against nuclear structures. Finally, an insufficient clearance of infectious agents and the absence or suboptimal functioning of C4 and/or C1q complement system proteins, which has been observed in patients with immunodeficiencies, might induce autoreactive T and B cell responses. Recent data have shown that altered expressions of particular microRNAs from infected B lymphocytes might cause the production of autoantibodies [22–25]. Moreover, it has been demonstrated that many viruses induce the expression of type 1 interferon (INF) genes (INF1 and other INF-related cytokines); this mechanism, known as “interferon signature”, has been shown to exert a relevant role in many autoimmune diseases [26, 27]. Other recent studies have demonstrated the role of hypomethylated bacterial and viral DNA in inducing immune changes, similar to those observed in patients with SLE [28].
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Specifically during childhood, the developing immune system might be vulnerable to external factors, such as infectious agents. Autoimmunity might be triggered through the cumulative effect of repeated infections, which might be clinically apparent, paucisymptomatic, or asymptomatic [29–31]. Clinical manifestations in SLE are closely related to the presence of specific autoantibodies, which can be induced by particular infectious agents. In particular, researchers have shown that high IgM titers against rubella virus were associated with psychosis or depression among patients with neuropsychiatric SLE [32]. Other authors have demonstrated that high titers of Epstein–Barr virus (EBV) antibodies were correlated with skin and joint SLE manifestations [33]. More recent studies have also revealed that infections might induce regulatory CD4+/CD25+ T cells, which might suppress host immune responses against self or non-self molecules. All these findings have suggested that infections might play a direct role in the overall regulation of immunity, either protecting from or facilitating the onset of the autoimmune disease [34–37].
Viruses and pathogenesis of systemic lupus erythematosus Reports associating viral infections and SLE in the medical literature are copious [38]. EBV has been suggested for a long time as a potential trigger of SLE. Since 1971, many efforts have been directed to finding a correlation between EBV and autoimmune diseases. Studies in this direction have been conducted on SLE patients that had higher anti-EBV antibody titers compared to healthy subjects [39, 40]. Some studies have reported a prevalence of 99 % of EBV infection in young SLE patients, compared with 70 % prevalence in the control group [41, 42]. Specifically, a study published in 2001 (192 SLE patients) demonstrated that all but one had been exposed to EBV, suggesting the etiological contribution of this virus [43]. SLE patients compared to healthy controls have also been shown to possess elevated titers of anti-EBNA-1 and EBV-VCA IgA, as well as EBV-EA/D, EBV-EA/R IgG and IgA [1]. Moon and coworkers have shown that EBV load (measured by real-time polymerase chain reaction, PCR) in the sera from SLE patients was increased by 15- to 40-fold compared to control subjects. These results suggested that EBV has an active lytic cycle with high viral replication in SLE patients [44, 45]. Moreover, it has been hypothesized that EBV-infected B cells might also express virus-encoded antiapoptotic molecules, becoming, therefore, resistant to apoptosis [46]. Several groups have demonstrated that the T cells increasing INF production (mediated by EBV) is another mechanism that induces autoimmunity [19, 47–49]. Repeated or re-activated EBV infection, which results in increased EBV IgA and IgG seroprevalence, may be also associated with SLE [50]. Different EBV antigens can exhibit
either structural, molecular, or functional mimicry with SLE antigens or other critical immune-regulatory components. Immunocompetent subjects, when infected by EBV, show little or no EBV-mRNA expression; in contrast, SLE patients have abnormal expression of four viral mRNAs (BZLF-1, LMP-1 and 2, EBNA-1) in their peripheral blood mononuclear cells (PBMCs), indicating an active replication or reactivation of the virus in these patients. Evaluating the levels of EBV mRNA in PBMCs, researchers have found a 1.7-fold increase of BCRF-1, EBNA-1, and LMP-2 mRNAs in SLE patients compared to controls. All these findings lead to the conclusion that keeping control of the EBV infection seems to be difficult in patients with active SLE [1]. In the last several years, studies on human endogenous retroviruses (HERVs) have led to the conclusion that HERVs are potential and very important contributors of several autoimmune diseases, including SLE. In this regard, several groups have shown that HERVs were first integrated into the human genome 30–40 millions years ago, therefore, being the possible molecular link between human genome and environmental factors in SLE pathogenesis. According to these studies, HERV-encoded proteins should be considered as self-antigens, and should be tolerated by the host’s immune system (though they may trigger the breakdown of immunologic tolerance) [51–53]. HERVs might also affect the expression of genes regulating both the immune response and acquired tolerance [54]. In addition, autoantibodies to an endogenous retroviral element-encoded nuclear protein autoantigen, HRES-1, are detectable in a distinct subset of patients with SLE [55]. The existence of transfusion-transmitted viruses (TTVs), which are characterized by high genetic diversity, have recently been discovered. Their prevalence is higher in SLE patients compared to healthy subjects. Both the higher TTV prevalence and the molecular mimicry with the HERV-encoded nuclear proteins might contribute to the generation of antinuclear antibodies, abnormal T and B cell functions, and selfreactivity in SLE patients [40]. HTLV-1 and HIV-1 retroviruses have also been implicated in the pathogenesis of SLE [56]. Specifically, either dysregulation of the apoptotic mechanism and a shift from a T-helper type 1 (Th1) towards a T-helper type 2 (Th2) cytokine profile has been observed in SLE and HIV-infected patients [57]. Moreover, both types of patients probably share a common mechanism mediating the subversion of apoptosis and production of autoantibodies [52, 58]. A variety of rheumatologic manifestations, mainly rheumatoid arthritis, systemic vasculitis, and SLE, can be encountered in the course of parvovirus B19 infections. Parvovirus infections might be accompanied by transient subclinical autoimmunity, which also mimics or exacerbates SLE in predisposed individuals [59]. Similarities in both clinical and serological parameters following parvovirus infection and SLE at the
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onset may lead to a less accurate diagnosis between these two conditions. Indeed, parvovirus B19 infection mimicking SLE usually fulfills less than four ACR criteria for SLE; in addition, it rarely includes hemolytic anemia, cardiac or renal abnormalities, and it is usually associated with short-lived low titers of autoantibodies [60]. Several studies have also demonstrated a correlation between cytomegalovirus (CMV) infection and SLE. The presence of anti-CMV IgM or CMV-DNA has been detected in patients with initial symptoms of SLE, showing the hypothetical etiological role of the virus [61, 62]. In particular, CMV infections have been associated with the “vascular” SLE, showing more frequently Raynaud’s phenomenon and less frequently typical kidney involvement [63]. The relationship between hepatitis C virus (HCV) and SLE has not yet been defined. Some studies have demonstrated a significantly higher prevalence of HCV infection among SLE patients compared to healthy controls [64], but this correlation has not been confirmed [65, 66]. Among RNA viruses, C-type oncornaviruses have been supposed to be associated with SLE. However, although extensive studies have been conducted, the presence of C-type oncornaviruses in lymphoblastoid cell lines harboring endogenous EBV, derived from patients with active SLE, has not yet been demonstrated. In this respect, other studies have showed a non-specific increase in the titer of antibodies against measles and parainfluenza type 1 in patients with SLE [44]. However, a relevant role of these agents in triggering the onset of SLE has not been suggested so far.
The relationship between bacteria and systemic lupus erythematosus Bacterial infections might also play a role in the development of SLE. The inflammation triggered by any bacteria induces cellular damage and increases the presence of cellular debris, activating B lymphocytes, or promoting the release of autoantibodies [27, 67]. The presence of a bacterial infection triggers the immune system through specific products, such as bacterial lipopolysaccharides or nucleic acid-containing immune complexes. Pathogen-associated molecular patterns (PAMPs) interact with Toll-like receptors (TLRs) and nonTLR internal receptors of antigen-presenting cells, monocytes, and B and T lymphocytes. The binding of TLRs induces plasmacytoid dendritic cells to release interferon (IFN), leading to the production of proinflammatory cytokines and destabilizing innate immunity processes [44, 68, 69]. Recent clinical studies have placed new emphasis on the role of TLRs, specifically TLR-7 and TLR-9, in the promotion of autoantibody production. Pharmacologic modulation of TLRdirected pathways might offer new additional therapeutic approaches for the treatment of SLE [70].
Parasites and development of SLE Parasitic infections may induce variable immunomodulatory effects. The relationship between parasitic infections and autoimmunity remains to be elucidated [71]. There is still no definite agreement on parasitic involvement in the pathogenesis of SLE, but a possible link between Toxoplasma gondii and rheumatoid arthritis has recently been proposed [72].
The protective effect of infectious agents from autoimmune processes It has been demonstrated that some infectious agents have a protective rather than a causative role towards the development of SLE [32]. The beneficial effects of viral, parasitic, and fungal infections have been explained to derive from a shift toward a more predominant Th-2 immunological phenotype [72]. Based on this approach, infections might confer a generic protection from autoimmunity; therefore, the recent increase in the incidence of autoimmune diseases in children of Western countries would have been related to the theory of a reduced infectious pressure, due to improved hygiene and sanitary conditions [73]. Furthermore, animal models provide evidence that various autoimmune diseases are suppressed by helminth infections [74]. Infections with Plasmodium falciparum, the protozoan causing the most severe form of malaria, are believed to generate a lower risk to develop SLE [75]. This hypothesis is reflected in the observation that, although people of African descent have higher rates of SLE than Caucasians, the prevalence of SLE in Africa is low, particularly when associated with the presence of malaria [74–76]. Animal models suggest a protection for SLE nephropathy due to Toxoplasma gondii infection [34, 77]. Schistosoma mansoni and japonicum have also been related to protective effects towards autoimmune diseases [78]. Infections could also be protective for SLE by other mechanisms, such as antigenic competition, which would induce decreased responses against self-antigens [79, 80]. Bacteria and viruses could also protect against autoimmune diseases acting on TLRs; the binding between pathogens and TLRs would trigger the production of cytokines that could downregulate autoimmune responses [80]. Helicobacter pylori seronegativity has also been related to an increased risk of development of SLE, suggesting, again, that this pathogen might exert a protective role [81, 82]. Finally, hepatitis B virus (HBV) has been hypothesized as having a protective role because of the lower prevalence of anti-HBV antibodies in SLE patients compared to healthy subjects. All these data confirm the immunomodulatory effects of HBV infection, probably mediated by IFN production,
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which might protect an infected subject from the pathogenesis of autoimmune diseases, including SLE [83].
Genetic predisposition to systemic lupus erythematosus and infections The primary involvement of genetics in SLE was formerly shown by the high concordance rate in monozygotic twins (approximately 25 %) compared with dizygotic twins (only 2 %) [84]. However, genetic risk factors for SLE are complex and still not well established. These include complement and mannose-binding lectin (MBL) deficiency, impaired IFN release, and STAT4 protein (a transcription factor belonging to the Signal Transducer and Activator of Transcription protein family) production [22]. Immune deficiency might result in insufficient clearance of exogenous pathogens during infections, therefore, increasing the risk of autoimmunity [44, 85, 86]. In addition, different genes located in the human leucocyte antigen (HLA) locus, and involved in the regulation of the immune system, have been associated with SLE [22, 84]. Susceptibility loci on HLA-DR2 and two non-MHC immune regulatory genes (CTLA and PTPN22) have been related to the risk of SLE development [87]. In addition, the innate immune system has also been suggested to have a role in the autoimmune response, as proved by recent studies on TLR-7 and TLR-9 [70, 88]. Although several studies suggested that the interaction of genetic factors with infectious agents may have a strong role in autoimmunity, this topic is still controversial and further research is needed in order to better understand their dynamic interplay. Finally, recent studies have indicated that a peculiar genetic background may increase the risk of serious infections in SLE. Patients with MBL deficiency, associated with homozygous MBL variant alleles, have been reported to be at increased risk of infections. SLE patients homozygous for MBL variant alleles had a 4-fold increase in the incidence of infections [89]. Furthermore, it has been shown that at least one-third of SLE patients with C1q deficiency may suffer from recurrent bacterial infections, including otitis media, meningitides, and pneumonia [90].
Vaccinations and systemic lupus erythematosus There is plenty of medical literature reporting that SLE might be triggered by vaccinations. The existing data do not link directly the vaccines and the autoimmune phenomena in a causal relationship; nevertheless, a temporal connection has been described. Bacterial and viral components, or adjuvants of vaccines, have been associated with SLE onset or flare-up. In particular, it has been described that five healthy patients
developed SLE 2–3 weeks after immunization by a combination of vaccines for typhoid, influenza, meningococcal, tetanus toxoid, measles, mumps, and rubella [91]. Several case reports have also associated hepatitis B vaccine with SLE, but, unfortunately, no studies have ascertained any causal relationship. Data on the safety and efficacy of this vaccination for SLE patients have not yet been established [92]. Associations between influenza vaccination and SLE are rare; however, the safety and efficacy of this vaccine have been clearly proven in patients with SLE [93]. Finally, more than 10 years ago, Hidalgo-Tenorio and colleagues have demonstrated that pneumococcal vaccination is not associated with substantial changes in the evolution of SLE [94].
The risk of infections in systemic lupus erythematosus Despite the improvement in the management of SLE in recent years, infections represent a leading cause of morbidity and mortality for these patients. The common sites of infections are respiratory airways, the urinary tract, soft tissue, and skin. Bacteria are the most commonly implicated agents, followed by viruses and fungi. Among Gram-positive bacteria, Streptococcus pneumoniae is the most common cause of respiratory tract infections, while Staphylococcus aureus causes skin, soft tissue, bone, and joint infections. Gramnegative bacteria such as Escherichia coli are most commonly involved in urinary tract infections. Also, Klebsiella pneumoniae and Pseudomonas spp. are frequent causes of infections in SLE patients [95, 96]. Pneumococcal invasive soft tissue infections, such as cellulitis and fasciitis, are uncommon [97]. Septicemia has been described in patients with SLE, mainly caused by Staphylococcus aureus, Escherichia coli, and Salmonella spp., and associated with poor long-term outcomes [98]. The incidence rate of tuberculosis (TB) is higher in SLE patients, depending on the specific geographical area. In this regard, the prevalence of TB for SLE patients in endemic areas is 5 % [99]. Patients with SLE are also susceptible to opportunistic infections, but non-tuberculous mycobacterial infections have also been described. These infections tend to develop later in the course of the disease compared to those caused by Mycobacterium tuberculosis [100]. Viral infections commonly reported in SLE patients are mostly related to varicella-zoster virus, CMV, and human papillomavirus (HPV). Severe and atypical manifestations caused by CMV have been described, mostly with respiratory or gastrointestinal symptoms and SLE flare like manifestations [101]. Some studies have also demonstrated a higher risk of hepatitis B re-activation in SLE patients, even if this
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situation has been mostly reported in patients with lymphoma [102]. Among fungal infections, those from Candida spp., Pneumocystis jirovecii, and Cryptococcus neoformans are frequently reported in patients with SLE. Common manifestations of Cryptococcus neoformans are meningitis and pneumonia, while Pneumocystis jirovecii and Candida albicans lead to severe pulmonary and genitourinary or gastrointestinal tract infections, respectively [103]. The higher rate of infections in patients suffering from SLE can be explained by different causes. Primarily, they can be caused by immune system dysfunction, which involves phagocytes activity, chemotaxis, and the identification of exogenous pathogens; secondarily, by cytokine production and pathogen clearance, which can lead to a reduced ability to respond to infections; finally, by neutropenia or lymphopenia, resulting from a dysfunctional macrophage–monocyte system. Hypogammaglobulinemia and impaired complement function can also be found in SLE subjects, justifying the vulnerability to infections of these patients [104]. The risk of infections is significantly associated with the disease activity, particularly with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), a global score index developed for the assessment of SLE activity [105].
treatment of severe and refractory manifestations of SLE. Related side effects have included higher risks of infections (mild and severe), mostly from pneumonia or sepsis due to bacterial pathogens; however, it has been demonstrated that these tend to occur especially within the first 6 months of administration [104, 107]. The efficacy and safety of belimumab (a human monoclonal antibody that inhibits B-cell activating factor, also known as B-lymphocyte stimulator) in SLE has been demonstrated in two randomized controlled studies. Data have shown that serious infections are reported in 8 % of adult patients with SLE [108]. Antimalarials drugs, prescribed for cutaneous or mild articular manifestations of SLE, have been shown to be protective from parasitic and also viral, fungal, and bacterial infections in SLE subjects [108]. Their use has allowed to reduce corticosteroid and immunosuppressive drug doses, leading to reduced risks of infectious complications. All these data suggest that it is crucial to find the lowest corticosteroid dose and the lowest number of immunosuppressant agents sufficient to control SLE clinical manifestations or prevent SLE reactivation. It is also very useful to closely monitor patients and vaccinate them for preventable diseases.
Conclusion Drugs and infections in systemic lupus erythematosus Pharmacological measures in SLE revolve around four main classes of drugs: non-steroidal anti-inflammatory drugs (NSAIDs), antimalarials, corticosteroids, and cytotoxic or immunosuppressive agents (cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine). Cyclophosphamide and azathioprine are the two most commonly used cytotoxic agents and they, in combination with corticosteroids, need to be employed early in order to prevent or minimize irreversible damage to major organs. The potential side effects of corticosteroids and cytotoxic agents include infections, particularly bacterial ones. Drug types and doses are also crucial for SLE patients, because they define the magnitude of risk of becoming infected. In this regard, in leukocytopenic patients, prolonged high-dose therapy with cyclophosphamide has been correlated with a significant risk of infectious diseases, especially when associated with glucocorticoids [103]. Corticosteroids have been associated with susceptibility to infections due to their anti-inflammatory activity, which interferes with T lymphocyte-mediated immunity, monocyte and macrophages system, and also endothelial cells. Long systemic treatments (>3 weeks) and high dosages are also associated with the greater likelihood of developing infections [106]. New biological drugs, such as rituximab (an anti-CD20 monoclonal antibody), have been recently introduced for the
The etiopathogenesis of systemic lupus erythematosus (SLE) is still obscure and remains far from being completely elucidated. Environmental and genetic factors have been implicated in the induction and progression of this disease. Among infections, particularly Epstein–Barr virus (EBV), parvovirus B19, retrovirus, and cytomegalovirus (CMV) infections might play a pivotal role in the pathogenesis. The multifaceted interactions between infections and autoimmunity reveal many possibilities for either causative or protective associations. Indeed, some infections (primarily protozoan infections), might confer protection from autoimmune processes, depending on the unique interaction between microorganisms and the host. Further studies are needed in order to conclude that infectious agents are, indeed, one of the causes of SLE and to address the potential clinical sequelae of infections in the field of autoimmunity. Acknowledgments The authors declare no conflict of interest. This review was supported by a grant from the Italian Ministry of Health (Bando Giovani Ricercatori 2009).
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REVIEW
Infections and systemic lupus erythematosus S. Esposito & S. Bosis & M. Semino & D. Rigante
Received: 9 February 2014 / Accepted: 20 March 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that presents a protean spectrum of clinical manifestations, and may affect any organ. The typical course of SLE is insidious, slow, and progressive, with potential exacerbations and remissions, and even dramatically acute and rapidly fatal outcomes. Recently, infections have been shown to be highly associated with the onset and/or exacerbations of SLE, and their possible causative and/or protective role has been largely emphasized in the medical literature. However, the etiopathogenesis of SLE is still obscure and far from being completely elucidated. Among infections, particularly Epstein–Barr virus (EBV), parvovirus B19, retrovirus, and cytomegalovirus (CMV) infections might play a pivotal pathogenetic role. The multifaceted interactions between infections and autoimmunity reveal many possibilities for either causative or protective associations. Indeed, some infections, primarily protozoan infections, might confer protection from autoimmune processes, depending on the unique interaction between the microorganism and host. Further studies are needed in order to demonstrate that infectious agents might, indeed, be causative of SLE, and to address the potential clinical sequelae of infections in the field of autoimmunity.
S. Esposito (*) : S. Bosis : M. Semino Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Commenda n. 9, 20122 Milano, Italy e-mail: [email protected] D. Rigante Institute of Pediatrics, Università Cattolica Sacro Cuore, Rome, Italy
Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that may affect any organ, presenting a protean spectrum of clinical manifestations. The global incidence of SLE is 6–35 new cases per 100,000 per year, with a higher frequency among women than men (90 % of patients are women at reproductive age) [1]. In Northern Europe, the prevalence rates of SLE range from approximately 40 cases per 100,000 white persons to more than 200 per 100,000 among blacks. In the United States, the prevalence rates vary between 3.2 and 250 per 100,000 in different ethnic groups [2–12]. This disease is rare in Africa, though common in African descendants around the world. Specifically, both the incidence and prevalence rates in people of African or Asian background are approximately 2–3 times higher than in the white population; moreover, the disease is more common in Aboriginal Australians and some Native American groups of Canada and the United States. SLE can occur at any age, but it manifests more frequently after 5 years of age, with increased prevalence after the first decade [7, 13, 14]. The incidence and prevalence rates of SLE in adults are considerably higher than in childhood (less than 1 per 100,000 in children under 16 years old in Europe and North America) [2]. At the molecular level, the disease is characterized by a persistent inflammatory state that is detrimental for multiple organs, including skin, joints, vessels, kidneys, serous membranes, central nervous system, and blood. Such chronic damage is due to both immune dysregulation and hyperproduction of different autoantibodies and immune complexes. The clinical manifestation is characterized by ethnicity, gender, age, and socioeconomic factors [1, 15, 16]. The diagnosis of SLE is based on the criteria established from the American College of Rheumatology (ACR), and the more recent Systemic Lupus International Collaborating Clinics classification criteria, drafted in 2012 [17, 18]. These criteria include the
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presence of dermatologic signs, arthritis, and serositis, variably combined with renal, neurologic, and hematologic disorders. Additional diagnostic criteria are SLE-typical immunologic abnormalities, such as antinuclear antibodies (80–90 % of patients), double-stranded DNA-directed autoantibodies (58–70 % of patients), and antibodies directed to other nuclear antigens, such as histones and small nuclear ribonucleoproteins (in a minor group of patients). Four or more criteria (including at least one clinical and one immunological) are necessary for the diagnosis of SLE. Criteria can be satisfied either serially or simultaneously, during any interval of observation, and in the absence of any another explanation in the patient’s clinical picture [17, 18]. The typical course of SLE is insidious, slow, and progressive, and presents cycles of remission and acute phases, which can potentially and rapidly become fatal. The classical symptoms at the onset or during the exacerbation of the disease are fever, fatigue, anorexia, myalgia, and weight loss, all variously intertwined with specific organ-related inflammatory signs [4, 5]. Because of the fact that the overall outcome is highly variable, ranging from remission to death, the long-term prognosis still remains poor. In recent years, the life expectancy for subjects with SLE has greatly improved, nowadays reaching a 15-year survival rate of 80 % [2, 6]. Pediatric SLE (starting at an age less than 16 years) is usually more aggressive than adult SLE, often severely involving major organs, including the kidneys and central nervous system. Moreover, SLE in childhood is associated with increased mortality risk and reduced remission rates. Major causes of death include renal disease, severe disease flares with significant organ damage, and infections [3, 6]. The etiology and pathogenesis of SLE remain still unraveled. It is believed that SLE represents a complex multifactorial disease arising from a combination of genetic susceptibility, hormonal, and environmental factors (including infections, ultraviolet radiation, medications, drugs, and chemicals), which lead to the production and perpetuation of aberrant autoimmune responses. Recently, infections have been shown to be highly associated with the onset and/or exacerbations of SLE, and their causative and/or protective role has been largely emphasized in the medical literature [19–22]. The aim of this review was to screen the medical literature of the last 15 years and investigate the role of infectious agents in the pathogenesis of SLE.
Infections and autoimmunity Host defense against microbial agents are based on the ability of the immune system to distinguish “self” from “non-self” molecules. In patients with SLE, such ability is lost, and autoantibodies (SLE-specific and/or typical of different rheumatologic diseases) are found in the blood. The reason for the
presence of these autoantibodies is still under debate; however, they are useful biomarkers for SLE diagnosis. It has been reported that aberrations of the physiological and protective processes of the immune system may occur during viral, bacterial, parasitic, or fungal infections in genetically prone subjects [20, 21]. In particular, the association between infections and autoimmunity has been a topic of discussion among researchers for a long time, and many theories have been suggested to explain the autoreactivity observed in some individuals. Different etiopathogenetic mechanisms have been associated with the activation of autoreactive T and B cells, and it has been hypothesized that these mechanisms are mediated by diverse infectious agents. For example, molecular mimicry is one of these, and it is based on the activation of autoimmune responses by microbial peptides that possess a structure similar to human self-antigens. A variety of viruses and bacteria can produce superantigens that bind the variable domain of T cell receptors and a wide variety of major histocompatibility complex (MHC) class II molecules. This process activates a large number of T lymphocytes with different antigenic specificity, and also induces autoimmune reactions. The enhanced presentation of autoantigens by antigen-presenting cells at the inflammatory site could be followed by the priming of large numbers of T cells. This process of “epitope spreading” might contribute to the development of autoimmune responses. Another suggested mechanism, known as “bystander activation”, is characterized by the increase of cytokine production, which induces the expansion of previously activated T cells within the inflammatory site. Another possibility is that lymphotropic viruses might activate lymphocytes, causing increased production of antibodies and circulating immune complexes, which might damage tissues and organs of the host. Dysregulation of the apoptotic pathway in host cells might also be a possible mechanism, either by exposing nuclear material to the immune system or by causing the production of autoantibodies against nuclear structures. Finally, an insufficient clearance of infectious agents and the absence or suboptimal functioning of C4 and/or C1q complement system proteins, which has been observed in patients with immunodeficiencies, might induce autoreactive T and B cell responses. Recent data have shown that altered expressions of particular microRNAs from infected B lymphocytes might cause the production of autoantibodies [22–25]. Moreover, it has been demonstrated that many viruses induce the expression of type 1 interferon (INF) genes (INF1 and other INF-related cytokines); this mechanism, known as “interferon signature”, has been shown to exert a relevant role in many autoimmune diseases [26, 27]. Other recent studies have demonstrated the role of hypomethylated bacterial and viral DNA in inducing immune changes, similar to those observed in patients with SLE [28].
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Specifically during childhood, the developing immune system might be vulnerable to external factors, such as infectious agents. Autoimmunity might be triggered through the cumulative effect of repeated infections, which might be clinically apparent, paucisymptomatic, or asymptomatic [29–31]. Clinical manifestations in SLE are closely related to the presence of specific autoantibodies, which can be induced by particular infectious agents. In particular, researchers have shown that high IgM titers against rubella virus were associated with psychosis or depression among patients with neuropsychiatric SLE [32]. Other authors have demonstrated that high titers of Epstein–Barr virus (EBV) antibodies were correlated with skin and joint SLE manifestations [33]. More recent studies have also revealed that infections might induce regulatory CD4+/CD25+ T cells, which might suppress host immune responses against self or non-self molecules. All these findings have suggested that infections might play a direct role in the overall regulation of immunity, either protecting from or facilitating the onset of the autoimmune disease [34–37].
Viruses and pathogenesis of systemic lupus erythematosus Reports associating viral infections and SLE in the medical literature are copious [38]. EBV has been suggested for a long time as a potential trigger of SLE. Since 1971, many efforts have been directed to finding a correlation between EBV and autoimmune diseases. Studies in this direction have been conducted on SLE patients that had higher anti-EBV antibody titers compared to healthy subjects [39, 40]. Some studies have reported a prevalence of 99 % of EBV infection in young SLE patients, compared with 70 % prevalence in the control group [41, 42]. Specifically, a study published in 2001 (192 SLE patients) demonstrated that all but one had been exposed to EBV, suggesting the etiological contribution of this virus [43]. SLE patients compared to healthy controls have also been shown to possess elevated titers of anti-EBNA-1 and EBV-VCA IgA, as well as EBV-EA/D, EBV-EA/R IgG and IgA [1]. Moon and coworkers have shown that EBV load (measured by real-time polymerase chain reaction, PCR) in the sera from SLE patients was increased by 15- to 40-fold compared to control subjects. These results suggested that EBV has an active lytic cycle with high viral replication in SLE patients [44, 45]. Moreover, it has been hypothesized that EBV-infected B cells might also express virus-encoded antiapoptotic molecules, becoming, therefore, resistant to apoptosis [46]. Several groups have demonstrated that the T cells increasing INF production (mediated by EBV) is another mechanism that induces autoimmunity [19, 47–49]. Repeated or re-activated EBV infection, which results in increased EBV IgA and IgG seroprevalence, may be also associated with SLE [50]. Different EBV antigens can exhibit
either structural, molecular, or functional mimicry with SLE antigens or other critical immune-regulatory components. Immunocompetent subjects, when infected by EBV, show little or no EBV-mRNA expression; in contrast, SLE patients have abnormal expression of four viral mRNAs (BZLF-1, LMP-1 and 2, EBNA-1) in their peripheral blood mononuclear cells (PBMCs), indicating an active replication or reactivation of the virus in these patients. Evaluating the levels of EBV mRNA in PBMCs, researchers have found a 1.7-fold increase of BCRF-1, EBNA-1, and LMP-2 mRNAs in SLE patients compared to controls. All these findings lead to the conclusion that keeping control of the EBV infection seems to be difficult in patients with active SLE [1]. In the last several years, studies on human endogenous retroviruses (HERVs) have led to the conclusion that HERVs are potential and very important contributors of several autoimmune diseases, including SLE. In this regard, several groups have shown that HERVs were first integrated into the human genome 30–40 millions years ago, therefore, being the possible molecular link between human genome and environmental factors in SLE pathogenesis. According to these studies, HERV-encoded proteins should be considered as self-antigens, and should be tolerated by the host’s immune system (though they may trigger the breakdown of immunologic tolerance) [51–53]. HERVs might also affect the expression of genes regulating both the immune response and acquired tolerance [54]. In addition, autoantibodies to an endogenous retroviral element-encoded nuclear protein autoantigen, HRES-1, are detectable in a distinct subset of patients with SLE [55]. The existence of transfusion-transmitted viruses (TTVs), which are characterized by high genetic diversity, have recently been discovered. Their prevalence is higher in SLE patients compared to healthy subjects. Both the higher TTV prevalence and the molecular mimicry with the HERV-encoded nuclear proteins might contribute to the generation of antinuclear antibodies, abnormal T and B cell functions, and selfreactivity in SLE patients [40]. HTLV-1 and HIV-1 retroviruses have also been implicated in the pathogenesis of SLE [56]. Specifically, either dysregulation of the apoptotic mechanism and a shift from a T-helper type 1 (Th1) towards a T-helper type 2 (Th2) cytokine profile has been observed in SLE and HIV-infected patients [57]. Moreover, both types of patients probably share a common mechanism mediating the subversion of apoptosis and production of autoantibodies [52, 58]. A variety of rheumatologic manifestations, mainly rheumatoid arthritis, systemic vasculitis, and SLE, can be encountered in the course of parvovirus B19 infections. Parvovirus infections might be accompanied by transient subclinical autoimmunity, which also mimics or exacerbates SLE in predisposed individuals [59]. Similarities in both clinical and serological parameters following parvovirus infection and SLE at the
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onset may lead to a less accurate diagnosis between these two conditions. Indeed, parvovirus B19 infection mimicking SLE usually fulfills less than four ACR criteria for SLE; in addition, it rarely includes hemolytic anemia, cardiac or renal abnormalities, and it is usually associated with short-lived low titers of autoantibodies [60]. Several studies have also demonstrated a correlation between cytomegalovirus (CMV) infection and SLE. The presence of anti-CMV IgM or CMV-DNA has been detected in patients with initial symptoms of SLE, showing the hypothetical etiological role of the virus [61, 62]. In particular, CMV infections have been associated with the “vascular” SLE, showing more frequently Raynaud’s phenomenon and less frequently typical kidney involvement [63]. The relationship between hepatitis C virus (HCV) and SLE has not yet been defined. Some studies have demonstrated a significantly higher prevalence of HCV infection among SLE patients compared to healthy controls [64], but this correlation has not been confirmed [65, 66]. Among RNA viruses, C-type oncornaviruses have been supposed to be associated with SLE. However, although extensive studies have been conducted, the presence of C-type oncornaviruses in lymphoblastoid cell lines harboring endogenous EBV, derived from patients with active SLE, has not yet been demonstrated. In this respect, other studies have showed a non-specific increase in the titer of antibodies against measles and parainfluenza type 1 in patients with SLE [44]. However, a relevant role of these agents in triggering the onset of SLE has not been suggested so far.
The relationship between bacteria and systemic lupus erythematosus Bacterial infections might also play a role in the development of SLE. The inflammation triggered by any bacteria induces cellular damage and increases the presence of cellular debris, activating B lymphocytes, or promoting the release of autoantibodies [27, 67]. The presence of a bacterial infection triggers the immune system through specific products, such as bacterial lipopolysaccharides or nucleic acid-containing immune complexes. Pathogen-associated molecular patterns (PAMPs) interact with Toll-like receptors (TLRs) and nonTLR internal receptors of antigen-presenting cells, monocytes, and B and T lymphocytes. The binding of TLRs induces plasmacytoid dendritic cells to release interferon (IFN), leading to the production of proinflammatory cytokines and destabilizing innate immunity processes [44, 68, 69]. Recent clinical studies have placed new emphasis on the role of TLRs, specifically TLR-7 and TLR-9, in the promotion of autoantibody production. Pharmacologic modulation of TLRdirected pathways might offer new additional therapeutic approaches for the treatment of SLE [70].
Parasites and development of SLE Parasitic infections may induce variable immunomodulatory effects. The relationship between parasitic infections and autoimmunity remains to be elucidated [71]. There is still no definite agreement on parasitic involvement in the pathogenesis of SLE, but a possible link between Toxoplasma gondii and rheumatoid arthritis has recently been proposed [72].
The protective effect of infectious agents from autoimmune processes It has been demonstrated that some infectious agents have a protective rather than a causative role towards the development of SLE [32]. The beneficial effects of viral, parasitic, and fungal infections have been explained to derive from a shift toward a more predominant Th-2 immunological phenotype [72]. Based on this approach, infections might confer a generic protection from autoimmunity; therefore, the recent increase in the incidence of autoimmune diseases in children of Western countries would have been related to the theory of a reduced infectious pressure, due to improved hygiene and sanitary conditions [73]. Furthermore, animal models provide evidence that various autoimmune diseases are suppressed by helminth infections [74]. Infections with Plasmodium falciparum, the protozoan causing the most severe form of malaria, are believed to generate a lower risk to develop SLE [75]. This hypothesis is reflected in the observation that, although people of African descent have higher rates of SLE than Caucasians, the prevalence of SLE in Africa is low, particularly when associated with the presence of malaria [74–76]. Animal models suggest a protection for SLE nephropathy due to Toxoplasma gondii infection [34, 77]. Schistosoma mansoni and japonicum have also been related to protective effects towards autoimmune diseases [78]. Infections could also be protective for SLE by other mechanisms, such as antigenic competition, which would induce decreased responses against self-antigens [79, 80]. Bacteria and viruses could also protect against autoimmune diseases acting on TLRs; the binding between pathogens and TLRs would trigger the production of cytokines that could downregulate autoimmune responses [80]. Helicobacter pylori seronegativity has also been related to an increased risk of development of SLE, suggesting, again, that this pathogen might exert a protective role [81, 82]. Finally, hepatitis B virus (HBV) has been hypothesized as having a protective role because of the lower prevalence of anti-HBV antibodies in SLE patients compared to healthy subjects. All these data confirm the immunomodulatory effects of HBV infection, probably mediated by IFN production,
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which might protect an infected subject from the pathogenesis of autoimmune diseases, including SLE [83].
Genetic predisposition to systemic lupus erythematosus and infections The primary involvement of genetics in SLE was formerly shown by the high concordance rate in monozygotic twins (approximately 25 %) compared with dizygotic twins (only 2 %) [84]. However, genetic risk factors for SLE are complex and still not well established. These include complement and mannose-binding lectin (MBL) deficiency, impaired IFN release, and STAT4 protein (a transcription factor belonging to the Signal Transducer and Activator of Transcription protein family) production [22]. Immune deficiency might result in insufficient clearance of exogenous pathogens during infections, therefore, increasing the risk of autoimmunity [44, 85, 86]. In addition, different genes located in the human leucocyte antigen (HLA) locus, and involved in the regulation of the immune system, have been associated with SLE [22, 84]. Susceptibility loci on HLA-DR2 and two non-MHC immune regulatory genes (CTLA and PTPN22) have been related to the risk of SLE development [87]. In addition, the innate immune system has also been suggested to have a role in the autoimmune response, as proved by recent studies on TLR-7 and TLR-9 [70, 88]. Although several studies suggested that the interaction of genetic factors with infectious agents may have a strong role in autoimmunity, this topic is still controversial and further research is needed in order to better understand their dynamic interplay. Finally, recent studies have indicated that a peculiar genetic background may increase the risk of serious infections in SLE. Patients with MBL deficiency, associated with homozygous MBL variant alleles, have been reported to be at increased risk of infections. SLE patients homozygous for MBL variant alleles had a 4-fold increase in the incidence of infections [89]. Furthermore, it has been shown that at least one-third of SLE patients with C1q deficiency may suffer from recurrent bacterial infections, including otitis media, meningitides, and pneumonia [90].
Vaccinations and systemic lupus erythematosus There is plenty of medical literature reporting that SLE might be triggered by vaccinations. The existing data do not link directly the vaccines and the autoimmune phenomena in a causal relationship; nevertheless, a temporal connection has been described. Bacterial and viral components, or adjuvants of vaccines, have been associated with SLE onset or flare-up. In particular, it has been described that five healthy patients
developed SLE 2–3 weeks after immunization by a combination of vaccines for typhoid, influenza, meningococcal, tetanus toxoid, measles, mumps, and rubella [91]. Several case reports have also associated hepatitis B vaccine with SLE, but, unfortunately, no studies have ascertained any causal relationship. Data on the safety and efficacy of this vaccination for SLE patients have not yet been established [92]. Associations between influenza vaccination and SLE are rare; however, the safety and efficacy of this vaccine have been clearly proven in patients with SLE [93]. Finally, more than 10 years ago, Hidalgo-Tenorio and colleagues have demonstrated that pneumococcal vaccination is not associated with substantial changes in the evolution of SLE [94].
The risk of infections in systemic lupus erythematosus Despite the improvement in the management of SLE in recent years, infections represent a leading cause of morbidity and mortality for these patients. The common sites of infections are respiratory airways, the urinary tract, soft tissue, and skin. Bacteria are the most commonly implicated agents, followed by viruses and fungi. Among Gram-positive bacteria, Streptococcus pneumoniae is the most common cause of respiratory tract infections, while Staphylococcus aureus causes skin, soft tissue, bone, and joint infections. Gramnegative bacteria such as Escherichia coli are most commonly involved in urinary tract infections. Also, Klebsiella pneumoniae and Pseudomonas spp. are frequent causes of infections in SLE patients [95, 96]. Pneumococcal invasive soft tissue infections, such as cellulitis and fasciitis, are uncommon [97]. Septicemia has been described in patients with SLE, mainly caused by Staphylococcus aureus, Escherichia coli, and Salmonella spp., and associated with poor long-term outcomes [98]. The incidence rate of tuberculosis (TB) is higher in SLE patients, depending on the specific geographical area. In this regard, the prevalence of TB for SLE patients in endemic areas is 5 % [99]. Patients with SLE are also susceptible to opportunistic infections, but non-tuberculous mycobacterial infections have also been described. These infections tend to develop later in the course of the disease compared to those caused by Mycobacterium tuberculosis [100]. Viral infections commonly reported in SLE patients are mostly related to varicella-zoster virus, CMV, and human papillomavirus (HPV). Severe and atypical manifestations caused by CMV have been described, mostly with respiratory or gastrointestinal symptoms and SLE flare like manifestations [101]. Some studies have also demonstrated a higher risk of hepatitis B re-activation in SLE patients, even if this
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situation has been mostly reported in patients with lymphoma [102]. Among fungal infections, those from Candida spp., Pneumocystis jirovecii, and Cryptococcus neoformans are frequently reported in patients with SLE. Common manifestations of Cryptococcus neoformans are meningitis and pneumonia, while Pneumocystis jirovecii and Candida albicans lead to severe pulmonary and genitourinary or gastrointestinal tract infections, respectively [103]. The higher rate of infections in patients suffering from SLE can be explained by different causes. Primarily, they can be caused by immune system dysfunction, which involves phagocytes activity, chemotaxis, and the identification of exogenous pathogens; secondarily, by cytokine production and pathogen clearance, which can lead to a reduced ability to respond to infections; finally, by neutropenia or lymphopenia, resulting from a dysfunctional macrophage–monocyte system. Hypogammaglobulinemia and impaired complement function can also be found in SLE subjects, justifying the vulnerability to infections of these patients [104]. The risk of infections is significantly associated with the disease activity, particularly with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), a global score index developed for the assessment of SLE activity [105].
treatment of severe and refractory manifestations of SLE. Related side effects have included higher risks of infections (mild and severe), mostly from pneumonia or sepsis due to bacterial pathogens; however, it has been demonstrated that these tend to occur especially within the first 6 months of administration [104, 107]. The efficacy and safety of belimumab (a human monoclonal antibody that inhibits B-cell activating factor, also known as B-lymphocyte stimulator) in SLE has been demonstrated in two randomized controlled studies. Data have shown that serious infections are reported in 8 % of adult patients with SLE [108]. Antimalarials drugs, prescribed for cutaneous or mild articular manifestations of SLE, have been shown to be protective from parasitic and also viral, fungal, and bacterial infections in SLE subjects [108]. Their use has allowed to reduce corticosteroid and immunosuppressive drug doses, leading to reduced risks of infectious complications. All these data suggest that it is crucial to find the lowest corticosteroid dose and the lowest number of immunosuppressant agents sufficient to control SLE clinical manifestations or prevent SLE reactivation. It is also very useful to closely monitor patients and vaccinate them for preventable diseases.
Conclusion Drugs and infections in systemic lupus erythematosus Pharmacological measures in SLE revolve around four main classes of drugs: non-steroidal anti-inflammatory drugs (NSAIDs), antimalarials, corticosteroids, and cytotoxic or immunosuppressive agents (cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine). Cyclophosphamide and azathioprine are the two most commonly used cytotoxic agents and they, in combination with corticosteroids, need to be employed early in order to prevent or minimize irreversible damage to major organs. The potential side effects of corticosteroids and cytotoxic agents include infections, particularly bacterial ones. Drug types and doses are also crucial for SLE patients, because they define the magnitude of risk of becoming infected. In this regard, in leukocytopenic patients, prolonged high-dose therapy with cyclophosphamide has been correlated with a significant risk of infectious diseases, especially when associated with glucocorticoids [103]. Corticosteroids have been associated with susceptibility to infections due to their anti-inflammatory activity, which interferes with T lymphocyte-mediated immunity, monocyte and macrophages system, and also endothelial cells. Long systemic treatments (>3 weeks) and high dosages are also associated with the greater likelihood of developing infections [106]. New biological drugs, such as rituximab (an anti-CD20 monoclonal antibody), have been recently introduced for the
The etiopathogenesis of systemic lupus erythematosus (SLE) is still obscure and remains far from being completely elucidated. Environmental and genetic factors have been implicated in the induction and progression of this disease. Among infections, particularly Epstein–Barr virus (EBV), parvovirus B19, retrovirus, and cytomegalovirus (CMV) infections might play a pivotal role in the pathogenesis. The multifaceted interactions between infections and autoimmunity reveal many possibilities for either causative or protective associations. Indeed, some infections (primarily protozoan infections), might confer protection from autoimmune processes, depending on the unique interaction between microorganisms and the host. Further studies are needed in order to conclude that infectious agents are, indeed, one of the causes of SLE and to address the potential clinical sequelae of infections in the field of autoimmunity. Acknowledgments The authors declare no conflict of interest. This review was supported by a grant from the Italian Ministry of Health (Bando Giovani Ricercatori 2009).
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