**2. Epidemiology**

The prevalence of SLE and LN varies based on age, gender, geographical location, socioeconomic status and ethnicity. There are also disproportionate differences in the incidence and prevalence, depending upon the validated classification criteria or methods of case ascertainment used.

#### **2.1 Systemic lupus erythematosus (SLE)**

In a large retrospective study performed in the United Kingdom (UK) involving more than 7,000 SLE cases between 1999 and 2012, the overall annual incidence of SLE was 4.9 cases per 100,000 population per year with overall prevalence of 97 per 100,000 population; highest in Afro-Caribbean ethnic subgroup (517 per 100,000), followed by the Indian subgroup (193 per 100,000) while Caucasian subgroup was 134 per 100,000 [9]. Other studies found similar estimates with annual incidence between 4 and 8 cases per 100,000 population per year. Expectedly, the worldwide prevalence of SLE also varies between 30 to 90 cases per 100,000 population, highest in the African populations, lowest in Caucasians, with Hispanic and Asian subgroups in between the two extremes [10, 11].

All studies worldwide have demonstrated marked predominance of women in SLE, between 6 and 9 times higher than men. In the United States (US) and UK, the peak incidence was in women aged between 40 and 59 [10, 12]; in contrast, a population based study in Taiwan involving almost 7000 SLE patients revealed earlier peak incidence in women aged between 20 and 29 [13], a consistent trend among other studies in the Asia-Pacific region [14].

#### **2.2 Lupus nephritis (LN)**

Renal involvement occurs in 25–50% of SLE patients at the time of diagnosis [15]. The cumulative incidence, again, varies according to ethnicities. In a US study involving three ethnic subgroups, the incidence of LN was found to be the highest among the African subgroup (69%) followed by Hispanics (61%) and Caucasians (29%) [16]. In the Asia-Pacific region, the cumulative incidence of LN varies between 30% and 82%, lowest in Australian and highest in Malaysian populations respectively [14].

Despite higher overall incidence of SLE in women than in men, strikingly, renal involvement was found to be 50% higher in SLE men in a meta-analysis involving nearly 12,000 SLE patients across multiple countries [17]. Left untreated, LN carries significant morbidity and mortality, with the mortality rate estimated to be 6 times higher than general population. However, with the current therapeutic options, the 10-year survival for patients with LN can exceed 98% [18].

### **3. Pathogenesis**

The pathogenesis of LN is complex and achieving full understanding of its pathophysiologic mechanisms has proved challenging due to the molecular and phenotypic heterogeneity. Genetic predisposition, epigenetic dysregulation and environmental triggers are all likely to contribute to the disease expression [1, 19, 20]. Dysregulation of both innate and adaptive immune responses manifested by disturbance in apoptotic cell clearance, cytokines stimulation, B-cell immunity and T-cell function leads to glomerular and/or tubulointerstitial injury.

Production of autoantibodies targeting self-DNA, other self-nuclear antigens and non-nuclear materials results from loss of immune self-tolerance and autoimmunity in genetically predisposed individuals. Formation of immune complexes (ICs) may occur in circulation and deposits in various organ systems including the kidneys. Antibodies can also directly target in situ nephritogenic antigens at the major resident renal cells (mesangial cells, glomerular endothelial cells, tubular epithelial cells and podocytes) [21]. Co-stimulation by Fc receptors (FcRs) and endosomal Toll-like receptors (TLRs) leads to activation of the complement

**37**

*Lupus Nephritis: Current Updates*

activation in situ [26, 27].

B cell therapies [30].

*DOI: http://dx.doi.org/10.5772/intechopen.96891*

system and subsequent release of cytokines and chemokines leading to renal tissue injury [22–25]. Anti-C1q antibodies, while not exclusive to LN, are strongly associated with renal inflammation and severe LN, amplifying complement

by dendritic cells (DCs), interleukins (eg. IL 12/23), JAK1, TYK2 and various STAT proteins and 2) NFκB are both implicated early in the innate immune response and play major roles in the pathogenesis [28, 29]. Adaptive responses including persistent activation and interaction of aberrant polyclonal B and T cells involving multiple co-stimulatory molecules promote chronic inflammation and renal tissue damage. Studies have also uncovered that formation of long-lived memory T-cells and plasma cells that reside in survival niches in bone marrow and inflamed tissue render them resistant to conventional immunosuppression or

B cell activation factor (BAFF)/B-lymphocyte stimulator (BLyS) promotes formation of tertiary lymphoid structures (TLSs) that contribute to lymphocyte priming and autoantibody production within the kidneys [31] while evidence in patients and animal models have demonstrated high levels of IL-17 producing T cells in LN [32]. Several other regulators of apoptosis have also been implicated in the development of LN including dysregulation of autophagy, BCL-2, phosphatase and tensin homologue (PTEN), mannose-binding lectin (MBL) and neutrophil

More than 10 genome-wide association studies (GWAS) have been conducted thus far with more than 50 genes implicated involving various pathogenic mechanisms in the pathogenesis of SLE, some associated with LN [2, 41]. These candidate genes are likely to undergo further evaluation and validation from deep sequencing and mechanistic studies. *Mohan et al.* have elegantly categorised the implicated genes into four functional groups; genes that influence 1) lymphocyte activation, particularly B cells (eg. BLK, STAT4, TNFSF4, HLA-DR) 2) innate immune signalling (notably NFκB and IFN-I; eg. IKZF1, IRF5, TLR9, TNFAIP3) 3) intra-renal signalling (eg. ACE, KLK) and 4) handling of apoptotic material, chromatin and ICs (eg. ATG5, ITGAM, FCGR2A/3A/3B); genetic interaction from multiple

The TLR7 gene, which is located at chromosome X, has recently been the focus of considerable research in SLE and LN. Theories regarding the contribution of TLR7 gene have included 1) Enhanced TLR7 protein expression in renal DCs and macrophages which correlated with renal disease parameters in murine models [42] 2) Emerging evidence that TLR7 dosage is a key pathogenic factor to the pathogenesis of SLE: *Dillon et al.* assembled the largest group consisting of 316 men with SLE and found high prevalence of SLE in X chromosome aneuploides such as Klinefelter's syndrome (KS; 47, XXY) and de la Chapelle's syndrome (46, XX male) [43] while recently, Souyris and colleagues provided proof that TLR7gene evades X chromosome inactivation in immune cells in women and KS men, and proposed this as a mechanism for the elevated risk of SLE in women and KS [44], which may

Current non-invasive SLE biomarkers such as proteinuria or active urine sediment, serum creatinine, anti dsDNA and hypocomplementemia could not reliably confirm the presence, severity and/or chronicity, or predict the outcome of LN. Many novel biomarkers are currently being explored in the management and

extracellular traps (NETs) among several others [33–40].

categories is required for severe LN to develop [2].

partially explain the high preponderance of SLE in females.

**4. Diagnosis and classification**

Overactivation of 1) Interferon (IFN)-I signalling pathway, which is regulated

*Lupus - Need to Know*

**2.1 Systemic lupus erythematosus (SLE)**

subgroups in between the two extremes [10, 11].

among other studies in the Asia-Pacific region [14].

**2.2 Lupus nephritis (LN)**

respectively [14].

**3. Pathogenesis**

to glomerular and/or tubulointerstitial injury.

In a large retrospective study performed in the United Kingdom (UK) involving more than 7,000 SLE cases between 1999 and 2012, the overall annual incidence of SLE was 4.9 cases per 100,000 population per year with overall prevalence of 97 per 100,000 population; highest in Afro-Caribbean ethnic subgroup (517 per 100,000), followed by the Indian subgroup (193 per 100,000) while Caucasian subgroup was 134 per 100,000 [9]. Other studies found similar estimates with annual incidence between 4 and 8 cases per 100,000 population per year. Expectedly, the worldwide prevalence of SLE also varies between 30 to 90 cases per 100,000 population, highest in the African populations, lowest in Caucasians, with Hispanic and Asian

All studies worldwide have demonstrated marked predominance of women in SLE, between 6 and 9 times higher than men. In the United States (US) and UK, the peak incidence was in women aged between 40 and 59 [10, 12]; in contrast, a population based study in Taiwan involving almost 7000 SLE patients revealed earlier peak incidence in women aged between 20 and 29 [13], a consistent trend

Renal involvement occurs in 25–50% of SLE patients at the time of diagnosis [15]. The cumulative incidence, again, varies according to ethnicities. In a US study involving three ethnic subgroups, the incidence of LN was found to be the highest among the African subgroup (69%) followed by Hispanics (61%) and Caucasians (29%) [16]. In the Asia-Pacific region, the cumulative incidence of LN varies between 30% and 82%, lowest in Australian and highest in Malaysian populations

Despite higher overall incidence of SLE in women than in men, strikingly, renal

The pathogenesis of LN is complex and achieving full understanding of its pathophysiologic mechanisms has proved challenging due to the molecular and phenotypic heterogeneity. Genetic predisposition, epigenetic dysregulation and environmental triggers are all likely to contribute to the disease expression [1, 19, 20]. Dysregulation of both innate and adaptive immune responses manifested by disturbance in apoptotic cell clearance, cytokines stimulation, B-cell immunity and T-cell function leads

Production of autoantibodies targeting self-DNA, other self-nuclear antigens and non-nuclear materials results from loss of immune self-tolerance and autoimmunity in genetically predisposed individuals. Formation of immune complexes (ICs) may occur in circulation and deposits in various organ systems including the kidneys. Antibodies can also directly target in situ nephritogenic antigens at the major resident renal cells (mesangial cells, glomerular endothelial cells, tubular epithelial cells and podocytes) [21]. Co-stimulation by Fc receptors (FcRs) and endosomal Toll-like receptors (TLRs) leads to activation of the complement

involvement was found to be 50% higher in SLE men in a meta-analysis involving nearly 12,000 SLE patients across multiple countries [17]. Left untreated, LN carries significant morbidity and mortality, with the mortality rate estimated to be 6 times higher than general population. However, with the current therapeutic

options, the 10-year survival for patients with LN can exceed 98% [18].

**36**

system and subsequent release of cytokines and chemokines leading to renal tissue injury [22–25]. Anti-C1q antibodies, while not exclusive to LN, are strongly associated with renal inflammation and severe LN, amplifying complement activation in situ [26, 27].

Overactivation of 1) Interferon (IFN)-I signalling pathway, which is regulated by dendritic cells (DCs), interleukins (eg. IL 12/23), JAK1, TYK2 and various STAT proteins and 2) NFκB are both implicated early in the innate immune response and play major roles in the pathogenesis [28, 29]. Adaptive responses including persistent activation and interaction of aberrant polyclonal B and T cells involving multiple co-stimulatory molecules promote chronic inflammation and renal tissue damage. Studies have also uncovered that formation of long-lived memory T-cells and plasma cells that reside in survival niches in bone marrow and inflamed tissue render them resistant to conventional immunosuppression or B cell therapies [30].

B cell activation factor (BAFF)/B-lymphocyte stimulator (BLyS) promotes formation of tertiary lymphoid structures (TLSs) that contribute to lymphocyte priming and autoantibody production within the kidneys [31] while evidence in patients and animal models have demonstrated high levels of IL-17 producing T cells in LN [32]. Several other regulators of apoptosis have also been implicated in the development of LN including dysregulation of autophagy, BCL-2, phosphatase and tensin homologue (PTEN), mannose-binding lectin (MBL) and neutrophil extracellular traps (NETs) among several others [33–40].

More than 10 genome-wide association studies (GWAS) have been conducted thus far with more than 50 genes implicated involving various pathogenic mechanisms in the pathogenesis of SLE, some associated with LN [2, 41]. These candidate genes are likely to undergo further evaluation and validation from deep sequencing and mechanistic studies. *Mohan et al.* have elegantly categorised the implicated genes into four functional groups; genes that influence 1) lymphocyte activation, particularly B cells (eg. BLK, STAT4, TNFSF4, HLA-DR) 2) innate immune signalling (notably NFκB and IFN-I; eg. IKZF1, IRF5, TLR9, TNFAIP3) 3) intra-renal signalling (eg. ACE, KLK) and 4) handling of apoptotic material, chromatin and ICs (eg. ATG5, ITGAM, FCGR2A/3A/3B); genetic interaction from multiple categories is required for severe LN to develop [2].

The TLR7 gene, which is located at chromosome X, has recently been the focus of considerable research in SLE and LN. Theories regarding the contribution of TLR7 gene have included 1) Enhanced TLR7 protein expression in renal DCs and macrophages which correlated with renal disease parameters in murine models [42] 2) Emerging evidence that TLR7 dosage is a key pathogenic factor to the pathogenesis of SLE: *Dillon et al.* assembled the largest group consisting of 316 men with SLE and found high prevalence of SLE in X chromosome aneuploides such as Klinefelter's syndrome (KS; 47, XXY) and de la Chapelle's syndrome (46, XX male) [43] while recently, Souyris and colleagues provided proof that TLR7gene evades X chromosome inactivation in immune cells in women and KS men, and proposed this as a mechanism for the elevated risk of SLE in women and KS [44], which may partially explain the high preponderance of SLE in females.
