ABSTRACT
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect any organ of the body. Depression is one of the most frequent disorders in SLE, ranging from 17 to 75% of prevalence, although subtle neuropsychiatric syndromes like symptoms of depressive and anxiety axes are often considered as “non-neuropsychiatric SLE”. Recent data suggest SLE patients also suffer from sleep disturbances like frequent awakenings and unrestorative sleep, and worse sleep quality has been found to be a fellow traveller with this disease.
Relationship between depression and sleep disturbances has been established previously in other categories of patients, but only a few studies examined sleep disturbances with objective methods in SLE patients. Therefore, the aim of this study was to evaluate sleep in SLE patients in comparison with a cohort of age and sex-matched controls using actigraphy, that has been proved to be an efficient and reliable tool to identify sleep disturbances. The presence of mood disorders, temperament, health-related quality of life and subjective perception of sleep were evaluated with specific questionnaires: Beck Depression Inventory, Self Rating Anxiety Scale, Brief COPE, Pittsburgh Sleep Quality Index, Insomnia Severity Index, Perceived Stress Scale, Resilience Scale for adult, Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, Brief TEMPS-M, Lupus QoL and Short Form Health survey 36 (in SLE patients and controls respectively).
The strongest predictors of the SLE group were mainly higher scores in Beck Depression Inventory and Self Rating Anxiety Scale index, lower Sleep Efficiency and greater Total Sleep Time.
Statistically significant differences were found between depressed SLE patients and non-depressed SLE patients in several parameters: burden to others Lupus QoL sub scale score, pain sub scale score, Perceived Stress Scale score, Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scale score and body image sub scale. In fact, lower scores in FACIT fatigue scale, burden to others, pain and body image domains while Perceived Stress Scale score was higher in depressed SLE patients. In SLE group, fatigue, as measured by FACIT score, was strongly negative correlated with Beck Depression Inventory score and positively correlated with physical subscale score.
Within SLE groups with differentially analyzed two subgroups, fibromyalgic and non fibromyalgic patients, we identified a statistically significant difference was found in pain domain, with lower scores in fibromyalgic patients, while no significant difference was found between patients with joint involvement and patients without joint involvement, addressing fibromyalgia as the factor with greater impact over pain. Instead, SAS index was not correlated with objective indices of sleep disturbances, while it strongly correlated with subjective indices of sleep disorders (Pittsburgh Sleep Quality Index and Insomnia Severity Index, specifically).
In conclusion, SLE is a chronic disease that has great impact on mood and sleep quality and identification of this problems together with suggestion of therapeutic interventions that may improve the quality of life of these patients.
TABLE OF CONTENTS ABSTRACT ... 1 INTRODUCTION ... 4 Definition of SLE ... 4 History... 4 Epidemiology ... 5 Etiology ... 7 Animal models ... 7
Genes, gender ratio and familial aggregation in SLE ... 9
Pathogenesis ... 12
Infections... 13
UV exposure ... 16
Environmental factors and toxicants: smoking, alcohol, chemicals, medications ... 16
Hormones ... 18
Epigenetics ... 20
Altered immune processes ... 22
Diagnosis... 24 Lupus flare ... 25 Clinical manifestations... 26 Cutaneous manifestations ... 28 Renal involvement ... 32 Joint involvement ... 35 Serologic abnormalities ... 36 Pulmonary involvement ... 38 Gastrointestinal involvement ... 40 Cardiovascular manifestations ... 42 Neuropsychiatric SLE ... 45 Prognosis ... 53 Treatment ... 53
Treatment for lupus nephritis ... 54
Treatment for neuropsychiatric SLE ... 54
Treatment for inflammatory arthritis and myositis related to lupus ... 55
Treatment for cutaneous lupus ... 55
Treatment for hematologic manifestations ... 55
Biologic therapies ... 56
Adjunctive therapies ... 56
Treatment complications ... 56
Steroids neuropsychiatric reactions ... 59
Overlap syndromes ... 60
Fibromyalgia ... 61
Quality of life and functional disability in SLE ... 63
Specific clinical manifestations and HRQoL ... 65
Fatigue... 65
Physical activity ... 67
Sleep disturbances in SLE ... 68
Disease activity, sleep and specific clinical manifestations... 69
Subjective evaluation of sleep versus objective methods ... 70
Sleep disturbances and autoimmunity: which one comes first? ... 72
THE STUDY ... 73
Aims of the study ... 73
Materials and methods ... 73
Recruitment ... 73
Subjects ... 74
Questionnaires and sleep diary ... 75
Actigraphy... 79
Procedure ... 79
Data analysis ... 80
Results ... 80
Multiple linear regression ... 80
Mann-Whitney Rank sum test ... 85
Pearson correlation... 91
Conclusion ... 95
Discussion ... 96
BIBLIOGRAPHY ... 98
APPENDICES ... 112
APPENDIX 1: Resilience Scale For Adult ... 112
APPENDIX 2: Perceived Stress Scale ... 115
APPENDIX 3: Self Rating Anxiety Scale ... 116
APPENDIX 4: Brief TEMPS-M ... 117
APPENDIX 5: Brief COPE ... 119
APPENDIX 6: Pittsburgh Sleep Quality Index ... 120
APPENDIX 7: Insomnia Severity Index ... 123
APPENDIX 8: Functional Assessment of Chronic Illness Therapy ... 124
APPENDIX 9: Beck Depression Inventory - I ... 125
APPENDIX 10: Lupus QoL ... 127
APPENDIX 11: Short Form Health Survey SF-36 ... 131
INTRODUCTION
Definition of SLE
Systemic Lupus Erythematosus is a connective tissue disease. Connective tissue diseases are heterogeneous disorders that have the following common features: inflammation of skin, joints, and other structures rich in connective tissue; as well as altered patterns of immunoregulation, including production of autoantibodies and abnormalities of cell-mediated immunity. Distinct clinical entities can be defined but manifestations may vary considerably from one patient to another, and overlap of clinical features between and among specific diseases can occur [1].
To summarize, SLE is a chronic inflammatory systemic disease, caused by an autoimmune attack to the organism.
History
The word “lupus” is a latin word meaning “wolf”. In Middle Age times, “lupus” named a broad and loose category of ulcers. According to medieval physicians, the branching patterns of veins around tumours evoked the claws of a crab (“cancer” in Latin), while the lesions of lupus seemed similar to the bites of wolves.
In 1851 the French dermatologist Alphée Cazenave described a condition he called lupus érythémateux. This condition was characterized by a red rash on the cheeks, occurring most commonly in middleaged women, and leaving permanent scars but no erosions (see fig. 1).
Figure 1 From “A Treatise on the Diseases of the Skin” by Henry W. Stelwagon and Henry Kennedy Gaskill 1923
20 years later, the Viennese pathologist Moriz Kaposi noticed that people diagnosed with lupus érythémateux also displayed more general symptoms such as fever, weight loss, and arthritis.
At the end of the 19th century the Canadian physician William Osler published his observations about heart, lung and kidney complications in these patients, creating a new disease category of systemic lupus erythematosus (SLE).Working at the Mayo Clinic in 1948, Malcolm Hargraves observed phagocytes engulfing free nuclear material in bone marrow samples from patients with SLE, concluding that the condition was autoimmune. Through the 1950s and 1960s American clinicians developed new drug regimens, based on corticosteroids in conjunction with synthetic antimalarials [2].
Yet, the etiology of SLE remains unknown, although this disease is better portrayed nowadays and new characteristics of this condition have been described.
Epidemiology
SLE is a disease that is more common in female than male, with a women-to-men ratio of 9:1. Based on clinical experiences alone, it was established that the disease generally affected females in 80–90% of the cases [3]. In females, incidence of the disease is usually highest at 15–44 years of age, while its prevalence maximal at 45–64 years (childbearing age), suggesting hormones play a role in the pathogenesis of SLE [3].
A burden in SLE incidence has been described over time in USA, but actually effective temporal increase has been observed only from 1955 to 1974, probably because of changes in environmental factors but also thanks to increased recognition of the disease and improved diagnostic methods.
Fig. 2 Incidence of SLE worldwide, from “Epidemiology of SLE: a comparison of worldwide disease burden” N. Danchenko et al. 206 [3]
There are also disparities in ethnic groups. As reviewed by Danchenko et al. 2006 [3], incidence seems to be higher in Afro Caribbean and Asian, and these ethnies appear also to be at higher risk of developing a more aggressive form of the disease (fig.. 2).
Prevalence, regardless of the ethnicity, appears to be higher in the following countries: Spain, Italy, Martinique, USA (fig. 3).
Fig. 3 Prevalence of SLE worldwide, from “Epidemiology of SLE: a comparison of worldwide disease burden” N. Danchenko et al. 2006 [3]
This difference may be explained by a genetic predisposition to develop SLE and by a difference in environmental changes such variable UV exposition, prevalence of different major bacteria infections.
Country-specific health care issues can also contribute to true discrepancies in SLE burden. Accessibility and affordability of health care determined by health care system influences the number of SLE diagnosis, as well as availability of sensitive diagnostic tests. Artificial causes of different SLE burden across countries among studies may be disparities in case identification, data sources (hospital records review, physicians surveys, major population surveys, use of population-based databases and registries), analytical issues, difference in diagnostic criteria chosen [3].
To summarize, SLE is more common in those of Hispanic origin, those of African descent in North America, or with a Caribbean background in the UK, those of Asian descent
(from India, Pakistan and China), as well as those from countries around the Pacific, including North American Indians, Australian Aborigines and New Zealand Maoris. Moreover, Hispanics, African–Americans, African–Caribbean, South Asians and Chinese presenta an earlier onset of SLE, more renal involvement, earlier damage and often higher mortality than Caucasians[4].
Etiology
Etiology of SLE is still unknown, yet many hypothesis toward the cause of this disease have been made.
Animal models
Many theories are endorsed by animal models of human SLE. Mouse models studied are spontaneous or induced form of lupus, although none of them reassume all the clinical features of human SLE but each one rather develop one specific lupus phenotype. The models known nowadays are the following:
Spontaneous mouse models of SLE:
o NZB/W F1: F1 hybrid between the NZB and NZW strains. NZB mice show limited hemolytic autoimmune anemia, whereas NZW mice are nonautoimmune. F1 hybrid shows the following characteristics: higher incidence in female mice, splenomegaly, elevated serum ANA mostly directed against DNA, immuno complex-induced nephritis that develops on 5-6 months of age leading to renal failure and death within 6 months.
o New Zealand mixed: this model derives from an accidental backcross between NZB/W F1 and NZW followed by brother–sister mating that generated 27 different recombinant inbred strains of New Zealand. Clinical manifestations are comparable with those of NZB/W F1 mice, but they differ in genetic background as far as NZM show homozygous genomes, which has facilitated genetic analyses.
o SWBxNZB F1 mice, called SNF1, have a marked difference in gender mucosal immune responsiveness, with increased mucosal immune responsiveness and with higher levels of pro-inflammatory molecules compared with male counterparts[5]. More details about gut microbiota in SLE are given in the chapter “Pathogenesis”.
o MRL/lpr mouse: one of the MRL substrains carries a spontaneous mutation named lpr for lymphoproliferation and it is characterized by accumulation of double negative (CD4-CD8-) B220þ T cells. Double negative T cells are autoreactive [21] and expanded in SLE patients [22], making this model specifically relevant to SLE pathogenesis
Clinical manifestations include: kidney damage through the production of anti dsDNA antibody, skin damage due to the presence of anti Sm antibody, massive lymphadenopathy.
o BXSB/Yaa: It is a recombinant inbred strain derived from the back cross of B6 X SB/Le F1 to SB/Le. This mouse shows a lupus-like phenotype characterized by lymphoid hyperplasia, immune complex-mediated nephritis that leads to death in 5 months in male mice and in 14 months in female mice, ANA and high-serum retroviral glycoprotein gp70 titers. BXSB/Yaa strain is uniquely suited to model the consequences of an overeactive TLR7/Type 1 interferon pathway and the presence of the Yaa locus accelerates SLE disease development in these mice [6], although this locus was not identified in human male SLE patients.
Induced mouse models of SLE:
o Pristane-induced lupus: Pristane is an isoprenoid alkane; its injection in peritoneal cavity causes ascitic fluid rich in mAbs like antiribonucleoprotein, anti-DNA and antihistone autoantibodies. As consequence of pristane injection, immuno complex deposit in kidney with subsequent nephritis, underline the importance of environment in SLE pathogenesis. In these mice, pristane induces a strong IFN-1 type response, that is found in many SLE patients as well.
o Chronic graft versus host disease models (cGVHD): these models are obtained through the injection of donor lymphocytes into a semiallogenic recipient to induce a lupus-like syndrome that develops in a few weeks. The main responsible for this lupus-like syndrome in this model are T CD4+ cells.
These animal models are used to study immune response in lupus-like syndrome. As shown in the previous paragraphs, spontaneous mouse models of SLE mainly highlights
the importance of genetic predisposition in this disease; on the other side, lupus-like syndrome induced by environmental manipulation are a proof that environment is involved in SLE pathogenesis as well. It was also demonstrated that cGVHD models of lupus with specific genetic background are protected against the development of lupus, underlining how both genetics and environment play a crucial role in the development of SLE. [7]
Genes, gender ratio and familial aggregation in SLE
Heritability is defined as the proportion of the phenotypic variance explained by genetic factors, while the familial transmission is defined as the function of the difference of normal deviation of the threshold from the mean liability between individuals with affected relatives and the healthy population [8]. The reason why studies found different results in familiarità in SLE could rely in the incorrect use of these two terms as synonims, in fact heritability accounts for genetic characteristics, while familial transmission account for both genetic and environmental factors.
There is a strong imbalance in gender ratio in SLE, and this may due to hormonal factors or an important role could be played by X chromosome.
A higher incidence of Systemic lupus is observed in patients affected by Klinefelter syndrome. Klinefelter syndrome is a genetic disease caused by a nondisjunction of the X chromosome during meiosis that, in case of fertilization, leads to a male individual with XXY karyotype. Klinefelter patients who develop SLE show a disease phenotype similar to women with mild SLE.
Nondisjunction of X chromosome during meiosis lead to one cell with two chromosomes and to one cell with no sexual chromosome. If the cell with no sexual chromosome is fertilized o fertilizes an egg cell, that will give rise to Turner syndrome. This syndrome is characterized by the presence of X0 karyotype and female phenotype with reduced fertility caused by oligomenorrhea and specific dysmorphic features. The prevalence of SLE in Turner patients was observed to be dimished relative to normal females: only three cases have been reported, maybe because karyotyping is not usually performed in these women[9].
Patients with SLE exhibit mitochondria T cells dysfunction, characterized by elevated mitochondrial transmembrane potentials and subsequent increased production of reactive
oxygen species (ROS) [10]. This alteration suggests a maternally transmitted predisposition to SLE.
It was hypothesized that human leukocyte antigen (HLA) and related genes are concerned in this disorder, although DRB3, DRB4 and DRB5 do not change the risk of developing SLE [11], while single nucleotide polymorphisms (SNPs) of CFB, MICB and MSH5 increase SLE susceptibility[12][13]. Among the large family of cytokines, SNPs of IL-6, IL-10, IL12B, IL-17F, IL31, IL-32 and IL-33 are associated with higher risk to develop SLE[14][15][16][17][18][19]. Specific SNPs of the IL-27 genes are associated with reduced SLE risk [18], a SNP of the IL-17F gene is associated with the production of anti-double stranded (ds) DNA antibodies [17] and a SNP in the IL-19 gene is associated with LN , SNPs of several other molecules such as BLK, CCR5, ficolin, Fcγ receptors, MX1, PLA2R1, T-bet, TLR-9, TNF-α, TNFAIP3, the vitamin D receptor have been associated with higher risk of SLE [20][21][22][23][24][25][26] or LN [27][28].
CD80 and ALOX5AP SNPs have been associated with SLE susceptibility and genetic interactions between BLK and DDX6 and between TNFSF4 and PXK have been observed in Asian population [29]. In European subjects a new locus associated with SLE has been discovered on chromosome 12 falling within an intergenic region, located upstream of PRICKLE1 and interleukin-1 receptor associated kinase 4 (IRAK4).
There are various form of SLE associated with an autosomal deficiency states, like genetic deficiency in complement proteins (C1q, C1r, C1s, C2, C4A, C4B) [30]. Other loci predisposing to SLE are: inhibitory Gc gamma binding receptor, endogenous DNase (Trex1) that leads to an autoimmune syndrome similar to SLE[31], exogenous DNase I and II. DNase activity is present in healthy people but it is increased in serum of SLE patients undergoing a relapse of their disease[32].
Many reports show a familial nature of Systemic lupus. Deapen and colleagues[33] found a 10-fold increased concordance in monozygotic compared to dizygotic twins, although the concordance is not complete.
Javierre and colleagues investigated DNA methylation status of 807 CpG-containing promoters of genes in SLE discordant MZ Twins [34]. There are significant differences in genes encoding for immune function, such as defense response, cell activation, immune response, cell proliferation, and cytokine production, all of which are potentially relevant in autoimmune inflammatory diseases. This broad range of associated functions suggests
that critical cell types and biological pathways involved in autoimmunity are affected by these aberrant DNA methylation changes. They found also alteration in ribosomal genes, such as a significant decrease in the 18S and 28S segments for the SLE siblings of twin pairs and hypomethylation of 18S and 28S in SLE siblings with respect to their corresponding healthy siblings.
O’Hanlon and colleagues [35] found out that probands and unrelated, matched controls differed significantly in gene expression for 104 probes corresponding to 92 identifiable genes. Those differences were mainly observed in genes involved in several overlapping pathways including immune responses (16%), signaling pathways (24%), transcription/ translation regulators (26%), and metabolic functions (15%). Interferon (IFN)-response genes (IFI27, OASF, PLSCR1, EIF2AK2, TNFAIP6, and TNFSF10) were up-regulated in probands compared to unrelated controls. Many of the abnormally expressed genes played regulatory roles in multiple cellular pathways. Gene expression levels for unaffected twins appeared intermediate between that of probands and unrelated controls (32% of the total probes). By contrast, in unaffected twins intermediate ordering was observed in 81% of the probes (81%) whose expression differed significantly between probands and unrelated controls.
Familial aggregation in SLE was examined by many studies in the past but, yet, most of them did not differentiate genetic and shared environmental factors, therefore they more accurately estimated familial transmission and not heritability as defined above, overestimating the genetic predisposition in this disease. In contrast to heritability, quantitative estimates of an individual’s risk of SLE are more useful for genetic counseling, however, reliable measures, such as relative risks (RRs), are largely unavailable or of limited reliability.
Efforts to define the pathogenesis of SLE focusing on genetic factors, and genome-wide association studies have successfully identified more than 30 susceptibility loci for SLE[36], although these findings account for less than 10% of the phenotypic variation observed [37].
A study by Kuo and colleagues [8] examined Taiwan population and calculated the relative risk of developing SLE in the relatives of patients affected by SLE, including parent-child relationship, full sibling pairs and twin pairs. Spouse of the patients were used as controls, comparing the liability threshold among individuals with an affected spouse with that of the general population, as far as spouses are supposed to share only the family environment
and the differences in liability threshold between siblings and spouse are contributed to by heritability. The individual risk of SLE and other autoimmune diseases was increased in families that include patients with SLE (RR 17.04% in individuals with 1 type of affected first-degree relative, and 35.09% in those having 2 or more relatives affected) and estimated heritability was 43.9%, significantly lower than previous estimates of 66% [38].
Epigenetic studies about autoimmune diseases are showing promising results. SLE seems to be the result of genetic predisposition and environmental factors that still have to be identified, and epigenetics efforts have the aim to bridge these two elements, suggesting specific environmental factors may induce reversibile, although heritable, modifications of gene expression. Such processes may in fact explain monozygotic twin discordance in autoimmune diseases and highlight the relevant role of these alterations in SLE pathogenesis. As far as these modifications may play a role in pathogenesis, these studies will be examined in the following chapter.
Pathogenesis
Immunity is defined as resistance to disease. The collection of cells, tissues, and molecules that mediate resistance to infections is called the immune system, and the coordinated reaction of these cells and molecules to infectious microbes is the immune response[39].
Immune system is composed of two defense mechanisms: innate immunity, adaptative immunity. Innate immunity mediates the initial protection against infections. Adaptive immunity, on the other side, develops more slowly and mediates the later and more effective defense against infections[39]. The acquired immune system is important in resolving an infection that is initially controlled by innate immunity and confers memory upon surviving individuals, so that reinfection is much less likely. Exogenous stimuli to the immune system are products of bacteria and viruses, and they’re called pathogen associated molecular patterns (PAMPs) [40]. Dendritic cells recognize PAMPs using pathogen recognition receptors, such as Toll-like receptors (TLRs). Necrotic debris from the cell death pathways, bacterial lipopolysaccharide, viral RNA and viral DNA act on TLRs [41]. A subset of dendritic cells, plasmacytoid dendritic cells (pDCs), is the body's major producer of type 1 IFNs, that is observed to be altered in SLE patients[42].
Paradoxically, invertebrates, lacking in acquired immune system, don’t seem to be more susceptible to infections than vertebrates[43][44], while even a minor congenital
deficiency in vertebrate acquired immunity is often incompatible with life, so questions about evolutionary advantages of acquired immune system have been raised [45].
The advantages of the adaptive immune system of vertebrates rely in combating an infectious agent that has gained purchase despite barriers and other innate mechanisms of immunity, but this advantage can be seen as an “evolutionary misstep”, with great short time benefit see but a long-term price to pay, with no possible turning back from the addiction to these elaborate and sophisticated immune response mechanisms[45].
One of this “missteps” is represented by autoimmune attack, although even innate system may also overreact, contributing to inflammatory components to autoimmunity[40][46]. Autoimmune diseases are the result of the loss of immune tolerance, defined as unresponsiveness to self antigens [39].
Physiologically, immune system recognizes self antigens and doesn’t react to them. The “tunable activation thresholds hypothesis” (TAT hypothesis) offers an explanation for the ability of T lymphocytes to be sensitive to stimulation by foreign ligands presented at low concentrations but to “ignore” the much more abundant self ligands that have only moderately lower affinity for the same TCR[47]. This tunable activation may be deficient in genetically predisposed individuals and, after an exogenous stimulus, immune system in these subjects may begin to recognize self antigens as pathological antigens and consequently attack self, giving rise to autoimmunity.
It is hypothesized that in autoimmune disorders immune system is wrongly instructed to react against self after specific, but yet unknown, environmental triggers, from viral and bacterial infection to toxicants, hormones, UV exposure and drugs.
Infections
Viral infections are supposed to play a role in autoimmunity through B cell activation and T cell infection. Both raise in autoantibodies and autoreactive T cells have been observed arising during a viral infection [48]. The supposed mechanism behind these findings is that viruses share antigenic sites or determinants with self components. This can be seen as the price to pay for crossreactivity, whose advantage is to increase rapidity in xenoantigen recognition[49].
Molecular mimicry may be structural or functional. Structural molecular mimicry occurs when a viral peptide has an amino acid sequence similar or identical to an amino acid
sequence of a self peptide, resulting in cross-reactive T-cell and B-cell responses. A potentially autoreactive T cell, possessing T-cell receptors that recognize both a foreign (viral) peptide and a selfpeptide, is activated by a virus-derived peptide. Thus, in addition to mediating an antiviral response, the T cell is also capable of mediating self-directed responses[50].
Francis and Perl examined the relationship between SLE and infections in a 2010 study [50]. The microrganisms examined were:
Epstein-Barr virus (EBV): the main differences between SLE patients and controls are: higher prevalence of EBV infection (99% in young SLE patients compared with 70% prevalence in controls); both latent and lytic genes after infection in mononuclear cells from SLE patients; 10–15-fold higher load in the peripheral blood of SLE patients compared with controls. Moreover, the production of the viral protein EBV nuclear antigen (EBNA)-1, antibodies against cross-react with lupus-associated autoantigens, including Ro, Sm B/B′ and SmD1, in lupus patients. B cells infected by EBV may also acquire antiapoptotic potential.
Cytomegalovirus (CMV): there are several case reports of lupus associated with human CMV (HCMV) infection, determined by either the presence of anti-HCMV IgM or viral DNA detected at the time of flare-up of symptoms of lupus, implicating HCMV as a possible etiologic agent in lupus.
Parvovirus B19: the infected patients by this virus exhibit clinical findings similar to some of clinical manifestations of SLE, like anemia, thrombocytopenia and arthritis. Infection by Parvovirus B19 may mimic SLE and induce elevation of rheumatoid factor, antiphospholipid, antilymphocyte and antinuclear antibodies after the peak of viremia; and, although in most cases the production of these antibodies cease after few weeks, in some cases autoimmune response persist and lead to arthritis and vasculitis.
Human Immunodeficiency Virus (HIV): a shift from a T helper (Th)1 to Th2-type cytokine profile is seen in both HIV infection and SLE, as well as clinical manifestations like anemia, leucopenia, thrombocytopenia, polymyositis and vasculitis. These observations suggest that there is a common mechanism mediating the increased apoptosis through increase of Th2-type cytokine production and autoantibody production in SLE and AIDS. Another interesting finding is the homology and immunologic cross-reactivity of a region of the protein
of U1snRNP lupus autoantigen with a p30 gag protein of most mammalian type C retroviruses.
Coxsackie virus: Coxsackie virus 2B protein has 87% amino acids homology with the 222–229 region of the major linear antibody binding site of Ro 60 kD autoantigen [51].
Human endogenous retroviruses (HERVs): they are fossil viruses that started to be integrated into the human genome about 30–40 million years ago and now make up 8% of the genome. Different antibodies to gag and env regions of HERVs have been reported in patients with autoimmune disorders, including SLE, and, in addition, the 70 k/U1 small nuclear RNA (snRNP) is a human autoantigen that has homology and cross-reactivity with a p30 gag retroviral protein[51].
A proof of the possible implication of HERVs in SLE pathogenesis is the demonstration of elevated serum levels of a retroviral glycoprotein (gp69/71) in NZBxNZW/F1 mice, together with virion glycoprotein deposits in glomerular lesions and high levels of circulating interferon as observed in patients with lupus[52].
Other viruses implicated[53]: transfusion- transmitted virus, Human Herpes Virus (HHV-6), HHV-7, HHV-8, Human Papilloma Virus (HPV), Dengue virus, human T cell lymphotropic virus (HTLV)
In a study by Gan et al. 2015[54] about twins and viral infections as possible triggers of autoimmune diseases, it was demonstrated that certain viral genes were expressed at higher levels in probands with systemic autoimmune disease (SAID) than unaffected twins and matched healthy controls. Specifically herpes simplex virus-2 was the only human viral pathogen detected with an increased viral gene expression in SAID probands. Interestingly, unaffected twins showed a viral gene expression intermediate between probands and healthy controls. These results suggest that environmental factors, such as infections, may be responsible for the discordance for SLE in monozygotic twins.
While all these studies point to infections as possible trigger of autoimmune diseases, others, summarized by Francis and Perl [50], hypothesize that specific microrganisms may be protective. Toxoplasma gondii infection may prevent lupus-like syndrome development in NZW/B mice, with reduced production of autoantibodies. Immunoregulatory events leading to Helicobacter pylori seropositivity correlate inversely with the risk of developing SLE, as well as malaria protects against the development of autoimmune disease such as
SLE probably through a higher production of TNF alpha. In fact, as a consequence to reduced ability to generate TNF, in low endemic areas for malaria there is a greater risk of developing autoimmune disease, such as SLE; this is a likely explanation for the higher rate of SLE in African–Americans. The protective role against autoimmunity of some specific infectious pathogens and the rise of autoimmune diseases in the last decades can be explained by the “hygiene hypothesis”: the reduced of microbial exposure in children for better hygiene conditions cause missing immune deviation from Th2 to Th1 and reduced activation of T-regulatory cells caused by reduced stimulation of the immune system [55].
UV exposure
Ultraviolet (UV) light, in particular UV-A1 and UV-B, can induce disease flares in patients with SLE and trigger disease onset [56].
Caricchio et al. [57] also proved that the ability of UV light to induce SLE or lupus flares appears to be dose dependent. The mechanism is UV-B induced apoptosis of keratinocytes and other dermal cells, with release of a large amount of autoantigens and pro-inflammatory cytokines to the circulation, triggering autoimmune-related systemic inflammation. In fact, in low doses of UV-B, normal cascade-dependent apoptosis has been induced in keratinocytes, while moderate and high doses cause DNA fragmentation, increase in IL-1α expression and necrosis of keratinocytes. Taken together, intermediate- and high-dose UV-B exposures promote pro-inflammatory apoptosis and necrosis, accompanied by the release of autoantigens and huge amount of pro-inflammatory cytokines, which trigger inflammatory response.
Environmental factors and toxicants: smoking, alcohol, chemicals, medications
Cigarette smoke dependance is now considered a disease itself, encoded by the International Classification of Disease, and no longer a mere risk factor for various diseases. A few case-control studies have found that previous and current smoking were associated with the risk of SLE and discoid lupus [58], and current smoking appeared to be a stronger risk factor for SLE than past smoking. A meta-analysis [59] of two cohort and seven prevalent studies found a very weak association (odds ratio (OR) 1.5, 95% confidence interval (95% CI): 1.09–2.08) for the development of SLE in current smoking vs. never smokers. There is no increase in risk of SLE as ex-smokers as compared with never-smokers. Interestingly, after adjustment for alcohol consumption and socioeconomic
status, which confound smoking status, the ORs augmented to 2.07 (95% CI: 1.33–3.23) and 1.76 (95% CI: 1.09–2.83), respectively, indicating that smoking per se was able to increase the risk of SLE. As confirmed by the review of Takvorian et al. [60], most of the studies evidenced that current smoking could be a stronger risk factor than former smoking, suggesting that smoking status could confer an immediate risk for SLE, related also with the average number of cigarettes smoked per day, cigarette-years of smoking, fraction smoked per cigarette and degree of smoke inhalation, with an OR at 1.31 (95% CI 1.02–1.70). On the other hand, the cessation of smoking seems associated with a reduction of the risk, which seems to return to that observed in subjects who have never smoked. Moreover, the consumption of smoke is associated with poor response to antimalarial drugs, both chloroquine and hydroxychloroquine drugs [61][62][63].
The association between SLE and alcohol is more ambigous[64]. No clear association has yet been convincingly reported with respect to the potential risk of the development of SLE and alcohol consumption, especially since the habit of smoking and alcohol intake often coexist, with confounding results [65][60]. Contrast results have been reported, with an increase of the risk in North America with alcohol consumption[64], a reduced risk according to a study based on the population of Kyushu [66] and no protective role of alcohol consumption according to an Internet-based study [67]. In a meta-analysis of six prevalent studies, a significant protective effect of moderate alcohol consumption against SLE was found (OR 0.72, 95% CI: 0.547–0.954) in those lupus patients who were treated for SLE for less than 10 years [68]. These differences in results may be due to the type of alcoholic consumed, in fact moderate consumption of red wine has many health benefits [69][70].
In a review by Mak and Tai [64], the relationship between SLE and many environmental toxicants, as well as medications, has been examined and the results are the following:
Crystalline silica exposure: Silica is an adjuvant that can induce the production of IL-1 and tumor necrosis factor α (TNF α). The Carolina Lupus Study suggested that crystalline silica did confer a risk of development of SLE, and the results were replicated by two subsequent studies; moreover, in another study, the prevalence of SLE related to silica exposure was 0.1/100, with a relative risk (RR) of 2.53 (95% CI: 0.30–21.64) compared with the general population.
Chlorinated compounds polychlorinated biphenyls/dibenzofurans (PCBs/PCDFs): these compounds may contaminate rice oil in Asia. This is associated with an
excessive frequency of lupus development amongst the exposure group after a 24-yearperiod, in addition to death related to liver disease.
Occupational exposures to mercury (Hg), liquid solvents and pesticides: they have been demonstrated to increase the likelihood for SLE development. Both organic and elementary Hg can induce anti-nuclear antibody (ANA) in murine models, as well as in humans. Occupation exposure of Hg was reported to increase the odds of developing SLE (OR 3.6, 95% CI: 1.3–10.0), and amongst the dental professionals, the OR of SLE development based on analyses of self-reported Hg exposure is 7.1 (95% CI: 2.2–23.4).
Use of lipstick and hair dye: they both have been reported to induce onset of SLE. Lipstick has been shown to induce photosensitivity and lupus flares, as well as the production of anti-dsDNA antibodies and progression of renal disease in NZB/W F1 mice. In an Internet-based case-control study, the use of lipstick at least thrice weekly was found to be associated with the occurrence of SLE, after adjustment for age, hair dye use and alcohol consumption, with an OR of 1.71 (95% CI: 1.04– 2.82). More frequent use of lipstick (seven days weekly) and early use of lipstick (before the age of 16) were associated with even marginally higher risks for the development of lupus, with ORs of 1.75 (95% CI: 0.89–3.44) and 1.95 (95% CI: 1.01–3.76), respectively. While the risk of induction of lupus by hair dye treatment, which contains aromatic amines, is theoretically present, it is largely refuted by large observational studies in human lupus. In a cross-sectional study performed in South and North Carolina, which involved 265 lupus patients and 355 healthy controls, the use of hair dye in women was shown to be associated with a small, yet marginally significant risk of SLE (OR 1.5, 95% CI: 1.0–2.2). In addition, use of hair dye for six years or more appeared to increase the risk (OR 1.7, 95% CI: 1.0– 2.7). However, in a prospective study in Spain, which followed 91 lupus patients and 22 patients with cutaneous lupus for 12 years, the use of hair dye treatment was not associated with disease flares and damage accrual in both groups.
Medications: well-known implicated drugs in lupus-like syndrome are procainamide, hydralazine, anti-TNF drugs.
Hormones
Systemic lupus erythematosus affects females 9 times more frequently than men, as mentioned previously [71].
Many theories about this marked gender ratio have been shown during the years, but there is no agreement among scientists. There are studies provided compelling evidence that an alteration in sex hormones levels is one of the factors that might contribute to the predominance of SLE in the female population.
It has been observed that estradiol (E2) administration, a highly active metabolite of estrogen, accelerates disease onset in females, whereas administration of testosterone ameliorates disease progression[72]. In fact, Estrogen receptors, ERα and ERβ, are expressed in B cells, demonstrating that the B cell is a target for the action of estrogen. Consequently, estrogen administration is sufficient to break tolerance of high-affinity DNA-reactive B cells. In a study by Chang et al., the estrogen-treated population displayed a lupus phenotype characterized by a rise in serum anti-DNA titers, glomerular immune complex deposition, and expansion and activation of DNA-reactive B cells [73]. An alteration in the ratio of transitional T1: A T2 B cell was also observed due to the relative increase in T2 cells in estrogen-treated groups and BCR-mediated apoptosis is reduced in the transitional B cell population[74]. These results confirmed impaired negative selection occurring at the transitional B cell stage.
BCL-2 gene is directly E2 responsive and its increased expression in B cells has been shown to disturb the negative selection of auto-reactive B cells; however, increased BCL-2 expression alone is not sufficient to induce an autoimmune phenotype [75]. Another element found was the increase of CD22 and SHP-1 in E2-treated mice. It is possible that a weakened BCR signal, resulting from increased CD22 and/or SHP-1 levels, favor the escape of B cells from the negative selection, due to diminished susceptibility to BCR-mediated apoptosis of transitional cells and for the expansion of marginal zone B cells.
In the NZW/B F1 model, deficiency of the estrogen receptor-α was shown to have a reduction of the production of anti-histone and anti-dsDNA IgG, accompanied by attenuating glomerulonephritis and increasing survival, both in female and male mice[76]. However, repletion of estrogens in ovariectomized adult NZW/B F1 mice reduced albuminuria and did not appear to increase the progress of lupus in these mice[77].
In clinical practice, a number of case series described the induction of SLE and disease flares in SLE patients who took combined oral contraceptive pills, but a randomized controlled trial found that combined oral contraceptives did not confer a higher risk of disease flares in women with clinically stable SLE [78]. On the other hand, another
randomized controlled trial did find a higher risk of mild to moderate lupus flares in postmenopausal women with SLE who used hormone replacement therapy[79].
Pregnancy is a paraphysiological condition characterized by a higher amount of estrogens. Pregnancy may have a role in lupus flares, more than etiology itself, so it will be thereby discussed in the chapter “Lupus flares”.
Epigenetics
Epigenetics was first defined in 1940s by Conrad Waddington as “the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being”, that refers to all molecular pathways modulating the expression of a genotype into a particular phenotype [80][81].
The main epigenetic processes consist of DNA methylation, histone acetylation and noncoding RNAs.
DNA methylation is a relatively stable and heritable epigenetic mark. It is characterized by the addition of a methyl group to the 5’ carbon in the pyrimidine ring of a cytosine residue, typically occurring in the context of cytosineguanine dinucleotides (CpG) in mammal DNA. The methylated status of CpG sites in a promoter region generally blocks the accessibility to transcriptional activators and consequently inhibits gene transcription, as a repressive “lock”, while an unmethylated state at the promoter permits transcription.
Histone acetylation is an epigenetic modification of chromatine. Histones are highly conserved protein that forms nucleosomes, the basic subunit of chromatin, in concert with DNA. Each nucleosome consists of a histone core containing two copies of histones H2A, H2B, H3 and H4, which wraps 146 base pairs of genomic DNA around its outer surface. Histone modification, like acetylation, methylation, ubiquitination, and sumoylation, affects local chromatin conformation and thereby alters its accessibility. Histone acetylation, generally occurring at lysine residues of histone tails, is associated with an open chromatin state that increases gene transcription, while the deacetylated histone exhibits a repressive effect on transcription. The acetylation process can be catalyzed by various histone acetyltransferases (HATs) such as PCAF, Tip60, and p300/CBP; histone deacetylation is mediated by a series of histone deacetylases (HDACs) including HDAC1 and sirtuins (i.e., SIRT1-7). Similarly, histone methylation and demethylation are catalyzed by histone methyltransferases (HMTs) and histone demethylases (HDMs), respectively.
Noncoding RNA refers to a large variety of transcripts without the ability of coding proteins, such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). MicroRNAs negatively regulate gene expression by causing mRNA destabilization or cleavage or by inhibiting translation.
In a review by Long et al. about epigenetics and autoimmune diseases (2016)[82], the importance of epigenetic alterations in SLE patients and animal models cells is highlighted. The main modifications observed are:
DNA hypomethylation-sensitive genes: Javierre et al. in 2010 found a lower DNA methylation in the blood leukocytes of SLE patients compared with their respective monozygotic twin, as mentioned before. Other studies[83] also demonstrated that there are genes positively (RAB22A, STX1B2, and LGALS3BP) or negatively (DNASE1L1 and PREX1) correlated with disease activity in SLE. Many of the hypomethymetilated genes are a series of interferon-regulated genes, whose expression is not elevated in naive T CD4+ cells but increased in total T CD4+ cells from lupus patients, suggesting naive T CD4+ cells may have been epigenetically modified and instructed for a rapid expression upon stimulation [84]. Modification of specific histones: the main alterations reported consist of a global site-specific histone H3 and H4 hypoacetylation in both splenocytes of MRL/lpr lupus mice[85] and CD4+ T cells from patients with SLE as well as several key enzymes regulating histone acetylation and deacetylation, as HATs and HDACs, respectively, are abnormally expressed in CD4+ T cells from patients with active SLE, among which SIRT1 is overexpressed while CREBBP, P300, HDAC2, and HDAC7 are downregulated. On the other side, enhanced histone acetylation has been associated with overexpression of cytokine genes such as TNF-a and IL-17 in lupus[86][87]. Nearly 63% of the genes with increased H4ac in SLE patients monocytes have upstream IRF1 (interferon regulatory factor 1) binding sites and exhibit the potential to be regulated by IRF1, consistent with the previous knowledge of type-I interferon hyper-responsiveness in lupus [88].
Aberrant expression of HMTs and HDMs, the enzymes that regulate histone methylation and demethylation, respectively, may contribute to the imbalance of histone methylation status in the pathogenesis of lupus. A decreased expression of the histone methyltransferases SUV39H2 and EZH2 has been observed in CD4+ T cells of patients with SLE. Several HDMs also show altered expression levels in
CD4+ T cells of MRL/lpr lupus mice compared to normal controls, among which JMJD3 is up-regulated[89].
Noncoding RNAs: In peripheral blood mononuclear cells (PBMCs) from SLE patients, microRNA 155 and 146a expression appear to be down-regulated [90][42].
The up-regulated expression of miR-21, miR-148a, miR-126, and miR-29b in circulating CD4+ T cells from SLE patients can directly or indirectly suppress DNMT1 and thus contribute to DNA hypomethylation in SLE CD4+ T cells [42][91][92].
lncRNAs show a differential expression in patients with autoimmune diseases such as SLE, polymyositis/dermatomyositis, RA, T1DM, MS, and autoimmune thyroid, indicating growth arrest-specific transcript, also known as GAS5, as a lncRNA gene potentially implicated in the pathogenesis of SLE [93]. This lncRNA plays essential roles in normal growth arrest, apoptosis, and cell cycle both in T-cell lines and non-transformed lymphocytes [94]. The down-regulated GAS5 may inhibit cell cycle and apoptosis, and thus may contribute to the promotion of antigen exposure and production of autoantibodies [95].
Altered immune processes
Other processes implicated in SLE pathogenesis concern innate immunity. It was observed by Lood et al. demonstrated that mitochondrial DNA is a leading actor in the scenario of NETosis being able to drive this phenomenon in neutrophils isolated from SLE patients (32) and NETosis in SLE can also be enhanced by circulating apoptotic microparticles (33). Neutrophils can produce IL-6 upon stimulation and IFNα has been recently identified as a powerful stimulus of IL-6 production in SLE (34). Abnormalities of DCs isolated from patients with SLE have also been reported being the expression and function of the inhibitory receptor immunoglobulin-like transcript 4 hampered in this disease (35).
As mentioned previously in “Animal models”[5], gut microbiota alterations have been linked to B and T cells alterations and subsequent enhanced proinflammatory cytokine production in SF1 mice, particularly in female mice, possibly explainig the marked gender bias in SLE even in animal models. Gaudreau et al. in fact demonstrated that both plasma cell- and gut-imprinted- α4β7 T cell frequencies were significantly higher in the spleen and
gut mucosa of female (SWR 3 NZB)F1 (SNF1) mice and that female SNF1 mice also carried large numbers of interleukin (IL)-17-, IL-22- and IL-9-producing cells in the lamina propria (LP) compared to their male counterparts. This indicates that the gut immune system may play a role in the initiation and progression of disease in SLE and the associated gender bias. Moving to the human counterpart, SLE but not healthy control fecal microbiota is able to induce the differentiation of CD4+ naïve T lymphocytes into Th17 cells thereby hampering the Treg/Th17 cell ratio [96]. Th17 cells can also be induced upon binding of ICs to FcγRIIIa on CD4+ Tcells through Syk phosphorylation [97].
Other immune cell functions altered in SLE are the following:
Follicular T helper cells (Tfh): they are expanded mainly in patients with more active disease and are directly correlated to parameters related to B-cell hyperactivity such as including serum IgG, Ics and autoantibodies [98].
CD8+ T cells: the demonstration of signalling lymphocytic activation molecule family member 4 (SLAMF4) has been linked to reduced cytotoxic activity and may explain at least in part the reduced response to infections in SLE patients [99]. Among recently identified T lymphocyte subpopulations,
DN T cells: these are a T lymphocyte subpopulation that can be induced by IL-6 and IL-23. They are expanded in SLE and are associated with disease activity [100].
Angiogenic T cells (Tang): they are a specific T cell subset involved in the repair of damaged endothelium. They are expanded in SLE, especially in patients displaying anti-dsDNA antibodies [101]. In SLE patients, these cells also display features of immune-senescence like lacking CD28 on the cell surface [102]. Interestingly, the total proportion of circulating CD28- cells is strongly associated with disease activity and in particolar with lupus nephritis [103].
B lymphocytes: pronounced Syk and Btk phosphorylation was observed in these cells from patients with active SLE compared to those of healthy individuals. Syk and Btk transduce activation signal through B cell receptor (BCR) and mediate crosstalk between BCR and TLRs and the JAK-STAT pathway [104]. The glucocorticoid-induced leucine zipper (GILZ) protein, an endogenous mediator of anti-inflammatory effects of glu cocorticoids (GC), is downregulated in SLE naïve B cells [105]. Even the complement receptor type 1 is downregulated, although its inhibitory capacity is not impaired [106]. Regulatory B (Breg) cells are also decreased in patients with lupus nephritis [107].
Diagnosis
The American College of Rheumatology (ACR) published diagnostic criteria for SLE in 1982, which were revised in 1997. The Systemic Lupus Collaborating Clinics (SLICC) international group undertook the evaluation and further revision of the above criteria resulting in a new classification system that is based on clinical and immunologic manifestations. It was determined that the SLICC 2012 criteria were more sensitive and may allow patients to be classified with SLE earlier in the disease course.
Table 1 “Criteria classification for SLE” [108]
In the clinical setting, these criteria can be used as an aid in diagnosis, but formal diagnostic criteria for SLE are lacking. A diagnosis of SLE is made if 4 criteria are met.
Lupus flare
“A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment”[109].
Predictors of lupus flares are [110]:
Anti-dsDNA positivity: OR: 2.3 (95%CI=1.03–5.12); p=0.063. Actually, other studies have demonstrated that changes in anti-dsDNA values are more predictive of flare than their presence or absence[111][112][113]. Anti-dsDNA fluctuating and increasing values were highly predictive of flares.
Therapy with steroids (mean prednisone dosage = 11.5±7.1 mg/daily) not combined with immunosuppressant and/or antimalarial: it was found to be significantly associated with occurrence of flare [OR: 3.2 (95%CI = 1.30–7.62); p = 0.015
Other biomarkers like inflammatory cytokines are still under evaluation[114].
Causes of lupus flares are heterogeneous[114]. Among them, one of the most common causes is tapering. This flare likely represents a recrudescence of prior subclinical disease activity and generally resolves with resumption of the previously successful regimen.
Ultraviolet (UV) light is the most widely recognized trigger of SLE flares. UV exposure may lead to photosensitivity rash, but also other symptoms such as arthralgia, weakness, and headaches. Mechanism of these effects are still under investigation. UV light exposure is known to directly damage DNA and proteins in cells, leading to keratinocyte cell death and the release of proinflammatory cytokines, such as interleukin-1α and tumor necrosis factor-α, and, at the same time, UV light is known to affect the localization of characteristic autoantigens such as Ro, Sm, and RNP, redirecting them to the cell surface or to the surface of apoptotic vesicles. All these processes can be responsible for SLE flares[114].
Hormones are supposed to play a role in SLE, both because gender ratio is quite marked (see chapter “Genetics, gender ratio and hereditability”) but also because estrogens seem to enhance immune system activation via several effects, as previously discussed (see “Pathogenesis – Hormones”). Whether or not lupus flares are increased during pregnancy
has been a subject of some dispute. A meta-analysis of studies regarding pregnant SLE patients reported an overall flare rate of 25.6 %, with 16.1 % of flares consisting of nephritis [115]. The largest single study of pregnancy outcomes, using data obtained from the PROMISSE cohort, showed that severe flare rates by weeks 23 and 35 of gestation were 2.5 and 3 %, respectively, while rates of mild-moderate flares were 12.7 and 9.6 %. Maternal flares, higher disease activity, and smaller increases in C3 levels later in pregnancy predicted adverse pregnancy outcomes [116]. A confounding element, cause of this apparently low rates of flares, is the exclusion of patients with significant proteinuria, elevated creatinine, and prednisone dose higher than 20 mg/day at baseline. In older and retrospective pregnancy studies, flare rates are much higher, especially if patients had active lupus in the 6 months before pregnancy (up to 77 %, though estimates vary widely) [117] [118]–[121].
Bacterial and viral infections are often cited by SLE patients as triggers for their disease; but the association between specific infections and specific patients is less clear[114]. Parvovirus B19 and CMV have been reported to cause both induction of SLE and flare, and other studies have also demonstrated that the abnormally high frequency of EBV-infected cells in patients with SLE is associated with the occurrence of SLE disease flares[50].
Clinical manifestations
Systemic lupus erythematosus is a chronic inflammatory disease that can affect any organ of the body, with heterogeneous clinical manifestations from patient to patient and during the course of the disease in the same patient.
Clinical manifestations include:
Cutaneous manifestations
Musculoskeletal manifestations: myositis, arthralgias, arthritis, osteonecrosis, tendon involvement
Renal involvement Serological abnormalities
Neuropsychiatric manifestations: central nervous system manifestations, peripheral nervous system manifestations, psychiatric manifestations
Pulmonary involvement Cardiovascular manifestations
Table 2: Cumulative percentage incidence of clinical and laboratory manifestations in SLE, from “Glucocorticoid Therapy in Systemic Lupus Erythematosus – Clinical Analysis of 1,125 Patients with SLE”[122]
Cutaneous manifestations
Cutaneous manifestations occur in approximately 80% of patients during the course of the disease[123] and they are the first sign of SLE in up to 25% of cases.
Skin involvement in SLE is classified in specific and non specific lupus erythematosus lesions. specific lesions were classified as acute, subacute, or chronic lesions and were either localized, disseminated, or generalized [124].
Acute lesions: they include malar rash, generalized erythema, bullous lupus. Subacute lesions: anular lesions, policyclic lesions, psoriasiform lesions Chronic lesions: discoid lupus, lupus profundus.
Those manifestations are well summarized and described by Ribero et al. in a 2017 review[124].
Acute lesions
“Malar” or “butterfly” rash (fig. 4) is is characterized by small, discrete erythematous macules, papules and plaques or a more widespread congestive erythema in the central areas of the face, such as on the nose, chin, front, cheeks andmalar regions, sparing nasolabial folds and periorbital regions, in contrast with dermatomyositis rash (fig. 5). Acute Cutaneous Lupus Erythematosus (ACLE) can affect the earlobes, scalp and neck. Lesions may become confluent,with scaling, erosions and crusting.
Widespread erythematous macular and papular lesions are another kind of ACLE manifestations. They are generalized and affect the lateral aspect of the arms, elbows,
Fig. 4
On the left, malar rash in a patient affected by SLE, typically sparing nasolabial folds and periorbital regions; on
the right, a woman affected by dermatomyositis who
clearly displays a complete different type
of rash, affecting periorbital regions
shoulders, knees, and trunk. They are mainly localized on UV-exposed areas and they usually appear after a sun exposure.
Erythematous lesions of the hands are typically found between the metacarpophalangeal joints and interphalangeal joints and the knuckles are spared, while the opposite is observed in dermatomyositis. Palms and soles may also be affected.
ACLE usually regresses after therapy without any sequelae or leaving transient pigmentary changes, especially in dark-skin people.
Bullous lupus (fig. 6) is characterized by the presence of vesicles and bullae on sun-exposed areas or widespread. They may arise on clinically normal-appearing or inflamed skin. They have an arciform or figurate distribution pattern and are accompanied by a burning sensation.
Bullous LE does not develop scarring neither milia formation
Fig. 6 Bullous lupus erythematosus. Blistering lesions in an individual previously diagnosed with SLE. From “The cutaneous spectrum of SLE” by Ribero et al. 2017.[124]
Subacute Cutaneous Lupus Erythematosus
The lesions of SCLE (fig.7) symmetrically affect the V area of the neck, upper trunk, shoulders, and arms. SCLE is characterized by erythematous macules or papules
that evolve into scaly
papulosquamous psoriasiform lesions or into annular patches and plaques in approximately 50% of cases, respectively; although even large polycyclic lesions may be observed.
Fig. 7 From “The cutaneous spectrum of SLE” by Ribero et al. 2017.[124] Typical lesions of subacute cutaneous lupus erythematosus with annular and
Healing results in postinflammatory hyper- and/or hypopigmentation, grayish atrophic scarring and telangiectasias.
Chronic Cutaneous Lupus Erythematosus
Chronic Cutaneous Lupus Erythematosus (CCLE) usually affects the ears, the face, the scalp and/or the neck. CCLE is characterized by the presence of a variable sized coin-shaped erythematous plaque associated with an adherent follicular hyperkeratosis. There is first erythema with follicular hyperkeratosis, which then evolution to atrophy, pigmentary changes and scarring (fig. 8).
Sequelae consist in permanent scars and, if scalp is affected, in alopecia (fig. 9).
Both figures come from “The cutaneous spectrum of SLE” by Ribero et al.
2017.[124]
Fig. 8 Discoid lupus of the cheek Fig. 9 Discoidlupus of the scalp with scarring alopecia. Erythema, depigmentation, and follicular
hyperkeratosis are visible
Other skin lesions in SLE: dermal and hypodermal damage Other skin lesions in SLE are the following:
Lupus tumidus: it is characterized by highly photosensitive erythematous papules and plaques, without skin surface alteration
Papular mucinosis: Abnormal accumulation of glycosaminoglycans between collagen fibers in the dermis
Reticular Erythematous Mucinosis: erythematous plaque-like clinical aspect is predominant, and it involves symmetrically the upper chest
Lupus Panniculitis: also known as lupus profundus. It is characterized by painful indurated dermo-hypodermal nodules or plaques, affecting the thighs, the upper arms or the cheek area of the face. These lesions potentially result in skin depression and scarring.
Photosensitivity
The definition of photosensitivity is “skin rash resulting from an unusual reaction to sunlight by patient history or physician observation”, although this definition is not enough precise. In fact, some experts consider photosensitivity an induction of skin lesions following sun exposure, whereas others also consider sunburn and aggravation of the disease in the spring and summer times[125].
Importantly, UV light exposure is not only able to induce and exacerbate lesions of almost all subtypes of CLE [126], but can also trigger organ involvement in SLE, including lupus nephritis[127].
Nail and nailfold involvement
As reviewed by La Paglia et al.[128], there is a large variety of nail abnormalities in SLE patients and also a great variety of nailfold videocapillaroscopy (NVC) abnormalities, similar to early scleroderma pattern. Higuera et al. found NVC abnormalities in 43,8% of the nail distrophy (ND) patients and in 13.8% of the patients without ND. They observed an association between ND with an increase damage index and with NVC abnormalities.
Non SLE-specific cutaneous involvement Non SLE-specific cutaneous involvement include:
Vascular lesions: vasculitis, teleangiectasie, livaedo reticularis, chronic ulcers, peripheric gangrena, rheumatoid nodules
Oral and mucosal ulcers
Non scarring frontal or widespread alopecia Panniculitis
Orticarioid lesions Sclerodactilia Cutaneous calcinosis
Renal involvement
Lupus nephritis (LN) is one of the most serious complications of SLE and it is the major predictor of poor prognosis.
The development of nephritis in patients with SLE involves multiple pathogenic pathways including aberrant apoptosis, autoantibody production, immune complex deposition and complement activation[129].
LN is classified thanks to renal biopsy. The KDIGO, ACR and EULAR/ERA– EDTA guidelines recommend that a renal biopsy is performed to confirm the diagnosis, assess disease activity and/or chronicity and guide treatment. In general, renal biopsy should be considered when a patient with SLE develops proteinuria (>500 mg per day or >3+ on urine dipstick), active urine sediments or evidence of renal insufficiency (defined by an estimated glomerular filtration rate <60 ml/min/1.73 m2)[129].
International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of LN [130]:
Table 3 “The classification of glomerulonephritis in SLE Revisited”[130]
The clinical presentations of LN are: nephrosic syndrome, persistent proteinuria, acute kidney injury, end-stage renal disease (ESRD).
Microscopic hematuria is mostly discovered by screening urinalysis. Macroscopic hematuria is relatively rare; it usually indicates very severe renal involvement [131].
Rapidly progressive glomerulonephritis (RPGN) is defined as doubling of serum creatinine within a three-month period, usually in the context of proliferative glomerulonephritis, fibrinoid necrosis and cellular crescents in the renal biopsy[131].
Proteinuria is primarily a reflection of the extent of involvement of peripheral glomerular capillary loops. Thus, the degree of proteinuria tends to increase incrementally within the classes of mesangial to focal proliferative to diffuse proliferative lupus nephritis;
membranous nephropathy, which involves essentially all glomerular capillary loops, is characteristically accompanied by heavy proteinuria. Nephrotic range proteinuria is defined as proteinuria greater than 3.5 g per day; this degree of proteinuria usually causes the nephrotic syndrome which includes hypoalbuminemia, hyperlipidemia and, in the absence of diuretic therapy, peripheral edema [131].
Renal failure, by convention, refers to loss of glomerular filtration function. In SLE, renal failure is primarily caused by the hypercellularity and inflammation within the glomerulus, though nephrotoxic drugs and other prerenal and postrenal causes of azotemia should always be considered. Sudden, acute renal failure is exceptional; rapidly progressive renalfailure (RPGN as defined above) occurs in a small fraction of lupus patients. Mostly, renal function fluctuates in parallel with remissions and exacerbations of lupus nephritis; chronic renal insufficiency results from cumulative damage and loss of nephrons, ultimately producing end-stage renal disease (ESRD). Renal tubular dysfunctions, such as impaired urine concentrating ability and renal tubular acidosis, are rarely clinically significant or demanding of therapy[131].
Tubulointerstitial (TIN) features are often under-recognised in SLE. Renal biopsies from 142 patients who underwent repeat biopsy (RB) were evaluated for: inflammatory interstitial infiltrates; interstitial fibrosis; tubulitis; and tubular atrophy. A study of evaluation of renal biopsies for inflammatory infiltrates, interstitial fibrosis, tubulitis and tubular atrophy confirmed the presence of at least one TIN lesion in up to 60% of patients at first biopsy and 75% at RB. The transition from moderate-severe to absent-mild findings was frequent, especially for tubulitis (and inflammatory infiltrates), regressing in around 70% of the cases, while tubular atrophy and interstitial fibrosis showed the highest rate of worsening between the reference and the second biopsy patients [128].
The presence of autoantibodies directed against several cytoplasmic (ANCA) plays a very important role in the pathogenesis of LN. Multisystem damage and higher frequency of antinucleosome antibodies, antihistone antibodies, antimitochondrial M2 antibodies, and anticardiolipin antibodies occurred in positive LN patients compared to ANCA-negative. Moreover, ANCA-positive As reviewed by La Paglia et al.[128], LN patients show high scores on the pathological chronic renal index and have poor renal outcomes. In an international multi- ethnic/racial observational cohort of newly diagnosed SLE patients, LN occorre in 38.3% of subjects, often as the initial presentation with a poor prognosis in terms of end-stage renal disease (ESRD). SLE ESRD patients with anti-phospholipid
