Lupus disease awareness

Lupus epidemiology

Prevalence and incidence

Systemic lupus erythematosus (SLE), the most common form of lupus, is considered a rare disease, though there is considerable variation in estimates of its incidence and prevalence around the world (Figure 1)¹. A systematic review published in 2017 found that the incidence of SLE tended to be higher in America, Asia and Australasia than in European countries, with the highest incidences reported in North America (23.2/100,000 person-years, 95% CI: 22.4, 24.0) and the lowest in Africa (0.3/100,000 person-years) and Ukraine (0.3/100,000 person-years, 95% CI: 0, 1.5)¹. Similar variation has been observed in reported prevalence values, which range from 3.2 cases per 100,000 in India to 517.5 cases per 100,000 in UK Afro-Caribbean populations^2–4.

Figure 1. The global prevalence (A) and incidence (B) of SLE (Adapted¹).

Despite substantial geographical variation in the incidence of SLE, peak incidence is consistently reported during reproductive age years, with a mean age at initial diagnosis estimated at 24 and 35 years^5,6. It is worth noting that although data suggest that rates of SLE are increasing, this could be, at least in part, attributable to improved disease awareness and patient survival in recent decades⁷.

Gender

Women aged 20–40 years make up 80–90% of SLE cases⁸

SLE is considerably more common in women than men, with an estimated female-to-male ratio of 9:1, though some reports suggest that this figure could be as high as 15:1^1,2,9,10. This gender bias is not unusual among autoimmune diseases but is particularly pronounced in SLE. Various hypotheses have been proposed to explain why this might be the case^6,9. For example, it has been suggested that oestrogen may play a role in the pathogenesis of this disease, given that SLE is most common among women of childbearing age⁶. Similarly, investigations into the potential role of the X chromosome have yielded interesting results, including the identification of several genetic variants associated with increased risk of SLE located on the X chromosome, as well as the observation of higher rates of Klinefelter syndrome (47, XXY) among men with SLE, compared with the general population^6,11.

Ethnicity

In general, the prevalence of SLE is higher in non-Caucasians than in Caucasians⁵. Indeed, though figures vary, SLE is thought to be up to 4 times more prevalent among black women and 2–5 times more prevalent in Asian and Hispanic women than in Caucasian counterparts^6,9,12–14. Particularly high rates of SLE have been reported in black and Indo-Asian populations in the UK and some estimates suggest that the prevalence of SLE could be up to 8 times that of Caucasian individuals².

SLE is more common in Black, Hispanic and Asian populations than in Caucasians⁶

Moreover, disease severity and long-term outcomes are worse in non-Caucasian groups and patients of African, Hispanic and Asian descent are more likely than Caucasians to experience haematological, serosal, neurological and renal manifestations of their disease⁷.

Mortality

Historically, SLE was regarded as an acute fatal disease^15,16. However, the development of more advanced diagnostic tools and therapeutic options has led to a significant improvement in 5-year survival from just 50% in the 1950s to over 90% today¹⁵. Nevertheless, risk of death among patients with SLE remains 2–5-fold higher than in the general population¹⁷.

Despite improved disease awareness and the development of more effective treatment options, SLE is still associated with an increased risk of morbidity and mortality^17,18

The elevated risk of morbidity and mortality associated with SLE is perhaps unsurprising given the potentially severe multisystemic nature of this disease¹⁷. Various factors, including ethnicity, gender and geographical region, are thought to influence patients’ mortality risk¹⁷. Patients with SLE are more likely to develop a wide range of different comorbidities, compared with healthy individuals, accounting for an estimated 27.6% of variation in mortality between these two groups¹⁹. Cardiovascular disease is the leading cause of death among patients with SLE, followed by infection and severe disease activity¹⁷.

Genetics

Various studies have confirmed a genetic contribution in SLE²⁰. Heritability of SLE is thought to be 43–66% and the concordance rate in monozygotic twins is estimated at 24%, compared with just 2% in dizygotic twins²¹. To date, genome-wide association studies have identified more than 90 different loci associated with increased SLE risk^21,22. Genetic variants include those that increase the availability of self-antigens or contribute to innate immune cell activation or adaptive immune system dysfunction²³. For most patients, multiple genes are thought to contribute to the development of SLE but, in some cases, disease may be monogenic, arising as the result of a single gene mutation²⁴. Examples of genes associated with SLE risk include those that encode immune components, such as HLA, IRF5, ITGAM, STAT4, BLK and CTLA4²⁵. Studies investigating the role of epigenetic dysfunction in SLE have also revealed that alterations in DNA methylation patterns may play an important role in the pathogenesis of SLE²⁶.

Lupus pathophysiology

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease in which almost any tissue or organ can be affected^25,27. Despite considerable improvements in the prognosis of SLE, our understanding of the pathogenesis of this disease remains incomplete^18,28,29. Significant disease heterogeneity has led to challenges in characterising the different disease phenotypes and identifying the precise causes of the disease²⁸. Nevertheless, SLE is thought to involve the complex interplay between genetics and various environmental risk factors including exposure to certain viruses, chemicals and ultraviolet radiation, as well as vitamin D deficiency, immunological factors and sex hormones, particularly oestrogenl^25,26. Innate and adaptive immune responses directed against autoantigens are central to the pathogenesis of SLE²⁹ (Figure 2).

Figure 2. Pathogenesis of SLE (Adapted^23,30). CD40, cluster of differentiation 40; DC, dendritic cells; EBV, Epstein-Barr virus; IFN, interferon; MHC, major histocompatibility complex; NET, neutrophil extracellular traps; PDC, plasmacytoid dendritic cell; PMN, polymorphonuclear neutrophil; TCR, T cell receptor; TLR, toll-like receptor.

The source of autoantigens in SLE is hypothesised to be apoptotic or necrotic cells, including neutrophil extracellular traps (NETs) that are released by neutrophils as they undergo cell death^31,32. During apoptosis, cells release apoptotic bodies, which contain cellular fragments, including nuclear antigens²⁸. Normally, nuclear antigens are largely inaccessible to immune cells, as apoptotic material is rapidly disposed of by phagocytes such as macrophages^28,31,33. In genetically susceptible individuals, increased apoptosis and less effective clearance may lead to accumulation of nuclear antigens, a key event in the pathogenesis of SLE^33,34. Antigen presenting cells, such as myeloid dendritic cells, present nuclear antigens to T cells, which become activated as a result³⁴. Activated T cells help autoreactive B cells to generate antinuclear antibodies³⁴. These autoantibodies bind nuclear antigens, forming immune complexes that migrate to different organs and tissues throughout the body, where they are deposited^29,34. This elicits a local inflammatory response that causes cellular damage via activation of the complement system^29,35. Immune complexes perpetuate the cycle of inflammation via further activation of myeloid dendritic cells³¹.

Pathogenesis of SLE involves the breakdown of self-tolerance and generation of autoantibodies²⁸

Uptake of immune complexes by plasmocytoid dendritic cells via Fc receptors also occurs³⁶. Immune complexes are engulfed into endosomes, where they activate toll-like receptors (TLRs), particularly TLR7 and TLR9. This ultimately leads to the production of several different cytokines, including interferon-α (IFN-α), which has several effects, including upregulation of B cell activating factor (BAFF or BLyS), reduced function of Treg cells and plasma cell induction^28,31,36. NETs may also induce production of IFN-α by plasmocytoid dendritic cells³¹.

Lupus disease states

Systemic lupus erythematosus (SLE) has a relapsing and remitting course. Periods of remission are punctuated by flares that is usually very difficult to predict and are characterised by increased disease activity. The clinical presentation of SLE is highly heterogeneous as a result of variable patterns of organ involvement and disease severity among patients, as Professor Petri explains in the video below²⁵.

Clinical manifestations

The clinical manifestations of SLE may change over the course of the disease and periods of months or even years may elapse before the emergence of different symptoms³⁷. The myriad signs and symptoms associated with SLE are summarised in Figure 3.

Figure 3. Summary of the signs and symptoms of SLE showing cumulative frequencies for each (Adapted³⁸).

Constitutional symptoms

Constitutional symptoms such as fever that cannot be explained by an infection, extreme fatigue and weight loss are frequently reported in patients with SLE^39,40. These symptoms are very common, affecting >90% of patients, and are often among the first symptoms to become apparent³⁹.

Cutaneous manifestations

Cutaneous involvement is common, with many patients experiencing photosensitivity and an associated malar or ‘butterfly’ rash, which generally extends across the nasal bridge and cheeks but may also appear on other areas of the body⁴⁰. This rash is typically raised and does not usually become apparent until several days after UV exposure, lasting several weeks thereafter²⁵. Alopecia, Raynaud’s phenomenon and ulcers located in the nose or mouth may also be features of cutaneous involvement in patients with SLE⁴⁰.

Musculoskeletal manifestations

Musculoskeletal involvement is reported in up to 95% of patients⁴¹. The associated symptoms often become apparent early in the disease course and are reported as the presenting symptom in around half of all cases⁴¹. Patients frequently report painful or stiff joints that may appear inflamed some or all of the time⁴⁰. These debilitating symptoms can have a profound impact on patients’ quality of life and contribute significantly to work disability^42,43. There is a wide clinical spectrum of musculoskeletal involvement. Transient and migratory arthralgia are very common, while a smaller proportion of patients may experience deforming and/or erosive arthropathy^41,44. Less commonly, patients with musculoskeletal involvement may experience myositis, fibromyalgia, bone fracture and osteonecrosis⁴¹.

Renal manifestations

SLE affecting the kidneys is known as lupus nephritis⁴⁵. An estimated 50% of patients with SLE have renal involvement in which decreased kidney function may lead to abnormal serum creatinine levels and proteinuria⁴⁰. Symptoms of lupus nephritis include oedema, foamy urine, polyuria, nocturia and hypertension⁴⁵. Renal disease activity is a key prognostic factor and many patients with SLE may ultimately develop end-stage renal disease, which can prove fatal^40,45.

Around 50% of patients with SLE have renal involvement⁴⁰

Cardiovascular manifestations

Cardiac involvement, which can affect any of the heart’s structures, is associated with increased morbidity and mortality in SLE⁴⁶. It is thought that more than half of patients with SLE may have cardiac involvement, though this is often asymptomatic⁴⁷. Pericarditis is the most common cardiac manifestation of SLE, though valvular disease and myocarditis may be present in some patients⁴⁸.

Pulmonary manifestations

Between 20% and 90% of patients with SLE report pulmonary involvement at some point over the course of their disease⁴⁹. Among these patients, the extent of respiratory involvement varies considerably, ranging from asymptomatic pleural disease to acute respiratory failure⁴⁸. The major respiratory issues associated with SLE are pleuritis, acute lupus pneumonitis, chronic lupus pneumonitis, pulmonary hypertension and ‘shrinking lung’ syndrome^49,50. Patients with these conditions may experience painful breathing, coughing or dyspnoea⁴⁰.

Neuropsychiatric manifestations

Neuropsychiatric lupus (NPSLE) is associated with a broad range of symptoms that arise as a result of autoantibody infiltration of the brain. NPSLE includes central and peripheral nervous system manifestations ⁵¹. Almost half of patients with SLE experience neuropsychiatric symptoms at some point during the course of their disease⁵¹. Headaches, depression, anxiety, seizures, stroke or cognitive impairment may occur in patients with central nervous system involvement⁴⁰.

Almost half of patients with SLE experience neuropsychiatric and peripheral nervous system manifestations⁵¹

Complications

SLE is associated with a diverse range of complications that may arise as a result of the disease itself or the drugs that are used to treat it. The nature of these complications depends on which organs are affected and vary in severity between patients^39,52.

Joint deformities

Patients with severe musculoskeletal involvement may develop joint deformities as the result of arthropathy, the most common manifestation of SLE⁵³. While most patients with SLE experience non-deforming arthropathies, 5–15% may develop a more chronic and disabling form, resulting in deformities comparable to those observed in patients with rheumatoid arthritis^53,54. These chronic joint deformities are known as Jaccoud’s arthropathy and commonly include swan neck, thumb subluxation, ulnar deviation and boutonniere⁵⁵. Unlike in rhupus syndrome, which is widely considered an unusual combination of rheumatoid arthritis and SLE, Jaccoud’s arthropathy generally appears non-erosive at X-ray and occurs as a result of ligament and tendon involvement⁵⁴.

Kidney failure

Lupus nephritis is among the most common and severe complications of SLE, affecting around 50% of patients^40,56. Renal involvement often develops within 5 years of initial diagnosis⁵⁶. Though the development of immunosuppressants has improved the prognosis of patients with lupus nephritis, rates of chronic kidney disease and end-stage renal disease remain undesirably high among these patients, and as such lupus nephritis is considered an important risk factor for morbidity and mortality in SLE⁵⁶.

Lupus nephritis often develops within 5 years of initial diagnosis⁵⁶

Myocardial infarction

Cardiac complications are seen in around half of all cases of SLE and are considered a major mortality risk among these patients⁵⁷. Compared with the general population, the risk of myocardial infarction is up to ninefold higher in patients with SLE and there is some evidence to suggest a link between SLE and accelerated atherosclerosis^57,58.

Stroke

Patients with SLE are at increased risk of ischaemic and haemorrhagic stroke, compared with the general population⁵⁹. Indeed, it is thought that 3–20% of patients with SLE are affected, accounting for 20–30% of deaths in this group⁶⁰. In these patients, stroke generally occurs within a few years of initial diagnosis and can be attributed to inflammation, endothelial activation or a prothrombotic state as a result of antiphospholipid antibodies⁶¹. Several comorbidities associated with SLE are considered major cardiovascular risk factors and may lead to stroke later on in the disease course⁶¹. 

Rates of stroke are particularly high among younger patients among whom risk may be up to ten times that of healthy individuals⁶¹. Risk of stroke is also thought to be higher among patients of black or Hispanic descent than among Caucasians⁵⁸. Interestingly, in some cases, stroke may represent the first manifestation of SLE, though this is quite unusual⁶⁰.

Scarring

Up to 85% of patients with SLE may have some form of skin involvement over the course of their disease⁶². After arthritis, cutaneous involvement is the second most common manifestation of SLE and can have an adverse impact on patients’ quality of life⁶³. These cutaneous manifestations of SLE can be disfiguring, leaving patients with skin atrophy and scarring, particularly in the case of discoid rashes^25,64. In addition, scarring alopecia may leave patients with permanent hair loss as a result of follicular stem cell destruction⁶³.

Pregnancy complications

Given that SLE most commonly affects women of childbearing age, it is particularly important to consider the impact of this disease on pregnancy outcomes⁶⁵. Patients with high disease activity are advised to delay pregnancy until they have achieved better disease control in order to mitigate the risk of fetal or maternal complications⁶⁵. Potential maternal complications of SLE include lupus flares, gestational diabetes and pre-eclampsia⁶⁵. Risks to the fetus include miscarriage, intrauterine fetal death, preterm membrane rupture, premature birth, intrauterine growth restriction and neonatal lupus⁶⁵.

Osteonecrosis

Osteonecrosis is thought to affect 10–15% of patients with SLE, though this figure is considerably higher when taking into account those with asymptomatic lesions⁶⁶. Reduced blood flow to the bone results in the death of bone marrow and trabecular bone^66,67. This can have a considerable adverse impact on patients’ quality of life and may result in significant disability⁶⁶. Glucocorticoid use is an important risk factor for osteonecrosis, which most commonly affects the femoral head and ultimately necessitates joint arthroplasty in the majority of patients⁶⁸.

Bone fractures

Patients with musculoskeletal involvement are prone to osteoporosis and bone fractures. In addition to general osteoporosis risk factors, SLE is associated with disease-related risk factors including inflammation and the use of certain drugs, particularly glucocorticoids^69,70.

Low bone mineral density is common in SLE and symptomatic bone fractures are thought to occur in 6–12.5% of patients following diagnosis^69,70. These most commonly affect the femur, vertebra, rib, foot, ankle or arm. Rates of prevalent vertebral fractures are considerably higher, though often underreported⁶⁹.

Ocular complications

Ocular involvement is reported in around one-third of patients with SLE and can be sight-threatening if not treated appropriately^71,72. Keratoconjunctivitis sicca, also known as dry eye disease or secondary Sjögren’s syndrome, is the most common ocular manifestion associated with SLE⁷¹. Patients with SLE are also at risk of developing cataracts, particularly posterior subscapular cataracts; however, this is due to the use of glucocorticoids. Although a cornerstone of SLE treatment, the use of glucocorticoids is a major risk factor and predisposes to cataracts, even at low doses⁷². Risk factors for cataract in the general population, such as female sex and non-Caucasian race, may also apply to a large proportion of the SLE population⁷². Retinal toxicity is a long-term complication associated with the use of antimalarials, which are recommended for the treatment of SLE⁷³.

Lupus burden of disease

Burden of disease

As survival rates in systemic lupus erythematosus (SLE) improve, there is growing interest in the burden that this increasingly common disease places on both patients and society⁷⁴. In the video below, Professor Petri shares her perspective on what makes SLE such a burdensome disease.

Humanistic burden

Despite significant improvements in our ability to recognise and treat SLE, it remains a burdensome disease. The manifestations of SLE are highly varied and associated with a range of disabling symptoms, many of which are ‘invisible’ and poorly understood by those who are unfamiliar with this disease⁸.

Quality of life among patients with SLE is thought to be similar to that of people living with AIDS⁸

Health-related quality of life (HRQoL) is an important consideration in SLE^8,75. This takes into account the physical, mental and social wellbeing of patients and may be influenced by a wide range of different disease-related and environmental factors⁸. Multiple general and disease-specific tools have been developed to help quantify these aspects of patients’ experiences (Table 1)⁷⁶.

Table 1. Examples of patient-reported outcome measures used in patients with SLE (Adapted⁷⁶)

The fatigue and pain associated with SLE often affects patients’ ability to participate in physical activities, putting them at increased risk of developing both physical and mental comorbidities^8,75. The mental impact of inactivity is compounded by body image concerns associated with weight gain and changes to the skin, which include facial erythema and the development of a discoid rash, as well as potential scarring, hair loss and skin atrophy^8,75. Anxiety and depression are very common among patients with SLE, with the mental functioning of patients adversely affected by their reduced ability to carry out normal daily activities and decreased physical ability^77,78.

SLE also represents a significant social burden for many patients⁷⁵. Though social functioning may be improved in patients with a strong support network, many patients report feelings of isolation^8,75,79. Photosensitivity may prevent some patients from participating in outdoor activities, and fatigue will often lead to the cancellation of social engagements⁸. As many of the most debilitating symptoms of SLE are not immediately visible, this lack of participation may be misinterpreted by friends or relatives^8,79. Patients may also experience difficulties in forming new relationships, particularly intimate relationships. Rates of sexual dysfunction among women with SLE are high as a result of physical discomfort, low self-esteem and psychological problems⁸.

The importance of determining health-related quality of life in patients with SLE is highlighted in the EULAR guideline, which recommends that this should be assessed during every clinical visit^75,80. Interestingly, though many studies suggest that HRQoL correlates with disease activity, evidence regarding this is inconsistent².

Economic burden

In addition to the substantial humanistic impact of SLE, this disease is also considered economically burdensome^2,81. For example, the association between SLE and increased rates of work disability and absenteeism is well established, contributing to the considerable indirect cost of this disease⁸¹. One study found that patients with SLE were significantly less likely than those without SLE to be in full-time employment (24% vs. 50%, p<0.05). Among those who were employed, high rates of absenteeism and presenteeism were reported⁸¹. Furthermore, of the 344 SLE patients included in this study, 31% were not working and not seeking work at the time of the study, as compared with just 4% of healthy controls (P<0.05)⁸¹.

From the perspective of patients, the frustrations of work loss related to their illness may be compounded by the high direct costs of living with a chronic disease. The direct costs incurred by patients may arise as the result of high healthcare resource utilisation, with the added indirect cost of childcare and travel to and from appointments².

As a result of the high economic cost of reduced work productivity and absenteeism, as well as high healthcare resource utilisation, SLE also represents a significant societal burden^2,74,81. However, determining the direct and indirect economic costs of SLE is challenging and estimates vary considerably between studies².

Lupus unmet medical needs

In the video below, Professor Petri provides detail on the major challenges and unmet needs that remain in the field of SLE.

Despite significant advances in the field, there remain a large number of unmet needs associated with SLE⁸². An important example is the lack of therapeutic options for the treatment of severe refractory disease⁸². This puts patients at risk of developing irreversible long-term organ damage and means that mortality risk remains unacceptably high^37,82. From the patient perspective, even among those who achieve remission, certain symptoms often persist to the detriment of their quality of life³⁷. Fatigue, for example, though not life-threatening, is a common complaint among patients with SLE³⁷. Current therapeutic options do not provide relief from this debilitating symptom, which may continue to have an adverse impact on patients even in cases where treatment is considered objectively effective³⁷.

Lupus diagnosis

Diagnosing systemic lupus erythematosus (SLE) can be challenging because of its phenotypic heterogeneity as well as the highly variable and often non-specific nature of its signs and symptoms⁸³. Consequently, diagnosis is often delayed and many patients are initially misdiagnosed with a different condition that has a similar presentation, such a rheumatoid arthritis, rosacea, dermatomyositis, undifferentiated connective tissue disease, Hashimoto’s disease, Sjögren’s syndrome or fibromyalgia⁸⁴. Diagnosis is considered particularly challenging in patients with early-stage disease who have few signs and symptoms, those who are negative for antinuclear antibodies (ANAs) (up to 20% of cases) or have organ-dominant forms of disease, and those with unusual presentations³⁸.

SLE diagnosis is based on clinical findings in combination with laboratory investigation³⁸. The development of three major sets of classification criteria by the American College of Rheumatology (ACR; 1997), the Systemic Lupus Collaborating Clinics (SLICC; 2012) and American College of Rheumatology and the European League against Rheumatism (EULAR; 2019) has facilitated earlier classification of SLE, but it is worth noting that patients are not necessarily required to fulfil these criteria in order to receive a diagnosis^38,85–87.

Three major sets of criteria have been developed to facilitate the earlier classification of SLE^38,85–87

The ACR preliminary criteria for the classification of SLE were first published in 1971 but were subsequently revised in 1982 and then again in 1997. Based on these, classification of SLE requires patients to meet at least 4 out of a possible 11 criteria (malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, antinuclear antibodies, haematologic disorder, immunologic disorder, neurologic disorder, renal disorder and serositis)^87,88.

In 2012, SLICC produced a refined set of clinical and immunological criteria (Table 2)⁸⁶. A sample of 690 patients and controls was used to validate these criteria, which were found to be more sensitive than the previous ACR criteria⁸⁶. Classification of SLE requires patients to meet four or more of the SLICC criteria, including at least one clinical criterion and one laboratory criterion, or have biopsy proven lupus nephritis with a positive ANA or anti-dsDNA test⁸⁶.

Table 2. The Systemic Lupus Collaborating Clinics (SLICC) classification criteria for SLE (Adapted⁸⁶). ANA, anti-nuclear antibodies; anti-Sm, anti-Smith; C3/C4, complement component 3/4; CH50, 50% haemolytic complement; dsDNA, double-stranded DNA.

In 2019, the ACR and EULAR published their new classification criteria for SLE⁸⁵. If patients meet the entry criterion of at least one positive ANA test, they should be assessed with respect to 24 clinical and immunological criteria, each of which is weighted from 2–10 points (Figure 4). Those with a total score of ≥10 points are classified as having SLE.

Figure 4. 2019 EULAR/ACR classification criteria for SLE (Adapted⁸⁵). *Do not count additional criteria within the same domain; in an assay with 90% specificity against relevant disease controls. Anti-β2GP1, anti-β2 glycoprotein 1; C3/4, complement component 3/4; dsDNA, double-stranded DNA SLE, systemic lupus erythematosus.

Despite increased awareness of SLE and improvements to the classification criteria, making a diagnosis in the early stages of the disease remains a challenge. Delays in the diagnosis and treatment of SLE are associated with a worse prognosis, highlighting the importance of early diagnosis⁸³.

References

1. Rees F, Doherty M, Grainge MJ, Lanyon P, Zhang W. The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies. Rheumatology. 2017;56(11):1945–1961.
2. Carter EE, Barr SG, Clarke AE. The global burden of SLE: Prevalence, health disparities and socioeconomic impact. Nat Rev Rheumatol. 2016;12(10):605–620.
3. Malaviya AN, Singh RR, Singh YN, Kapoor SK, Kumar A. Prevalence of Systemic Lupus Erythematosus in India. Lupus. 1993;2(2):115–118.
4. Rees F, Doherty M, Grainge M, Davenport G, Lanyon P, Zhang W. The incidence and prevalence of systemic lupus erythematosus in the UK, 1999-2012. Ann Rheum Dis. 2016;75(1):136–141.
5. Pons-Estel GJ, Ugarte-Gil MF, Alarcón GS. Epidemiology of systemic lupus erythematosus. Expert Rev Clin Immunol. 2017;13(8):799–814.
6. Nusbaum JS, Mirza I, Shum J, Freilich RW, Cohen RE, Pillinger MH, et al. Sex Differences in Systemic Lupus Erythematosus: Epidemiology, Clinical Considerations, and Disease Pathogenesis. Mayo Clin Proc. 2020;95(2):384–394.
7. Yeoh SA, Dias SS, Isenberg DA. Advances in systemic lupus erythematosus. Medicine (United Kingdom). 2018;46(2):84–92.
8. Olesińska M, Saletra A. Quality of life in systemic lupus erythematosus and its measurement. Reumatologia. 2018;56(1):45–54.
9. Izmirly PM, Wan I, Sahl S, Buyon JP, Belmont HM, Salmon JE, et al. The Incidence and Prevalence of Systemic Lupus Erythematosus in New York County (Manhattan), New York: The Manhattan Lupus Surveillance Program. Arthritis Rheumatol. 2017;69(10):2006–2017.
10. Deligny C, Thomas L, Dubreuil F, Théodose C, Garsaud AM, Numéric P, et al. Lupus systémique en Martinique: Enquête épidémiologique. Rev Med Interne. 2002;23(1):21–29.
11. Scofield RH, Bruner GR, Namjou B, Kimberly RP, Ramsey-Goldman R, Petri M, et al. Klinefelter’s syndrome (47,XXY) in male systemic lupus erythematosus patients: Support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum. 2008;58(8):2511–2517.
12. Dall’Era M, Cisternas MG, Snipes K, Herrinton LJ, Gordon C, Helmick CG. The Incidence and Prevalence of Systemic Lupus Erythematosus in San Francisco County, California: The California Lupus Surveillance Project. Arthritis Rheumatol. 2017;69(10):1996–2005.
13. Somers EC, Marder W, Cagnoli P, Lewis EE, DeGuire P, Gordon C, et al. Population-based incidence and prevalence of systemic lupus erythematosus: The Michigan lupus epidemiology and surveillance program. Arthritis Rheumatol. 2014;66(2):369–378.
14. Lim SS, Bayakly AR, Helmick CG, Gordon C, Easley KA, Drenkard C. The incidence and prevalence of systemic lupus erythematosus, 2002-2004: The Georgia lupus registry. Arthritis Rheumatol. 2014;66(2):357–368.
15. Borchers AT, Keen CL, Shoenfeld Y, Gershwin ME. Surviving the butterfly and the wolf: Mortality trends in systemic lupus erythematosus. Autoimmun Rev. 2004;3(6):423–453.
16. Kernder A, Elefante E, Chehab G, Tani C, Mosca M, Schneider M. The patient’s perspective: Are quality of life and disease burden a possible treatment target in systemic lupus erythematosus? Rheumatol (United Kingdom). 2020;59(Suppl 5):V63–V68.
17. Fors Nieves CE, Izmirly PM. Mortality in Systemic Lupus Erythematosus: an Updated Review. Curr Rheumatol Rep. 2016;18(4):1–7.
18. Fan Y, Hao YJ, Zhang ZL. Systemic lupus erythematosus: year in review 2019. Chin Med J (Engl). 2020;133(18):2189–2196.
19. Kuo CF, Jun Chou I, Rees F, Grainge MJ, Lanyon P, Davenport G, et al. Temporal relationships between systemic lupus erythematosus and comorbidities. Rheumatol (United Kingdom). 2019;58(5):840–848.
20. Lewis MJ, Jawad AS. The effect of ethnicity and genetic ancestry on the epidemiology, clinical features and outcome of systemic lupus erythematosus. Rheumatology (Oxford). 2017;56(1):i67–i77.
21. Wang YF, Zhang Y, Lin Z, Zhang H, Wang TY, Cao Y, et al. Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups. Nat Commun. 2021;12(1):1–13.
22. Su C, Johnson ME, Torres A, Thomas RM, Manduchi E, Sharma P, et al. Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells. Nat Commun. 2020;11(1):1–17.
23. Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, Van Vollenhoven R, et al. Systemic lupus erythematosus. Nat Rev Dis Prim. 2016;2(1):16039.
24. Fike AJ, Elcheva I, Rahman ZSM. The Post-GWAS Era: How to Validate the Contribution of Gene Variants in Lupus. Curr Rheumatol Rep. 2019;21(1):3.
25. Fava A, Petri M. Systemic lupus erythematosus: Diagnosis and clinical management. J Autoimmun. 2019;96:1–13.
26. Teruel M, Sawalha AH. Epigenetic Variability in Systemic Lupus Erythematosus: What We Learned from Genome-Wide DNA Methylation Studies. Current Rheumatology Reports. 2017;19(6):1–10.
27. Pisetsky DS. The immunopathogenesis and immunopathology of systemic lupus erythematosus. In: Lupus Erythematosus: Clinical Evaluation and Treatment. 2013. Springer New York: 13–26.
28. Tsokos GC, Lo MS, Reis PC, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol. 2016;12(12):716–730.
29. Pan L, Lu MP, Wang JH, Xu M, Yang SR. Immunological pathogenesis and treatment of systemic lupus erythematosus. World J Pediatr. 2020;16(1):19–30.
30. Hay EM. Systemic lupus erythematosus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. British Journal of Rheumatology. 1992. New York. McGraw-Hill: 207.
31. Rekvig OP, Van Der Vlag J. The pathogenesis and diagnosis of systemic lupus erythematosus: Still not resolved. Semin Immunopathol. 2014;36(3):301–311.
32. Salemme R, Peralta LN, Meka SH, Pushpanathan N, Alexander JJ. The Role of NETosis in Systemic Lupus Erythematosus. J Cell Immunol. 2019;1(2):33.
33. Pravda J. Systemic Lupus Erythematosus: Pathogenesis at the Functional Limit of Redox Homeostasis. Oxid Med Cell Longev. 2019;1651724.
34. George Bertsias, Richard Cervera, Dimitrios T Boumpas. Systemic Lupus Erythematosus: Pathogenesis and Clinical Features. EULAR. 2012;476–505.
35. Pabón-Porras MA, Molina-Ríos S, Flórez-Suárez JB, Coral-Alvarado PX, Méndez-Patarroyo P, Quintana-López G. Rheumatoid arthritis and systemic lupus erythematosus: Pathophysiological mechanisms related to innate immune system. SAGE Open Med. 2019;7:205031211987614.
36. Sifuentes Giraldo WA, García Villanueva MJ, Boteanu AL, Lois Iglesias A, Zea Mendoza AC. New Therapeutic Targets in Systemic Lupus. Reumatol Clínica (English Ed. 2012;8(4):201–207.
37. Basta F, Fasola F, Triantafyllias K, Schwarting A. Systemic Lupus Erythematosus (SLE) Therapy: The Old and the New. Rheumatol Ther. 2020;7(3):433–446.
38. Fanouriakis A, Tziolos N, Bertsias G, Boumpas DT. Update οn the diagnosis and management of systemic lupus erythematosus. Ann Rheum Dis. 2021;80(1):14–25.
39. Vaillant AAJ, Goyal A, Bansal P, Varacallo M. Systemic Lupus Erythematosus (SLE) - StatPearls - NCBI Bookshelf. StatPearls [Internet]. 2020. https://www.ncbi.nlm.nih.gov/books/NBK535405/. Accessed 19 March 2021.
40. Maidhof W, Hilas O. Lupus: An overview of the disease and management options. P T. 2012;37(4):240–249.
41. Torrente-Segarra V, Salman Monte TC, Corominas H. Musculoskeletal involvement and ultrasonography update in systemic lupus erythematosus: New insights and review. Eur J Rheumatol. 2018;5(2):127.
42. Mahmoud K, Zayat A, Vital EM. Musculoskeletal manifestations of systemic lupus erythmatosus. Curr Opin Rheumatol. 2017;29(5):486–492.
43. Piga M, Congia M, Gabba A, Figus F, Floris A, Mathieu A, et al. Musculoskeletal manifestations as determinants of quality of life impairment in patients with systemic lupus erythematosus. Lupus. 2018;27(2):190–198.
44. Di Matteo A, Isidori M, Corradini D, Cipolletta E, McShane A, De Angelis R, et al. Ultrasound in the assessment of musculoskeletal involvement in systemic lupus erythematosus: state of the art and perspectives. Lupus. 2019;28(5):583–590.
45. Musa R, Brent LH, Qurie A. Lupus Nephritis. 2021. StatPearls Publishing http://www.ncbi.nlm.nih.gov/pubmed/29762992. Accessed 19 March 2021.
46. Burkard T, Trendelenburg M, Daikeler T, Hess C, Bremerich J, Haaf P, et al. The heart in systemic lupus erythematosus – A comprehensive approach by cardiovascular magnetic resonance tomography. PLoS One. 2018;13(10):e0202105.
47. Nikdoust F, Abedini M, Tabatabaei A. Cardiac Involvement in Systemic Lupus Erythematosus: Echocardiographic Evaluation. Iran Hear J. 2017;18(2):23–29.
48. Tselios K, Urowitz MB. Cardiovascular and Pulmonary Manifestations of Systemic Lupus Erythematosus. Curr Rheumatol Rev. 2017;13(3):206–218.
49. Amarnani R, Yeoh SA, Denneny EK, Wincup C. Lupus and the Lungs: The Assessment and Management of Pulmonary Manifestations of Systemic Lupus Erythematosus. Front Med (Lausanne). 2021;7:610257.
50. How Lupus Affects the Lungs : Johns Hopkins Lupus Center. https://www.hopkinslupus.org/lupus-info/lupus-affects-body/lupus-lungs/. Accessed 23 March 2021.
51. Kivity S, Agmon-Levin N, Zandman-Goddard G, Chapman J, Shoenfeld Y. Neuropsychiatric lupus: A mosaic of clinical presentations. BMC Medicine. 2015;13(1):43.
52. Arango M-T, Shoenfeld Y, Cervera R, Anaya J-M. Infection and autoimmune diseases. In: Juan-Manuel Anaya, Yehuda Shoenfeld, Adriana Rojos-Villarraga, Roger A Levy, Richard Cervera, editors. Autoimmunity: From Bench to Bedside. 2013. Bogota (Columbia). El Rosario University Press: 237–378.
53. Pipili C, Sfritzeri A, Cholongitas E. Deforming arthropathy in systemic lupus erythematosus. Eur J Inten Med. 2008;19(7):482–487.
54. Gabba A, Piga M, Vacca A, Porru G, Garau P, Cauli A, et al. Joint and tendon involvement in systemic lupus erythematosus: an ultrasound study of hands and wrists in 108 patients. Rheumatology. 2012;51(12):2278–2285.
55. Santiago M. Jaccoud-type lupus arthropathy: practical classification criteria. Lupus Sci Med. 2020;7:405.
56. Anders HJ, Saxena R, Zhao M hui, Parodis I, Salmon JE, Mohan C. Lupus nephritis. Nat Revi Dis Primers. 2020;6(1):7.
57. Kreps M.D. A, Paltoo B.A. K, McFarlane M.D I. Cardiac Manifestations in Systemic Lupus Erythematosus: A Case Report and Review of the Literature. Am J Med Case Reports. 2018;6(9):180–183.
58. Liu Y, Kaplan MJ. Cardiovascular disease in systemic lupus erythematosus: an update. Curr Opin Rheumatol. 2018;30(5):441–448.
59. Guraieb-Chahín P, Cantú-Brito C, Soto-Mota A, Guerrero-Torres L, Flores-Silva F, Chiquete E, et al. Stroke in systemic lupus erythematosus: epidemiology, mechanism, and long-term outcome. Lupus. 2020;29(5):437–445.
60. Ioannidis S, Mavridis M, Mitsias PD. Ischemic stroke as initial manifestation of systemic lupus erythematosus: A case report and review of the literature. eNeurologicalSci. 2018;13:26–30.
61. Nikolopoulos D, Fanouriakis A, Boumpas D. Cerebrovascular Events in Systemic Lupus Erythematosus: Diagnosis and Management. Mediterr J Rheumatol. 2019;30(1):7–15.
62. Uva L, Miguel D, Pinheiro C, Freitas JP, Marques Gomes M, Filipe P. Cutaneous manifestations of systemic lupus erythematosus. Autoimmune Dis. 2012;2012:834291.
63. Udompanich S, Chanprapaph K, Suchonwanit P. Hair and Scalp Changes in Cutaneous and Systemic Lupus Erythematosus. Am J Clin Dermatol. 2018;19(5):679–694.
64. Ehmouda zaid F, Abudsalam N. Cutaneous Manifestation of Systemic Lupus Erythematosus [SLE], Correlation with Specific Organ Involvement, Specific Auto Antibodies and Disease Activity and Outcome. Dermatol Case Rep. 2016;1(2):1000108.
65. Petri M. Pregnancy and Systemic Lupus Erythematosus. Best Pract Res Clin Obstet Gynaecol. 2020;64:24–30.
66. Hussein S, Suitner M, Béland-Bonenfant S, Baril-Dionne A, Vandermeer B, Santesso N, et al. Monitoring of osteonecrosis in systemic lupus erythematosus: A systematic review and metaanalysis. J Rheumatol. 2018;45(10):1462–1476.
67. Caramaschi P, Biasi D, Dal Forno I, Adami S. Osteonecrosis in systemic lupus erythematosus: An early, frequent, and not always symptomatic complication. Autoimmune Dis. 2012;2012:725249.
68. Kallas R, Li J, Petri M. Predictors of osteonecrosis in systemic lupus erythematosus: A prospective cohort study. [Online ahead of print]. Arthritis Care Res (Hoboken). 2020. doi:10.1002/acr.24541.
69. Bultink IEM. Osteoporosis and fractures in systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2012;64(1):2–8.
70. Carli L, Tani C, Spera V, Vagelli R, Vagnani S, Mazzantini M, et al. Risk factors for osteoporosis and fragility fractures in patients with systemic lupus erythematosus. Lupus Sci Med. 2016;3(1):e000098.
71. Dammacco R. Systemic lupus erythematosus and ocular involvement: an overview. Clin Exp Med. 2018;18(2):135–149.
72. Alderaan K, Sekicki V, Magder LS, Petri M. Risk factors for cataracts in systemic lupus erythematosus (SLE). Rheumatol Int. 2015;35(4):701–708.
73. Fanouriakis A, Bertsias GK, Boumpas DiT. Chloroquine as alternative antimalarial in systemic lupus erythematosus. Response to ‘2019 update of the EULAR recommendations for the management of SLE: Don’t forget chloroquine’ by Figueroa-Parra et al. Ann Rheum Dis. 2020;79(9):e115–e115.
74. Meacock R, Dale N, Harrison MJ. The humanistic and economic burden of systemic lupus erythematosus: A systematic review. Pharmacoeconomics. 2013;31(1):49–61.
75. Elera-Fitzcarrald C, Fuentes A, González LA, Burgos PI, Alarcón GS, Ugarte-Gil MF. Factors affecting quality of life in patients with systemic lupus erythematosus: important considerations and potential interventions. Expert Rev Clin Immunol. 2018;14(11):915–931.
76. Izadi Z, Gandrup J, Katz PP, Yazdany J. Patient-reported outcome measures for use in clinical trials of SLE: A review. Lupus Sci Med. 2018;5(1):e000279.
77. Pereira MG, Duarte S, Ferraz A, Santos M, Fontes L. Quality of life in patients with systemic lupus erythematosus: the mediator role of psychological morbidity and disease activity. Psychol Health Med. 2020;25(10):1247–1257.
78. Golder V, Ooi JJY, Antony AS, Ko T, Morton S, Kandane-Rathnayake R, et al. Discordance of patient and physician health status concerns in systemic lupus erythematosus. Lupus. 2018;27(3):501–506.
79. Mazzoni D, Cicognani E, Prati G. Health-related quality of life in systemic lupus erythematosus: a longitudinal study on the impact of problematic support and self-efficacy. Lupus. 2017;26(2):125–131.
80. Fanouriakis A, Kostopoulou M, Alunno A, Aringer M, Bajema I, Boletis JN, et al. 2019 Update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019;78(6):736–745.
81. Utset TO, Baskaran A, Segal BM, Trupin L, Ogale S, Herberich E, et al. Work disability, lost productivity and associated risk factors in patients diagnosed with systemic lupus erythematosus. Lupus Sci Med. 2015;2(1):e000058.
82. Lateef A, Petri M. Unmet medical needs in systemic lupus erythematosus. Arthritis Res Ther. 2012;14(SUPPL. 4):S4.
83. Sebastiani GD, Prevete I, Piga M, Iuliano A, Bettio S, Bortoluzzi A, et al. The importance of an early diagnosis in systemic lupus erythematosus. Lupus. 2016;18(3–4):212–215.
84. Piga M, Arnaud L. The main challenges in systemic lupus erythematosus: Where do we stand? J Clin Med. 2021;10:243.
85. Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 2019;78(9):1151–1159.
86. Petri M, Orbai AM, Alarcõn GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64(8):2677–2686.
87. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.
88. Tan EM, Cohen AS, Fries JF, Masi AT, Mcshane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25(11):1271–1277.