Systemic lupus erythematosus (SLE) is an autoimmune disorder that can affect many organ systems and all age groups in both genders, but the great majority of SLE patients are women who are diagnosed during childbearing ages. Given the chronic character and the relatively young age of onset, SLE is associated with an accumulation of damage over the disease course, often causing increasing morbidity and negatively impacting the health-related quality of life. Ultimately accrual of damage also contributes to increased mortality. Damage in SLE is a combination of direct damage from the disease and, substantially, side effects of lupus treatments. Thus, the relationship between accumulated damage and the effects of treatments, especially glucocorticoids usage, in several domains in the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SLICC/ACR Damage Index [SDI]) has long been discussed and researched.

The SDI [1], published in 1996 primarily for research purposes, has since become widespread and is by far the most used instrument to measure and objectify the accumulation of damage in SLE at a yearly interval longitudinally. In this review, we aimed to give a thorough summary of the latest research about the main domains of damage in SLE. We also present representative data from two large SLE cohorts, the Toronto cohort in Canada and the Karolinska cohort in Sweden, both followed with the SDI over many years.

Cardiovascular disease (CVD) is one of the most common causes of premature mortality in patients with SLE [2]. The high risk for CVD was already reported in 1976 [3] and has since gained increasing attention. But, twenty years ago few studies addressed the details of the high cardiovascular risk, and many combined outcomes which could include different types of arterial events and sometimes also venous thromboembolism. During the past two decades our view has become more differentiated, and we are now aware that risk factors vary with type of event and that risk prediction tools for the general population underestimate cardiovascular risk in SLE [4]. Thus, specific lupus associated risk factors contribute toward cardiovascular events and are the focus of more recent studies.

We have learned that relative to the general population, the risk is highest in younger patients and during the first years after disease onset [[5], [6], [7]]. The risk is also dependent on the SLE clinical phenotype, where especially patients with antiphospholipid antibodies (aPL) [8] and patients with nephritis and impaired renal function [5,9,10] are at higher risk than other SLE subgroups. Furthermore, treatment with glucocorticoids adds to the risk. Both a high cumulative dose [8], the average daily dose [11], and a high current dose (>20 mg prednisolone daily) [12] have been associated with cardiovascular events. However, high disease activity is also considered a risk factor for CVD [12], making it difficult to disentangle the contribution of glucocorticoids per se and the indication for their use, i.e., active disease and often nephritis. Furthermore, several studies, primarily published during the past decade, have demonstrated that some SLE risk genes, e.g., STAT4, also contribute to higher cardiovascular risk [13].

More recent data demonstrate that ischemic heart disease (IHD) and ischemic cerebrovascular disease (ICVD) have partly different risk profiles, where aPL is a strong risk factor for ICVD [9], while nephritis and impaired renal function appears to be more convincingly linked to accelerated atherosclerosis [14] and IHD [9].

In addition to premature mortality, approximately 10–16 % of lupus patients have a history of one or several arterial events [4,15]. This situation is often associated with impaired health-related quality of life (HRQoL) and affects negatively work productivity and economic impact. A previous cardiovascular event is proof of clinical vascular disease, a strong risk factor for further events, and an indication for secondary prevention [16]. Thus, it is a major task for clinicians to early identify those at risk and offer tailored prophylactic treatment to prevent the first cardiovascular event.

Based on an extensive literature review, EULAR has published guidelines for cardiovascular risk management in patients with systemic autoimmune diseases, including SLE [17]. These state that all lupus patients should be screened for traditional modifiable cardiovascular risk factors such as smoking, overweight, sedentary lifestyle, hyperlipidemia, high blood pressure, etc. Lifestyle interventions and treatment should be started early when indicated. Commonly used risk prediction tools, e.g., SCORE or Framingham risk score, only include traditional risk factors, and they underestimate the risk for cardiovascular events in SLE [4]. Excess cardiovascular events that could not be predicted with Framingham risk score tend to be mainly stroke rather than myocardial infarction [17]. In a study that evaluated SCORE's accuracy, 5 of 9 cardiovascular deaths could not be predicted in a sample of 124 patients aged between 40 and 65 years [18]. QRISK3 qualifies a greater number of SLE patients as having a high 10-year cardiovascular risk in comparison to Framingham and ACC/AHA risk scores [19]. In another study, the modified FRS and QRISK3 showed very similar results for the prediction of cardiovascular events and outperformed the traditional FRS while the SLE cardiovascular risk equation (SLECRE) showed the highest sensitivity but also the lowest specificity [4]. The more specific lupus-related risk factors, e.g. active disease, low C3 and history of positive lupus anticoagulant included in the SLECRE [20], and lupus per se in the QRISK3 score [21], seem to have the most significant impact, but are not included in the instruments used in the general population. Consequently, the EULAR recommendations state that SLE patients who are aPL carriers should receive long-term prophylactic treatment with low-dose aspirin, especially if there is a high-risk aPL profile [17]. Lupus nephritis and glucocorticoid treatment are other lupus-related risk factors that need to be addressed. With modern treatment guidelines using less glucocorticoids and new biological treatments, it should be possible to better control disease activity and minimize glucocorticoid use, which expectantly will reduce the cardiovascular risk and damage overall. New treatments for lupus nephritis will hopefully also preserve renal function and reduce cardiovascular risk further. Hydroxychloroquine lowers blood lipids and has a beneficial effect on cardiovascular risk [16], strengthening the indication to give HCQ to all lupus patients. However, it is not known if the decline in vascular disease observed in the general population is fully reflected in SLE; hopefully, as in the large SLICC inception cohort, future studies will also report a lower incidence of CVD than previously reported [16].

The incidence of venous thrombosis and pulmonary embolism (PE), together referred to as venous thromboembolism (VTE), is enhanced in SLE compared to the age-matched general population. According to literature reviews and meta-analyses, the relative risk (RR) for VTE is increased by 3.5–4.4-fold, with even higher relative risks reported in Chinese SLE patients [22]. The RR is highest in younger patients [22] and early, often in the first year, after diagnosis [23,24]. Many studies have reported that the sub-group of patients who are positive for aPL are at particularly high risk [[24], [25], [26]], especially if there are concomitant signs of complement activation, e.g., deposition of C4d on platelets [27]. Smoking [24], nephritis [28], and comorbidities [22] also contribute to the risk of VTE. In hospitalized SLE patients, VTE was associated with a higher risk of complications, including mortality, greater disability, and longer hospital stays [29].

No studies have to date addressed primary prevention of VTE in SLE. Still, existing data suggest that newly diagnosed patients, especially during flares with high disease activity, particularly in patients with lupus nephritis in the context of low serum albumin, or positivity for aPL, need to be closely monitored and should possibly be given prophylactic treatment with low molecular weight heparin (LMWH) or anti-factor Xa in risk situations. Pregnancy is such a high-risk period for VTE, and present recommendations include low-dose aspirin combined with individually tailored dosages of LMWH during pregnancy and puerperium [30]. Also, SLE patients hospitalized for any reason should be closely monitored for VTE and prophylactic treatment may be offered in selected cases.

Chronic kidney disease (CKD) in adult patients with SLE, often referred to as lupus nephritis (LN), is associated with increased morbidity and is one of the leading causes of mortality [[31], [32], [33]]. It is frequently accompanied by increased healthcare utilization due to hospitalizations, outpatient visits, and the need for dialysis or transplantation in the advanced stages of CKD, imposing a significant burden on patients and the health system [34]. Similarly, CKD is a strong independent risk factor for CVD [35], another major cause of higher mortality rates in lupus patients [32].

Although the exact prevalence varies depending on factors such as disease duration, ethnic background, and the used diagnostic criteria [36], it is estimated that nearly 40 % (31%–48 %) of adults with SLE develop LN, the majority within the first 5-years of disease onset, however, it can occur at any point throughout the disease evolution [37]. With the increased use of immunosuppressive agents and better control of associated factors such as hypertension and proteinuria, the 10-year risk of end-stage renal disease (ESRD) in LN substantially declined from the 1970s until the mid-1990s, however during the last two decades it plateaued at 17 % (6%–19 %) in developed countries [38].

Several studies have investigated the factors associated with progression to ESRD in LN. The most common findings included the initial level of serum creatinine (>1.5 mg/dL), hypocomplementemia, nephrotic range proteinuria, concomitant uncontrolled hypertension, black and Hispanic ancestry, non-adherence to treatment, and biopsy findings such as diffuse proliferative LN, a high chronicity index, tubular atrophy, and tubulointerstitial inflammation [[37], [38], [39], [40], [41]]. Notably, renal flares further increase the risk of progression [36]. Similarly, various genetic risk variants have been linked with a higher risk of progression (APOL1, MYH9, UMOD, and podocytopathy genes) [36]. However, CKD progression is not inevitable, and not all lupus patients with advanced CKD progress to ESRD (in the Toronto cohort only 38 % of patients with CKD stages 3b–4 progressed to stages 4 or 5 during a 10-year follow-up period) [42]. This implies the need for aggressive treatment of LN to modify the factors leading to renal damage [43].

The past few years have witnessed significant developments that have reshaped our understanding and approach toward managing LN. For instance, treatment modalities have evolved to be more customized, factoring in individual characteristics like disease activity, kidney histology, and other risk variables. The introduction of targeted immunosuppressive therapies, such as biologics, which specifically modulate dysregulated immune pathways, has diversified therapeutic options. Furthermore, the shift towards combining therapies right from the onset of LN to address multiple pathways, instead of a sequential approach, is gaining increasing acceptance. Moreover, substantial strides have been made in searching for reliable diagnostic and predictive biomarkers. The influence of these advancements on disease progression and associated morbidity and mortality is anticipated to become apparent in the forthcoming years.

Studies have reported hospitalization rates in SLE patients ranging from 13 % to 56 % [44]. This wide variance could be attributed to differences in study design and patient populations. However, across studies the two leading causes of hospitalization are consistent: disease flare and infections [45].

Extended hospital stays, invasive procedures, and treatments can lead to physical discomfort, complications, and functional limitations. Hospitalizations often result in high healthcare costs, including expenses related to hospital stays, medications, and follow-up care. Infections are also a leading cause of morbidity and mortality in lupus patients [46,47]. Compared to the general population, the RR of infections in SLE patients is 2–6 times higher [47,48].

In SLE, bacterial infections are the primary causative agents, followed by viruses and fungi. The responsible bacteria remain consistent with those seen in the general public, encompassing species like Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli [47]. In addition to the underlying immune dysregulation intrinsic to the disease, other factors that contribute to the increased susceptibility to infections in adult SLE patients are high disease activity, the use of glucocorticoids, and other immunosuppressant agents [[46], [47], [48]].

Infections pose a significant challenge in the management of adult patients with SLE. They can not only mimic lupus symptoms but can also instigate disease flares. Additionally, when infections arise amidst active disease, they restrict the extent to which immunosuppression can be applied.

To reduce the risk of infections and complications in SLE patients we should ensure up-to-date immunizations, and educate patients on infection prevention strategies, early recognition of infection signs and symptoms to seek for timely medical evaluation and treatment.

Metabolic syndrome (MetS) is a state of chronic low-grade inflammation that results in higher cardiovascular risk. This syndrome, a combination of insulin resistance, hypertension, low HDL, high levels of triglycerides, and obesity (large waist circumference), is more frequent in patients with SLE than in the general population [49], with a reported prevalence of up to 45.2 %. A meta-analysis estimated a prevalence of 26 % [50]. In another cohort, the most prevalent component of MetS was hypertension, with a prevalence of 59 % [51]. There are several hypotheses about MetS physiopathology [52]. Current understanding mostly favors the mechanisms that follow the pro-inflammatory response to outgrown adipose tissue with proinflammatory cytokines such as TNF-alpha, leptin, IL-6, PAI-1, and CRP, leading to insulin resistance and oxidative stress [49]. In SLE, disease or treatment-related factors that possibly interfere with those cascades are to be further investigated. In the concept of metabolic syndrome, glucocorticoids have known adverse effects on adipose tissue; they cause insulin resistance and changes in lipid and glucose metabolism. In a previous study, MetS was not found to be associated with glucocorticoid use or cumulative glucocorticoid dose; however, it was associated with baseline organ damage (SDI >0). Nevertheless, MetS remains significant following adjustment for damage accrual. No significant association was found with high disease activity over time (Adjusted Mean SLEDAI-2K [AMS] ≥4) (OR 1.44; 95 % CI: 0.64–3.21) or Lupus Low Disease Activity State (LLDAS) (OR 0.97; 95 % CI: 0.40–2.32) [52]. Even if free fatty acids (FFAs) were hypothesized to contribute to accelerated atherosclerosis and cardiovascular risk in SLE patients, as those can be elevated in blood due to inflammation-induced insulin resistance, this relation could not be shown in a previous study [53]. In this study, levels of FFAs were mainly related to BMI but not to inflammatory markers such as IL-6, TNF-alpha, or treatment (prednisolone, hydroxychloroquine, methotrexate, azathioprine, mycophenolate mofetil) [53].

The incidence of osteoporosis and osteoporotic fractures is higher in patients with adult SLE than in the general population. A more than two-fold increased risk for osteoporosis was reported in patients with SLE compared to controls [54,55]. In a meta-analysis, the prevalence of low bone mineral density (BMD), osteopenia, and osteoporosis were 45 % (95 % CI: 38–51), 38 % (95 % CI: 31%–45 %), and 13 % (95 %CI: 11%–16 %), respectively [56]. Both male and female SLE patients have lower BMD compared to controls [57].

Fractures also cause significant morbidity in SLE; SLE patients have a 1.8-fold risk for any bone fracture and a four-fold risk for vertebral fractures [58]. Several disease-related and independent factors are associated with these fractures. The bone structure in SLE patients differs from that of the general population; this difference results from several disease and treatment-related factors. Previous studies have shown close links between the immune system and bone metabolism with the engagement of several immune cells (T-cells, macrophages, osteoclasts, etc.) and cytokines (IL-1, IL-6, IL-17, and TNF-alpha) [59]. The OPG/RANKL/RANK system regulates bone metabolism. RANKL induces differentiation and maturation of precursor osteoclasts, and OPG reduces the binding of RANK to its ligand RANKL, thus inhibiting osteoclast differentiation and promoting proliferation of osteoblast and osteogenesis. Decreased levels of serum OPG and an increased ratio of RANKL/OPG were reported in SLE patients [60].

Another critical factor is the vitamin D-PTH-bone cascade. SLE patients are at increased risk of impairment of this system. Several factors contribute to this risk, such as physicians' recommendations to avoid sunlight and to use broad-spectrum sunscreens, treatment with glucocorticoids and its consequences. Additionally, lupus nephritis may cause a deficit of 1–25 hydroxylation of vitamin D, leading to secondary hyperparathyroidism with decreased intestinal calcium absorption.

In a previous meta-analysis, menopause, disease duration, and prednisone use were risk factors for osteoporosis. At the same time, disease duration, age, higher BMI, history of previous bone fracture, glucocorticoids use, seizures, cerebrovascular events, and a high score on the SDI were risk factors for fractures [56]. As age and cumulative glucocorticoids dose is shown as risk factors with high impact for low BMD/osteoporosis [61], a meta-analysis also identified, disease duration, duration of glucocorticoid therapy, high SDI, and menopause as risk factors for osteoporosis together with those mentioned before. But no association with daily glucocorticoid dose, SLEDAI, or BMI was observed [54]. A meta-regression analysis found that osteoporosis with fractures was associated with average daily glucocorticoids dose [11].

Modifiable contributing factors for both fractures and osteoporosis are mainly lifestyle factors (physical activity, smoking, etc.), systemic inflammation as a result of disease activity, disease damage, and glucocorticoids usage, which all correlate to each other and also to other factors that are reported previously. There are not enough studies to conclude about risk levels regarding glucocorticoids dosage, the effect, and the dosage of vitamin D and calcium supplements. The current understanding of prevention strategy is to achieve low or no disease activity with the lowest possible glucocorticoids dosage.

Avascular necrosis of the bone (AVN or aseptic osteonecrosis) is a well-recognized complication of SLE caused by insufficient circulation to the bone. The course is typically progressive and may, depending on location, cause deformities and impair the ability to move, thus contributing to a lower HRQoL. On the other hand, AVN is often asymptomatic.

The reported prevalence of symptomatic and asymptomatic AVN varies widely and depends on study methodology and case ascertainment. One meta-analysis has reported a prevalence of symptomatic AVN of 9.0 % (95 % CI: 7.4%–10.6 %), with AVN of the femoral head as the most common location (8.0 %, 95 % CI: 5.9%–10.1 %) [62]. Similar rates have also been reported separately for symptomatic AVN in studies using MRI as the diagnostic tool: 10.6 % [63], 7.0 % [64], and 8 % [65]. The same meta-analysis reported a higher prevalence for asymptomatic AVN, 28.5 % (95 % CI: 19.5%–37.6 %), while previous studies included in this meta-analysis reported even higher prevalence ranging from 44 % to 52 % [62,66,67].

Disruption of the blood supply leading to subchondral necrosis is considered the final common pathway of AVN which can result from several factors contributed by genetic predisposition, traumatic insult to blood supplies (femoral neck fractures), coagulopathy, vasculitis, thromboembolism, etc. Eventually, these processes lead to elevated intraosseous pressure and bone ischemia [62,[66], [67], [68], [69]]. Glucocorticoids are the leading risk factor for the development of AVN. Their effects on endothelial cells, hypercoagulability, fat cell hypertrophy, and their ability to inhibit angiogenesis may reduce blood flow and oxygen delivery through micro-vessels. Additional yet-to-be-discovered disease-related factors in SLE are also believed to contribute.

A recent large study has evaluated the glucocorticoids dosage in relation to the risk of developing AVN. The authors report that more than one month of treatment with prednisone with a dosage of 20–39 mg daily increased the risk of AVN, while a daily dosage of ≥40 mg for one month had a higher risk for AVN development. Interestingly, the authors reported that pulse methylprednisolone did not increase the risk of developing AVN; meanwhile, smoking was a significant risk factor [70]. Authors in another study reported that early SLE onset, arthritis, existing organ damage (SDI≥1) at registration, anti-RNP positivity, and high maximum glucocorticoid daily dose were associated with a higher risk of developing AVN [71]. According to the results of the meta-regression analysis from Ugarte-Gil MF et al., a higher average cumulative glucocorticoids dose is associated with the occurrence of AVN(11).

With a prevalence of 38 % (95 % CI: 33%–43 %) [72] cognitive impairment (CI) is one of the most common manifestations of neuropsychiatric SLE (NPSLE) [[72], [73], [74]]. This variation in reported prevalence can be attributed to various factors, particularly to the absence of an universally agreed-upon screening and diagnostics tools and differences in studies' design and populations's sociodemographics [75,76].

Notably, in comparison to both healthy individuals and rheumatoid arthritis patients, those with SLE face an elevated risk of developing CI (RR of 2.80 and 1.80, respectively) [72]. It can adversely affect daily functioning, employment status, and health-related quality of life (HRQoL) [[77], [78], [79], [80]] leading to additional burden on lupus patients.

It has been reported that more than 50 % of SLE patients with other NPSLE disorders, particularly stroke and seizures, have CI [81]. However, CI may occur in the absence of other NPSLE manifestations and active disease [77,82]. Several factors have been linked to the development of CI in SLE patients. These factors include depression, prolonged duration of the disease, and the presence of aPLs [76]. Generally, CI's clinical evolution is relatively stable and it infrequently develops into severe dementia [76,83]. Nonetheless, SLE patients with low cognitive abilities at baseline tend to persist at lower cognitive levels over time [84]. Importantly, depression serves as an obstacle to cognitive improvement and is also linked to cognitive decline over time [[83], [84], [85]].

Nearly twenty-five years have passed since the ACR committee proposed the 1-h, neuropsychological battery (NB) to assess cognitive functioning in SLE patients, that was subsequently validated in 2004 [86,87]. While the ACR battery is the current gold standard, its cost and time-intensive nature make it more suitable for research than for clinical application, and even in the research setting the original form of the battery is scarcely employed with studies often incorporating a diverse range of other neuropsychological tests and CI definitions [75].

Over the past decade, there has been a substantial increase in the quantity of studies concentrating on CI in the context of SLE [75]. As the exploration of cognition in SLE continues to expand, it becomes essential to establish a comprehensive and standardized methodology for defining and assessing CI, ensuring both clinical feasibility and uniformity across the field.

The prevalence of depression and anxiety in SLE patients varies widely depending on the study population and definition. A recent systematic review and meta-analysis found a 35 % (95 % CI: 30 %–40 %) pooled prevalence of depression, and 25.8 % (95 % CI: 19.2%–32.9 %) of anxiety [88]. Like CI, mood disorders negatively impact patients’ HRQoL and work ability [89,90] and can affect treatment adherence, leading to suboptimal disease control. Depression and anxiety in SLE result from a complex interplay of biological, social, and psychological elements [91,92].

The incorporation of multidisciplinary care teams, including rheumatologists, psychologists, and social workers, may improve the comprehensive management of mood disorders in lupus patients. Additionally, effective control of lupus disease activity through appropriate pharmacological interventions and regular follow-up can help mitigate the development of mood disorders. Similarly, patient education on stress management techniques, self-care strategies, and coping skills can contribute to better mental health outcomes. Furthermore, encouraging strong social support networks, including family, friends, and lupus support groups, can provide emotional support and reduce the risk of mood disorders [93].

More than half of SLE patients experienced hair loss during the disease evolution [94]. It can be driven from lupus as well as non-lupus causes; thus, a thorough evaluation is essential before attributing it to SLE [94,95]. While various types of hair loss can manifest in the context of SLE, scarring alopecia stands up because the cicatricial nature leads to everlasting alopecia.

In SLE patients, discoid lupus erythematosus (DLE) accounts for the majority of scarring alopecia and skin scarring cases [94,95]. Significantly, DLE often impacts areas of the body that are hard to conceal from sight, including the face, ears, and scalp [95]. Visible hair loss and scarring may result in emotional distress, anxiety and depression [96], reduced self-esteem, social stigma, and impaired social interactions, resulting in a negative impact on patient's quality of life.

Over the past twenty years, the advent of targeted therapies, such as biologics and small-molecule inhibitors, has broadened the treatment landscape for lupus, providing enhanced control over disease activity. However, these treatments are not yet universally accessible. As such, their long-term effect on reducing the incidence of scarring and alopecia remains to be seen. For now, the most effective preventive approach is prompt diagnosis and timely treatment before irreversible damage is established. Additionally, it is vital for patients who smoke to consider cessation, as tobacco use is an independent risk factor for cutaneous involvement in SLE, can intensify the disease's severity, and reduce the potency of antimalarials [95,97].

Over the last twenty years, the occurrence of cataract blindness has decreased as the frequency of cataract surgeries has risen, thanks to advancements in surgical techniques and proactive surgical campaigns. Yet, in middle-income and low-income nations, cataracts continue to be the primary source of blindness, contributing to 50 % of such cases [98]. Being female, living with diabetes or hypertension, using glucocorticoids, and exposure to ultraviolet B rays are among the factors that elevate the risk of cataract formation in the general population [98]. Given that many of these are linked with both SLE and its complications, it is not surprising that SLE patients are at a higher risk of cataract development at a younger age range (20–29 years old) [99].

With estimates ranging from 5 % to 32 %, cataract is the most prevalent ocular damage in SLE patients [100] and the second most prevalent SDI item.

Glucocorticoids are a known major risk factor for its development [100,101]. Notably, Khaled Alderaan et al. found that the risk escalates with prolonged exposure to a dose of ≥10 mg of prednisone or its equivalent. Specifically, those on this dosage for a decade or more face a threefold increase in risk (RR, 3.1). On the other hand, individuals on this dose for 3–10 years have their risk doubled (RR, 2.3) [100]. Therefore, cataracts are an additional reason why healthcare providers should carefully monitor and optimize glucocorticoids usage, aiming for the lowest effective dose and time exposure. Interestingly, in this study disease activity and hypertension were also found risk factors for cataract development in SLE patients, irrespective of the glucocorticoid dose [100]. This underscores the significance of managing blood pressure and monitoring disease activity.

Dryness in the mouth and the eyes, sicca symptoms, or secondary Sjögren's syndrome, are caused by immunological destruction of the salivary and lacrimal glands. Permanent damage is the cause of these symptoms, but the loss of saliva and tears are not part of the SDI and are, therefore, often disregarded when damage is reported in SLE. However, sicca symptoms are common and constitute an additional burden on lupus patients. Larger studies report frequencies in SLE that range between 14 % and 23 % [102,103], depending on definition and ethnicity. In summary, sicca symptoms are more common in white and female SLE patients, and it is more common in patients with a later SLE onset, but the frequency also increases with age and disease duration. Sicca symptoms are furthermore often, but not always, associated with a particular SLE phenotype, which is characterized by SSA and SSB autoantibodies [102].

There is, to date, no preventive or curative treatment for sicca symptoms. According to EULAR recommendations, topical oral and ocular agents are the first line of treatment [104].

During the past two decades improved understanding and treatment have resulted in declining frequencies of several of the damage items recorded in the SDI. This is clearly illustrated in Fig. 1 which displays a decrease in the majority of the organ-systems of the SDI based on data from the Toronto cohort and the Karolinska cohort. Though there is local variation, we observed an increasing fraction of patients with no damage (see Fig. 2), and specifically decreasing figures for the ocular, musculoskeletal, and neuropsychiatric damage domains in two independent cohorts. On the other hand, it is notable that CVD, renal, skin, and pulmonary domains remained essentially unchanged over the last 2 decades. It is re important to remember that the CVD domain in the SDI includes IHD, valvular disease, and pericarditis, while strokes fall within the neuropsychiatric domain, and peripheral arterial disease within the peripheral vacular domain. Thus, these results can not be readily compared to more detailed studies of cardiovascular events.

Overall accrual of damage in SLE is still extensive. A major focus has hitherto been to prevent physical impairment caused by renal and vascular disease. However, bone health, scarring, alopecia and sicca symptoms are other factors which can readily be measured and where we need to be more proactive with prevention. Neuropsychiatric symptoms such as CI, mood disorders and anxiety are common and challenging to measure, contributing to difficulties regarding early identification, treatment and follow up. Also, we need to be aware of the side effects of lupus medications, not least glucocorticoids but also immunosuppressants, which both contribute to higher infection rates and to damage in several organ domains.

SLE treatment now seems to enter a new era where we will be able to reduce glucocorticoid usage in favor of new approved medications, and others are in pipeline. Hopefully, the new therapies for lupus will further facilitate the prevention of damage in many organ systems, similar to the decline pattern that we have witnessed with cardiovascular events. With respect to damage, the studies that support the use of these new medications rely on selected patients and relatively short term follow up. Though this will take time, it is important to perform real life, long-term clinical studies with focus on damage accrual and HRQoL. An update of the SDI is ongoing [105] and will be a useful instrument for these tasks. It will likely incorporate some additional damage domains and modern diagnostic investigations, enhancement of its face/content validity and ability to better capture change longitudinally.