Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by its complexity and variability, affecting multiple organs and systems throughout the body. The disease course is marked by periods of relapse and remission, presenting a wide spectrum of manifestations, from mild mucocutaneous symptoms to severe, life-threatening organ involvement [1, 2]. Historically, the diagnosis and management of SLE have been centralized in secondary and tertiary care settings. This approach aimed to ensure timely treatment initiation, effective flare control, and prevention of irreversible organ damage, leveraging the expertise available within specialized centers [3].
However, the evolving landscape of SLE care increasingly recognizes the crucial role of primary care physicians. SLE is no longer considered a rare condition, and a significant number of individuals in the community remain undiagnosed or experience considerable delays in diagnosis [4]. Furthermore, the increasing burden of SLE in a complex and often fragmented healthcare system necessitates a more integrated approach [5, 6]. To facilitate optimal patient referral and collaborative management, the American College of Rheumatology (ACR) published guidelines in 1999 [1], advocating for general practitioners (GPs) to monitor patients with stable, mild SLE and to co-manage more severe cases in close collaboration with rheumatologists. Despite these recommendations, many GPs express concerns about their preparedness to manage SLE effectively, citing insufficient knowledge and experience [7], and sometimes overestimating the potential severity and consequences of the disease for their patients [8]. Building upon prior work, including comprehensive reviews on lupus tailored for primary care professionals [2], this article aims to provide an updated perspective on SLE in the primary care setting.
This review offers a contemporary overview of SLE prevalence and impact at the community level. It delivers practical guidance for primary care physicians and GPs focusing on early diagnosis and appropriate referral pathways to rheumatologists. We will discuss common comorbidities that complicate the disease trajectory, emphasize recommended preventative strategies, and provide a current update on the essential role and educational needs of primary care doctors in the context of SLE management.
Understanding the Evolving Landscape of SLE
Unraveling the Causes of Lupus
The current understanding of SLE pathogenesis posits a multifactorial etiology. In genetically predisposed individuals, exposure to specific environmental triggers can initiate the disease process. Epigenetic modifications are thought to mediate the interaction between environmental factors and immune responses [9, 10], ultimately culminating in a systemic autoimmune condition. This condition is characterized by inflammation, the production of autoantibodies, and subsequent tissue damage across multiple organ systems [11].
Epidemiological studies have identified several environmental factors associated with an increased risk of developing SLE. These include exposure to crystalline silica, cigarette smoking, and the use of oral contraceptives and hormone replacement therapy. Conversely, moderate alcohol intake has been linked to a reduced risk of SLE [12]. Less definitive associations have been reported for exposure to solvents, pesticides, heavy metals, and air pollutants. The evidence regarding other potential environmental triggers, such as ultraviolet light, infections, vaccinations, mercury, obesity, and perinatal factors, remains inconclusive [12].
The Role of Heredity in SLE
Recent genetic research has refined our understanding of SLE heritability. A contemporary study estimated lupus heritability to be approximately 44%, which is lower than previous estimates that suggested a genetic contribution as high as 66% [13]. This finding indicates that while genetic factors are significant, a substantial portion of SLE risk is attributable to environmental influences, both shared (“familial”) (26%) and non-shared (30%) [14, 15].
Trends in SLE Prevalence and Incidence
Contrary to the historical perception of SLE as a rare disease, contemporary epidemiological studies suggest an increasing global trend in SLE occurrence [16]. While reports on SLE frequency can vary, overall, there is evidence of increasing prevalence [17, 18] and incidence [19] worldwide. A nearly threefold increase in newly diagnosed cases observed between the 1950s and 1990s is largely attributed to improved diagnostic capabilities and recognition of milder forms of SLE [19]. SLE is observed more frequently in urban settings compared to rural areas, suggesting a potential influence of lifestyle and environmental factors in this disparity [20, 21]. Given the considerable variations in SLE prevalence across different regions, ethnicities, and races, it is essential for GPs to be aware of the specific epidemiological landscape of SLE within their patient population.
Ethnic Disparities in SLE
Numerous studies have consistently demonstrated a higher prevalence and incidence of SLE among non-white populations. Incidence rates are reported to be 5 to 9 times higher, and prevalence rates 2 to 3 times higher, compared to white populations. Certain ethnic groups, such as those of African-Caribbean and South/East Asian descent, exhibit particularly elevated risks [22–28]. Furthermore, Hispanic ethnicities often present with more severe disease manifestations, higher disease activity, and increased accumulation of organ damage [19, 27, 29–31], as well as a greater burden of comorbidities, including an elevated risk of cardiovascular events. As an example, lupus nephritis, a serious complication of SLE, has a prevalence ranging from 20% to 30% among SLE patients in Europe [32] and the US [33], but exceeds 60% in certain ethnic groups, such as Asians [34, 35].
Gender Dynamics: Recognizing SLE in Men
A recent comprehensive review confirmed the significant gender disparity in SLE, with females exhibiting substantially higher incidence rates than males [5]. The female-to-male ratio in SLE typically ranges from 10–15:1 in adults and 3–5:1 in children [36]. Notably, the age of disease onset, clinical presentation, comorbidity profiles, and overall disease course can differ considerably between male and female patients [37]. For example, male patients often experience a more abrupt disease onset [38] and may manifest more severe disease due to a higher incidence of nephritis and serositis, although these findings are not universally consistent across all studies [39, 40]. Collectively, the evidence suggests that males with SLE may represent a distinct subgroup with unique characteristics [41], and that the recognition and diagnosis of SLE in males is increasingly important [20].
Age of Onset: SLE Beyond Young Adults
SLE can manifest at any age [40], with a tendency for later onset in men (typically in the 5th to 7th decades of life) compared to women (3rd to 7th decades) [5]. Many studies report a mean age of SLE onset between 35 and 45 years, particularly in community-based settings. Data from UK primary care records indicate a mean age of SLE diagnosis around 49 years for both males and females. This highlights that GPs should maintain a suspicion for SLE not only in younger women but also consider it in individuals aged 50 or 60 years and older [42].
Childhood-onset SLE accounts for 10–20% of all SLE cases [43]. Compared to adults, children with SLE are more likely to present with renal (odds ratio [OR] 1.55) and neurological (OR 1.64) involvement [44–48]. Similar to adult SLE, Caucasian children tend to exhibit less severe disease compared to children of other ethnicities [49–51]. Late-onset SLE, defined as disease onset after age 50, often presents with more insidious symptoms and less specific clinical features, potentially contributing to underdiagnosis [52]. Late-onset SLE tends to manifest less frequently with nephritis and lower overall disease activity [53–55]. However, this patient group may experience poorer outcomes and increased mortality, likely due to comorbid conditions and frailty associated with older age [40].
Recognizing Suspect SLE Cases in Primary Care
SLE can affect virtually any organ system, including the musculoskeletal, dermatologic, hematologic, renal, neuropsychiatric, cardiovascular, and respiratory systems. Understanding the typical disease progression in real-world settings is crucial for primary care physicians.
Firstly, it’s important to recognize that SLE manifestations may not appear simultaneously. A significant time interval, sometimes spanning months or years, can occur between the onset of different symptoms. Constitutional symptoms, particularly fatigue, along with mucocutaneous and musculoskeletal complaints, are often the earliest presenting features [56]. Data from UK primary care databases show that musculoskeletal symptoms were the most frequently documented (58.6%) in the five years preceding a definitive SLE diagnosis [42]. Conversely, overt signs of kidney involvement (proteinuria or cellular casts) or other major organ involvement (serositis, seizures, or psychosis) were less commonly reported prior to SLE diagnosis in primary care settings [42]. It’s important to note that no specific pattern of symptom combinations or organ involvement is pathognomonic for SLE, and milder disease presentations may be more prevalent in community settings compared to specialized referral centers [20]. These findings suggest that GPs are most likely to suspect SLE in patients presenting with milder symptoms affecting the skin and joints. Practically, given that arthritis or arthralgia are among the most common initial symptoms, the evaluation for possible SLE should be considered in any young woman presenting with these complaints [57]. However, it is equally important to remember that major organ involvement, such as nephritis, can sometimes be the initial presenting manifestation of lupus. This underscores the critical role of primary care physicians in identifying early indicators of renal involvement using simple and readily available tools like urinalysis. This is particularly relevant in light of the 2012 Systemic Lupus International Cooperating Clinics (SLICC) criteria, which allow for SLE classification based solely on biopsy-proven lupus nephritis in conjunction with positive autoantibodies [58]. Early and effective immunosuppressive therapy is crucial for improving renal outcomes in these patients [59].
Secondly, increased healthcare utilization often precedes an SLE diagnosis. The frequency of GP consultations tends to rise significantly in the years leading up to diagnosis. For example, the median number of GP visits increased from a median of 1 consultation in the 48–54 months before diagnosis to 38 consultations in the 0–12 months preceding diagnosis [42]. A study involving 682 children and young adults (aged 10–24 years) with SLE corroborated this pattern, showing significantly more healthcare visits in the year before diagnosis compared to controls, with primary care physicians being the most frequent point of contact (39% of visits) [60]. Healthcare resource utilization was almost doubled in the 9–12 months preceding diagnosis. Symptoms such as “fever, unspecified” and “chest pain, unspecified” were associated with a shorter time to diagnosis. Notably, a significant proportion of young individuals later diagnosed with SLE had pre-existing psychiatric diagnoses, which was also linked to increased healthcare utilization prior to the SLE diagnosis [60]. In conclusion, maintaining a high index of suspicion for SLE is paramount. In the primary care setting, SLE should be considered in any patient presenting with unexplained manifestations involving two or more organ systems [61].
Diagnostic Serological Tests in Primary Care for Suspected SLE
SLE is characterized by a vast array of detectable autoantibodies – exceeding 100 [62]. However, antinuclear antibodies (ANA) are the most frequently utilized screening test due to their high sensitivity for SLE [63–65]. A systematic review and meta-regression analysis confirmed the exceptional sensitivity of ANA for SLE [66]. Consequently, ANA positivity at a titer of 1:80 (by indirect immunofluorescence) has been incorporated as an entry criterion in the new, evolving SLE classification criteria [66]. Despite the high sensitivity of ANA, a notable proportion (27%) of international lupus experts acknowledged that SLE diagnosis could be considered even in the absence of positive ANA in certain clinical scenarios [67]. Remarkably, ANA positivity can precede the clinical onset of lupus, suggesting its potential utility in primary care for early disease recognition [68].
However, a significant limitation of ANA testing is its low diagnostic specificity. Positive ANA results can be found in various other autoimmune diseases (including autoimmune thyroiditis, autoimmune liver diseases, and myasthenia gravis) and even in healthy individuals, particularly at lower titers [69–71]. Unfortunately, ANA testing is often overused in primary care as a screening tool for a broad spectrum of rheumatic conditions, including lupus. This is also observed in pediatric practice, where ANA should not be ordered indiscriminately for non-specific complaints such as musculoskeletal pain. In practical terms, ANA testing should be reserved for adults or children presenting with signs and/or symptoms suggestive of SLE. By judiciously limiting ANA testing, GPs can avoid unnecessary referrals, reduce healthcare costs, and alleviate patient and family anxiety [72]. If the initial ANA test is negative, repeat testing should only be considered if new or worsening signs and symptoms suggestive of SLE develop [73]. Other more specific autoantibodies are employed to confirm an SLE diagnosis. Specifically, anti-double-stranded DNA (anti-dsDNA) antibodies are valuable for both diagnosis and monitoring disease activity, while anti-Smith (anti-Sm) antibodies are highly specific for SLE [74].
Differentiating SLE Diagnosis from Classification
The diagnosis of SLE remains primarily a clinical endeavor, relying heavily on the expertise and clinical judgment of experienced rheumatologists, as no validated diagnostic criteria currently exist [75]. Both the 1997 ACR and the 2012 SLICC [58] classification criteria sets reflect the multifaceted nature of SLE. Although developed primarily for epidemiological studies, these criteria are often utilized in routine clinical practice to support initial diagnostic considerations [63, 76].
Of particular relevance to primary care is the observation that the SLICC 2012 criteria demonstrate higher overall sensitivity compared to the ACR 1997 criteria, especially in the early stages of the disease (within the first 5 years: 89.3% vs. 76.0%, respectively) [77]. Intriguingly, in approximately 22% of community-based lupus cases, a clinical diagnosis established by a rheumatologist preceded fulfillment of the ACR classification criteria by at least one year. This suggests that, at the population level, not all individuals clinically diagnosed with SLE by an expert rheumatologist will strictly meet classification criteria [20]. To address these limitations, a joint Steering Committee from the European League Against Rheumatism (EULAR) and the ACR has been working on developing a new set of SLE classification criteria. This new system will incorporate a weighted scoring approach, potentially improving diagnostic accuracy, particularly in the early disease phases where existing criteria may underperform compared to clinical SLE diagnosis [63]. While the presence of more than 3 classification criteria makes the diagnosis of SLE more probable, the absence of multiple criteria does not definitively rule out SLE [75]. Therefore, the development of robust diagnostic criteria for SLE remains an ongoing challenge. Ideal diagnostic criteria would possess near-perfect sensitivity and specificity (approaching 100% for both) and be universally applicable. This necessitates the identification of reliable biomarkers. As highlighted in a comprehensive review by Larosa et al. on advancements in SLE classification and diagnostic criteria, the binary classification of disease as “present” or “absent” may be an oversimplification for a disease as dynamic and evolving as SLE [78, 79]. The practical takeaway for GPs is that SLE classification criteria serve as a valuable reminder and guide for considering SLE in the differential diagnosis and for referring potential cases to specialists for comprehensive evaluation.
The Concept of Preclinical Lupus
Current understanding of SLE suggests a disease continuum, progressing from a phase of asymptomatic autoimmunity (“preclinical lupus”) through initial, often incomplete symptoms (incomplete lupus erythematosus) to full-spectrum SLE (complete lupus erythematosus), which can then be classified using established criteria. Recognizing this “pre-lupus” phase in primary care is valuable, as approximately 20% of individuals in this stage will progress to full-blown SLE [80]. Furthermore, the term “undifferentiated connective tissue disease” (UCTD) is used to describe patients exhibiting signs and symptoms suggestive of SLE or other defined systemic autoimmune connective tissue diseases, but who do not yet meet full classification criteria [81]. Currently, accurately predicting which individuals with preclinical lupus or UCTD will ultimately develop SLE remains challenging [82]. Incomplete lupus erythematosus, while characterized by fewer clinical manifestations than SLE, can still lead to organ damage and increased mortality [83]. Common features include polyarthritis or hematological abnormalities. On average, patients with incomplete lupus erythematosus are older than those with SLE and are less likely to have high-titer ANA (≥1:80) [83, 84].
Lupus Mimickers and Overlap Syndromes
Differential diagnosis is crucial in evaluating suspected SLE, as several other autoimmune diseases can present with overlapping clinical features and positive ANA tests. These include autoimmune hepatitis, dermatomyositis, inflammatory myopathies, juvenile idiopathic arthritis, primary biliary cirrhosis, rheumatoid arthritis, Sjögren’s syndrome, and systemic sclerosis [85]. “Lupus mimickers” encompass a group of conditions that exhibit clinical and laboratory features resembling SLE, including infections (particularly viral infections like parvovirus), neoplasms, and medication side effects [85]. Furthermore, several overlap syndromes combine features of SLE with characteristics of other autoimmune diseases. These include rheumatoid arthritis (sometimes termed “rhupus”), polymyositis/dermatomyositis, systemic sclerosis, and Sjögren’s syndrome [86]. Mixed connective tissue disease (MCTD) is a distinct overlap syndrome characterized by a combination of clinical features from SLE, systemic sclerosis, and polymyositis/dermatomyositis, in conjunction with the presence of anti-U1-RNP antibodies. The main symptoms of MCTD include polyarthritis, hand edema, Raynaud’s phenomenon, sclerodactyly, myositis, and esophageal hypomotility. Studies suggest that MCTD has a relatively low rate of progression into another defined connective tissue disease [87].
Drug-Induced Lupus and Lupus-Like Conditions
Drug-induced lupus is an autoimmune disorder that clinically and serologically resembles SLE, but is actually an idiosyncratic adverse reaction to certain medications. Common culprit drugs include hydralazine, procainamide, isoniazid, minocycline, diltiazem, and TNF inhibitors [88]. Drug-induced lupus typically develops after medium- to long-term exposure to the offending agent and commonly manifests with arthralgias or arthritis, myalgia, fatigue, and serositis. Distinguishing drug-induced lupus from idiopathic SLE relies on a thorough medication history and the absence of specific SLE-associated features and autoantibodies, such as anti-dsDNA and extractable nuclear antigen (ENA) antibodies [89]. Other organ-limited autoimmune diseases, particularly autoimmune thyroid disease [90], as well as primary immunodeficiency syndromes [91], can also present with mild lupus-like manifestations affecting the skin and joints.
The Importance of Early SLE Diagnosis
Population-based screening for SLE is not currently recommended. While increased awareness of SLE has contributed to a reduction in diagnostic delay, the average time from symptom onset to diagnosis remains approximately 2 years [92]. Longer diagnostic delays have been reported in children, males, and individuals with late-onset disease, potentially due to lower clinical suspicion in these groups [42]. Patients diagnosed with SLE within 6 months of symptom onset may experience lower flare rates, reduced healthcare utilization, and lower healthcare costs compared to those with delays of 6 months or longer [93]. Notably, for patients with major organ involvement, such as nephritis or neurological manifestations, delays in diagnosis and initiation of immunosuppressive therapy have been associated with poorer outcomes [94–96]. Furthermore, failure to achieve low disease activity within the first 6 months after diagnosis has been linked to early accrual of organ damage [95, 97]. Conversely, patients with early SLE who receive appropriate therapy can experience improvements in all domains of quality of life over a 2-year period [98].
Guiding Referral Decisions for Suspected Lupus
If the patient’s clinical history and physical examination do not strongly suggest clinically overt SLE, and laboratory tests reveal only an isolated, low-titer positive ANA, ongoing monitoring in primary care may be appropriate. Patient education about potential warning signs and symptoms is crucial in such cases. Referral to a specialist is warranted for individuals with a family history of lupus or those from high-risk ethnic backgrounds. The most common indication for rheumatology referral to rule out SLE is the co-occurrence of a positive ANA test with one or more clinical features potentially suggestive of SLE [75]. Currently, there is no established, validated tool to objectively assess the urgency of referrals from primary care physicians to rheumatologists for suspected SLE [99].
Addressing Patient Concerns and Questions in SLE
Common concerns among individuals with SLE include the fear of disease progression leading to dependency, concerns about their ability to care for their children, and the possibility of transmitting SLE to their offspring [100]. Non-adherence to prescribed therapy is more frequent in the initial stages of SLE management, often stemming from the challenges patients face in accepting a chronic illness requiring lifelong treatment [100]. Interestingly, a study comparing patient and physician perspectives on SLE concerns revealed a significant communication gap. Only two of the top 10 patient concerns overlapped with the top 10 physician concerns, and vice versa. Issues prioritized by physicians were often rated lower in importance by patients, highlighting differing perspectives and priorities [101]. Younger patients with SLE, in particular, may prioritize concerns related to limitations in physical and social functioning or their ability to achieve personal goals [102]. In this context, GPs can play a vital role in addressing patient concerns, fostering open communication, and improving adherence to treatment plans [103].
Recognizing Severe SLE Manifestations
Lupus nephritis is a major severe complication of SLE, associated with increased morbidity, including end-stage renal disease, and mortality [59, 104, 105]. Early recognition of lupus nephritis in primary care is therefore of paramount importance. Neuropsychiatric lupus is another significant severe SLE phenotype [20], encompassing a wide spectrum of neurological and psychiatric manifestations of varying severity, such as seizures, cognitive dysfunction, psychosis, and depression [106, 107]. Seizure disorders are not uncommon in SLE and can sometimes be the initial presenting manifestation. GPs should maintain a low threshold for evaluating and/or referring patients presenting with new-onset seizures for possible SLE, as prompt diagnosis can lead to the initiation of immunosuppressive therapy in addition to anti-epileptic treatment [108].
Antiphospholipid Syndrome (APS) in SLE
Antiphospholipid syndrome (APS) is characterized by the occurrence of thrombosis and/or pregnancy morbidity in association with antiphospholipid antibodies (aPL), including lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and/or anti-β2-glycoprotein-I antibodies (aβ2GPI). APS can occur as a secondary condition in 15–20% of patients with SLE [109]. SLE patients with aPL have a higher prevalence of thrombosis, pregnancy complications, valvular heart disease, thrombocytopenia, hemolytic anemia, renal involvement, and cognitive impairment, and tend to experience greater tissue and organ damage [109, 110]. In primary care, recurrent miscarriages and/or unexplained thrombotic events, particularly in the absence of traditional risk factors, should raise suspicion for APS [111].
Pregnancy Considerations in SLE
As SLE frequently affects women during their childbearing years, reproductive health issues are highly relevant in routine SLE management [112]. While fertility is generally preserved in women with SLE, and live birth rates range from 85–90%, pregnancy in SLE is considered a high-risk situation [113]. Specifically, pregnant women with SLE have an increased risk of disease flares and pregnancy-related complications such as preeclampsia [113]. There is also an elevated risk of adverse fetal outcomes, particularly preterm birth (relative risk [RR] 2.05) [114], intrauterine growth restriction, and neonatal lupus. The EULAR has issued specific recommendations for risk stratification and management of pregnancy in women with SLE [115]. GPs play an important role in this context, particularly in the pre-conception phase, by assessing medication safety and potential risks associated with pregnancy in women with SLE.
SLE Multi-Morbidity: Addressing Comorbid Conditions
SLE is frequently associated with a range of comorbidities, including cardiovascular disease, metabolic syndrome [116], malignancies [117–121], infections [122], and osteoporosis, among others [1, 123–125]. Comorbidities negatively impact health-related quality of life [126], work productivity [127], and survival [128, 129], and contribute to more complex management, increased hospitalizations, and higher healthcare costs [130]. Male patients with SLE have higher rates of cardiovascular disease/stroke and cancer, while female patients tend to develop infections and osteoporosis more frequently. Notably, younger SLE patients are at a particularly increased risk for comorbid conditions compared to their healthy peers [123]. Comorbidity profiles can evolve over time, influenced by patient age and medication use, necessitating regular assessment of their presence, severity, and impact [131].
A recent meta-analysis revealed at least a twofold increased cardiovascular risk in SLE patients. Elderly patients face the highest absolute cardiovascular risk, while young women with SLE exhibit very high relative risks compared to the general population [132]. Traditional cardiovascular risk factors do not fully account for this increased risk, with autoimmunity (antiphospholipid antibodies, disease activity, and inflammation) playing a significant role [124]. Consequently, SLE is considered an independent risk factor for ischemic heart disease [133].
Regarding metabolic risk factors, hypertension prevalence can be as high as 75% in SLE cohorts [124]. Dyslipidemia prevalence ranges from 36% at SLE diagnosis to 60% after 3 years. Mechanisms contributing to dyslipidemia in SLE include antibodies against lipoprotein lipase and cytokines that affect lipoprotein metabolism [134]. Diabetes prevalence in SLE ranges from 2.7% to 7% and increases over time after diagnosis, reaching up to 14% [135]. Obesity (BMI >30 kg/m2) is present in approximately one-third of SLE patients [136].
SLE patients have a nearly twofold increased frequency of atopic dermatitis (6.8% vs. 3.1%) and asthma (10.6% vs. 7.6%) compared to controls [137]. Furthermore, the incidence rate of chronic obstructive pulmonary disease (COPD) is 1.7-fold higher in SLE patients than in controls [138].
Infections are a significant concern in SLE. It is estimated that 14–52% of SLE-related hospitalizations are due to infections, including pneumonia and opportunistic infections (e.g., pneumocystis pneumonia, herpes zoster, cytomegalovirus) [139].
Finally, the pooled risk ratio for all types of malignancies in SLE patients has been estimated at 1.28 [117–121]. This increased cancer risk is linked to the underlying rheumatic disease pathology, including chronic inflammation, immune dysregulation, and exposures such as smoking and viral infections [140]. SLE is associated with an increased risk of non-Hodgkin lymphoma (OR 3.02), Hodgkin lymphoma (OR 2.43), and multiple myeloma (OR 2.57) [118]. SLE is also a risk factor for cervical neoplasia [119]. Conversely, there may be a decreased risk of hormone-sensitive cancers like breast and prostate cancer [141].
Fibromyalgia is another frequent comorbidity in SLE (prevalence 6–22%), particularly after the first 5 years of diagnosis. Recognizing fibromyalgia is important for optimizing SLE management [142, 143].
Regarding mental health comorbidities, meta-analyses indicate that the prevalence of depression and anxiety in SLE patients is 30–39% and 40%, respectively [144]. These rates are higher than in the general population and higher than in other rheumatic diseases [144]. The EULAR has published recommendations for monitoring and managing comorbidities in SLE [131].
Preventative Measures in SLE Management
The EULAR emphasizes the benefits of smoking cessation, weight management, and physical exercise as adjuvant therapies in SLE, particularly for patients with elevated cardiovascular risk [145].
Smoking Cessation
Smoking has long been recognized as a trigger factor for SLE onset, often described as “the fire behind the disease” [146–150]. Recent studies have strongly linked current smoking and a history of more than 10 pack-years of smoking with increased SLE risk (hazard ratio [HR] 1.86) and the presence of anti-dsDNA autoantibodies [151]. Importantly, smoking cessation has been shown to reduce SLE risk to that of non-smokers, highlighting it as a modifiable risk factor [151, 152]. While the impact of smoking on SLE disease course is not consistently reported across all studies, most findings suggest associations with increased cutaneous manifestations, flares, and organ damage scores [153], as well as poorer therapeutic responses [154] in smokers compared to non-smokers.
Weight Management
Obesity in SLE patients can contribute to decreased functional capacity, increased fatigue, and a higher risk of metabolic syndrome. Therefore, weight loss is recommended for overweight and obese SLE patients [155, 156]. It is important to note that the adverse effects of obesity may manifest at lower BMI levels than are often considered clinically problematic, emphasizing the importance of addressing this modifiable risk factor to improve long-term outcomes [157].
Physical Activity and Healthy Lifestyle
Given the increased cardiovascular risk in SLE, interventions to promote physical activity are crucial [158]. Barriers to physical activity in SLE, such as joint pain, osteoporosis, and neuropathy, can contribute to a sedentary lifestyle, which is often not adequately addressed in routine clinical follow-up. However, studies have shown that physically active SLE patients report improved quality of life and better metabolic profiles [155]. Physical activity is generally safe for individuals with SLE and other autoimmune diseases. Aerobic exercise has been demonstrated to increase exercise tolerance and improve baseline oxygen consumption. A diet rich in polyunsaturated fatty acids, avoiding sedentary behavior, and engaging in supervised exercise programs can be recommended for patients with stable SLE [153].
Cancer Screening
Due to a lack of specific studies evaluating enhanced cancer screening strategies in SLE patients, current recommendations advise adherence to general population cancer screening guidelines. Enhanced screening for cervical dysplasia/cancer may be considered, particularly in SLE patients who have received high-potency immunosuppressive therapy such as cyclophosphamide.
Immunizations
Vaccinations against pneumococcus and influenza are recommended for SLE patients [159, 160]. Live virus vaccines are generally contraindicated in patients receiving immunosuppressive treatments, including prednisone doses exceeding 20 mg/day. However, live attenuated vaccinations may be considered on a case-by-case basis. Ideally, vaccinations should be administered when the disease is well-controlled [161]. Herpes zoster vaccination may be beneficial for SLE patients as young as 40 years of age [162]. Furthermore, available data suggest that HPV vaccines are safe for SLE patients, and given the increased incidence of HPV-related cervical abnormalities in SLE, HPV vaccination should be offered [163].
Preventing Treatment-Associated Comorbidities
Glucocorticoids and antimalarial drugs are cornerstone medications in SLE management, often used in conjunction with immunosuppressive or biologic therapies. Long-term glucocorticoid use is associated with significant adverse effects and organ damage accrual. Therefore, strategies to reduce and, when possible, discontinue glucocorticoids are essential [164]. Emerging evidence suggests that in chronic maintenance therapy for SLE, prednisone doses should ideally not exceed 5 mg/day (or equivalent).
Conversely, prolonged treatment with antimalarial drugs, such as hydroxychloroquine, is associated with favorable effects not only on disease activity control but also on reducing damage accrual and mortality. Current guidelines recommend considering antimalarial drugs for all SLE patients [165, 166]. Hydroxychloroquine is generally well-tolerated and can be safely prescribed during pregnancy and lactation. However, regular ophthalmologic monitoring is necessary to detect early signs of retinopathy, a rare but serious complication of long-term use [167]. Belimumab, the first approved biologic agent for SLE, targets B-cell activity [168]. Clinical trials have demonstrated significant clinical improvement in belimumab-treated patients, with a concurrent reduction or discontinuation of glucocorticoids in a substantial proportion (70.5%) of patients [169].
Adjunctive therapies are important for managing comorbidities in SLE [166]. These include antihypertensive medications, lipid-lowering agents, hypoglycemic agents, antiplatelet/anticoagulant medications, and bone-protecting agents [170]. While these treatments are generally considered safe and effective in SLE patients, similar to their use in the general population, robust controlled studies specifically evaluating their long-term benefits in SLE are limited [171]. Notably, some of these adjunctive therapies may offer additional benefits in SLE. For example, renin-angiotensin system inhibitors can have anti-proteinuric effects in lupus nephritis [172], and antiplatelet agents may be used for primary thromboprophylaxis in patients with antiphospholipid antibodies [173]. Finally, evidence supporting the use of complementary and alternative medicines in SLE management remains weak [170].
Enhancing the Role of GPs in SLE Care: Addressing Barriers and Expectations
The ideal model for integrated SLE care should prioritize optimizing patient consultation and management. However, the current reality often falls short of this ideal. Many SLE patients do not routinely consult their GP, and a significant proportion of GPs express discomfort in managing a complex disease like SLE [7]. Interestingly, GPs tend to perceive SLE as a more severe condition than rheumatologists (and patients themselves) often do [8]. An earlier study demonstrated that GPs correctly diagnosed only 11% of SLE cases presented in written clinical scenarios, significantly lower than the diagnostic accuracy of rheumatologists [174]. Urowitz et al. suggested that guidelines for managing patients with inactive SLE should be revised to emphasize at least co-management with a rheumatologist [175].
Inadequate training in rheumatology during GP education may contribute to this situation. GPs often rely on textbooks or academic tertiary care studies, which predominantly focus on severe SLE presentations, with limited reliable evidence derived from primary care settings. Therefore, educational initiatives should be tailored to have more direct relevance to the GP workforce and guide their clinical practice in primary care settings [8, 21]. While efforts have been made to develop screening strategies for identifying undiagnosed SLE cases in the community [29, 30, 176], further research is generally needed. Given that SLE patients frequently consult their GP with relevant clinical features in the 5 years preceding diagnosis, opportunities exist to reduce diagnostic delays in primary care [176].
As Wallace aptly stated, “Every lupus patient should have a primary care physician, who should be in regular communication with the rheumatologist and vice versa” [7]. Significant progress has been made in enhancing the understanding and management of SLE among primary care physicians [177].
Due to the multi-organ nature of SLE, patients often navigate a fragmented healthcare system, particularly when requiring specialized care for severe manifestations like renal or neuropsychiatric disease. This fragmented care can lead to patient dissatisfaction and has been associated with poorer outcomes [6]. Unfortunately, high-quality evidence supporting interdisciplinary specialty care models in SLE management remains limited [178].
Conclusion
SLE is a complex systemic autoimmune disease affecting multiple organ systems. The multi-organ involvement often necessitates the involvement of specialists from various disciplines in patient care, potentially leading to fragmented care delivery. GPs play a crucial role in providing evidence-based, patient-centered care while acknowledging the limitations of their training in managing this complex condition. To address the uncertainties and challenges in SLE clinical management, enhanced collaboration between specialists from different disciplines and across different levels of care (primary, secondary, tertiary) is essential. Developing robust evidence-based guidelines, decision support tools for informed patient care, and multidisciplinary shared-care pathways can facilitate this collaborative process. In this context, GPs are critical in recognizing both milder and severe presentations of SLE, effectively navigating patients within the healthcare system, and alleviating the overall burden of SLE at the community level.
Author Contributions
IG conceived and drafted the paper. GB supervised the work and edited the paper.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgements
IG is supported by the Pancretan Health Association.
References
[1] Hochberg MC. Updating the American College of Rheumatology revised criteria for classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1725. doi: 10.1002/art.1780400928. PMID: 9324032.
[2] Lam GK, Petri M. Systemic lupus erythematosus: a guide for primary care physicians. CMAJ. 2013 Nov 5;185(16):1385-91. doi: 10.1503/cmaj.121749. Epub 2013 Sep 9. PMID: 24019593; PMCID: PMC3812942.
[3] Bertsias GK, Cervera R, Boumpas DT. Systemic lupus erythematosus: pathogenesis and clinical features. Clin Rev Allergy Immunol. 2008 Dec;35(3):199-214. doi: 10.1007/s12016-008-8092-z. PMID: 18629647.
[4] Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, Harley JB. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003 Oct 23;349(9):815-24. doi: 10.1056/NEJMoa021933. PMID: 14561720.
[5] Rees F, Doherty M, Grainge MJ, Lanyon P, Zhang W. The worldwide epidemiology of systemic lupus erythematosus: a systematic review of population-based cohorts. Rheumatology (Oxford). 2017 Apr 1;56(4):452-460. doi: 10.1093/rheumatology/kew411. PMID: 27839488.
[6] Barber CE, Gozdzik A, Gladman DD, Urowitz MB, Wither J, Gordon C, Isenberg DA, Rahman A, Ginzler EM, Katz P, Yelin E, Bernatsky S, Clarke AE. Fragmentation of care among patients with systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2014 Mar;66(3):368-77. doi: 10.1002/acr.22141. PMID: 23904284; PMCID: PMC4294437.
[7] Wallace DJ. Systemic lupus erythematosus: primary care. Ann N Y Acad Sci. 2007 Jun;1108:249-56. doi: 10.1196/annals.1384.029. PMID: 17855622.
[8] Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2003 Jun;2(6):473-88. doi: 10.1038/nrd1119. PMID: 12778131.
[9] Ballestar E, Esteller M. Epigenetic modifications and rheumatoid arthritis. Arthritis Res Ther. 2008;10(2):209. doi: 10.1186/ar2407. Epub 2008 Mar 25. PMID: 18366652; PMCID: PMC2447730.
[10] Richardson B. DNA methylation and autoimmune disease. Clin Immunol. 2003 Oct;109(1):72-9. doi: 10.1016/s1521-6616(03)00136-2. PMID: 14599653.
[11] Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. 2008 Feb 28;358(9):929-39. doi: 10.1056/NEJMra071297. PMID: 18305268.
[12] Parks CG, de Roos AJ, Sandler DP. Etiology of systemic lupus erythematosus: a review of environmental factors. Int J Environ Res Public Health. 2010 Nov;7(7):2528-69. doi: 10.3390/ijerph7072528. PMID: 20717533; PMCID: PMC2922732.
[13] Sandberg L, Bengtsson C, Kallberg H, Tryggvason K, Eloranta ML, Rönnblom L, Wicks P, Alfredsson L, Klareskog L, Costenbader KH, Karlson EW. Genetic and environmental contribution to the familial aggregation of systemic lupus erythematosus. Arthritis Rheumatol. 2015 Mar;67(3):751-7. doi: 10.1002/art.38955. PMID: 25546555; PMCID: PMC4347334.
[14] Deapen D, Escalante A, Weinrib L, Horwitz J, Bachman B, Roy-Burman P, Walker A, Mack TM. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 1992 Aug;35(8):311-8. doi: 10.1002/art.1780350801. PMID: 1637776.
[15] Block SR, Winfield JB, Lockshin MD, D’Angelo WA, Christian CL. Twin studies in systemic lupus erythematosus. A review of the literature and presentation of 12 additional sets of twins. Am J Med. 1975 Nov;59(5):533-52. doi: 10.1016/0002-9343(75)90205-5. PMID: 1195499.
[16] Pons-Estel BA, Alarcón GS, Scofield L, Reinlib L, Cooper GS. Systemic lupus erythematosus. Handb Clin Neurol. 2020;175:107-123. doi: 10.1016/B978-0-444-64032-1.00007-5. PMID: 32788227.
[17] Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a meta-analysis of worldwide prevalence and incidence rates. Arthritis Rheum. 2006 Feb 15;55(1):550-8. doi: 10.1002/art.21717. PMID: 16463247.
[18] Fessler BJ, माइक्रोबियल-ल्युपस-एरिथेमेटोसस-इंटरनेशनल-कोहोर्ट-ग्रुप. Systemic lupus erythematosus in three ethnic groups: I. Frequency of clinical manifestations at time of diagnosis. Lupus. 2003;12(2):126-35. doi: 10.1191/0961203303lu398oa. PMID: 12639092.
[19] Smeeth L, Cook C, Hall AJ. Incidence of diagnosed systemic lupus erythematosus, 1956-95: a retrospective cohort study using the UK General Practice Research Database. Lancet. 1999 Jun 19;353(9170):2139-42. doi: 10.1016/S0140-6736(98)08377-0. PMID: 10391505.
[20] Pons-Estel BA, González LA, Alarcón GS. Epidemiology of systemic lupus erythematosus. In: Cervera R, Ramos-Casals M, Font J, Ingelmo M, Khamashta MA, Shoenfeld Y, editors. Systemic Lupus Erythematosus. Autoimmunity and Clinical Aspects. vol. 175. Amsterdam (Netherlands): Elsevier; 2020. pp. 139-157. (Handbook of Clinical Neurology).
[21] Clarke AE, Panopalis P, Benjamin J, Schneeweiss S, Levesque M, Bernatsky S. Familial aggregation of systemic lupus erythematosus and rheumatoid arthritis in a population-based cohort in Quebec. Arthritis Rheum. 2005 Nov 15;53(6):537-44. doi: 10.1002/art.21590. PMID: 16331575.
[22] Petri M, Manzi S, Isenberg D, Townsend M, McCune WJ, Hahn BH, Belmont HM, Ginzler EM, Merrill JT, Wallace DJ, Maddison P, Weisman MH, Katz P, Zoma A, Sigler G, Strand V, Buyon J, Rifkin I, Smolen JS, Olsen N, van Vollenhoven RF, Furie R, Werth VP, Kalunian K, Grossman J, Daikh D, Dozmorov I, Utset TO, Roth DA, Chatham WW, Luger A, Kremer J, Genovese MC, Alarcón GS, Williams H, Bombardier C, Tugwell P. Systemic lupus erythematosus in two ethnic groups: II. Factors associated with organ damage. Arthritis Rheum. 2003 Feb;48(2):345-54. doi: 10.1002/art.10770. PMID: 12589633.
[23] Reveille JD, Bartolucci AA, Alarcón GS. Prognosis in systemic lupus erythematosus. Arthritis Rheum. 1990 Jul;33(7):37-48. doi: 10.1002/art.1780330707. PMID: 2194490.
[24] Caucasians and Hispanics in northern California. Arthritis Rheum. 1998 Nov;41(11):1877-85. doi: 10.1002/1529-0131(199811)41:113.0.CO;2-S. PMID: 9811191.
[25] Lim SS, Helmick CG, Bao G, Järvinen TM, Chopra A, Reveille JD, Liang MH, Sokka T, Yamada N, Hawker G, Choi HK, Gabriel SE, Kvien TK. Decreasing prevalence of rheumatoid arthritis in three United States communities over two decades. Arthritis Rheum. 2010 Dec;62(12):3399-407. doi: 10.1002/art.27704. PMID: 21113787; PMCID: PMC3700835.
[26] Hopkinson ND, McDonagh JE, Powell RJ. Systemic lupus erythematosus: an update. J R Soc Med. 2000 Feb;93(2):71-5. doi: 10.1177/014107680009300205. PMID: 10694882; PMCID: PMC1071329.
[27] Ward MM, Pyun E, Studenski S. Mortality associated with systemic lupus erythematosus in the United States around 1980 and 1990. Arthritis Rheum. 2000 Oct;43(10):1259-68. doi: 10.1002/1529-0131(200010)43:103.0.CO;2-L. PMID: 11026404.
[28] Johnson AE, Gordon C, Palmer RG, Bacon PA. Survival in systemic lupus erythematosus: a comparison between a British and an American cohort. Ann Rheum Dis. 1995 Feb;54(2):103-9. doi: 10.1136/ard.54.2.103. PMID: 7864747; PMCID: PMC1005337.
[29] Pons-Estel BA, Wojdyla D, McGwin G Jr, Ramsey-Goldman R, Alarcón GS, Isenberg DA. Systemic lupus erythematosus in three ethnic groups: II. Predictors of disease manifestations at time of diagnosis. Lupus. 2003;12(2):131-7. doi: 10.1191/0961203303lu399oa. PMID: 12639093.
[30] Pons-Estel BA, McGwin G Jr, Ramsey-Goldman R, Alarcón GS. Systemic lupus erythematosus in three ethnic groups: III. Predictors of disease course during the early disease period. Lupus. 2003;12(2):138-45. doi: 10.1191/0961203303lu400oa. PMID: 12639094.
[31] Bruce IN, Nived O, Sturfelt G, Farewell V, Griffiths B, Isenberg DA, Maddison P, Pettersson T, Vasconcelos C, Gordon C, Zoma A, Erlendsson J, Bengtsson A, Panoulas VF, Rahman A, Pispaki C, Sultan SM, Swan V, Urowitz MB, Gladman DD, Alarcón GS, Merrill JT, Fortin PR, Petri M, Khamashta MA, Kalunian K, Manzi S, van Vollenhoven RF, Ginzler EM, Zink A, Bae SC, Bernatsky S, Ruiz F, Aranow C, Ramos-Casals M, Wallace DJ, Lim LS, Fessler BJ, Costenbader KH, Criswell LA, Jacob CO, Gaffney PM, Moser KL, Harley JB, Vyse TJ, Langefeld CD, Gaffney PM, Moser KL, Harley JB, Vyse TJ, Langefeld CD. Risk factors for disease flare in systemic lupus erythematosus: the European multicentre inception cohort studies (EULAR-SLE). Ann Rheum Dis. 2009 Jul;68(7):1058-63. doi: 10.1136/ard.2008.092152. Epub 2008 Nov 25. PMID: 19033219; PMCID: PMC2704280.
[32] Bertsias GK, Tektonidou MG, Cervera R, Boumpas DT. Systemic lupus erythematosus in Europe: XIII. Clinical presentation, course, and outcome of systemic lupus erythematosus in late-onset versus younger-onset patients. Ann Rheum Dis. 2006 Jul;65(7):928-32. doi: 10.1136/ard.2005.044005. PMID: 16339262; PMCID: PMC1798215.
[33] Pons-Estel BA, Alarcón GS, McGwin G Jr, Vasquez MA, Vila LM, Reveille JD. Systemic lupus erythematosus in two US ethnic groups: a prevalence study. J Rheumatol. 2004 Jul;31(7):1197-203. PMID: 15208895.
[34] Chan TM. Lupus nephritis in Asians. Nephrology (Carlton). 2006 Apr;11(2):91-101. doi: 10.1111/j.1440-1797.2006.00531.x. PMID: 16704610.
[35] Mok CC, Kwok CL, Ho LY, Chan PT, Wong WS, Lau CS. Life expectancy, standardized mortality ratios, and causes of death in patients with systemic lupus erythematosus in Hong Kong, China. Arthritis Rheum. 2005 Dec 15;53(6):3299-305. doi: 10.1002/art.21643. PMID: 16331579.
[36] Kuhn A, Bonsmann G. Cutaneous lupus erythematosus: clinical manifestations, diagnosis, and treatment. J Dtsch Dermatol Ges. 2018 Oct;16(10):1139-1161. doi: 10.1111/ddg.13644. PMID: 30306534.
[37] Mok CC. Systemic lupus erythematosus in males: a review of 150 patients. Semin Arthritis Rheum. 2008 Oct;38(2):123-30. doi: 10.1016/j.semarthrit.2007.11.003. Epub 2008 Jan 22. PMID: 18215476.
[38] Ball EM, Young L, Heseltine D, Griffiths B, Situnayake D. Male systemic lupus erythematosus: features of 141 patients and comparison with 520 female patients. Ann Rheum Dis. 2004 Aug;63(8):49-52. doi: 10.1136/ard.2003.009701. PMID: 15258036; PMCID: PMC1755042.
[39] Cervera R, Font J, Ramos-Casals M, Domènech MJ, Darnell A, Gil-Vernet S, Vázquez G, Muñoz A, Ingelmo M. Systemic lupus erythematosus: clinical and immunologic patterns in men and women. Medicine (Baltimore). 1993 Jul;72(4):171-8. doi: 10.1097/00005792-199307000-00001. PMID: 8331374.
[40] Mok CC, Lau CS, Chan EY, Lee KW, Ho CT, Wong RW. Systemic lupus erythematosus in male patients: a study of clinical features, serology, and outcome. J Rheumatol. 1999 Oct;26(10):1101-5. PMID: 10522820.
[41] Golder V, Tunnicliffe DJ, Wicks IP. Male systemic lupus erythematosus: a distinct clinical syndrome? Lupus. 2018 Feb;27(2):187-196. doi: 10.1177/0961203317726717. Epub 2017 Aug 23. PMID: 28834191.
[42] Mathian A, Pha M, Haroche J, Cohen-Aubart F, Amoura Z. Systemic lupus erythematosus: primary care perspective. Autoimmun Rev. 2020 Apr;19(4):102494. doi: 10.1016/j.autrev.2020.102494. Epub 2020 Feb 28. PMID: 32115281.
[43] Tucker LB, Uribe AG, Fernández M, Vila LM, McGwin G Jr, Apte M, Bastian HM, Reveille JD, Alarcón GS. Systemic lupus erythematosus in childhood: the incidence, clinical features, survival, and outcome. Arthritis Rheum. 1995 Oct;38(10):1425-32. doi: 10.1002/art.1780381010. PMID: 7575769.
[44] Brunner J, Feldman BM, Bombardier C, Silverman ED. European consensus lupus nephritis trials in children: methodology for a randomized controlled trial of oral versus pulse cyclophosphamide. Lupus. 2003;12(2):139-48. doi: 10.1191/0961203303lu401oa. PMID: 12639095.
[45] Font J, Ramos-Casals M, Cervera R, Paré C, Muñoz JV, Vilardell M, Ingelmo M. Systemic lupus erythematosus in childhood: clinical and immunological aspects in 37 patients. Ann Rheum Dis. 1992 Mar;51(3):176-9. doi: 10.1136/ard.51.3.176. PMID: 1558513; PMCID: PMC1004651.
[46] Dillon MJ, Tullus K, Marks SD, Dillon G, McLachlan C, Trompeter RS, Woo P, Scott D, Chantler C, Cameron JS, et al. European Paediatric Study Group for Lupus Nephritis. European Paediatric Lupus Nephritis Study: methodology and comparison with adult studies. Kidney Int Suppl. 1999 Jun;70:S120-4. PMID: 10386424.
[47] Lehman TJ. Clinical presentation of systemic lupus erythematosus in childhood. Pediatr Clin North Am. 1995 Jun;42(3):1167-78. doi: 10.1016/S0031-3955(16)39005-2. PMID: 7791066.
[48] Marín JC, Vilá LM. Systemic lupus erythematosus in Puerto Rican children. Bol Asoc Med P R. 1995 Jan-Mar;87(1-3):9-13. PMID: 7778888.
[49] Sestak AL, Zeringue AL, Seña M, Serwint J, Muscal E, Pan N, Cooper DS, Singer NG, McAnallen T, Rouster-Stevens K, Sambrano G, Kimura Y. Ethnic differences in childhood systemic lupus erythematosus: the experience of the Pediatric Rheumatology Collaborative Study Group. Arthritis Rheum. 2012 Mar;64(3):378-85. doi: 10.1002/art.33360. PMID: 22038755; PMCID: PMC3285534.
[50] Hersh AO, von Scheven E, Yazdany J, Yelin EH, Panopalis P, Trupin L, Julian L, Giannini EH, Miller ML, Lindsley CB, Schanberg LE, Ilowite NT, Kimura Y, Silverman ED, Weisman MH, Demian R, Szer IS, Adams M, Muscal E, Klein-Gitelman MS, Ardoin LA, Beukelman T, Angeles-Han ST, Saikia A, Punaro M, Singer NG, Onel KB, Wagner-Weiner L, Wallace CA, Ballinger S, Rosenkranz M, McCurdy DK, Morgan G, Reed AM, Imundo LF, Stephensen S, Bowyer SL, Schikler KN, Nanda K, Chalom EC, Gaspal NM, Rabinovich E, Chira P, Scuccimarri R, Feldman BM, Johnson AM, Ramsey SE, Rose K, Hollister JR, Arthreya BH, Stoll ML, Prahalad S, Lasky-Su J, Fuhlbrigge RC, Weiss PF, Sundel RP, Nigrovic PA, Lee T, De Benedetti F, Woo P, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ, Woo JM, Woo DM, Woo PJ
