Systemic lupus erythematosus (SLE) is a complex autoimmune multisystem disease with a varying severity of organ involvement. The clinical profile of SLE often challenges accurate diagnostic evaluation because of the unpredictable course of the disease, which is complicated by comorbidities that could be life-threatening. While improved life expectancy and quality of life have emerged from recent advances in treatment options, they have also exposed new challenges.
A considerably higher prevalence of subclinical atherosclerosis and increased risk for cardiovascular disease (CVD) has been recognized as a cause of death in patients with SLE compared with healthy control participants.1,2,3 A multinational study of 9547 patients with SLE reported 1255 deaths, of which approximately 30% were because of CVD.4 Although known CVD risk factors may be considered, it does not fully explain the disproportionately higher death rate from CVD among the SLE population compared with healthy individuals of the same age and sex.5 Between a 7- to 10-fold increased risk of developing CVD has been reported across the SLE patient population, and a 50-fold higher risk has been reported in women with SLE aged between 35 and 44 years.5
The disproportionately elevated CVD risk among patients with SLE may be contributed by the dysfunction of the immune system and inflammation, promoting atherosclerosis. “There is accumulating evidence that inflammation increases the risk for CVD. Our group has shown that patients with SLE have increased platelet activity, and we know that platelet activity induces build-up of coronary plaque and progression to CV events,” noted Jeffrey S. Berger, MD, associate professor of medicine and surgery and director of the Center for the Prevention of Cardiovascular Disease at the New York University School of Medicine.
Michael S. Garshick, MD, director of the Cardio-Rheumatology Clinic at the New York University School of Medicine, added that inflammation and traditional risk factors can synergistically increase CV risk in the SLE population. However, the evidence linking specific inflammatory and/or immunologic factors to elevated atherosclerosis and CVD risk has been challenging. Identifying specific factors may pave the way to the development of CVD risk predictive biomarkers, and potentially, targeted immunomodulatory therapies to reduce CVD risk.
Challenges and Unmet Needs of a Heterogeneous Disease
Lupus, a multisystem disease with a wide variety of clinical manifestations and an unpredictable course, presents significant diagnostic challenges that inevitably result in disease progression and reduced quality of life. The jointly published American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) SLE classification recommend a weighted approach for a more accurate and timely SLE diagnosis.6 This classification criteria is an improvement from the ACR 1997 SLE classification that required fulfilment of a minimum of 4 of 11 criteria for SLE diagnosis,7 and also the EULAR 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria based on clinical or immunologic presentations with the requirement that patients meet 4 criteria for diagnosis.8
In addition to diagnostic challenges, SLE treatment options, including antimalarials, steroids, nonbiologic disease-modifying antirheumatic drugs, and targeted therapies, have several limitations.9 Some of these agents have been associated with severe drug-induced toxicity, organ function deterioration, and complications, especially among patients with refractory disease and/or lupus nephritis.9 Despite decades of investigative trials, the majority of biologic agents have produced unsatisfactory results, with belimumab being the only biologic therapy approved for SLE treatment.10-12 However, several novel agents are currently in development, particularly for patients with refractory SLE. Some of these drugs include B cell- and type I interferon-targeted therapies, agents targeting T-cell co-stimulation blockade, as well as interleukin (IL)-2, cytokines, and complement-targeted therapies.11
Currently, the SLE classification criteria and the available treatment options do not specifically target the pathophysiologic processes that lead to increased CVD risk in SLE. Theoretically, CV risk screening and patient stratification can translate to prompt treatment initiation to mitigate or delay the pathophysiologic changes leading to increased CVD.1,13 However, this approach may be hampered by the lack of standardized imaging assessment of atherosclerosis and the lack of consistency and reproducibility of the imaging results reported.14 Thus, there remains an unmet need for predictive biomarkers of CVD risk and therapies that specifically target immunologic factors associated with inflammation and elevated CVD.
Predictive Biomarkers of Atherosclerosis, CVD Risk, and Potential for Targeted Therapy
Increased arterial stiffness due to atherosclerotic plaque is correlated with markers of inflammation.13 Several molecular biomarkers of atherosclerosis have been identified, some of which are associated with CV events and mortality.14,15 Despite these observations, the current knowledge of inflammation and specific markers of atherosclerosis have not yet translated into practical CVD risk stratification approaches and the prevention of atherosclerosis progression to a CV event.14
Although the precise mechanisms involved in the development of premature atherosclerosis in patients with SLE are currently unknown, there is some evidence that dysregulation of innate and adaptive immune system, inflammation, and early onset arterial stiffness may be contributory factors.13,16,17 Traditional risk factors, including hypertension, hyperlipidemia, diabetes mellitus, and smoking, and SLE-specific risk factors, such as disease activity and duration, kidney disease, presence of antiphospholipid antibodies, and C-reactive protein levels, do not fully account for the elevated CVD risk among patients with SLE.18 Residual CVD risk persists when the known risk factors are managed.
Among the unknown risk factors that may contribute to the residual CVD risk in patients with SLE, bone mineral density (BMD) is a candidate that is known to have an inverse relationship with CVD.19 Patients with either clinical or subclinical CVD have lower BMD levels compared with those without a CV event.19 Low BMD, osteoporosis, and osteopenia have been prevalent in patients with SLE. Furthermore, studies in patients with osteoporosis show that low BMD and increased bone loss were associated with CVD.20
Bone metabolism is regulated by an interplay of several biological entities, including 25(OH) vitamin D3 (25-OHD), parathormone (PTH), osteoprotegerin (OPG), and receptor activator of nuclear factor-kappa-Β ligand (RANKL). These biological entities are also classical markers of osteoporosis and CVD.21 The demonstrated link between the low concentration of 25-OHD and poor CV-related outcomes support further exploration of 25-OHD as a primary target for elevated CVD in patients with SLE.22
A recent study in 138 patients found a close correlation between atherosclerosis and elevated PTH concentration (>65 pg/mL).22 Low BMD was associated with increased arterial wall thickness, indicative of the presence of plaque. However, 25-OHD did not correlate with elevated risk for atherosclerosis.22 The study suggested that high PTH serum concentration may be a potential biomarker for atherosclerosis risk in patients with SLE.
“Biomarkers of autoimmunity and altered bone metabolism can potentially provide a practical approach to patient CVD risk assessment and stratification,” said Clio P. Mavragani, MD, PhD, a co-author of the paper, a rheumatologist, and an associate professor in the Medical School of the National Kapodistrian University of Athens, Greece. He added, “Serum PTH – a hormone which regulates calcium metabolism – has been recently shown by our group to serve as a marker of subclinical atherosclerosis in patients with lupus.”
In addition, the researchers of the study found that elevated PTH reflected underlying vitamin D deficiency. Overall, the study findings suggested that adequate serum vitamin D levels may reduce the risk for atherosclerosis in patients with SLE; however, further confirmatory studies are needed.
Subclinical atherosclerosis develops early in patients with SLE, and warrants timely screening and cardioprotective interventions, including optimal management of traditional CVD risk factors. Recent studies have suggested that altered bone metabolism may provide biomarkers for a practical approach to patient CVD risk assessment. The multisystem and unpredictable disease course of SLE requires a multidisciplinary care approach, which, if not well-coordinated and evidence-based, can result in fragmented care.
Professor Mavragani suggests a holistic approach aimed at controlling disease activity, minimizing potential side effects of medications, and addressing significant comorbidities, such as subclinical atherosclerosis, osteoporosis, and psychosocial issues. Professor Berger advises that both the patient with SLE and the treating physician recognize that CVD is relatively common in this population. He noted that clinicians must also recognize that patients with SLE are relatively younger and mostly women, populations among whom heart disease and stroke may be undiagnosed.
- Gustafsson JT, Herlitz Lindberg M, Gunnarsson I, et al. Excess atherosclerosis in systemic lupus erythematosus,-A matter of renal involvement: Case control study of 281 SLE patients and 281 individually matched population controls. PLoS One. 2017;12(4):e0174572. doi: 10.1371/journal.pone.0174572
- Gartshteyn Y, Braverman G, Mahtani S, Geraldino-Pardilla L, Bokhari S, Askanase A. Prevalence of coronary artery calcification in young patients with SLE of predominantly Hispanic and African-American descent. Lupus Sci Med. 2019;6(1):e000330. doi:10.1136/lupus-2019-000330
- Katz G, Smilowitz NR, Blazer A, Clancy R, Buyon JP, Berger JS. Systemic lupus erythematosus and increased prevalence of atherosclerotic cardiovascular disease in hospitalized patients. Mayo Clin Proc. 2019;94(8):1436-1443. doi:10.1016/j.mayocp.2019.01.044
- Bernatsky S, Boivin JF, Joseph L. Mortality in systemic lupus erythematosus. Arthritis Rheum. 2006;54(8):2550-2557. doi:10.1002/art.21955
- Manzi S, Meilahn EN, Rairie JE, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham study. Am J Epidemiol. 1997;145(5):408-415. doi:10.1093/oxfordjournals.aje.a009122
- Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for systemic lupus erythematosus. Arthritis Rheumatol. 2019;71(9):1400-1412. doi:10.1002/art.40930
- Lam NC, Ghetu MV, Bieniek ML. Systemic lupus erythematosus: primary care approach to diagnosis and management. Am Fam Physician. 2016;94(4):284-94.
- Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64(8):2677-86. doi:10.1002/art.34473
- Davis LS, Reimold AM. Research and therapeutics-traditional and emerging therapies in systemic lupus erythematosus. Rheumatology (Oxford). 2017;56(1):100-113. doi:10.1093/rheumatology/kew417
- Bakshi J, Segura BT, Wincup C, Rahman A. Unmet needs in the pathogenesis and treatment of systemic lupus erythematosus. Clin Rev Allergy Immunol. 2018;55(3):352-367. doi:10.1007/s12016-017-8640-5
- Samotij D, Reich A. Biologics in the treatment of lupus erythematosus: a critical literature review. Biomed Res Int. 2019;2019:8142368. doi:10.1155/2019/8142368
- Dubey AK, Handu SS, Dubey S, Sharma P, Sharma KK, Ahmed QM. Belimumab: First targeted biological treatment for systemic lupus erythematosus. J Pharmacol Pharmacother. 2011;2(4):317-9. doi:10.4103/0976-500X.85930
- Mercurio V, Lobasso A, Barbieri L, et al. inflammatory, serological and vascular determinants of cardiovascular disease in systemic lupus erythematosus patients. Int J Mol Sci. 2019;20(9):2154. doi:10.3390/ijms20092154
- Teixeira V, Tam LS. Novel insights in systemic lupus erythematosus and atherosclerosis. Front Med (Lausanne). 2018;4:262. doi:10.3389/fmed.2017.00262
- Wigren M, Svenungsson E, Mattisson IY, et al. Cardiovascular disease in systemic lupus erythematosus is associated with increased levels of biomarkers reflecting receptor-activated apoptosis. Atherosclerosis. 2018;270:1-7. doi:10.1016/j.atherosclerosis.2018.01.022
- Liu T, Shi N, Zhang S, Silverman GJ, Duan XW, Zhang S, Niu H. Systemic lupus erythematosus aggravates atherosclerosis by promoting IgG deposition and inflammatory cell imbalance. Lupus. 2020;29(3):273-282. doi:10.1177/0961203320904779
- Liu Y, Kaplan MJ. Cardiovascular disease in systemic lupus erythematosus: an update. Curr Opin Rheumatol. 2018;30(5):441-448. doi:10.1097/BOR.0000000000000528
- Stojan G, Petri M. Atherosclerosis in systemic lupus erythematosus. J Cardiovasc Pharmacol. 2013;62(3):255-262. doi:10.1097/FJC.0b013e31829dd857
- Rodríguez-Carrio J, Martínez-Zapico A, Cabezas-Rodríguez I, et al. Clinical and subclinical cardiovascular disease in female SLE patients: interplay between body mass index and bone mineral density. Nutr Metab Cardiovasc Dis. 2019;29(2):135-143. doi:10.1016/j.numecd.2018.09.007
- Xia J, Luo R, Guo S, et al. Prevalence and risk factors of reduced bone mineral density in systemic lupus erythematosus patients: a meta-analysis. Biomed Res Int. 2019;2019:3731648. doi:10.1155/2019/3731648
- Domiciano DS, Machado LG, Lopes JB, Figueiredo CP, et al. Bone mineral density and parathyroid hormone as independent risk factors for mortality in community-dwelling older adults: a population-based prospective cohort study in Brazil. The São Paulo Ageing & Health (SPAH) study. J Bone Miner Res. 2016;31(6):1146-57. doi:10.1002/jbmr.2795
- Giannelou M, Skarlis C, Stamouli A, Antypa E, Moutsopoulos HM, Mavragani CP. Atherosclerosis in SLE: a potential role for serum parathormone levels. Lupus Sci Med. 2020;7(1):e000393. doi:10.1136/lupus-2020-000393