Editor’s Pick: Immunometabolism in Rheumatic Disease: The Role in Pathogenesis and Implications for Treatment - European Medical Journal

Editor’s Pick: Immunometabolism in Rheumatic Disease: The Role in Pathogenesis and Implications for Treatment

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Chris Wincup,1 George Robinson,1 Shi-Nan Luong,1,2 *Thomas McDonnell1

No specific funding was required for the writing of this review. Dr Wincup is funded by Versus Arthritis (21992). Dr McDonnell is funded by Lupus UK (177748). Dr Robinson is funded by Lupus UK and the Rosetrees Trust. Dr Luong is funded by Arthritis Australia and the Australian Government Research Training Program Scholarship. The authors have declared no additional conflicts of interest.


Figures 1 and 2 were created with Biorender.com. Dr Wincup was responsible for writing the ‘Introduction’, ‘Glycolysis, mitochondria, and energy metabolism’ and ‘Conclusion’ sections. Dr Robinson was responsible for writing the ‘Lipid metabolism’ section. Dr Luong was responsible for writing the ‘Protein kinase and amino acid metabolism’ section. Dr McDonnell was responsible for editing the manuscript and organising the review. All authors reviewed and approved the manuscript’s content before submission.

EMJ Rheumatol. ;6[1]:81-89. DOI/10.33590/emjrheumatol/10311626. https://doi.org/10.33590/emjrheumatol/10311626.
Immunometabolism, mitochondrial DNA, rheumatology.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.


Rheumatic diseases collectively are complex disorders, often with multifactorial origins ranging from genetic risk factors to viral triggers. In many cases, the exact pathogenic mechanisms are poorly understood. Treatment response is often difficult to predict, and significant research is currently being undertaken to investigate new avenues for potential novel therapies. Immunometabolism, the study of the interface between immunological and metabolic processes, represents one such avenue at the forefront of this research and links cellular metabolism with the various changes in immunophenotypes observed across a variety of rheumatic disorders. Abnormal mitochondrial function and dysregulation of energy metabolism has been proposed as a potential mechanism for the pathogenesis of systemic lupus erythematosus, inflammatory arthritis, and vasculitis. Furthermore, various metabolomic and amino acid changes have been observed across rheumatic diseases during activation of the immune and inflammatory response, thus representing an attractive prospect for medication development. In this review, the authors focus on immunometabolism in rheumatic disease, looking at mitochondrial dysfunction, fatty acid metabolism, and protein and amino acid changes across the disease spectrum. In particular, the authors evaluate the implications for the understanding of disease pathogenesis and explore the potential for immunometabolic intervention as a means of treatment.


The field of immunometabolism is a rapidly expanding area of research that centres around understanding the interrelationship between immunological and metabolic processes.1 Activation of the immune system is a dynamic process that requires significant immune metabolic reprogramming to induce and maintain proliferation of immune cells, as well as activation and engagement of effector cellular function.2 Immunometabolism encompasses the roles of glycolytic and mitochondrial-derived energy metabolism, regulation of fatty acid oxidation and lipid synthesis, and protein kinase and amino acid metabolism.3 A summary of the key immune cell metabolic pathways is highlighted in Figure 1.

Figure 1: Summary of the key immune cell metabolic pathways.

In recent years, significant research has shed new light on the pathogenesis of various diseases with abnormal immunometabolism, including the development of atherosclerosis,4,5 diabetes,6,7 multiple sclerosis (MS),8 and malignancy.9 This has resulted in further research investigating the potential to alter the immunological–metabolic interface, which may represent a possible novel route towards new therapeutic targets.

Autoimmune rheumatic diseases are associated with activation of both the innate and adaptive immune system and results in the generation of autoantibodies and pro-inflammatory cytokines. This heterogenous group of disorders are typically characterised by a number of shared pathological mechanisms with a variety of different immunometabolic pathways implicated.

In this review, the authors describe the role of metabolic pathways during immune activation, evaluate the latest evidence supporting the role of changes in immunometabolism in various rheumatic diseases, and consider how this may lead to potential novel future therapeutic options.

Glycolysis, Mitochondria, and Energy Metabolism

Cellular metabolism is dependent upon two key metabolic pathways that are required to produce energy in the form of adenosine triphosphate (ATP): glycolysis and oxidative phosphorylation. In health, glycolysis is the metabolic pathway that converts glucose to pyruvate and hydrogen ions, which are essential for ATP generation. In the context of immune cell activation, metabolic reprogramming in glycolysis pathways are required for the induction and maintenance of cellular proliferation. Macrophages activated by lipopolysaccharide (LPS) have been demonstrated to switch their core metabolism to the glycolysis pathways. However, this change in metabolism pathways has been associated with an accumulation of a number of Kreb cycle intermediates, such as succinate, which stimulates IL-1β production and may induce a pro-inflammatory state.10 Furthermore, metabolites, including fumarate and itaconate, have been implicated in this adaptive immune response.11,12

In the pathogenesis of autoimmune rheumatic diseases, glycolytic pathways have been studied in the context of autoreactive T cells in systemic lupus erythematosus (SLE), which are dependent upon glycolysis for early inflammatory effector functions. The activity of calcium/calmodulin-dependent protein kinase 4 has been suggested to be responsible for glycolytic pathways and, in turn, contributes to aberrant expression of the GLUT1 receptor in active SLE.13 Yin et al.14 previously demonstrated that by normalising T cell metabolism through inhibition of glycolysis with 2-deoxy-d-glucose, interferon-γ production in a murine SLE model was reduced. Whilst glycolysis has been implicated in the initial immune response, T cells that become chronically activated predominantly generate ATP from mitochondrial oxidative phosphorylation rather than glycolysis.15

In comparison to glycolytic energy metabolism, mitochondria produce ATP through oxidative phosphorylation using oxygen and nutrients, which is driven via an electrochemical gradient along the inner mitochondrial membrane. Mitochondria also represent the major source of reactive oxygen species (ROS) generation. A number of studies have observed that mitochondria can be potent activators of the immune-mediated inflammatory response.16,17 In recent years, the study of mitochondria dysfunction, altered bioenergetic conditions, and ROS production have been investigated in the pathogenesis of a number of rheumatic diseases.

Mitochondria contain their own genetic material in the form of mitochondrial DNA (mtDNA) and this has also been implicated in the pathogenesis of various rheumatic diseases. Impaired energy metabolism can induce mitochondrial hypoxia, which has been shown to cause point mutations in mtDNA taken from the synovial tissue of patients with inflammatory arthritis. Further research showed the addition of antioxidants (in this case N-acetylcysteine [NAC]) rescue these mutations.18 In addition, effective treatment with anti-TNF-alpha therapy has been demonstrated to reverse these mtDNA mutations.19 Mitochondrial dysfunction results in damage to the structure of the organelle and ultimately in the release of mitochondrial genetic material from the cell into the microenvironment. This circulating cell free mtDNA can be detected in plasma and has been implicated in the pathogenesis of granulomatosis with polyangiitis (GPA), in which levels of mtDNA were found to be significantly elevated in those who were untreated, suggesting this may be a potentially novel biomarker.20

There is growing evidence from a number of studies supporting the role of abnormal mitochondrial function in the pathogenesis of osteoarthritis (OA). OA chondrocytes stimulated by IL-1β have been noted to demonstrate high levels of ROS generation and mitochondrial membrane damage, which has been associated with a higher incidence of apoptosis.21 Rheumatoid arthritis (RA) synovial fibroblasts have also demonstrated significant mitochondrial dysfunction and abnormal autophagy, which has also been seen in chondrocytes derived from patients with OA.22,23

The role of oxidative stress in the pathogenesis of SLE is well described,24 however, the implications for mitochondrial dysfunction resulting in ROS production in the pathogenesis of the disease is a more recent area of interest.25 Mitochondrial electron transport chain complex one has been reported as the main source of oxidative stress in peripheral lymphocytes in SLE. Furthermore, it was noted that NAC inhibited ROS production and proposed that this may be of possible therapeutic benefit.26 Mitochondrial ROS have also been found to induce the formation of neutrophil extracellular traps (NET) through NETosis,27 which has been implicated in the development of various autoimmune rheumatic disorders. A study by Lood et al.27 found that mitochondria-derived ROS are essential for the induction of maximal NETosis in SLE. The authors also noted that inhibition of ROS formation in vivo resulted in a reduction in both type I interferon signature and disease severity in murine models. It was concluded that both NET and pro-inflammatory oxidised mtDNA play a key role in the pathogenesis of SLE.27 Figure 2 summarises the ways in which mitochondrial dysfunction can result in ROS generation, NETosis, and the release of mtDNA. Previous animal studies have also implicated NETosis in the development of antibody-mediated thrombosis in antiphospholipid syndrome.28,29 Mitochondrial oxygen consumption was also noted to be elevated in the liver of 4-week-old lupus-prone mice, which led to the formation of anti-phospholipid antibodies prior to the onset of the disease phenotype. Furthermore, this was observed to be corrected with the addition of rapamycin,30 a drug that targets and modulates autophagy pathways.

Figure 2: Summary of how mitochondrial dysfunction can result in reactive oxygen species generation, NETosis, and the release of mitochondrial DNA.
Mitochondrial dysfunction can induce damage to the outer mitochondrial membrane, which in turn can lead to the generation of reactive oxygen species and induce oxidative stress. Significant mitochondrial damage can result in mitochondrial DNA release, and, in turn, this circulating antigenic mitochondrial DNA may result in the formation of autoantibodies directed against mitochondrial genetic content. mtDNA: mitochondrial DNA; ROS: reactive oxygen species.

Lipid Metabolism

Lipids are a critical aspect of metabolism, playing fundamental roles in cell membrane composition, membrane receptor signalling, and energy storage. The key lipids for cellular function include cholesterol, phospholipids, fatty acids, triglycerides, and glycosphingolipids (GSL). Lipid metabolism is implicated in a wide range of diseases including cardiovascular disease (CVD) and nonalcoholic fatty liver disease; however, more recent studies have shown a significant role for lipids in regulating inflammation and driving autoimmune diseases.31-33

Lipid metabolism is used in different ways depending on the immune cell. For example, regulatory T cells (Treg) use lipids for their anti-inflammatory functions through beta-oxidation in the mitochondria and generate ATP through oxidative phosphorylation, whereas effector T cells depend more highly on glycolytic over lipid mediated processes for the growth and proliferation necessary for their functions.31 Lipids also play a significant role in the immune cell membrane in signalling platforms called lipid rafts.32,33 These comprise signalling proteins, GSL, and cholesterol, which together mediate T cell and B cell receptor signalling through co-receptor recruitment to the raft.

CVD is a major complication of autoimmune diseases and this is largely due to prolonged inflammation and dyslipidaemia.34 Dyslipidaemia broadly relates to the disrupted balance between low-density and high-density lipoproteins (LDL and HDL), which are pro-atherogenic and anti-atherogenic, respectively. Lipoproteins are responsible for transporting processed lipids, such as cholesterol and triglycerides, to HDL and from LDL in the liver.35 SLE is a common example of an autoimmune disease heavily influenced by dyslipidaemia, and CVD has been shown to be the leading cause of mortality for SLE,36,37 largely due to atherosclerosis. During atherosclerosis, macrophages take up the oxidised form of LDL in arteries, eventually resulting in macrophage foam cell formation and the formation of fatty lesions in the arterial wall. Rupture of the vessel wall can occur with excessive build-up of these fatty lesions, resulting in the recruitment of platelets, thus leading to narrowing of the arterial lumen.38 It has also recently been shown that lipoproteins can control the balance of lipids in the immune cell membrane, thus controlling inflammation, another key driver of atherosclerosis.39 In addition, lipid rafts have also been shown to be disrupted in SLE.32,40 Jury et al.41,42 showed an increase in cholesterol and GSL at the membrane to increased T cell receptor signalling at lipid rafts, and that a therapeutic intervention of GSL synthesis can normalise this signalling and reduce inflammation. Cholesterol is known to be involved in T cell activation,43 thus it is another metabolic target for therapeutic agents, such as statins. Altered lipid rafts have also been shown to impact B cell receptor signalling in SLE.44 Cholesterol has also been found to play a number of roles in the activated immune response. In autoimmunity, cholesterol metabolism has been implicated in the production of IFN-γ and immune complexes,45 which have a significant role in the pathogenesis of a number of rheumatic conditions.

Similarly, despite being a disease associated with inflammation of the joints, comorbid conditions in RA have also been related to dyslipidaemia and CVD;46 however, data is conflicting.47 This is again likely to relate to the generalised effect of lipid metabolism and inflammation on early atherosclerosis in RA.34 Active RA patients have been shown to have increased circulating HDL-cholesterol, and one study has demonstrated that this is also the case for untreated patients.48 In addition, a separate study showed that smaller sizes of LDL and HDL, commonly shown to have more pro and anti-atherogenic effects respectively than their larger counterparts, were increased and decreased in the serum of RA patients, respectively.49,50

Current treatments for rheumatic disorders have been shown to influence lipid metabolism. An example in SLE is the use of hydroxychloroquine (an antimalarial agent), which has been shown to reduce levels of circulating LDL.51 In contrast, the prolonged use of corticosteroids in SLE is associated with driving further dyslipidaemia, despite its preferential effects on inflammation.52,53 In addition, RA patients treated with glucocorticoids display increased levels of HDL.54 Regarding lipid modification therapy, high dose statins (80 mg/day) are currently being trialled as a new therapy for patients with MS and the Phase II trial showed reduced rates of brain atrophy and disability progression in patients with secondary progressive disease.55,56 In addition, RA patients treated with statins have shown improvements in erythrocyte sedimentation rate and C-reactive protein compared to patients on conventional standard of care therapy after 6 months of follow-up.57 However, evidence that statins are beneficial in SLE patients, in terms of reducing cardiovascular risk and/or inflammation, is mixed. Some smaller studies have shown a beneficial effect;58-61 however, the Lupus Atherosclerosis Prevention Study62 and Atherosclerosis Prevention in Paediatric Lupus Erythematosus study63 did not identify any beneficial effects of statins on disease activity or CVD risk measurements. Follow-up analysis has identified that patients with higher baseline C-reactive protein did, however, have improved CVD risk measures following the trial.64,65 Thus, the success of future trials may depend on correct stratification of patients based on lipid profile and improved suitability of primary outcome measures.

Lipid metabolism is a key player in autoimmunity, and the therapeutic targeting of specific pathways holds promise for dual mediation of inflammation and CVD. The pathways that need to be targeted and the impact of these physiologically will need to be carefully considered, including the differential role of lipid metabolism across immune cell subsets. Further studies are required, but this opens the possibility of modulating diet to influence lipid metabolism as a potential treatment for autoimmune disease.

Protein Kinase and Amino Acid Metabolism

Proteins, peptides, and amino acids play an important role in immunometabolism in both health and disease, particularly with their effects on T cell differentiation and function. An imbalance between the pro-inflammatory T helper cell subsets, Th1 and Th17 cells, and anti-inflammatory Foxp3+ Treg, with the subsequent loss of self-tolerance, is thought to contribute to autoimmune disease.66,67 Normally T cell differentiation into various cell subsets relies on the activation of the mTOR, a serine-threonine protein kinase that is present in two different complexes: mTORC1 and mTORC2.68 It also helps maintain cell homeostasis by regulating metabolic signals and nutrient availability to drive genetic programmes involved in cell growth, activation, energy use, proliferation, and survival.68-71 Through sensing cell energy status and the available metabolites, mTOR is capable of altering cellular activity.68 mTORC1 activation alters T cell metabolism to provide the essential constituents required for Th1 and Th17 cell proliferation and differentiation; however, this signalling is also necessary for the suppressive function of Treg.71

In patients with SLE, mTORC1 activation occurs in CD4+ T cells.69 This activation of mTORC1 may be driven by mitochondrial dysfunction secondary to the depletion of the tripeptide glutathione;72 through hyperactivation of the pentose phosphate pathway and increased transaldolase activity;70,73 or by a rise in the tryptophan metabolite kynurenine, which has immunomodulatory functions.70,74 In rare cases, genetic activation of mTORC1 is possible.70,75 mTORC1 activation may also represent a biomarker of autoimmune inflammation68,69 and has been implicated in the pathogenesis of SLE in several ways. For example, activation has been detected after an increase in glycolysis and suppression of autophagy (including mitophagy) with subsequent mitochondrial dysfunction.70 T cell necrosis, decrease in Treg populations, and an increase in pro-inflammatory Th17 and double-negative (CD4-CD8-) T cells76,77 have also been observed. Double-negative T cells then in turn stimulate B cells to produce autoantibodies in SLE.77 Similarly in RA, there are metabolic interactions between enzymatic proteins in T cells, which are believed to play a key role in chronic inflammation underlying the disease.78 T cells in RA are chronically activated, and thus undergo metabolic reprogramming, ultimately existing in a state of energy deprivation.78 In early RA, this process occurs in lymphoid organs, with reduced activity of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in CD4+ T cells.78,79 PFKFB3 is an enzyme that normally produces fructose 2,6-bisphosphate, which, in turn, activates the rate limiting enzyme in glycolysis, phosphofructokinase 1.67,78 Reduced PFKFB3 activity results in a decrease in glycolysis, lower pyruvate and ATP levels, and shunting of glucose into the pentose phosphate pathway.78,79 These T cells are predisposed to apoptosis and fail to induce autophagy, a process normally required for cells to recycle their internal biosynthetic precursors for energy generation.78

While shunting to the pentose phosphate pathway allows T cells to produce biosynthetic precursors required for clonal expansion, it has significant metabolic and functional consequences in RA.67 Higher levels of nicotinamide adenine dinucleotide phosphate (NADPH) and reduced glutathione are produced, which neutralises ROS.67 ROS normally act as messengers required for appropriate T cell activation, proliferation, migration, and apoptosis via oxidant signalling.67,78,79 As a result of the depletion of ROS, oxidation-dependent cell signalling becomes dysregulated and there is insufficient activation of the cell cycle kinase ATM.67 Thus, T cells become hyperproliferative and favour differentiation into pro-inflammatory Th1 and Th17 cell lineages.67,79 In the later stages of RA, T cells invade peripheral tissues, such as synovial joints, interacting with B cells, plasma cells, antigen presenting cells, and tissue resident cells to create a lymphoid structure.67,80 This lymphoid structure has hypermetabolic activity with immune cells continuing to release metabolites that promote inflammation in the surrounding synovial tissue.67

Increased understanding of these pathways could lead to more precise treatment of autoimmune rheumatic diseases because specific metabolic pathways could potentially be targeted to modify an immune cell response.81 For example, both rapamycin (also known as sirolimus) and NAC inhibit mTORC1 and decrease disease activity in SLE patients.72,82-84 A recent single-arm, open-label Phase I/II trial of 43 patients with treatment resistant and/or treatment intolerant SLE, found that disease activity improved following 12 months of sirolimus, particularly in those with mucocutaneous and musculoskeletal symptoms.84 Sirolimus decreased IL-4 and IL-17 expression by pro-inflammatory double-negative and CD4+ T cells and upregulated Treg.84 Unfortunately, the benefits of sirolimus are counterbalanced by commonly observed side effects including infection, hyperlipidaemia, and hyperglycaemia,68,85 which is a concern in SLE because infections and CVD contribute greatly to mortality.86 In comparison, NAC has few side effects72 and the rationale behind its use is based on studies suggesting that both oxidative stress and reduced glutathione play a key role in the pathogenesis of SLE via abnormal T cell activation.87,88 As well as inhibiting mTORC1, NAC reverses glutathione depletion, reduces double-negative T cell proliferation, and upregulates Treg.72 Larger randomised controlled trials are required to further evaluate the effectiveness of sirolimus and NAC in SLE and other autoimmune rheumatic disorders characterised by abnormal mTOR activation.


In conclusion, recent advances in the understanding of the role of abnormal immunometabolism have shed new light on the pathogenesis of a number of rheumatic diseases. Similarly, research into lipid metabolism is revealing the ways in which rheumatic diseases are associated with non-traditional mechanisms of CVD. Understanding these complex interactions between metabolism and inflammation raises exciting opportunities to develop new innovative treatment options. For example, there is the possibility of using a variety of novel therapeutic agents including antioxidants (such as NAC) or even dietary modification (as a means of changing lipid profile) to ultimately improve disease activity and reducing symptoms in the future.

Pearce EJ, Pearce EL. Immunometabolism in 2017: Driving immunity: All roads lead to metabolism. Nat Rev Immunol. 2018;18(2):81-2. Chang CH et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell. 2013;153(6):1239-51. O'Neill LA et al. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16(9):553-65. Groh L et al. Monocyte and macrophage immunometabolism in atherosclerosis. Semin Immunopathol. 2018;40(2):203-14. Koelwyn GJ et al. Regulation of macrophage immunometabolism in atherosclerosis. Nat immunol. 2018;19(6):526-37. Kohlgruber AC et al. Adipose tissue at the nexus of systemic and cellular immunometabolism. Semin Immunol. 2016;28(5):431-40. Lenin R et al. Altered immunometabolism at the interface of increased endoplasmic reticulum (ER) stress in patients with type 2 diabetes. J Leukoc Biol. 2015;98(4):615-22. Luu M et al. The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nat Comm. 2019;10(1):760. Dyck L, Lynch L. Cancer, obesity and immunometabolism - Connecting the dots. Cancer Lett. 2018;417:11-20. Tannahill GM et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature. 2013;496(7444):238-42. Arts RJ et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metabol. 2016;24(6):807-19. Tang C et al. 4-Octyl itaconate activates Nrf2 signaling to inhibit pro-inflammatory cytokine production in peripheral blood mononuclear cells of systemic lupus erythematosus patients. Cell Physiol Biochem. 2018;51(2):979-90. Koga T et al. Promotion of calcium/calmodulin-dependent protein kinase 4 by GLUT1-dependent glycolysis in systemic lupus erythematosus. Arthritis Rheumatol. 2019;71(5):766-72. Yin Y et al. Normalization of CD4+ T cell metabolism reverses lupus. Sci Transl Med. 2015;7(274):274. Wahl DR et al. Characterization of the metabolic phenotype of chronically activated lymphocytes. Lupus. 2010;19(13):1492-501. Liu PS, Ho PC. Mitochondria: A master regulator in macrophage and T cell immunity. Mitochondrion. 2018;41:45-50. West AP et al. Mitochondria in innate immune responses. Nat Rev Immunol. 2011;11(6):389-402. Biniecka M et al. Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis. Arthritis Rheum. 2011;63(8):2172-82. Biniecka M et al. Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxia-induced mitochondrial mutagenesis in inflammatory arthritis. Arthritis Res Ther. 2011;13(4):R121. Surmiak MP et al. Circulating mitochondrial DNA in serum of patients with granulomatosis with polyangiitis. Clin Exper Immunol. 2015;181(1):150-5. Ansari MY et al. Parkin clearance of dysfunctional mitochondria regulates ROS levels and increases survival of human chondrocytes. Osteoarthritis Cartilage. 2018;26(8):1087-97. Biniecka M et al. Dysregulated bioenergetics: A key regulator of joint inflammation. Ann Rheum Dis. 2016;75(12):2192-200. Kim EK et al. IL-17-mediated mitochondrial dysfunction impairs apoptosis in rheumatoid arthritis synovial fibroblasts through activation of autophagy. Cell Death Dis. 2017;8(1):e2565. Sporn MB et al. Prospects for prevention and treatment of cancer with selective PPARgamma modulators (SPARMs). Trends Mol Med. 2001;7(9):395-400. Perl A et al. Assessment of mitochondrial dysfunction in lymphocytes of patients with systemic lupus erythematosus. Methods Mol Biol. 2012;900:61-89. Doherty E et al. Increased mitochondrial electron transport chain activity at complex I is regulated by N-acetylcysteine in lymphocytes of patients with systemic lupus erythematosus. Antiox Redox Signal. 2014;21(1):56-65. Lood C et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22(2):146-53. Meng H et al. In vivo role of neutrophil extracellular traps in antiphospholipid antibody-mediated venous thrombosis. Arthritis Rheumatol. 2017;69(3):655-67. Yalavarthi S et al. Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: A newly identified mechanism of thrombosis in the antiphospholipid syndrome. Arthritis Rheumatol. 2015;67(11):2990-3003. Oaks Z et al. Mitochondrial dysfunction in the liver and antiphospholipid antibody production precede disease onset and respond to rapamycin in lupus-prone mice. Arthritis Rheumatol. 2016;68(11):2728-39. Gerriets VA, Rathmell JC. Metabolic pathways in T cell fate and function. Trends Immunol. 2012;33(4):168-73. Jury EC et al. Lipid rafts in T cell signalling and disease. Semin Cell Dev Biol. 2007;18(5):608-15. Pierce SK. Lipid rafts and B-cell activation. Nat Rev Immunol. 2002;2(2):96-105. Hahn BH et al. The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: Roles of inflammation and dyslipidemia. J Autoimmun. 2007;28(2-3):69-75. Ramasamy I. Recent advances in physiological lipoprotein metabolism. Clin Chem Lab Med. 2014;52(12):1695-727. Cervera R et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period - A comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore). 2003;82(5):299-308. Bernatsky S et al. Mortality in systemic lupus erythematosus. Arthritis Rheum. 2006;54(8):2550-7. Hegele RA. The pathogenesis of atherosclerosis. Clinica Chimica Acta. 1996;246(1-2):21-38. Pohl J et al. FAT/CD36-mediated long-chain fatty acid uptake in adipocytes requires plasma membrane rafts. Mol Biol Cell. 2005;16(1):24-31. Jury EC et al. Altered lipid raft-associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus. J Clin Invest. 2004;113(8):1176-87. Jury EC et al. Atorvastatin restores Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus. J Immunol. 2006;177(10):7416-22. McDonald G et al. Normalizing glycosphingolipids restores function in CD4(+) T cells from lupus patients. J Clin Invest. 2014;124(2):712-24. Surls J et al. Increased membrane cholesterol in lymphocytes diverts T-Cells toward an inflammatory response. PLoS One. 2012;7(6):e38733. Flores-Borja F et al. Altered lipid raft-associated proximal signaling and translocation of CD45 tyrosine phosphatase in B lymphocytes from patients with systemic lupus erythematosus. Arthritis Rheum. 2007;56(1):291-302. Reiss AB et al. Immune complexes and IFN-gamma decrease cholesterol 27-hydroxylase in human arterial endothelium and macrophages. J Lipid Res. 2001;42(11):1913-22. Ranganath VK et al. Comorbidities are associated with poorer outcomes in community patients with rheumatoid arthritis. Rheumatology. 2013;52(10):1809-17. Garcia-Gomez C et al. Inflammation, lipid metabolism and cardiovascular risk in rheumatoid arthritis: A qualitative relationship? World J Orthoped. 2014;5(3):304-11. Choi HK, Seeger JD. Lipid profiles among US elderly with untreated rheumatoid arthritis - The Third National Health and Nutrition Examination Survey. J Rheumatol. 2005;32(12):2311-6. Toms TE et al. Dyslipidaemia in rheumatological autoimmune diseases. Open Cardiovasc Med J. 2011;5:64-75. Rizzo M et al. Atherogenic lipoprotein phenotype and LDL size and subclasses in drug-naive patients with early rheumatoid arthritis. Atherosclerosis. 2009;207(2):502-6. Babary H et al. Favorable effects of hydroxychloroquine on serum low density lipid in patients with systemic lupus erythematosus: A systematic review and meta-analysis. Int J Rheum Dis. 2018;21(1):84-92. Liu DR et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9:25. Sholter DE, Armstrong PW. Adverse effects of corticosteroids on the cardiovascular system. Can J Cardiol. 2000;16(4):505-11. Garcia-Gomez C et al. High HDL-cholesterol in women with rheumatoid arthritis on low-dose glucocorticoid therapy. Euro J Clin Invest. 2008;38(9):686-92. Chataway J et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): A randomised, placebo-controlled, Phase 2 trial. Lancet. 2014;383(9936):2213-21. Ifergan I et al. Statins reduce human blood-brain barrier permeability and restrict leukocyte migration: Relevance to multiple sclerosis. Ann Neurol. 2006;60(1):45-55. Das S et al. Outcome of rheumatoid arthritis following adjunct statin therapy. Indian J Pharmacol. 2015;47(6):605-9. Yu H-H et al. Statin reduces mortality and morbidity in systemic lupus erythematosus patients with hyperlipidemia: A nationwide population-based cohort study. Atherosclerosis. 2015;243(1):11-8. Ruiz-Limon P et al. Atherosclerosis and cardiovascular disease in systemic lupus erythematosus: Effects of in vivo statin treatment. Ann Rheum Dis. 2015;74(7):1450-8. Erkan D et al. A prospective open-label pilot study of fluvastatin on proinflammatory and prothrombotic biomarkers in antiphospholipid antibody positive patients. Ann Rheum Dis. 2014;73(6):1176-80. Ardoin SP et al. Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein. Ann Rheum Dis. 2014;73(3):557-66. Petri MA et al. Lupus Atherosclerosis Prevention Study (LAPS). Ann Rheum Dis. 2011;70(5):760-5. Schanberg LE et al. Use of atorvastatin in systemic lupus erythematosus in children and adolescents. Arthritis Rheum. 2012;64(1):285-96. Ardoin SP et al. Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein. Ann Rheum Dis. 2014;73(3):557-66. Robinson A et al. Vitamin D status is a determinant of the effect of atorvastatin on carotid intima medial thickening progression rate in children with lupus: An Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) substudy. Lupus Sci Med. 2014;1(1):e000037. Freitag J et al. Immunometabolism and autoimmunity. Immunol Cell Biol. 2016;94(10):925-34. Weyand CM. Immunometabolism in early and late stages of rheumatoid arthritis. Nat Rev Rheumatol. 2017;13(5):291-301. Perl A. Activation of mTOR mechanistic target of rapamycin in rheumatic diseases. Nat Rev Rheumtol. 2016;12(3):169-82. Li W et al. Metabolic factors that contribute to lupus pathogenesis. Crit Rev Immunol. 2016;36(1):75-98. Morel L. Immunometabolism in systemic lupus erythematosus. Nat Rev Rheumatol. 2017;13(5):280-90. Hu Z et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature. 2013;499(7459):485. Lai ZW et al. N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: A randomized, doubl-ind, placebo-controlled trial. Arthritis Rheum. 2012;64(9):2937-46. Fernandez DR et al. Activation of mammalian target of rapamycin controls the loss of TCRzeta in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation. J Immunol. 2009;182(4):2063. Perl A et al. Comprehensive metabolome analyses reveal N-acetylcysteine-responsive accumulation of kynurenine in systemic lupus erythematosus: Implications for activation of the mechanistic target of rapamycin. Metabolomics. 2015;11(5):1157-74. Psarelis S, Nikiphorou E. Coexistence of SLE, tuberous sclerosis and aggressive natural killer-cell leukaemia: Coincidence or correlated? Lupus. 2017;26(1):107-8. Lai Z-W et al. Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus. J Immunol. 2013;191(5):2236. Kato H, Perl A. Mechanistic target of rapamycin complex 1 expands Th17 and IL-4+ CD4-CD8- double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus. J Immunol. 2014;192(9):4134-44. Yang Z et al. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J Exper Med. 2013;210(10):2119. Yang Z et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci Transl Med. 2016;8(331):331ra38. Takemura S et al. Lymphoid neogenesis in rheumatoid synovitis. J Immunol. 2001;167(2):1072. Jillian PR et al. Fine tuning of immunometabolism for the treatment of rheumatic diseases. Nat Rev Rheum. 2017;13(5):313-20. Fernandez D et al. Rapamycin reduces disease activity and normalizes T cell activation–induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum. 2006;54(9):2983-8. Eriksson P et al. Clinical experience of sirolimus regarding efficacy and safety in systemic lupus erythematosus. Frontiers Pharmacol. 2019;10:82. Lai ZW et al. Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: A single-arm, open-label, Phase 1/2 trial. Lancet. 2018;391(10126):1186-96. Wei-Xiang Q et al. Incidence and risk of treatment-related mortality with mTOR inhibitors everolimus and temsirolimus in cancer patients: A meta-analysis. PLoS ONE. 2013;8(6):e65166. Trager MJ, Ward MM. Mortality and causes of death in systemic lupus erythematosus. Curr Opin Rheumatol. 2001;13(5):345-51. Perl A. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat Rev Rheumatol. 2013;9(11):674-86. Gergely Jr P et al. Persistent mitochondrial hyperpolarization increased reactive oxygen intermediate production and cytoplasmic alkalinization characterize altered IL-10 signaling in patients with systemic lupus erythematosus. J Immunol. 2002;169(2):1092-101.

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