A Comprehensive Literature Review on Managing Systemic Lupus Erythematosus: Addressing Cardiovascular Disease Risk in Females and Its Autoimmune Disease Associations

Abstract

This review aimed to evaluate the mechanism of premature cardiovascular disease (CVD) in systemic lupus erythematosus (SLE) patients, particularly in the female population, and emphasize the need for early management interventions; explore the association between SLE and two autoimmune diseases, myasthenia gravis (MG) and antiphospholipid antibody syndrome (APS), and their management strategies; and evaluate the effectiveness of pharmacological and non-pharmacological interventions in managing SLE, focusing on premenopausal females, females of childbearing age, and pregnant patients. We conducted a comprehensive literature review to achieve these objectives using various databases, including PubMed, Google Scholar, and Cochrane. The collected data were analyzed and synthesized to provide an evidence-based overview of SLE, its management strategies as an independent disease, and some disease associations. The treatment should be focused on remission, preventing organ damage, and improving the overall quality of life (QOL). Extensive emphasis should also be focused on diagnosing SLE and concurrent underlying secondary diseases timely and managing them appropriately.

Keywords: adverse pregnancy outcomes; antiphospholipid antibody syndrome; cardiac manifestations; myasthenia gravis; serum biomarkers; systemic lupus erythematosus; therapeutic interventions.

Figure 1. Classification criteria for systemic lupus erythematosus.

ANA, antinuclear antibody; SLE, systemic lupus erythematosus; anti-β2GP1, anti-β-2-glycoprotein 1; anti-dsDNA, anti-double-stranded DNA Reproduced under the terms of the Creative Commons attribution license: Aringer M, Costenbader K, Daikh D, et al.: 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 2019, 78:1151-9. 10.1136/annrheumdis-2018-214819 [17] and 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, 71:1400-12. 10.1002/art.40930 [18]

Figure 2. Mechanism of action of hydroxychloroquine.

(a) HCQ enters and accumulates in lysosomes along a pH gradient. In lysosomes, hydroxychloroquine inhibits the degradation of cargo derived externally (via endocytosis or phagocytosis) or internally (via the autophagy pathway) in autolysosomes by increasing the pH to prevent the activity of lysosomal enzymes. Inhibition of lysosomal activity can prevent MHC class II-mediated autoantigen presentation. (b) Hydroxychloroquine can also accumulate in endosomes and bind to the minor groove of double-stranded DNA. This drug can inhibit TLR signaling by altering the pH of endosomes (involved in TLR processing) and/or preventing TLR-7 and TLR-9 from binding their ligands (RNA and DNA, respectively). Hydroxychloroquine can also inhibit the activity of the nucleic acid sensor cGAS by interfering with its binding to cytosolic DNA. By preventing TLR signaling and cGAS-STING signaling, hydroxychloroquine can reduce the production of pro-inflammatory cytokines, including type I interferons. HCQ, hydroxychloroquine; MHC, major histocompatibility complex; DNA, deoxyribonucleic acid; TLR, Toll-like receptor; RNA, ribonucleic acid; cGAMP, cyclic GMP-AMP; cGAS, cGAMP synthase; STING, stimulator of interferon genes Reproduced under the terms of the Creative Commons attribution license: Schrezenmeier E, Dörner T: Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020, 16:155-66. 10.1038/s41584-020-0372-x [51]

Figure 3. Genomic mechanisms of glucocorticoid-induced anti-inflammation.

GCs bind to their cytosolic GCR, which subsequently loses its chaperoning proteins, such as Hsp. Homodimers are formed, travel to the nucleus, bind to the GRE, and upregulate the expression of certain genes (e.g., lipocortin-1 and genes involved in metabolism), a mechanism called transactivation. mGC-GCR can bind to transcription factors such as AP-1 and NF-kβ, inhibiting the transcription of their target genes (e.g., IL-2 and TNF-α) by a mechanism called transrepression. Further, direct binding of mGC-GCR alongside AP-1 on composite GREs leads to transrepression. GC, glucocorticoid; GCR, glucocorticoid receptor; Hsp, heat shock proteins; GRE, glucocorticoid response element; mGC-GCR, monomeric GC-GCR complex; AP-1, activator protein 1; NF-kβ, nuclear factor kappa β; IL-2, interleukin-2; TNF-α, tumor necrosis factor-α Reproduced under the terms of the Creative Commons attribution license: Téllez Arévalo AM, Quaye A, Rojas-Rodríguez LC, Poole BD, Baracaldo-Santamaría D, Tellez Freitas CM: Synthetic pharmacotherapy for systemic lupus erythematosus: potential mechanisms of action, efficacy, and safety. Medicina (Kaunas). 2022, 59:10.3390/medicina59010056 [62]

Figure 4. Immunomodulatory effects of azathioprine.

Azathioprine is cleaved non-enzymatically into either 6-mercaptopurine or imidazole derivatives (such as mercapto-imidazole) by sulfhydryl-containing compounds; these imidazole derivatives are thought to have weak immunomodulatory effects. 6-Mercaptopurine is further metabolized by xanthine oxidase and TPMT into 6-thiouric acid and 6-MMP, respectively, which are both non-toxic. In a stepwise manner, 6-mercaptopurine can also be metabolized to toxic 6-thioguanosine nucleotides, which inhibit effective DNA synthesis and cell proliferation. Firstly, 6-mercaptopurine is converted to 6-thioinosine monophosphate by HPRT; 6-thioinosine monophosphate is metabolized to 6-thioxanthosine monophosphate by IMPDH, which is subsequently converted to 6-thioguanosine monophosphate by GMP synthase. Inhibition of cell proliferation is the main immunosuppressive effect of azathioprine on lymphocytes. 6-Thioinosine monophosphate can also be metabolized by TPMT to 6-methylthioinosine 5′-monophosphate, which is thought to reduce the availability of nucleotides in cells. TPMT, thiopurine S-methyltransferase; 6-MMP, 6-methyl mercaptopurine; DNA, deoxyribonucleic acid; HPRT, hypoxanthine-guanine phosphoribosyltransferase; IMPDH, inosine-5′monophosphate-dehydrogenase; GMP, guanosine monophosphate Reproduced under the terms of the Creative Commons attribution license: Broen JC, van Laar JM: Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology. Nat Rev Rheumatol. 2020, 16:167-78. 10.1038/s41584-020-0374-8 [82]

Figure 5. Inhibition of nucleotide synthesis by mycophenolate mofetil.

MMF is metabolized into MPA by carboxylesterases; the latter inhibits the synthesis of guanine nucleotides through the de novo purine synthesis pathway. This pathway begins with the conversion of 5-ribose phosphate to PRPP. PRPP is subsequently converted to IMP, which is dehydrogenated to XMP by IMPDH and subsequently dehydrogenated to GMP by GMP synthase. GMP is converted to GTP and dGTP, which are needed for DNA synthesis. MPA is a strong inhibitor of IMPDH, and the inhibition of IMPDH leads to low availability of nucleotides (GMP, GTP, and dGTP) and hence prevents DNA replication and subsequently cell proliferation. MMF, mycophenolate mofetil; MPA, mycophenolic acid; PRPP, 5-phosphoribosyl-1-pyrophosphate; IMP, inosine monophosphate; XMP, xanthine monophosphate; IMPDH, inosine monophosphate dehydrogenase; GMP, guanosine monophosphate; GTP, guanosine triphosphate; dGTP, deoxyguanosine triphosphate; DNA, deoxyribonucleic acid Reproduced under the terms of the Creative Commons attribution license: Broen JC, van Laar JM: Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology. Nat Rev Rheumatol. 2020, 16:167-78. 10.1038/s41584-020-0374-8 [82]

Figure 6. Inhibition of T cells by tacrolimus.

In T cells, TCR signaling increases levels of calcium in the cytoplasm, which leads to the activation of the calcineurin-NFAT pathway. In this pathway, dephosphorylation of NFAT leads to the activation and nuclear translocation of NFAT and the transcription of IL-2. Tacrolimus binds to FKBP, and this tacrolimus-FKBP complex suppresses the activation of the calcineurin-NFAT pathway, leading to a reduction in IL-2 production and inhibiting early activation of T cells. TCR, T-cell receptor; NFAT, nuclear factor of activated T cell; IL-2, interleukin-2; FKBP, FK506-binding protein; APC, antigen-presenting cell; MHC, major histocompatibility complex Reproduced under the terms of the Creative Commons attribution license: Broen JC, van Laar JM: Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology. Nat Rev Rheumatol. 2020, 16:167-78. 10.1038/s41584-020-0374-8 [82]

Figure 7. Targeted biological agents available and in present or previous clinical trials of systemic lupus erythematosus.

pDC, plasmacytoid dendritic cell; BLyS, B lymphocyte stimulator; TNF-α, tumor necrosis factor-α; APC, antigen-presenting cell Reproduced under the terms of the Creative Commons attribution license: Murphy G, Lisnevskaia L, Isenberg D: Systemic lupus erythematosus and other autoimmune rheumatic diseases: challenges to treatment. Lancet. 2013, 382:809-18. 10.1016/S0140-6736(13)60889-2 [110]

Figure 8. Management of SLΕ drugs, treatment strategy, targets of therapy, and adjunct therapy.

Determination of severity in SLE is based on (a) the involvement of major organs or organ-threatening disease, (b) concomitant activity from multiple non-major organs, and (c) the need for the use of high doses of glucocorticoids and/or immunosuppressive therapy. SLE, systemic lupus erythematosus; aPL, antiphospholipid antibody; AZA, azathioprine; BEL, belimumab; CNI, calcineurin inhibitors; CYC, pulse cyclophosphamide; EULAR, European League Against Rheumatism; GC, glucocorticoids; PO, per oral; IM, intramuscular; IV, intravenous; MTX, methotrexate; HCQ, hydroxychloroquine; MMF, mycophenolate mofetil; RTX, rituximab; SLEDAI, SLE Disease Activity Index Reproduced under the terms of the Creative Commons attribution license: Fanouriakis A, Tziolos N, Bertsias G, Boumpas DT: Update οn the diagnosis and management of systemic lupus erythematosus. Ann Rheum Dis. 2021, 80:14-25. 10.1136/annrheumdis-2020-218272 [111]

Figure 9. Mechanism of action of telitacicept.

Telitacicept binds to a BLyS and APRIL and thereby prevents them from binding to BAFF-R, BCMA, and TACI receptors expressed on the B-cell surface, suppressing BLyS and APRIL signaling and inhibiting the development and survival of mature B cells and plasma cells. A3, APRIL homotrimers; B3, BLyS homotrimers; A2B, heterotrimers of two APRIL and one BLyS molecules; AB2, heterotrimers of one APRIL and two BLyS molecules BLyS, B lymphocyte stimulator; APRIL, a proliferation-inducing ligand; BAFF-R, B-cell activating factor receptor; BCMA, B-cell maturation antigen; TCAI, transmembrane activator and calcium modulator and cyclophilin ligand interactor Reproduced under the terms of the Creative Commons attribution license: Fan Y, Gao D, Zhang Z: Telitacicept, a novel humanized, recombinant TACI-Fc fusion protein, for the treatment of systemic lupus erythematosus. Drugs Today (Barc). 2022, 58:23-32. 10.1358/dot.2022.58.1.3352743 [230]

Figure 10. Practical algorithm for the management of fatigue in patients with SLE.

SLE, systemic lupus erythematosus; PROs, patient-reported outcomes; βhCG, β-human chorionic gonadotropin; Hb, hemoglobin; CRP, C-reactive protein; BNP, brain natriuretic peptide; TSH, thyroid-stimulating hormone; FSS, fatigue severity scale; VAS, visual analog scale Reproduced under the terms of the Creative Commons attribution license: Mertz P, Schlencker A, Schneider M, Gavand PE, Martin T, Arnaud L: Towards a practical management of fatigue in systemic lupus erythematosus. Lupus Sci Med. 2020, 7:10.1136/lupus-2020-000441 [257]