Riesgo Cardiovascular en Lupus

Open Access Review
Article DOI: 10.7759/cureus.43725
A Comprehensive Literature Review on Managing

Systemic Lupus Erythematosus: Addressing
Received 06/13/2023
Cardiovascular Disease Risk in Females and Its
Review began 07/29/2023
Review ended 08/13/2023 Autoimmune Disease Associations
Published 08/18/2023
Saleha Dar 1 , Sabina Koirala 2 , Arooba Khan 3 , Mounika Deepthi Bellary 4 , Arya V. Patel 5 , Bejoi Mathew 6 ,
© Copyright 2023
Rahul Singh 7 , Nahida Baigam 8 , Waleed Razzaq 9 , Zain U. Abdin 10 , Uzzam Ahmed Khawaja 11, 12
Dar et al. This is an open access article
distributed under the terms of the Creative
Commons Attribution License CC-BY 4.0., 1. Department of Adult Medicine, Louisiana State University Health Sciences Center, Shreveport, USA 2. Department of
which permits unrestricted use, distribution, Medicine, Gandaki Medical College, Pokhara, NPL 3. Department of Internal Medicine, Khyber Medical College,
and reproduction in any medium, provided
Peshawar, PAK 4. Department of Medicine, Dr. YSR University of Health Sciences, Andhra Pradesh, IND 5. Department
the original author and source are credited.
of Internal Medicine, Smt. Nathiba Hargovandas Lakhmichand (NHL) Municipal Medical College, Ahmedabad, IND 6.
Department of Internal Medicine, Sri Devaraj Urs Medical College, Kolar, IND 7. Department of Medicine, Armed Forces
Medical College, Pune, IND 8. Department of Medicine, Association of Physicians of Pakistani Descent of North
America (APPNA), Westmont, USA 9. Department of Internal Medicine, Services Hospital Lahore, Lahore, PAK 10.
Department of Medicine, District Head Quarter Hospital, Faisalabad, PAK 11. Department of Pulmonary and Critical
Care Medicine, Jinnah Medical and Dental College, Karachi, PAK 12. Department of Clinical and Translational
Research, Dr. Ferrer BioPharma, South Miami, USA
Corresponding author: Uzzam Ahmed Khawaja, uzzamahmedkhawaja@gmail.com
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.
Categories: Internal Medicine, Medical Education, Allergy/Immunology

Keywords: antiphospholipid antibody syndrome, myasthenia gravis, therapeutic interventions, cardiac
manifestations, systemic lupus erythematosus, adverse pregnancy outcomes, serum biomarkers
Introduction And Background

Systemic lupus erythematosus (SLE) can be defined as a chronic multisystem autoimmune disease with a
wide range of systemic manifestations involving almost all organs and tissues with its effects varying from
minor cutaneous involvement to major organ damage. The burden of SLE and its survival rates vary across
Asia-Pacific countries, with crude incidence rates (100,000 per year) ranging from 0.9 to 3.1,
while prevalence rates range from 4.3 to 45.3 (per 100,000). A higher rate of renal involvement, which is one
of the main systems involved in death, was reported for Asians as compared to whites [1]. Most of the
pathology in SLE is due to immune complex (IC) deposition in various organs, which leads to the activation
of complement and other mediators of inflammation. The symptoms of SLE vary widely. Fatigue in SLE is
multifactorial [2]. SLE attacks the immune system, which, in addition to the immunosuppressive drugs used
to treat the disease, reduces the body’s ability to fight infections [3]. General symptoms include weight loss,
appetite loss, headache, myalgias, arthralgias, fever, and malaise. Weight gain may also happen due to
corticosteroid treatment or nephrotic syndrome anasarca [4]. Involvement of the musculoskeletal system is
common in patients with SLE [5]. Arthritis, arthralgia, osteonecrosis, and myopathy are the main
manifestations [6]. Dermatological manifestations include a malar rash, which comprises an erythematous
rash over the cheeks and nasal bridge.
Other features include photosensitivity, discoid rash, and alopecia. Telangiectasias, urticaria, vasculitic
purpura, bullous lesions, panniculitis, livedo reticularis (LR), and Raynaud’s phenomenon are features that
are related to but not specific to SLE. Deposits of immunoglobulins are found in all cases of SLE, but only
50% lead to nephritis [2]. Sepsis and renal failure are two main causes of death in patients with SLE, and the
kidney is the most common organ involved. Glomerular disease usually manifests in the first few years and
is usually asymptomatic. Symptoms of uremia and fluid overload may be caused by acute or chronic renal
failure. Nephritic syndrome may present as hematuria and hypertension, while nephrotic syndrome may
How to cite this article

Dar S, Koirala S, Khan A, et al. (August 18, 2023) A Comprehensive Literature Review on Managing Systemic Lupus Erythematosus: Addressing
Cardiovascular Disease Risk in Females and Its Autoimmune Disease Associations. Cureus 15(8): e43725. DOI 10.7759/cureus.43725
present as edema, weight gain, or hyperlipidemia. Lupus nephritis is one of the most common
manifestations of SLE and one of the most damaging too. It is caused by the deposition of immune
complexes and occurs in more than 50% of SLE patients [7]. Of patients with SLE, 25%-75% report
neurological involvement [8]. SLE may cause status epilepticus, aseptic meningitis, optic neuropathy,
myelopathy, and transverse myelitis with spastic paraparesis [7]. Stroke and transient ischemic attack may
be related to antiphospholipid antibody syndrome (APS) or vasculitis. Migraines may be related to APS [9].
Headache and mood disorders might be the most common neurological manifestations of SLE [10,11].
Serositis can affect both the cardiac and pulmonary systems, and pleurisy with pleuritic chest pain with or
without pleural effusion is the most common pulmonary manifestation of SLE [2]. Alveolar hemorrhage,
pulmonary hypertension (PH), and thromboembolic disease are some of the other effects of SLE on the
pulmonary system [2]. Oral ulcers are common in SLE, and abdominal pain may signify peritonitis,
pancreatitis, mesenteric ischemia, and vasculitis. Autoimmune hepatitis leading to jaundice can also occur
[7].
The most common cardiac presentation of SLE is pericarditis. Myocarditis leading to heart failure can also
occur. Libman-Sacks endocarditis is also a manifestation of SLE, while coronary vasculitis presenting as
angina can occur rarely. Accelerated ischemic heart disease is also commonly associated with SLE.
Vasculitis, peripheral vascular disease, digital ulcers, livedo reticularis, and Raynaud’s phenomenon are
common vascular manifestations of SLE [3]. Conjunctivitis, interstitial keratitis, episcleritis, and diffuse or
nodular scleritis can occur with SLE, with keratoconjunctivitis sicca being the most common ocular
manifestation [12,13]. SLE is associated with worse pregnancy outcomes with an increased risk of fetal death
in utero, spontaneous abortions, and fetal retardations [8]. Neonatal lupus affects 3% of babies born to
mothers with SLE [4]. Patients with SLE suffer from thyroid dysfunction more commonly than the general
population [14]. The rate of fractures in lupus is five times higher than in the general population [15].
Glucocorticoid use can suppress pituitary function, while vitamin D deficiency is common due to avoidance
of sun exposure [16]. Cytopenias such as leukopenia, lymphopenia, anemia, or thrombocytopenia can be seen
in SLE, while leukopenia and lymphopenia are more common. ESR is frequently elevated in active disease,
and plasma homocysteine levels are considered a risk factor for stroke in SLE [2].
Diagnosis and classification criteria

SLE diagnosis can be challenging given a wide variety of clinical features with the potential for multiple
organ system involvement, as well as the overlap of clinical features with other autoimmune conditions.
Initial evaluation requires a comprehensive history and physical examination along with a careful
interpretation of relevant laboratory testing. It is also important to know that there are no diagnostic criteria
established for the diagnosis of SLE so far. Current practices, therefore, rely on classification criteria to
identify SLE cases. The 2019 European League Against Rheumatism/American College of Rheumatology
(EULAR/ACR) classification criteria [17,18] for systemic lupus erythematosus has improved sensitivity
(96.1%) and specificity (93.4%) compared to previous American College of Rheumatology (ACR) 1997 [19]
and Systemic Lupus International Collaborating Clinics (SLICC) 2012 criteria [20]. Table 1 demonstrates the
improvement in specificity from the previous ACR 1997 while maintaining the sensitivity of SLICC 2012
criteria.
2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 2 of 34

ACR 1997 criteria SLICC 2012 criteria EULAR/ACR 2019 criteria
Derivation
Sensitivity (95% CI) 0.85 (0.81-0.88) 0.97 (0.95-0.98) 0.98 (0.97-0.99)
Specificity (95% CI) 0.95 (0.93-0.97) 0.90 (0.87-0.92) 0.96 (0.95-0.98)
Combined (95% CI) 1.80 (1.76-1.83) 1.87 (1.84-1.90) 1.94 (1.92-1.96)
Validation
Sensitivity (95% CI) 0.83 (0.80-0.85) 0.97 (0.95-0.98) 0.96 (0.95-0.98)
Specificity (95% CI) 0.93 (0.91-0.95) 0.84 (0.80-0.87) 0.93 (0.91-0.95)
Combined (95% CI) 1.76 (1.73-1.80) 1.80 (1.77-1.84) 1.90 (1.87-1.92)
TABLE 1: Operating characteristics of new EULAR/ACR 2019 criteria compared to ACR 1997 and
SLICC 2012 classification criteria.
ACR, American College of Rheumatology; SLICC, Systemic Lupus International Collaborating Clinics; CI, confidence intervals; EULAR, European League
Against Rheumatism
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]
The recent classification designates antinuclear antibody (ANA) positivity as the qualifying factor to enter
the SLE criteria given its high sensitivity. It also emphasizes the concept that all criteria must only be taken
into account if there is no alternative cause suspected and the manifestation is most likely explained by SLE.
Moreover, the presence of at least one clinical criterion is a must along with 10 or more points to classify as
having SLE. Figure 1 discusses these points further along with a mention of clinical and immunologic
criteria that are central to this classification.

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]
While the sensitivity of the most recent EULAR/ACR classification criteria is 96%-99%, it should be kept in
mind that about 1%-4% of cases of SLE can be missed if the classification is strictly followed for the purpose
of diagnosis. We must also keep in mind that while the classification encompasses several clinical and
immunologic manifestations of the disease, it does not incorporate various other and less common features
[21]. This is particularly pertinent to diagnosing patients with ANA-negative disease [22,23]. Table 2
summarizes other features relevant to the diagnosis of a disease that is not included in the EULAR/ACR 2019
criteria.

EULAR/ACR 2019 classification
Domain Other features relevant for SLE diagnosis
criteria
Autoantibodies
ANA (obligatory entry criterion) Anti-

1 Sm: 6, anti-dsDNA (highly specific
test): 6 Anti-Ro/anti-La, anti-U1RNP, anti-dsDNA (tests of lesser specificity), anti-
nucleosome/anti-chromatin, anti-histone, anti-C1q, anti-ribosomal P, positive Coombs
Anti-cardiolipin (medium to high titer): test without hemolysis, false-positive serology for syphilis
2 2, anti-β-2-glycoprotein 1: 2, lupus
anticoagulant: 2
Complement
3 C3 and C4 low: 4, C3 or C4 low: 3 CH50 low, complement split products on erythrocytes
Mucocutaneous manifestations
ACLE: 6, SCLE: 4, DLE: 4, oral Lupus tumidus, lupus panniculitis/lupus profundus, chilblains lupus, leukocytoclastic
4
ulcers: 2, non-scarring alopecia: 2 vasculitis, urticarial vasculitis, nasal ulcers
Lupus nephritis
ISN/RPS class III or IV nephritis: 10,

5 ISN/RPS class II or V nephritis: 8, IgA nephritis, cellular casts
proteinuria >0.5 g/day: 4
Musculoskeletal manifestations
6 Joint involvement: 6 Myositis
Serositis
Acute pericarditis: 6, pleural or

7 Sterile peritonitis
pericardial effusion: 5
Neuropsychiatric manifestations
(Transverse) myelitis (often APS-related), chorea, mononeuritis multiplex, cranial

8 Seizure: 5, psychosis: 3, delirium: 2
neuropathy, peripheral neuropathy, lupus headache
Hematological manifestations
Thrombocytopenia: 4, autoimmune Thrombotic thrombocytopenic purpura, other forms of hemolytic anemia, anemia of
9
hemolytic anemia: 4, leukopenia: 3 chronic disease, lymphopenia
Constitutional symptoms
10 Fever:2 Arthralgias, myalgias, fatigue, lymphadenopathy
Other uncommon SLE organ manifestations
Pneumonitis, interstitial lung disease, pulmonary artery hypertension, Libman-Sacks

endocarditis (APS-related), myocarditis, hepatitis, pancreatitis. gastrointestinal
vasculitis, interstitial cystitis
TABLE 2: Organ domains and relevant features included/not included in the EULAR/ACR 2019
criteria.
ISN, International Society of Nephrology; RPS, Renal Pathology Society; ACR, American College of Rheumatology; EULAR, European League Against
Rheumatism; ACLE, acute cutaneous lupus erythematosus; SCLE, subacute cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; ANA,
antinuclear antibody; APS, antiphospholipid syndrome
Reproduced under the terms of the Creative Commons attribution license: Aringer M, Johnson SR: Classifying and diagnosing systemic lupus
erythematosus in the 21st century. Rheumatology (Oxford). 2020, 59:v4-v11. 10.1093/rheumatology/keaa379 [21]
Hence, making the diagnosis through an individualized approach is of utmost importance to avoid excluding
potential SLE patients from receiving appropriate therapies [24].

Treatment of SLE in general
Immunomodulators
Hydroxychloroquine (HCQ): Hydroxychloroquine (HCQ) modulates the immune response pleiotropically by

inhibiting B-cell receptor and Toll-like receptor (TLR) signaling, as well as intracellular TLR-3 and TLR-7
activation, which is important in nucleic acid sensing [25,26]. It raises lysosomal pH, interfering with major
histocompatibility complex (MHC) antigen binding and thus processing autoantigens and cytokine
secretions [27]. By interfering with the stimulator of interferon gene (STING) pathway, HCQ has an anti-type
1 interferon effect [28]. Unless there is a clear contraindication, HCQ is recommended for all patients with
SLE. It is the only medication that has been shown to increase survival in lupus patients [29,30]. It has been
shown to reduce lupus flares [31], prevent organ damage [32] including cardiovascular events [33] and triple
mycophenolate response in lupus nephritis [34], prevent seizures [35,36], and lower the risk of developing
neuropsychiatric lupus [37]. HCQ alleviates skin manifestations [38,39] and arthritis [40]. HCQ improves
lipids [27], lowers insulin resistance [41] and the risk of thrombosis [42,43], and improves bone density [44].
HCQ has no immunosuppressive properties and does not increase the risk of infection or cancer [45,46].
Retinal toxicity is a rare complication that becomes more common after 20 years of treatment [47]. Retinal
screening is done at the beginning, at five years, and then every year [48]. The screening test of choice is
optical coherence tomography [49]. Hyperpigmentation is possible, while cardiomegaly and myopathy are
two extremely rare complications. The daily dose should not exceed the threshold of 5 mg/kg real body
weight based on existing evidence, which suggests that the risk of toxicity is very low for doses less than 5
mg/kg real body weight. It is worth noting that the efficacy of HCQ in lupus has been established in studies
with a prescribed dose of 6.5 mg/kg/day, so it remains to be seen whether a lower dose will have comparable
clinical effects. Patients in long-term remission may have their dose reduced, although no formal studies
have addressed this strategy. In patients with cutaneous manifestations and HCQ-induced retinal toxicity,
quinacrine, an alternative antimalarial, may be considered [50]. Figure 2 illustrates the mechanism of action
of HCQ.

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]
Corticosteroids: By non-selectively decreasing the expression of adhesion molecules and cytokines (such as
interleukin (IL)-2, IL-6, tumor necrosis factor-α (TNF-α), and prostaglandins), corticosteroids have strong
anti-inflammatory and immunosuppressive effects. The initial to long-term goal should be to reduce the
daily dose to less than 7.5 mg/day of prednisone equivalent or to stop them because long-term
glucocorticoid therapy can have several adverse effects, including irreversible organ damage [52-55].
Continuous glucocorticoid doses > 7.5 mg/day carry a markedly increased risk, and some studies even
indicated a lower dose as potentially harmful [56-59]. As a result, the management strategy is to use
corticosteroids as bridging therapy (oral or intramuscular (IM)) as part of an induction regimen or to treat an
acute flare rather than as a maintenance treatment [60]. After ruling out infections, high-dose intravenous
(IV) methylprednisolone (typically 250-1,000 mg/day for three days) is frequently used in acute, organ-
threatening diseases (such as renal and neuropsychiatric) [61]. Figure 3 illustrates the genomic mechanisms
of glucocorticoid-induced anti-inflammation.

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]
Immunosuppressants
Methotrexate: Methotrexate is an antimetabolite that prevents the synthesis of purines by irreversibly

binding to the enzyme dihydrofolate reductase and thus inhibits DNA synthesis, repair, and replication.
Although the mechanism of its anti-inflammatory effects is not fully understood, it goes beyond arresting
the cell cycle through folate depletion. For instance, co-administration of folate reduces side effects while
not impairing its efficacy. Reduced circulating pro-inflammatory T cells, increased anti-inflammatory
adenosine signaling, apoptosis of activated lymphocytes, reduced reactive oxygen species, and decreased
adhesion molecules on endothelial and synovial cells are some pleiotropic effects of low-dose methotrexate
[63]. Methotrexate (15-20 mg per week) was effective in treating cutaneous and articular disease, according
to Carneiro and Sato [64], and it made it easier to lower the dosage of prednisone. A steroid-sparing effect
was demonstrated by Fortin et al. [65], along with a decline in disease activity. A 60% improvement in the
joint count was discovered by Rahman et al. [66]. Methotrexate is an effective and widely used treatment for
cutaneous disease resistant to antimalarial and topical medications [67]. However, because it is a teratogen,
methotrexate cannot be used during pregnancy.
Cyclophosphamide (CYC): A highly toxic alkylating agent, cyclophosphamide suppresses the production of
antibodies by depleting T and B cells [68]. Cyclophosphamide (CYC) should only be used as a last resort in
non-major organ manifestations that are refractory to other treatments and should only be considered in
organ-threatening diseases (renal, cardiopulmonary, or neuropsychiatric). Due to its gonadotoxic effects, it
should be used with caution in females and males of fertile age [69-71]. In premenopausal patients with SLE,
concurrent use of gonadotropin hormone-releasing hormone (GnRH) analogs reduces the ovarian reserve
reduction brought on by CYC therapy [72-74]. Prior to starting treatment, it is important to provide
information about the potential for ovarian cryopreservation. Infections and other risks associated with CYC
therapy, such as cancer, should also be taken into account [75,76].
Azathioprine: Azathioprine, a purine analog, is inactive until it is metabolized by the liver and erythrocytes

into mercaptopurine, at which point it inhibits DNA synthesis and prevents immune system cell
proliferation. There is a high prevalence of gastrointestinal tract toxicity, oral ulcers, nausea, vomiting,
diarrhea, and epigastric pain. Leukopenia and, less frequently, thrombocytopenia and anemia are the results
of dose-related toxicity to the bone marrow [77]. Compared to corticosteroids alone, azathioprine has been
shown in two small randomized studies to decrease mortality, the frequency of flare-ups, and corticosteroid
use, including in patients with severe renal or central nervous system (CNS) disease [78,79]. Azathioprine is
frequently used as a corticosteroid-sparing agent in extra-renal lupus [80]. As the metabolite 6-methyl
mercaptopurine (6-MMP) is not produced in the developing fetus, azathioprine is still a great option for
controlling renal and extra-renal disease during pregnancy [81]. Figure 4 illustrates the immunomodulatory
effects of azathioprine.
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]
Mycophenolate mofetil (MMF): The rate-limiting enzyme in the synthesis of guanosine nucleotides, inosine
monophosphate dehydrogenase, is inhibited by mycophenolate mofetil, a prodrug of mycophenolic acid, an
effective immunosuppressant for both renal and non-renal lupus (although not in neuropsychiatric disease)
[83-85]. Enteric-coated mycophenolate sodium (EC-MPS) outperformed azathioprine in a recent
randomized, open-label trial for extra-renal SLE in terms of achieving remission and lowering flares [86].
However, because of its teratogenic potential, it needs to be discontinued at least six weeks prior to
conception, and a higher price compared to azathioprine or methotrexate limits its ability to be
recommended universally in females of reproductive age with non-renal manifestations. Figure 5 illustrates
the inhibition of nucleotide synthesis by mycophenolate mofetil.

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
78. 10.1038/s41584-020-0374-8 [82]
Calcineurin inhibitors: Calcineurin inhibitors block T cells through the inhibition of calcineurin [76]. This
inhibits T cells and lowers levels of IL-1b, interferon-gamma (IFN-γ), IL-6, and IL-10 by preventing
transcription factors such as nuclear factor of activated T cells (NFAT) from translocating. B-cell activation is
also compromised, in addition to class switching and immunoglobulin production. Furthermore, calcineurin
inhibitors stabilize podocytes and decrease mesangial proliferation in the kidneys, improving proteinuria
[87-89]. Tacrolimus is preferred for SLE. Tacrolimus has been shown to be additive to mycophenolate mofetil
for the treatment of lupus nephritis in particular [90] and has been studied as a monotherapy and as a
component of a multi-targeted approach [90-92]. Other studies have shown that tacrolimus is a suitable
substitute for mycophenolate mofetil [93]. A meta-analysis found that tacrolimus was superior to CYC for
lupus nephritis induction therapy [94]. Tacrolimus is a treatment option for refractory cutaneous disease
during pregnancy [95] and can be applied topically. Figure 6 illustrates the inhibition of T cells by tacrolimus.

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
78. 10.1038/s41584-020-0374-8 [82]
Biological Agents
Belimumab: In SLE, irregular B-cell pathways are usually present. B cells play a role in autoantibody
production, T-cell antigen presentation, and cytokine release (including interferon-α, IL-6, IL-10, B-cell
activating factor (BAFF), TNF-α, and a proliferation-inducing ligand (APRIL)) [96]. Belimumab, a fully
humanized monoclonal antibody, binds to soluble BAFF, resulting in a decrease in the number of peripheral
naive and transitional activated B cells [97,98]. Belimumab should be considered in extra-renal disease with
insufficient control (ongoing disease activity or frequent flares) to first-line treatments (typically a
combination of HCQ and prednisone with or without immunosuppressive agents) and an inability to taper
glucocorticoid daily dose to acceptable levels (i.e., maximum of 7.5 mg/day). Belimumab may benefit
patients with persistent disease; patients with high disease activity (e.g., Systemic Lupus Erythematosus
Disease Activity Index (SLEDAI) > 10), prednisone dose > 7.5 mg/day, and serological activity (low C3/C4 and
high anti-dsDNA titers), with cutaneous, musculoskeletal, and serological manifestations, are more likely to
respond [99-101].
Rituximab (RTX): Rituximab (RTX) is a chimeric monoclonal antibody that kills mature B cells and B-cell
precursors by attacking CD20 on B cells. Due to the negative findings of randomized controlled trials (RCTs),
RTX is currently only used off-label in patients with severe renal or extra-renal (primarily hematological and
neuropsychiatric) disease that is resistant to other immunosuppressive agents and/or belimumab or in

patients who have contraindications to these medications. More than one immunosuppressive drug must
have failed before RTX is administered [102-105], with the possible exception of severe autoimmune
thrombocytopenia (ITP) and hemolytic anemia, for which RTX has shown efficacy in both lupus patients and
those with isolated immune thrombocytopenia (ITP) [106-108]. In lupus nephritis, RTX is typically
considered when first-line therapies (CYC and MMF) have failed or when the condition is relapsing
[102,109]. Other therapies such as anifrolumab, baricitinib, and atacicept are under study. Figure 7 illustrates
targeted biological agents available in present or previous clinical trials of systemic lupus erythematosus.
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 illustrates the overview of the management of SLE based on the severity of the disease.

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]
Review
Managing SLE in the premenopausal period, females of childbearing
age, and pregnancy
Recent SLE epidemiological studies report the global prevalence of SLE to be 15.87-108.92 per 100,000
persons, with 1.4-15.13 new cases per 100,000 persons per year [112]. Studies show that the disease
prevalence and incidence are several folds in females compared to males [112,113] with a prevalence ratio
ranging between 7:1 and 15:1 between females of childbearing age and males [114,115]. Given that SLE
affects females of reproductive age, understanding issues regarding reproductive health including fertility,
family planning, contraception, pregnancy implications, drug safety during pregnancy, and breastfeeding is
of utmost importance.
Reproductive Ability
Several risk factors play a role in decreasing fertility in females with SLE [116]. Chronic disease activity and
recurrent flares diminish ovarian reserves by creating a state of inflammation within the ovaries and
disturbing the hypothalamic pituitary ovarian axis [117-119]. A cross-sectional study also demonstrated an
association between premature ovarian failure and specific SLE-related autoantibodies as well as different
immunosuppressants used to treat the disease [120].
Management of SLE in Pregnant Mothers
For a long time, doctors advised females with SLE to put off having children out of fear of a disease flare or a
bad outcome for the fetus. Having patients under good control on drugs suitable for pregnancy before
conception is a crucial part of managing SLE during pregnancy. Patients should preferably be cared for by a
multidisciplinary team with expertise in rheumatic illnesses and maternal-fetal medicine. There is a lack of
information on the safety of medications for females who are pregnant or nursing. Providers have long
adhered to the A, B, C, D, and X pregnancy grades established by the US Food and Drug Administration (FDA)
[121]. Table 3 lists the medications that can be safely used or discontinued during pregnancy.

Medications to continue during pregnancy Medications to discontinue prior to pregnancy
Prenatal multivitamin Cyclophosphamide
Low-dose aspirin Mycophenolate mofetil
Hydroxychloroquine Methotrexate
Prednisone (moderate dose) Leflunomide
Azathioprine
Aspirin (81 mg)
TABLE 3: Medications to continue or discontinue during pregnancy.

Reproduced under the terms of the Creative Commons attribution license: A better family plan. (2007). Accessed: May 3, 2023: https://www.the-
rheumatologist.org/article/a-better-family-plan/5/ [122]
Contraception and Family Planning
Studies report that many females with SLE do not use effective contraception adequately [123,124].
Extensive contraception counseling should be provided to avoid the risks of unwanted pregnancies during
periods of moderate to severe disease activity and teratogen intake. Counseling should include
individualized discussions about effective available contraceptive options and should take disease-related
factors into account, especially disease activity and the risk of thrombosis (presence of antiphospholipid
antibodies (aPL) in particular). Table 4 illustrates the association of these factors with various contraceptive
modalities.

Copper Progesterone-
Clinical presentation LNG IUD DMPA COC Vaginal ring Patch
IUD only pill
Risk of Similar Higher

No
SLE, low disease No increase osteoporosis estrogen estrogen
Effective, long-acting increase
activity, (-) aPL flare with prolonged level to COC, levels than
flare
use no data COC, avoid
Risk of
SLE, active disease, (- No increase osteoporosis
Effective, long-acting No studies, avoid
) aPL flare with prolonged
use
Risk of
SLE stable on
Effective, long-acting, no infection data but No increase osteoporosis
immunosuppressive Check for medication interactions
likely low-risk flare with prolonged
medication, (-) aPL
use
Risk of
SLE with renal No increase osteoporosis Avoid drospirenone-containing COC due
Effective, long-acting
impairment, (-) aPL flare with prolonged to risk of hyperkalemia
use
Low/no
Effective, Low/uncertain
SLE with (+) aPL Low/no increase thrombosis increase Increased risk of thrombosis, avoid
long- acting risk thrombosis
thrombosis
SLE with Increase Low/no increase thrombosis; Low/no

Low/uncertain
thrombosis/on menstrual decreases menstrual bleeding increase Increased risk of thrombosis, avoid
risk thrombosis
anticoagulation bleeding /amenorrhea thrombosis
TABLE 4: Summary of recommendations for contraceptives in SLE patients.

Note: Etonogestrel implant not included due to lack of data
SLE, systemic lupus erythematosus; APS, antiphospholipid syndrome; IUD, intrauterine device; LNG, levonorgestrel; DMPA, depot medroxyprogesterone
acetate; COC, combined oral contraceptive; vaginal ring, combined hormonal vaginal ring; patch, combined hormonal patch; aPL, antiphospholipid
antibody
Reproduced under the terms of the Creative Commons attribution license: Summary of recommendations for contraceptives in SLE/APS patients. (2023).
Accessed: April 28, 2023: https://www.uptodate.com/contents/image?
imageKey=RHEUM%25252F98708&topicKey=RHEUM%25252F95507&search=contraception%20in%20sle&rank=1%25257E150&source=see_link [125]
Copper and levonorgestrel intrauterine devices (IUDs) are safe options compatible with all levels of disease
activity [126] and have the advantage of providing long-term contraception. Both IUDs can also be safely
used in patients with concomitant aPL. Levonorgestrel IUD has the additional benefit of controlling
menorrhagia in patients who are on anticoagulation medications [127]. Previous concerns regarding the
increased risk of pelvic infections with a copper IUD have not been entirely supported in many studies [128].
Moreover, immunosuppressive therapy is not a contraindication for using IUDs [129]. Other options, for the
purpose of long-term contraception, include subdermal progestin-based implants. Progestin-only
contraception does not increase the risk of thromboembolism as seen in a large meta-analysis study [130].
Among hormonal contraceptives, combined oral contraceptive (COC) pills, and progesterone-only pills,
safety has been established for use in inactive or stable active disease with negative antiphospholipid
antibodies (aPL) [126-131]. However, the use of combined hormonal contraceptive pills should be
discouraged in patients with positive antiphospholipid antibodies (aPL) [126]. A case-control study found
that in patients with positive aPL, COCs increased the risk of arterial thrombosis [132]. Lastly, other
combined hormonal contraceptives such as vaginal rings and transdermal patches have estrogen levels
either similar or more to COCs, respectively, and hence should be avoided for use in SLE [133]. The use of
depot medroxyprogesterone acetate (DMPA) injections should be avoided for long-term contraception in
patients being treated with corticosteroids due to the potential risk of osteoporosis [134].
Pregnancy
The management of SLE in pregnant females is guided by the risk of disease-related complications for
pregnant females and the fetus, as well as the benefits versus risks associated with different therapies

available for this population.
Adverse Pregnancy Outcomes and Predictors
SLE is associated with an increased risk of obstetric complications and unfavorable pregnancy outcomes.
Preeclampsia is the most frequently occurring complication among several others, including increased
length of hospital stay, hypertension, intrauterine growth retardation (IUGR), preterm birth, and stillbirth
[135-140]. Increased disease activity, in the preconception period, is strongly associated with adverse
pregnancy outcomes including premature birth and fetal loss [141], and pregnancy should be delayed for at
least six months after remission is achieved [135,141]. In addition to a high SLEDAI score, having lupus
nephritis within six months before pregnancy is associated with higher rates of maternal complications
including disease flares during pregnancy [142,143]. Other factors associated with adverse outcomes are
major organ involvement, the presence of anti-Ro/La antibodies [144,145], and the presence of
hypercoagulability [146]. Discontinuation of hydroxychloroquine is associated with the risk of disease flares
during pregnancy and the postpartum period [147,148] as well as preeclampsia [149].
Management Therapies During Pregnancy and Lactation
Pregnancies were previously discouraged given the high risk of lupus flares and adverse obstetric outcomes,
but advancements in medical knowledge and the development of compatible medication have made
successful pregnancies possible. The teratogenicity of medication must be considered while treating
pregnant patients. Table 5 summarizes the recommendations regarding the use of various medications
during pregnancy and lactation period.
Medication Preconception During pregnancy Lactation
Compatible
Hydroxychloroquine + + +
Sulfasalazine + + +
Azathioprine + + +
Cyclosporine + + +
Tacrolimus + + +
Prednisone Keep dose <20 mg/day Keep dose <20 mg/day Keep dose <20 mg/day
NSAIDs Discontinue with difficulty conceiving Stop at week 20 +
Stop at conception
Belimumab Stop with positive pregnancy test - +
Rituximab Stop with positive pregnancy test - +
Abatacept Stop with positive pregnancy test - +
TABLE 5: Safety of common SLE treatments during pregnancy and lactation.

SLE, systemic lupus erythematosus; NSAIDs, nonsteroidal anti-inflammatory drugs
Reproduced under the terms of the Creative Commons attribution license: Dao KH, Bermas BL: Systemic lupus erythematosus management in pregnancy.
Int J Womens Health. 2022, 14:199-211. 10.2147/IJWH.S282604 [150]
Stopping hydroxychloroquine (HCQ) precipitates flares of lupus, while continuation during the pregnancy
decreases the need for average glucocorticoid dosing [147,148,151]. HCQ is known to be safe for the fetus. A
case series study documented no association between HCQ and congenital abnormalities [152]. Another
double-blinded placebo-controlled study documented higher delivery age and Apgar score with zero
incidences of ophthalmological and auditory abnormalities in early childhood [151]. Moreover, it can be
safely continued during breastfeeding [153]. According to the US Preventive Services Task Force (USPSTF)
recommendation statement, low-dose aspirin should be initiated from approximately 12 weeks of gestation
in females at high risk of developing preeclampsia, which includes patients with SLE [154]. The lowest
possible dose of prednisone should be used to control the disease as glucocorticoids are well known to cause
gestational complications such as hypertension and diabetes. While earlier studies have mentioned an
increased risk of cleft palate, a large study of 51,973 infants exposed to glucocorticoids in utero did not

demonstrate this association [155]. Prednisone transfer to breast milk is minimal and is considered safe for
the nursing infant when taken in low doses (<20 mg/day) [156].
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to help control pain in patients with
musculoskeletal involvement. The US Food and Drug Administration (FDA) recommends against using
NSAIDs around 20 weeks of gestation due to the risk of fetal renal dysfunction leading to oligohydramnios
[157,158]. NSAIDs are widely used as analgesics after parturition to treat pain in postpartum females and are
generally considered safe [159]. Azathioprine use in central nervous system (CNS) disease and lupus
nephritis is associated with improved survival and fewer hospitalizations [78]. A study of 178 pregnancies
showed that the rate of poor pregnancy outcomes did not differ between the azathioprine-exposed and non-
exposed groups, and no congenital abnormalities were noted in the infants [160]. Calcineurin inhibitors such
as tacrolimus and cyclosporine are well known for achieving and maintaining remission in moderate to
severe lupus, including lupus nephritis, and can be used as options where other modalities are either not
tolerated or contraindicated, such as during gestation. A study of 54 pregnancies showed no difference in
adverse maternal and fetal outcomes between tacrolimus-exposed and non-exposed pregnancies [161].
Subsequently, an observational study of 60 pregnancies did not demonstrate a difference in rates of fetal
mortality, preterm delivery, hypertensive disorders of gestation, and small for gestational age infants in
either of the groups [162]. Limited observation of cyclosporine also suggests an acceptable benefit/risk ratio
for use in pregnancy [163].
Biological medications such as rituximab and belimumab are immunoglobulin G (IgG)-based medications
that do not significantly cross the placenta until after 12 weeks of gestation. Hence, they can be cautiously
continued through conception and should be stopped after the first missed period where possible.
Alternatively, several studies [164-166] have provided enough evidence to support the continued use of
biologics throughout pregnancies where alternate therapies fail to achieve disease control. Cyclosporine,
tacrolimus, azathioprine, and anti-TNF-α inhibitors are also considered safe to be used during the lactation
period [156].
Antineoplastic therapies and leflunomide are used for moderate to severe disease/major organ involvement
but are strictly contraindicated in pregnancy [72,167-170]. The teratogenicity of CYC has been extensively
studied in the past and is well known to cause fetal malformations and CNS and musculoskeletal defects
[171] if used in the first trimester of pregnancy. Mycophenolate mofetil is one of the most commonly used
drugs for lupus nephritis. It is not only associated with pregnancy loss [172] but is also associated with
multiple fetal malformations including facial, esophageal, and ear defects [173-176]. Methotrexate is also a
well-known abortifacient, hence resulting in pregnancy loss simultaneously predisposing the exposed fetus
to intrauterine growth restriction and CNS, skull, and other musculoskeletal defects [177]. Leflunomide,
while not yet established to be a human teratogen, is known to be embryotoxic and teratogenic in non-
human models. Hence, it is classified as pregnancy category X by the FDA [178]. Leflunomide has a half-life
of two weeks, and it can take a long time for levels to become undetectable in the blood after the therapy is
discontinued [179]. Patients who wish to become pregnant should undergo a washout procedure with
cholestyramine to aid in the elimination of the drug before conception [179,180]. Literature on CYC,
mycophenolate, methotrexate, and leflunomide pertaining to breastfeeding is not sufficient to support or
contradict their use during lactation. While most of the other therapies appear to be safe, these medications
should not be continued during lactation [167].
Cardiovascular disease (CVD) risk in premenopausal patients with SLE

Cardiovascular disease (CVD) is one of the main causes of mortality globally [181]. Obesity, smoking,
hypertension, physical inactivity, dyslipidemia, and diabetes were considered to be risk factors for CVD in
females. However, in recent years, other risk factors have risen dramatically, which include preterm delivery,
hypertensive disorders in pregnancy, breast cancer treatment, depression, and autoimmune diseases such as
rheumatoid arthritis (RA) and SLE [182]. SLE affects every aspect of the immune system, and humoral
autoimmunity with the development of specific autoantibodies and serum cytokine dysregulation are the
disease hallmarks. Female bias in autoimmunity might be attributed to a variety of factors, which include
the obvious sex-related variations in the immune systems of males and females that lead to females’
increased immunologic reactivity and may predispose them to acquire an autoimmune illness, possibly
because estrogen inhibits Th1- dependent disorders but potentiates Th2-dependent disorders [183]. The
prevalence of premature CVD in premenopausal females with SLE is estimated to be up to 50 times higher
than in the general population with a male/female ratio of 9:1 [184].
The mechanism of CVD in premenopausal females with SLE is multifactorial. They are induced because of
accelerated atherosclerosis, and autoimmune disorders are related to an increase in cardiovascular illnesses.
These are presently regarded as nontraditional risk factors, with an increase in coronary and cerebral-
vascular mortality [185]. Chronic inflammation associated with SLE leads to endothelial dysfunction, which
is a key factor in the pathogenesis of CVD. This inflammation also increases the risk of atherosclerosis and
promotes the development of thrombosis. It leads to the aging of vessels and raises the cumulative
cardiovascular risk, just like metabolic syndrome, obesity, diabetes, chronic renal insufficiency, and sleep
apnea syndrome (SAS) [185]. The recruitment of monocytes to the artery wall is an important step in the
development of atherosclerosis and endothelial production of vascular cell adhesion molecule-1 (VCAM-1),

which contributes to this process [186].
SLE is an inflammatory systemic illness with a typical sequela of early atherosclerosis [187]. Circulating
immune complexes (IC) are also widely seen in the serum of SLE patients and are responsible for many of the
disease’s acute inflammatory symptoms. Our findings that immune complex IC-C1q reduces cholesterol 27-
hydroxylase mRNA and protein levels in endothelial cells and macrophages add to the theory that IC-C1q
contributes to the development of atherosclerosis and may alter crucial metabolic processes in the vessel
wall. Circulating IC, therefore, promotes atherosclerosis through two mechanisms, either by encouraging
macrophage recruitment to the arterial wall and/or by decreasing endothelial and macrophage capacity to
undertake reverse cholesterol transport by lowering intracellular cholesterol 27-hydroxylase levels. The
immune response to self-antigens causes tissue damage or dysfunction in autoimmune diseases, which can
occur systemically or affect specific organs or body systems. Numerous studies have linked IFN-α to SLE.
During self-material uptake, IFN-α activates antigen-presenting cells, breaking immunologic self-tolerance
[188]. Many SLE patients have increased serum IFN-α, which correlates with disease activity [189,190].
Recombinant human IFN-α used to treat chronic viral hepatitis and cancer may produce de novo SLE [191].
IFN-α-induced SLE usually disappears after discontinuation [192,193]. Of healthy first-degree relatives of
SLE patients, 20% have excessively high serum IFN-α compared to 5% of healthy unrelated persons [194].
These findings imply that elevated serum IFN-α is heritable for SLE [194]. Patients and healthy first-degree
relatives have the highest serum IFN-α activity during peak SLE incidence [195]. Polygenic inheritance may
explain SLE families’ elevated IFN-α characteristics. These studies strengthen the idea that IFN-α pathway
dysregulation causes human SLE. Also, there was a trend toward an inverse connection between age and
serum IFN-α activity in both male and female patient groups, as well as male and female healthy relatives
[195].
Managing CVD manifestations of SLE in premenopausal females

There are several therapeutic interventions that can be used to mitigate CVD manifestations in
premenopausal females with SLE.
Lifestyle Modifications
Lifestyle modifications such as regular exercise, healthy diet, and smoking cessation can reduce the risk of
CVD in this population [196], considering that obesity is more common among patients with SLE than in the
general population [197], with prevalence ranging from 28% to 50% [198]. Established risk factors such as
hypertension, dyslipidemia, and diabetes must be managed appropriately [199].
NSAIDs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage SLE-related symptoms and
should be used cautiously in patients with a high risk of CVD. NSAIDs are used to treat fever, arthritis,
serositis, and headaches in over 80% of individuals with SLE. NSAID-induced hepatotoxicity, acute renal
failure, cutaneous and allergy responses, and aseptic meningitis is enhanced in SLE patients. However,
NSAIDs should be safely recommended to most lupus patients if their administration is reevaluated on a
frequent basis [200]. Long-term NSAID use has no elevated CVD risks, according to studies, while some
studies also suggest an increased CVD risk. More research into other autoimmune/auto-inflammatory
disorders is needed to see if they have similar effects [201].
Reduction of Lipids
As cellular processes require both energy and associated signaling, lipogenesis is a prime therapeutic focus.
Furthermore, immunocytes rely on lipids to exert their specialized roles in response to stimuli; hence, it is
important to strike a balance between the effects of lipid metabolism on immunocytes and the internal
environment in order to investigate additional targets. Furthermore, several factors have been implicated in
the complicated pathways of lipid metabolism that operate directly or indirectly on SLE. The importance of
studying the consequences of interfering with lipid metabolism in appropriate in vivo models, in particular
in combination with standard immunosuppressive medications, is emphasized by the role that lipids play in
the immune system, particularly among various cell populations [202]. Thus, statins, which are lipid-
lowering agents, may be used to reduce the risk of atherosclerosis in these patients, but the proven benefit
still requires more data to establish the same [203].
Corticosteroids
Long-term use of corticosteroids for their anti-inflammatory and immunosuppressive effects has been a
mainstay of SLE treatment for decades. Just around 10% of prednisolone and prednisone are able to
penetrate the placenta because they are inactivated by 11-hydroxysteroid dehydrogenase [204].
Inflammatory rashes on the skin can be treated with topical steroids, and intralesional preparations are an
option for discoid lupus that has progressed to a severe stage. Intra-articular steroid injections, with or

without a local anesthetic agent, may be a more direct and preferred therapy of choice for localized soft
tissue and joint involvement. Due to their pro-atherogenic qualities, corticosteroids have been linked to
deleterious effects on metabolic parameters such as body fat distribution, blood pressure, and glucose
metabolism [205-207]. According to research [208,209], they increase low-density lipoprotein (LDL)
cholesterol and triglyceride levels while decreasing high-density lipoprotein (HDL) cholesterol. There is
growing evidence that inflammation itself predisposes to atherosclerosis, and steroids can reduce this risk
[206], so it is important to evaluate the benefit/risk ratio of reducing chronic inflammation versus side
effects and cardiovascular risk on an individual basis. Long-term usage of corticosteroids for the treatment
of SLE [210] has been linked to weight increase (from under 10 to over 30 pounds). Therefore, the increased
risk of cardiovascular disease associated with the excess body weight seen in SLE patients on prolonged use
of corticosteroids creates a vicious loop in which weight gain might maintain disease activity and
necessitate the maintenance of these medications.
Aspirin
Aspirin therapy may also be considered in selected patients with a high risk of thrombosis. To more precisely
define its function in these patients, controlled, prospective investigations are required [211].
Hydroxychloroquine
Hydroxychloroquine (HCQ), a regularly used SLE treatment, may have cardioprotective benefits and is
linked to a lower incidence of CVD in these patients. HCQ may lower the incidence of flares, allowing for a
decrease in steroid dosage, lessen organ damage, and prevent the thrombotic effects of antiphospholipid
antibodies. The medication is generally safe and can be given to pregnant women [212].
Myasthenia gravis (MG) and SLE

SLE generally has a relapsing and remitting course, and in 90% of cases, it is seen in females of childbearing
age. Its severity varies from mild to rapidly progressing, along with symptoms such as facial rash,
photosensitivity, arthritis, fever, serositis, cytopenia, and oral ulcers [213]. On the other hand, myasthenia
gravis (MG) is a rare organ-specific autoimmune disease of the neuromuscular junction characterized by
autoantibodies against the nicotinic acetylcholine receptor (nACHR), the lipoprotein receptor-related
protein 4 (LRP4), or the muscle-specific tyrosine kinase (MuSK) receptors [214]. This leads to the blockage of
the neuromuscular junction resulting in muscular weakness, which improves with rest and worsens with
muscle use. It generally occurs in females of age <40 years with ocular symptoms (diplopia and ptosis);
slurred speech; difficulty in swallowing, chewing, walking, and lifting objects; facial weakness; and dyspnea
[215]. Rarely, SLE and MG have similar features that precede one another or can coexist in a patient [214].
However, it is quite interesting to note that in patients undergoing thymectomy for MG, the association
between SLE and MG has been reported. For example, a case report of a 48-year-old female stated the
occurrence of SLE and secondary antiphospholipid syndrome (APS) 28 years post-thymectomy for MG, with
thymectomy being the sparkling factor [216]. Thymectomy is the first-line treatment for generalized or
serious myasthenia because thymic abnormalities are frequently seen in MG patients and the thymus is
known to produce autoantibodies [215,217]. Thymectomy, however, has no impact in cases of SLE that have
already been diagnosed [217]. A study was conducted among 13 patients with MG and preexisting SLE, out of
which 11 had sufficient data available. Table 6 summarizes the diagnoses of these patients based on the
standards established by the ACR [218].

Total number 11
ACR criteria for SLE diagnosis Number (%)
Malar rash 2 (18.2%)
Oral ulcers 2 (18.2%)
Photosensitivity 2 (18.2%)
Renal disorder 2 (18.2%)
Discoid rash 3 (27.3%)
Neurological disorder 4 (36.4%)
Serositis 6 (54.5%)
Hematological disorder 8 (72.7%)
Arthritis 10 (90.9%)
Immunologic disorder* 10 (90.9%)
Antinuclear antibody 11 (100%)
TABLE 6: Common clinical characterizations in SLE and MG overlap as noted in 11 out of 13

patients.
*Anti-DNA or anti-Smith, anti-cardiolipin antibodies, or lupus anticoagulant
ACR, American College of Rheumatology; SLE, systemic lupus erythematosus; MG, myasthenia gravis
Reproduced under the terms of the Creative Commons attribution license: Kigawa N, Pineau C, Clarke AE, et al.: Development of myasthenia gravis in
systemic lupus erythematosus. Eur J Case Rep Intern Med. 2014, 1:10.12890/2014_000020 [218]
Immunologic Link in the Pathogenesis
The pathogenesis of both conditions has been linked to an alpha-chemokine subfamily (CXC) in particular
[219,220]. According to studies, these chemokines are in charge of several immunoreactive cell mobility via
chemoattraction. Additionally, they are involved in angiogenesis and may facilitate the activation of
dendritic cells, monocytes, T cells, B cells, NK cells, basophils, and eosinophils [221]. Studies on animal
models have demonstrated that CXCL13 interacts with B and T lymphocytes, causing the precipitation of
SLE in patients with established MG [219]. Granulocyte-macrophage colony-stimulating factor (GM-CSF),
which can be found exogenously and endogenously, is also a contributing component in the development of
both diseases. It is worth noting that, in addition to vascular endothelial cells, fibroblasts, mast cells,
monocytes, and macrophages, T and B cells are all involved in the endogenous synthesis of GM-CSF,
indicating its significant immunologic association [222].
Thymectomy and the Increasing Risk for Autoimmune Diseases
The thymus is where T cells mature. Pathological processes in the thymus induce cell dysfunction and
activate autoreactive CD4+ T lymphocytes, which interact with B lymphocytes to produce
autoantibodies [223]. By suppressing the activity of CD4+ T lymphocytes, regulatory T lymphocytes are in
charge of stopping the autoimmune process. It has been suggested that the absence or dysfunction of
regulatory CD4+ CD25+ T lymphocytes is a cause of connective tissue disorders and consequently of MG and
SLE [223]. The occurrence of systemic autoimmune disorders in patients who underwent thymectomy for MG
has been documented in some situations [217]. Loss of central tolerance to its antigen and increased
autoantibody production are side effects of thymectomy [224]. Polyarthritis and polyarthralgia were the
most prevalent symptoms in post-thymectomy SLE cases, and laboratory results revealed mild T-cell
lymphopenia, hypergammaglobulinemia, and B-cell hyperreactivity [225]. Many autoimmune illnesses,
including SLE, Hashimoto’s disease, APS, idiopathic portal hypertension, and cutaneous vessel vasculitis,
can be made worse by thymectomy [225]. Table 7 displays the prevalence and concomitance of SLE and MG
as reported in various articles [224,226-228].

SLE Gender Age at diagnosis Thymectomy associated with
SN MG (n) Prevalence Reference
(concomitant) (M:F) (Av) SLE
1 127 1 0:01 48.8 - 0.80% [14]
2 132 5 1:04 24-58 2/5 3.78% [15]
3 78 6 0:06 44.5 2/6 7.70% [16]
SLE MG Gender Age at diagnosis

SN - Prevalence -
(n) (concomitant) (M:F) (Av)
1 1300 17 0:17 34.5 - 1.30% [12]
TABLE 7: Prevalence and concomitance of SLE and MG.

n, total number; Av, average; M, male; F, female; MG, myasthenia gravis; SLE, systemic lupus erythematosus
Reproduced under the terms of the Creative Commons attribution license: Tanovska N, Novotni G, Sazdova-Burneska S, et al.: Myasthenia gravis and
associated diseases. Open Access Maced J Med Sci. 2018, 6:472-8. 10.3889/oamjms.2018.110 [226], Bekircan-Kurt CE, Tuncer Kurne A, Erdem-
Ozdamar S, Kalyoncu U, Karabudak R, Tan E: The course of myasthenia gravis with systemic lupus erythematosus. Eur Neurol. 2014, 72:326-
9. 10.1159/000365568 [227], and Sthoeger Z, Neiman A, Elbirt D, et al.: High prevalence of systemic lupus erythematosus in 78 myasthenia gravis
patients: a clinical and serologic study. Am J Med Sci. 2006, 331:4-9. 10.1097/00000441-200601000-00004 [228]
Although it was believed that HCQ can lead to the development of MG, patients who received this
medication for SLE displayed weaker MG symptoms than other patients [224,226]. Antimalarial medications
directly impact the neuromuscular junction, frequently leading to neuromyopathy and atrophic muscle
fibers in muscle biopsies [224]. When symptoms persist even after discontinuing HCQ, MG should be ruled
out because the drug can cause ocular symptoms and symmetrical muscle weakness [214].
Simultaneous Management of Both Diseases
Four patients with SLE-MG overlap syndrome were reported in a case series; two underwent thymectomy
after the diagnosis of MG was established and received pyridostigmine, while the third case initially
responded poorly to pyridostigmine and was later identified as having SLE-myositis overlap syndrome [217].
This series shows various treatment plans for different cases. For the case series reported by Minchenberg et
al. [217], the events and the treatment are shown in Table 8.
Variables/findings Case 1 Case 2 Case 3 Case 4
Age/gender 56/F 57/M 58/F 62/F
Age at MG onset 10 54 58 (initially diagnosed as SLE) 33
SLE Present Present Present Present
Thymectomy Yes No No Yes
Thymectomy, HCQ (discontinued by personal Thymectomy,

Treatment (initial) Cholinesterase inhibitor
pyridostigmine decision) pyridostigmine
Mycophenolate mofetil,
Treatment (later) HCQ None HCQ
HCQ
TABLE 8: A case series of four patients who underwent thymectomy and other treatment
strategies for SLE and MG overlap management.
M, male; F, female; MG, myasthenia gravis; SLE, systemic lupus erythematosus; APS, antiphospholipid syndrome; HCQ, hydroxychloroquine
Reproduced under the terms of the Creative Commons attribution license: Minchenberg SB, Chaparala G, Oaks Z, Banki K, Perl A: Systemic lupus
erythematosus-myasthenia gravis overlap syndrome: presentation and treatment depend on prior thymectomy. Clin Immunol. 2018, 194:100-
4. 10.1016/j.clim.2018.07.007 [217]
Telitacicept (Tai'ai®) is a fusion protein made up of a recombinant transmembrane activator, calcium

modulator, and cyclophilin ligand interactor (TACI) receptor fused to the fragment crystallizable (Fc) region
of human immunoglobulin G (IgG). For the therapy of B-cell-mediated autoimmune conditions such as SLE,
rheumatoid arthritis (RA), and multiple sclerosis (MS), Yantai Rongchang Pharmaceutical is developing
telitacicept through its subsidiary RemeGen. Telitacicept inhibits the growth and survival of mature B cells
and plasma cells by binding to and inhibiting the action of two cell-signaling molecules, B lymphocyte
stimulator (BLyS) and a proliferation-inducing ligand (APRIL). The use of telitacicept for the treatment of
patients with active SLE was given its initial permission in China in March 2021. China is currently
conducting clinical trials of telitacicept for a number of additional indications, such as IgA nephropathy, MS,
MG, neuromyelitis optica, spectrum diseases, RA, and Sjögren’s syndrome. The development of telitacicept,
which resulted in this first approval for SLE, has been summarized in this paper [229]. Figure 9 shows the
mechanism of action of telitacicept.
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]
Managing antiphospholipid antibody syndrome (APS) with SLE

Antiphospholipid syndrome (APS) can be defined as the association of thrombosis and/or pregnancy
morbidity with antiphospholipid antibodies (aPL), lupus anticoagulant (LA), anticardiolipin antibodies
(aCL), and/or anti-β2-glycoprotein-I antibodies (aβ2GPI) [231]. APS can either be primary, which occurs in
otherwise healthy individuals without an underlying disease, or it can occur simultaneously with
autoimmune diseases, particularly SLE. Patients with SLE and APS can develop valvular heart disease,
pulmonary hypertension (PH), livedo reticularis (LR)/racemosa, thrombocytopenia, hemolytic anemia, renal
thrombotic microangiopathy (TMA), and cognitive dysfunction [232]. SLE and aPL-positive patients can
both progress to end-organ damage with one-third of SLE patients progressing to end-organ damage within
five years of diagnosis and one-third of aPL patients progressing to end-organ damage within 10 years of
disease [233]. Around 30%-40% of patients with SLE test positive for aPL [234]. The risk of vascular events
and death in SLE increases due to aPL [235,236]. Nearly 40% of aPL-positive patients among all SLE patients
develop arterial and/or deep venous thrombosis (DVT) as compared to 10%-20% of aPL-negative patients
[237]. Wahl et al. [238] conducted a meta-analysis that showed that patients with SLE and LA are at six times
greater risk of developing venous thromboembolism and at 11 times greater risk of developing recurrent
venous thromboembolism as compared to those without LA. Patients having SLE with aPL are twice at risk of
developing DVT/pulmonary embolism (PE) and four times at risk of developing recurrent DVT after the first
event as compared to those without aCL.
Pregnancy morbidity in patients with SLE and aPL is 25%-47%, while that in SLE without aPL is 0%-38%
[239,240]. In patients with lupus nephritis, aPL increases the risk of maternal hypertension and premature
births. aPL is also associated with an increased rate of induced abortion [241]. The presence of valvular
lesions is 40%-50% in aPL-positive lupus, while it is around 20% in aPL-negative SLE [242]. The frequency
of pulmonary hypertension in patients with SLE and aPL is 15%-100%, and in SLE without aPL, it is 11%-

55% [243]. A meta-analysis conducted by DeFilippis et al. [244] showed that the percentage of livedo
reticularis in aPL-positive SLE was 27%, and in aPL-negative SLE, it was 11%. SLE patients with LA or aCL
are three times more likely to have thrombocytopenia as compared to those without LA or aCL, as shown by
a meta-analysis conducted by Love et al. [237]. Autoimmune hemolytic anemia is found in 20%-28% of aPL-
positive SLE, while its percentage is 1%-9% in aPL-negative SLE patients [245]. aPL nephropathy is present
in 25%-39% of aPL-positive SLE patients, and its prevalence in aPL-negative SLE is 4%-16% [245]. A study
conducted by Coín et al. [246] showed the prevalence of cognitive impairment in aPL-positive SLE patients
to be 21% as compared to 11.9% in aPL-negative SLE patients.
In the majority of the cases, there is no difference in the management of aPL-positive patients with or
without lupus. There are however certain exceptions. Multiple studies on aPL-positive patients with or
without systemic autoimmune diseases suggested that low-dose aspirin may play a role in protecting against
the first episode of thrombosis in aPL-positive SLE patients [247-249]. The use of low-dose aspirin in the
first pregnancy in a patient with aPL-positive SLE is justified as both pregnancy and SLE are risk factors for
thrombosis and low-dose aspirin may decrease the risk of preeclampsia in high-risk patients [245]. A few
case reports have pointed out that adding warfarin, heparin, or aspirin to the standard treatment in patients
with aPL nephropathy is beneficial [250-253]. The European League Against Rheumatism and European
Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) suggested the use of
hydroxychloroquine and/or antiplatelet/anticoagulant for lupus patients with aPL nephropathy [254]. A
recent study suggested that lupus patients with APS had higher activation of the mTOR pathway as
compared to those lupus patients without APS. For patients with aPL nephropathy who required kidney
transplantation, those who were treated with rapamycin (10 patients) had decreased vascular proliferation,
and no recurrence of vascular lesions proliferation was observed. At 144 months post-transplantation, seven
of 10 (70%) aPL nephropathy patients treated with rapamycin had a functioning allograft in comparison with
only three of 27 (11%) patients who were not treated with rapamycin [255]. The use of low-dose aspirin
remains controversial for primary thrombosis and pregnancy morbidity prevention and so is the use of
anticoagulation in lupus nephritis patients with aPL nephropathy [245].
Non-pharmacological interventions for the improvement of fatigue,

depression, pain, and quality of life (QOL) in SLE patients
Fatigue, pain, and depression significantly influence the overall quality of life of SLE patients, in
conjunction with disease activity. Therefore, it is imperative to implement effective interventions aimed at
improving the quality of life (QOL) for these individuals. In a literature review published in 2016, a total of
12 randomized studies with 846 participants, comprising seven randomized trials, one non-randomized
trial, and four prospective observational studies, were analyzed. The review concluded that physical
exercise, behavioral and psychological interventions, acupuncture, dietary modifications, and phototherapy
demonstrated efficacy in mitigating fatigue among SLE patients. Notably, aerobic exercise emerged as the
most effective intervention, although the study findings were not always uniform [256]. A strategy was
suggested to assess and handle fatigue among SLE patients. The proposed approach entails examining
potential non-lupus factors that could contribute to fatigue, monitoring disease activity, evaluating for
anxiety and depression, and administering suitable interventions such as managing non-lupus etiologies,
treating active disease, and utilizing medication and psychological interventions to manage anxiety and
depression [257]. Figure 10 shows the management of fatigue in SLE.

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]
Another approach to manage fatigue, exhaustion, and pain is balneotherapy. It is a therapeutic approach
that utilizes the healing properties of mineral waters, mud, and natural gases from springs that are widely
acknowledged and accepted for their medicinal and legal benefits. The main objective of balneotherapy is to
provide a rehabilitative and restorative effect on the body. According to the research findings, incorporating
balneotherapy as a supplementary component to non-pharmacological treatments may potentially result in
advantageous outcomes for individuals with SLE who are in remission or have minimal disease activity.
Specifically, it may help to alleviate non-inflammatory pain and fatigue, thereby enhancing the QOL for
these patients [258]. Physical exercise is an essential component of managing SLE, as it can effectively
reduce fatigue and depression and enhance the overall QOL. In a study conducted on 20 patients diagnosed
with SLE and 25 control patients, both groups underwent a three-month strengthening exercise program.
The participants’ depression level was assessed using the self-rating depression scale, QOL was measured
using a questionnaire, and the severity of fatigue was assessed using the fatigue severity scale. The study
also utilized the six-minute walk test, two-minute step test, and body mass index (BMI) to evaluate the
participants’ physical health before and after the three-month exercise program [259].
The inclusion of a psychoeducational program in the management of SLE patients resulted in an

improvement in depression, anxiety, perceived stress, QOL, satisfaction with treatment, and medication
adherence but did not have an impact on disease activity, according to a study that enrolled 80 SLE patients
divided equally into intervention and control groups. The intervention group received 12 group sessions of
psychotherapy and patient education, while disease activity was evaluated using the SLEDAI. Various
questionnaires were administered, including the Symptom Checklist-90-Revised (SCL-90-R), perceived
stress scale (PSS), Short Form 36 (SF36), Treatment Satisfaction Questionnaire for Medications (TSQM), and
Medication Adherence Rating Scale-5 (MARS-5) [260].
Further research studies should be conducted on non-pharmacological interventions to enhance the QOL of
SLE patients. These studies should involve larger sample sizes to increase statistical power and longer
follow-up periods to obtain more comprehensive results.
Conclusions
Systemic lupus erythematosus (SLE) is a complex autoimmune disease that requires individualized
management. ANA positivity is the current qualifying factor for SLE criteria, but the diagnosis should be
made through an individualized approach to avoid excluding potential patients from appropriate therapies.
Females of reproductive age with SLE require careful management of fertility, pregnancy, and drug safety.
Chronic inflammation associated with SLE leads to endothelial dysfunction, hastening vessel aging and
raising cumulative cardiovascular risk. Thymectomy in myasthenia gravis (MG) patients has been associated
with an increased risk of developing autoimmune diseases such as SLE, but it has no impact on cases of SLE
that have already been diagnosed. The association between SLE and MG suggests a potential role for

hydroxychloroquine (HCQ) in alleviating MG symptoms in SLE patients. Antiphospholipid syndrome (APS)
is associated with an increased risk of thrombosis, pregnancy morbidity, and end-organ damage in SLE
patients. Low-dose aspirin can protect against thrombosis in aPL-positive SLE patients. Non-
pharmacological interventions such as exercise, psychotherapy, and balneotherapy can improve the quality
of life of SLE patients. Optimal outcomes for SLE patients require a multidisciplinary approach involving
rheumatologists, obstetricians, and other specialists.
Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.
Acknowledgements
All authors contributed equally to the study conceptualization, extensive literature review, manuscript
writing, and critical proofreading prior to manuscript submission. Saleha Dar and Sabina Koirala share first
authorship. Uzzam Ahmed Khawaja mentored and supervised the manuscript.
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Open Access Review

Article DOI: 10.7759/cureus.43725

A Comprehensive Literature Review on Managing

Corresponding author: Uzzam Ahmed Khawaja, uzzamahmedkhawaja@gmail.com

Categories: Internal Medicine, Medical Education, Allergy/Immunology

Introduction And Background

How to cite this article

Diagnosis and classification criteria

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 2 of 34

Sensitivity (95% CI) 0.85 (0.81-0.88) 0.97 (0.95-0.98) 0.98 (0.97-0.99)

Specificity (95% CI) 0.95 (0.93-0.97) 0.90 (0.87-0.92) 0.96 (0.95-0.98)

Combined (95% CI) 1.80 (1.76-1.83) 1.87 (1.84-1.90) 1.94 (1.92-1.96)

Sensitivity (95% CI) 0.83 (0.80-0.85) 0.97 (0.95-0.98) 0.96 (0.95-0.98)

Specificity (95% CI) 0.93 (0.91-0.95) 0.84 (0.80-0.87) 0.93 (0.91-0.95)

Combined (95% CI) 1.76 (1.73-1.80) 1.80 (1.77-1.84) 1.90 (1.87-1.92)

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 3 of 34

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 4 of 34

ANA (obligatory entry criterion) Anti-

3 C3 and C4 low: 4, C3 or C4 low: 3 CH50 low, complement split products on erythrocytes

ISN/RPS class III or IV nephritis: 10,

6 Joint involvement: 6 Myositis

Acute pericarditis: 6, pleural or

(Transverse) myelitis (often APS-related), chorea, mononeuritis multiplex, cranial

10 Fever:2 Arthralgias, myalgias, fatigue, lymphadenopathy

Other uncommon SLE organ manifestations

Pneumonitis, interstitial lung disease, pulmonary artery hypertension, Libman-Sacks

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 5 of 34

Hydroxychloroquine (HCQ): Hydroxychloroquine (HCQ) modulates the immune response pleiotropically by

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 6 of 34

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 7 of 34

Methotrexate: Methotrexate is an antimetabolite that prevents the synthesis of purines by irreversibly

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 8 of 34

FIGURE 4: Immunomodulatory effects of azathioprine.

TPMT, thiopurine S-methyltransferase; 6-MMP, 6-methyl mercaptopurine; DNA, deoxyribonucleic acid;

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 9 of 34

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 10 of 34

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 11 of 34

FIGURE 7: Targeted biological agents available and in present or

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 12 of 34

Management of SLE in Pregnant Mothers

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 13 of 34

Prenatal multivitamin Cyclophosphamide

Low-dose aspirin Mycophenolate mofetil

Prednisone (moderate dose) Leflunomide

Aspirin (81 mg)

TABLE 3: Medications to continue or discontinue during pregnancy.

Contraception and Family Planning

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 14 of 34

Risk of Similar Higher

SLE with Increase Low/no increase thrombosis; Low/no

TABLE 4: Summary of recommendations for contraceptives in SLE patients.

2023 Dar et al. Cureus 15(8): e43725. DOI 10.7759/cureus.43725 15 of 34

Adverse Pregnancy Outcomes and Predictors

Management Therapies During Pregnancy and Lactation

Medication Preconception During pregnancy Lactation

NSAIDs Discontinue with difficulty conceiving Stop at week 20 +

Belimumab Stop with positive pregnancy test - +

Rituximab Stop with positive pregnancy test - +

Abatacept Stop with positive pregnancy test - +