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DOI: 10.7759/cureus.3288
Systemic Lupus Erythematosus: An
Overview of the Disease Pathology and Its
Management
Asad Ali 1 , Zohaib Sayyed 2 , Muhammad Atif Ameer 3 , Abdul Wahab Arif 4 , FNU Kiran 5 ,
Ayesha Iftikhar 6 , Waleed Iftikhar 7 , Malik Qistas Ahmad 8 , Muhammad Bilal Malik 9 , Vijay
Kumar 10 , Arjan Dass 10 , Shahzad Ahmed. Sami 11 , FNU Sapna 12 , Neha Waqas 13
1. Medicine, CMH Lahore Medical College and Institute of Dentistry, Lahore, PAK 2. Pediatrics/im,
Shaikh Khalifa Bin Zayed Al-Nahyan Medical and Dental College, Bahawalpur, PAK 3. Department of
Internal Medicine, Lahore Medical and Dental College, Lahore, PAK 4. Medicine, Shaikh Zayed Hospital,
Lahore, PAK 5. Internal Medicine, Basic Health Unit Larhi, Gambat, Gambat, PAK 6. Internal Medicine,
Nishtar University, Multan, Multan, PAK 7. Internal Medicine, CMH Lahore Medical College and Institute
of Dentistry, Lahore, PAK 8. Hematology-Oncology, University of Arizona Cancer Center, Tucson, USA 9.
Internal Medicine, Shifa College Of Medicine, Islamabad, PAK 10. Internal Medicine, Ghulam Muhammad
Mahar Medical College, Sukkur, PAK 11. Internal Medicine, CMH Medical and Dental College, Lahore,
PAK 12. Internal Medicine, Burhani Hospital, Karachi, PAK 13. Surgery, Shaikh Khalifa Bin Zayed Al
Nahyan Medical & Dental College, Broken Bow, PAK
 Corresponding author: Neha Waqas, 1nehawaqas@gmail.com
Disclosures can be found in Additional Information at the end of the article
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with varied natural
history and multisystemic involvement. The pathogenesis is multifactorial and complex
precipitating the formation of autoantibodies. One of the main factors in SLE is the interaction
between environmental triggers and genetic factors. Genome-wide association study
technology has led to the identification of more than 80 loci which produce key proteins that
lead to small pathophysiological changes and are associated with SLE. There has been an
improvement in the management of the disease with newly standardized scores that have been
validated in assessing disease activity and quality of life, and have helped in clinical care as
well as research. The last five decades have seen a marked improvement in the prognosis of
SLE, thanks to better general care and the development of newer immunosuppressive drugs,
more specifically biological agents.
Categories: Family/General Practice, Internal Medicine, Rheumatology
Keywords: auto-antibodies, autoimmune disease, multisystemic, biological agents,
immunosuppressives, neuropsychiatric systemic lupus erythematosus, remission, inflammatory,
therapeutic, immunology
Introduction And Background
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with a
wide spectrum of clinical and serological manifestations caused by autoantibody production,
complement activation, and immune complex deposition. The etiopathogenesis of SLE is not
entirely clear, but it is believed that it results from the complex interaction between genetic
and hormonal factors, and environmental exposures [1-2]. SLE has an unpredictable course
that represents a challenge in the understanding of this disease. Hence, efforts have been
directed toward the identification of its different pathogenic pathways, which in turn allows
How to cite this article
Ali A, Sayyed Z, Ameer M, et al. (September 11, 2018) Systemic Lupus Erythematosus: An Overview of the
Disease Pathology and Its Management. Cureus 10(9): e3288. DOI 10.7759/cureus.3288
evaluating the activity and progression of the disease and its responses to the different
therapeutic approaches, all this through pre-established scores. This article focuses on new
concepts in SLE and advances in the management of the disease.

Epidemiology
SLE is a rare disease with an incidence of approximately 1–10 per 100,000 person-years and a
prevalence of 20–200 per 100,000 person-years. It predominantly affects young women and
middle-aged women. Though there is not much difference between the two sexes in terms of
disease manifestation or severity, greater severity is noted at extreme ages of life. A higher SLE
incidence is reported in Asian (especially Chinese), African, and Hispanic populations. These
last two populations are especially associated with high disease activity and damage. Besides
age, corticosteroid use, disease activity, and duration are other predictors of poor outcomes in
SLE.

Pathogenesis
The pathogenesis of SLE is characterized by the formation of autoantibodies and a breakdown
in the immune milieu of the body leading to an unregMionr
 the pathogenesis of SLE [1-2]. The complex pathogenesis of SLE seems to be the cumulative
effect of multiple proteins that have a role in innate and adaptive immunity (including immune
complex processing, clearance of cellular debris, type I interferon (IFN) and toll-like receptors
(TLR) signaling, and lymphocyte activation).

In this sense, the research done in the last 10 years has revealed the role of IFN signature in the
pathogenesis of SLE, given that this IFN system is linked to more than 50% of lupus
susceptibility genes. It has a major role in almost all the steps of the innate and adaptive
immune response [7-12]. Similarly, the human leukocyte antigen (HLA) locus has been found to
have the strongest link to SLE. In fact, the class II region comprising HLA-DRB1 (human
leukocyte antigen – antigen D, isotype R, beta chain), -DQA1 (major histocompatibility
complex, class II, DQ alpha 1), and -DQB1 (major histocompatibility complex, class II, DQ beta
1) has the most well-defined links. They are also associated with specific clinical and serological
properties like DRB1 with renal involvement and HLA-DR serotype system gene 2 (DR2) with
anti-Smith (anti-Sm) and HLA-DR gene 3 (DR3) with anti-Sjögren-syndrome-related antigen A,
also called anti-Ro antibodies [2].

Finally, current research highlights the role of genetic abnormalities as a basic cause for
susceptibility to the induction and maintenance of the chronic phase of the disease, as they
alter the presentation of antigens as a link between innate and adaptive immunities. Epigenetic
modifications, such as DNA methylation, post-translational histone modification and
microRNAs (miRNAs), are also important causes for pathogenicity.

Classification criteria
In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) group introduced a set
of validated criteria with higher sensitivity than the revised American College of Rheumatology
criteria which had been in vogue since 1971. The American College of Rheumatology included
fluorescence antinuclear antibody and antibody to native DNA and Sm antigen in 1982 [1].
Some criteria were redefined (neurological involvement, arthritis) while others were
reorganized to reduce redundancy (photosensitivity, malar rash). Antinuclear antibodies
(ANA), anti-double-stranded DNA antibodies (anti-dsDNA) and antiphospholipid antibodies
(APLA) are among the antibodies that are now considered for different inclusion criteria, each
one of which may contribute to the classification. Low complement level has also been recently
added.

To label a patient as having SLE, at least four criteria from the combined list of clinical and
immunological criteria should be present, including one clinical and one immunological
criterion, according to the SLICC criteria [13]. If the patient has biopsy-proven lupus nephritis
(LN) with a positive ANA and anti-dsDNA, then that is sufficient to call it SLE. The requirement
of one clinical and one immunological criterion is to avoid patients without clinical features or
antibodies [14-16].

Review
Pathology and management
The clinician should have a proper understanding of pathogenesis, immunology, laboratory
evaluation, and updated treatment options when diagnosing and treating SLE [17]. SLE is
characterized by periods of remission and exacerbation (flares) with prolonged periods of
subclinical activity, thus making it a very unpredictable disease. It can affect almost every
organ in the body, more so during a flare. In milder versions of the disease, joints and skin are
the main affected organs. In moderate forms, more organs are involved, but it is the severe form
where the heart and kidneys are affected that makes this disease so lethal. Approximately 30%-

2018 Ali et al. Cureus 10(9): e3288. DOI 10.7759/cureus.3288 3 of 8

 50% of these patients have renal involvement, and it is usually reported in the early phase of
the disease, so measures must be taken to prevent organ damage since this condition is
clinically silent. Anti-Smith antibodies, anti-C1q antibodies, low complement, and anti-dsDNA
are associated with renal involvement [18].

Gastrointestinal (GI) symptoms and hepatic features are present in 39%–67% of patients. These
together with the cardiovascular manifestations must be distinguished from those produced by
infections, comorbid conditions, and adverse drug events.

Neuropsychiatric SLE may present in many forms considering that it can involve the central
and peripheral nervous systems with either a focal or diffuse syndrome. Headaches, although
they are a frequent manifestation, have no relation to the activity of the disease; however, the
clinician must remain alert to the possibility of subarachnoid hemorrhage or cortical venous
thrombosis. "Brain fog,” cognitive decline, and depression are also common [19-20].

SLE patients were found to have an increased risk of various malignancies. Bernatsky et al., in a
large multicentre international study, showed that SLE patients had a three times higher
likelihood of developing hematological malignancies, especially non-Hodgkin’s lymphoma and
leukemia, with a small increased risk of lung, thyroid, and vulvar cancers, and cervical
dysplasia [21]. The use of immunosuppressant drugs, the presence of certain SLE-related
autoantibodies, chronic immune dysregulation, environmental factors, and shared genetic
susceptibility are among the factors that potentially mediate malignancy risk in patients with
SLE.

Miscarriages, intrauterine growth restriction (IUGR), and preterm birth are a few of the
complications that increase the pregnancy risks with SLE [22-24]. The risk is higher in patients
with LN and antiphospholipid antibody (APLA) syndrome. There is also a risk of neonatal heart
block in mothers with anti-Sjögren-syndrome-related antigen A, also called anti-Ro antibody
positive mothers (incidence of 2%). The risk increases in the subsequent pregnancy by 15% if
the previous pregnancy had resulted in a neonatal heart block. Optimal control of SLE four
months before pregnancy improves outcomes [3].

Indices
The British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus
Erythematosus Disease Activity Index (SLEDAI) are the most widely used indices to define
disease activity [18], with the purpose of addressing the therapeutic effect of various drugs.
However, these indices must be considered complementary considering the poor correlation
between the different aspects measured by them.

Biomarker refers to any genetic, molecular, biochemical, or cellular alteration or any physical
sign that allows for the recognition and objective measurement of normal or altered biological
processes, to diagnose a disease or monitor its prognostics. With the advent of the post-
genomic era, the use of these highly developed molecular tools has extended the diagnostic and
prognostic approaches to diseases, including SLE [24]. Nevertheless, additional validation and
definition of the clinical applicability of these methods are still necessary.

Genomics is a branch of molecular biology responsible for studying the structure and
functionality of cellular DNA. Its role in SLE study is to identify the genetic risk loci responsible
for susceptibility to the disease. In fact, at least 50 genes associated with SLE have been
identified; however, the risk of this disease results from multiple defective alleles at different
loci. In this sense, the risk of SLE heredity is 15%–20% depending on the size of the cumulative
effect of the identified loci.

2018 Ali et al. Cureus 10(9): e3288. DOI 10.7759/cureus.3288 4 of 8

 Micro RNAs (miRNAs) are small, single-stranded, non-coding RNA molecules that negatively
regulate the post-transcriptional genetic expression binding target mRNA with the subsequent
degradation or blockage. There is ample evidence of its role in regulating adaptive and innate
immune responses. Therefore, multiple studies have tried to determine its value as a potential
biomarker for SLE.

Urinary miRNAs measurement offers a less invasive approach to the study of SLE. Urine
contains RNA in extracellular vesicles that can be classified according to their morphology,
size, and biochemical composition in exosomes, ectosomes, and apoptotic bodies. The
exosomes have value in SLE study because they are rich in miRNAs.

Transcriptomics is the exhaustive study of the genetic expression of the transcript mRNA,
which allows the discovery of pathophysiological pathways in complex diseases, including SLE.
This biological tool allows the identification of the interferon signature and found that a high
level of interferon alpha (IFN-ɑ) in the serum of patients with SLE correlated positively with
the clinical activity of the disease.

Proteomics is the comprehensive study of the entire set of proteins expressed by a genome in a
specific cell at a particular time. Hundreds of proteins have been defined as biomarkers with
this important study, but they are still awaiting new trials and clinical validation.

Treatment
The treatment for this malady depends on the organs and systems involved as well as the
severity. It can include topical applications for skin problems, nonsteroidal anti-inflammatory
drugs (NSAIDs) for musculoskeletal diseases, and immunosuppression.

Corticosteroids have an immunosuppressive and anti-inflammatory effect through the

modification of genomic and non-genomic pathways. The organ system affected and the
severity of the disease guide the dosage and administration route of the drug. In life-
threatening or organ-threatening disease, intravenous methylprednisolone as pulsed therapy is
used, while in mild disease, an antimalarial in conjunction with prednisolone 5–15 mg/day or a
steroid-sparing agent is used. Poor responders to steroids and patients with particular
manifestations of SLE benefit with a combination of steroids and other immunosuppressive
drugs. Prednisolone may be indicated in women with a desire to conceive, during pregnancy or
lactation.

Hydroxychloroquine (HCQ) has been noticed to have immunomodulatory properties that are
used to treat arthritis and cutaneous flares, protect against ultraviolet (UV) rays, improve sicca
symptoms, treat milder disease, and improve the cardiovascular profile of a patient by reducing
cholesterol, the risk of diabetes, and carotid plaque development; it also has antithrombotic
properties. Furthermore, it can also be indicated during pregnancy or lactation. There are case
reports of cardiotoxicity, which is a serious but very rare adverse event. There is also a rare risk
of retinal toxicity.

Immunosuppressive agents are frequently indicated to reduce the risk of long-term damage
accrual, control active disease, and as steroid-sparing agents [3]. Azathioprine is the most
commonly used cytotoxic agent in lupus, and it is usually initiated for the control moderate
activity of lupus, the prevention of flares, maintenance therapy after remission, and steroid
dose reduction. Also, it is the preferred drug for fertility preservation and during pregnancy.

Cyclophosphamide is primarily used in the treatment of GI, muscle, and pulmonary

manifestations. While mycophenolate mofetil (MMF) was shown to be a good induction agent

2018 Ali et al. Cureus 10(9): e3288. DOI 10.7759/cureus.3288 5 of 8

 (as effective as cyclophosphamide), when combined with steroids, it can reduce moderate and
severe lupus disease activity, reduce renal and non-renal flares; it also aids in steroid dose
reduction and is well tolerated. It is more effective than azathioprine and less toxic than
cyclophosphamide. Cyclophosphamide and MMF are both contraindicated during pregnancy
and lactation.

In refractory cases, other drugs can be used. Cyclosporin and tacrolimus inhibit calcineurin
which in turn inhibits the production of cytokines and lymphocyte proliferation—especially T-
helper cells [25]. Cyclosporin is useful as a steroid-sparing agent in patients with normal renal
function. There is some evidence to suggest that tacrolimus can be used in case of induction of
LN.

Direct B cell elimination or inhibition of B cell survival agents leading to B cell depletion has
been the most widely used and logical biological option in SLE [3].

Atacicept is a fully human recombinant fusion protein that blocks the activity of both A
proliferation-inducing ligand (APRIL) and B-lymphocyte stimulator (BLyS) – B cell activating
factors, which according to some studies have the property of preventing flares and reducing
the activity of the disease. However, a more extensive investigation is necessary to demonstrate
its efficacy and safety profile. Belimumab is a human monoclonal IgG1 that binds to BLyS, an
important B cell stimulator protein (also known as BAFF, B cell activating factor). The efficacy
of Belimumab in reducing disease activity and in the prevention of flares was adequately
demonstrated in A Study of Belimumab in Subjects With Systemic Lupus Erythematosus
(BLISS-76 AND BLISS-52) clinical trials. It was even more beneficial in moderate–severe
seropositive lupus (mostly musculoskeletal and cutaneous disease).

A fully humanized IgG2/IgG4 monoclonal antibody against C5, which has undergone phase 1
trial, is eculizumab. In the United Kingdom, the only biological agent approved for SLE is
belimumab, and further studies are required. Few approaches like blocking the Fc Gamma II
receptor and the CD40 ligand are at various levels of development but, have yet to be approved
for SLE.

Rituximab acts against CD20 on the surface of pre-B cells maturing to memory B cells. It is a
human/mouse chimeric monoclonal antibody. This binding leads to apoptosis of B cells and
does not prevent stem cell regeneration. Its properties have been amply demonstrated in the
reduction of disease activity in lupus of moderate to severe severity in refractory non-renal
cases, in addition to its role in the reduction of steroid doses. In many open-label studies,
rituximab has shown efficacy in arthritis, fatigue, renal disease, and serositis and skin
involvement in SLE. It is safe and tolerated well either as an alone agent or in combination with
cyclophosphamide.

Another monoclonal antibody against the CD20 antigen, ofatumumab (unlike rituximab, it is
fully humanized), has been demonstrated in case studies to be effective in treating SLE. It
promises to be a useful therapy in SLE patients who cannot tolerate rituximab. IFN-ɑ-blocking
agents like anifrolumab, rontalizumab, and sifalizumab are now under evaluation for the
treatment of SLE. Preliminary trials have shown initial promise with sifalizumab and
anifrolumab patients with a high IFN-ɑ signature. Rontalizumab was evaluated in phase II
randomized trial and was not effective enough in its primary outcome.

Interleukin-6 (IL-6) receptor blocker tocilizumab, TNF-ɑ blockers, and abatacept (it blocks the
linkage between T-cells and antigen-presenting cells) are other monoclonal antibodies that
were found to be of some benefit in small populations.

2018 Ali et al. Cureus 10(9): e3288. DOI 10.7759/cureus.3288 6 of 8

 Remission
Treat to Target for SLE is an international initiative established to give recommendations to
treat each patient based on a unique target. This novel approach contributes to the
improvement of the clinical management of the disease, for which the measurement of results
and therapeutic options must be made available. One of the targets was “Remission of systemic
symptoms and organ manifestations.” SLE treatment is geared toward treating the active
disease to lead it to a low activity state and finally remission with treatment, and the ultimate
aim is to get the patient to remain in remission even off treatment. In SLE, the studies on
remission have used various terms to define remission, including the absence of serological and
clinical activity, clinically quiescent but serologically active, and whether the state was
achieved on or off treatment.

Definitions of Remission in SLE (DORIS), a large international task force, has published eight
key statements and three principles for defining remission due to a lack of consensus in its
definition. The aim is to harmonize efforts in research. According to this 2017 consensus,
remission is defined as the clinical absence of the disease, given by absence of disease activity
in a clinical and organ-based laboratory test, ignoring serum complement and anti-dsDNA
antibodies. Absence or presence of treatment needs to be mentioned while defining remission.

Conclusions
With the recent advancements in understanding the pathogenetic mechanisms and
immunopathogenesis of SLE, the focus has shifted toward the control of disease activity, flares
control, management of comorbidities (e.g., cardiovascular problems and infections), and
keeping the disease in remission with optimized therapy. The introduction of corticosteroids
and immunosuppressive agents has improved the prognosis of those affected. However, SLE
poses a significant impact for the mortality and morbidity of the patients. We still need new
research and randomized controlled trials aiming at devising targeted treatment protocols for
this multisystemic disease.

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.

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