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Complications of systemic lupus erythematosus: A review

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 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine

Article received on September 30, 2018 and accepted for publishing on November 1, 2018.
REVIEW ARTICLE

Complications of systemic lupus erythematosus: A review

Georgiana Iftimie1, Anca Pantea Stoian2, Bogdan Socea1,3, Ion Motofei1,3, Dragoș Marcu1,4, Raluca S.
Costache1,5, Camelia Diaconu1,6

Abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune condition, which often evolves
with severe complications. In SLE, autoantibodies appear, with systemic inflammation and multiple
tissue destructions. SLE is the most common form of lupus and is considered more severe than other
forms. SLE can affect many parts of the body, including the kidneys, heart, lungs, brain, blood, and skin.
Symptoms vary among patients. SLE can follow an unpredictable pattern of remissions (symptoms
improve) and flares (symptoms worsen). Renal involvement is one of the most severe complications in
SLE patients. The process of depositing the immune complexes in the kidneys could lead to the
appearance of lupus nephritis. If the treatment is early and treat-to-target, it can change the course of
the renal disease.
Keywords: systemic lupus erythematosus, renal complications, target treatment

INTRODUCTION decades, probably due to the 1University of Medicine

and Pharmacy „Carol
development of diagnostic
Systemic lupus erythematosus (SLE) is a complex Davila”, Bucharest,
methods. [2] Romania
autoimmune condition, characterized by an 2University of Medicine
exaggerated activity of the immune system, which and Pharmacy “Carol
ETIOLOGY OF SLE
often evolves with severe complications. In SLE, Davila”, Department of
Diabetes and Nutrition,
autoantibodies appear, with inflammation and The etiology of SLE includes
Bucharest, Romania
multiple tissue destructions. genetic, environmental, hor- 3St. Pantelimon Hospital,
monal and immune factors, Department of General
Surgery, Bucharest,
EPIDEMIOLOGY OF SLE which have a strong impor-
Romania
tance in triggering the disease. 4
Urology Department,
SLE is a disease that appears particularly in young
Central University
people, aged between 15 and 45 years, mainly young Genetic factors plays an Emergency Military
women. 10-15 times more women than men have SLE. important role in triggering Hospital, Bucharest,
Romania
The black population is more commonly affected by SLE. The monozygotic twins`
5Gastroenterology
the disease, 2-3 times more than the white population, disease risk is about 57% Department, Central
and develop more aggressive forms [1]. The incidence higher compared to hetero- University Emergency
Military Hospital,
of the disease has increased significantly over the last zygote twins’ risk.[3]
Bucharest, Romania
6
The existence of genetic Clinical Emergency
Corresponding author: Camelia Diaconu PhD Hospital of Bucharest,
susceptibility is also supported Bucharest, Romania
drcameliadiaconu@gmail.com

9
by the presence of other autoimmune diseases, such
as autoimmune thyro-iditis, hemolytic anemia,
idiopathic thrombocytopenic purpura [4,5]. SLE is
associated with a multigenic determinism. The
correlation with the major histocompatibility complex
(MHC) on the short arm of the chromosome 6 has a
particular importance in the development of the
autoimmune processes in SLE [6]. Clinical studies have
demonstrated the association of certain haplotypes of
HLA DR (DR2 and DR3), DQ (DQ6), B8, components of
the complement system (C2 and C4) with various
clinical and immunological manifestations. Other
genes, like C1q, the Fcγ receptor gene may be
involved.
The environmental factors involved in the SLE are:
ultraviolet rays (UV), that can trigger the autoimmune
processes, justifying the occurrence or exacerbation of
clinical manifestations after exposure to sun; both
viral and bacterial infections: antibodies anti Epstein-
Barr virus are present in the serum of SLE patients;
bacterial triggers (bacterial DNA, membrane lipopoly-
saccharides, endotoxins) were described as factors
that can induce an exaggerated immune response;
medications that may cause SLE or "lupus-like"
phenomena: hydralazine, procainamide, isoniazide,
chlorpromazine, methyldopa, penicillamine,
minocycline, TNF alpha inhibitors, alpha-interferon;
other possible environmental factors: nutritional,
vitamin D deficiency, smoking.[7-10]
Hormonal factors: the increased prevalence of the
disease in women is supported by increased levels of
estrogen and prolactin. Dihydroepiandrosterone has
low values in SLE patients.[11] Birth control and
substitution therapy hormone increases the risk of
developing SLE in the women with a certain genetic
susceptibility.[12]
Immune factors. Lymphocytes T and B, monocytes,
macrophages and neutrophils have increased
production of autoantibodies in SLE patients.[13] The
formation of autoantibodies has a central role in the
appearance of SLE complications. The main antibodies
are antinuclear antibodies (ANA). Anti-DNA antibodies
(Ac anti-ADNdc) are the most specific for diagnosis,
being correlated with disease’ activity. Anti-histone
antibodies are associated with drug-induced SLE.
10
Other types of antibodies are: anti-Chromatin;
antibodies to RNA structures and ribonucleoproteins;
anti Smith antibodies, only described in SLE;
antiprotetic P ribosomal antibodies.[14]
Autoantibodies in SLE participate in lesions of various
organs through the formation of immune complexes
(by immune response of type III) or by the direct action
of these antibodies (by type II cytotoxic reaction) [15].
Pathogenic alterations can be secondary to deposition
of circulating immune complexes, but also the
formation in situ of immune complexes, especially at
renal, cutaneous, vascular, nervous system level,
causing inflammatory phenomena because of
activation of the complement system.[16]
Lupus has different forms: systemic, cutaneous, drug-
induced, and neonatal.
The systemic form is the most severe and complex,
leading to kidney, heart, lung, brain, blood and skin
complications. Symptoms vary among patients. SLE
can follow an unpredictable pattern of remissions
(symptoms improve) and flares (symptoms worsen).
Cutaneous lupus is a form of lupus that involves only
the skin and causes rashes. These rashes may appear
anywhere, but are usually found on the face, neck, and
scalp. When the cutaneous lesions had an atypical
localization, a differential diagnosis is needed [17-19].
This type of lupus usually does not involve the internal
organs, but a number of patients living with cutaneous
lupus will develop systemic lupus.
Drug-induced lupus can occur after the intake of high
doses of certain drugs. The symptoms are similar to
systemic lupus, but usually disappear when the drug is
stopped or can manifest six months to one year. The
antinuclear antibody (ANA) test may remain positive
for years.
Neonatal lupus is present in newborns of a woman
with lupus or another autoimmune disease. This
condition can cause skin rashes, anemia or liver
complications. Symptoms usually disappear after a
few months and do not cause permanent damage.
Some babies with neonatal lupus can be born with a
severe heart defect.[18]
 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine
COMPLICATIONS OF SLE
SLE is a complex, multifactorial and polymorphic
disease that may lead to severe complications.
Muscular complications. Muscular pain, commonly
encountered in many diseases, may occur frequently
in SLE patients with progressive evolution and it can
often lead to a misdiagnose [20,21]. It is often located
in the scapular-humeral belt and symptoms like
myalgia and muscle weakness often appear.[19]
Finally, franc myositis is associated with the increase in
serum muscle enzymes, aminotranspherases or
creatine kinase levels.[22] The pain is, in many cases,
very severe an requires multimodal treatment.
Osteoarticular complications. Arthritis in SLE
resembles that of rheumatoid arthritis, symmetrically
affecting the small joints of the hands. In the case of
SLE, arthritis is non-erosive. A special form of SLE
arthritis is Jaccoud arthropathy, with deformations
“swan neckline” type. When erosive arthritis occurs in
SLE, it is called rhupus. Osteoporosis can occur
frequently in SLE patients and is directly related to the
high risk of fractures [23]. The surgical management of
these fractures is complicated, especially due to bone
fragility, needing limited periosteum stripping in order
to prevent further damage of the bone [24].
Osteoporosis can also be associated with the adverse
effects of cortisone therapy in these patients.
Cardio-vascular complications. The most common are
pericarditis, which may range from asymptomatic to
accumulation of moderate fluid, and myocarditis, with
global hypokinesia at echocardiography.[25] A typical
lesion that may occur in SLE patients is Libman-Sacks
verrucous endocarditis, with thickening of the mitral
and aortic valve [26-28]. The presence of
antiphospholipid antibodies appears to be directly
related to valvular damage.[29]
Pulmonary complications. Pleural effusion is the most
common, is bilateral, and associated with the presence
of antinuclear antibodies. In patients with SLE,
impairment may be at the level of parenchyma, with
lupus pneumonia or alveolar hemorrhage, or at the
pulmonary vessels level, with pulmonary
hypertension.[30,31]
Gastrointestinal complications may vary from
mesenteric vasculitis or intestinal obstruction
syndromes to peritonitis, pancreatitis or inflammatory
bowel syndromes [32,33]. The most common
symptoms are abdominal pain, nausea, anorexia, and
vomiting [34,35]. Hepatomegaly and hepatic enzyme
elevations are found in 30% of patients, hepatorenal
syndrome can appear [36], and Budd Chiari syndrome
may also be associated with the presence of
antiphospholipid antibodies.[37-39]
Neuro-psihiatric complications are the least
understood complications. They may involve either
the central nervous system, causing aseptic
meningitis, seizures, anxiety syndrome, psychosis, or
the peripheral nervous system, with myasthenia
gravis, mononeuritis, autonomic neuropathy or
polyneuropathy. Endothelial dysfunction may be
responsible for the passage of autoantibodies to the
nervous system and the occurrence of the lesions.[40]
Renal complications are one of the most serious
complications in SLE patients [41-43]. The process of
depositing the immune complexes in the kidneys could
lead to the appearance of lupus nephritis.[44] The
classification of ISN RPS 2004 of lupus nephritis is
universally accepted:
ƒ Class I: Minimal mesangial lupus nephritis, with
normal glomeruli by microscopic evaluation, but
mesangial immune deposits at immunofluorescence.
ƒ Class II: Mesangial proliferative nephritis, with
mesangial hyperplasia at the optical microscope, but
mesangial immune deposits on immunofluorescence.
ƒ Class III: Focal proliferative nephritis, involving less
than half of the glomeruli, with or without mesangial
involvement. Subgroups: IIIA (active lesions); IIIA/C
(active and chronic lesions); IIIC (inactive lesions).
ƒ Class IV: Diffuse proliferative nephritis, involving
more than half of the glomeruli.
ƒ Class V: Membranous nephritis.
ƒ Class VI: Sclerotic nephritis with no active lesions.
Other less common forms of lupus renal disease
include interstitial nephritis, drug-induced and
vascular disease, when the renal vessels are
affected.[40,44,45]
Paraclinical, the parameters evaluated are: 24-h
11
proteinuria, with values above 0.5 g/24 h; active
urinary sediment with diffractional red blood cells and
cell cylinders; serum creatinine above the upper limit
of the laboratory, low creatinine clearance, low
complement and high titer of double-stranded DNA
antibodies.[46]
Usually, about 25–50% of lupus patients have
abnormalities of the renal function, starting early or
during the evolution of the disease. The renal
complications seem to be discovered in the first three
years after the diagnosis of SLE.[47,48] Regarding the
ethnic origin, different studies revealed that renal
impairment is significantly worse in black subjects than
in white patients with lupus nephritis.[49-51]
Proteinuria is considered to be the essential piece in
the lupus nephritis structure. In a review on lupus
nephritis, proteinuria was reported in 100% of
patients, with nephrotic syndrome in 45–65%.[47]
Microscopic hematuria was found in about 80% of
patients during the disease course.[46]
A recent retrospective study, exploring the
determinants of earlier renal disease in patients with
SLE, found that features like young age, non-European
origin and male sex have a great impact on the disease
[52]. Approximately 10–15% of patients with lupus
nephritis, despite treatment, progress to end-stage
renal failure.[49] Features predictive of end-stage
renal disease in patients with severe lupus nephritis
included higher baseline serum creatinine level and
failure to obtain remission, with increased level of
potassium, which can lead to arrhythmic events53. In
this stage of disease evolution, the anesthetic risk for
this patients is high, being necessary a strictly
perioperative management in order to prevent further
complications.[54]
Anti-phospholipidic syndrome (APS) is a disorder
associated with recurrent arterial or venous
thrombotic events and pregnancy morbidity, along
with the presence of antiphospholipid antibodies
(anticardiolipin antibodies and/or lupus anticoagulant)
[55]. Renal disease in APS is characterized by
interstitial tubular or glomerular injury due to
obstruction of the vessels. Renal manifestations
include thrombotic microangiopathy, renal vein
12
thrombosis, renal infarction, renal artery stenosis or
malignant arterial hypertension.[56] APS nephropathy
was found to be statistically correlated with arterial
thrombosis, fetal loss, and the presence of lupus
anticoagulant. These characteristics seem to be linked
to an increased prevalence of hypertension, raised
serum creatinine, and interstitial renal fibrosis.[57]
The therapy of renal disease in SLE is a challenge for
the practitioner. An early and targeted intervention
can influence the disease’ course. The mortality of SLE
decreased considerably after the introduction of
cyclophosphamide as the major weapon against lupus
nephritis, the renal disease no longer impairing the
survival rates of these patients. The results of a recent
study sustain the role of combined therapy with
intravenous pulses of cyclophosphamide and
methylprednisolone in the improvement of lupus
nephritis [58,59]. However, the long-term use of
cyclophosphamide can cause major side effects, such
as bone marrow suppression, hemorrhagic cystitis [60-
63], gonadal toxicity and, eventually, the development
of neoplastic disorders or can complicate some
surgical procedures [64-66], with subsequent
infections.[67-70] On the other hand, studies have
very good results on long-term remission rates and the
ability to achieve a second remission with currently
recommended intravenous cyclophosphamide
regimens. Concerning the new therapeutic options
[71,72], it seems that biological agents, such as
blockers of other co-stimulatory pathways (for
example, CTLA4-Ig), monoclonal antibody against
CD20, anticomplement (anti-C5b) and anti-cytokine
treatment, induction of T and B cell tolerance, and
hormonotherapy, could be involved in the
management of lupus nephritis, but these therapies
still have no sustainable evidence.[73-75]
CONCLUSIONS
SLE is an autoimmune disease in which self-tolerance
is lost, with polymorphic manifestations that
represent a real challenge, both for diagnosis and for
treatment. SLE often involves severe complication in
the various systems of the body, causing a decrease in
the patient’s quality of life. Renal impairment is one of
the most serious complications and could lead to end-
 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine
stage renal failure. Lately, the focus is on early
diagnosis and targeted-treatment for the good
management of these patients.
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