Department of Dermatology:

INVESTIGATIONS OF SYSTEMIC
LUPUS ERYTHEMATOSUS
Assessed by:
Prof Dr Abdel Aal ElKamshoushi
1. NURAMALINA BINTI YAHAYA (10-5257)
2. NOOR HAKIMAH HIDAYAH BT MOHD
RAHIM (10-5-258)
3. NURHAKIM BIN IBRAHIM (10-5-259)
4. MEDHAT AHMED ELSAYED YOUSSEF
(1037)

INVESTIGATIONS OF SYSTEMIC
LUPUS ERYTHEMATOSUS
Introduction
Systemic lupus erythematosus (SLE) is a chronic inflammatory
autoimmune disease. It can affect nearly every organ system in the body
which the symptoms may vary widely between individuals.
The classic presentation of a triad of fever, joint pain and rash in a woman
of childbearing age should prompt investigation into the diagnosis of SLE

Laboratory Findings
(By Nuramalina Binti Yahaya 10-5-257)
There is no definitive test for diagnosing SLE but some laboratory test can
be very helpful in supporting the diagnosis of SLE.
There are several standard laboratory studies of SLE:
1. Complete blood count, CBC
It is very essential test because all cellular elements of blood can be
affected.
It helps screen for leucopenia, lymphopenia, anaemia,
thrombocytopenia and prolonged activated partial thromboplastin
time (aPTT).
2. Serum creatinine may be used in the diagnosis of kidney affection
in SLE
3. Urinalysis
The result will be low serum albumin with persistent proteinuria and
membranous GN.
Also with microscopic analysis, red and white blood cells casts in
urinary sediment may be present in proliferative GN.
Other laboratory tests that may be used are:
1. Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
It is nonspecific finding of SLE as it indicates systemic inflammation.
However, it can be used in order to monitor the patient because
when both markers are markedly elevated, suspect of increase
activity of infectious process are occurred.
2. Complement levels.

Measuring the complement level are also can be used because C3

and C4 may decrease in patient with active SLE due to consumption
of immune complex-induced inflammation.

3. Liver function test

Liver test result may be mildly elevated in acute SLE or in response
of certain drug treatment.
4. Creatine kinase assay
Creatine kinase level may be elevated in myositis and overlap
syndromes.
5. Spot protein/ spot creatinine ratio [1]

Tests for Autoantibodies (ANA Test):

(By Noor Hakimah Hidayah BT Mohd Rahim 10-5-258)
Antinuclear Antibodies (ANAs).
1. A primary test for SLE checks for antinuclear antibodies (ANA),
which attack the cell nucleus. Its sensitivity = 99%; specificity =
49%.
2. High levels of ANA are found in more than 98% of patients with
SLE. Other conditions, however, also cause high levels of ANA, so a
positive test is not a definite diagnosis for SLE:2.1 Antinuclear antibodies may be strongly present in other
autoimmune diseases (such as scleroderma, Sjgren syndrome, or
rheumatoid arthritis).
2.2 They also may be weakly present in about 20 - 40% of healthy
women.
2.3 Some drugs can also produce positive antibody tests, including
hydralazine, procainamide, isoniazid, and chlorpromazine.
3. A negative ANA test makes a diagnosis of SLE unlikely but not
impossible. High or low concentrations of ANA also do not
necessarily indicate the severity of the disease, since antibodies
tend to come and go in patients with SLE.
4. In general, the ANA test is considered a screening test:

4.1 If SLE-like symptoms are present and the ANA test is positive,
other tests for SLE will be administered.
4.2 If SLE-like symptoms are not present and the test is positive,
either look for other causes, or the results will be ignored if the
patient is feeling healthy.

ANA Subtypes.
5. Anti-double stranded DNA (Anti-ds DNA) is more likely to be found
only in patients with SLE. It may play an important role in injury to
blood vessels found in SLE, and high levels often indicate kidney
involvement. Anti-ds DNA levels tend to fluctuate over time and
may even disappear.
6. Anti-Sm antibodies are also usually found only with SLE. Levels
are more constant and are more likely to be detected in AfricanAmerican patients. Although many lupus patients may not have this
antibody, its presence almost always indicates SLE.
7. When the ANA is negative but the diagnosis is still strongly
suspected, a test for anti-Ro (also called anti-SSA) and anti-La (also
called anti-SSB) antibodies may identify patients with a rare
condition called ANA negative, Ro lupus. These autoantibodies may
be involved in the sun-sensitive rashes experienced by patients with
SLE and are also found in association with neonatal lupus syndrome,
in which a pregnant mother's antibodies cross the placenta and
cause inflammation in the developing child's skin or heart.
8. Antiphospholipid antibodies. Around half of patients with SLE
have antiphospholipid antibodies, which increase the risk for blood
clots, strokes, and pregnancy complications. If suspects SLE blood
abnormalities, tests may be able to detect the presence of the two
major antiphospholipid antibodies: lupus coagulant antibody and
anticardioplin antibody.
9. As with the ANA, these antibodies have a tendency to appear and
disappear. Patients who have these autoantibodies as well as blood
clotting problems or frequent miscarriages are diagnosed with
antiphospholipid syndrome (APS), which often occurs in SLE but can
also develop independently. [2]

Diagram 1 : Clinical associations of autoantibodies in SLE patients

Diagram 2 : ANAs in SLE

Radiography Investigations of SLE

(By Nurhakim Ibrahim bin Ibrahim)
There are certain radioimaging technique that can be used to help in the
diagnosis.
Joint radiography

Joint radiography often provides little evidence of systemic lupus

erythematosus (SLE), even in the presence of Jaccoud arthropathy
('reversible' joint deformities) with deformity or subluxations such swan
neck appearance. The most common radiographs in SLE show
periarticular osteopenia and soft-tissue swelling without erosions.

And when the x ray is done in the hip joint, there is probability to find the
avascular necrosis due to prolonged used of steroid as a treatment.

Chest radiography and chest CT scanning

These modalities can be used to monitor interstitial lung disease and to
assess for pneumonitis, pulmonary emboli, and alveolar hemorrhage when
we use to do the chest imaging.

This chest x-ray is taken from a patient with lupus demonstrates a rightsided pleural effusion (yellow arrow) and atelectasis with scarring in the
left lung base (blue arrow). In severe complications, a fibrothorax may
develop.
Echocardiography
Echocardiography is used to assess for pericardial effusion, pulmonary
hypertension, or verrucous Libman-Sacks endocarditis

Libman-Sacks endocarditis is the most characteristic cardiac

manifestation of lupus. It is characterized by clusters of verrucae on the
ventricular surface of the mitral valve. These lesions consist of
accumulation of immune complexes, platelets, and mononuclear cells.
This can lead to heart failure, valvular dysfunction, emboli, and secondary
infective endocarditis. Diagnosis is best made via echocardiography,
which may reveal the characteristic valvular masses (arrows).
[IVS = interventricular septum; LA = left atrium; LV = left ventricle.]

Brain magnetic resonance imaging (MRI)/magnetic resonance

angiography (MRA)
Brain magnetic resonance imaging (MRI)/magnetic resonance angiography
(MRA) is used to evaluate for central nervous system (CNS) lupus whitematter changes (see the following image), vasculitis, or stroke, although
findings are often nonspecific and may be absent in as many as 42% of
cases with neuropsychiatric symptoms

This brain magnetic resonance image (MRI) demonstrates an area of

ischemia in the right periventricular white matter of a 41-year-old woman
with long-standing systemic lupus erythematosus (SLE).

Cardiac MRI
There are some investigators have suggested that cardiac MRI (CMR)
provides an excellent alternative to clinical assessment,
electrocardiography, and echocardiography for diagnosing SLE
myocarditis. They reported that patients who were positive for infectious
myocarditis on CMR were more symptomatic than those with active SLE
disease and that more than 50% of patients with CMR-positive myocarditis
had a concurrent positive endomyocardial biopsy. [3]

Clinical Manifestations and Investigations for

Systems affected in SLE:
(By Medhat Ahmed Elsayed Youssef 1037)
Renal System

Kidney involvement in SLE is common, with 74% of patients being

affectedat some time in the course of disease, and is a poor prognostic
indicator. Renalpathology is generally attributed to the deposition of
circulating immunecomplexes or in situ formation of these complexes in
glomeruli and resultsin the activation of complement and subsequent
recruitment of inflammatorycells. In addition to glomerular inflammation,
necrosis, and scarring, renal pathology is characterized by vascular
lesions, including thrombotic microangiopathy
and extraglomerular vasculitis, and tubulointerstitial disease, including
tubular atrophy and interstitial fibrosis. Hypertension may be a
consequence of significant renal involvement. Most cases of lupus
nephritis present a complex immunopathologic picture, but, in general,
the pattern of renal disease reflects the site of deposition
of immunoglobulins and the quality of the effector mechanisms they
induce. Mesangial deposition of immunoglobulin induces mesangial cell
proliferation and is associated with microscopic hematuria and mild
proteinuria Subendothelial deposition of immune complexes results in
proliferative and exudative inflammation, together with hematuria, mild
to moderate proteinuria, and reduced glomerular filtration rate.
Subepithelial deposition of immune complexes adjacent to podocytes and
along the glomerular basement membrane can result in membranous
nephritis with nephrotic-range proteinuria. In addition, antiphospholipid
antibodies may
support the development of thrombotic or inflammatory vascular lesions
within or external to glomeruli.
A World Health Organization classification of lupus nephritis lesions
wasfirst published in 1975 with subsequent revisions. These classifications
were reviewed and rigorously reexamined in the revised International
Society of
Nephrology and Renal Pathology Society classification criteria for lupus
glomerulonephritis (GN) (Table 274-3). Class I and II GN involves
mesangial deposition of immune complexes (class I without and class II
with mesangial hypercellularity), class III describes focal GN involving less
than 50% of total glomeruli, class IV includes diffuse GN involving 50% or
more of glomeruli, class V designates membranous lupus nephritis, and
class VI is characterized by advanced sclerotic lesions. Classes III and IV
have subdivisions for active
and sclerotic lesions, and class IV also has subdivisions for segmental and
contributes to nephrotic syndrome. This complication can be evaluated by
renal ultrasound.

Cardiovascular System

Pericarditis and valve nodules were among the first clinical manifestations
described in SLE. It is only recently that the extent of premature
atherosclerotic disease has been well documented. Pericarditis (Chapter
77) is the most common cardiac manifestation, but it is sometimes
recognized only on imaging studies or at autopsy. It is a component of the
generalized serositis that is often a feature of SLE and is associated with
local autoantibodies and immune complexes. Pericarditis is usually
manifested as substernal chest pain that is improved by bending forward
and can be exacerbated by inspiration or coughing. The symptoms and
effusions associated with pericarditis are quite responsive to moderatedose (20 to 30 mg/day of prednisone) corticosteroid
treatment. Structural valve abnormalities in SLE range from sterile
nodules originally described by Libman and Sacks to nonspecific valve
thickening. The nodules are immobile and usually located on the atrial
side of the mitral valve and sometimes on the arterial side of the aortic
valve. Right-sided lesions are rare.
These structural changes may in some cases result in valvular
regurgitation. Although valve nodules are detected in most patients with
SLE at autopsy, clinically significant valvular heart disease is much less
common (1 to 18%). The verrucous valvular lesions of Libman and Sacks
are most likely inflammatory in nature and may be associated with the
presence of antiphospholipid antibodies. Premature and accelerated
atherosclerosis is increasingly recognized as being prevalent in lupus
patients, and preclinical atherosclerotic carotid plaque has been
documented in 37% of SLE patients as opposed to 15% of age- and sexmatched controls. Traditional cardiovascular risk factors apply, but the
diagnosis of SLE is itself a significant risk factor for premature
atherosclerosis. Although the lupus-specific mechanisms that confer
additional risk for atherosclerosis have not been defined, it is likely that
chronic inflammation associated with immune system activation
contributes to the accumulation of vascular damage. Mortality from
atherosclerosis may be up to 10 times greater in patients with SLE than in
age- and sex-matched controls. Although not specific to SLE, Raynauds
phenomenon (Chapter 80), characterized by episodic vasospasm and
occlusion of the digital arteries in response to cold and emotional stress, is
a feature in up to 60% of SLE patients and contributes to pain and
sometimes necrosis of the distal ends of extremities. The character of the
digits classically changes from pallor to cyanosis and then to rubor as
vascular perfusion becomes impaired. In addition, small arteries,
arterioles, and capillaries can be affected by vasculitis and fibrinoid
necrosis with clinical manifestations that include periungual
telangiectases,
abdominal pain, and neuropsychiatric symptoms.
Pulmonary System

Pleuritis is the most frequent manifestation of pulmonary involvement in

SLE and occurs in about 30% of patients at some point in their disease
course. Pleuritis is characterized by pain on respiration and exudative
effusions.
Parenchymal disease is less common but may be based on several distinct
mechanisms, including pneumonitis in the absence of documented
infection and sometimes involving alveolar hemorrhage (in up to 12% of
patients), pulmonary embolism secondary to peripheral thrombosis, or
pulmonary hypertension with increased pulmonary resistance and
impaired diffusing capacity.
Neuropsychiatric Involvement
Clinical features of SLE that involve the nervous system include both
neurologic
psychiatric manifestations. The central and peripheral nervous systems
can be affected by the disease. The American College of Rheumatology
has identified 19 neuropsychiatric syndromes that can be associated with
SLE, and validation of these neuropsychiatric findings has been
substantiated in several independent studies (The most common
manifestations) that are probably attributable to SLE cerebritis include
cognitive dysfunction,
present in 17 to 66% of SLE patients; psychosis or mood disorder, the
former reported in up to 8% of patients; cerebrovascular disease in 5 to
18% of patients; and seizures, present in 6 to 51% of patients. Headaches
are
also common. Because none of these CNS manifestations are found
exclusively in SLE, it can be difficult to be certain that a neuropsychiatric
complaint or symptom can be attributed to SLE. Evaluation of
neuropsychiatric lupus depends on a careful clinical history and physical
and laboratory examinations and, in some cases, imaging studies imaging
is useful for detecting intracranial abnormalities, which are seen in 19 to
70% of patients and include white matter lesions, cerebral infarction,
venous sinus thrombosis, and sometimes atrophy. More sophisticated
imaging techniques such as magnetic resonance angiography and
magnetic
resonance spectroscopy can be used to assess cerebral blood flow or
neuronal
metabolism.
Cranial nerve and ocular involvement, most likely based on vasculopathy
and focal ischemia, can sometimes affect vision. Ocular examination of
the retina can reveal cotton-wool spots as a result of retinal ischemia or

necrosis. Although rare, transverse myelopathy, frequently associated

with antiphospholipid antibodies, can have devastating consequences,
including paraplegia. Sensorimotor neuropathies, often asymmetrical, are
more
common (up to 28%) and are based on damage to small nerve fibers with
vasculopathy in the small arteries that supply the nerve fibers. As is the
case with lupus nephritis, the pathophysiologic mechanisms that account
for the neuropsychiatric manifestations of SLE are diverse and complex.
Recent data suggest that autoantibodies cross-reactive with neuronal cell
surface glutamate receptors and DNA may mediate excitotoxic death of
neurons and are proposed to contribute to cognitive dysfunction.
Antibodies directed against ribosomal P protein have also been associated
with neuropsychiatric lupus, and antiphospholipid antibodies can
contribute to a procoagulant state, vascular thrombosis, and cerebral
ischemia. Cerebral vasculopathy has been clearly demonstrated by
angiographic and pathologic studies. Noninflammatory small vessel
vasculopathy is the most
common lesion and can be associated with microinfarcts. Inflammatory
mediators, including the cytokines interleukin-6 and interferon-, and
matrix metalloproteinases may also contribute to the neuropsychiatric
manifestations of SLE.
Gastrointestinal System
Although uncommon, vasculitis of the gastrointestinal tract or mesentery
can result in pain and bowel necrosis. Less common than pleuritis and
pericarditis, peritonitis can manifest as peritoneal effusion and abdominal
pain. Pancreatitis occurs in less than 10% of patients but may also be due
to vascular pathology. Lupoid hepatitis, a syndrome that was named for
the presence of positive ANAs in patients with chronic active hepatitis, is a
misnomer because elevated transaminases are only rarely seen in lupus
patients.
Lymphadenopathy
About one third of SLE patients demonstrate diffuse lymphadenopathy at
some time during the course of their disease. The nodes are often
nontender, and lymphoma is sometimes considered in the differential
diagnosis. Biopsy usually reveals follicular hyperplasia, although some
histopathologic findings appear similar to the histiocytic necrotizing
lymphadenitis that is a feature of Kikuchis disease, a self-limited
syndrome characterized by fever and lymphadenopathy.
Recent multicenter studies have determined the frequency of
malignancies in patients with SLE and have found a significant increase in
hematologic malignancies, particularly non-Hodgkins lymphoma.
Splenomegaly is sometimes seen in SLE, and spleen pathology is

characterized by a classic onion-skin histology that appears as concentric

circles of collagen matrix surrounding splenic arteries and arterioles.
Lupus Pregnancy and Neonatal Lupus
Whether pregnancy increases the likelihood of lupus exacerbation has
been debated, with differences on this point presented by different
investigators. However, abundant data indicate that patients with SLE
have worse fetal outcomes than healthy individuals. Gestational
hypertension, fetal growth restriction, and fetal distress are increased in
patients with SLE and may lead to fetal loss or premature delivery.
Preeclampsia can contribute to a poor outcome in both the mother and
fetus and can be difficult to distinguish from a lupus flare associated with
lupus nephritis. Neonatal lupus is a distinct entity that can occur in infants
of mothers with or without a diagnosis of SLE. The syndrome is
characterized by cutaneous lesions and congenital heart block in the
infant and the presence of antibodies to the Ro (SSA) or La (SSB) RNAbinding proteins (or both) in the mother. Mortality in babies with a
congenital heart block is 15 to 31%. Deposition of anti-Ro IgG in the fetal
heart, indicative of transplacental transfer of maternal autoantibody, and
dense connective tissue encompassing the conduction system have been
demonstrated in autopsy specimens. Prenatal testing of lupus mothers for
the presence of anti-Ro and anti-La antibodies is appropriate, and careful
monitoring with fetal echocardiography starting at week 16
of pregnancy can detect conduction defects. Fluorinated corticosteroids
such as dexamethasone have been effective in reversing heart block in
some cases.
Antiphospholipid Antibody Syndrome
Antiphospholipid antibodies represent a distinct class of autoantibodies
that are seen in about one third of SLE patients but can also be present in
individuals who do not carry a diagnosis of SLE . Although
these antibodies were initially thought to be specific for phospholipids
exposed in cell membranes, particularly after flipping of the membranes
of apoptotic cells, extensive data support their primary reactivity with
phospholipid-binding proteins, particularly 2GPI. Whether in primary
antiphospholipid syndrome or in SLE, antiphospholipid antibodies have
been associated with venous and arterial thromboses. In addition to
vascular
thromboses, clinical manifestations of antiphospholipid syndrome include
thrombotic microangiopathic glomerular disease, cardiac valve lesions,
livedo reticularis, thrombocytopenia, hemolytic anemia, and CNS
disease. Recent data indicate that these autoantibodies can contribute to
fetal loss and growth restriction by binding to the placenta, activating the
complement system, and inducing inflammation. Catastrophic

antiphospholipid syndrome, triggered by the acute onset of multisystemic

(three or more organs) thrombosis, is resistant to anticoagulation
treatment and is fatal in approximately 50% of cases.
Investigations for Follow up of Disease:
It is useful to follow tests that indicate the status of organ involvement
known to be present during SLE flares. These might include hemoglobin
levels, platelet counts, urinalysis, and serum levels of creatinine or
albumin. There is great interest in identification of additional markers of
disease activity. Candidates include levels of anti-DNA antibodies, several
components of complement (C3 is most widely available), activated
complement products (including those that bind to the C4d receptor on
erythrocytes), IFN-inducible genes, soluble IL-2, and urinary adiponectin or
monocyte chemotactic protein 1. None is uniformly agreed upon as a
reliable indicator of flare or of response to therapeutic interventions. The
physician should determine for each patient whether certain laboratory
test changes predict flare. If so, altering therapy in response to these
changes has been shown to prevent flares. In addition, given the
increased prevalence of atherosclerosis in SLE, it is advisable to follow the
recommendations of the National Cholesterol Education Program for
testing and treatment, including scoring of SLE as an independent risk
factor, similar to diabetes mellitus. [4]

REFERENCES
[1] http://www.webmd.com/lupus/guide/laboratory-tests-useddiagnose-evaluate-sle?page=2
http://emedicine.medscape.com/article/332244-overview
[2] http://umm.edu/health/medical/reports/articles/systemic-lupuserythematosus
http://www.docstoc.com/docs/445715/Systemic-Lupus-ErythematosusDefinition
http://en.wikipedia.org/wiki/Systemic_lupus_erythematosus#Laboratory_te
sts
[3] http://emedicine.medscape.com/article/332244-overview
http://emedicine.medscape.com/article/332244-clinical

http://radiopaedia.org/articles/musculoskeletal-manifestations-of-systemiclupus-erythematosus
[4] Goldmans Cecil Medicine 24th Edition