SECTION
CLINICAL ASPECTS
IV OF SLE
Chapter Overview and Clinical
22
Presentation
Andrea Hinojosa-Azaola and Jorge Snchez-Guerrero
Systemic lupus erythematosus (SLE) is considered the most clinically
and serologically diverse autoimmune disease because it can affect
almost any organ and display a broad spectrum of manifestations.1
It may manifest as a mild disease with skin or joint involvement only
or may be severe, affecting vital organs such as the kidney, central
nervous system (CNS), and heart. This is why SLE has been addressed
as a constellation of different clinical variants, or better, as a galaxy,2
considering that clinical manifestations not only differ from patient
to patient but also show considerable geographic and ethnic varia-
tion. This diversity is related to the role of genetic and environmental
factors as well as abnormalities of the immune system that influence
both susceptibility and clinical expression.3,4
This chapter presents an overview of the clinical presentation of
SLE; the following chapters detail its involvement in specific organs.
HISTORY
Considering the broad spectrum of clinical and immunologic mani-
festations displayed by patients with SLE, it is important to cover the
items presented in Table 22-1, which reviews the cumulative inci-
dence of clinical manifestations in several SLE cohorts.
Regardless of their age and gender, Hispanics, African Americans,
and Asians tend to have more hematologic, serosal, neurologic, and
renal manifestations and to accrue more damage and at a faster pace
than Caucasians.5 Africans progress more commonly to end-stage
renal disease (ESRD), show higher activity at diagnosis and in disease
course, and are more commonly affected by discoid rash than Euro-
peans (they present more frequently with malar rash and photosen-
sitivity). Asian and Arab patients show higher frequency of renal
disease and damage than Europeans.6 On the other hand, Hispanics
are more heterogeneous in their disease manifestations, with their
clinical profile depending on their African, European, or mestizo
ethnicity.7 This heterogeneity reflects genetic, environmental, socio-
economic, and access to medical care differences.8
CHIEF COMPLAINT
The presenting complaint varies in patients with SLE. Table 22-2 lists
the manifestations noted at the diagnosis of SLE in several studies,
and Figure 22-1 shows the preceding factors, onset, and progression
of the disease.
In the LUpus in MInorities, NAture vs. Nurture (LUMINA) studys
multiethnic cohort, the most common initial manifestation of SLE
was arthritis (34.5%), followed by photosensitivity (18.8%) and anti-
nuclear antibody (ANA) positivity (14.2%).9 In addition, Cervera
compared early and late manifestations in a cohort of 1000 patients
304
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and found that the majority of manifestations occurred more fre-
quently during the first 5 years.10 It is useful to identify the initial SLE
manifestations because the long-term prognosis differs with respect
to them.11
One of the most challenging issues in attributing clinical manifes-
tations to SLE is to define when the disease begins. The lag time
between the onset of SLE and its diagnosis reported in major cohorts
was almost 50 months before 1980, 28 months in the years 1980 to
1989, 15 months in the years 1990 to 1999, and 9 months after 2000.12
This difference results from the introduction of ANA testing and
advances in the knowledge of autoimmune diseases over time.
Although currently there are no reliable clinical or serologic pre-
dictors that allow the identification of SLE at an early stage, there is
evidence that at least one autoantibody (more frequently an ANA) is
present during a mean time of 3.3 years before the diagnosis of SLE
in 88% of patients.13
Mariz tested for ANAs in 918 healthy individuals and in 153
patients with autoimmune rheumatic diseases, and found positive
results in 118 (13%) of the former group and in 138 (90%) of the
latter group, with higher titers and distinctive patterns present
in patients with autoimmune rheumatic diseases.14 When 40 of
the ANA-positive healthy individuals were reevaluated after 3.6 to
5 years, all remained healthy and 73% continued testing ANA
positive.
VARIATIONS IN CLINICAL PRESENTATION
Incomplete Lupus
It is common for rheumatologists to care for patients who are thought
to have SLE but do not meet criteria. These patients are considered
by some to have incomplete, subclinical, incipient, possible,
mild, latent, or variant SLE.9,15 It is likely, however, that some of
these cases are part of the disease spectrum.
The most accepted terms are incomplete lupus and latent lupus,
defined as the presence of symptoms related to one organ system plus
the presence of ANAs.
In a multicenter European study involving 122 patients with
incomplete lupus, SLE developed in 22 patients according to the ACR
criteria in the first year, and in 3 additional patients within 3 years.
These patients presented with cutaneous and musculoskeletal activity
as well as leukopenia.16
Ganczarczyk followed 22 patients with latent lupus prospectively
for at least 5 years and found that they differed from patients with
SLE in the lack of renal and central nervous system involvement as
well as the lower frequency of anti-DNA antibody and depressed
 Chapter 22 F Overview and Clinical Presentation 305

TABLE 22-1 Cumulative Incidence of SLE Manifestations

Cumulative Incidence (%)
Dubois and Estes and Hochberg Pistiner Cervera etal Font etal Pons-Estel
Tuffanelli Christian etal (150 etal (464 (Euro-Lupus; (600 etal (GLADEL;
(520 cases; (150 cases; cases; cases; 1000 cases; cases; 1214 cases;
MANIFESTATION 1964)31 1971)46 1985)47 1991)27 1993)26 2004)1 2004)7
Systemic:
Fever 84 77 41 52 42 57
Weight loss 51 27
Musculoskeletal:
Arthritis and arthralgia 92 95 76 91 84 83 93
Myalgias 48 5 5 79 9 7 18
Aseptic bone necrosis 5 7 24 5 1
Cardiorespiratory:
Pericarditis 31 19 23 12 17
Myocarditis 8 8 3 2 3
Hypertension 25 46 25 27
Pleural effusion 30 40 57 12 28 22
Cutaneous-vascular:
Skin lesions, all types 72 81 88 55 90
Butterfly area lesions 57 39 61 34 58 54 61
Alopecia 21 37 45 31 18 58
Oral/nasal ulcers 9 7 23 19 24 30 42
Photosensitivity 33 45 37 45 41 56
Urticaria 7 13
Raynaud 18 21 44 24 34 22 28
Discoid lesions 29 14 15 23 10 6 12
Neurologic:
CNS damage, all types 26 59 39 27 18 26
Peripheral neuritis 12 7 21 1
Psychosis 12 37 16 5 12 4
Seizures 14 26 13 6 12 8
Ocular:
Cytoid bodies 10
Uveitis 1 1
Renal:
Proteinuria /abnormal sediment 46 53 31 31 39 34 46
Nephrotic syndrome 23 26 13 14 7
Gastrointestinal:
Diarrhea 6
Ascites 1
Abdominal pain 19
Bowel hemorrhage 6
Hemic-lymphatic:
Adenopathy 59 36 10 12 1 15
Anemia (<11g hemoglobin per dL) 57 73 57 30 20
Hemolytic anemia 14 27 8 8 8 12
Leukopenia (<4500 leukocytes/mL) 43 66 41 51 66 42
Thrombocytopenia (<100,000 platelets/mL) 7 19 30 16 22 31 19
Continued

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306 SECTION IV F Clinical Aspects of SLE

TABLE 22-1 Cumulative Incidence of SLE Manifestationscontd

Cumulative Incidence (%)
Dubois and Estes and Hochberg Pistiner Cervera etal Font etal Pons-Estel
Tuffanelli Christian etal (150 etal (464 (Euro-Lupus; (600 etal (GLADEL;
(520 cases; (150 cases; cases; cases; 1000 cases; cases; 1214 cases;
MANIFESTATION 1964)31 1971)46 1985)47 1991)27 1993)26 2004)1 2004)7
Serologic*:
False-positive VDRL result 24 26 30
LE cell preparation 76 78 71 42
ANA 87 94 96 96 99 98
Low C3 59 39 31 49
Anti-DNA 28 40 78 90 71
Anti-Sm 17 6 10 13 48
Anti-SSa (Ro) 32 18 25 23 49
Anti-RNP 34 14 13 14 51
Anticardiolipin IgG/IgM 38 (any) 24/13 15/9 51/41
ANA, antinuclear antibody (test); CNS, central nervous system; GLADEL, Grupo Latino Americano de Estudio de Lupus; Ig, immunoglobulin.
*In this section, the manifestation is a positive result of the test listed unless otherwise specified.

TABLE 22-2 Main Initial Manifestations of SLE

Incidence (%)
Dubois and Tuffanelli Cervera etal (Euro-Lupus; Font etal (600 Pons-Estel etal (GLADEL;
MANIFESTATION (520 cases; 1964)31 1000 cases; 1993)26 cases; 2004)1 1214 cases) 20047
Arthritis and arthralgia 46 69 64 67
Myositis 2 4 3 8
Any cutaneous involvement 57 46
Discoid lupus 11 6 5
Malar rash 6 40 24
Photosensitivity 1 29 25
Oral ulcers 11 11
Raynaud phenomenon 2 18 10
Fatigue 4
Fever 4 36 29
Lymphadenopathy 1 7 5
Serositis 1 17 4
Lung involvement 3 1 0.5
Renal involvement 3 16 12 5
Neurologic involvement 1 12 7 4
Thrombocytopenia 9 5
Hemolytic anemia 2 4 2
Thrombosis 4 1 1
GLADEL, Grupo Latino Americano de Estudio de Lupus.

complement levels.17 Seven patients (32%) eventually had SLE, and
no predictive factors distinguished them from the 15 who did not.
In a Swedish study of 28 patients with incomplete lupus identified
between 1981 and 1992, SLE developed in 16 patients (57%) in a
median time of 5.3 years. Malar rash and anticardiolipin antibodies
were predictors of SLE, and patients in whom the disease developed
were more prone to organ damage.18
Late-Onset Lupus
Late-onset SLE, which has been defined as age of onset at or after 50
years, is an uncommon condition that occurs with a frequency of
12% to 18%.19 The less awareness of its occurrence, insidious onset,
and fewer classic manifestations have led to a delay between the onset
and diagnosis. Table 22-3 summarizes the main characteristics of
patients with late-onset SLE in large studies.

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 Chapter 22 F Overview and Clinical Presentation 307

SLE Age is known to have an important effect on the clinical expression

diagnosis of the disease.20 Although it has been recognized that patients
Clinical
SLE triggers with late-onset SLE have lower levels of activity and less major
Environmental, genetic, organ involvement, other studies have identified increasing age as an
hormonal, others independent factor for poor outcome in terms of damage accrual
and mortality.5,20-23 Factors associated with age (i.e., comorbidities)
Immunological may explain these findings, rather than true differences in disease
dysregulation phenotype.
Subclinical

SLE
onset Male Lupus
Systemic lupus erythematosus is often considered a womans disease
because of the striking differences in prevalence related to sex. Nev-
ertheless, males with SLE have their own distinguishing characteris-
Time tics in terms of clinical manifestations and outcome.
Data accumulated in the literature account for approximately 4%
FIGURE 22-1 Preceding factors, onset, and progression of systemic lupus ery-
thematosus (SLE).
to 22% of male patients in lupus series, but up to 30% in studies

TABLE 22-3 Frequency of Clinical Features in Patients with Late-Onset SLE*

Frequency (%)
Euro-Lupus LUMINA Cohort 1000 Faces of Lupus Study
MANIFESTATION (93 Cases; 1993)26 (73 Cases; 2006)22 (161 Cases; 2010)19
Any cutaneous 69
Malar rash 33 51
Photosensitivity 29 55
Discoid lesions 7 18
Oral/nasal ulcerations 20 58
Arthritis 73 84
Myositis 10 74 4
Nephropathy 22 29 24
Proteinuria 38
Neurologic (any) 16 53 4
Seizures 20
Psychosis 25
Hematologic 68
Thrombocytopenia 28 34
Hemolytic anemia 9 13
Serositis 38 32
Pericarditis 45
Fever 51 8
Raynaud phenomenon 22 47
Lymphadenopathy 3
ANAs 97 97
Antidouble-stranded 77 79
DNA
Anti-Sm 18 11
Low complement 25
Anti-Ro (SSa) 16 23 28
Anti-La (SSb) 6 11
AntiU1-RNP 5 14
ACL IgG/IgM 13/15 55 (any)
ACL, anticardiolipin (antibody); ANA, antinuclear antibody; Ig, immunoglobulin; LUMINA, LUpus in MInorities, NAture versus nurture study;
*Late-onset defined as onset at or after 50 years of age.

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308 SECTION IV F Clinical Aspects of SLE
considering familial aggregation. Lupus is 8 to 15 times more
common in women at childbearing age than in age-matched men;
before puberty this ratio is 2:1 to 6:1, and after menopause 3:1 to
8:1.24
In a cohort of 107 Latin American male patients with SLE, there
was a higher prevalence of renal disease, vascular thrombosis, and
anti-dsDNA antibodies, as well as a greater use of moderate to high
doses of corticosteroids, in comparison with female patients.25 Other
large studies have confirmed the finding of greater renal involvement
in men.26-28 Furthermore, in the LUMINA study, men accrued
damage early, predisposing them to accrue more damage subse-
quently.29,30 Additional clinical manifestations found to be more
common among males with lupus include serositis, neurologic
and cutaneous manifestations, hepatosplenomegaly, cardiovascular
manifestations, fever and weight loss at onset, hypertension, and
vasculitis.24
CONSTITUTIONAL SYMPTOMS
The constitutional symptoms fever, weight loss, malaise, fatigue,
and lymphadenopathy are common in patients with SLE and do
not fit into any organ-system classification; therefore, they are dis-
cussed here.
Fever
Fever is a common manifestation of active SLE and is also a frequent
cause of hospital admission. Fever occurred in 84% of patients in a
report by Dubois31 and in 42% in the report by Font1; whereas in the
Euro-Lupus cohort it was observed in 36% of patients at onset and
in 52% during evolution.26 Fever was present in more patients with
early-onset versus late-onset disease in a large Canadian study19 and
was more common in whites than mestizos in a multiethnic cohort.7
The reported prevalence of fever attributed to SLE has declined pro-
gressively, perhaps resulting from a frequent use of nonsteroidal anti-
inflammatory drugs.
The attribution of fever to SLE holds only after other causes, such
as infections, are excluded. Some definitions for this condition
include the one by Rovin, as follows: in the absence of infection
despite extensive testing, presence of an illness typical of active SLE
accompanying the fever, and no evidence for infection despite the
increase in or addition of steroid therapy.32
In a retrospective analysis of 160 hospitalized patients with SLE,
Stahl identified 83 febrile episodes in 63 patients.33 Of these, 60%
were attributed to active SLE, 23% to infections, and 17% to miscel-
laneous causes. In the patients with active SLE without infection, the
peak temperature range was 38 C to 40.6 C, with an intermittent
pattern. Other SLE manifestations associated with fever were derma-
titis, arthritis, and pleuropericarditis.
In comparison with patients with SLE and fever of infectious etiol-
ogy, patients with fever due to lupus are more likely to have lower C3
and higher levels of disease activity.34 A close correlation between
serum concentrations of interferon alpha (but not interleukin-1 or
tumor necrosis factor alpha) and fever was observed in 25 untreated
patients with SLE, suggesting the possible involvement of interferon
alpha in its pathogenesis.35
Lymphadenopathy
Lymphadenopathy in SLE represents a benign finding, with a
mononucleosis-like behavior, and it can be seen in any phase of the
disease.36
In the study by Dubois generalized adenopathy was observed in
59% of patients, and localized (cervical) adenopathy in 24%.31 As an
initial manifestation, adenopathy was reported in 7% of the patients
from the Euro-Lupus cohort26; in the multiethnic Grupo Latino
Americano de Estudio de Lupus (GLADEL) cohort, it was present in
5% of subjects at disease onset, and in 15% during evolution.7
Lupus lymphadenopathy involves mainly the cervical and axillary
regions, and the lymph nodes are soft, mobile, painful, and nonad-
herent to deep planes. Other clinical manifestations, such as malar
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erythema, photosensitivity, alopecia, oral ulcers, fever, weight loss,
nocturnal diaphoresis, and hepatosplenomegaly, are usually present.36
In cases of significant lymphadenopathy, lymph node biopsy is
indicated to rule out infectious and lymphoproliferative disorders.37,38
Histopathologic findings include coagulative necrosis with hema-
toxylin bodies, reactive follicular hyperplasia, and a Castlemans
diseaselike pattern.39 Of these, lymph node necrosis with hematoxy-
lin bodies is considered a distinctive finding for SLE, although it is
rarely seen in biopsy specimens.40
Weight Loss
Anorexia and weight loss are also manifestations of SLE. The inci-
dence of weight loss in large series was found to range from 17% to
51%,31 showing variations among different ethnic groups.6,7 The
extent of weight loss almost always is less than 10% and precedes the
diagnosis of SLE.
Lom-Orta reported five patients with SLE who presented with
severe protein-calorie malnutrition.41 In these patients, malnutrition
overshadowed other manifestations of SLE, and in some, it delayed
the diagnosis. Corticosteroid treatment and proper food intake
resulted in prompt improvement of both SLE and malnutrition. An
interesting finding in these patients was that of a significant hyper-
gammaglobulinemia as well as high titers of ANA and rheumatoid
factor. Some immunologic alterations are common to patients with
primary malnutrition and SLE, such as diminished T lymphocyte
levels and a reduction in the capacity to generate spontaneous sup-
pressor T cells.
Malaise and Fatigue
Fatigue is one of the most common symptoms experienced by
patients with SLE, affecting up to 80%, and often the most disabling
symptom.42 In the majority of cases several confounding factors, such
as disease activity, mood disorders, poor sleeping patterns, low levels
of aerobic exercise, medications, and fibromyalgia, concur. Fatigue is
a primary contributor to functional disability and visits to health care
providers, and its association with disease activity is controversial.43
Tench reported fatigue in 81% and poor sleep quality in 60% of
120 patients with SLE.42 Fatigue correlated negatively with all mea-
sures of functioning, was higher in patients with active disease, and
was associated with anxiety and depression. On the other hand, Jump
found that active disease or therapy did not predict self-reported
levels of fatigue in 127 patients with SLE, but pain and depression
did.43 A report by Bruce of 81 patients with SLE supports the finding
of no correlation between fatigue and activity or damage of the
disease.44
In the LUMINA multiethnic cohort, fatigue was reported in 92%
of patients. The variables significantly associated with this symptom
were Caucasian ethnicity, constitutional symptoms (fever, weight
loss), higher levels of pain, abnormal illness-related behaviors, and
helplessness.45
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