++
Systemic lupus erythematosus (SLE) represents the prototype of
a pediatric autoimmune disease with the presence of autoantibodies
as its hallmark. The incidence of SLE diagnosed prior to age 18
is approximately 10 to 20 new cases per 100,000 population per year
with an overall prevalence of 1 to 2 cases per 1000 adolescents
ages 12 to 18. Both the incidence and prevalence rates are higher
in African Americans, Asians, Southeast Asians, and Hispanics. The
female predominance (4–4.5:1) in pediatric patients is
lower than in adults (9:1).1 The mean age at diagnosis
is approximately 12 to 13 years, but presentation as young as age
3 or 4 is routinely reported.2 Presentation prior
to age 1 is very rare and may manifest as congenital nephrotic syndrome.
++
Neonatal lupus erythematosus (NLE) must not be mistaken for early-onset
SLE. NLE is a disease caused by the transplacental passage of maternal
autoantibodies, and the fetus/neonate is an innocent bystander
with a normal immune system that is not actively producing autoantibodies.
However, some of these children may develop true SLE many years
later. Early-onset pediatric SLE is a disease in which the child
produces autoantibodies and the immune abnormalities are intrinsic
to the child’s immune system.
++
Although the triggering mechanisms are not fully defined, the
production of autoantibodies is the hallmark of SLE. These autoantibodies
are usually directed against histone, nonhistone, RNA-binding, cytoplasmic,
and nuclear proteins. Antinuclear antibody (ANA) occurs in most,
if not all, patients with SLE. With more sensitive detection systems,
ANA-negative SLE is very rare but still does occur (<5% of cases). Anti-DNA
antibodies are present in approximately 50% to 60% of
patients, while antibodies directed against the small nuclear ribonuclear
proteins (anti-Sm and anti-70kDa RNP antibodies) occur in 40% to
50% of patients.3 Antibodies directed
against small cytoplasmic ribonuclear proteins (anti-Ro and/or anti-La
antibodies) occur in 30% to 40% of patients, anticardiolipin
antibodies in 40% to 50% of patients, and rheumatoid
factor 15% to 20% of patients. Antiribosomal P
antibodies are present in approximately 25% to 30% of
patients and may be associated with psychosis and depression.4,5
++
Antiphospholipid and anticardiolipin antibodies are detected
in approximately 50% of patients.6 One
specific antiphopholipid antibody worth noting is the lupus anticoagulant (LAC),
an antibody that reacts with phospholipids in the reagent used in
the partial thromboplastin time (PTT) determination. The LAC is
often seen in conjunction with anticardiolipin antibodies. Patients
with LAC do not bleed; instead, they have an increased incidence
of deep vein thrombosis, thromboemboli, or, less commonly, arterial
thrombosis. Antiphospholipid antibodies are associated with multiple
neurologic manifestations including stroke, seizures, chorea, and other movement
disorders; pseudotumor cerebri; and migraine headache; as well as
with nonneurologic disorders such as thrombosis, thrombocytopenia,
or recurrent abortion.6–9 Most, if not
all, pediatric patients with evidence of venous thromboembolic disease
will have evidence of LAC.
+++
Clinical Presentations
++
In 1997 the American College of Rheumatology (ACR) revised the
criteria for classification of SLE (Table 204-1).10 These
criteria were not to be used to diagnosis and separate SLE patients
from normal individuals but for classification of patients with
an autoimmune into SLE as opposed to another autoimmune disease. The purpose
is to compare one group of patients with another. Patients are classified
as having definite SLE if they meet 4 out of 11 criteria, but most
series report 10% to 15% of patients who have
only 3 criteria.
++
++
Arthritis, dermatitis, and nephritis are the most common manifestations,
but any organ may be affected (Table 204-2).
Systemic symptoms reflecting a generalized inflammatory process
(fever, malaise, weight loss, and lethargy) are very common. In
80% to 90% of patients, a disease manifestation
either occurs within the first year of diagnosis or it fails to
arise. The exception is central nervous system (CNS) disease, in
which up to 25% of patients will have their first episode
of CNS involvement more than one year after diagnosis. Flares of
SLE tend to be similar to the initial presentation but generally
less with systemic inflammation in patients that are followed closely.
++
++
The incidence of renal involvement varies between 48% to
90% of patients.11-13 An extensive discussion
of the diagnosis and management of renal complications of SLE is provided
in Chapter 472.
+++
Central Nervous
System
++
Central nervous system (CNS) disease or neuropsychiatric (NP-SLE)
involvement occurs in 20% to 40% of patients and
is associated with significant morbidity and mortality.18-21 Both the
central and/or the peripheral nervous systems may be involved
with multiple syndromes and presentations (eTable
204.1). In 1999 the American College of Rheumatology developed a
new nomenclature and case definition for neuropsychiatric SLE (eTable 204.1).22
++
++
Psychiatric illnesses range from mood disorders to depression
to frank organic brain syndrome. Neurocognitive testing detects
impairments in cognitive function or learning difficulties in a
high percentage of patients, but the true incidence is unknown.
++
Depression secondary to active disease must be differentiated
from a secondary depression arising from environmental factors or from
medication side effects. Overt psychosis or organic brain syndrome
occurs in approximately 10% of all patients with SLE and
may be attributed to endogenous CNS disease, metabolic imbalance,
or infection, the latter sometimes precipitated by steroid therapy.
In most patients with psychosis or organic brain syndrome, a lumbar
puncture is indicated.
++
Seizures, seen in approximately 10% to 20% of
patients, may be the presenting sign of more significant organic
brain disease, the result of an infarction, or the sole manifestation of
CNS involvement. Movement disorders encompass cerebellar ataxia,
hemiballismus, tremor, parkinsonian-like movements, and chorea.
SLE, or antiphospholipid antibody syndrome, is currently the most
common cause of chorea in developed countries.23
++
Cranial nerve involvement is more common than peripheral neuropathy.
Rarely, hemiparesis or transverse myelitis may occur. Although not
studied in children, the incidence of autonomic dysfunction in adults
is 40% to 50%, is usually mild, and may lead to
changes in heart rate.
++
Headache occurs in up to 25% of patients with SLE. The
typical headache responds to mild analgesia.24 However,
a severe, unremitting headache, sometimes referred to as a lupus
headache, usually reflects active disease or CNS vasculitis, or
it may represent cerebral vein thrombosis. In all cases of unremitting
headache, appropriate investigations must be performed to rule out
cerebral vein thrombosis or infection.25 A more
benign cause of headache is pseudotumor cerebri ascribable either
to the underlying disease or to steroid medication. Migraine-like
headaches are common and likely reflect active CNS SLE.
++
Examination and culture of cerebrospinal fluid (CSF) are performed
to rule out the possibility of CSF infection or hemorrhage. An elevated CSF
protein and/or CSF white blood cell count in the absence
of infection is suggestive of cerebritis.20 Neuroradiologic
investigation of the central nervous system (CT or MRI scan) may demonstrate
specific structural lesions such as infarction, embolus, cerebral
vein thrombosis, and subdural or intracranial hemorrhage, but these
modalities are generally not helpful in measuring overall CNS disease
activity.2 6 MRI is the imaging modality of choice
in patients suspected of having CNS involvement. Levels of complement
proteins and anti-DNA antibodies, which may correlate with disease
activity at other sites, may be normal with CNS involvement.
++
The therapy of CNS disease varies with the manifestation. Most
clinicians do not treat isolated cognitive impairment. Active psychosis and/or
organic brain syndrome are potentially life-threatening complications
and should be treated aggressively with an immunosuppressive regimen that
includes high-dose corticosteroids and azathioprine, MMF, or cyclophosphamide. Psychotropic
drugs serve as adjunctive, but not primary, therapy.
++
Skin involvement manifesting as malar rash, discoid rash, or
photosensitivity occurs in 60% to 90% of patients
with SLE.27 A rash in the malar area involving
cheeks and nasolabial folds is quite specific; dermatomyositis is
the only other disease in the differential diagnosis (Figs.
204-1 and 205-1). A discoid rash is
rarer than a malar rash. Although isolated discoid lupus is commonly
seen in adults, all pediatric patients with a discoid rash must
be followed for the development of true SLE. Many but not all patients
exhibit photosensitivity, and sun exposure may lead to a flare of
skin and/or systemic disease. Sun-exposed areas should
be protected with light clothing and a sunscreen with a high ultraviolet
(UV) light protection rating against both UVA and UVB. The rash
of subacute cutaneous SLE appears as an annular rash with a raised
border and central sparing; it, too, has a photosensitive component
and is often associated with anti-Ro and anti-La antibodies. Alopecia,
listed in the original classification, occurs in 25% to
35% of patients. In pediatric patients, alopecia in the
presence of a systemic autoimmune disease is quite specific for
SLE. A vasculitic rash consisting of oral or nasal erosions or ulcers
on the arms, legs, or ears may occur in up to 25% of patients and
is often associated with systemic involvement (eFig.
204.1).
++
++
+++
Musculoskeletal
Involvement
++
As many as 90% of patients exhibit joint involvement,
typically a polyarticular arthritis that affects both large and
small joints; severe pain and significant morning stiffness occur
in half the patients, whereas in the other 50% polyarthritis
may produce few symptoms. Control of extra-articular sites of disease
activity is frequently sufficient to treat the arthritis. An arthritic
flare may herald a more generalized flare. Therapy with nonsteroidal anti-inflammatory
agents and antimalarial agents may control arthritis as an isolated symptom,
but low-dose corticosteroid therapy is frequently required.
++
Patients with SLE are at a high risk for the development of avascular
necrosis (AVN) of many joints; this complication is likely secondary
to a combination of the disease process, to antiphospholipid antibodies,
and/or to the use of corticosteroids. AVN occurs in 5% to
10% of patients who present with acute pain, joint tenderness,
and effusion. Septic arthritis and osteomyelitis must always also
be considered if a fever is present.
+++
Hematologic
Involvement
++
Anemia, thrombocytopenia, and leukopenia occur in 50% to
75% of patients. Only a Coomb-positive hemolytic anemia
satisfies the diagnostic criteria of the American College of Rheumatology,
but both normochromic, normocytic anemia and microcytic, hypochromic anemia
are more common in SLE. The Coomb test is positive in approximately
30% to 40% of patients, but less than 10% of
patients have overt hemolysis.28 Thrombocytopenia
is present in 30% to 45% and may precede the diagnosis
of SLE. SLE should be considered in all children and adolescents
with chronic thrombocytopenia.28-30 Leukopenia
occurs in 20% to 40% of cases (lymphopenia and/or
granulocytopenia). Pancytopenia may also occur, and when present
one must consider the concomitant presence of a herpes family viral
infection or macrophage activation syndrome.
++
Anticardiolipin antibodies are the most common antiphospholipid
antibody seen in pediatric SLE.31,32 Lupus anticoagulant (LAC),
is seen in approximately 20% of cases as discussed above.
Up to 50% of patients with the LAC will present with or
develop evidence of a thromboembolic event.33
++
Although 20% to 30% of patients have splenomegaly
on physical examination, of more importance is the presence of functional
asplenia, which may increase the incidence of sepsis.
++
Although cardiac tamponade is rare, symptomatic pericarditis
occurs in approximately 20% to 25% of patients
and is commonly associated with pleurisy. In contrast, clinically
important myocarditis or endocarditis is uncommon (<10% of patients).
Longer survival times and the use of corticosteroid therapy have
led to an increase in atherosclerotic heart disease and myocardial
infarction.34,35 Other factors predisposing to
atherosclerotic heart disease include hypertension, hyperlipidemia,
antiphospholipid antibodies, and coronary vasculitis. Coronary arteritis
can be associated with acute myocardial infarction. Valvular cardiac
involvement is commonly seen in autopsy studies, but it is rarely
clinically significant.
++
The reported incidence of pulmonary involvement varies between
25% and 75% of all patients with SLE. There are
protean pulmonary manifestations ranging from severe life-threatening
pulmonary hemorrhage or infection to a chronic interstitial lung
disease to asymptomatic abnormalities on pulmonary function tests. Decreased
diffusion capacity is the most common abnormality. Abnormalities
of pulmonary function tests account for the 75% incidence
of lung disease. In the acutely ill patient with severe lung disease,
the differential diagnosis includes acute lupus pneumonitis, pulmonary
hemorrhage, or pulmonary infection; the latter may be present even
prior to steroid or immunosuppressive treatment. Pleural involvement
occurs in up to 30% of cases, is commonly seen in association
with pericarditis, and is usually easy to treat.
+++
Gastrointestinal
Disease
++
Gastrointestinal (GI) involvement occurs in 20% to 40% of
patients. Abdominal pain is the most common GI symptom and can be
the result of peritoneal inflammation (serositis), vasculitis, pancreatitis,
and/or direct bowel wall involvement (enteritis). Peritoneal
inflammation of underlying SLE must be differentiated from an infective
peritonitis. Pancreatitis is a rare cause of abdominal pain in pediatric
SLE and may arise from the use of corticosteroids and azathioprine.
++
Hepatomegaly occurs in 40% to 50% of patients.
Abnormalities on liver function tests are seen in up to 25% of
patients, but are usually mild and transient. When jaundice is a
prominent feature in a patient with SLE, then a second disease,
such as obstruction, hemolysis, or viral hepatitis, is the likely
cause. Patients with SLE are at an increased risk to develop drug hepatotoxicity.
+++
Endocrine Involvement
++
The thyroid is the most common endocrine organ involved in SLE,
with antithyroid antibodies present in 40% to 50% of
patients and clinical hypothyroidism in 10% to 20%.
Grave disease is much less common than hypothyroidism. Steroid-induced
diabetes mellitus occurs in as many as 10% of patients,
but a lower percentage require insulin treatment. Rarely, hypoparathyroidism
and growth hormone deficiency have been reported.
+++
Complications
of Treatment
++
Although steroids are the mainstay of therapy in patients with
severe disease, side effects are frequent and include avascular
necrosis (described above); osteoporosis with fracture or vertebral
body collapse; growth failure; cataracts; glaucoma; steroid-induced
diabetes mellitus; hyperlipidemia; hypertension; and premature atherosclerosis.34-37 Unfortunately, patients
with pediatric-onset SLE generally require steroids more frequently
and at higher doses than adults.1,38 Therefore,
although steroids can be lifesaving in SLE, every attempt should
be made to avoid their use or to use the minimal dose required.
++
The rational use of cytotoxic agents is limited by the lack of
good clinical studies; their use should be reserved for severe and/or
life-threatening disease. Azathioprine has a good safety profile,
but leukopenia and increased susceptibility to infection must be
considered in all patients using this medication. In addition to
all the side effects of azathioprine, long-term use of cyclophosphamide
is associated with an increased risk of malignancy and infertility.
Mycophenolate mofetil (MMF) has been successfully used in large
trials of adults with proliferative lupus nephritis. The outcome
of these patients is equal or superior to that of patients treated
with cyclophosphamide with less toxicity. Smaller pediatric cases
have shown similar good results with MMF. Many pediatric rheumatologists
will treat almost all patients with hydroxychloroquine (5–6
mg/kg/day) because studies suggest that its use
is associated with fewer disease flares and an improved lipid profile. Because
the major toxicity is ophthalmologic, patients require retinal examinations
every 6 to 9 months.