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686 Part SIX Systemic Immune Diseases

TABLE 51.1 american College of rheumatology Criteria for Systemic Lupus Erythematosus
Criteria Description
Malar rash Fixed malar erythema, flat or raised
Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
Photosensitivity Skin rash as an unusual reaction to sunlight, by patient history or physician observation
Oral ulcers Oral and nasopharyngeal ulcers, usually painless, observed by physician
Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion
Serositis Pleuritis (convincing history of pleuritic pain or rub heard by physician or evidence of pleural effusion)
or
Pericarditis (documented by electrocardiogram or rub or evidence of pericardial effusion)
Renal disorder Persistent proteinuria > 0.5 grams per day or > than 3+ if quantification not performed
or
Cellular casts may be red cell, hemoglobin, granular, tubular, or mixed
Neurological Seizures—in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance
disorder or
Psychosis—in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte
imbalance
Hematological Hemolytic anemia—with reticulocytosis
disorder or
Leukopenia (<4000/mm total on two or more occasions)
3
or
Lymphopenia (<1500/mm on two or more occasions)
3
or
Thrombocytopenia (<100 000/mm in the absence of offending drugs)
3
Immunological Anti-ds DNA: antibody to native DNA in abnormal titer
disorder or
Anti-Sm: presence of antibody to Sm nuclear antigen
or
Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of immunoglobulin G (IgG) or IgM
anticardiolipin antibodies; (2) a positive test for lupus coagulant using a standard method; or (3) a false-positive serological test for
syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent
treponemal antibody absorption test
Antinuclear An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of
antibodies drugs known to be associated with “drug-induced lupus” syndrome

be greater in lupus patients compared with their healthy peers increasing with age. Common ANA specificities found in lupus
even after controlling for traditional risk factors, suggesting that patients include double-stranded (ds) DNA, single-stranded (ss)
lupus per se confers a risk for atherosclerotic events. DNA, extractable nuclear antigens (Sm, RNP, Ro, and La), histones,
and chromatin. Specific ANAs are associated with disease subsets
IMMUNOPATHOGENESIS such as anti-Ro antibodies with subacute cutaneous and neonatal
6
SLE, anti-dsDNA, and anti-C1q antibodies with renal disease.
The immune system is designed to protect the host against foreign Most autoantibody titers do not correlate with disease activity;
pathogens and to remove cellular debris without damaging self. anti-ds DNA antibodies are a notable exception. Their fluctuation
With their universal production of autoantibodies and charac- with disease activity suggests a pathogenic role for this autoan-
teristic pathological findings of inflammation, vasculitis, vascu- tibody, and monitoring their titer helps to predict impending
lopathy, and immune complex deposition, SLE patients display disease flare in some patients.
a failure to maintain immune tolerance and immune homeostasis.
The heterogeneity of disease manifestations reflects the multiplic- The Predisposed Host: Genetic Contributions
ity of genetic, hormonal, and immune abnormalities and the SLE is a multigenic disease. Most disease-associated alleles are
diversity of environmental triggers or modifiers contributing to present in healthy individuals. Only when multiple alleles are
clinical disease (Table 51.3). Progression from initial autoreactivity present, along with an appropriate environmental trigger, will
to clinical disease occurs over time (Fig. 51.1), with the first a lupus-like phenotype arise. Familial disease clustering and a
detectable immune abnormalities of either the presence of serum higher disease concordance in monozygotic than dizygotic twins
autoantibodies or the increased expression of interferon (IFN)- suggest both an underlying genetic susceptibility and the impor-
inducible gene in blood cells (the IFN signature). tance of environmental or epigenetic factors. Cell types with
highest expression of genes for which there are SLE susceptibility
Autoantibodies alleles are B cells and dendritic cells (DCs), suggesting that these
ANAs are present in over 98% of patients diagnosed with SLE. cell lineages may be drivers of disease. This is an intriguing
Their presence is not specific to SLE, as they are observed in hypothesis, as it suggests that alterations in B-cell tolerance
patients with other autoimmune diseases, malignancies, and viral mechanisms and alterations in antigen presentation to T- effector
(hepatitis) and parasitic (malaria) infections as well as in response and T-regulatory cells and altered cytokine production are central
to environmental triggers such as therapeutic agents (see section to disease pathogenesis.
on drug-induced lupus, below). Furthermore, ANAs are found Presumed susceptibility genes identified in humans include
in low titer in 5% of the general population, with prevalence those affecting lymphocyte activation, proliferation and apoptosis,