Page 727 - Clinical Immunology_ Principles and Practice ( PDFDrive )

700 Part SIX Systemic Immune Diseases

This distinction between focal and diffuse CNS NPSLE and potential for the diagnosis of CNS NPSLE syndromes that can also be
mechanisms is essential for the development of treatment strategies. used to monitor therapy.
Thrombotic events associated with APL antibodies are treated PNS NPSLE events are recognized on the basis of clinical
with anticoagulation, whereas high-dose corticosteroids and presentation with diagnostic studies such as electromyography
immunosuppression in combination with neuroleptic and anti- and peripheral nerve biopsy.
seizure medications are generally required for treatment of diffuse Antiphospholipid antibody syndrome is described in detail
CNS events. Because there is no intervening BBB, peripheral nerves in Chapter 61.
are more accessible to circulating complement, autoantibodies,
and inflammatory molecules, and vasculitis of epineural arteries Drug-Induced Lupus
is a common finding in PNS NPSLE. Treatment consists of Until recently, drug-induced lupus referred to a clinical syndrome
corticosteroids and immunosuppression or intravenous immu- characterized by constitutional, musculoskeletal symptoms and
noglobulin (IVIG). serositis that resembles mild lupus and occurs after exposure to
a number of drugs (most notably procainamide, hydralazine,
NPSLE Assessment and Attribution chlorpromazine, and methyldopa). Drug-induced lupus has been
The diagnosis of diffuse CNS NPSLE is frequently difficult, and associated with ANA and antihistone antibodies, whereas genera-
the clinical evaluation of a patient with presumed CNS NPSLE tion of more specific autoantibodies such as anti-DNA antibodies
mandates an exhaustive search for other potential causes. CSF has been rare. Symptoms generally begin weeks to months after
examination is useful for excluding infection or malignant cells. initiation of the inciting therapeutic agent and resolve within
Although CSF in NPSLE can be characterized by a lymphocytosis weeks after the drug is discontinued; autoantibodies can persist
and increased immunoglobulin with elevated total protein, IgG for up to 12 months. Host factors affecting drug metabolization
index, and oligoclonal bands, these abnormalities are not (e.g., slow acetylation of procainamide and hydralazine) contribute
consistently present. Numerous autoantibodies (ANA, anti- to the risk of developing drug-induced lupus. Multiple potential
dsDNA, anticardiolipin, antiribosomal P, anti–N-methyl mechanisms resulting in the loss of self-tolerance have been
D-aspartate receptor [NMDAR], antineuronal, anti-RNP, suggested for this classic model. One of the most extensively
anti-Sm) and various cytokines have been identified in the CSF explored is inhibition of DNA methylation with TLR activation,
of patients with SLE; however, none is specific for active NPSLE resulting in overexpression of costimulatory molecules such as
or individual CNS NPSLE syndromes, and routine testing is leukocyte function–associated antigen-1 (LFA-1) on T cells and
not recommended. MRI is extremely sensitive for detection of enhanced T-cell help. 74
structural lesions and new ischemic lesions associated with focal Since the introduction of anti-TNF agents, a different variant
CNS NPSLE, but it is frequently not helpful in diagnosing active of drug-induced lupus has been recognized. Up to 30% of patients
diffuse CNS NPSLE, as MRI studies may be normal in patients receiving TNF blockade develop autoantibodies, including a
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with psychiatric syndromes and global CNS dysfunction. positive ANA and antibodies to dsDNA. A minority of patients
Imaging studies of neuronal function, positron emission develop anti-DNA antibodies, nephritis, and vasculitis. The
tomography (PET), and single-photon emission computed pathogenesis of this immunological deregulation is not known.
tomography (SPECT) scans measuring cerebral glucose uptake
and blood flow, respectively, magnetic resonance spectroscopy, Treatment
and functional MRI (fMRI) correlate to a limited extent with tHEraPEUtIC PrINCIPLES
diffuse CNS NPSLE. These scans must be interpreted carefully Goals of Therapy in SLE
because atrophy with neuronal cell loss leads to changes in
metabolism and blood flow. Cerebral angiograms can be helpful I. Suppression of inflammation
if a diagnosis of cerebral vasculitis is considered; however, CNS • Induction of remission
vasculitis is rare, with true vasculitis in only 5–8% of autopsies. • Maintenance of remission
• Preservation of organ function
More commonly, a bland vasculopathy with degenerative and II. Suppression of immune activation
proliferative changes in small vessels, perivascular infiltrates, • Modulation of the immune response
microinfarcts, and microhemorrhages is present. III. Treatment/prevention of drug-related toxicities
There are no serological tests specific for CNS NPSLE. Serologi-
cal evidence of disease activity (elevated anti-DNA antibodies
and low complement) may help to diagnose CNS NPSLE,
particularly if combined with other clinical signs of active disease. The goals of lupus treatment are to stop and reverse ongoing
However, CNS NPSLE can also flare in the absence of serological organ inflammation, to prevent or limit irreversible organ damage,
and clinical disease activity. Cognitive impairment in particular and to suppress the immune response driving the inflammation
tends to develop insidiously, irrespective of peripheral disease and prevent flares. Therapeutic agents, and combinations thereof,
activity. Recent data from murine models and in vitro studies can be used for induction of remission, maintenance of remission,
strongly support the role of specific autoantibodies directed or prevention of flare. The efficacy of therapeutic agents must
against NMDAR, phospholipid, α tubulin, neuronal surface P be balanced against their potential toxicity. Thus treatment must
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antigen, and ribosomal P in NPSLE. Anti-NMDAR and anti-P be tailored to the individual patient based on disease manifesta-
antibodies have been identified in the serum, CSF, and brain of tions. In general, milder disease requires treatment with less
SLE patients and have been associated with cognitive and depres- potent or lower doses of antiinflammatory and immunosup-
sive syndromes in some SLE patients. CSF anti-NMDAR antibod- pressive medications than more active, severe disease affecting
ies have also been reported to be increased in patients with acute major organs such as the kidney or brain (Table 51.4). Individual
confusional state. The current challenge is to identify easily patient responses to a given medication will vary, and patients
accessible, sensitive, and specific serological or imaging biomarkers must be monitored closely for response as well as toxicity.