Review Article

Neurologic Complications
Address correspondence to
Dr Jonathan M. Goldstein,
Department of Neurology,
Belaire Building, 5th floor,

of Rheumatic Disease Hospital for Special Surgery,

525 East 71st St, New York,
NY 10021,
GoldsteinJ@HSS.edu.
Jonathan M. Goldstein, MD
Relationship Disclosure:
Dr Goldstein has served on
advisory panels for CSL-Behring
ABSTRACT and Grifols and as a speaker for
Athena Diagnostics, Inc.
Purpose of Review: This article discusses the specific neurologic issues that arise in Unlabeled Use of
patients with rheumatic diseases such as rheumatoid arthritis, systemic lupus Products/Investigational
erythematosus, and Sjögren syndrome. Diagnosis and management are discussed. Use Disclosure:
Dr Goldstein discusses the
Recent Findings: Advances include advanced imaging, serologic and CSF markers, unlabeled use of
and targeted immune-modulating therapies. The use of these modalities are discussed cyclophosphamide, rituximab,
in detail. methotrexate, azathioprine,
mycophenolate mofetil, and
Summary: Rheumatic disorders are quite common and can result in disabling but cyclosporine.
many times treatable neurologic sequelae. The key is early diagnosis and management. * 2014, American Academy
Awareness of the common presentations and current modalities of diagnosis and of Neurology.
treatment is critical to improved outcomes.

Continuum (Minneap Minn) 2014;20(3):657–669.

INTRODUCTION of 0.8% to 1% worldwide and is twice as

Rheumatic diseases are a collection of
chronic inflammatory conditions stem-
ming from autoimmune attack on con-
nective tissue. The systemic nature of
these diseases can result in secondary
neurologic symptoms, either as a direct
result of immunologic attack or by
indirect degradation of supporting struc-
tures. Neurotoxic effects of treatment can
also cause complex neurologic symp-
toms. This article presents updated in-
sights into the neurologic complications
of common rheumatic diseases, includ-
ing diagnostic recommendations and
therapeutic options. Cases are discussed
to highlight characteristic presentations
and managements of neurologic compli-
cations in this patient population.
DISEASES
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is character-
ized by symmetric, progressive joint
deformation due to proliferation of the
synovium and resultant inflammation,
laxity, and erosion. RA has a prevalence
common in women as in men. The
etiology of the disease is multifactorial,
with some evidence of heritable suscep-
tibility. The American College of Rheu-
matology has developed criteria for the
diagnosis of RA. The course of the disease
is highly variable and is correlated with
genetic polymorphisms at a region of
HLA-DRB1, T-cell receptor, and IL1A loci.
RA is associated with significant morbid-
ity, with half of RA patients unable to
work at 10 years post onset; early
diagnosis and aggressive treatment of
RA provides the best opportunity to
slow erosion and maintain joint function.
The systemic inflammation is linked to
the high rate of cardiovascular disease in
these patients, with average life expec-
tancy decreased by 5 to 7 years.1
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) pre-
sents as a complex pattern of multiorgan
inflammation and involves multiple auto-
antibodies. Estimates of prevalence of SLE
range between 0.5 to 1.5 per million in

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 Rheumatic Disease
KEY POINTS
h Neurologic disorders
can be seen in patients
with primary rheumatic
diseases.
h Rheumatic diseases are
relatively common and
cause a great deal of
morbidity and mortality
in affected patients.
658 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
the United States, with a female-to-male
ratio of 9:1. Ethnogenetic susceptibility to
SLE is highVthe prevalence of SLE in
African American women of childbearing
age is reportedly as high as 1 in
500Valthough socioeconomic status
plays a larger role than ethnicity in the
mortality of SLE patients. Environment-
induced epigenetic changes are likely to
play a large role in SLE as well. SLE
involves humoral immune dysfunction
and is characterized by B-cell production
of a range of self-antigen immunoglobu-
lins; immune complexes subsequently
form and contain autoantigen nucleic
acids, nucleic acidYassociated proteins,
and autoantibodies.2,3 The onset of the
disease may be insidious, with facial
rash, mild thrombocytopenia, anemia,
or general malaise; or acute, with
dyspnea, hemoptysis, or sudden alter-
ation in mental status. Patients with SLE
have a fivefold greater mortality risk
than the general population, with a
high incidence of morbidity due to
infection, diabetes mellitus, vascular
disease, bone disease, and certain can-
cers. Acute onset is associated with
greater disease activity in SLE.4
Sjögren Syndrome
Sjögren syndrome is a systemic autoim-
mune epithelitis characterized by salivary
and lacrimal dysfunction due to lympho-
cytic and plasma cellular infiltration,
although much of the morbidity involves
extraglandular disease. Keratoconjuncti-
vitis sicca and xerostomia (lacrimal and
salivary gland involvement, respectively)
are the most prominent features of
Sjögren syndrome, but it often presents
with a variety of manifestations, including
vascular and neurologic involvement.
Sjögren syndrome can occur as primary
disease or as a complex secondary syn-
drome in the context of another autoim-
mune disease; approximately half of
Sjögren syndrome cases occur in associ-
ation with other connective tissue dis-
ease, typically RA.5 Primary Sjögren
syndrome has a prevalence of 0.09% to
3.5%, with an incidence of 3.9 to 5.3 per
100,000.6 The American College of
Rheumatology estimates between
400,000 and 3.1 million adults experi-
ence Sjögren syndrome with a female to
male ratio of 10:1.
EPIDEMIOLOGY OF NEUROLOGIC
COMPLICATIONS
Rheumatoid Arthritis
RA patients experience a relatively low
incidence of cerebral complications and a
high incidence of spinal cord involve-
ment. Typical neurologic complications in
RA appear late in the course of the disease
and usually involve the peripheral ner-
vous system; many of these neuropathies
are caused by vasculopathy secondary to
systemic inflammation or by nerve en-
trapment secondary to musculoskeletal
degradation characteristic of the disease.
Evidence suggests many RA patients
experience subclinical neuropathies;
therefore, the true incidence and emer-
gence patterns of RA-associated neuro-
logic complications may be unknown.7
Systemic Lupus Erythematosus
SLE is associated with the highest inci-
dence of neurologic sequelae among all
rheumatic diseases. Between 25% and
70% of SLE patients will experience
neurologic or psychological symptoms,
with 12% of these sequelae established
before a diagnosis of SLE and another
12% presenting with neuropsychiatric
symptoms at the time of diagnosis.8 Up
to 50% of SLE patients will experience
CNS complications. A significant per-
centage of SLE patients develop distinct
neuropsychiatric symptoms during the
course of the disease; 17% to 30% will
be diagnosed with neuropsychiatric SLE
(NPSLE).9,10 While NPSLE patients gen-
erally do better than SLE patients with
psychiatric symptoms not related to the
disease, NPSLE patients have worse
June 2014

outcomes than SLE patients without
NPSLE, and recognition and treatment
of this subset may be critical for disease
prognosis.9,11 The high incidence of
antiphospholipid syndrome and cerebro-
vascular disease in SLE patients contrib-
utes to morbidity and mortality in SLE.
Sjögren Syndrome
Estimates of neurologic involvement in
Sjögren syndrome range from 0% to 70%,
but the prevalence is probably closer to
20%. Peripheral nervous system (PNS)
dysfunction in Sjögren syndrome in-
cludes symmetric sensorimotor poly-
neuropathy and cranial neuropathy as
common findings; PNS involvement in
primary Sjögren syndrome has an esti-
mated prevalence of 20%. CNS involve-
ment in primary Sjögren syndrome is less
frequent; approximately 1% to 8% of
Sjögren syndrome patients show CNS
dysfunction, including mild cognitive def-
icits, headache, and spinal cord involve-
ment in primary Sjögren syndrome. The
majority (63%) of Sjögren syndrome pa-
tients with CNS involvement will also have
PNS abnormalities. Central deficits precede
the diagnosis of primary Sjögren syndrome
in many cases. Patients who have primary
Sjögren syndrome with neurologic involve-
ment are generally older than those
without neurologic symptoms.6,8,12
COMPLICATION CATEGORIES
Vasculitis
Vasculopathy is common in systemic
autoimmune disease and contributes to
many of the neurologic presentations in
rheumatic disease. Direct autoimmune-
mediated destruction and chronic sys-
temic inflammation contribute to vascular
degradation. Homogenous noninflam-
matory fibrointimal hyperplasia results
in progressive vascular occlusion, caus-
ing collateral vessel formation and
digital vessel infarction, while poly-
arteritic lesions result in intravascular
occlusion and thrombosis and carry a
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KEY POINT
worse prognosis than noninflammatory h Neurologic complications
lesions. Histologically, polyarteritic le- of rheumatoid arthritis,
sions affect small- to medium-sized systemic lupus
arteries, with all vascular layers under- erythematosus, and
going mononuclear infiltration, nonde- Sjögren syndrome are
structive fibrinoid necrosis of the frequent. These include
internal elastic lamina, and intimal stroke, myelopathy, and
proliferation.13,14 Microvessel vasculitis peripheral neuropathies.
in the vasa nervorum contributes to
the peripheral neuropathies associated
with rheumatic disease (Case 9-1).
Systemic rheumatoid vasculitis is asso-
ciated with an increased risk of cardio-
vascular morbidity and mortality. Cerebral
vasculitis may occur with or without
systemic vasculitis and may be fatal unless
promptly diagnosed and managed.
The major peripheral neurologic
complications in RA (distal sensory
neuropathy and mononeuritis multi-
plex) are directly caused by vascular
degradation, and this implied vascular
involvement carries great prognostic
weight. RA patients with such overt
vascular involvement have early-onset
cardiovascular disease and are twice as
likely to experience myocardial infarction
as compared with healthy age-matched
controls within a 10-year period.13 Vas-
cular disease may account for one-third
of all mortality in RA patients.15
Vascular complications are observed
in 10% to 40% of patients with SLE and
can cause multiorgan pathology. The
immune complexes observed in SLE are
known to activate endothelial cells and
elicit a proinflammatory and proliferative
response, contributing to the pathologic
development of vasculitis.16 Concur-
rent antiphospholipid syndrome in SLE
patients may play a role in vascular
complications as a result of the
antiphospholipid syndrome prothrom-
botic effect, but this is difficult to discern
from small vessel vasculopathy.17 SLE
patients have an increased risk of stroke,
but increasing evidence suggests that
CNS complications and myelopathies in
lupus are rarely caused by vasculitis.
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 Rheumatic Disease

KEY POINT
h Stroke risk is elevated in
patients with rheumatic
Case 9-1
A 48-year-old man with rheumatoid arthritis presented for a neurologic
diseases because of
consultation at the request of his primary care physician because of a
increased atherogenesis.
3-week history of right leg pain and footdrop and more recent left arm
pain and wrist drop. On examination, the patient had marked weakness of
right ankle dorsiflexion and left wrist extension. Sensation was decreased
in the distribution of the right peroneal nerve and left superficial radial
nerve. Nerve conduction study showed an absent right superficial peroneal
sensory potential and an absent left radial sensory potential. Needle EMG
demonstrated fibrillation potentials and decreased recruitment in the right
tibialis anterior and peroneus longus and the left extensor digitorum and
extensor indicis proprius. Other aspects of the nerve conduction study and EMG
were within normal limits. Biopsy of the left superficial radial nerve showed a
polymorphonuclear infiltrate in epineurial blood vessels with fibrinoid necrosis
in the vessel wall. Axon loss was noted. The patient was treated with high-dose
IV methylprednisolone and IV cyclophosphamide. Improvement of strength
was noted over the next 4 months.
Comment. Peripheral nervous system vasculitis (mononeuritis multiplex)
is a fulminant complication of rheumatic disorders and requires prompt
diagnosis and management. A good outcome can be obtained if
treatment is initiated quickly.

Vasculopathy plays a larger role than botic risk through suppression of

simple vessel occlusion in the pathogen-
esis of peripheral neuropathies in SLE.16
Primary Sjögren syndrome is rarely
associated with vascular disease as an
early manifestation, in contrast to RA
and SLE. The true incidence is difficult
to characterize as vasculopathy occurs in
late-stage disease in the presence of
multiple confounding risk factors.15
Small vessel vasculitis and ischemia is
implicated in small fiber neuropathy,
multiple mononeuropathies, and auto-
nomic neuropathy described in primary
Sjögren syndrome. Subtle peripheral
neuropathy may be present in 20% to
50% of Sjögren syndrome patients.
Axonal polyneuropathies are the most
common and clinically present as distal
and symmetric. Although rare, cerebral
vasculitis is implicated in some of the
diffuse encephalitic complications of
Sjögren syndrome.12
Stroke
Systemic inflammation in rheumatic dis-
ease increases atherogenesis and throm-
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anticoagulation and fibrinolysis and in-
creased procoagulant production. While
Sjögren syndrome is associated with
enhanced atherogenesis and carries an
increased risk of ischemic stroke early in
the disease course, RA and SLE have a
much more defined role in risk of
atherosclerosis, thrombosis, and subse-
quent stroke. Both RA and SLE show a
small but significantly increased risk of
ischemic and hemorrhagic stroke within
a year of a hospitalization for rheumatic
disease, and RA carries this elevated risk
for up to 10 years.18
The moderate stroke risk in RA has a
late evolution in the course of the disease
compared with other cardiovascular com-
plications that are early onset in these
patients. RA does not cause large-artery
cerebrovascular disease, but systemic
inflammation is well established as an
accelerant of atherosclerosis in the RA
population and probably plays a role in
the increased risk of stroke over time;
procoagulable factors may be up-
regulated in established RA, and it is
June 2014

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possible that this late-stage increase in
hypercoagulability may account for the
slow evolution of increased stroke risk in
RA patients.19 In addition, posterior
embolic stroke may result from direct
occlusion of the vertebrobasilar circula-
tion secondary to rheumatic degradation
of the transverse ligament and subse-
quent atlantoaxial subluxation. Vertebral
artery compression due to cervical sub-
luxation occurs in 5% of RA patients; the
insidious destruction of the atlantoaxial
joint over time also contributes to the
late onset of RA stroke risk.20
Cerebrovascular disease is one of the
neuropsychiatric manifestations of SLE.
While all neuropsychiatric syndromes in
SLE patients have a strong negative
impact on morbidity, only cerebrovas-
cular disease and myelopathy are asso-
ciated with increased risk of mortality.10
It is estimated that 3% to 15% of SLE
patients will experience stroke at some
point in the disease course. Large studies
of stroke hospitalizations among SLE
patients have described an unadjusted
odds ratio of 1.9 of stroke among this
population, with an increased risk of all
types of stroke except subarachnoid
hemorrhage. While the risk of stroke in
SLE shows age-dependent increases
along with the general population, the
youngest SLE patients have the highest
stroke risk in comparison with their
healthy conterparts.21 This may be be-
cause of the difficulty in diagnosing SLE
and better disease management after
definitive diagnosis.
Encephalitis
Although the brain is theoretically
protected from potentially destructive
autoantibodies by the blood-brain bar-
rier (BBB), the increased risk of cere-
brovascular events in rheumatic
patients is indicative that some patients
can develop significant breaches. CNS
injury in rheumatic disease is multifac-
torial and poorly understood at a path-
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KEY POINT
ophysiologic level, but serum and CSF h Hypercoagulability is of
antineuronal antibodies, prothrombotic great concern in
factors, and chronic systemic inflamma- systemic lupus
tion are contributory. TNF and IL1B erythematosus. The
increase cerebral inflammation and possibility of an
have receptors on the BBB. These underlying rheumatic
cytokines, in conjunction with prosta- disease should be
glandins, may also play a role in increas- considered in patients
ing BBB permeability and leukocyte with vascular events.
migrations through Rho-dependent
pathways.22
Cerebral manifestations of RA are
infrequent complications of the disease
but include rheumatoid nodulosis and
vasculitis. Nodules typically develop in
the dura, meninges, or choroid plexus
but have been reported in the brain
parenchyma; rheumatic nodules are
often asymptomatic, so the true inci-
dence and pattern of these lesions
remains unknown. Cerebral vasculitis in
RA is rare and develops in the meninges,
choroid plexus, and parenchyma.
Patients with established, seropositive,
active RA and other extraarticular
manifestations of the disease appear to
be at higher risk of developing CNS
complications.14,23
CNS involvement is seen in about
50% of SLE cases and carries a worse
prognosis than PNS disease. The 5-year
survival figure of patients with encepha-
litic SLE is 55%, compared with 75% to
90% of those with nonencephalitic
SLE.24,25 Neuropsychiatric complica-
tions are so pervasive in SLE that the
American College of Rheumatology has
developed definitions, reporting stan-
dards, and diagnostic recommendations
for 19 neuropsychiatric syndromes asso-
ciated with SLE (Table 9-126). These
neurologic entities range in severity from
mild cognitive deficits and headache
(present in 50% of SLE patients) to
psychosis, seizure, and stroke (reported
in approximately 10% of SLE patients).
Memory disturbance is the most com-
mon cognitive deficit and may herald
the diagnosis of the disease.17 The
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 Rheumatic Disease

KEY POINT
h Encephalopathy is
TABLE 9-1 Neuropsychiatric
common in systemic
lupus erythematosus
and can be seen in the
other rheumatic
diseases.
SLE increase the permeability of the
BBB, creating antineuronal antibody
Syndromes in
Systemic Lupus Erythematosus access to the cerebral circulation.16
as Defined by the American Antiphospholipid antibodies, present
College of Rheumatologya in 2% to 5% of healthy individuals, are
detected in 50% to 60% of SLE patients
b Central Manifestations with CNS complications, and in 20% of
Acute confusional state SLE patients without central neurologic
Anxiety disorder symptoms. While antiphospholipid an-
Aseptic meningitis tibodies are recognized for their con-
Cerebrovascular disease tributions to a prothrombotic state,
Cognitive disorder they have cross-reactivity with myelin
Demyelinating syndrome and brain phospholipids, creating com-
Headache
plex pathophysiologic mechanisms for
neurologic injury beyond thrombotic
Mood disorder
infarction.
Movement disorder
Cerebral involvement in primary
Myelopathy
Sjögren syndrome is controversial, with
Psychosis initial reports probably overestimating
Seizure disorder the prevalence of CNS involvement due
b Peripheral Manifestations to primary disease; more recent esti-
Autonomic neuropathy mates put CNS involvement in primary
Cranial neuropathy Sjögren syndrome between 1% and
Guillain-Barré syndrome 8%, although this may not capture
Mononeuropathy mild or minor complications.6 Sjögren
Myasthenia gravis
syndromeYrelated CNS manifestations
can occur very early in the disease course.
Plexopathy
Focal encephalopathic manifestations
Polyneuropathy
such as seizure, aphasia, and movement
a
Reprinted from American College of disorders are more common than diffuse
Rheumatology, Arthritis Rheum.26
B 1999, by the American College of patterns of involvement such as subacute
Rheumatology. onlinelibrary.wiley.com/doi/ encephalopathy, aseptic meningitis, and
10.1002/1529-0131(199904)42:4%
3C599::AID-ANR2%3E3.0.CO;2-F/abstract.
psychiatric abnormalities. Onset may be
recurrent and must be distinguished
from multiple sclerosis (MS).12

majority of symptoms of NPSLE will
develop within the first 6 to 12 months
after initial SLE diagnosis, but onset may
occur at any time, The clinician must
recognize these complications, rule out
nonYSLE-attributable causes of neuro-
psychiatric events, and monitor for
antiphospholipid syndrome comorbidity
in order to properly diagnose and treat
the patient with NPSLE.9,25
Animal experiments have shown that
the immune complexes characteristic of
662 www.ContinuumJournal.com
Myelopathy
Myelopathies secondary to atlantoaxial
subluxation are common in RA pa-
tients. The extent of damage observed
on imaging does not always correlate
with the presence of clinical signs of
spinal cord compression; approxi-
mately 15% of RA patients with radio-
graphic lesions are asymptomatic.
Atlantoaxial subluxation in RA patients
may occur in isolation or in combina-
tion with cranial settling (vertical trans-
location of the dens). Lower cervical
June 2014

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spine involvement, including multi-
level anterior dislocation, occurs in
up to 29% of RA patients later in the
disease course. Cervical spine changes
start early in the course of RA, and
these abnormalities typically progress
from C1-C2 dislocation to cranial set-
tling to lower cervical spine involve-
ment. Severity of RA (indicated by
seropositivity, high C-reactive protein
at disease onset, and polyarthritis) is
predictive of the extent of progression
of cervical spine involvement. Acquired
cervical syringomyelia has also been
described secondary to atlantoaxial
subluxation in RA.27Y29
Inflammatory myelopathy, some-
times in the form of a catastrophic,
longitudinally extensive transverse mye-
litis, may occur in patients with rheuma-
tologic disease, particularly SLE and
primary Sjögren syndrome. As noted by
Wingerchuk and Weinshenker30 in their
recent article, neuromy-
elitis optica (NMO) is commonly asso-
ciated with systemic autoimmune
diseases, and this association is increas-
ingly accepted as NMO that is concom-
itant with systemic autoimmune disease.
KEY POINT
Please refer to the article ‘‘Acute Dissem- h Spinal cord involvement
inated Encephalomyelitis, Transverse is a potentially serious
Myelitis, and Neuromyelitis Optica’’ by complication of
Dean M. Wingerchuk, MD, MSc, rheumatic diseases.
FRCP(IC), FAAN; and Brian G.
Weinshenker, MD, FRCP(IC), in the
August 2013 Multiple Sclerosis issue of
(Volume 19, Number 4)
for further discussion of NMO and its
management.
In addition to the spinal cord disor-
ders mentioned above, lymphocytic
infiltration of spinal roots and dorsal
root ganglion degeneration is particu-
larly associated with Sjögren syndrome
and presents as a progressive sensory
ganglionopathy (Case 9-2).6,12
DIAGNOSIS OF NEUROLOGIC
COMPLICATIONS
Rheumatic vascular disease presents
with symptoms not normally observed
in cardiovascular diseases. Early manifes-
tations of rheumatic vasculitis may pres-
ent as scleroderma, including fibrosis of
the skin, sclerodactyly, and Raynaud
phenomenon.13 The presence of these
symptoms in the context of neurologic

Case 9-2
A 41-year-old woman with a diagnosis of Sjögren syndrome presented to
the office with a 2-month history of difficulty with balance and numbness
in her legs and face. Neurologic examination revealed a prominent loss of
pinprick and vibration in the legs and decreased pinprick in the first and
second divisions of the right trigeminal nerve. Her strength was normal
but she was areflexic and had impaired position sense in the legs and a
positive Romberg sign. MRI of the brain and spinal cord was normal, as
was CSF examination. Anti-Ro antibody was positive. Anti-Hu antibody was
negative in the blood and CSF. EMG showed decreased sensory nerve
action potential amplitudes in all sensory nerves. Motor studies and needle
examination were normal.
Comment. Sjögren syndrome can be associated with a sensory
ganglionopathy. Although a sensory ganglionopathy is more frequently
seen in association with lung cancer, this condition must be considered in a
patient with Sjögren syndrome. Treatment with immunotherapy such as IV
immunoglobulin or other immunosuppressants should be initiated,
although evidence for efficacy remains unproven.

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 Rheumatic Disease
KEY POINT
h Use of the proper abnormalities increases the likelihood
imaging technique is of neurovascular pathology and lowers
critical to a prompt and the threshold for vascular studies in
accurate diagnosis of affected patients. Transesophageal
vasculopathy associated echocardiology and carotid ultrasound
with a rheumatologic in combination with serologic analysis of
disorder and may a prothrombotic state may be indicated,
include MRI, magnetic especially in light of cerebrovascular or
resonance angiography, vasculopathic history. Neither MRI nor
CT angiography, or CT can distinguish small vessel vasculitis
conventional angiography.
from thrombosis; positron emission to-
mography (PET) imaging can detect
these metabolic and perfusion abnor-
malities but is still considered investiga-
tional.17 For suspected vasculopathy,
conventional arteriograms are superior
to magnetic resonance or CT angiogra-
phy. Isotype (eg, immunoglobulins M,
G, and A) and titer of lupus anticoagu-
lant, anticardiolipin, and antiY"2 -
glycoprotein I are recommended and
can be diagnostic for comorbid
antiphospholipid syndrome. Peripheral
neuropathy is often associated with
vasculitis, and autonomic dysfunction
may also involve antiacetylcholine re-
ceptor antibodies at the autonomic
ganglia. Of note, in a large study on
antibodies in neurologic patients,
Sjögren syndrome was the only connec-
tive tissue disorder with detectable
antineuronal antibodies.12,31
The American College of Rheumatol-
ogy has outlined basic laboratory matri-
ces and imaging guidelines to aid in
differentiation of neuropsychiatric SLE
symptoms and disease activity from
other neurologic diseases. CNS-SLE syn-
drome and CNS-Sjögren syndrome with
recurrent symptoms, antineuronal anti-
body titers, and small multifocal white
matter abnormalities on MRI can resem-
ble MS, and differentiation remains
challenging. Stroke, TIA, seizure, head-
ache, and isolated peripheral neuropa-
thy are not common in MS, as they are in
SLE and Sjögren syndrome. MS will
typically show oligoclonal banding on
CSF evaluation, but this can also be
664 www.ContinuumJournal.com
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observed in SLE. MRI is the preferred
imaging modality for investigating en-
cephalopathic rheumatic involvement,
with CT being suitable in the face of
general MRI contraindications or in cases
of suspected acute hemorrhage. MRI
with gadolinium is the most sensitive
method of evaluating CNS lesion pres-
ence, extent, and progression; single-
photon emission computed tomogra-
phy (SPECT), PET, and diffusion and
perfusion MRI are investigational in this
context. MRI abnormalities in SLE are
typically subcortical and static, as op-
posed to the dynamic periventricular,
cortical, basal ganglia, and corpus
callosum lesions in MS. Encephalopathic
involvement in primary Sjögren syn-
drome is associated with MRI abnor-
malities approximately 50% of the time,
with lesions described as small, diffuse
punctate white matter hyperintensities
in subcortical and periventricular re-
gions on T2-weighted and fluid-
attenuated inversion recovery (FLAIR)
sequence. Rarely, these lesions become
confluent and indicate vascular pathol-
ogy; diffuse encephalopathic involve-
ment in primary Sjögren syndrome
presenting as memory impairment, cog-
nitive dysfunction, and psychiatric prob-
lems is not associated with MRI changes
or CSF abnormalities, but angiographic
and technetium-99m (99mTc)YSPECT
changes have been described.12 Inflam-
matory and possible demyelinating le-
sions are rare in Sjögren syndrome and
tend to appear in younger patients
without hypertension.6,16 Patients with
possible CNS-Sjögren syndrome should
also undergo serologic evaluation for
Sjögren antibodies with anti-Ro (Sjögren
syndrome A [SSA]) and anti-La (Sjögren
syndrome B [SSB]) titers.32 Evaluation of
the CSF is of particular importance in
diagnosing primary Sjögren syndrome
neurologic complications and distin-
guishing between Sjögren syndrome
and MS. Disease activity in Sjögren
June 2014
syndrome is correlated with increased
immunoglobulin G index in many pa-
tients. CSF oligoclonal banding may be
helpful, as banding occurs at a much
lower frequency in patients with primary
Sjögren syndrome (20% to 25% of
primary Sjögren syndrome versus 90%
of MS patients); it is unstable and will
often be resolved in the patient with
primary Sjögren syndrome after steroid
therapy.
NPSLE remains challenging to diag-
nose in light of the subjective nature of
many of the neurologic concerns, the
high frequency of many of the 19 defined
neuropsychiatric entities within the gen-
eral population, and the lack of specific
diagnostic criteria for SLE-associated neu-
ropsychiatric events. Emergence of neu-
rologic sequelae in SLE may be associated
with inflammatory flare, and diagnostic
workup should begin with detection of
serologic and CSF acute-phase markers
of inflammation of disease activity; ele-
vated erythrocyte sedimentation rate and
decreased complement are associated
with disease flare.33 The presence of
antiribosomal P protein antibodies is
considered investigational but is highly
specific for SLE and is informative in the
presence of neuropsychiatric symptoms
without an SLE diagnosis. Basic CSF
Gram stain and culture can evaluate
bacterial cause or comorbidity with neu-
ropsychiatric symptoms, and neuro-
syphilis should be excluded. EEG
changes in NPSLE are nonspecific. EEG
monitoring is indicated in seizure and
encephalopathic presentations.
Myelitis is best diagnosed on MRI,
enabling exclusion of compressive he-
matoma, tumors, and spinal deformi-
ties. Hyperintensity on T2-weighted
imaging in combination with elevated
CSF protein and cell count is consistent
with myelitis, but extensive CSF workup
is essential to exclude an infectious
cause before therapeutic immunosup-
pression therapy can safely begin. It is
Continuum (Minneap Minn) 2014;20(3):657–669
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
of note that the high concurrence of
antiphospholipid antibodies in rheu-
matic disease can cause a false positive
result for CSF oligoclonal banding.16,34
Spinal imaging can direct the differen-
tial against MS, as spinal lesions span-
ning multiple segments are rare in MS
but would be consistent with the
longitudinally extensive myelitis of an
NMO-spectrum disorder in patients
with systemic autoimmune disease. In
patients with rheumatologic disease
who have possible NMO, workup
should proceed as in any patient with
this neurologic syndrome (eg, assess-
ment for aquaporin-4 antibodies).
The prevalence and early emergence
of cervical spine involvement in RA
suggests that clinicians order imaging
studies early in the course of RA and in
cases of rapid disease progression. Radio-
graphs in maximum flexion and extension
or dynamic MRI can reveal the extent of
dislocation that neutral films may miss.
Treatment
The treatment of neurologic complica-
tions of rheumatic diseases involves
both controlling the underlying im-
mune attack on the nervous system
as well as the treatment of the specific
neurologic symptoms caused by the
immune attack, such as seizures and
neuropathic pain. Neurologists are
often consulted for the treatment of
symptoms, but in some cases are also
involved in the primary treatment of
the underlying rheumatic illness if the
primary complications are neurologic
in nature. Because neurologists may
be less comfortable with the latter, this
discussion will focus on immunosup-
pressive and immunomodulatory ther-
apy in the treatment of the underlying
autoimmune rheumatic disorders.
The most common treatments for
immune-mediated complications in-
clude corticosteroids, methotrexate,
and azathioprine, which, as ‘‘nontargeted
www.ContinuumJournal.com 665
 Rheumatic Disease
KEY POINT
h Treatment of neurologic TABLE 9-2 Nontargeted Immune Therapy
complications frequently
requires treating the Drug Mechanism
underlying rheumatic
Glucocorticoid Multiple
disease in addition to
managing the Methotrexate Folate inhibition
neurologic process.
Azathioprine Inhibits purine synthesis
Mycophenolate Inhibits DNA/ribonucleic Oral
mofetil acid synthesis in leukocytes
Cyclophosphamide Alkylating agent
Cyclosporine T-cell inhibition
therapies,’’ induce generalized immuno-
suppression via multiple mechanisms
(Table 9-2). Generally, nontargeted
immune therapies are still used first
line for neurologic complications of
rheumatic diseases, with corticosteroids
being the most common, followed by
methotrexate and cyclophosphamide.
IV pulse steroids are effective at rapidly
suppressing the immune attack across
many rheumatic disorders. Cyclophos-
phamide is often used in controlling the
neurologic complications of some of
the vasculitides. Since many rheumatic
diseases are chronic, longer-term treat-
ment may be required to prevent
further neurologic complications, and
oral corticosteroids have historically
been prescribed for this purpose; how-
ever, other agents, such as azathioprine
and mycophenolate mofetil, may be
used as long-term immunosuppressants
and are steroid-sparing, reducing the
long-term effects of corticosteroids.
Over the past few decades, more
specific targeted treatments (‘‘bio-
logics’’) have been introduced to the
market as treatments for specific rheu-
matic diseases. As opposed to the
nontargeted therapies, targeted thera-
pies work by inhibiting or stimulating
specific pathways and targets involved
in autoimmunity, including tumor ne-
crosis factor, interleukin-6, interleukin
666 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Route Use
IV, oral, IM Acute therapy
Oral, IV, Steroid sparing
subcutaneous
Oral Steroid sparing
Steroid sparing
Oral, IV Acute therapy in
severe disease
Oral Short-term
treatment
12/23, T-cells, and B-cells. Currently
approved targeted therapies are sum-
marized in Table 9-3.
The proper use of targeted or
nontargeted immunotherapy requires
experience and collaboration between
specialists, and unless the neurologist
has expertise with the biologic targeted
therapies, a rheumatologist should be
consulted and involved in administration
of therapy. Regardless of the type of
therapy chosen, patients being treated
must be monitored for general adverse
effects of immunosuppression, such as
opportunistic infections as well as spe-
cific drug-related side effects, such as
osteoporosis from corticosteroids or liver
injury from azathioprine. There is also a
rare but established risk of worsening of
underlying multiple sclerosis in patients
using TNF-! antagonists.35 The choice
of therapy is determined by multiple
factors, including patient comorbidities,
response to previous medications, se-
verity of organ system involvement, and
renal and hepatic function. Many ran-
domized and nonrandomized trials of
medications have been performed, with
varying results.36Y46 There is a great deal
of promise for the targeted biologic
therapies, which provide the advantage
of directly modifying the immune attack
with less risk of inducing generalized
immune suppression and undesirable
June 2014
 KEY POINT

TABLE 9-3 Targeted Immune Therapy h The use of immune

therapies must be done
Drug Mechanism Route Usea with an understanding
of the risk. It is
Etanercept, infliximab, Tumor necrosis Subcutaneous Rheumatoid
important to collaborate
adalimumab, certolizumab factor-! blocker except IV arthritis,
pegol, golimumab infliximab psoriatic with specialists
arthritis experienced in the use
of these drugs.
Rituximab Anti-CD20 IV Rheumatoid
arthritis
Belimumab Antibody to B-cell IV Systemic lupus
stimulator erythematosus
Abatacept T-cell IV, Rheumatoid
costimulation subcutaneous arthritis
molecule
Tocilizumab Anti interleukin-6 IV, Rheumatoid
subcutaneous arthritis,
juvenile
rheumatoid
arthritis
Ustekinumab Anti interleukin Subcutaneous Psoriatic
12/23 arthritis,
psoriasis
a
All drugs on this table are under investigation for other unlabeled uses.

side effects. However, concerns re-
main with these therapies as they
have been implicated in reactivating
latent bacterial and viral infections,
including causing progressive multifocal
leukoencephalopathy. As understanding
of the mechanism of rheumatic disease
improves and more experience is gained
with the newer targeted biologic agents,
a paradigm shift in treatment of the
rheumatic diseases is occurring with less
reliance on the traditional nontargeted
therapies and increased use of these
targeted therapies.
CONCLUSION
Rheumatic disorders are quite prevalent,
as are their neurologic complications.
Having a thorough understanding of the
major rheumatic disorders (ie, RA, SLE,
and Sjögren syndrome) is important
when evaluating patients presenting with
neurologic manifestations. The use of
immune therapies, both nontargeted
and targeted, requires close collaboration
between specialists. This is best accom-
plished with neurologists and rheumatol-
ogists working as a team.
ACKNOWLEDGMENT
The author greatly appreciates the
assistance of Erica Giles at Yale Uni-
versity School of Medicine in the
preparation and review of this article.
REFERENCES
1. Brooks P. Rheumatoid arthritis: aetiology
and clinical features. Medicine 2006;34(10):
379Y382.
2. Sun W, Jiao Y, Cui B, et al. Immune
complexes activate human endothelium
involving the cell-signaling HMGB1-RAGE
axis in the pathogenesis of lupus vasculitis.
Lab Invest 2013;93(6):626Y638.
3. Frieri M. Mechanisms of disease for the clinician:
systemic lupus erythematosus. Ann Allergy
Asthma Immunol 2013;110(4):228Y232.
4. Chng H. Management of connective tissue
diseases. In: Weisman M, Weinblatt M, Louie J,
Van Vollenhoven R, editors. Targeted

Continuum (Minneap Minn) 2014;20(3):657–669 www.ContinuumJournal.com 667

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Rheumatic Disease
treatment of rheumatic diseases. Philadelphia:
Saunders, 2010;83Y90.
5. Haga HJ, Naderi Y, Moreno AM, Peen E. A
study of the prevalence of sicca symptoms
and secondary Sjögren’s syndrome in
patients with rheumatoid arthritis, and its
association to disease activity and treatment
profile. Int J Rheum Dis 2012;15(3):284Y288.
6. Massara A, Bonazza S, Castellino G, et al.
Central nervous system involvement in
Sjögren’s syndrome: unusual, but not
unremarkableVclinical, serological characteristics
and outcomes in a large cohort of Italian patients.
Rheumatology (Oxford) 2010;49(8):1540Y1549.
7. Agarwal V, Singh R, Wiclaf CS, et al. A
clinical, electrophysiological, and pathological
study of neuropathy in rheumatoid arthritis.
Clin Rheumatol 2008;27(7):841Y844.
8. Cikes N. Central nervous system involvement
in systemic connective tissue diseases. Clin
Neurol Neurosurg 2006;108(3):311Y317.
9. Hanly JG, Urowitz MB, Su L, et al. Prospective
analysis of neuropsychiatric events in an
international disease inception cohort of
patients with systemic lupus erythematosus.
Ann Rheum Dis 2010;69(3):529Y535.
10. Wang M, Gladman DD, Ibañez D, Urowitz MB.
Long-term outcome of early neuropsychiatric
events due to active disease in systemic
lupus erythematosus. Arthritis Care Res
(Hoboken) 2012;64(6):833Y837.
11. Bertsias GK, Ioannidis JP, Aringer M, et al.
EULAR recommendations for the management
of systemic lupus erythematosus with
neuropsychiatric manifestations: report of a
task force of the EULAR standing committee
for clinical affairs. Ann Rheum Dis 2010;69(12):
2074Y2082.
12. Tobón GJ, Pers JO, Devauchelle-Pensec V,
Youinou P. Neurological disorders in primary
Sjögren’s syndrome. Autoimmune Dis 2012;2012:
645967.
13. Hayton M, Federation of European Societies
for Surgery of the Hand. Vascular and
neurological considerations in rheumatoid
arthritis. Presented at: 11th Congress of the
Federation of European Societies for Surgery
of the Hand; June 2006;Glasgow, Scotland.
14. Caballol Pons N, Montala N, Valverde J, et al.
Isolated cerebral vasculitis associated with
rheumatoid arthritis. Joint Bone Spine
2010;77(4):361Y363.
15. Soltész P, Kerekes G, Dér H, et al. Comparative
assessment of vascular function in autoimmune
rheumatic diseases: considerations of
prevention and treatment. Autoimmun Rev
2011;10(7):416Y425.
668 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
16. Ferreira S, D’Cruz DP, Hughes GR. Multiple
sclerosis, neuropsychiatric lupus and
antiphospholipid syndrome: where do we
stand? Rheumatology (Oxford) 2005;44(4):
434Y442.
17. Monov S, Monova D. Classification criteria
for neuropsychiatric systemic lupus
erythematosus: do they need a discussion?
Hippokratia 2008;12(2):103Y107.
18. Zöller B, Li X, Sundquist J, Sundquist K. Risk of
subsequent ischemic and hemorrhagic stroke
in patients hospitalized for immune-mediated
diseases: a nationwide follow-up study from
Sweden. BMC Neurol 2012;12:41.
19. Holmqvist M, Gränsmark E, Mantel A, et al.
Occurrence and relative risk of stroke in
incident and prevalent contemporary
rheumatoid arthritis. Ann Rheum Dis
2013;72(4):541Y546.
20. Kuroki T, Ueno Y, Takeda I, et al. Recurrent
embolic strokes associated with vertical
atlantoaxial subluxation in a patient with
rheumatoid arthritis: a case report and
review of literature. J Stroke Cerebrovasc Dis
2013;22(8):e676Ye681.
21. Krishnan E. Stroke subtypes among young
patients with systemic lupus erythematosus.
Am J Med 2005;118(12):1415.
22. Fung A, Vizcaychipi M, Lloyd D, et al. Central
nervous system inflammation in disease
related conditions: mechanistic prospects.
Brain Res 2012;1446:144Y155.
23. Guadalupe Loya-de la Cerda D, Avilés-Solís JC,
Delgado-Montemayor MJ, et al. Isolated
rheumatoid arthritis-associated cerebral
vasculitis: a diagnostic challenge. Joint Bone
Spine 2013;80(1):88Y90.
24. Scolding NJ, Joseph FG. The neuropathology
and pathogenesis of systemic lupus
erythematosus. Neuropathol Appl Neurobiol
2002;28(3):173Y189.
25. Lateef A, Petri M. Unmet medical needs in
systemic lupus erythematosus. Arthritis Res
Ther 2012;14(suppl 4):S4.
26. American College of Rheumatology.
The American College of Rheumatology
nomenclature and case definitions for
neuropsychiatric lupus syndromes. Arthritis
Rheum 1999;42(4):599Y608.
27. Bouchaud-Chabot A, Lioté F. Cervical spine
involvement in rheumatoid arthritis. A
review. Joint Bone Spine 2002;69(2):141Y154.
28. Wasserman BR, Moskovich R, Razi AE.
Rheumatoid arthritis of the cervical
spineVclinical considerations. Bull NYU
Hosp Jt Dis 2011;69(2):136Y148.
29. Kimura Y, Seichi A, Gomi A, et al. Acquired
Chiari malformation secondary to
June 2014
 atlantoaxial vertical subluxation in a patient
with rheumatoid arthritis combined with
atlanto-occipital assimilation. Neurol Med
Chir (Tokyo) 2012;52(9):683Y686.
30. Wingerchuk DM, Weinshenker BG. Acute
disseminated encephalomyelitis, transverse
myelitis, and neuromyelitis optica. Continuum
(Minneap Minn) 2013;19(4 Multiple Sclerosis):
944Y967.
31. Vianello M, Vitaliani R, Pezzani R, et al.
The spectrum of antineuronal autoantibodies
in a series of neurological patients. J Neurol
Sci 2004;220(1Y2):29Y36.
32. Akasbi M, Berenguer J, Saiz A, et al. White
matter abnormalities in primary Sjögren
syndrome. QJM 2012;105(5):433Y443.
33. Gafter-Gvili A, Leibovici L, Molad Y. Elevation
of inflammatory markers in patients with
systemic lupus erythematosus is associated
with poorer outcome. Biomed Pharmacother
2013;67(1):48Y52.
34. White C, Leonard B, Patel A. Longitudinally
extensive transverse myelitis: a catastrophic
presentation of a flare-up of systemic lupus
erythematosus. CMAJ 2012;184(3):E197Y200.
35. US Food and Drug Administration. Safety
update on TNF-! antagonists: infliximab and
etanercept. www.fda.gov/ohrms/dockets/ac/01/
briefing/3779b2_01_cber_safety_revision2.pdf.
Accessed April 15, 2014.
36. Cohen SB. Targeting the B cell in rheumatoid
arthritis. Best Pract Res Clin Rheumatol
2010;24(4):553Y563.
37. Ezeonyeji AN, Isenberg DA. Early treatment
with rituximab in newly diagnosed systemic
lupus erythematosus patients: a
steroid-sparing regimen. Rheumatology
(Oxford) 2012;51(3):476Y481.
38. Miller AV, Ranatunga SK. Immunotherapies
in rheumatologic disorders. Med Clin
North Am 2012;96(3):475Y496.
Continuum (Minneap Minn) 2014;20(3):657–669
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
39. Nam JL, Villeneuve E, Hensor EM, et al.
Remission induction comparing infliximab
and high-dose intravenous steroid, followed
by treat-to-target: a double-blind,
randomised, controlled trial in new-onset,
treatment-naive, rheumatoid arthritis
(the IDEA study). Ann Rheum Dis 2014;73(1):
75Y85.
40. Oglesby A, Shaul AJ, Pokora T, et al. Adverse
event burden, resource use, and costs
associated with immunosuppressant
medications for the treatment of systemic
lupus erythematosus: a systematic literature
review. Int J Rheumatol 2013;2013:347520.
41. Ramos-Casals M, Brito-Zerón P. Emerging
biological therapies in primary Sjogren’s
syndrome. Rheumatology (Oxford)
2007;46(9):1389Y1396.
42. St Clair EW, Levesque MC, Prak ET, et al. Rituximab
therapy for primary Sjögren’s syndrome: an
open-label clinical trial and mechanistic analysis.
Arthritis Rheum 2013;65(4):1097Y1106.
43. Aringer M, Burkhardt H, Burmester GR, et al.
Current state of evidence on ‘off-label’
therapeutic options for systemic lupus
erythematosus, including biological
immunosuppressive agents, in Germany,
Austria and SwitzerlandVa consensus
report. Lupus 2012;21(4):386Y401.
44. Gotkine M, Vaknin-Dembinsky A. Neurologic
manifestations of systemic immunopathological
diseases. Curr Treat Options Neurol 2012;14(3):
276Y292.
45. Emery P, Sebba A, Huizinga TW. Biologic
and oral disease-modifying antirheumatic
drug monotherapy in rheumatoid arthritis.
Ann Rheum Dis 2013;72(12):1897Y1904.
46. Mavragani CP, Nezos A, Moutsopoulos HM.
New advances in the classification, pathogenesis
and treatment of Sjogren’s syndrome.
Curr Opin Rheumatol 2013;25(5):623Y629.
www.ContinuumJournal.com 669