SLE

Peripheral Neuropathy in Patients

with Systemic Lupus Erythematosus
Brandusa Florica, MD,* Ellie Aghdassi, PhD,† Jiandong Su, BSc,†
Dafna D. Gladman, MD,* Murray B. Urowitz, MD,* and
Paul R. Fortin, MD*,†

Objective: In patients with systemic lupus erythematosus (SLE), to determine 1) the prevalence
and clinical features of peripheral neuropathies (PN) and whether they were SLE related, 2)
whether there are associations between other SLE features and PN.
Methods: Patients who met the American College of Rheumatology case definition criteria for SLE
peripheral neuropsychiatric syndromes were selected from the University of Toronto Lupus Clinic
database. Demographic data and SLE-related clinical and laboratory data were extracted. Health-
related quality of life was assessed using the mental and physical component summary score of the
SF-36 questionnaire. In a nested case-control study, SLE patients with PN were matched by
disease duration and compared with those without PN.
Results: Of 1533 patients in the database, 207 (14%) had PN. Of these, 40% were non-SLE-
related. Polyneuropathy was diagnosed in 56%, mononeuritis multiplex in 9%, cranial neuropa-
thy in 13%, and mononeuropathy in 11% of patients. Asymmetric presentation was most com-
mon (59%) and distal weakness occurred in 34%. Electrophysiologic studies indicated axonal
neuropathy in 70% and signs of demyelination in 20% of patients. Compared with patients
without PN, those with PN had significantly more central nervous system involvement, higher
SLE-disease activity index 2000 and lower SF-36-PCS.
Conclusions: The prevalence of PN is relatively high in SLE and occurs more frequently in patients
with central nervous system involvement and high SLE-disease activity index. There is a predilec-
tion for asymmetric and lower extremities involvement, especially peroneal and sural nerves. This
manifestation of the disease has a significant impact on the patient’s quality of life.
© 2011 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41:203-211
Keywords: systemic lupus erythematosus, quality of life, peripheral neuropathy, neuropsychiatric lupus

T he frequency of neuropsychiatric manifestations

*Division of Rheumatology, Department of Medicine, The University Health Net-
work and University of Toronto, Toronto, Ontario, Canada.
†Division of Health Care and Outcome Research, Toronto Western Research Insti-
tute, Toronto, Ontario, Canada.
Dr. Paul R. Fortin is a Distinguished Senior Investigator of The Arthritis Society
with additional support from the Arthritis Centre of Excellence, University of To-
ronto. Ellie Aghdassi and Jiandong Su are supported by Canadian Network for
Improved Outcomes in SLE (CaNIOS), which is supported in part by Lupus Canada,
Lupus Ontario, the Lupus Foundation of Ontario, and BC Lupus as well as from the
Arthritis and Autoimmune Research Centre Foundation. The Centre for Prognostic
Studies in Rheumatic Disease-University of Toronto Lupus Clinic is supported in part
by The Smythe Foundation, Lupus Ontario, and the Dance for the Cure, the Flare for
Fashion, and the Lupus Foundation of Ontario.
Address reprint requests to Paul R. Fortin, MD, MPH, FRCP(C), Director of
Clinical Research, Arthritis Centre of Excellence, Toronto Western Hospital, Room
MP-10-304, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. E-mail:
pfortin@uhnresearch.ca
0049-0172/11/$-see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.semarthrit.2011.04.001
in patients with systemic lupus erythematosus
(NPSLE) is relatively high, ranging from 37% to
over 90% of patients according to different published
studies (1-3). These differences are likely a reflection of
selection of different patient populations or of the use of
different definitions and criteria to diagnose the nervous
system manifestations. Because of this divergence in the
nomenclature of the nervous system manifestations in sys-
temic lupus erythematosus (SLE), the American College
of Rheumatology (ACR) proposed in 1999 a set of case
definitions, reporting standards, and diagnostic testing
recommendations for 19 NPSLE syndromes that include
peripheral nervous system manifestations (4).
The central nervous system (CNS) manifestations of
SLE have received a lot of attention in the last 20 years
203
204
with many studies reporting on their prevalence, clinical
manifestations, and possible pathogenic mechanisms.
The peripheral nervous system manifestations have, on
the other hand, received little attention despite their po-
tential significant impact on the patient’s quality of life.
In the literature, studies on the peripheral nervous sys-
tem (PN) manifestations are mostly represented by case
reports or case series with a small number of patients. In
addition, the PN has not been well characterized in SLE
in terms of onset, severity, clinical associations, and elec-
trophysiological findings and there is no guideline for
their treatment. Therefore, the primary objective of our
study was to characterize PN in SLE with respect to the
patient’s clinical lupus manifestations, serologic markers,
and electrophysiological findings. A secondary objective
was to determine whether any of these characteristics are
associated with the development of PN in SLE.
POPULATION AND METHODS
Subjects
Subjects for this study were selected from the University
of Toronto Lupus Clinic database, one of the Canadian
Network for Improved Outcomes in SLE centers that has
collected clinical and laboratory data prospectively and
according to a standard protocol since 1970. All patients
fulfilled the ACR classification criteria for SLE or fulfilled
3 criteria with either skin or kidney biopsy evidence of
SLE (5,6). The University of Toronto Lupus Clinic has
continuous approval from the University Health Net-
work Research Ethics Board and informed consent was
obtained from all patients for accessing their data for re-
search studies.
For an accurate capture and description of the PN
manifestations in SLE, the database was searched for pa-
tients with distal or proximal weakness and/or sensory
loss, diagnosed polyneuropathies, mononeuritis simple or
multiplex, cranial neuropathy, plexopathy or radiculopa-
thy, and abnormal electrophysiology. A further chart re-
view was performed for the identified patients to confirm
clinical findings, determine the contributing factors, and
document the diagnostic investigations, treatments, and
outcome. Peripheral neuropathies were defined according
to the ACR nomenclature and case definitions for neuro-
psychiatric syndromes in SLE (4) found online at http:///
www.rheumatology.org/publications/ar/1999/499.
Attribution to SLE was considered when PN was pres-
ent in the absence of other more common etiologies and
when the rheumatologist and/or neurologist listed this
attribution as the etiology of the PN. The decision was
based on the clinical evaluation and subsequent investiga-
tions included in the ACR nomenclature and case defini-
tions for each of the peripheral nervous system syndromes
in SLE and after exclusion criteria were considered and
association factors documented (4). PN secondary to dia-
betes mellitus, hypothyroidism, vitamin B12 deficiency, in-
fectious causes, Sjögren’s syndrome, alcohol abuse, drug tox-
Peripheral neuropathy in SLE
icity, compression syndromes, and inherited neuropathies
were categorized as “non-SLE-related.” PN were “possibly
SLE-related” when SLE remained the more likely etiology
despite concomitant possible other etiologies that were not
deemed as causing the PN.
Lupus patients with PN were matched by gender and
SLE duration (⫾12 months) at the time of PN diagnosis
to SLE patients without evidence of PN. Attention was
given to also match according to whether patients were
from the University of Toronto Lupus Clinic inception
cohort, defined as first seen in the clinic within 12 months
of diagnosis of SLE, or from the noninception cohort.
Data Collection
Demographic, clinical, and laboratory data were captured
within 1 year of the diagnosis of the PN for cases and a
similar reference point for the controls.
The cases of PNs identified were further characterized
at the time of neurologic diagnosis in terms of age, gender,
ethnicity, time from SLE diagnosis to onset of PN, and
the period of follow-up. For patients with more than one
type of PN, the time of first event was recorded as the date
of onset of the PN. Data included features of peripheral
neurologic event: acute versus chronic, sensory and/or
motor involvement of peripheral nerves, proximal/distal
location of the neurologic symptoms, diffuse or localized
involvement, and symmetry of the findings. The periph-
eral nerves affected were specified. The electrophysiolog-
ical study results were noted when available, including the
signs of neuropathic changes, denervation, axonal neu-
ropathy, or peripheral nerve demyelination. In addition,
results of magnetic resonance imaging examination were
reviewed for signs of nerve or nerve root enhancement, as
a marker of inflammatory demyelination, and to rule out
nerve root compression. When available, nerve and rele-
vant muscle biopsy results were recorded. The final neu-
rologic diagnosis was also abstracted from the chart re-
view.
Manifestations of SLE at the time of diagnosis of PN
were recorded using 1982 ACR classification criteria (5).
Other lupus-related variables including the SLE Disease
Activity Index 2000 (SLEDAI-2K) and the Systemic Lu-
pus International Collaborating Clinics Damage Index
were also recorded within 3 months of PN onset and at
the reference point in time for patients without PN (7-9).
Serologic investigations included platelet count, anti-
cardiolipin antibodies, lupus anticoagulant, complement
levels C3 and C4, and antibodies to double-stranded
DNA at the time PN onset for the cases and at the equiv-
alent reference point for the controls.
Treatment and medications recorded included steroid,
pulse steroid, hydroxychloroquine, immunosuppressive
drugs: cyclophosphamide, azathioprine, mycophenolate
mofetil, intravenous immunoglobulins, plasma exchange,
or other relevant treatments were also recorded at the time
B. Florica et al.
of PN onset for the cases and at the equivalent reference
point for the controls.
To capture both the physician’s and the patient’s as-
sessment, 2 outcome measures of PN SLE were used. The
first measure was a physician-generated scale, for an indi-
vidual PN SLE event comparing the change in neuropa-
thy status between the onset of the event and last fol-
low-up appointment. “Improved” status was defined by
chart review as at least 50% recovery of signs and/or
symptoms, “no response” with less than 50% recovery, or
“worse” with progression of the condition.
The second measure of the outcome was a patient eval-
uation, within 3 months of PN diagnosis, of the impact of
the condition on health-related quality of life using the
Medical Outcome Study Short Form 36 (SF-36) (10). It
consists of a self-administered instrument with 36 ques-
tions that cover 8 dimensions of well-being: physical
functioning, role limitations due to physical problems,
bodily pain, vitality, general health perceptions, social
functioning, role limitations due to emotional problems,
and mental health. These 8 scales, weighted according to
normative data, are scored from 0 to 100, higher scores
reflecting better health-related quality of life (10,11).
Two psychometrically based summary measures: the
physical component summary (PCS) score and the men-
tal component summary score (12), were derived from
the SF-36 questionnaire and scores ⬍48 are considered
impaired. Age- and gender-standardized scores were cal-
culated using Canadian normative values (13).
Statistical Analysis
Data were analyzed using SAS statistical program version
9.1 (SAS Institute Inc., Cary, NC). Descriptive statistics
including percentages, mean ⫾ SD, or median and inter-
quartile range were used. Comparisons between demo-
graphic and clinical characteristics of patients with SLE
(SLE-related and possibly SLE-related) and non-SLE
causes of PN were done using unpaired Student’s t test or
␹2 test.
In the case-control study, the statistical significance of
the differences in demographics, clinical presentation,
laboratory markers, treatment use, and outcome was as-
sessed using conditional logistic regression test.
RESULTS
Patients’ Characteristics
A total of 1533 patients with SLE were included in the
database registry of the University of Toronto Lupus
Clinic, between January 1970 and May 2010. After the
electronic search of the database, 215 patients were se-
lected for chart review and among those 207 (13.5%)
patients were confirmed to have at least 1 peripheral neu-
rologic condition as defined by the ACR nomenclature
and case definition of these manifestations. Eight patients
were excluded due to incomplete data. Among patients,
205
103 were part of the inception cohort and thus were en-
rolled within the first year of their diagnosis of SLE. The
207 patients with PN were 85% women, with a mean
(SD) age of 44.5 (15.1) years and a mean (SD) disease
duration of 8.3 (9.2) years at the time of diagnosis of PN.
Peripheral Nervous System Manifestations
A total of 207 (13.5%) patients experienced at least one
peripheral nervous system manifestation included in the
ACR nomenclature and case definitions of neuropsychi-
atric events in SLE. The mean (SD) follow-up period,
after PN diagnosis, was 10.7 (9.6) years. The most com-
mon PN observed was peripheral polyneuropathy, with a
predominance of the sensory form, present in 76 (36.7%)
patients and the sensory-motor variant in 39 (18.8%)
patients. The majority of patients with polyneuropathy
experienced chronic peripheral polyneuropathy (40% of
207 patients) lasting more than 2 months (14). Twenty-
three (11.1%) patients had a peripheral mononeuropathy
and 26 (12.5%) had a cranial neuropathy. Nineteen
(9.2%) patients suffered from mononeuritis multiplex
and only 11 (5.3%) were diagnosed with chronic inflam-
matory demyelinating polyradiculoneuropathy (CIDP).
Two patients had findings consistent with acute inflam-
matory demyelinating polyradiculoneuropathy (AIDP),
1 was SLE-related and the other was non-SLE-related.
Seven patients were diagnosed with radiculopathy and 2
with plexopathy, but the events were not considered SLE-
related. We did not observe cases of the remaining periph-
eral nervous system manifestations included in ACR no-
menclature and case definition: there was no documented
autonomic neuropathy or myasthenia gravis among our
patients.
An asymmetric presentation of the peripheral neuro-
logic manifestation was most commonly seen (59.3%).
Distal weakness, at the onset, occurred in 34.2% of the
patients. In the lower extremities, the most commonly
involved nerves were the sural nerve (55.2%) and the
peroneal nerve (53.9%). Upper extremity neurologic in-
volvements covered most frequently the median nerve
(37.3%) and the ulnar nerve (30.4%). The cranial nerves
III, V, VI, and VII were affected occasionally. One patient
could have experienced more than 1 peripheral nerve in-
volvement at the same time.
From the total number of SLE patients with peripheral
nervous system manifestations, 125 (60.3%) patients ex-
perienced PN attributed to SLE (76 patients with SLE-
related PN and 49 with possible SLE-related PN) and 82
(39.6%) patients had non-SLE-related PN. The most fre-
quent etiologies of non-SLE-related PN were compressive
neuropathy (nerve or root compression) in 35 (42.6%),
followed by medication toxicity in 23 (28%), and hypo-
thyroidism in 19 (23.1%). Only 14 (17%) patients had
peripheral neurologic manifestations attributed to con-
comitant diabetes mellitus. Other causes of non-SLE-re-
lated PN included ethanol abuse, paraproteinemia,
206 Peripheral neuropathy in SLE

Table 1 Characteristics of Patients with SLE-Related and Non-SLE-Related Peripheral Neuropathy

SLE-Related PN Non-SLE-Related PN
(n ⫽ 125) (n ⫽ 82) P Value
Age (yr) 35.2 ⫾ 14.4 38.6 ⫾ 15.4 0.12
SLE duration (yr) 6.4 ⫾ 8.0 9.8 ⫾ 10.2 0.01
Arthritis [n (%)] 42 (35) 18 (24) 0.09
Skin rash [n (%)] 4 (7) 2 (7) 1.00
Central nervous system involvement [n (%)] 18 (15) 10 (13) 0.69
Renal [n (%)] 47 (39) 33 (43) 0.61
ANA ⱖ80 [n (%)]* 61 (52) 34 (44) 0.30
Ds-DNA-positive (by Farr) [n (%)] 45 (44) 15 (29) 0.69
Positive antiphospholipid antibody [n (%)] 26 (22) 17 (22) 0.95
SLE-disease activity index [median (IQR)] 11.0 (4.0, 16.0) 5.0 (2.0, 8.0) ⬍0.0001
SLICC damage index [median (IQR)] 1.0 (0.0, 2.0) 1.0 (0.0, 2.0) 0.39
Electromyography/nerve conduction Study 75 (89) 34 (81) 0.20
positive findings [n (%)]
Pure sensory polyneuropathy [n (%)] 31 (25) 30 (37) 0.07
Sensory-motor polyneuropathy [n (%)] 25 (20) 10 (12) 0.15
Mononeuritis Multiplex [n (%)] 19 (15) 0 (0) 0.0002
Steroid treatment [n (%)] 102 (90) 41 (79) 0.04
Immunosuppressive treatment [n (%)] 48 (47) 15 (35) 0.19
Cyclophosphamide [n (%)] 9 (7) 1 (1) 0.049
Outcome-improved [n (%)] 82 (66) 45 (55) 0.12
SF-36 physical component summary score 35.4 ⫾ 11.5 34.0 ⫾ 11.0 0.54
SF-36 mental component summary score 46.1 ⫾ 11.2 41.9 ⫾ 13.0 0.08
Results are reported as mean ⫾ SD unless otherwise specified. Comparison between the 2 groups was done using logistic regression analysis
and P ⬍ 0.05 is considered statistically significant difference.
PN, peripheral neuropathy; SLE, systemic lupus erythematosus.
*ANA was available in 118/125 patients and 77/82 patients in each group within 3 months of PN diagnosis. However, dsDNA (Farr) was
available in 102/125 patients and 52/82 patients, respectively. Overall, if we report on ANA positivity since the diagnosis of SLE, we have
101/125 and 72/82 patients in each group.

Sjögren’s syndrome, uremia, and viral hepatitis in a lim-
ited number of patients.
Demographic and clinical characteristics of patients
with SLE- and non-SLE-related PN are reported in Table
1. Patients with SLE-related PN had significantly shorter
SLE duration and tended to be younger compared with
those with non-SLE-related PN. The ACR classification
criteria were equally found in both groups of patients
except for a trend toward a higher prevalence of arthritis at
the time of neurologic diagnosis in patients with SLE-
related PN than those with non-SLE-related PN. Serolog-
ical markers and the presence of antiphospholipid anti-
bodies were similar between the 2 groups. However,
patients with SLE-related PN had a significantly higher
median SLEDAI-2K (11.00, Interquartile range: 4.0-
16.0) than those with non-SLE-related PN (5.0, Inter-
quartile range: 2.0-8.0; P ⬍0.001). When comparing
only definitely SLE-related PN with non-SLE-related
PN, the results were similar (data not shown).
The presentations with polyneuropathy, either pure
sensory or the sensory motor variant, were similarly dis-
tributed in both SLE-related and non-SLE-related PN.
Mononeuritis multiplex, however, was always SLE-re-
lated in our patients after excluding other possible etiolo-
gies. Mononeuritis multiplex could occur at any time, at
the onset of SLE or later during its evolution. Assessment
of the health-related quality of life showed a similar PCS
in both SLE and non-SLE-related PN groups (Table 1).
The electrophysiological investigations that were part
of PN workup were more often performed in patients
with SLE-related PN and possibly SLE-related PN, than
in those with non-SLE-related causes (87% versus 65% of
patients). Electrophysiological studies were conducted
when there were clinical signs of weakness, but 23 of 61
patients with pure sensory deficit on clinical examination
did not undergo further electrophysiological testing and
the diagnosis was made on clinical grounds alone. The
main findings on nerve conduction studies were signs of
axonal neuropathy in the majority (78%) of the patients,
with no statistical differences among the SLE-related,
possibly SLE-related, and non SLE-related groups:
37(74%) versus 23 (82%) versus 24 (69%) of patients,
respectively (Table 2). Only a small number of patients
(n ⫽ 10) underwent nerve biopsy to confirm the diagno-
sis: all patients had perineural inflammatory infiltrate, two
biopsies showed axonal degeneration, and one biopsy in-
dicated demyelination.
As expected, the treatment with steroids or pulse ste-
roids was used significantly more often for patients with
SLE-related PN than those with non-SLE-related PN.
There was no difference between the two groups with
respect to the use of immunosuppressive medications and
B. Florica et al. 207

Table 2 Electromyography/Nerve Conduction Study Findings of Patients with SLE-Related Peripheral Neuropathy, Possible
SLE-Related Peripheral Neuropathy, and Non-SLE-Related Peripheral Neuropathy
SLE-Related PN Possible SLE-Related PN Non SLE-Related PN
(n ⫽ 54) (n ⫽ 30) (n ⫽ 42) P Value
Axonal neuropathy, N (%) 37 (74) 23 (82) 24 (69) 0.470
Demyelinating neuropathy, N (%) 12 (24) 8 (29) 8 (23) 0.860
Mixed axonal and demyelinating 5 (9) 6 (20) 4 (10) 0.292
neuropathy, N (%)
The results in Table 2 are reported as the number and percentage of patients with SLE-related, possible SLE-related and non-SLE related PN
who underwent EMG/NCS (n ⫽ 54, 30, and 42, respectively). This EMG/NCS was diagnostic in 49 (91%), 26 (87%), and 34 (81%) of
patients in each group, respectively.
PN, peripheral neuropathy; SLE, systemic lupus erythematosus. There was no statistical difference between the groups of patients.

cyclophosphamide (Table 3). According to the physi-
cian’s assessment, the PN improved in 65.8% of patients
with SLE-related PN and 54.9% of patients with non-
SLE-related PN, and this was not significantly different
between the two groups.
Case-Control Study
In our case-control study, we were able to match (by
gender and SLE duration) 197 of the SLE patients with
PN to 197 control SLE patients without PN. The mean
SLE duration at the time of PN diagnosis was 8.7 years
and the number of ACR criteria for SLE classification was
similar in both groups (Table 4). In both groups most
patients were female (86.3%) and the majority were Cau-
casian. The age at SLE diagnosis was significantly higher
in patients with PN and they were more likely to have
CNS involvement (14.2%) compared with patients with-
out PN (CNS involvement: 6.6%, P ⫽ 0.02). Both
groups had moderate global disease activity and minimal
cumulative organ damage, according to the median SLE-
DAI 2K and Systemic Lupus International Collaborating
Clinics Damage Index scores. However, the SLEDAI
score within three months of diagnosis of PN was both
statistically and clinically significantly higher in patients
with PN with a median score of 8.0 versus a score of 6.0
for the patients without PN (P ⫽ 0.007) with an average
difference of two SLEDAI 2K units. A subanalysis of SLE-
DAI 2K scores without CNS component indicated no
statistical significant difference between the two groups,
but there was a trend toward a higher disease activity in
patients with PN 6.0 (4.0,10.0) compared with those
without PN 4.0 (2.0,8.0), P ⫽ 0.11, with a difference of
two SLEDAI 2K units.
There was no significant difference in lupus serology
such as antinuclear antibody, anti-double-stranded DNA
antibody, and antibodies to the extractable nuclear anti-
gens (anti-Smith, RNP, Ro/SSA, and La/SSB) or comple-
ment levels between the two groups. However, specific
nervous system antibodies such as anti-ribosomal P,
NMDA R2, and anti-neural antibodies are not routinely
assessed in our clinic. Cases with PN were more likely to
receive treatment with steroids (74%) than the controls
(59.4%; P ⫽ 0.003) and tended to be more frequently on
immunosuppressive treatment. The health-related qual-
ity of life measured using age- and gender-standardized
PCS and mental component summary scores revealed a
statistically and clinically significantly lower PCS score for
patients with PN compared with patients with no PN
(Table 4).
A subgroup analysis, including only the definitely SLE-
related PN and their controls (74 pairs), gave similar re-
sults in terms of significantly higher SLEDAI 2K, more
frequent CNS involvement, more frequent steroid use,
and lower PCS score for the cases. The only difference was
a statistically significant higher SLEDAI 2K even without
the CNS items for the cases (data not shown).
DISCUSSION
Peripheral nervous system involvement in SLE patients is
a clinical entity associated with significant morbidity and
poor health-related quality of life. Treating physicians are
uncomfortable with the diagnosis and management of

Table 3 Management and Outcome of Peripheral Neuropathy in SLE Patients

SLE-Related PN Possible SLE-Related PN Non-SLE-Related PN
(n ⫽ 76) (n ⫽ 49) (n ⫽ 82) P Value
Steroid treatment, N (%) 67 (96) 35 (81) 41 (79) 0.013
Pulse steroid, N (%) 14 (20) 1 (3) 2 (4) 0.01
Cyclophosphamide, N (%) 8 (10.5) 1 (2.0) 1 (1.2) 0.014
Outcome—improved, N (%) 50 (66) 32 (65) 45 (55) 0.30
Results are reported as number of patients (%).
PN, peripheral neuropathy; SLE, systemic lupus erythematosus.
208 Peripheral neuropathy in SLE

Table 4 Demographic and Clinical Characteristics of Patients with SLE with or without Peripheral Neurologic
Manifestations
Patients with PN Patients without PN
Characteristics (n ⫽ 197)* (n ⫽ 197) P Value
Race [n (%)]
Caucasian 159 (81) 156 (80) 0.68
Black 17 (9) 11 (6)
Chinese 13 (7) 14 (7)
Other 27 (4) 15 (8)
Age at SLE diagnosis (yr) 36.5 ⫾ 14.9 31.7 ⫾ 14.1 0.0004
Female [n (%)] 170 (86) 170 (86) 1.00
SLE duration (yr) 8.7 ⫾ 8.9 8.5 ⫾ 8.8 0.56
ACR criteria 5.5 ⫾ 2.0 5.5 ⫾ 1.9 0.84
Arthritis [n (%)] 60 (31) 45 (23) 0.12
Skin rash [n (%)] 6 (7) 11 (12) 0.48
Central nervous system involvement [n (%)] 28 (14) 13 (7) 0.02
Renal disease [n (%)] 80 (41) 90 (46) 0.30
SLE-disease activity index [median (IQR)] 8.0 (4.0, 14.0) 6.0 (2.0, 9.0) 0.01
SLICC damage index [median (IQR)] 1.0 (0.0, 2.0) 0.0 (0.0, 1.0) 0.18
Positive ds-DNA (Farr) [n (%)] 60 (39) 62 (38) 0.89
low C3 [n (%)] 38 (20) 39 (21) 0.68
low C4 [n (%)] 37 (23) 39 (22) 0.89
Antiphospholipid antibody [n (%)] 43 (22) 40 (20) 0.62
Platelet count ⬍150 [n (%)] 25 (13) 19 (10) 0.34
Steroid treatment [n (%)] 145 (74) 117 (59) 0.002
Immunosuppressive treatment [n (%)] 53 (27) 39 (20) 0.09
SF-36 physical component summary score 35.0 ⫾ 11.3 38.3 ⫾ 11.2 0.04
SF-36 mental component summary score 44.7 ⫾ 11.9 46.8 ⫾ 12.6 0.88
Results are reported as mean ⫾ SD unless otherwise specified. P ⬍ 0.05 is considered statistically significant difference.
PN, peripheral neuropathy; SLE, systemic lupus erythematosus; ACR, American College of Rheumatology.
*Only 197 of 207 patients with PN described in text were matched to control patients without PN.

these manifestations since few studies have reported on
the peripheral nervous system complications of lupus.
Physicians are too often left with limited data from a few
case reports, case series, or small studies to rely on when
treating persons with lupus who have peripheral neurop-
athy and this may delay their diagnosis and treatment.
This study is the first to investigate peripheral nervous
system manifestations in a large cohort of SLE patients.
While other studies have presented the prevalence of pe-
ripheral neuropathy in SLE as part of NP SLE, our study
focused on PN prevalence, its characteristics, and its var-
ious clinical manifestations.
In our cohort, 13.5% of SLE patients had at least one
PN event. This was a lower prevalence than the 32%
reported by Brey and coworkers (2) in 128 SLE patients,
with mean disease duration of 8 years. Most other studies
on the prevalence of NPSLE included only a few features
of peripheral nervous system involvement. In an interna-
tional multicenter study by Hanly and coworkers (15),
158 (28%) of 572 patients had NP SLE and only 6.1 to
11.7% of patients had NP events that were SLE related.
In that study (15), from a total of 242 NP events, 9.5%
were presented as peripheral nervous system involvement,
which is consistent with our findings. In 2 subsequent
studies (16,17) with a larger sample size and in patients
with up to 3 years’ disease duration, 33.5% and 40.3%
experienced at least one NP event of which 23.6% was
attributed to SLE and only 7% involved peripheral ner-
vous system, lower than what we observed in our study.
This may partly be explained by the shorter SLE duration
of up to three years in these studies as opposed to 10.7
years in our study. Furthermore, in those studies (15-17),
the peripheral neuropathies that did not undergo electro-
physiological confirmation study were excluded, which
may also underestimate the prevalence of PN. Yet, in
other studies (18,29), when electrophysiological studies
were performed, the prevalence of PN in SLE was docu-
mented as being as high as 21% with more symptoms
versus 6% in healthy controls. In another study, McNich-
oll and coworkers (19) reported nerve conduction abnor-
malities in 33% of SLE patients at baseline and in 56% of
patients at 2-years’ follow-up. Both of these studies had
relatively small sample sizes, which makes them suscepti-
ble to selection and ascertainment biases.
The limitations of our study include the retrospective
review of the characteristics of the peripheral neuropathy,
with the possibility of missing important information for
the accurate diagnosis of PN. However, all the data used
were recorded prospectively, in a predefined format and
the attribution to SLE or non-SLE was established
through an additional detailed chart review. Another lim-
itation is the fact that almost one half of the patients used
B. Florica et al.
in our analysis were not part of the inception cohort and
not seen from the onset of SLE. So, part of their disease
history may be missing, including the PN initial events.
We tried to account for this limitation by performing a
case-control subanalysis and by matching patients from
each category for the analysis of patients with or without
PN. A subgroup analysis of these patients gave similar
final results in terms of clinical characteristics. Finally,
there was a possibility that the associated features in those
patients with PN definitively due to SLE compared with
those due to other causes might have been unduly influ-
enced by instances of PN designated as possibly due to
PN. However, a subgroup analysis, including only the
definitely SLE-related PN and their controls, gave similar
results. Despite these limitations, to our knowledge, this
study is the only large study solely focused on the descrip-
tion of peripheral neuropathy in SLE.
An important contribution of our study was to charac-
terize patients with different manifestation of PN. In
keeping with previous data (20), the most common clin-
ical presentation of PN was a distal axonal sensory or
sensory-motor polyneuropathy with acute or subacute
onset. Most patients presented with late and relatively
mild decreased sensation that initially involved the lower
extremities. In our cohort of patients, an asymmetrical
involvement of the extremities was the most frequent pre-
sentation and this is also consistent with previous reports.
Sural, peroneal, and median nerves were the most fre-
quently involved.
Mononeuropathies, single or multiplex, were the sec-
ond most common presentation. In most cases, the onset
was dramatic with sudden weakness in different nerve
territories. Martinez-Taboada and coworkers (21) de-
scribed 2 SLE patients with severe mononeuritic multi-
plex secondary to necrotizing vasculitis of small- and me-
dium-size vessels. One patient presented with neurologic
involvement at the onset of the disease and the other later
in the course of the disease after discontinuation of steroid
and chloroquine treatment. Matsuki and coworkers (22)
reported a 61-year-old patient with weakness of the lower
extremities concomitant to onset of SLE, and diagnosed
with mononeuritis multiplex.
CIDP was another severe form of PN present in our
study. The clinical impairment was even more severe with
inability to walk due to proximal weakness. Vina and
coworkers (23) reviewed a total of 13 patients with CIDP
reported in the literature from 1950 to 2004. A majority
(9/13) presented with their CIDP before or at the onset of
SLE; 10 of 13 had weakness in both upper and lower
extremities and also had dermatological and arthritic
manifestations of SLE. Hantson and coworkers (24) re-
ported a severe form of CIDP, presenting with a Guillain-
Barré syndrome-like picture, in one patient who devel-
oped rapidly progressive quadriplegia and acute
respiratory failure. AIDP, an ascending motor radiculo-
neuropathy that resembles Guillain-Barré syndrome, was
a relatively rare condition in our cohort, observed in only
209
two patients. AIDP in SLE is only presented in the liter-
ature as case reports (24-26).
A major challenge to clinicians is whether one can at-
tribute these neurologic events to SLE or not. With the
exception of the association between antiphospholipid
antibodies and cerebrovascular events, most of NPSLE
manifestations do not have specific immunopathogenic
etiologies or mechanisms and alternative etiologies should
be considered and ruled out before attributing them to
SLE. The ACR nomenclature and case definition of
NPSLE is helpful in this direction (4). Hanly and cowork-
ers (15-17) in an international multicenter inception co-
hort of SLE patients classified all PNs as not attributable
to SLE if there was no electrophysiologic confirmation.
However, ACR recommends that the diagnosis should be
based on clinical findings and/or electrophysiological test-
ing. This may explain why their reported prevalence of
PN was lower than the prevalence in our study and may be
underestimated. However, the process of attribution of
neurologic events to SLE or not is not always an easy,
clear-cut process. For example, compression or entrap-
ment neuropathies, frequent causes of PN, may be the
result of local inflammation involving the adjacent joint
structures and, although not the direct result of autoim-
mune process, they could still be considered attributable
to SLE. PN could also present as complications of other
organ involvement in SLE (renal failure, liver failure),
nutritional deficiency, or even as side effects of different
drugs (steroid-induced diabetes, antimalarial drugs, aza-
thioprine).
A close analysis of patients with SLE-related versus
non-SLE-related PNs indicated shorter disease duration
at the time of neurologic diagnosis in patients with SLE-
related PN. As expected, mononeuritic multiplex was
more likely to be SLE-related and patients with SLE-
related PN were more likely to have active disease at the
time of diagnosis of the PN, but there was no difference
between the two groups with respect to SLE immune
markers, platelets count, or presence of antiphospholipid
antibodies. This was consistent with the findings of Hanly
and coworkers (27). Psychosis was the only manifestation
associated with antiribosomal P antibody and ischemic
cerebrovascular disease was associated with the presence
of lupus anticoagulant (27).
In our patients, there were also no significant differ-
ences between electrophysiological findings in the pre-
specified groups of patients, demonstrating the difficulty
of differentiating the attribution to SLE or other causes
based on nerve conduction studies. The most frequent
findings were signs of axonal neuropathy. The same ax-
onal neuropathies signs were reported as the most fre-
quent occurrence by Brey and coworkers (2) and Huynh
and coworkers (28).
Although peripheral neuropathy in SLE may be very
disabling, affecting the quality of life of relatively young
people, there are no large randomized controlled trials to
evaluate this potentially treatable condition. In this study,
210
PN resulted in impaired quality of life especially in the
physical component, regardless of the attribution to SLE
or non-SLE. A previous study, reporting the NPSLE over-
all, found a better outcome for the events attributed to
SLE (16). However, the mean study follow-up period of
these patients was relatively short (21 months). In terms
of treatment, Barile-Fabris and coworkers (29) random-
ized 32 patients with NPSLE to receive oral prednisone
and methylprednisolone IV or oral prednisone and cyclo-
phosphamide IV. The response rate for all NPSLE man-
ifestations was significantly higher in the cyclophosph-
amide group. Only 7 of these patients presented with
peripheral nerves involvement and the response was better
in this very small group, for patients who received cyclo-
phosphamide. The treatment of vasculitic peripheral neu-
ropathies, severe neurologic manifestations of primary
vasculitis, and connective tissue diseases was analyzed in a
retrospective study by Mathew and coworkers (30). From
106 cases, 94 used a corticosteroid-based treatment and
54 patients received cyclophosphamide. One-year sur-
vival was 90.3% and 72% of the patients had a good
outcome with subsequent improvement of their periph-
eral neuropathy. Ten percent of the patients relapsed with
their PN within 1 year, but only 1 of them had been on
cyclophosphamide treatment.
In our case-control study comparing patients with and
without PN, patients with PN were older at the time of
SLE diagnosis, had more frequent CNS involvement, had
higher disease activity score, and were more likely to be
treated with steroids and immunosuppressive medica-
tions. The age difference at diagnosis may have contrib-
uted to accumulation of comorbid conditions and the
development of PN. In addition, SLE patients are at
greater risk of developing diabetes, renal abnormalities,
and malabsorption leading to nutritional deficiencies that
could all contribute to the development of PN. A more
frequent CNS involvement and a higher disease activity
in patients with PN suggest an autoimmune etiology for
the PN manifestations in SLE with a predilection of the
immune response toward neurological tissue. It remains
to be determined whether any of these clinical character-
istics could predict the onset of PN in SLE.
CONCLUSION
Although the ACR criteria for classification of SLE do not
include PN, they are recognized as manifestations of the
disease and included in ACR case definitions for neuro-
psychiatric syndromes in SLE. In our cohort of SLE pa-
tients, PN was a prevalent condition in 13.5% of our
patients and was most often seen in those with an older
age at SLE diagnosis and with CNS manifestation and an
active disease at the time of the diagnosis of the PN.
Regardless of the attribution to SLE or non-SLE-related
factors, the patients with peripheral neuropathies have an
impaired quality of life reflected mainly by a significantly
low physical component score of the SF-36 health-related
Peripheral neuropathy in SLE
quality-of-life questionnaire. Large randomized controlled
trials are needed to determine which treatments should be
used to treat peripheral neuropathic manifestations in SLE
and to improve the quality of life and long-term outcome of
these patients.
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