First Impact Factor released in June 2010

and now listed in MEDLINE!

Early Intervention in Psychiatry 2012; ••: ••–•• doi:10.1111/j.1751-7893.2011.00339.x

Brief Report
Antinuclear antibodies testing as a routine
screening for systemic lupus erythematosus in
patients presenting first-episode psychosis eip_339 1..4

Célia Mantovani,1 Paulo Louzada-Junior,2 Emerson Arcoverde Nunes,1 Felipe Pinheiro de Figueiredo,1
Glício Rebouças Oliveira1 and Cristina Marta Del-Ben1

Abstract subsequently evaluated for autoanti-

1
Department of Neurosciences and
Behaviour, Division of Psychiatry and
2
Department of Internal Medicine,
Division of Rheumatology, Faculty of
Medicine of Ribeirão Preto, University of
São Paulo, Ribeirão Preto, São Paulo,
Brazil
Corresponding author: Dr Paulo
Louzada-Junior, Divisão de Imunologia
Clínica; Departamento de Clínica Médica,
Faculdade de Medicina de Ribeirão Preto
– Universidade de São Paulo, Avenida
Bandeirantes, 3900, 14049-900 Ribeirão
Preto, São Paulo, Brazil. Email:
plouzada@fmrp.usp.br
Aims: This report discusses the use of
antinuclear antibody (ANA) detection
as a screening test for neuropsychia-
try systemic lupus erythematosus
(NPSLE) in patients presenting a first-
episode psychosis.
Methods: We reviewed the medical
records of 85 patients admitted to an
emergency service due to first-
episode psychosis, during a 1-year
period, for whom ANA detection was
performed through an IFI HEp2 cell
assay. ANA-positive patients were
bodies and neuroimaging exams.
Results: Three patients presented as
ANA positive in the initial screening
and further investigation confirmed
NPSLE in two patients. The patients
were treated with antipsychotics and
cyclophosphamide pulses with satis-
factory outcomes.
Conclusion: Even though ANA detec-
tion is not specific, it is a low-cost pro-
cedure and could be an important
screening test for NPSLE in the early-
onset psychosis.

Received 31 July 2011; accepted 3 Key words: antinuclear antibodies, differential diagnosis, early onset
October 2011 psychosis, first-episode psychosis, systemic lupus erythematosus.

INTRODUCTION Laboratory and diagnostic testing traditionally

Systemic lupus erythematosus (SLE) is a prototypic
autoimmune disease characterized by the produc-
tion of antibodies to components of the cell
nucleus, in association with a diverse array of clini-
cal manifestations. In general, SLE affects 1 in 2000
individuals, although the prevalence varies accord-
ing to race, ethnicity and socio-economic status.1
It has been recognized that between 30% and 70%
of patients with SLE present central nervous
system involvement featuring neuropsychiatry SLE
(NPSLE).2 Although psychosis is a relatively rare
condition in SLE patients, it may occur as an index
manifestation of SLE, without any active lesions in
other organic systems.3 The occurrence of psychotic
symptoms at the onset of the disease has been
described in 3.6% of cases of SLE patients,4 and psy-
chosis seems to occur most often in early phases of
the disease.3
have not had a central role in the diagnosis and treat-
ment of patients with psychiatric disorders, even in a
first-episode psychosis (FEP). Most cases of FEP are
evaluated in emergency psychiatric units,5,6 and few
services perform subsidiary exams to exclude
general medical conditions as a cause of the psycho-
sis. This contrasts with other specialties of modern
medicine, which have come to rely heavily on labo-
ratory and imaging modalities to provide the infor-
mation necessary to diagnose and treat patients.
Several general medical conditions have been
associated with psychotic manifestations and,
although it is rare, NPSLE should be actively inves-
tigated as a cause of the psychosis, particularly in
patients with early onset of the symptoms. This
report discusses the insertion of a screening for
NPSLE in a clinical protocol for the differential diag-
nosis of patients with an early onset of psychosis, in
a psychiatric emergency setting.

© 2012 Blackwell Publishing Asia Pty Ltd 1

Antinuclear antibody and early psychosis
METHODS
Because several general medical conditions can be
associated with psychotic manifestations, our psy-
chiatric emergency unit has a clinical protocol for
the differential diagnosis of an FEP,7 including
detailed clinical history, physical examination,
blood tests (counting blood cells; serum glucose;
electrolytes; evaluation of renal, liver and thyroid
functions; and serology for HIV and syphilis) and
neuroimaging. In the case of abnormalities in this
screening assessment, clinical investigations are
continued jointly with other medical specialties,
according to the diagnostic hypothesis. We estab-
lished this routine because our unit is the only ref-
erence to psychiatric emergencies of a catchment
area (of 1.3 million inhabitants) that receive a wide
variety of patients in acute psychotic episodes.
Moreover, our unit is inserted in a general emer-
gency hospital, which also facilitates the contact
with other medical specialties.
In view of the data3,4 about the occurrence of psy-
chotic symptoms as an index manifestation of SLE,
antinuclear antibodies (ANAs) detection became
part of the screening assessment of patients admit-
ted to the psychiatric emergency unit due to a FEP.
In an attempt to verify the feasibility of this routine,
we reviewed the medical records of all patients
admitted because of a FEP in a 1-year period. The
presence of ANA was evaluated through an indirect
immunofluorescent assay using HEp2 cells as the
standardized substrate. The patients who presented
positive ANA were assessed by the rheumatology
team and had subsequent clinical and laboratorial
investigation, including searching for specific SLE
autoantibodies and neuroimaging exams.
RESULTS
Eighty-five patients of both sexes (54 males) fulfilled
the diagnostic criteria of a first episode of a psy-
chotic disorder or a mood episode with psychotic
features, according to DSM-IV criteria.8 Three of
them (two males and one female) presented with
positive results for ANA in the initial assessment.
After clinical and laboratorial investigation, two
patients fulfilled at least four of the 1997 ACR revised
criteria for the classification of SLE9,10 and met the
criteria for psychosis described in the 1999 ACR
nomenclature and case definitions for NP lupus
syndromes.11 In the third patient, complementary
tests have not confirmed the positive ANA found in
the screening assessment, which was considered as
a false positive result. In Table 1 we summarized the
2 © 2012 Blackwell Publishing Asia Pty Ltd
clinical and laboratorial findings on the patients
with the diagnosis of NPSLE confirmed. Both
patients gave written informed consent for the pub-
lication of data.
DISCUSSION
In a case series of 85 patients admitted to an emer-
gency psychiatric unit due to a FEP, we confirmed
the diagnosis of NPSLE in two cases. Both patients
were in the very early onset of psychosis (less than
15 days), had no clinical features or complaints in
the initial anamnesis suggestive of rheumatologic
disease, and presented only psychiatric symptoms
as the first SLE manifestation. Instead, the investi-
gation of autoimmune disorders was performed
because of a positive screening test (ANA).
In the further investigation, both patients were
shown to have positive anti-P-ribosomal and anti-
cardiolipin (aCL) antibodies. Various autoantibod-
ies have been implicated in the pathogenesis of
NPSLE, including aCLs and anti-P-ribosomal anti-
bodies.12 Because of their prothrombotic tendency,
aCLs may cause cerebral infarctions and are thus
correlated with focal neurological syndromes.
Although associations with non-focal neuropsychi-
atric manifestations have been reported, the role of
aCLs in the pathogenesis of neuropsychiatric symp-
toms in patients without cerebral infarcts is less
clear. On the other hand, anti-P-ribosomal antibod-
ies were shown to occur in association with SLE
neuropsychiatric manifestations, mainly psychosis
and depression.13
The pathogenic role of anti-P antibodies has
attracted considerable attention, giving rise to long-
term controversies as evidence has either contra-
dicted or confirmed their clinical association with
lupus psychosis. It has been shown that anti-P anti-
bodies recognize a new integral membrane protein
of the neuronal cell surface.14 In the brain, this neu-
ronal surface P antigen is preferentially distributed
in areas involved in memory, cognition and
emotion. When added to brain cellular cultures,
anti-P antibodies caused a rapid and sustained
increase in calcium influx in neurons, resulting in
apoptotic cell death. Injection of anti-P antibodies
into the brain of living rats also triggered neuronal
death by apoptosis. These results demonstrated a
neuropathogenic potential of anti-P antibodies that
can contribute as a mechanistic basis for psychiatric
lupus.14
In psychiatric settings, the current understanding
about the association of psychiatric manifestation
and NPSLE is largely based on case reports, with the
 C. Mantovani et al.

TABLE 1. Demographic and clinical characteristics of patients with the diagnosis of NPSLE

Characteristic Case 1 Case 2

Sex Female Male

Age (years) 41 48
Psychiatric symptoms Olfactory and auditory hallucinations, Violent and agitated behaviour, auditory
paranoid delusions and hostility hallucinations and paranoid delusions
Duration of psychiatric 10 14
symptoms (days)
Leukocytes (cel/mm3) 3 000 5 100
Lymphocytes (cel/mm3) 900 1 600
Platelets (cel/mm3) 150 000 55 000
Antinuclear antibody pattern Fine speckled cytoplasmatic staining pattern, Speckled nuclear staining pattern, 1:800, and
1:320 fine speckled cytoplasmatic staining
pattern, 1:320
Autoantibodies
Anticardiolipin Positive Positive
LA Negative Positive
Anti-P-Ribossomal Positive Positive
Anti-dsDNA Negative Negative
Anti-Sm Negative Negative
Anti-RNP Negative Negative
Anti-Ro Negative Negative
Antinucleosome Negative Negative
MRI Periarteriolar alterations in the white matter Infarctions in region of the distal arterioles of
in the right corona radiata cerebral media arteria
SPECT Perfusional increase in the right frontal and Moderate perfusion deficit in region of
temporal lobes cerebral media arteria
Positive ACR criteria for the Leucopoenia, lymphopenia, psychosis, Thrombocytopenia, psychosis, positive ANA,
classification of SLE positive ANA and positive anticardiolipin positive lupus anticoagulant and positive
antibody anticardiolipin antibody
Treatment Risperidone, 1 mg P.O., daily; Haloperidol, 5 mg P.O., daily;
Monthly intravenous cyclophosphamide Monthly intravenous cyclophosphamide
(1 000 mg) for 12 months (1 000 mg) for 12 months
Outcome after twelve months Antipsychotic medication was discontinued Antipsychotic medication was discontinued
of psychiatric admission and the patient had good recovery without and the patient had normalised platelet
further episodes of psychiatric counts and good recovery without further
manifestations episodes of psychiatric manifestations

ACR, American College of Rheumatology; ANA, antinuclear antibody; Anti-dsDNA, anti-double strand DNA antibody; anti-RNP, anti-ribonucleoprotein;
anti-Sm, anti-Smith; LA, lupus anticoagulant; MRI, magnetic resonance imaging; NPSLE, neuropsychiatry systemic lupus erythematosus; SPECT, single
photon computerised tomography.

diagnosis of NPSLE being made after a long period
of time15 or preceded by clinical abnormalities sug-
gestive of a general medical condition.16,17 To the
best of our knowledge, this is the first report of a
routine clinical investigation actively looking for the
occurrence of NPSLE in FEP, which was found in
2.4% of the sample studied. These data can have
important implications for clinical practice,
because a misdiagnosis in this kind of situation can
have a significantly deleterious effect on the prog-
nosis and diagnosis of the disease. However, a
screening test included in the routine assessment of
patients with FEP allowed for targeting of the differ-
ential diagnosis process and avoided the risk of mis-
diagnosing a treatable medical condition. Early
diagnosis is very important in NPSLE because early
immunosuppressive therapy is associated with a
better prognosis,18 and a relatively low cost screen-
ing test (around US$10) can prevent the financial
and social costs of mistakes in the diagnosis and the
consequent use of improper treatments.
The economic burden of SLE is massive, with a
mean annual direct costs ranging from $13 735 to
$20 926.19 In addition, the mean productivity cost to
individuals in working age was estimated at more
than $8000 per year.20 NPSLE is associated with
higher annual direct and indirect costs in compari-
son with SLE without neuropsychiatry manifesta-
tions, and it has been suggested that effective
control of neuropsychiatry symptoms could reduce
the costs of SLE.21 According to our results, in a FEP
cohort of 100 patients, the cost of ANA screening

© 2012 Blackwell Publishing Asia Pty Ltd 3

Antinuclear antibody and early psychosis
test, done on all patients, would be U$1000. In an
estimate of four positive screening tests, the costs
related to complementary blood tests (anti-dsDNA,
anti-Sm, anticardiolipin antibodies and lupus anti-
coagulant test) to confirm the diagnosis would be
around U$50 for each patient, in a total of $1200 for
the entire sample. This value is significantly lower
than those related to the losses due to unemploy-
ment, insurance, use of medical services, medica-
tions, among others that are related to SLE.
However, it is important to emphasize that,
although ANA has a high sensitivity (93%) due to its
low specificity (57%), a positive ANA must be inter-
preted considering all the clinical features,22 which
should be done by a specialized team.
Our study had several limitations. It was a retro-
spective study, based on data registered in the
records of the patients, and the sample size was rela-
tively small. These data should be taken cautiously
and the replication in independent samples is
needed before ANA could be used in routine daily
practice.
Although the evidence for the role of auto-
antibodies and antineuronal antibodies detectable
in the serum of SLE patients presenting neuropsy-
chiatric manifestations is controversial23 and nega-
tive ANA in SLE patients is a recognized condition
with a reported incidence of 5.0% to 8.9%,24 our
findings suggest that it may work as an important
screening test for the diagnosis of NPSLE. Further
studies are necessary to confirm the usefulness of
the screening for NPSLE in the assessment of
patients in early onset of psychosis.
ACKNOWLEDGEMENTS
P Louzada-Junior and CM Del-Ben are supported by
research fellowships from the ‘Conselho Nacional
de desenvolvimento Científico e Tecnológico’
(CNPq).
REFERENCES
1. Ward MM, Pyun E, Studenski S. Long-term survival in sys-
temic lupus erythematosus. Patient characteristics associated
with poorer outcomes. Arthritis Rheum 1995; 38: 274–83.
2. Huizinga T, Diamond B. Lupus and the central nervous
system. Lupus 2008; 17: 376–9.
3. Pego-Reigosa J, Isenberg D. Psychosis due to systemic lupus
erythematosus: characteristics and long-term outcome of
this rare manifestation of the disease. Rheumatology
(Oxford) 2008; 47: 1498–502.
4. Appenzeller S, Cendes F, Costallat L. Acute psychosis in sys-
temic lupus erythematosus. Rheumatol Int 2008; 28: 237–43.
4 © 2012 Blackwell Publishing Asia Pty Ltd
5. Menezes P, Scazufca M, Busatto G, Coutinho L, McGuire P,
Murray R. Incidence of first-contact psychosis in São Paulo,
Brazil. Br J Psychiatry Suppl 2007; 51: s102–6.
6. Anderson K, Fuhrer R, Malla A. The pathways to mental
health care of first-episode psychosis patients: a systematic
review. Psychol Med 2010; 40: 1585–97.
7. Del-Ben CM, Rufino A, de Azevedo-Marques JM, Menezes PR.
Differential diagnosis of first episode psychosis: importance
of optimal approach in psychiatric emergencies. Rev Bras
Psiquiatr 2010; 32: S78–86.
8. American Psychiatric Association. Diagnostic Criteria for
DSM-IV-TR. Washington, DC: Author, 2000.
9. Tan E, Cohen A, Fries J et al. The 1982 revised criteria for the
classification of systemic lupus erythematosus. Arthritis
Rheum 1982; 25: 1271–7.
10. Hochberg M. Updating the American College of Rheumatol-
ogy revised criteria for the classification of systemic lupus
erythematosus. Arthritis Rheum 1997; 40: 1725.
11. ACR. The American College of Rheumatology nomenclature
and case definitions for neuropsychiatric lupus syndromes.
Arthritis Rheum 1999; 42: 599–608.
12. Fragoso-Loyo H, Cabiedes J, Orozco-Narváez A et al. Serum
and cerebrospinal fluid autoantibodies in patients with neu-
ropsychiatric lupus erythematosus. Implications for diagnosis
and pathogenesis. PLoS ONE 2008; 3: e3347.
13. Zandman-Goddard G, Chapman J, Shoenfeld Y. Autoanti-
bodies involved in neuropsychiatric SLE and antiphospholipid
syndrome. Semin Arthritis Rheum 2007; 36: 297–315.
14. Matus S, Burgos PV, Bravo-Zehnder M et al. Antiribosomal-P
autoantibodies from psychiatric lupus target a novel neu-
ronal surface protein causing calcium influx and apoptosis. J
Exp Med 2007; 204: 3221–34.
15. Alao A, Chlebowski S, Chung C. Neuropsychiatric systemic
lupus erythematosus presenting as bipolar I disorder with
catatonic features. Psychosomatics 2009; 50: 543–7.
16. Khan S, Haddad P, Montague L, Summerton C. Systemic
lupus erythematosus presenting as mania. Acta Psychiatr
Scand 2000; 101: 406–8; discussion 8.
17. Huang H, Liu C, Liu C. Psychiatric manifestations in systemic
lupus erythematosus mimic psychotic prodrome: a case
report. Gen Hosp Psychiatry 2010; 32: e3–4.
18. Barile-Fabris L, Ariza-Andraca R, Olguín-Ortega L et al. Con-
trolled clinical trial of IV cyclophosphamide versus IV meth-
ylprednisolone in severe neurological manifestations in
systemic lupus erythematosus. Ann Rheum Dis 2005; 64:
620–5.
19. Slawsky KA, Fernandes AW, Fusfeld L, Manzi S, Goss TF. A
structured literature review of the direct costs of adult sys-
temic lupus erythematosus in the US. Arthritis Care Res
(Hoboken) 2011; 63: 1224–32.
20. Panopalis P, Yazdany J, Gillis JZ et al. Health care costs and
costs associated with changes in work productivity among
persons with systemic lupus erythematosus. Arthritis Rheum
2008; 59: 1788–95.
21. Zhu TY, Tam LS, Lee VW, Lee KK, Li EK. Systemic lupus
erythematosus with neuropsychiatric manifestation incurs
high disease costs: a cost-of-illness study in Hong Kong.
Rheumatology (Oxford) 2009; 48: 564–8.
22. Colglazier CL, Sutej PG. Laboratory testing in the rheumatic
diseases: a practical review. South Med J 2005; 98: 185–
91.
23. Greenwood DL, Gitlits VM, Alderuccio F, Sentry JW, Toh BH.
Autoantibodies in neuropsychiatric lupus. Autoimmunity
2002; 35: 79–86.
24. Bonfa E, Golombek SJ, Kaufman LD et al. Association
between lupus psychosis and anti-ribosomal P protein anti-
bodies. N Engl J Med 1987; 317: 265–71.