Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]

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Seminars in Arthritis and Rheumatism

journal homepage: www.elsevier.com/locate/semarthrit

Features associated with hematologic abnormalities and their impact

in patients with systemic lupus erythematosus: Data from a
multiethnic Latin American cohort
Luis A. González-Naranjo, MDa,n, Octavio Martínez Betancur, MDb,
Graciela S. Alarcón, MD, MPH, MACRc, Manuel F. Ugarte-Gil, MDd,e,
Daniel Jaramillo-Arroyave, MDf, Daniel Wojdyla, MScg, Guillermo J. Pons-Estel, MD, PhDh,
Federico Rondón-Herrera, MDf, Gloria M. Vásquez-Duque, MD, PhDa,
Gerardo Quintana-López, MD, MScf, Nilzio A. Da Silva, MDi, João C. Tavares Brenol, MD, PhDj,k,
Gil Reyes-Llerena, MDl, Virginia Pascual-Ramos, MDm, Mary C. Amigo, MD, FACPn,
Loreto Massardo, MDo, José Alfaro-Lozano, MDd, María I. Segami, MDp,
María H. Esteva-Spinetti, MDq, Antonio Iglesias-Gamarra, MDf, Bernardo A. Pons-Estel, MDr
a
Division of Rheumatology, Department of Internal Medicine, School of Medicine, Universidad de Antioquia, Calle 70 No. 52-21, Medellin, Antioquia 229,
Colombia
b
Department of Internal Medicine & Hematology, Universidad Nacional de Colombia, Bogotá, Colombia
c
Department of Medicine, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL
d
Servicio de Reumatología, Hospital Nacional Guillermo Almenara Irigoyen, EsSalud, Lima, Peru
e
Universidad Científica del Sur, Lima, Peru
f
Rheumatology Unit, Department of Internal Medicine, Universidad Nacional de Colombia, Bogotá, Colombia
g
Escuela de Estadística, Universidad Nacional de Rosario, Rosario, Argentina
h
Department of Autoimmune Diseases, Institut Clínic de Medicina i Dermatologia, Hospital Clínic, Barcelona, Spain
i
Rheumatology Unit, Faculdade de Medicina da Universidade Federal de Goias, Goiania, Brazil
j
Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
k
Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
l
Servicio Nacional de Reumatología, Centro de Investigaciones Médico Quirúrgicas (CIMEQ), La Habana, Cuba
m
Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Ciudad de México, Mexico
n
Reumatología, Centro Médico ABC, Ciudad de México, Mexico
o
Department of Clinical Immunology and Rheumatology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
p
Hospital Nacional “Edgardo Rebagliatti Martins”, Essalud, Lima, Peru
q
Servicio de Reumatología, Departamento de Medicina, Hospital Central de San Cristóbal, San Cristóbal, Venezuela
r
Servicio de Reumatología, Hospital Provincial de Rosario, Rosario, Argentina

a r t i c l e in fo a b s t r a c t

Objective: To examine hematological manifestations’ correlates and their impact on damage accrual and
mortality in SLE patients from the multiethnic, Latin American, GLADEL cohort.
Keywords:
Systemic lupus erythematosus
Methods: In patients with recent SLE diagnosis ( r 2 years), the association between follow-up
Hematologic manifestations hematological manifestations (per ACR criteria) and socio-demographic and clinical variables was
Autoimmune hemolytic anemia examined by univariable and multivariable logistic regressions; their impact on damage accrual and
Thrombocytopenia mortality was examined by Poisson and Cox proportional-hazards regression analyses, respectively.
Lymphopenia Results: Of 1437 patients, 948 (66.0%) developed Z1 hematological manifestation [5.5% hemolytic anemia
(AHA), 16.3% thrombocytopenia, and 56.4% lymphopenia] over 4.3 (3.3) follow-up years. Younger age, Mestizo
ethnicity, hematologic disorder (at/or before SLE diagnosis), and first damage recorded were associated with
hematological manifestations while antimalarials were negatively associated. AHA (at/or before SLE diagnosis),
anti-Sm, and anti-RNP antibodies were associated with subsequent AHA occurrence while musculoskeletal
involvement was negatively associated. Thrombocytopenia (at/or before SLE diagnosis), AHA, anti-phospholipid

n
Corresponding author.
E-mail address:

lagnvvn68@gmail.com (L.A. González-Naranjo).

http://dx.doi.org/10.1016/j.semarthrit.2015.11.003
0049-0172/& 2015 Elsevier Inc. All rights reserved.
2 L.A. González-Naranjo et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]

antibodies (aPLs), anti-SSA/Ro, anti-SSB/La antibodies, and first damage recorded were associated with
later thrombocytopenia occurrence. Lymphopenia (at/or before SLE diagnosis), younger age at diagnosis,
Mestizo ethnicity, having medical insurance, and first damage recorded were associated with subsequent
lymphopenia occurrence while antimalarials and azathioprine treatment were negatively associated. AHA was
associated with damage accrual and mortality after adjusting for variables known to affect these outcomes.
Conclusions: Mestizo ethnicity and early hematological manifestations are risk factors for their subsequent
occurrence while antimalarials have a protective effect. The associations between AHA and aPLs and
thrombocytopenia were corroborated. AHA contributes independently to damage accrual and diminished
survival.
& 2015 Elsevier Inc. All rights reserved.

Introduction Variables

Nearly all systemic lupus erythematosus (SLE) patients develop
hematological abnormalities, either isolated or in conjunction with
other manifestations, sometime during their disease course [1].
Anemia is seen in about 50% of SLE patients being anemia of
chronic disease, the most common followed by iron deficiency and
autoimmune hemolytic anemias (AHA) [1–4]. AHA, reported in
5–14% of SLE patients [1,3,4,5–9], is usually mediated by warm-
type IgG anti-erythrocyte antibodies [1,3,10], occurs with higher
frequency in African Americans and associates with anticardiolipin
antibodies (ACLs), thrombotic events, renal involvement, seizures,
serositis, lymphopenia, thrombocytopenia, damage accrual, and
higher mortality [7–9,11–14].
SLE-associated thrombocytopenia occurs in 7–30% of patients
[15–18], is mostly immune-mediated by anti-platelet antibodies
[1,15,19]; anti-thrombopoietin and anti-phospholipid antibodies
(aPLs) have also been implicated [15,20]. Thrombocytopenia in SLE
has been associated with ACLs, renal involvement, neurological
manifestations, AHA, leukopenia, and neutropenia [7,13,16,21] and
is an independent predictor of adverse outcomes (higher disease
activity, damage accrual, and mortality) [16,18,22,23].
Finally, leukopenia, reported in approximately 50% of patients,
especially in those with active disease, may occur due to lympho-
penia, neutropenia or both, being lymphopenia the most common
SLE hematological manifestation [1,2,24]. Circulating cytotoxic
lymphocyte antibodies occur in 36–90% of patients; their titers
correlate with the degree of lymphopenia [2]. In the LUMINA
(lupus in minorities: nature vs. nurture) study, lymphopenia was
associated with renal involvement, leukopenia, elevated anti-
dsDNA, and anti-Ro antibodies early and during the course of the
disease [25]. Marked (r 500/mm3) lymphopenia has been inde-
pendently associated with disease activity, damage accrual, neuro-
psychiatric manifestations, fever, and polyarthritis [24–26].
We hypothesized that these hematological manifestations will
be associated with more severe SLE clinical manifestations and
will impact damage accrual and mortality. We have now con-
ducted such analyses in patients from Grupo Latinoamericano de
Estudio del Lupus (GLADEL), a Latin American SLE cohort [27].
Patients and methods
Patients
GLADEL is an observational, multiethnic, longitudinal inception
cohort study started in 1997 [27]; it includes patients from 34
centers from nine Latin American countries under local institu-
tional review boards’ regulations and the Declaration of Helsinki’s
guidelines. Patients were evaluated at cohort entry and every 6
months thereafter.
Fulfillment of the American College of Rheumatology (ACR)
1982 SLE classification criteria [28] at diagnosis was not manda-
tory; rather SLE was a diagnosed by expert clinicians; eventually,
95.6% of the patients met the ACR criteria.
The dependent variable, overall, and specific SLE hematologic
manifestations occurring during the patients’ follow-up, were
defined according to the ACR criteria [28] as the presence of
AHA [anemia with reticulocytosis (hemoglobin levels r 11 g/dl
for women, r 13 g/dl for men, and corrected reticulocyte
count Z 3%], leukopenia ( r4000/mm3, Z2 occasions), lympho-
penia ( r1500/mm3, Z2 occasions), and/or thrombocytopenia
( r100,000/mm3) in the absence of offending drugs].
Independent variables. (1) Socioeconomic-demographic domain:
age at SLE diagnosis, gender, ethnicity [Caucasian, Mestizo, and
African-Latin American (ALA)], residence (rural vs. urban), marital
status, socioeconomic status (SES) (by the Graffar’s method),
medical insurance (full vs. partial/no coverage), and years of
education. (2) Clinical domain: ACR (including hematological
manifestations as previously defined) and non-ACR clinical man-
ifestations, immunological variables, damage accrual [SLICC/ACR
damage index (SDI)] [29], and disease activity [SLE Disease Activity
Index (SLEDAI)] [30]. Hematological manifestations were excluded
from the SLEDAI so that no activity could be attributed to these
variables. (3) Therapeutic domain: glucocorticoid exposure [oral
prednisone or equivalent (low r 20 mg/day, medium 20–60 mg/
day, and high Z 60 mg/day) or intravenous methylprednisolone],
antimalarials, methotrexate, azathioprine, and cyclophosphamide.
Clinical and therapeutic variables were those occurring on/or
before SLE diagnosis, except for damage, first recorded.
Statistical analyses
Disease and patient characteristics were compared between
patients with and without hematological manifestations; the
Chi-square and Student’s t-tests were used for categorical and
continuous variables, respectively; the Mann–Whitney test for
non-normally distributed variables. Variables with p r 0.1 in
these analyses were examined by univariable logistic regressions.
Variables with a p r 0.1 in these regressions and those considered
clinically important were included in multivariable logistic regres-
sions with the dependent variable being either overall or specific
hematologic SLE manifestations. Age, gender, and ethnicity were
entered into these regressions regardless of their significance.
Results are presented as odds ratios (ORs) with their 95% CIs;
significance was defined as a p r 0.05.
The impact of hematologic SLE manifestations on damage
accrual was examined by Poisson regression analysis after adjust-
ing for age at SLE diagnosis, gender, ethnicity, and other possible
confounding variables (SES, medical insurance, disease activity,
damage at baseline, antimalarial treatment, and oral prednisone
doses) [31,32]. Finally, the contribution of hematologic SLE man-
ifestations to mortality was examined with Cox univariable and
multivariable proportional-hazards regression analyses adjusting
for variables known to affect this outcome (SES, medical insurance,
damage, disease activity, infections, renal disease, and antimalarial
 L.A. González-Naranjo et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]] 3

treatment) [27,32,33] and including age at SLE diagnosis, gender, ALA exhibited the lowest frequency (11.5%); similarly for lympho-
and ethnicity. Significance was defined as a p r 0.05. penia, Mestizo predominated (50.4%), followed by Caucasian
Statistical analyses were performed using SPSS program, (35.4%) and ALA (14.2%).
version 21.0 (Chicago, IL).

Features associated with overall SLE hematological manifestations

Results
The univariable and multivariable analyses of the association
between variables from the different domains at or before SLE
Excluding 43 GLADEL patients from the ethnic group other,
diagnosis and the subsequent occurrence of overall hematological
1437 of the 1480 patients were studied: 645 Mestizos (44.9%), 606
manifestations are shown in Table 2(A). Variables independently
Caucasians (42.2%), and 186 ALAs (12.9%).
associated with the occurrence of hematologic manifestations over
After SLE diagnosis and during a mean (SD) follow-up time of
the course of follow-up were: younger age at diagnosis, Mestizo
4.3 (3.3) years, 948 (66.0%) patients [(89.8% women), mean (SD)
ethnicity, hematologic disorder, and the first damage recorded
age at diagnosis: 28.7 (11.9) years] developed hematologic
while antimalarial use was negatively associated.
manifestations secondary to lupus: 79 (5.5%) AHA, 234 (16.3%)
thrombocytopenia, 606 (42.2%) leukopenia, and 811 (56.4%)
lymphopenia. There were overlapping hematological manifesta- Features associated with SLE AHA
tions in some patients being the most common thrombocytopenia
and lymphopenia. Data for patients with and without overall The univariable and multivariable analyses of the association
hematological manifestation during the follow-up period are between variables from the different domains at or before SLE
depicted in Table 1. diagnosis and the subsequent occurrence of AHA are shown in
Among patients who developed overall hematological mani- Table 2(B). Having AHA was independently associated with its later
festations at follow-up, Mestizo was the predominant ethnic group occurrence whereas musculoskeletal manifestations were nega-
(48.2%), followed by Caucasian (38.4%), and ALA (13.4%). Among tively associated.
patients with AHA, Mestizo, and Caucasian (44.3%) were the
predominant groups, followed by ALA (11.4%); for thrombocyto-
penia, Mestizo (47.0%), and Caucasian (41.5%) predominated while Features associated with SLE thrombocytopenia

The univariable and multivariable analyses of the association

Table 1 between variables from the different domains at or before SLE
Socioeconomic-demographic, clinical, and therapeutic characteristics at or before diagnosis and the subsequent occurrence of thrombocytopenia are
SLE diagnosis according to the presence or absence of SLE hematological manifes- presented in Table 2(C). Having AHA and thrombocytopenia and
tations at follow-up in GLADEL patientsa
the first SDI score recorded were independently associated with
Characteristic Hematological SLE manifestations subsequent episodes of thrombocytopenia.

Present Absent p Value

(n ¼ 948) (n ¼ 489) Features associated with SLE lymphopenia

Age at diagnosis, years, mean (SD) 28.7 (11.9) 31.0 (13.1) 0.002 The univariable and multivariable analyses of the association
Sex, female (%) 853 (90.0) 437 (89.4) 0.716
between variables from the different domains at or before SLE
Ethnic group (%) diagnosis and the subsequent occurrence of lymphopenia are
Caucasian 364 (38.4) 242 (49.5) o0.001
presented in Table 2(D). Lymphopenia, younger age, Mestizo
Mestizo 457 (48.2) 188 (38.4)
ALA 127 (13.4) 59 (12.1) ethnicity, having medical insurance, and the first SDI recorded
were independently associated with lymphopenia over the course
Socio-economic status (%)
High 82 (8.6) 66 (13.5) 0.006
of the disease, whereas treatment with antimalarials and azathio-
Middle 267 (28.2) 147 (30.1) prine were negatively associated.
Low 599 (63.2) 276 (56.4)
Marital status (coupled) (%) 414 (43.7) 242 (49.5) 0.036

Clinical manifestations (%)

Anti-phospholipid antibodies (aPLs), thrombocytopenia, and AHA
Musculoskeletal 813 (85.8) 444 (90.8) 0.006 To assess if the presence of aPLs (IgG and/or IgM ACLs, and/or
Cutaneous 790 (83.3) 436 (89.2) 0.003 the lupus anticoagulant, and/or anti-beta2-glycoprotein-I) were
Hematologic disorder 596 (62.9) 181 (37.0) o0.001 associated with both, AHA and thrombocytopenia, only patients
Renal 154 (31.5) 365 (38.5) 0.009
(n ¼ 604) in whom these antibodies had been measured before
SLEDAI at baseline, mean (SD) 12.8 (7.9) 11.6 (7.2) 0.006
SDI first recorded, mean (SD) 1.00 (1.25) 0.64 (1.01) o0.001 the occurrence of these manifestations were included in these
analyses. aPLs were more frequent among patients with thrombo-
Medications (%)
Oral glucocorticoidsb
cytopenia than those without it (64.3% vs. 50.1%; p ¼ 0.006). The
None 473 (49.9) 228 (46.6) o0.001 univariable and multivariable analyses of the association between
Low dose (o20 mg/day) 162 (17.1) 126 (25.8) variables from the different domains at or before SLE diagnosis in
Medium dose (20–60 mg/day) 186 (19.6) 79 (16.2) patients in whom aPLs were measured and subsequent thrombo-
High dose (4 60 mg/day) 127 (13.4) 56 (11.5)
cytopenia occurrence are depicted in Table 3. aPLs, AHA, and
Methylprednisolone pulse therapy 86 (9.1) 25 (5.1) 0.008
Antimalarialsc 309 (32.6) 242 (49.5) o0.001 thrombocytopenia were independent predictors of the later occur-
rence of thrombocytopenia. When assessing specific aPL isotypes,
a
Only p values that were r0.10 are shown; ALA, African-Latin American; only IgG ACLs positivity was significantly associated (Table 4).
SLEDAI, systemic lupus erythematosus disease activity index; SDI, systemic In contrast, neither aPLs nor specific aPL isotypes were asso-
lupus International Collaborating Clinics/American College of Rheumatology
Damage Index.
ciated with the occurrence of AHA; their frequency was compara-
b
Prednisone or equivalent. ble in both, patients with and without these antibodies (52.5% vs.
c
Chloroquine and/or hydroxychloroquine. 56.8%; p ¼ 0.581).
4 L.A. González-Naranjo et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]

Table 2
Socioeconomic-demographic, clinical, and therapeutic characteristics at or before SLE diagnosis associated with overall and specific SLE hematological manifestations at
follow-up in GLADEL patients by univariable and multivariable logistics regression analyses: (A) overall hematological manifestations, (B) autoimmune hemolytic anemia,
(C) thrombocytopenia, and (D) lymphopenia

Characteristic Univariable Multivariable

OR 95% CI p Value OR 95% CI p Value

(A) Overall hematological manifestations

Age at diagnosis, years 0.99 0.98–0.99 0.007 0.98 0.97–0.99 0.004
Sex, female 1.08 0.73–1.61 0.705

Ethnic group
Caucasian Reference group
Mestizo 1.47 1.14–1.91 0.003 1.38 1.04–1.84 0.026
ALA 1.34 0.92–1.95 0.127

Socio-economic status
High Reference group
Middle 1.31 0.86–2.01 0.212
Low 1.58 1.06–2.35 0.024

Clinical manifestations
Musculoskeletal 0.69 0.47–1.01 0.056
Cutaneous 0.61 0.42–0.88 0.008
Hematological 3.16 2.46–4.06 r0.001 3.14 2.42–4.09 r 0.001
Renal 1.44 1.11–1.85 0.006
SLEDAI at baseline 1.02 1.01–1.04 0.011
SDI first recorded 1.37 1.22–1.55 r0.001 1.30 1.14–1.45 r 0.001

Medications
Oral glucocorticoidsa
None Reference group
Low dose (o20 mg/day) 0.65 0.48–0.89 0.007
Medium dose (20–60 mg/day) 1.22 0.88–1.70 0.238
High dose (4 60 mg/day) 1.09 0.74–1.62 0.641
Methylprednisolone pulse therapy 1.65 1.03–2.64 0.038
Antimalarialsb 0.49 0.38–0.63 o0.001 0.59 0.45–0.78 o 0.001

(B) Autoimmune hemolytic anemia

Age at diagnosis, years 0.99 0.97–1.01 0.360
Sex, female 0.69 0.32–1.50 0.352

Ethnic group
Caucasian Reference group
Mestizo 1.14 0.65–1.99 0.645
ALA 0.91 0.38–2.14 0.821

Clinical manifestations
Musculoskeletal 0.40 0.22–0.74 0.003 0.49 0.24–0.98 0.045
Pulmonary 5.67 2.35–13.67 r0.001
Hemolytic anemia 10.15 5.82–17.73 r0.001 7.34 3.97–13.60 r 0.001
Thrombocytopenia 1.75 0.94–3.26 0.077
SLEDAI at baseline 1.05 1.02–1.08 0.002
SDI first recorded 1.30 1.09–1.54 0.003

Medications
Oral glucocorticoidsa
None Reference group
Low dose (r20 mg/day) 0.23 0.08–0.66 0.006
Medium dose (20–60 mg/day) 0.55 0.26–1.15 0.109
High dose (Z60 mg/day) 0.78 0.35–1.70 0.527
Methylprednisolone pulse therapy 3.84 2.03–7.28 r0.001
Antimalarialsb 0.31 0.15–0.61 0.001

(C) Thrombocytopenia
Age at diagnosis, years 0.99 0.98–1.01 0.458
Sex, female 0.77 0.47–1.25 0.292

Ethnic group
Caucasian Reference group
Mestizo 1.02 0.74–1.42 0.900
ALA 0.72 0.42–1.21 0.212

Clinical manifestations
Musculoskeletal 0.66 0.43–1.01 0.058
Pulmonary 2.70 1.29–5.67 0.009
Hemolytic anemia 2.64 1.71–4.07 r0.001 1.71 1.04–2.82 0.036
Thrombocytopenia 6.90 4.85–9.83 r0.001 6.26 4.32–9.08 r 0.001
SLEDAI at baseline 1.02 1.00–1.04 0.019
SDI first recorded 1.33 1.19–1.49 r0.001 1.23 1.08–1.42 0.003

Medications
Methylprednisolone pulse therapy 2.27 1.42–3.63 0.001
Antimalarialsb 0.61 0.43–0.85 0.004
 L.A. González-Naranjo et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]] 5

Table 2 (continued )

Characteristic Univariable Multivariable

OR 95% CI p Value OR 95% CI p Value

(D) Lymphopenia
Age at diagnosis, years 0.99 0.98–1.00 0.073 0.99 0.98–0.99 0.021
Sex, female 0.98 0.67–1.45 0.931

Ethnic group
Caucasian Reference group
Mestizo 1.79 1.39–2.31 r0.001 1.65 1.24–2.19 0.001
ALA 1.77 1.23–2.56 0.002

Socioeconomic status
High Reference group
Middle 1.15 0.76–1.75 0.516
Low 1.52 1.03–2.25 0.037

Medical insurance
Full vs. partial/no coverage 1.22 0.97–1.55 0.095 1.65 1.25–2.17 r0.001

Clinical manifestations
Musculoskeletal 0.69 0.50–0.98 0.039
Cutaneous 0.59 0.42–0.82 0.002
Renal disease 1.39 1.09–1.78 0.007
Lymphopenia 3.93 3.05–5.07 r0.001 4.05 3.09–5.31 r0.001
SDI first recorded 1.35 1.21–1.51 r0.001 1.28 1.14–1.45 r0.001

Medications
Oral glucocorticoidsa
None Reference group
Low dose (r20 mg/day) 0.65 0.48–0.89 0.006
Medium dose (20–60 mg/day) 1.18 0.87–1.62 0.292
High dose (Z60 mg/day) 1.27 0.88–1.85 0.205
Antimalarialsb 0.52 0.41–0.66 r0.001 0.60 0.45–0.80 r0.001
Azathioprine 0.55 0.30–0.98 0.043 0.46 0.24–0.89 0.020

OR, odds ratio; ALA, African-Latin American; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; SDI, Systemic Lupus International Collaborating Clinics/American
College of Rheumatology Damage Index.
a
Prednisone or equivalent.
b
Chloroquine and/or hydroxychloroquine.

Hematologic manifestations and anti-dsDNA and extractable nuclear patients in whom these antibodies [anti-dsDNA (n ¼ 1045),
antigens (ENAs) antibodies anti-Sm (n ¼ 678), anti-RNP (n ¼ 580), anti-SSA/Ro (n ¼ 650),
To assess if the presence of anti-dsDNA and ENAs antibodies and anti-SSB/La (n ¼ 602)] were measured were included in these
were associated with specific hematologic SLE manifestations only analyses. Anti-Sm and anti-RNP were independent predictors of

Table 3
Socioeconomic-demographic, clinical, and therapeutic characteristics at or before SLE diagnosis associated with SLE thrombocytopenia at follow-up in GLADEL patients in
whom anti-phospholipid antibodies were measured (n ¼ 604) by univariable and multivariable logistics regression analyses

Characteristic Univariable Multivariablea

OR 95% CI p Value OR 95% CI p Value

Age at diagnosis, years 1.00 0.98–1.02 0.964

Sex, female 0.83 0.44–1.60 0.585

Ethnic group
Caucasian Reference group
Mestizo 0.97 0.63–1.49 0.871
ALA 0.66 0.34–1.49 0.236
Any anti-phospholipid antibodyb 1.80 1.18–2.74 0.006 1.76 1.11–2.79 0.017

Clinical manifestations
Musculoskeletal 0.52 0.30–0.88 0.016
Pulmonary 2.20 0.87–5.58 0.097
Hemolytic anemia 2.81 1.62–4.86 r 0.001 2.44 1.29–4.64 0.006
Lymphopenia 1.55 1.03–2.34 0.034
Thrombocytopenia 7.39 4.70–11.63 r 0.001 7.21 4.43–11.74 r0.001
Methylprednisolone pulse therapy 2.00 1.09–3.68 0.026

OR, odds ratio; ALA, African-Latin American.

a
In the multivariable analysis, in addition to the variables noted in this table, antimalarials were also included.
b
IgG and/or IgM anticardiolipin antibodies and/or lupus anticoagulant.
6 L.A. González-Naranjo et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
Table 4
Socioeconomic-demographic, clinical, and therapeutic characteristics at or before SLE diagnosis associated with SLE thrombocytopenia at follow-up in GLADEL patients in
whom IgG anticardiolipin antibodies were measured by univariable and multivariable logistics regression analyses
Characteristic Univariable
OR
Age at diagnosis, years 1.00
Sex, female 0.70
Ethnic group
Caucasian Reference group
Mestizo 0.88
ALA 0.52
Clinical manifestations
Hemolytic anemia 3.28
Thrombocytopenia 6.50
Anticardiolipin IgG 1.61
OR, odds ratio; ALA, African-Latin American.
AHA occurrence while anti-SSA/Ro and anti-SSB/La of thrombocy-
topenia occurrence (Table 5).
Hematologic manifestations and damage accrual
Overall and specific hematological manifestations were not
associated with damage accrual when examined by Poisson
regression multivariable analysis after adjusting for known con-
founders; the exception was AHA, which was independently
associated with damage accrual in the univariable (RR: 1.48; 95%
CI: 1.29–1.69; p r 0.001) and multivariable (RR: 1.81; 95%
CI: 1.03–1.36; p ¼ 0.020) analyses (Table 6).
Hematologic manifestations and mortality
Overall, hematological manifestations at SLE diagnosis or at any
time over the disease course did not contribute to mortality (HR:
1.02; 95% CI: 0.55–1.89; p ¼ 0.962 and HR: 0.92; 95% CI: 0.43–1.95;
p ¼ 0.82, respectively) when examined by multivariable propor-
tional Cox regression analyses after adjusting for known con-
founders. However, AHA occurring after SLE diagnosis did impact
on mortality in the univariable (HR: 2.63; 95% CI: 1.43–4.85;
p ¼ 0.002) and multivariable (HR: 2.53; 95% CI: 1.26–5.10;
p ¼ 0.009) analyses (data not shown).
Discussion
Hematological abnormalities are very frequent in SLE. In fact,
almost 80% of GLADEL patients experienced at least one hemato-
logical event during the entire observation period: 12.5% AHA,
24.1% thrombocytopenia, 51.4% leukopenia, and 66.3% lymphope-
nia. Since AHA was the only anemia type considered, the percent-
age of patients with hematological involvement may be even
greater [34]. These figures compare to those of a Danish study
[5], in which 67% of patients had them during the entire observa-
tion period: 11% AHA, 24% thrombocytopenia, 25% leukopenia, and
42% lymphopenia and those in LUMINA in which AHA occurred in
10.4% [9], lymphopenia in 81.9% at any time during the course of
the disease [25], and thrombocytopenia at or before baseline in
19.6% of SLE patients [16]. Similarly to GLADEL cohort, the
frequency of hematological manifestations was 79.1% in a cohort
of Colombian SLE patients [35].
We have assessed for the first time the hematological manifes-
tations’ correlates and their impact on damage accrual and mortal-
ity in SLE patients from the largest Latin American SLE cohort.
Remarkable observations, not previously reported, include: Mes-
tizo ethnicity was significantly associated with the later
Multivariable
95% CI p Value OR 95% CI p Value
0.98–1.02 0.855
0.33–1.49 0.356
0.53–1.45 0.604
0.23–1.17 0.112
1.76–6.13 r0.001 2.97 1.48–5.95 0.002
3.90–10.85 r0.001 6.87 4.02–11.76 r0.001
1.00–2.58 0.051 1.73 1.02–2.94 0.041
occurrence of overall hematological manifestations and lympho-
penia while antimalarials had a protective effect over their
occurrence. In our cohort nearly half the patients with overall
hematologic manifestations and half of those with lymphopenia
were Mestizos; the proportion of Mestizos was also high among
those with thrombocytopenia; these findings are quite different
from LUMINA in which hematological manifestations were no
more frequent in the Texan Hispanic patients as in the GLADEL
Mestizos with the exception of thrombocytopenia early in the
disease which was borderline significant [16]; in contrast, African
American ethnicity was independently associated with AHA [9].
Despite some phenotypic similarities between GLADEL Mestizo
patients and LUMINA’s Texan Hispanics neither their ancestral
genes nor other factors (socioeconomic, cultural) that may affect
the disease course are exactly the same; this may explain the
differences observed between these cohorts [36,37].
The protective effect of antimalarials over the subsequent
occurrence of overall hematological manifestations and lympho-
penia probably relates to their effect on disease activity, reducing
mild and major disease flares and retarding damage accrual
[38–41]. Inhibition of endogenous Toll-like receptor (TLR) activa-
tion resulting in a decreased proinflammatory cytokine profile
with the consequent decrease in antigen presentation is an
important mechanism of action of the antimalarials. The decrease
in SLE activity in response to hydroxychloroquine therapy corre-
lates with reduction in the production of interferon (IFN)-α,
suggesting the importance of inhibiting endogenous TLR activation
[40]. Likewise, azathioprine therapy was also negatively associated
with lymphopenia over time, suggesting azathioprine effective-
ness on disease activity as maintenance therapy after remission
of severe SLE manifestations or in those patients with recurrent
flares [42].
As in the PROFILE cohort [43] we found that anti-Sm antibodies
were associated with AHA. To our knowledge, however, we are the
first to report the association of anti-RNP antibodies with AHA
occurrence. On the other hand, anti-SSA/Ro and anti-SSB/La anti-
bodies were associated with thrombocytopenia. Anti-SSA/Ro anti-
bodies have been associated with thrombocytopenia in SLE; in
fact, some authors have suggested that anti-SSA/Ro antibodies may
be a useful marker for a subgroup of patients with idiopathic
thrombocytopenic purpura who later progress to SLE [44,45]. Anti-
SSA/Ro antibodies recognize Ro/SS-A antigen, which is constituted
by at least two different proteins, 60 kDa and 52 kDa, complexed
with one of four related human cytoplasmic (hY) RNAs. The Ro
complex is found in most tissues and cells (erythrocytes and
platelets) [46]. In human platelets, SS-A/Ro antigen, especially
 L.A. González-Naranjo et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]] 7

Table 5 Table 5 (continued )

Hematologic manifestations and extractable nuclear antigens (ENAs) antibodies in
GLADEL patients by multivariable logistics regression analyses: hemolytic anemia Characteristic OR 95% CI p Value
at follow-up and anti-Sm and anti-RNP and thrombocytopenia at follow-up and
anti-Ro and anti-La Clinical manifestations
Hemolytic anemia 1.87 0.82–4.23 0.135
Characteristic OR 95% CI p Value Thrombocytopenia 6.99 3.92–12.48 r0.001
Pulmonary 3.12 0.81–12.10 0.099
Anti-Sm antibodies and hemolytic anemia Ocular 0.28 0.08–0.99 0.048
Age at diagnosis, years 1.01 0.98–1.05 0.489 Anti-La 1.83 1.07–3.12 0.027
Sex, female 0.68 0.20–2.27 0.534
Medications
Ethnic group Methylprednisolone pulse 1.10 0.45–2.68 0.829
Caucasian Reference group therapy
Mestizo 1.59 0.63–4.01 0.331
ALA 1.32 0.44–3.96 0.625 OR, odds ratio; ALA, African-Latin American; SLEDAI, Systemic Lupus Erythemato-
SLEDAI at baseline 1.00 0.95–1.06 0.934 sus Disease Activity Index; SDI, Systemic Lupus International Collaborating Clinics/
SDI first recorded 1.17 0.87–1.58 0.305 American College of Rheumatology Damage Index.
a
Clinical manifestations Chloroquine and/or hydroxychloroquine.
Hemolytic anemia 6.92 2.80–17.11 r0.001 Statistically significant variables are indicated in bold.
Pulmonary 3.02 0.57–16.08 0.196
Anti-Sm 3.19 1.31–7.76 0.011
the 52 kDa isoform has been detected; hY3 and hY4 RNA have also
Medications
Methylprednisolone pulse 1.44 0.39–5.37 0.584
been found in platelets; the hY3 RNA has been associated with
therapy platelets’ function whereas the hY4 RNA seems to be necessary for
Cyclophosphamide 1.62 0.33–7.82 0.551 maintenance of all blood cells types [47]. Environmental factors
Antimalarialsa 0.39 0.14–1.12 0.08 such as exposure to ultraviolet radiation and viral infections may
Anti-RNP antibodies and hemolytic anemia cause translocation of the Ro complex to nucleocytoplasmic and
Age at diagnosis, years 1.02 0.98–1.06 0.259 membrane sites where it is not normally found, thereby leading to
Sex, female 0.55 0.13–2.29 0.410
the development of autoimmunity [46]. In our cohort, these
Ethnic group autoantibodies were neither measured in all patients nor were
Caucasian Reference group assayed at a central laboratory; therefore, we did not explore
Mestizo 1.17 0.41–3.34 0.764
correlations between specific hematological manifestations and
ALA 1.34 0.41–4.36 0.628
SLEDAI at baseline 1.02 0.96–1.08 0.616 autoantibody clusters in our cohort.
SDI first recorded 0.89 0.60–1.34 0.583 As reported by other authors, hematologic abnormalities are
Clinical manifestations common initial SLE manifestations [6,48,49], and, like any other
Hemolytic anemia 10.83 3.72–31.57 r0.001 organ system, they may be evident months or years later [50].
Thrombocytopenia 0.90 0.27–3.06 0.868 Overall, 54% of the GLADEL patients have one or more hemato-
Neurologic disorder 27.45 1.79–421.51 0.017 logical manifestation before SLE diagnosis. In this sense, we have
Pulmonary 0.93 0.08–10.42 0.951
shown that having hematological manifestations early in the
Anti-RNP 2.59 1.00–6.71 0.050
disease course is a risk factor for their subsequent occurrence.
Medications
For example, AHA recurred in about 25% of patients, consistent
Methylprednisolone pulse 1.77 0.44–7.17 0.423
therapy with the 20% reported in LUMINA [9]. Thrombocytopenia recurred
Cyclophosphamide 4.4 0.78–24.77 0.093 in 47% of patients, while Sultan et al. found at least a second
Antimalarialsa 0.39 0.12–1.25 0.114 episode of thrombocytopenia in about 24% of their patients [7].
Anti-SSA/Ro antibodies and thrombocytopenia The association between AHA and thrombocytopenia in SLE
Age at diagnosis, years 1.00 0.98–1.02 0.893 was also corroborated in our study for those patients who
Sex, female 0.87 0.38–1.97 0.734 developed thrombocytopenia during their follow-up [7–9,12,13].
Ethnic group The association of these two abnormalities suggests they have a
Caucasian Reference group common pathogenic mechanism: antibodies directed against red
Mestizo 0.87 0.49–1.56 0.639 cells and platelets’ membranes epitopes affecting both cell line-
ALA 0.66 0.33–1.31 0.231
SLEDAI at baseline 1.01 0.98–1.04 0.606
ages [7,12]. AHA and thrombocytopenia have also been found to
SDI first recorded 1.11 0.90–1.36 0.344

Clinical manifestations
Hemolytic anemia 1.87 0.85–4.08 0.118 Table 6
Thrombocytopenia 6.88 3.94–12.01 r0.001 Hemolytic anemia and damage accrual in GLADEL patients by Poisson regression
Pulmonary 2.95 0.83–10.51 0.096 multivariable analysisa
Anti-Ro 1.80 1.08–2.98 0.023
Variables RR 95% CI p Value
Medications
Methylprednisolone pulse 1.32 0.58–3.01 0.504 Damage accrual
therapy Hemolytic anemia 1.18 1.03–1.36 0.020
Anti-SSB/La antibodies and thrombocytopenia SLEDAI at baseline 1.01 1.00–1.01 0.005
Age at diagnosis, years 1.01 0.99–1.03 0.317 SDI first recorded 1.45 1.41–1.49 r0.001
Sex, female 0.74 0.32–1.73 0.492 Antimalarialsb 0.88 0.79–0.99 0.026

Ethnic group RR, rate ratio; HR, hazard ratio; ALA, African-Latin American; SLEDAI, Systemic
Caucasian Reference group Lupus Erythematosus Disease Activity Index; SDI, Systemic Lupus International
Mestizo 0.75 0.41–1.37 0.348 Collaborating Clinics/American College of Rheumatology Damage Index.
ALA 0.56 0.28–1.15 0.114 a
Variables included in the multivariable analysis were, in addition to the ones
SLEDAI at baseline 1.01 0.98–1.05 0.547 noted, the following: age at diagnosis, gender, ethnicity, socio-economic status,
SDI first recorded 1.11 0.89–1.39 0.337 medical insurance, and glucocorticoids dose.
b
chloroquine and/ or hydroxychloroquine.
8 L.A. González-Naranjo et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
have a significant association with aPL antibodies which may
result from these antibodies interacting with negatively charged
phospholipids in erythrocytes or platelets cell walls [7,51]. How-
ever, in our study we have only shown the association between
aPLs and thrombocytopenia but not AHA at follow-up. Some
investigators have reported the association between AHA and
IgM aPL antibodies while others have reported with IgG aPL
antibodies [12,17,51]. When examining these specific isotypes we
only found the association of IgG ACLs with thrombocytopenia but
not with AHA. Furthermore, other possible pathogenic pathways
for AHA include acquired deficiencies of the expression of two
complement regulatory erythrocyte proteins that protect them from
uncontrolled-mediate lysis, CD 55, or decay acceleration factor, and/
or CD 59, or membrane inhibitor of reactive lysis. The under-
expression of these molecules has also been reported in SLE patients
with autoimmune thrombocytopenia and lymphopenia [52].
Age at disease onset influences the SLE phenotype [53–55].
Younger age at diagnosis was associated with the occurrence of
overall hematologic manifestations and lymphopenia over the
course of follow-up; this had been previously reported by us
[54] and also in adolescent-onset LUMINA patients in whom there
was a tendency for adolescent patients to have more hematolog-
ical manifestations than adult-onset patients (96.8% vs. 80.4%,
p ¼ 0.066) [55]. Mok et al. [53] reported that their childhood
onset Chinese patients had more frequent hematologic manifes-
tation, specifically leukopenia, and thrombocytopenia at the time
of SLE diagnosis than older-age onset patients but no differences in
these manifestations were observed in subsequent years. It should
be noted that because of the different definitions used across
studies it is hard to compare them. Furthermore, the association of
younger age with lymphopenia over time may reflect the previ-
ously reported association of younger age and high disease activity
[24–26,56]. Lymphopenia occurring during episodes of disease
activity is independent of changes in therapy [24,57] and is a
predictor of subsequent higher disease activity and flares [58]. We
failed to confirm this association probably because lymphopenia
was not categorized as mild, moderate, and marked, the latter two
associated with disease activity [25,26]. Furthermore, we did not
evaluate flares or higher disease activity during the patients’
follow-up.
When examining the influence of hematological manifestations
on damage and mortality, only AHA occurring on or before
diagnosis was found to be independently associated with damage
accrual and with mortality when it occurred over the course of the
disease. This is not surprising given that at baseline, our AHA
patients had a more severe disease, and already had accrued
greater damage. Although the severity of AHA was not assessed,
severe acute episodes of hemolysis and a more severe disease may
have exerted an impact on damage. Consistent with our findings,
AHA was also found to exert an impact on damage in LUMINA [9].
AHA over the course of the disease was significantly associated
with mortality after adjusting for confounders including low SES
[32,33,59]. The mortality rate in patients with AHA from our
cohort was lower (10.3%) than that reported in LUMINA (20%)
[9], probably due to our shorter time of follow-up. Consistent with
our results, AHA was significantly associated with poorer survival
in patients from the Hopkins Lupus Cohort, regardless of when it
was present and after adjusting for known confounders [14].
Our study has some limitations; aPL antibodies were not
measured in all patients, so the effective sample size (42% of the
total) for these analyses was lower; furthermore, all autoanti-
bodies were not examined when the hematologic event occurred
and were not evaluated at a single reference center. In addition,
not all patients fulfilled the ACR SLE classification criteria and thus
their inclusion could have impacted in the results; however, over
95% of them met Z4 criteria at some point over their disease
course. Despite these limitations, our study provides important
information for clinicians caring for SLE patients. Hematologic
abnormalities are common initial manifestations of SLE and almost
all patients develop at least one over their disease course. Their
occurrence early on is a risk factor for their subsequent occurrence
while antimalarials are protective. We have corroborated the
association between AHA and thrombocytopenia and between
aPLs and thrombocytopenia. Young Mestizo patients who accrue
damage early on are at risk of developing subsequently hemato-
logical manifestations. Finally and importantly, AHA is usually
indicative of more severe disease with greater damage accrual
when it occurs early in the disease course and with poor survival
when occurs over the disease course.
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