Rheumatology International (2023) 43:1841–1848

https://doi.org/10.1007/s00296-023-05381-8
Rheumatology
INTERNATIONAL

OBSERVATIONAL RESEARCH

The relationship of neutrophil‑to‑lymphocyte ratio with health‑related

quality of life, depression, and disease activity in SLE: a cross‑sectional
study
Eleni Papachristodoulou1,2 · Loukas Kakoullis3,4 · Costas Christophi5 · Savvas Psarelis6 · Victor Hajiroussos7 ·
Konstantinos Parperis8

Received: 22 May 2023 / Accepted: 22 June 2023 / Published online: 5 July 2023
© The Author(s) 2023

Abstract
The neutrophil-to-lymphocyte ratio (NLR) emerged as a potential biomarker in SLE, but its association with several out-
comes remains unclear. We aimed to evaluate the relationship between NLR and SLE disease activity, damage, depression,
and health-related quality of life. A cross-sectional study was conducted, including 134 patients with SLE who visited the
Division of Rheumatology between November 2019 and June 2021. Demographics and clinical data including NLR, Safety
of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus disease activity index (SELENA–SLEDAI),
Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), physician
global assessment (PhGA), patient global assessment (PGA), patient health questionnaire (PHQ)-9, patient self-rated health,
and lupus quality of life (LupusQoL) scores, were collected. Patients were stratified into two groups and compared using
the NLR cut-off of 2.73, the 90th percentile value of healthy individuals. The analysis included t-test for continuous vari-
ables, χ2-test for categorical variables, and logistic regression adjusting for age, sex, BMI, and glucocorticoid use. Among
the 134 SLE patients, 47 (35%) had an NLR ≥ 2.73. The NLR ≥ 2.73 group had significantly higher rates of severe depres-
sion (PHQ ≥ 15), poor/fair self-rated health, and the presence of damage (SDI ≥ 1). These patients also scored significantly
lower in LupusQoL domains (physical health, planning, and body image), and higher in SELENA-SLEDAI, PhGA, and
PGA. Logistic regression confirmed that high NLR is associated with severe depression (PHQ ≥ 15) (OR:7.23, 2.03–25.74),
poor/fair self-rated health (OR:2.77,1.29–5.96), high SELENA-SLEDAI score(≥ 4) (OR:2.22,1.03–4.78), high PhGA (≥ 2)
(OR:3.76, 1.56–9.05), and presence of damage (SDI ≥ 1) (OR:2.67, 1.11–6.43). High NLR in SLE may indicate depression,
worse quality of life, active disease, and the presence of damage.

Keywords Systemic lupus erythematosus · Depression · Quality of life · Biomarker

5
* Konstantinos Parperis Department of Biostatistics and Epidemiology, Cyprus
[email protected] University of Technology, Limassol, Cyprus
6
1 Department of Rheumatology, Nicosia General Hospital,
Department of Medicine, University of Cyprus Medical
University of Cyprus Medical School, Nicosia, Cyprus
School, Nicosia, Cyprus
7
2 Ygia Polyclinic Hospital, Limassol, Cyprus
Department of Medicine, University of Patras School
8
of Health Sciences, Patras, Greece Department of Internal Medicine, Division of Rheumatology,
3 University of Cyprus Medical School, Palaios Dromos
Department of Internal Medicine, Mount Auburn Hospital,
Lefkosias Lemesou No. 215/6, Aglantzia, 2029 Nicosia,,
Cambridge, MA, USA
Cyprus
4
Harvard Medical School, Boston, MA, USA

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1842 Rheumatology International (2023) 43:1841–1848

Introduction met the American College of Rheumatology (ACR) and/

or Systemic Lupus International Collaborating Clinics
The neutrophil-to-lymphocyte ratio (NLR), is an easily (SLICC)-2012 SLE classification criteria [20] were over
accessible marker, obtained by dividing the neutrophil 18 years old and provided written informed consent. This
count by the number of lymphocytes from a routine blood study was conducted in accordance with the Declaration
sample, which can indicate the balance between adaptive of Helsinki and was approved by the National Bioethics
immunity and systemic inflammation [1]. It demonstrated Committee of Cyprus.
a prognostic value in various conditions, including cardio- During the clinic visit, a thorough clinical evaluation was
vascular diseases [2], cancer [3], and infections [4]. Recent performed, including history, physical examination, and lab-
studies have shown that NLR is associated with disease oratory work-up, which included blood cell counts. Patient
activity in different rheumatic diseases, including polymy- characteristics, such as gender, and age, as well as clinical
algia rheumatica [5], ankylosing spondylitis, rheumatoid characteristics, such as body mass index (BMI) (weight (kg)/
arthritis [6], and Behçet’s disease [7]. A meta-analysis of height2 ­(m2), and the use of glucocorticoids at the time of
nine studies demonstrated a positive correlation between study inclusion, were also recorded. In addition, during this
NLR and Systemic lupus erythematosus (SLE) disease visit, each patient was administered questionnaires evalu-
activity index (SLEDAI), with a correlation coefficient ating the quality of life, depression, disease activity, and
of 0.429 (95%CI = 0.288–0.552, P < 0.001) [8]. However, damage.
there is currently no universally accepted cut-off for NLR
usage in clinical practice [9–13], while its potential as a Physician‑reported measures
marker of other SLE outcomes, such as depression and
quality of life, has not yet been explored. Neutrophil‑to‑lymphocyte ratio
Patients with SLE have a higher prevalence of depres-
sion than the general population, which significantly A complete blood count was performed on study inclusion to
affects their quality of life [14]. The focus of manage- estimate the NLR and the patients were categorized into two
ment is primarily on achieving remission and maintain- groups based on their NLR values. High NLR was defined as
ing low disease activity, while HRQoL is not adequately values ≥ 2.73, which corresponds to the NLR values of the
incorporated into current SLE therapy targets [15]. How- 90th percentile of healthy individuals [21].
ever, patients with SLE can experience diminished qual-
ity of life despite adequate treatment response [16], while Disease activity
HRQoL and depression are important determinants of
treatment adherence and healthcare use [17, 18]. There- Disease activity was evaluated by the physician global
fore, an easily obtainable indicator of HRQoL and depres- assessment (PhGA) for SLE activity, and the Safety of Estro-
sion would be a valuable component of the management gens in Lupus Erythematosus National Assessment–Sys-
of SLE in daily practice. temic Lupus Erythematosus Disease Activity Index instru-
This study aims to expand upon prior research by exam- ment score (SELENA-SLEDAI) [22].
ining the relationship between NLR and disease activ- PhGA involves the clinician’s judgment and uses a cat-
ity in SLE, while also investigating its correlation with egorical scale from 0 to 3 to indicate disease activity. A
lupus-specific health-related quality of life (LupusQoL), score of 0 indicates no disease activity, 1 indicates mild,
depression, and other activity measures of SLE disease. To 2 indicates moderate, and 3 indicates severe disease activ-
our knowledge, this is the first study to comprehensively ity. Scores 2 and 3 were classified as having high disease
evaluate the relationship between NLR and health-related activity.
quality of life or depression in SLE patients. We also utilized the SELENA-SLEDAI, a validated
24-item instrument that quantifies the presence of symp-
toms, conditions, and laboratory findings, to evaluate dis-
ease activity in the 10 days preceding the visit [22]. Active
Materials and methods disease was defined as a score of ≥ 4.

This cross-sectional study was performed using the Disease damage

STROBE reporting guidelines [19] and included patients
diagnosed with SLE who presented to the Division of The Systemic Lupus International Collaborating Clinics/
Rheumatology at our institution between November 2019 American College of Rheumatology (SLICC/ACR) Dam-
and June 2021. Patients were eligible for inclusion if they age Index (SDI) was utilized to evaluate the severity of
SLE-induced damage on 12 organs or systems in the last six

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Rheumatology International (2023) 43:1841–1848 1843

months. These include neuropsychiatric (0–6), ocular (score range of 0–100, with higher scores signifying better quality
0–2), pulmonary (0–5), cardiovascular (0–6), peripheral of life and health status.
vascular (0–5), renal (0–3), gastrointestinal (0–6), gonadal
(0–1), endocrine damage (0–1), musculoskeletal (0–7), skin
Statistical analysis
(0–2), and malignancy (0–2). The SDI score ranges between
0 and 46 [23] Damage was defined as a score ≥ 1.
The data collected were retrospectively analyzed. Summary
statistics with regard to demographic and clinical charac-
Major depressive disorder (MDD) quantification
teristics were presented for all patients as well as for each
NLR group, using the cut-off value of 2.73. Mean (S.D.)
The presence and severity of depression were assessed by
was reported for normally distributed variables and median
the patient health questionnaire (PHQ)-9, which is a vali-
(q1, q3) was reported for not normally distributed varia-
dated 9-item tool that has been validated in the Greek popu-
bles. Comparison between groups was made utilizing the
lation with SLE [24]. Patients complete the PHQ-9 to exam-
student’s t-test or the Wilcoxon test, as appropriate. Cat-
ine the presence and severity of symptoms of depressive
egorical variables were presented as frequency (%) and χ2
symptoms in the last two weeks [25]. Scores range between
test of independence was utilized to compare them between
0–27, with higher scores indicating more severe symptoms
the two groups. Logistic regression models were utilized,
of depression. Scores ≥ 15 indicate severe or moderately
unadjusted, and after adjusting for age, gender, BMI, and
severe depression.
the use of glucocorticoids, to further assess the associations
between the high NLR group and the different outcomes
Patient‑reported measures
considered. Odds ratios (OR) were reported with the cor-
responding p-values and 95%CIs. All tests conducted were
Patient global assessment (PGA)
two-tailed, and an alpha level of significance of 0.05 was
used. No imputation of missing data was conducted. Statis-
Patient global assessment (PGA) was also used to assess
tical analyses were performed using SAS software, version
disease activity in SLE. Patients rated their disease activity
9.4.
on a scale from 0 to 10, with 0 indicating no disease activity
and 10 indicating maximum activity. A PGA score ≥ 7 was
considered indicative of high disease activity.
Results
Patient‑rated health
We included a total of 134 patients with SLE enrolled in the
Patient-rated health was assessed by asking patients, “How Cyprus Lupus Registry, of whom 116 (87.2%) were females
would you rate your current health status?”. Responses were with a mean age of 48 years (Table 1). Table 2 shows the
divided into “excellent or good” versus “fair or poor” [26]. median [Q1, Q3] and the percentage of the different scores
investigated in the study participants as well as in each NLR
Health‑related quality of life (HRQoL) group.
A high NLR (NLR ≥ 2.73) was detected in 47 (35%)
Health-related quality of life (HRQoL) was evaluated utiliz- patients, 39 (85%) of whom were females and the mean age
ing the LupusQol, a specific HRQoL measure for SLE that was 47 years. There were no significant differences in demo-
includes 34 items and 8 domains (pain, planning, physical graphic features between the two NLR groups (NLR ≥ 2.73
health, intimate relationships, body image, burden to others, vs NLR < 2.73) (Table 1). We also compared the indices
fatigue, and emotional health) [27]. Each domain has a score between the two groups, including PHQ-9 score, Lupus QoL

Table 1  Demographic characteristics

Overall NLR < 2.73 NLR >  = 2.73 p-value
N Mean ± S.D. or n(%) N Mean ± S.D. or n(%) N Mean ± S.D. or n(%)

Age 134 48.10 ± 15.05 87 48.66 ± 14.26 47 47.09 ± 16.54 0.566

Gender (% Female) 133 116 (87.2%) 87 77 (88.5%) 46 39 (84.8%) 0.541
BMI (kg/m2) 132 24.67 ± 4.94 86 24.49 ± 4.65 46 25.02 ± 5.46 0.557
Smoking Status (% Yes) 133 35 (26.3%) 87 25 (28.7%) 46 10 (21.7%) 0.383

S.D. Standard deviation, BMI Body Mass Index, NLR Neutrophil to lymphocyte ratio

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1844 Rheumatology International (2023) 43:1841–1848

Table 2  Activity index-SELENA-SLEDAI, Damage index-SLICC/ACR DI, Lupus QoL, PHQ9, Patient global assessment, Self-rated health,
and Physician global assessment
N Overall NLR < 2.73 NLR ≥ 2.73 p-value
Median [Q1, Q3] or N (%) N Median [Q1, Q3] or n (%) N Median [Q1, Q3] or n (%)

PHQ 9 132 86 46 0.033

% Minimal depression 0–4 54 (40.9%) 35 (40.7%) 19 (41.3%)
% Mild depression 5–9 37 (28.0%) 28 (32.6%) 9 (19.6%)
% Moderate depression 10–14 25 (18.9%) 18 (20.9%) 7 (15.2%)
%Moderately severe depression 9 (6.8%) 3 (3.5%) 6 (13.0%)
15–19
% Severe depression 20–27 7 (5.3%) 2 (2.3%) 5 (10.9%)
Depression (PHQ ≥ 10) 132 41 (31.1%) 86 23 (26.7%) 46 18 (39.1%) 0.143
Moderately Severe or Severe 132 16 (12.1%) 86 5 (5.8%) 46 11 (23.9%) 0.002
depression (PHQ ≥ 15)
Lupus QoL
Pain 131 75.0 [41.6, 91.7] 85 75.0 [50.0, 100.0] 46 66.6 [41.6, 83.3] 0.155
Planning 131 75.0 [41.6, 100.0] 85 83.3 [50.0, 100.0] 46 58.3 [33.3, 91.6] 0.010
Physical health 131 68.8 [34.3, 87.5] 85 75.0 [53.1, 93.7] 46 59.4 [28.1, 81.3] 0.012
Intimacy 60 75.0 [50.0, 75.0] 40 75.0 [50.0, 81.2] 20 50.0 [31.3, 75.0] 0.108
Body image 130 87.5 [66.6, 100.0] 85 91.6 [75.0, 100.0] 45 80.0 [55.0, 100.0] 0.028
Burden to others 130 75.0 [58.0, 100.0] 84 79.0 [58.3, 100.0] 46 75.0 [50.0, 100.0] 0.286
Fatigue 131 68.7 [50.0, 87.5] 85 62.5 [50.0, 87.5] 46 68.7 [37.5, 81.2] 0.502
Emotional health 131 79.1 [58.3, 91.6] 85 79.1 [66.6, 91.6] 46 72.9 [50.0, 88.0] 0.154
Self-rated health 134 87 47 0.001
% Poor 7 (5.2%) 2 (2.3%) 5 (10.6%)
% Fair 43 (32.1%) 23 (26.4%) 20 (42.6%)
% Good 67 (50.0%) 45 (51.7%) 22 (46.8%)
% Excellent 17 (12.7%) 17 (19.5%) 0 (0.0%)
Poor/Fair health
% Yes 50 (37.3.%) 25 (28.7%) 25 (53.2%) 0.005
Activity index -SELENA-SLEDAI 134 2 [0, 5] 87 2 [0, 4] 47 4 [2, 8] 0.002
Active disease (SELENA- 61 (45.5%) 33 (37.9%) 28 (59.6%) 0.016
SLEADI ≥ 4)
Physician global assessment 132 1 [0,2] 86 1 [0,1] 46 1 [1, 2] < .001
PhGA (high, scores 2 or 3) 37 (28.0%) 16 (18.6%) 21 (45.7%) < .001
Patient global assessment 134 4 [2, 5] 87 3 [1, 5] 47 5 [3.6] 0.001
PGA ≥ 7 16 (11.9%) 7 (8.0%) 9 (19.1%) 0.059
Damage index—SLICC/ACR DI 134 0 [0,1] 87 0 [0,1] 47 0 [0,2] 0.054
Damage (SLICC/ACR DI ≥ 1) 43 (32.1%) 23 (26.4%) 20 (42.6%) 0.057

SELENA-SLEDAI Safety of Estrogens in Lupus Erythematosus National Assessment—Systemic Lupus Erythematosus Disease Activity Index,
SLICC/ACR DI Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, Lupus QoL Lupus
Quality Of Life, PHQ Patient Health Questionnaire, PhGA Physicial global assessment, PGA Patient global assessment, NLR Neutrophil to lym-
phocyte ratio

domains, self-rated health, SELENA-SLEDAI, PhGA, PGA, the differences in the frequency of depression (PHQ ≥ 10)
and SDI, and the results are demonstrated in Table 2. between the two groups did not reach significance.

NLR and depression in SLE NLR and general health status in SLE

In regard to depression, high NLR was associated with Regarding the impact of SLE on HRQoL, significant differ-
the presence of moderately severe or severe depression ences were found between the high and low NLR groups in
(PHQ ≥ 15) (23.9% vs. 5.8%, p = 0.002) (Table 2). However, various LupusQoL domains (Table 2). Specifically, the high

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Rheumatology International (2023) 43:1841–1848 1845

NLR group had significantly worse planning (median 83 vs of high NLR with the presence of damage (SDI ≥ 1), which
58, p = 0.01), physical health (median 75 vs 59, p = 0.01), was found to be nonsignificant in the unadjusted model,
and body image (median 92 vs 80, p = 0.03) domains became significant following the adjustment. Specifically,
whereas, no significant differences were identified in the the model adjusting for patient demographics and glucocor-
domains of pain, intimacy, burden to others, fatigue, and ticoid use showed that high NLR was significantly associ-
emotional health. Additionally, a significant association was ated with moderately severe/severe depression, defined as
noted between high NLR and worse ratings in self-rated PHQ ≥ 15, with an odds ratio (OR) of 7.23 (95%CI: 2.03,
health, with a significantly higher portion of patients in the 25.74, p = 0.002), poor or fair self-reported health with an
high NLR group rating their health status as poor or fair. OR of 2.77 (95%CI: 1.29, 5.96, p = 0.009), high disease
activity (SLEDAI ≥ 4) with an OR of 2.22 (95%CI:1.03,
NLR and disease activity, as well as damage in SLE 4.78, p = 0.043), high PhGA (≥ 2) with an OR of 3.76
(95%CI:1.56, 9.05, p = 0.003) and presence of damage
The group of patients with high NLR exhibited higher (SDI ≥ 1) with an OR of 2.67 (95%CI:1.11, 6.43, p = 0.028).
disease activity based on the various indices evaluated Additional adjustment for increased disease activity and
(Table 2). Specifically, NLR ≥ 2.73 was associated with sig- presence of damage (SLEDAI ≥ 4 and SDI ≥ 1), demon-
nificantly higher disease activity scores measured with the strated that NLR retained its association with severe depres-
SELENA-SLEDAI, PhGA, and PGA score, Moreover, high sion (OR:6.99, 95%CI:1.85, 26.49, p = 0.004).
NLR was associated with the presence of active disease as
defined by SELENA-SLEDAI (≥ 4), PhGA (≥ 2), and PGA
(≥ 7)) scores albeit the latter did to achieve statistical sig- Discussion
nificance (p = 0.059). The high NLR group also displayed
a trend toward a higher SDI score (p = 0.054) and a greater The current study provides further evidence of the associa-
frequency of damage presence (SDI ≥ 1) (p = 0.057). tion between high NLR and active SLE disease, which is
consistent with previous studies [8–10]. Importantly, it was
The relationship of NLR with depression, general also found that high NLR, using a cut-off of 2.73, which
health status, disease activity, and damage adjusted corresponds to the 90th percentile of the healthy population
for age, gender, BMI, and glucocorticoid use [21], was significantly associated with the presence of severe
depression and worse health-related quality of life.
The current study utilized logistic regression models to The prevalence of depression in SLE patients is higher
examine the relationship between NLR and various indices compared to the general population [14]. Although major
of disease activity (Table 3). The unadjusted model indi- depression has been associated with NLR [28], this asso-
cated a significant association between high NLR and severe ciation has not been previously investigated in patients
depression (PHQ ≥ 15), poor or fair self-reported health, with SLE. In this study, an association was identified
high disease activity (SLEDAI ≥ 4), and high PhGA (≥ 2). between the presence of severe/moderately severe depres-
When adjusting for age, gender, BMI, and glucocorticoid sion (defined as PHQ-9 ≥ 15) and high NLR. While the
use, similar results were obtained. Notably, the association disease activity has been associated with both the severity

Table 3  Logistic regression Unadjusted models Models adjusted for age, gender,
analysis for the effect of BMI, and use of glucocorticoid
NLR ≥ 2.73
OR 95% CI p-value OR 95% CI p-value

Severe depression (PHQ ≥ 15) 5.09 (1.65, 15.74) 0.005 7.23 (2.03, 25.74) 0.002
Poor/fair self-rated health 2.82 (1.35, 5.89) 0.006 2.77 (1.29, 5.96) 0.009
High disease activity (SELENA- 2.41 (1.17, 4.98) 0.018 2.22 (1.03, 4.78) 0.043
SLEADI ≥ 4)
High PhGA (≥ 2) 3.68 (1.66, 8.14) 0.001 3.76 (1.56, 9.05) 0.003
High PGA (≥ 7) 2.71 (0.94, 7.82) 0.066 2.47 (0.81, 7.53) 0.111
Damage (SLICC/ACR DI ≥ 1) 2.06 (0.97, 4.36) 0.059 2.67 (1.11, 6.43) 0.028

OR odds ratio, CI confidence interval, PHQ Patient Health Questionnaire, SELENA-SLEDAI Safety of
Estrogens in Lupus Erythematosus National Assessment—Systemic Lupus Erythematosus Disease Activ-
ity Index, SLICC/ACR DI Systemic Lupus International Collaborating Clinics/American College of Rheu-
matology Damage Index, PhGA Physician global assessment, PGA Patient global assessment, BMI body
mass index

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of depression [29] and NLR values [8], the association PhGA, particularly those with a score of two or more, further
between high NLR and the presence of severe/moderately supporting the relationship of NLR with disease activity.
severe depression (defined as PHQ-9 ≥ 15) was replicated The prevalence of high NLR in the population of our
even after adjusting for various confounders, including study (35%) was higher than in the general population (10%)
age, gender, BMI, use of glucocorticoids, disease activity, [21], which is consistent with previous studies [8, 30]. This
and organ damage. These findings have important clinical disparity in NLR values indicates that certain features of
implications, as they suggest that high NLR may serve as the disease affect NLR. In particular, NLR has been associ-
a useful marker to identify moderate and severe depres- ated with key immunopathologic features of SLE: immune
sion in SLE, regardless of disease activity. This finding complex-mediated inflammation with the presence of anti-
could alert clinicians to screen SLE patients with high double-stranded DNA antibodies, type I interferon activity,
NLR for depression and refer them accordingly to mental circulating immunocomplexes, as well as neutrophil abnor-
health providers for further assessment and management. malities, such as enrichment for low-density granulocytes
Further studies examining this association in SLE patients and the neutrophil activation marker, calprotectin [21].
are necessary to confirm the findings of this study. This These associations support the relationship between high
study is the first to evaluate the association between NLR NLR and disease activity, underscoring the potential role of
and disease-specific HRQoL using the Lupus QoL. High NLR as a disease activity marker.
NLR was associated with reduced scores in the domains The present study also provides evidence that high NLR
of planning, physical health, and body image. These find- is associated with organ damage as measured by the SLICC/
ings highlight the relationship of high NLR with HRQoL ACR DI, suggesting that NLR may serve as a marker of
and indicate that NLR could serve as a useful tool for disease-related damage. This finding is consistent with
early recognition and prevention of poor quality of life Abdulrahman et al.[31] who also demonstrated a positive
in SLE. A strong association was also observed between correlation between SDI and NLR, among patients with
high NLR and poor self-reported health. Specifically, a lupus nephritis.
significantly higher percentage of patients in the high NLR This study has limitations that should be acknowledged.
group reported “poor” or “fair” health, with no patient Firstly, the relatively small number of patients included in
reporting “excellent” self-rated health in this group. This the study may have limited the statistical power. Secondly,
highlights the value of NLR as a marker of the patients’ due to the cross-sectional design of this study, NLR val-
overall sense of well-being. Although the impact of dis- ues were measured only at a specific point in time and this
ease activity as a potential cofounder cannot be excluded, may not reflect the longitudinal changes in NLR over time.
these findings provide insights into the potential role of Additionally, the study was conducted in Cyprus, a country
NLR as an indicator of the quality of life impairment, even with a predominantly Caucasian population; therefore, gen-
when considering the influence of disease activity. None- eralizing the results to patients from different racial groups
theless, to better understand the relationship between NLR should be done with caution. Moreover, it is important to
and quality of life measures in SLE, further research is note that there was no adjustment specifically for disease
warranted, adjusting for additional potential confounders activity when assessing the poor quality of life, which does
such as disease activity. not allow us to fully exclude the potential confounding effect
Previous studies investigated the association between NLR of disease activity on the observed association between NLR
and disease activity in SLE patients. These studies have sug- and quality of life. Finally, although the associations found
gested a variety of NLR cut-offs, as the optimal to indicate were adjusted for glucocorticoid use, other factors such as
high disease activity, ranging from 2.065 to 2.94 [9–13]. This the magnitude of the dose, other medications, and comor-
heterogeneity in values might reflect the differences in the bidities may also influence the NLR and therefore act as
characteristics of the population studied, the limited number potential confounding factors.
of participants, and the difference in the definition of active Further investigation with larger prospective cohort stud-
disease in each study. The present study demonstrated that ies is needed to validate our findings and better characterize
patients with NLR ≥ 2.73 had significantly higher scores of the relationship of NLR with HRQol, depression, and other
disease activity (SELENA-SLEDAI) and were more likely outcomes, such as treatment response and mortality.
to have active disease (SELENA-SLEDAI ≥ 4). Han et al.
[21], who also used the same NLR cut-off, found a significant
association between high NLR and the presence of active dis- Conclusion
ease, although a different definition of active disease was used
(SLEDAI-2 K > 0), and the difference in the disease activity In conclusion, the present study shows that in patients
score, in general, was not significant. Furthermore, our study with SLE, high NLR is associated with severe depression,
found that high NLR was associated with greater scores of poorer self-rated health, impaired health-related quality of

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Rheumatology International (2023) 43:1841–1848 1847

life, active disease, and the presence of underlying disease- adaptation, distribution and reproduction in any medium or format,
related damage. Consequently, the results of this study as long as you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons licence, and indicate
can guide clinicians to recognize lupus exacerbations if changes were made. The images or other third party material in this
or active disease early and commence treatment accord- article are included in the article's Creative Commons licence, unless
ingly. Regardless, clinical judgment and caution should indicated otherwise in a credit line to the material. If material is not
be exercised in the interpretation of NLR, given that NLR included in the article's Creative Commons licence and your intended
use is not permitted by statutory regulation or exceeds the permitted
has been shown to be increased in many inflammatory use, you will need to obtain permission directly from the copyright
processes like sepsis [32], and it is advisable to be used holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​
with other indicators of disease activity. Furthermore, high org/​licen​ses/​by/4.​0/.
NLR may signal the presence of underlying depression
and impaired quality of life. These suggest its potential to
serve as a valuable marker not only for disease activity but References
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Acknowledgements The authors would like to express our sincere Neutrophil lymphocyte ratio and cardiovascular disease
gratitude to all the study participants for their invaluable contribution risk: a systematic review and meta-analysis. Biomed Res Int
to the Cyprus Lupus Registry. Furthermore, the authors would like 2018:2703518. https://​doi.​org/​10.​1155/​2018/​27035​18
to acknowledge the financial support received from the University of 3. Templeton AJ, McNamara MG, Šeruga B et al (2014) Prog-
Cyprus through start-up funding. Part of this work was presented as a nostic role of neutrophil-to-lymphocyte ratio in solid tumors: a
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Author contributions All authors contributed substantially to the study with disease activity in polymyalgia rheumatica. J Clin Lab
conception and design of this work. Data collection was performed Anal 33:e23000. https://​doi.​org/​10.​1002/​jcla.​23000
by EP, LK, VH, and KP and the statistical analysis was performed by 6. Mercan R, Bitik B, Tufan A et al (2016) The association
CC. The first draft of the manuscript was written by EP and all authors between neutrophil/lymphocyte ratio and disease activity in
revised it critically for important intellectual content. This project was rheumatoid arthritis and ankylosing spondylitis. J Clin Lab Anal
coordinated by KP. The final manuscript was read and approved by 30:597–601. https://​doi.​org/​10.​1002/​jcla.​21908
all authors for publication. All authors agree to be accountable for all 7. Yolbas S, Yildirim A, Gozel N et al (2016) Hematological indi-
aspects of this work. ces may be useful in the diagnosis of systemic lupus erythema-
tosus and in determining disease activity in behçet’s disease.
Funding The study was supported by the start-up funding provided by Med Princ Pract Int J Kuwait Univ Heal Sci Cent 25:510–516.
the University of Cyprus. https://​doi.​org/​10.​1159/​00044​7948
8. Ma L, Zeng A, Chen B et al (2019) Neutrophil to lymphocyte
Data availability Data for this manuscript are not openly shared. ratio and platelet to lymphocyte ratio in patients with systemic
lupus erythematosus and their correlation with activity: a meta-
Declarations analysis. Int Immunopharmacol 76:105949. https://​doi.​org/​10.​
1016/J.​INTIMP.​2019.​105949
Conflict of interest Authors E.P, L.K, CC, SP, VH, KP declare that 9. Qin B, Ma N, Tang Q et al (2016) Neutrophil to lymphocyte
they have no conflict of interest. None of the authors has any financial ratio (NLR) and platelet to lymphocyte ratio (PLR) were useful
or non-financial interests that are directly or indirectly related to the markers in assessment of inflammatory response and disease
work submitted for this publication to disclose. activity in SLE patients. Mod Rheumatol 26:372–376. https://​
doi.​org/​10.​3109/​14397​595.​2015.​10911​36
Ethical approval This study was conducted in line with the principles 10. Soliman WM, Sherif NM, Ghanima IM, EL-Badawy MA (2018)
of the 1964 Declaration of Helsinki and its later amendments. The Neutrophil to lymphocyte and platelet to lymphocyte ratios in
study protocol number is EEBK/2019/03 and it was approved by the systemic lupus erythematosus: relation with disease activity and
National Bioethics Committee of Cyprus on March 4th, 2019. lupus nephritis. Reumatol Clin. https://​doi.​org/​10.​1016/j.​reuma.​
2018.​07.​008
Consent to participate Written informed consent was obtained from 11. Firizal AS, Sugianli AK, Hamijoyo L (2020) Cut off point of
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Open Access This article is licensed under a Creative Commons 12. Wu Y, Chen Y, Yang X et al (2016) Neutrophil-to-lymphocyte
Attribution 4.0 International License, which permits use, sharing, ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were

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