ORIGINAL RESEARCH

published: 16 April 2021

doi: 10.3389/fmed.2021.651249

Adverse Health-Related Quality of

Life Outcome Despite Adequate
Clinical Response to Treatment in
Systemic Lupus Erythematosus
Alvaro Gomez 1,2 , Victor Qiu 1,2 , Arvid Cederlund 1,2 , Alexander Borg 1,2 , Julius Lindblom 1,2 ,
Sharzad Emamikia 1,2 , Yvonne Enman 1,2 , Jon Lampa 1,2 and Ioannis Parodis 1,2*
1
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden, 2 Department of
Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden

Objective: To determine the prevalence of adverse health-related quality of life

(HRQoL) outcomes in patients with SLE who achieved an adequate clinical response
after a 52-week long standard therapy plus belimumab or placebo, and identify
contributing factors.
Edited by:
Methods: We included patients who met the primary endpoint of the BLISS-52
Chi Chiu Mok,
Tuen Mun Hospital, Hong Kong (NCT00424476) and BLISS-76 (NCT00410384) trials, i.e., SLE Responder Index 4 (total
Reviewed by: population: N = 760/1,684; placebo: N = 217/562; belimumab 1 mg/kg: N = 258/559;
Hsin-Hua Chen, belimumab 10 mg/kg: N = 285/563). Adverse HRQoL outcomes were defined as SF-36
Taichung Veterans General
Hospital, Taiwan
scale scores ≤ the 5th percentile derived from age- and sex-matched population-based
Gianluca Bagnato, norms, and FACIT-Fatigue scores <30. We investigated factors associated with adverse
University of Messina, Italy
HRQoL outcomes using logistic regression analysis.
*Correspondence:
Ioannis Parodis Results: We found clinically important diminutions of HRQoL in SLE patients compared
[email protected] with matched norms and high frequencies of adverse HRQoL outcomes, the highest in
SF-36 general health (29.1%), followed by FACIT-Fatigue (25.8%) and SF-36 physical
Specialty section:
This article was submitted to functioning (25.4%). Overall, frequencies were higher with increasing age. Black/African
Rheumatology, American and White/Caucasian patients reported higher frequencies than Asians and
a section of the journal
Frontiers in Medicine
Indigenous Americans, while Hispanics experienced adverse HRQoL outcome less
frequently than non-Hispanics. Established organ damage was associated with adverse
Received: 09 January 2021
Accepted: 22 March 2021 physical but not mental HRQoL outcomes; particularly, damage in the cardiovascular
Published: 16 April 2021 (OR: 2.12; 95% CI: 1.07–4.21; P = 0.032) and musculoskeletal (OR: 1.41; 95% CI:
Citation: 1.01–1.96; P = 0.041) domains was associated with adverse SF-36 physical component
Gomez A, Qiu V, Cederlund A, Borg A,
Lindblom J, Emamikia S, Enman Y, summary. Disease activity showed no impact on HRQoL outcomes. In multivariable
Lampa J and Parodis I (2021) Adverse logistic regression analysis, addition of belimumab to standard therapy was associated
Health-Related Quality of Life
with lower frequencies of adverse SF-36 physical functioning (OR: 0.59; 95% CI:
Outcome Despite Adequate Clinical
Response to Treatment in Systemic 0.39–0.91; P = 0.016) and FACIT-F (OR: 0.53; 95% CI: 0.34–0.81; P = 0.004).
Lupus Erythematosus.
Front. Med. 8:651249.
Conclusions: Despite adequate clinical response to standard therapy plus belimumab
doi: 10.3389/fmed.2021.651249 or placebo, a substantial proportion of SLE patients still reported adverse HRQoL

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Gomez et al. Adverse HRQoL Outcome in SLE

outcomes. While no impact was documented for disease activity, established organ
damage contributed to adverse outcome within physical HRQoL aspects and add-on
belimumab was shown to be protective against adverse physical functioning and
severe fatigue.

Keywords: systemic lupus erythematosus, health-related quality of life, patient-reported outcome, fatigue,
biologic drugs, patient perscpective

INTRODUCTION Rheumatology (ACR) criteria (16), an active disease defined as

a Safety of Estrogens in Lupus National Assessment Systemic
Systemic lupus erythematosus (SLE) is a chronic autoimmune Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI)
disease with a highly heterogeneous clinical presentation. A (17) score ≥6, and antinuclear antibody (ANA) titre ≥1:80
better understanding of the subtleties of the disease together with and/or serum anti-double stranded (ds)DNA antibody level ≥30
improvements in medical care have contributed to prolonged life IU/mL. Key exclusion criteria included pregnancy, severe active
expectancy for SLE patients over the past decades (1). However, lupus nephritis and active neuropsychiatric SLE. Patients mainly
people living with SLE still suffer from substantial diminutions of from Asia, Eastern Europe and Latin America were enrolled in
health-related quality of life (HRQoL) compared with the general BLISS-52, and from North America and Europe in BLISS-76.
population and with other chronic diseases (2). The primary endpoint of the trials was achievement of the
Divergent disease prevalence, clinical manifestations, disease SLE responder index 4 (SRI-4) at week 52, defined as ≥4 points
course and mortality rates between sexes and across ethnic reduction in the SELENA-SLEDAI score compared with baseline,
groups contribute to the heterogeneity of SLE (3, 4). Overall, no new classic British Isles Lupus Assessment Group Index
patients of Black/African American or Asian origin have an (BILAG) (18) A organ domain score and no more than one
increased risk for SLE than White/Caucasian individuals, and new BILAG B organ domain scores compared with baseline,
show more severe disease phenotypes. The implications of these and no worsening in the physician’s global assessment (PGA)
discrepancies across ethnic groups in SLE patients’ HRQoL by ≥0.30 points (range: 0–3) from baseline. Of 1,684 study
perception have not been thoroughly delineated. participants, 760 met the criteria for SRI-4 response at week 52,
Some studies have demonstrated that conventional and constituted the study population of this post-hoc analysis.
synthetic and biological disease-modifying agents contribute to The frequency of SRI-4 responders was 217/562 in the placebo
improvements in SLE patients’ HRQoL (5–9), and responders arm, 258/559 in the belimumab 1 mg/kg arm, and 285/563 in
to treatment have been shown to report greater improvements the belimumab 10 mg/kg arm. Accordingly, evaluation of adverse
than non-responders (10, 11). Although these observations HRQoL outcomes was based on patient reports at week 52 from
are clinically relevant, improvement following a therapeutic treatment initiation.
intervention does not necessarily signify that the individual has
achieved a satisfactory health perception. In rheumatoid arthritis Demographics and Clinical Characteristics
(RA), significant pain and severe fatigue persist in a substantial We retrieved data on disease activity assessed with the Systemic
proportion of patients who achieve a good clinical response to Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)
treatment or remission (12, 13). This paradoxical observation (19), and data on organ damage assessed with the Systemic Lupus
has not been thoroughly explored in SLE. International Collaborating Clinics (SLICC)/ACR Damage Index
In the present investigation, we aimed to determine the (SDI) (20).
prevalence of adverse HRQoL outcomes in patients with SLE Patients were stratified into four ancestry groups based on
who achieved an adequate clinical response after a 52-week long self-reports, i.e., Asian, Black/African American, Indigenous
period on standard therapy (ST) plus belimumab or placebo American and White/Caucasian. Additionally, they were
within the frame of two phase III clinical trials. We further stratified into Hispanics and non-Hispanics, as well as
compared frequencies of adverse HRQoL outcomes across subgroups based on their country of residence, as detailed
different age categories and ethnic groups, and sought to identify in Supplementary Table 1.
contributing factors.
Evaluation of HRQoL
MATERIALS AND METHODS HRQoL was assessed utilising the generic instruments Medical
Outcomes Study Short Form 36 (SF-36) health survey (21)
Study Design and Population and Functional Assessment of Chronic Illness Therapy (FACIT)
We designed a post-hoc analysis of data from two randomised, Fatigue (FACIT-F) scale (22). Importantly, the psychometric
double blind, phase III clinical trials, i.e., BLISS-52 properties of these two instruments have been reviewed in
(NCT00424476) (14) and BLISS-76 (NCT00410384) (15), compliance with the US Food and Drug Administration
which comprised 865 and 819 SLE patients, respectively. (FDA) (23) under the auspices of the Outcome Measures
Inclusion criteria for both trials were age ≥18 years, SLE in Rheumatology (OMERACT) SLE working group, and are
diagnosis according to the revised 1997 American College of suggested as secondary endpoints in clinical trials (24).

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Gomez et al. Adverse HRQoL Outcome in SLE

The SF-36 is a questionnaire used for assessment of HRQoL Statistics

over the preceding 4 weeks. Computation of patients’ responses Data are presented as number (percentage) or mean ± standard
to 36 questions results in eight subscales, each representing deviation (SD) and, in case of non-normal distributions, the
a distinct HRQoL aspect, i.e., physical functioning (PF), role median and interquartile range (IQR) are indicated. Pearson’s
physical (RP), bodily pain (BP), general health (GH), social chi-square or Fisher’s exact tests were used to investigate
functioning (SF), vitality (VT), role emotional (RE) and mental associations between dichotomous variables. Comparisons of
health (MH). SF-36 subscale scores were calculated according continuous data between SLE patients and age- and sex-
to the SF-36v2 manual (25), and transformed to generate matched norms, as well as comparisons between baseline and
subscale scores ranging from 0 to 100. Subsequently, the SF- week 52, were performed using the Wilcoxon signed-rank test.
36 subscale scores are weighted into two summary scores, i.e., Comparisons of continuous data between unrelated groups were
the physical component summary (PCS) and mental component conducted using the Mann-Whitney U test, and across more
summary (MCS). The component summary scores are norm- than two groups using the Kruskal-Wallis test. Multivariable
based, with a mean of 50 and a standard deviation of 10. logistic regression models were created in order to assess
All subscales contribute to the derivation of PCS and MCS, independence and priority of potential factors associated with
albeit differently weighted in each one of them. PF, RP, BP, adverse HRQoL outcomes.
and GH are referred to as the physical aspects, and SF, VT, P-values <0.05 were considered statistically significant.
RE, and MH are referred to as the mental aspects of SF- Missing data were imputed using the last observation carried
36. Higher scores in SF-36 items are interpreted as better forward (LOCF) or next observation carried backward (NOCB)
HRQoL perceptions. As suggested in literature, we determined methods as appropriate. The IBM SPSS version 25 software (IBM
the minimal clinically important difference (MCID) for PCS Corp., NY, USA) was used for statistical analysis.
and MCS as scores ≥2.5 and for SF-36 subscales as scores
≥5.0 (26). After management of missing values, all SRI- Ethics
4 responders had available SF-36 registrations at week 52 Data from the BLISS trials were made available by
(N = 760). GlaxoSmithKline (Uxbridge, UK) through the Clinical Study
The FACIT-F is a survey that evaluates the level of fatigue over Data Request consortium. The BLISS-52 and BLISS-76 study
the preceding seven days (22). Patient responses to the 13 items of protocols were approved by regional ethics review boards
FACIT-F are transformed into a score ranging from 0 (maximal for all participating centres, and the protocol of the present
fatigue) to 52 (minimal fatigue). After management of missing study was approved by the Swedish Ethical Review Authority
values, the number of SRI-4 responders with available FACIT-F (2019-05498).
registrations at week 52 was 745.
RESULTS
Definition of Adverse HRQoL Demographics and Clinical Characteristics
To our knowledge, no established definitions of adverse HRQoL Demographics and clinical characteristics of the SRI-4
outcomes based on specific cut-offs in SF-36 subscale and responders (N = 760) are presented in Table 1. They were
component summary scores exist for SLE. We created a US mainly women (94.3%) of middle-age (37.3 ± 11.4 years) with
population-based reference group, pairwise matched for age and a median disease duration of 3.9 (IQR: 1.2–8.5) years. The
sex with the BLISS study participants, using normative data from most represented ancestries were White/Caucasian (46.2%) and
the SF-36 health survey user manual (27, 28). Indigenous American (27.6%), whereas 42.0% of the patients
First, we compared the mean SF-36 subscale and component reported Hispanic ethnicity. The mean SLEDAI-2K score at
summary scores of SRI-4 responders with the corresponding week 52 was 3.8 (±2.9), and 453 patients (59.6%) had zero SDI
scores as derived from the age- and sex-matched norms. Next, scores (IQR: 0–1).
we determined adverse HRQoL. In a cohort of patients with
RA, Druce et al. defined severe fatigue as SF-36 VT scores HRQoL Outcome at Week 52 of Treatment
corresponding to the 5th percentile of VT scores derived from As illustrated in Figure 1, patients with SLE who achieved SRI-
a Scottish general population-based reference group that was 4 response reported worse HRQoL at week 52 from treatment
matched for age and sex with the patients (29). Following a initiation than US population-based norms individually matched
similar approach, we defined adverse HRQoL outcomes in SF- for age and sex (P < 0.001 for all SF-36 scales), which
36 as subscale or component summary scores equal to or less exceeded the MCID in all SF-36 items but VT (Figures 1A,B;
than the normative 5th percentile (NP5), as derived from the Supplementary Table 2). The differences were most prominent
reference group described above. Following this process, the NP5 for GH, RP and PF, yielding 4.2, 3.6, and 3.5 times the
for each SF-36 scale yielded the following values, as previously MCID lower mean scores than the matched norms, respectively.
reported by our group (30): PF ≤52.5; RP ≤29.8; BP ≤38.6; GH Figure 2 delineates proportions of SRI-4 responders who
≤41.0; VT ≤25.4; SF ≤46.2; RE ≤26.6; MH ≤43.4; PCS ≤36.0; reported adverse HRQoL outcomes at week 52 from treatment
MCS ≤34.5. initiation. Overall, proportions of patients experiencing adverse
FACIT-F values <30 represent severe fatigue (22), and herein HRQoL outcomes were higher within physical vs. mental aspects,
designated adverse FACIT-F outcome. with GH (29.1%) and PF (25.4%) being the SF-36 domains

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Gomez et al. Adverse HRQoL Outcome in SLE

TABLE 1 | Demographics and clinical characteristics of SRI-4 responders in the pooled BLISS study population.

SRI-4 responders Hispanics Non-Hispanics P-value

N = 760 N = 319 N = 441

Patient characteristics
Age at baseline (years) 37.3 ± 11.4 36.5 ± 10.6 37.9 ± 11.9 0.170
Female sex 717 (94.3%) 302 (94.7%) 415 (94.1%) 0.739
Ancestries
Asian 144 (18.9%) 0 144 (32.7%) <0.001
Black/African American 55 (7.2%) 99 (31.0%) 252 (57.1%) <0.001
Indigenous American* 210 (27.6%) 15 (4.7%) 40 (9.1%) 0.022
White/Caucasian 351 (46.2%) 205 (64.3%) 5 (1.1%) <0.001
Clinical data
SLE duration at baseline (years) 5.8 (1.2–8.5) 5.1 (1.0–7.8) 6.3 (1.4–9.0) 0.017
SLEDAI-2K score
Baseline 10.7 ± 3.6 10.6 ± 3.5 10.7 ± 3.6 0.888
Week 52 3.8 ± 2.9 3.6 ± 2.7 3.9 ± 3.0 0.332
SDI score
Baseline 0.7 ± 1.1 0.0 (0.0–1.0) 0.5 ± 1.0 0.0 (0.0–1.0) 0.8 ± 1.2 0.0 (0.0–1.0) <0.001
Week 52 0.7 ± 1.2 0.0 (0.0–1.0) 0.5 ± 1.0 0.0 (0.0–1.0) 0.9 ± 1.3 0.0 (0.0–1.0) <0.001
SDI score > 0
Baseline 293 (38.6%) 90 (28.2%) 203 (46.0%) <0.001
Week 52 307 (40.4%) 96 (30.1%) 211 (47.8%) <0.001
Serological profile at baseline
Anti-dsDNA (+) 517 (68.0%) 216 (67.7%) 301 (68.3%) 0.874
Anti-Sm (+) 224 (29.6%); N = 758 109 (34.2%) 115 (26.2%); N = 439 0.018
Low C3 311 (40.9%) 122 (38.2%) 189 (42.9%) 0.202
Low C4 395 (52.0%) 165 (51.7%) 230 (52.2%) 0.907
Prednisone eq. dose (mg/day)
Baseline 11.7 ± 9.0 12.5 ± 9.1 11.1 ± 9.0 0.028
Week 52 8.7 ± 6.8; N = 754 9.4 ± 7.2; N = 318 8.2 ± 6.6; N = 436 0.022
Antimalarial agents at week 52† 478 (62.9%) 223 (69.9%) 255 (57.8%) 0.001
Immunosuppressants at week 52
Azathioprine 149 (19.6%) 76 (23.8%) 73 (16.6%) 0.013
Methotrexate 78 (10.3%) 36 (11.3%) 42 (9.5%) 0.430
Mycophenolic acid 72 (9.5%) 25 (7.8%) 47 (10.7%) 0.190
Other immunosuppressants‡ 15 (2.0%) 6 (1.9%) 9 (2.0%) 0.876
Trial intervention
Placebo 217 (28.6%) 95 (29.8%) 122 (27.7%) 0.524
Belimumab 1 mg/kg 258 (33.9%) 113 (35.4%) 145 (32.9%) 0.465
Belimumab 10 mg/kg 285 (37.5%) 111 (34.8%) 174 (39.5%) 0.190

Data are presented as numbers (percentage) or means ± standard deviation. In case of non-normal distributions, medians (interquartile range) are indicated. In case of missing values,
the total number of patients with available data is indicated. Statistically significant P-values are in bold.
*Alaska Native or American Indian from North, South or Central America.
† Hydroxychloroquine, chloroquine, mepacrine, mepacrine hydrochloride or quinine sulphate.
‡ Cyclosporine, oral cyclophosphamide, leflunomide, mizoribine or thalidomide.

C3, complement component protein 3; C4, complement component protein 4; dsDNA, double stranded DNA; SDI, Systemic Lupus International Collaborating Clinics (SLICC)/American
College of Rheumatology (ACR) Damage Index; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000; Sm, Smith; SRI-4, SLE Responder Index 4.

yielding the highest frequencies (Figure 2A). SF-36 VT scores observed for SF-36 GH ≤NP5 (29.1% vs. 47.2%). Moreover,
≤NP5 were reported by 10.7% of SRI-4 responders, whereas SRI-4 responders displayed improvements in all SF-36 subscale
25.8% reported FACIT-F scores <30. As expected, frequencies scores from baseline through week 52 (Figure 1B); while
of adverse HRQoL outcome at week 52 were lower in SRI- they generally reported similar scores to non-responders at
4 responders compared with non-responders with regard to baseline (Figure 1C), they scored higher in all subscales at
all SF-36 items and FACIT-F score <30 (P < 0.001 for all; week 52 (Figure 1D). Consequently, SRI-4 responders reported
Supplementary Table 3), with the greatest absolute difference lower proportions of adverse HRQoL at week 52 compared

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Gomez et al. Adverse HRQoL Outcome in SLE

FIGURE 1 | SF-36 scores among SRI-4 responders and non-responders before and after trial intervention. The bar chart (A) illustrates comparisons of SF-36
component summary scores between SRI-4 responders at week 52 and age- and sex-matched US population-based norms. The height of the bars represents mean
scores, while the height of the whiskers above the bars represents standard deviation. The radial charts illustrate comparisons of mean SF-36 subscale scores
between (A) SRI-4 responders at week 52 and age- and sex-matched US population-based norms, (B) baseline and week 52 in SRI-4 responders, (C) SRI-4
responders and non-responders at baseline, and (D) SRI-4 responders and non-responders at week 52. Asterisks indicate statistically significant associations. BP,
bodily pain; GH, general health; MCID, minimal clinically important difference; MCS, mental component summary; MH, mental health; NP5, normative 5th percentile;
PCS, physical component summary; PF, physical functioning; RE, role emotional; RP, role physical; SF, social functioning; SF-36, short form 36 health survey; SLE,
systemic lupus erythematosus; VT, vitality; 1, delta (difference).

with baseline (P < 0.001 for all SF-36 items and FACIT-F; in Figure 3, proportions of patients with adverse SF-36
Supplementary Table 4). PCS differed across ancestries (P = 0.018); Black/African
Americans showed the highest frequency (21.8%), followed
Adverse HRQoL Outcomes Across Age by White/Caucasians (21.4%), while Asian and Indigenous
Categories American patients reported the lowest frequencies (12.5 and
We observed gradually higher frequencies of adverse HRQoL 12.9%, respectively). Similar patterns were observed for adverse
outcomes within SF-36 physical subscales with increasing age PF (P = 0.019) and GH (P = 0.003), within which Black/African
category (Figure 2B); of 62 patients aged 55+ years, 26 (41.9%) Americans reported the highest (38.2 and 36.4%, respectively)
reported adverse PF and 25 (40.3%) reported adverse GH. The and Indigenous Americans the lowest (19.0 and 20.5%,
frequency of adverse HRQoL outcomes within SF-36 mental respectively) frequencies.
subscales also increased with age, but peaked in the category of Within the SF-36 mental scales, proportions of patients
45–54 years. We found greater proportions of patients reporting reporting adverse HRQoL outcomes differed regarding MCS
FACIT-F scores <30 within higher age categories, which however (P = 0.007), VT (P < 0.001) and MH (P = 0.002). With
plateaued from 35 years of age (Figures 2B,C). regard to these three SF-36 scales, White/Caucasians showed the
highest frequencies (21.4, 16.2, and 14.2%, respectively), whereas
Comparisons Across Ancestries Indigenous Americans reported the lowest frequencies in all SF-
Table 2 shows demographics and clinical characteristics of the 36 mental subscales, i.e., 8.1% within SF, 5.2% within MH and
study participants stratified by their ancestry. As delineated 3.8% within VT and RE (Figure 3).

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Gomez et al. Adverse HRQoL Outcome in SLE

FIGURE 2 | Adverse HRQoL outcome despite clinical improvement. This figure illustrates the prevalence of adverse HRQoL outcomes. Panel (A) shows frequencies
of adverse HRQoL outcome defined as SF-36 physical and mental scale scores ≤NP5, and panel (B) shows their cumulative frequencies within different age
categories. Panel (C) shows frequencies of FACIT-F scores <30, including frequencies within different age categories. BP, bodily pain; FACIT-F, Functional Assessment
of Chronic Illness Therapy–Fatigue; GH, general health; MCS, mental component summary; MH, mental health; n, number of patients reporting adverse HRQoL
outcomes; N, total number of patients with available data; NP5, normative 5th percentile; PCS, physical component summary; PF, physical functioning; RE, role
emotional; RP, role physical; SF, social functioning; SF-36, short form 36 health survey; SLE, systemic lupus erythematosus; VT, vitality.

Comparisons Across Country Groups vs. 6.3; 1.4–9.0 years; P = 0.017), and fewer patients among
A similar analysis, albeit stratifying the patients by country Hispanics had SDI scores >0 at baseline (28.2 vs. 46.0%;
groups, is presented in Figure 4. The demographics and clinical P < 0.001) and week 52 (30.1 vs. 47.8%; P < 0.001). At
characteristics of these groups are shown in Table 3. week 52, Hispanics were on slightly higher mean prednisone
Patients residing in Canada/USA most frequently reported or prednisone equivalent doses (9.4 ± 7.2 vs. 8.2 ± 6.6
adverse outcome in all physical SF-36 items (13.2–45.0%), mg/day; P = 0.022), and a higher percentage among them
whereas patients from Latin America showed the lowest were on antimalarial agents (69.9 vs. 57.8%; P = 0.001;
frequencies (5.5–21.4%). Within mental HRQoL aspects, patients Table 1).
residing in Canada/USA and Europe/Israel most frequently As seen in Figure 5, frequencies of patients reporting adverse
reported adverse VT (19.2 and 17.6%, respectively) and HRQoL outcomes in the physical domains of SF-36 were
FACIT-F (45.7 and 31.8%, respectively), and the highest lower in Hispanics vs. non-Hispanics regarding PCS (12.2 vs.
frequencies of adverse MH were seen among patients from 21.1%; odds ratio, OR: 0.52; 95% confidence interval, CI: 0.35–
Europe/Israel (15.5%). 0.58; P = 0.001), PF (19.7 vs. 29.5%; OR: 0.59; 95% CI:
0.42–0.83; P = 0.002) and GH (21.0 vs. 34.9%; OR: 0.50;
Comparisons Between Hispanics and 95% CI: 0.36–0.69; P < 0.001). With regard to the mental
Non-hispanics compartment of SF-36, a lower proportion of Hispanic patients
Patients of Hispanic/Latin American ethnicity had shorter reported adverse VT (4.1%) compared with non-Hispanics
disease duration than non-Hispanics (median; IQR: 5.1; 1.0–7.8 (15.4%; OR: 0.23; 95% CI: 0.13–0.43; P < 0.001). Likewise,

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Gomez et al. Adverse HRQoL Outcome in SLE

TABLE 2 | Demographics and clinical characteristics of patients across different ancestries.

Asian Black/ Indigenous American White/ P-value

N = 144 African American N = 210 Caucasian
N = 55 N = 351

Patient characteristics
Age at baseline (years) 32.7 ± 9.4 38.5 ± 11.9 36.7 ± 10.4 39.4 ± 12.0 <0.001
Female sex 136 (94.4%) 53 (96.4%) 201 (95.7%) 327 (93.2%) 0.556
Clinical data
SLE duration at baseline (years) 5.0 (0.7–7.5) 6.5 (1.2–9.0) 4.7 (0.9–6.8) 6.7 (1.6–10.4) 0.002
SLEDAI-2K score
Baseline 11.3 ± 3.6 10.3 ± 3.3 10.6 ± 3.5 10.5 ± 3.6 0.060
Week 52 4.5 ± 3.0 3.6 ± 2.6 3.6 ± 2.8 3.7 ± 2.9 0.260
SDI score
Baseline 0.5 ± 1.0 0.0 (0.0–1.0) 0.9 ± 1.3 0.0 (1.0–1.0) 0.4 ± 0.9 0.0 (0.0–1.0) 0.8 ± 1.3 0.0 (0.0–1.0) <0.001
Week 52 0.6 ± 1.0 0.0 (0.0–1.0) 1.0 ± 1.5 0.0 (1.0–1.0) 0.4 ± 0.9 0.0 (0.0–1.0) 0.9 ± 1.3 0.0 (0.0–1.0) <0.001
SDI score > 0
Baseline 48 (33.3%) 28 (50.9%) 54 (25.7%) 163 (46.4%) <0.001
Week 52 50 (34.7%) 29 (52.7%) 57 (27.1%) 171 (48.7%) <0.001
Serological profile at baseline
Anti-dsDNA (+) 122 (84.7%) 37 (67.3%) 141 (67.1%) 217 (61.8%) <0.001
Anti-Sm (+) 55 (38.2%) 22 (40.0%) 74 (35.2%) 73 (20.9%) <0.001
Low C3 88 (61.1%) 18 (32.7%) 86 (41.0%) 119 (33.9%) <0.001
Low C4 85 (59.0%) 17 (30.9%) 113 (53.8%) 180 (51.3%) 0.005
Prednisone eq. dose (mg/day)
Baseline 13.3 ± 9.3 12.6 ± 10.0 12.0 ± 8.2 10.7 ± 9.2 0.236
Week 52 8.4 ± 5.1; N = 143 9.9 ± 8.7; N = 54 9.3 ± 6.7; N = 209 8.3 ± 7.2; N = 348 0.010
Antimalarial agents at week 52† 83 (57.6%) 35 (63.6%) 147 (70.0%) 213 (60.7%) 0.072
Immunosuppressants at week 52
Azathioprine 23 (16.0%) 11 (20.0%) 54 (25.7%) 61 (17.4%) 0.063
Methotrexate 4 (2.8%) 7 (12.7%) 30 (14.3%) 37 (10.5%) 0.005
Mycophenolic acid 11 (7.6%) 9 (16.4%) 14 (6.7%) 38 (10.8%) 0.098
Other immunosuppressants‡ 2 (1.4%) 2 (3.6%) 3 (1.4%) 8 (2.3%) 0.675
Trial intervention
Placebo 41 (28.5%) 22 (40.0%) 61 (29.0%) 93 (26.5%) 0.232
Belimumab 1 mg/kg 44 (30.6%) 15 (27.3%) 74 (35.2%) 125 (35.6%) 0.490
Belimumab 10 mg/kg 59 (41.0%) 18 (32.7%) 75 (35.7%) 133 (37.9%) 0.663

Data are presented as numbers (percentage) or means ± standard deviation. In case of non-normal distributions, medians (interquartile range) are indicated. In case of missing values,
the total number of patients with available data is indicated. Statistically significant P-values are in bold.
*Alaska Native or American Indian from North, South or Central America.
† Hydroxychloroquine, chloroquine, mepacrine, mepacrine hydrochloride or quinine sulphate.
‡ Cyclosporine, oral cyclophosphamide, leflunomide, mizoribine or thalidomide.

C3, complement component protein 3; C4, complement component protein 4; dsDNA, double stranded DNA; SDI, Systemic Lupus International Collaborating Clinics (SLICC)/American
College of Rheumatology (ACR) Damage Index; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000; Sm, Smith.

the proportion of patients with FACIT-F scores <30 was lower well as patients with low C3 (43.6 vs. 28.0%; P = 0.001)
among Hispanics (15.7 vs. 33.3%; OR: 0.37; 95% CI: 0.26–0.53; and low C4 (54.8 vs. 38.6%; P = 0.001) levels at baseline
P < 0.001). were seen among patients who reported non-adverse PCS at
week 52. Notably, a higher proportion of anti-Sm positive
Factors Associated With Adverse HRQoL patients was seen within patients who reported non-adverse MCS
First, we compared demographic and clinical characteristics of (31.5 vs. 19.8%; P = 0.009; Supplementary Table 6). Patients
patients with adverse vs. non-adverse PCS, MCS and FACIT- with FACIT-F scores ≥30 at week 52 were younger and had
F at week 52. Compared with those reporting adverse PCS, lower SDI scores compared with patients with severe fatigue
individuals with non-adverse PCS were younger and had lower (Supplementary Table 7). Moreover, more patients within the
SDI scores (Supplementary Table 5). Higher proportions of non-severe fatigue group were anti-dsDNA (71.4 vs. 57.8%;
anti-dsDNA positive (70.7 vs. 55.3%; P = 0.001) patients as P < 0.001) and anti-Sm (32.7 vs. 20.8%; P = 0.002) positive at

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Gomez et al. Adverse HRQoL Outcome in SLE

FIGURE 3 | Adverse HRQoL outcome despite clinical improvement across different ancestries. This figure illustrates comparisons of the prevalence of adverse
HRQoL outcomes at week 52 from treatment initiation across patients with SLE of Asian, Black/African American, Indigenous American, and White/Caucasian
ancestries. (A,B) Delineate proportions of patients reporting SF-36 scores below or equal to the 5th percentile of the corresponding scores as derived from a general
population of the same age and sex, within physical and mental aspects, respectively. (C) Delineates proportions of patients reporting FACIT-F scores <30, signifying
severe fatigue. The number of patients reporting adverse HRQoL outcomes (n) is indicated below the respective bar. P-values derived from chi-square tests. BP,
bodily pain; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; GH, general health; MCS, mental component summary; MH, mental health; NP5,
normative 5th percentile; PCS, physical component summary; PF, physical functioning; RE, role emotional; RP, role physical; SF, social functioning; SF-36, short form
36 health survey; VT, vitality.

baseline, and more had been treated with belimumab 10 mg/kg and VT (OR: 0.34; 95% CI: 0.18–0.64; P = 0.001), as well
(39.8 vs. 29.2%; P = 0.009). as with FACIT-F scores <30 (OR: 0.31; 95% CI: 0.46–0.70;
Subsequently, we created multivariable logistic regression P < 0.001).
models to assess independence and account for confounding Increasing SDI scores at week 52, representing organ damage
potentiality. Covariates in the models included age, sex, ancestry, accrued from disease onset until the evaluation, were associated
Hispanic ethnicity, SLEDAI-2K and SDI scores at week 52, and with adverse HRQoL outcomes within physical SF-36 scales,
the trial intervention, i.e., belimumab 10 mg/kg or 1 mg/kg with including PCS (OR: 1.25; 95% CI: 1.07–1.45; P = 0.004), PF
placebo as the reference comparator. (OR: 1.31; 95% CI: 1.13–1.51; P < 0.001) and GH (OR: 1.16;
Increasing age was associated with adverse HRQoL outcome 95% CI: 1.01–1.33; P = 0.040), but not within mental SF-36
in all physical and mental SF-36 scales, except for MCS, and scales or FACIT-F. We found no significant association between
with adverse FACIT-F (Figure 6). White/Caucasian ancestry was SLEDAI-2K scores and adverse HRQoL outcomes (Figure 6).
associated with adverse RP (OR: 1.95; 95% CI: 1.06–3.59; P Notably, addition of belimumab 10 mg/kg to ST was associated
= 0.033), VT (OR: 2.17; 95% CI: 1.28–3.68; P = 0.004) and with lower frequencies of adverse PF (OR: 0.59; 95% CI: 0.39–
MH (OR: 2.37; 95% CI: 1.39–4.05; P = 0.002), as well as 0.91; P = 0.016) and FACIT-F (OR: 0.53; 95% CI: 0.34–0.81;
with FACIT-F scores <30 (OR: 1.47; 95% CI: 1.02–2.11; P P = 0.004). Similar results were seen for age, sex, SLEDAI-
= 0.039). Conversely, Hispanic ethnicity was associated with 2K, SDI and belimumab use when we included country groups
lower proportions of adverse PF (OR: 0.59; 95% CI: 0.39–0.88; instead of ancestries or ethnic origin as covariates in the models
P = 0.010), GH (OR: 0.59; 95% CI: 0.40–0.85; P = 0.005) (Supplementary Figure 1).

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Gomez et al. Adverse HRQoL Outcome in SLE

FIGURE 4 | Adverse HRQoL outcome despite clinical improvement across different country groups. This figure illustrates comparisons of the prevalence of adverse
HRQoL outcomes at week 52 from treatment initiation across patients with SLE from Asia Pacific, Canada/USA, Europe, and Latin America. (A,B) Delineate
proportions of patients reporting SF-36 scores below or equal to the 5th percentile of the corresponding scores as derived from a general population of the same age
and sex, within physical and mental aspects, respectively. (C) Delineates proportions of patients reporting FACIT-F scores <30, signifying severe fatigue. The number
of patients reporting adverse HRQoL outcomes (n) is indicated below the respective bar. P-values derived from chi-square tests. BP, bodily pain; FACIT-F, Functional
Assessment of Chronic Illness Therapy-Fatigue; GH, general health; MCS, mental component summary; MH, mental health, NP5, normative 5th percentile; PCS,
physical component summary; PF, physical functioning; RE, role emotional; RP, role physical; SF, social functioning; SF-36, short form 36 health survey; VT, vitality.

Next, in order to determine the type of established Finally, damage in the neuropsychiatric (OR: 1.56; 95% CI:
organ damage accrued from disease onset until the time of 1.04–2.16; P = 0.031) and gastrointestinal (OR: 2.01; 95% CI:
evaluation (week 52) that accounted for the observed association 1.05–3.82; P = 0.034) domains was associated with severe
between SDI scores and adverse HRQoL outcomes, we fatigue (FACIT-F scores <30) in the univariable but not the
created separate univariable and multivariable logistic regression multivariable models.
models for each one of the SDI organ domains (Figure 7,
Supplementary Tables 8–10). Damage in the neuropsychiatric, DISCUSSION
cardiovascular, gastrointestinal and musculoskeletal domains
was associated with adverse PCS in univariable models; Herein, we investigated frequencies of adverse HRQoL outcome
this association remained significant after adjustment for the and contributing factors in 760 patients with SLE who showed
cardiovascular (OR: 2.12; 95% CI: 1.07–4.21; P = 0.032) and adequate clinical response to a 52-week long intervention with
musculoskeletal (OR: 1.41; 95% CI: 1.01–1.96; P = 0.041) standard therapy along with belimumab or placebo, using
domains. With regard to mental aspects, damage in the previously reported definitions (30). We observed clinically
neuropsychiatric domain was associated with adverse SF-36 SF important diminutions of patient-reported HRQoL in multiple
(OR: 1.55; 95% CI: 1.01–2.38 P = 0.044) and MH (OR: 1.59; physical, mental and social aspects compared with the general
95% CI: 1.00–2.53; P = 0.050), whereas renal damage was population, and high frequencies of adverse HRQoL outcomes,
associated with adverse RE (OR: 3.70; 95% CI: 1.01–13.57; P especially within physical domains of SF-36 and FACIT-F.
= 0.048) in univariable analyses; however, these associations Overall, higher frequencies of adverse HRQoL outcomes
did not reach statistical significance in the adjusted models. were seen with increasing age. Black/African American and

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Gomez et al. Adverse HRQoL Outcome in SLE

TABLE 3 | Demographics and clinical characteristics of patients across different country groups.

Asia Pacific Canada/USA Europe# Latin America P-value

N = 143 N = 151 N = 176 N = 290

Patient characteristics
Age at baseline (years) 32.9 ± 9.9 41.7 ± 11.6 38.1 ± 12.0 36.7 ± 10.7 <0.001
Female sex 135 (94.4%) 139 (92.1%) 167 (94.9%) 276 (95.2%) 0.582
Ancestries
Asian 138 (96.5%) 5 (3.3%) 1 (0.6%) 0 <0.001
Black/African American 0 39 (25.8%) 1 (0.6%) 15 (5.2%) <0.001
Indigenous American* 1 (0.7%) 8 (5.3%) 1 (0.6%) 200 (69.0%) <0.001
White/Caucasian 4 (2.8%) 99 (65.6%) 173 (98.3%) 75 (25.9%) <0.001
Hispanic ethnicity 0 34 (22.5%) 0 285 (98.3%) <0.001
Clinical data
SLE duration at baseline (years) 3.6 (0.8–7.4) 4.9 (1.4–9.6) 5.0 (1.7–10.3) 3.2 (1.0–7.3) 0.004
SLEDAI-2K score
Baseline 11.4 ± 3.6 10.3 ± 3.4 10.5 ± 3.8 10.6 ± 3.5 0.016
Week 52 3.8 ± 2.3 3.5 ± 2.5 3.8 ± 3.2 3.3 ± 2.4 0.074
SDI score
Baseline 0.5 ± 0.9 0.0 (0.0–1.0) 1.1 ± 1.5 0.0 (1.0–1.0) 0.7 ± 1.1 0.0 (0.0–1.0) 0.5 ± 1.0 0.0 (0.0–1.0) <0.001
Week 52 0.6 ± 1.0 0.0 (0.0–1.0) 1.2 ± 1.6 0.0 (0.0–2.0) 0.8 ± 1.1 0.0 (0.0–1.0) 0.5 ± 1.0 0.0 (0.0–1.0) <0.001
SDI score > 0
Baseline 47 (32.9%) 87 (57.6%) 75 (42.6%) 84 (29.0%) <0.001
Week 52 49 (34.3%) 89 (58.9%) 79 (44.9%) 90 (31.0%) <0.001
Serological profile at baseline
Anti-dsDNA (+) 119 (83.2%) 80 (53.0%) 122 (69.3%) 196 (67.6%) <0.001
Anti-Sm (+) 53 (37.1%) 36 (23.8%) 36 (20.7%); N=174 99 (34.1%) 0.001
Low C3 86 (60.1%) 45 (29.8%) 71 (40.3%) 109 (37.6%) <0.001
Low C4 85 (59.4%) 55 (36.4%) 104 (59.1%) 151 (52.1%) <0.001
Prednisone eq. dose (mg/day)
Baseline 13.1 ± 9.2 7.1 ± 8.4 12.1 ± 8.0 13.1 ± 9.1 <0.001
Week 52 8.4 ± 5.2; N=142 5.3 ± 6.2; N=149 10.0 ± 7.0; N=174 9.9 ± 7.2; N=289 <0.001
Antimalarial agents at week 52† 85 (59.4%) 107 (70.9%) 84 (47.7%) 202 (69.7%) <0.001
Immunosuppressants at week 52
Azathioprine 22 (15.4%) 22 (14.6%) 33 (18.8%) 72 (24.8%) 0.027
Methotrexate 6 (4.2%) 24 (15.9%) 13 (7.4%) 35 (12.1%) 0.004
Mycophenolic acid 8 (5.6%) 23 (15.2%) 24 (13.6%) 17 (5.9%) 0.001
Other immunosuppressants‡ 3 (2.1%) 3 (2.0%) 3 (1.7%) 6 (2.1%) 0.993
Trial intervention
Placebo 42 (29.4%) 45 (29.8%) 42 (23.9%) 88 (30.3%) 0.472
Belimumab 1 mg/kg 42 (29.4%) 59 (39.1%) 57 (32.4%) 100 (34.5%) 0.343
Belimumab 10 mg/kg 59 (41.3%) 47 (31.1%) 77 (43.8%) 102 (35.2%) 0.069

Data are presented as numbers (percentage) or means ± standard deviation. In case of non-normal distributions, medians (interquartile range) are indicated. In case of missing values,
the total number of patients with available data is indicated. Statistically significant P-values are in bold.
*Alaska Native or American Indian from North, South or Central America.
† Hydroxychloroquine, chloroquine, mepacrine, mepacrine hydrochloride or quinine sulphate.
‡ Cyclosporine, oral cyclophosphamide, leflunomide, mizoribine or thalidomide.
# Including Israel.

C3, complement component protein 3; C4, complement component protein 4; dsDNA, double stranded DNA; SDI, Systemic Lupus International Collaborating Clinics (SLICC)/American
College of Rheumatology (ACR) Damage Index; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000; Sm, Smith.

White/Caucasian patients reported higher frequencies of adverse associated with lower frequencies of adverse physical functioning
HRQoL outcomes than Asians and Indigenous Americans, while and severe fatigue.
Hispanic/Latin American patients experienced adverse HRQoL Improvements in multiple HRQoL aspects following
less frequently than non-Hispanics. Importantly, addition of the treatment with conventional synthetic or biological disease-
licenced dose of intravenous belimumab to standard therapy was modifying agents have been documented in patients with SLE,

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Gomez et al. Adverse HRQoL Outcome in SLE

FIGURE 5 | Adverse HRQoL outcome despite clinical improvement in Hispanics versus non-Hispanics. This figure illustrates comparisons of the prevalence of
adverse HRQoL outcomes at week 52 from treatment initiation between patients with SLE of Hispanic/Latin American and non-Hispanic ethnicity. (A,B) Delineate
proportions of patients reporting SF-36 scores below or equal to the 5th percentile of the corresponding scores as derived from a general population of the same age
and sex, within physical and mental aspects, respectively. (C) Delineates proportions of patients reporting FACIT-F scores <30, signifying severe fatigue. In the forest
plots, circles designate the corresponding unadjusted odds ratios and whiskers designate 95% confidence intervals. The number of patients reporting adverse
HRQoL outcomes (n) is indicated below the respective bar. P-values derived from chi-square tests. Significant P-values are indicated with asterisks. BP, bodily pain;
FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; GH, general health; MCS, mental component summary; MH, mental health; NP5, normative 5th
percentile; PCS, physical component summary; PF, physical functioning; RE, role emotional; RP, role physical; SF, social functioning; SF-36, short form 36 health
survey; VT, vitality.

especially along with clinical improvements or attainment of low with SLE. First, we observed clinically important diminutions
disease activity or remission (5–9, 31), which we corroborated of patient-reported HRQoL in multiple aspects compared with
in the present study, demonstrating that treatment responders matched US population-based norms. In general health, role
improved in all SF-36 items during the study period and physical and physical functioning, these differences yielded 4.2,
reported higher SF-36 scores than non-responders to treatment. 3.6 and 3.5 times the MCID lower scores, respectively. Next,
However, it is important to emphasise that improvement does despite conservative definitions of adverse HRQoL outcomes,
not necessarily reflect a satisfactory health state perception. especially for SF-36, we found high frequencies at week 52
Studies of patients with RA have demonstrated considerable among responders. Ranging from 6.6% (for role emotional)
frequencies of persisting pain and severe fatigue among patients to 29.1% (for general health), these frequencies exceeded the
who achieved a good clinical response or remission following expected frequencies as derived from individually matched US
treatment (12, 13). In light of the above, we studied the population-based norms in all physical and mental aspects.
prevalence of HRQoL outcome in patients who met the primary Frequencies of adverse HRQoL outcome were more
endpoint of two phase III clinical trials of belimumab in patients prominent within physical compared with mental domains

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Gomez et al. Adverse HRQoL Outcome in SLE

FIGURE 6 | Factors associated with adverse HRQoL outcomes. The forest plots illustrate results from multivariable logistic regression models, with the SF-36
component summary scores ≤NP5 (A), physical subscale scores ≤NP5 (B), mental subscale scores ≤NP5 (C) and FACIT-F scores <30 (A) at week 52 from
treatment initiation as the dependant variables. Diamonds represent odds ratios and whiskers represent 95% confidence intervals. Asterisks indicate statistically
significant associations. BP, bodily pain; CI, confidence interval; FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; GH, general health; MCS, mental
component summary; MH, mental health; NP5, normative 5th percentile; OR, odds ratio; PCS, physical component summary; PF, physical functioning; RE, role
emotional; RP, role physical; SF, social functioning; SF-36, short form 36 health survey; VT, vitality.

of SF-36, which is consistent with the general trend in SLE of other factors in multivariable logistic regression models, in
patients as derived from real-world SF-36 data (32, 33). Since line with the known negative impact of age on SLE patient’s
SLE is a highly heterogeneous disease, the clinical phenotype HRQoL (37). Interestingly, anti-dsDNA positivity at baseline
is expected to impact on HRQoL. For instance, in a cohort was negatively associated with adverse outcome in physical
of patients with lupus nephritis, those with active disease HRQoL aspects and fatigue, as was anti-Sm positivity in
reported worse HRQoL in mental aspects than patients with mental HRQoL aspects and fatigue. Given the fact that more
inactive disease, but the groups did not differ in physical patients among responders had received belimumab rather than
health or pain (34). Most study participants in BLISS-52 and placebo (14, 15), this finding is in line with what is known
BLISS-76 had mucocutaneous (58.8%) and/or musculoskeletal about serological activity at baseline portending favourable
(43.6%) manifestations at baseline, which have been shown response to belimumab therapy in clinical (38–40) and HRQoL
to be associated with diminutions in physical HRQoL aspects (41) facets.
(35, 36) and may therefore partially explain the observed high Established organ damage (accrued from disease onset until
frequencies of adverse HRQoL outcomes in physical functioning the time of evaluation, i.e., at week 52) in the musculoskeletal,
and general health. mucocutaneous as well as cardiovascular and peripheral vascular
As expected, we observed increasing proportions of patients SDI domains was associated with adverse HRQoL outcomes in
reporting adverse HRQoL outcomes and severe fatigue with physical but not mental aspects. By contrast, neuropsychiatric
increasing age, especially in physical outcomes, with more than damage was associated with adverse outcome to treatment with
40% of SRI-4 responders aged 55+ years reporting adverse regard to social functioning, mental health and fatigue. The
physical functioning and general health. The association between latter finding, albeit not reaching statistical significance after
increasing age and adverse HRQoL outcomes was independent adjustment, may provide support for investigation of functional

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Gomez et al. Adverse HRQoL Outcome in SLE

A Univariable models PCS PF RP BP GH MCS VT SF RE MH FACIT-F OR

4
Ocular •
Neuropsychiatric •• • • • •
Renal •
3
Pulmonary
SDI organ domains

Cardiovascular •• • •
Peripheral vascular ••
2
Gastrointestinal • •
Musculoskeletal •• ••• •
Skin ••
1
Premature gonadal failure
Diabetes
Malignancy
0
B Multivariable models
4
Ocular •
Neuropsychiatric
Renal
3
Pulmonary
SDI organ domains

Cardiovascular •
Peripheral vascular ••
2
Gastrointestinal
Musculoskeletal • •••
Skin ••
1
Premature gonadal failure
Diabetes
Malignancy
0
PCS PF RP BP GH MCS VT SF RE MH FACIT-F
≤ NP5 ≤ NP5 < 30

• P < 0.05 •• P < 0.01 ••• P < 0.001

FIGURE 7 | Associations between SDI organ domains and adverse HRQoL outcomes. The heatmaps illustrate ORs deriving from univariable (A) and multivariable (B)
logistic regression models, with the SF-36 scale scores ≤NP5 and FACIT-F scores <30 at week 52 as the dependant variables. Dots indicate statistically significant
associations. BP, bodily pain; FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; GH, general health; MCS, mental component summary; MH,
mental health; OR, odds ratio; PCS, physical component summary; PF, physical functioning; RE, role emotional; RP, role physical; SF, social functioning; SF-36, short
form 36 health survey; VT, vitality.

or structural changes in the brain as potential contributors to and organ damage on HRQoL, with some studies implicating
the prominent fatigue in patients with SLE rather than or along a negative impact (43–45) and others reporting no evident
with neuroinflammation, as also implicated in multiple sclerosis connexion (37, 46, 47). These discrepancies could be partly
(42). Notably, we found no association between the degree of SLE explained by the different instruments used to measure patients’
disease activity and adverse HRQoL outcomes. Data in previous HRQoL, e.g., generic vs. disease-specific tools, or differences in
literature are conflicting regarding the effect of disease activity clinical phenotypes. For instance, severe active lupus nephritis

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Gomez et al. Adverse HRQoL Outcome in SLE

and neuropsychiatric SLE were excluded from the BLISS-52 and the administration route and, consequently, the visit frequency
BLISS-76 trials, which disallows generalisability of our findings to the care unit may have exerted a placebo effect in favour
to these subgroups. Additionally, our definitions were applied to of infliximab in SWEFOT, the preventive effects of biological
SRI-4 responders, i.e., patients who had attained a lower degree agents against adverse patient-reported outcomes seen in both
of activity relative to non-responders, which may constitute one studies are supportive of molecular trajectories underlying these
of the reasons underlying the lack of association between disease observations, and provide rationale for further investigation of
activity and patient-reported HRQoL outcomes. Nevertheless, the effects of biological therapies on HRQoL outcomes.
our data suggest that HRQoL outcomes are not solely dependent The post-hoc nature of our analysis constituted a
on clinical and serological features of disease activity, advocating major limitation. Furthermore, no data existed regarding
use of patient-reported HRQoL as an integral part of the clinical epidemiological characteristics and comorbid conditions with a
assessment, as per current recommendations (48). known impact on HRQoL, such as socioeconomical status, social
Patients of Black/African American and White/Caucasian relationships and co-existence of fibromyalgia or depression.
ancestry reported the highest frequencies of adverse outcomes We also lacked information about illness perceptions, which are
in most HRQoL domains. In logistic regression analysis, known to impact on HRQoL (52, 53). Finally, disease-specific
White/Caucasian ancestry was associated with adverse role instruments for assessing HRQoL were not utilised in the
physical, mental health and vitality using SF-36 and with BLISS trials; this likely underestimated HRQoL aspects of
severe fatigue using FACIT-F, independently of disease activity, particular relevance for SLE populations. The aforementioned
organ damage and add-on belimumab. Conversely, Asian limitations together with the selected population of the BLISS
ancestry was associated with lower frequencies of adverse vitality trials may collectively weaken the external validity of our
and severe fatigue. Additionally, Hispanic/Latin American findings. Nonetheless, strengths of this investigation included
ethnicity was associated with lower frequencies of adverse the large study population, participation of patients from 32
physical functioning, adverse general health, adverse vitality different countries which allowed us to compare patients of
and severe fatigue. Our findings are in line with observations different ancestries and ethnic origins, and the high degree of
from different multi-ethnic cohorts showing that patients completeness of the data provided from the CSDR consortium
of White/Caucasian ancestry generally report worse HRQoL which conferred power on statistical analyses and allowed
than non-White/Caucasians (32), Hispanics (33) or Asians inclusion of multiple factors in regression models.
(49), despite a high variability across the studies in terms In summary, substantial proportions of SLE patients reported
of study population, clinical features of the participants and adverse HRQoL outcomes despite a documented clinical
selection of comparators. However, in a study by Kiani et al., improvement after a 52-week long therapy, especially in
White/Caucasians reported higher scores in SF-36 physical physical aspects. Particularly high proportions were seen within
functioning and role emotional but lower scores in SF-36 Black/African American and White/Caucasian patients. Notably,
vitality than Black/African Americans (46). One explanation addition of belimumab 10 mg/kg to standard therapy exerted
for the discrepancies across ancestries and ethnic groups is a preventive effect against adverse physical functioning and
likely traced to known differences regarding disease prevalence, severe fatigue. Our results corroborate that HRQoL diminutions
clinical manifestations, disease activity and acquisition of organ constitute a substantial burden in patients with SLE, and
damage (3, 4). Importantly, the determinants of HRQoL are highlight the limitations of current therapeutic strategies. Further
multifactorial, and geographical, economical and sociocultural investigation of underlying factors is merited, for instance,
aspects are also expected to exert considerable influence on identification of potential explanations underlying the impact
patients’ HRQoL perception. of musculoskeletal, mucocutaneous and cardiovascular damage,
Data from both clinical trial and real-life settings suggest toward the development of personalised interventions aiming at
that the use of belimumab improves HRQoL along with improving HRQoL outcomes.
improvements in disease activity, reduction of glucocorticoid
doses, and prevention of severe flares (5, 6, 8, 9). In the
present investigation comprising only patients who showed
an adequate response to treatment, addition of belimumab DATA AVAILABILITY STATEMENT
10 mg/kg to standard therapy was associated with lower
The raw data supporting the conclusions of this article will be
proportions of adverse physical functioning and severe fatigue
made available by the authors, without undue reservation.
compared with standard therapy alone, independently of
disease activity and organ damage at the time of the final
evaluation. In the SWEFOT trial that compared addition of
infliximab with addition of sulfasalazine and hydroxychloroquine ETHICS STATEMENT
in methotrexate-refractory early RA patients, no difference
was found regarding proportions of patients achieving a The studies involving human participants were reviewed and
good secondary response to treatment, but patients receiving approved by Swedish Ethical Review Authority (2019-05498).
infliximab reported less cumulative pain and less refractory pain The patients/participants provided their written informed
after 21 months on the second-line therapy (50, 51). Although consent to participate in this study.

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Gomez et al. Adverse HRQoL Outcome in SLE

AUTHOR CONTRIBUTIONS Gustafsson Foundation (2019-12), Region Stockholm and

Karolinska Institutet.
AG, VQ, AC, YE, JLa, and IP: study conception and design.
AG, VQ, AC, AB, JLi, and IP: acquisition of data. AG, VQ, ACKNOWLEDGMENTS
AC, SE, YE, JLa, and IP: analysis and interpretation of data.
All authors were involved in the drafting of the manuscript The authors would like to thank GlaxoSmithKline (Uxbridge,
or revising it critically for important intellectual content, UK) for sharing the data from the BLISS-52 (NCT00424476)
and all authors approved the final version to be submitted and BLISS-76 (NCT00410384) trials with the Clinical Study Data
for publication. Request (CSDR) consortium, Dimitris Ladakis, Joaquin Matilla
and Martin Pehr for contributing to the management of data, as
FUNDING well as all participating patients.

This work was supported by the GlaxoSmithKline Investigator- SUPPLEMENTARY MATERIAL

Sponsored Studies (ISS) programme, and grants from
the Swedish Rheumatism Association (R-932236), King The Supplementary Material for this article can be found
Gustaf V’s 80-year Foundation (FAI-2019-0635), Professor online at: https://www.frontiersin.org/articles/10.3389/fmed.
Nanna Svartz Foundation (2019-00290), Ulla and Roland 2021.651249/full#supplementary-material

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Gomez et al. Adverse HRQoL Outcome in SLE

cohort of patients with systemic lupus erythematosus. RMD Open. (2020) The remaining authors declare that the research was conducted in the absence of
6:e001133. doi: 10.1136/rmdopen-2019-001133 any commercial or financial relationships that could be construed as a potential
53. Kotsis K, Voulgari PV, Tsifetaki N, Drosos AA, Carvalho AF, conflict of interest.
Hyphantis T. Illness perceptions and psychological distress associated
with physicalx health-related quality of life in primary Sjogren’s Copyright © 2021 Gomez, Qiu, Cederlund, Borg, Lindblom, Emamikia, Enman,
syndrome compared to systemic lupus erythematosus and rheumatoid Lampa and Parodis. This is an open-access article distributed under the terms
arthritis. Rheumatol Int. (2014) 34:1671–81. doi: 10.1007/s00296-014- of the Creative Commons Attribution License (CC BY). The use, distribution or
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