Journal of Autoimmunity xxx (2017) 1e8

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Journal of Autoimmunity
journal homepage: www.elsevier.com/locate/jautimm

Clinical predictors of response and discontinuation of belimumab in

patients with systemic lupus erythematosus in real life setting. Results
of a large, multicentric, nationwide study
Luca Iaccarino a, Laura Andreoli b, Elena Bartoloni Bocci c, Alessandra Bortoluzzi d,
Fulvia Ceccarelli e, Fabrizio Conti e, Rossella De Angelis f, Ginevra De Marchi g,
Salvatore De Vita g, Andrea Di Matteo f, Giacomo Emmi h, Lorenzo Emmi i, Mariele Gatto a,
Roberto Gerli c, Maria Gerosa j, Marcello Govoni d, Maddalena Larosa a, Pier Luigi Meroni j,
Marta Mosca k, Giulia Pazzola l, Rossella Reggia b, Francesca Saccon a, Carlo Salvarani l,
Chiara Tani k, Margherita Zen a, Anna Chiara Frigo m, Angela Tincani b, Andrea Doria a, *
a
Division of Rheumatology, Department of Medicine-DIMED, University of Padova, Padova, Italy
b
Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Brescia, Italy
c
Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy
d
Medical Sciences, UOC of Rheumatology, University Hospital S. Anna, Ferrara, Italy
e
Rheumatology Unit, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
f
Rheumatology Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy
g
Clinic of Rheumatology, Department of Medical and Biological Sciences, University Hospital “Santa Maria della Misericordia”, Udine, Italy
h
Internal Interdisciplinary Medicine, Centre for Rare Cardiovascular and Immunological Diseases, Lupus Clinic, AOU Careggi, Florence, Italy
i
Department of Surgery and Translational Medicine, University of Florence, Italy
j
Rheumatology Department, University of Milan, Istituto Ortopedico Gaetano Pini, Milano, Italy
k
Rheumatology Unit, University of Pisa, Pisa, Italy
l
Rheumatology Unit, Internal Medicine Department, Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia, Italy
m
Biostatistics, Epidemiology and Public Health Unit, Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To investigate efficacy, safety and survival of belimumab and to identify predictors of drug
Received 29 June 2017 response and drug discontinuation in patients with active SLE in clinical practice.
Received in revised form Patients and methods: Data of SLE patients, treated with belimumab, from 11 Italian prospective cohorts
6 September 2017
were analyzed. SLEDAI-2K, anti-dsDNA, C3, C4, prednisone daily dose, DAS-28, 24-h proteinuria, CLASIa
Accepted 11 September 2017
(Cutaneous LE Disease Area and Severity Index Activity) were recorded at baseline and every 6 months.
Available online xxx
SLE Responder Index-4 (SRI-4) was calculated at 12 and 24 months. Demographic and clinical features
and comorbidities were included in the univariate and multivariate analysis. Adverse events were
Keywords:
Systemic lupus erythematous
recorded at each visit. Statistics was performed using the SPSS software.
Belimumab Results: We studied 188 SLE patients, mean follow-up 17.5 ± 10.6 months. The most frequent manifes-
Biologic drugs tations, which required the use of belimumab, were polyarthritis (45.2%) and skin rashes (25.5%). SRI-4
Predictors of response was achieved by 77.0% and 68.7% of patients at 12 and 24-months. Independent predictors of 12-month
Drug survival response were SLEDAI-2K
10 (OR 40.46, p ¼ 0.001) and polyarthritis (OR 12.64, p ¼ 0.001) and of 24-
month response were SLEDAI-2K
10 (OR 15.97, p ¼ 0.008), polyarthritis (OR 32.36, p ¼ 0.006), and
prednisone
7.5 mg/day (OR 9.94, p ¼ 0.026). We observed a low rate of severe adverse events. Fifty-
eight patients (30.8%) discontinued belimumab after a mean follow-up of 10.4 ± 7.5 months. The drug
survival was 86.9%, 76.9%, 69.4%, 67.1%, and 61.9% at 6, 12, 18, 24, and 30 months, respectively. No factors
associated with drug discontinuation were found.
Conclusion: Belimumab is effective and safe when used in clinical practice setting.
© 2017 Elsevier Ltd. All rights reserved.

* Corresponding author. Division of Rheumatology, University of Padova, Via

Giustiniani, 2, 35128, Padova, Italy.
E-mail address: adoria@unipd.it (A. Doria).

http://dx.doi.org/10.1016/j.jaut.2017.09.004
0896-8411/© 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: L. Iaccarino, et al., Clinical predictors of response and discontinuation of belimumab in patients with systemic
lupus erythematosus in real life setting. Results of a large, multicentric, nationwide study, Journal of Autoimmunity (2017), http://dx.doi.org/
10.1016/j.jaut.2017.09.004
2 L. Iaccarino et al. / Journal of Autoimmunity xxx (2017) 1e8
1. Introduction
Despite the progresses in the treatment of systemic lupus ery-
thematosus (SLE), the long term prognosis of patients is still un-
satisfactory [1] and several urgent needs are still unmet. Indeed, a
high percentage of patients experiences persistent disease activity
or disease flares [2e4] requiring long term corticosteroid and
immunosuppressive treatment which leads to progressive damage
accrual and worsening of quality of life [2,5e14]. Among the
immunological targets identified in SLE, soluble B lymphocyte
stimulator (BLyS) seems to be very promising since excess of BLyS
may rescue lupus autoreactive B cells [15e17].
In the BLISS-52 and BLISS-76 [18,19] phase 3 randomized
controlled trials (RCTs), SLE patients treated with intravenous (IV)
belimumab, a soluble BLyS inhibitor, added to standard treatment
had a superior response rate (assessed by the SLE Responder Index-
4; SRI-4) than those treated with standard therapy alone (placebo
arm). These results led to the approval of belimumab by the Food
and Drug Administration (FDA) and European Medicines Agency
(EMA) for the treatment of patients with SLE. In Italy belimumab is
reimbursed in patients with active lupus manifestations despite
standard therapy, positive anti-double stranded (ds)-DNA and low
C3 or C4.
A number of post-hoc analysis which evaluated the pooled data
of phase 2 and 3 RCTs, identified some manifestations which best
responded to belimumab, such as musculoskeletal and mucocuta-
neous features, and some predictors of response including Safety of
Estrogens in Lupus Erythematosus National Assessment - SLE Dis-
ease Activity Index (SELENA-SLEDAI)
10, low complement, posi-
tive anti-double stranded (ds)DNA, and prednisone intake
7.5 mg/
day [20,21]. The results of the RCT carried out using subcutaneous
belimumab in SLE patients have recently been published and the
study met the primary endpoint [22], thus paving the way to a more
practical route of administration.
Recent studies investigating the effectiveness of belimumab in
clinical practice have confirmed it is capable of decreasing disease
activity, corticosteroid intake and flare rate, thereby hindering the
expected damage progression in patients with active SLE [23e31].
Moreover, belimumab use was associated with a low number of
unscheduled visits and a reduced rate of visits in the emergency
room (ER), being thus cost-effective [32e35].
So far, however, predictors of response to belimumab and sur-
vival of the drug have poorly been investigated in real life setting
[36]. The aim of our study was to evaluate effectiveness and safety
of belimumab and identify baseline predictors of drug response or
discontinuation in a clinical practice-based, large, multicentre,
nationwide cohort of patients with active SLE.
2. Patients and methods
2.1. Inclusion and exclusion criteria
We included in the study all SLE patients treated with belimu-
mab up to April 20th, 2016 in eleven Italian SLE referral centers. All
patients were prospectively followed according to the EULAR (Eu-
ropean League Against Rheumatism) recommendations [37,38] and
the inclusion of patients in this study did not interfere with current
clinical practice.
Inclusion criteria were 1) fulfillment of 1982 American College
of Rheumatology (ACR) revised criteria for SLE [39], 2) active (ac-
cording to SLE Disease Activity Index-2000 - SLEDAI-2K > 6) and
refractory SLE manifestations, 3) positive anti-dsDNA antibodies
either by Farr, indirect immunofluorescence (IIF) or Enzyme Linked
Immunosorbent Assay (ELISA) and 4) low C3 or C4 serum levels.
SLE manifestations were defined as refractory in case of drug
Please cite this article in press as: L. Iaccarino, et al., Clinical predictors of response and discontinuation of belimumab in patients with systemic
lupus erythematosus in real life setting. Results of a large, multicentric, nationwide study, Journal of Autoimmunity (2017), http://dx.doi.org/
10.1016/j.jaut.2017.09.004
intolerance, unresponsiveness or disease relapse in patients treated
with corticosteroids, antimalarials and/or immunosuppressants.
Patients with renal disease were considered as refractory if they
had a persistence of 24 h proteinuria >1 g after at least 1 year from
the start of the initial therapy or in case they experienced a renal
flare (24 h proteinuria >1 g following a previous complete response
or doubling of 24 h proteinuria in other cases) during the subse-
quent therapy.
Exclusion criteria were 1) severe and active lupus nephritis (24 h
proteinuria >6 g and/or creatinine > 2 mg/dl), 2) severe and active
neuropsychiatric lupus, 3) potentially life threatening SLE mani-
festations and 4) ongoing or planned pregnancy.
2.2. Treatment with belimumab
Belimumab was added to background therapy and was intra-
venously administrated at 10 mg/kg on day 1, 14, 28, and then every
28 days.
2.3. Clinical and serological variables
A complete medical history, physical examination and blood
samples were collected in all patients prior to the first belimumab
infusion; moreover, all patients underwent clinical examination
before each belimumab administration. The following clinical and
serological variables were collected at baseline and then every six
months in all patients: SLEDAI-2K score, prednisone daily intake,
complete blood count, anti-dsDNA antibody, C3 and C4. In addition,
we assessed disease activity score (DAS)-28 in patients with
arthritis, Cutaneous Lupus Erythematosus Disease Area and
Severity Index (CLASI) activity score in patients with skin mani-
festations. Serum creatinine, 24 h proteinuria, and urinary sedi-
ment were also examined in patients with renal involvement.
Anti-dsDNA levels were measured by ELISA, IIF or Farr assay. As
a measure of damage, Systemic Lupus International Collaborating
Clinics-Damage Index (SLICC-DI) score was calculated at baseline
and at 12, 18 and 24 months of follow-up. Being all patients pro-
spectively followed-up, all centers were requested to provide the
SLICC-DI calculated in the visit performed five years before the
initiation of belimumab, when available.
2.4. Outcome measures
SRI-4 [40] was used to assess the response to belimumab at 12
and 24 months. Therefore, SELENA-SLEDAI, British Isles Lupus
Assessment Group (BILAG)-2004 and physician global assessment
(PGA) were assessed at baseline, at 12 and 24 month of follow-up.
Disease flares were determined and assessed by SELENA-SLEDAI
flare index (SFI); number of flares was collected at 12 and 24
months before and after belimumab initiation.
Inadequate response was defined as severe flare according to SFI
or the persistence of moderate/high disease activity by physician
judgment.
2.5. Safety assessment
Adverse events (AEs) were carefully recorded at each clinical
evaluation for all patients during the follow-up. AE was defined as
follows: “any untoward medical occurrence in a patient treated
with a pharmaceutical product which does not necessarily have a
causal relationship with this treatment”. AEs were subdivided in
noninfectious or infectious AEs, infusion and hypersensitivity re-
actions. Infusion reactions were defined as AE related to belimu-
mab occurring within 6 h after drug administration;
hypersensitivity reactions were defined as AE related to belimumab
 L. Iaccarino et al. / Journal of Autoimmunity xxx (2017) 1e8
occurring within 6e48 h after administration. Relationship with
belimumab was established by physician's judgment. AE was
defined as severe (SAE) when hospitalization was required and/or
death and/or life-threatening manifestations occurred. Infection
was considered severe when hospitalization and/or intravenous
antibiotics were required and/or death occurred. Infusion and hy-
persensitivity reactions were considered severe when intensive
care unit support was required for treatment and/or death
occurred.
Co-morbidities were defined as a pre-existing condition not
related to lupus with potential influence on the patients' safety. Co-
morbidities were subdivided into chronic infections, hypertension,
neurologic disorders, psychiatric disorders, cancer (including
papilloma-related abnormalities), vasculopathy/cardiac abnormal-
ities, diabetes, and allergies.
2.6. Statistical analysis
Parametric and non-parametric tests were used according to the
type of variables. Values were usually expressed as
mean ± standard deviation (SD), except for CLASI score, which was
expressed as median (25 e75 ) due to non-parametric distribu-
tion. Comparison of continuous data with a parametric distribution
was performed using t-test, t-test for paired data and one way
analysis of variance (ANOVA) with Bonferroni's post hoc analysis;
continuous data with a non-parametric distribution were analyzed
using the Wilcoxon's rank sum test and Wilcoxon's test for paired
data. Univariate repeated measures ANOVA was used to test the
effect of time (i.e., treatment) on SLEDAI-2K, prednisone daily
dosage, DAS28, 24 h-proteinuria, C3, C4, and anti-dsDNA. Varia-
tions in the CLASI score were analyzed using ANOVA for ranks
(Friedman's test).
We investigated baseline predictors of response at 12 and 24
months, according to SRI-4. The following variables were included
in the univariate analysis: gender, age, age at SLE onset, disease
duration, SLEDAI-2K
10, prednisone dose
7.5 mg/day,
concomitant immunosuppressants (yes/no), antimalarial use (yes/
no), number of comorbidities, number of previous organ involve-
ment, type of major involvement (polyarthritis, skin rash, glomer-
ulonephritis, hematologic abnormalities) and number of flares (
1)
in the 24 months before belimumab initiation. Factors with a
p < 0.3 at univariate analysis were included into a multivariate
model. Backward stepwise multiple logistic regression analysis was
performed with SRI-4 as a dichotomous dependent variable (i.e.
SRI-4 achieved or not achieved at month 12 and at month 24), with
significance set at 5%. We also investigated serologic variables
during follow-up as potential predictors of response according to
SRI-4 at 12 and 24 months: anti-dsDNA negativization, C3
normalization, C4 normalization by Fisher's exact test.
Baseline predictors of drug discontinuation were also studied. In
the univariate analysis we used the same variables mentioned
above plus co-morbidities. Backward stepwise multiple logistic
regression analysis (significance set at 5%) was provided including
factors with a p < 0.3 at univariate analysis.
Density incidence of different AEs (infective, non infective and
hypersensitivity/infusional reactions) was expressed as patient/
year considering the time of exposure of each patient during
follow-up.
Statistics were performed using the SPSS (version 23.0, Chicago,
IL) software. P values less than 0.05 were considered statistically
significant.
2.7. Informed consent signature and funding
All patients signed an informed consent and the study was
Please cite this article in press as: L. Iaccarino, et al., Clinical predictors of response and discontinuation of belimumab in patients with systemic
lupus erythematosus in real life setting. Results of a large, multicentric, nationwide study, Journal of Autoimmunity (2017), http://dx.doi.org/
10.1016/j.jaut.2017.09.004
3
carried out according to Helsinki Declaration. This research did not
receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors.
3. Results
3.1. Baseline patient characteristics
One-hundred-eighty-eight patients were enrolled in the study.
The prominent refractory manifestations which required the use of
IV belimumab as add on therapy were arthritis in 85 patients
(45.2%), skin rashes in 48 (25.5%), hematologic disorders in 26
(13.8%) and glomerulonephritis in 24 (12.8%). Anti-dsDNA were
measured by ELISA in 97 patients (51.6%), by Farr assay in 29 pa-
tients (15.4%) and by IIF in 62 patients (33%). Demographic, clinical
and serological features, and concomitant treatments in patients
treated with belimumab are summarized in Table 1.
Beside prominent refractory manifestations, 108 (57.4%) pa-
tients had musculoskeletal manifestations, 62 (33%) mucocuta-
neous involvement, 48 (25.5%) hematologic abnormalities, 39
(20.7%) glomerulonephritis, and 73 (38.8%) constitutional
symptoms.
At baseline all patients were treated with corticosteroids (mean
prednisone dosage 11.1 ± 7.6 mg/day, range 5e25 mg/day) and 125
(66.5%) with hydroxychloroquine. Concomitant immunosuppres-
sants were administered to 124 patients (65.9%), including myco-
phenolate mofetil, azathioprine, methotrexate and cyclosporine A
(Table 1).
One-hundred-fifty-eight patients completed 6-month, 111 12-
month, 75 18-month, 54 24-month and 16 30-month of follow-
up. The mean follow-up period was 17.5 ± 10.6 months (median
14 months, range 3e36).
3.2. Activity indices
Clinical and serological variables during belimumab treatment
are reported in Table 2. SLEDAI-2K, prednisone daily dose, DAS28,
CLASI and 24 h proteinuria significantly decreased over time during
treatment. A significant increase in C3 and C4 serum level was also
observed.
3.3. SRI-4 and other response indices
SRI-4 was achieved by 77.0% and 68.7% of patients at 12 and 24
months of follow-up, respectively. In addition, among 54 patients
with at least 24 months of treatment, 83.7% of patients who ach-
ieved SRI-4 response at 12 months maintained the response at 24
months and 81.8% of patients non-responders at 12 months were
non-responders also at 24 months.
3.4. Univariate analysis
The rate of response to belimumab was higher in patients with
SLEDAI-2K score
10 and polyarthritis at 12 months (p ¼ 0.001 and
p ¼ 0.006, respectively) and 24 months (p ¼ 0.033 and p ¼ 0.005,
respectively). No significant differences in prednisone intake

7.5 mg/day, number of previous therapies, immunosuppressant
use (yes/no), antimalarial use (yes/no), number of comorbidities
and number of previous organ involvements were observed be-
tween responders and non-responders at 12 and 24 months of
follow-up.
No associations were found between SRI-4 and serologic vari-
ables (anti-dsDNA negativization, C3 normalization and/or C4
normalization) at 12 and 24 months of follow-up.
4 L. Iaccarino et al. / Journal of Autoimmunity xxx (2017) 1e8

Table 1 independent predictors of SRI-4 response to belimumab at 12

Demographic, clinical and serological features in 188 SLE patients treated with months were SLEDAI-2K
10 (Odds Ratio - OR 40.46; 95% Confi-
belimumab.
dence Interval - CI 4.14e395.26; p ¼ 0.001) and polyarthritis (OR
Patients number 188 12.64; 95%CI 2.88e55.48, p ¼ 0.001).
- Female, number (%) 174 (92.5) Baseline independent predictors of SRI-4 response at 24 months
- Male, number (%) 14 (7.5)
Age at the first infusion, mean ± SD, years 40.7 ± 10.1
were polyarthritis (OR 32.36; 95%CI 2.65e394.77; p ¼ 0.006),
Disease duration, mean ± SD, years 12.7 ± 8.5 SLEDAI-2K
10 (OR 15.97; 95%CI 2.04e124.94; p ¼ 0.008) and
Follow-up duration, mean ± SD, months 17.5 ± 10.6 corticosteroid dosage
7.5 mg/day (OR 9.94; 95%CI 1.04e94.81;
Refractory prominent clinical manifestations at baseline p ¼ 0.026). By contrast, immunosuppressive therapy at baseline
- Musculoskeletal, number of patients (%) 85 (45.2)
was a negative predictor of response to belimumab (OR 0.107; 95%
- Cutaneous, number of patients (%) 48 (25.5)
- Hematologic, number of patients (%) 26 (13.8) CI 0.013e0.89; p ¼ 0.039).
- Renal, number of patients (%) 24 (12.8)
- Constitutional, number of patients (%) 3 (1.6)
3.6. Disease flares
- Serositic, number of patients (%) 2 (1.1)
Disease features at baseline (mean ± SD)
- SLEDAI-2K score, mean ± SD 8.3 ± 3.3 We observed 72 flares in 54 patients (28.7%) during follow-up:
- Daily PDN intake, mean ± SD, mg 11.1 ± 7.6 33 (45.8%) were musculoskeletal, 25 (34.7%) mucocutaneous, 6
- CLASI activity score, median (25 e75 )a 4 (2e8) (8.3%) hematologic, 6 (8.3%) renal, 6 (8.3%) serositic, and 2 (2.8%)
- DAS-28 score, mean ± SD 4.2 ± 1.1
- 24 h proteinuria, mean ± SD, g/day 1.1 ± 0.7
neurologic. Four severe flares were observed in 4 patients: one skin
- SLICC-DI score, mean ± SD 0.85 ± 1.11 vasculitis, one hematologic, one renal and one musculoskeletal.
- Anti-dsDNA (ELISA, 97 pts), mean ± SD, UI/ml 376.1 ± 768.2 We compared the mean number of flares observed in our pa-
- Anti-dsDNA (Farr assay, 29 pts), mean ± SD, UI/ml 97.1 ± 194.4 tients during the 12 and 24 months before and after belimumab
- C3, mean ± SD, g/L 0.71 ± 0.21
initiation. The number of flares/patient was 1.00 ± 0.81 during the
- C4, mean ± SD, g/L 0.11 ± 0.06
Autoantibodies at baseline 12 months before vs 0.39 ± 0.56 during the 12 months after beli-
- ANA, number of positive patients (%) 188 (100) mumab initiation (p < 0.001) and 1.41 ± 1.25 in the 24 months
- Anti-dsDNA, number of positive patients (%) 188 (100) before vs 0.53 ± 0.83 in the 24 months after belimumab initiation
- Anti-SSA, number of positive patients (%) 90 (47.9) (p < 0.001). We analyzed also the number of patients having at least
- Anti-U1RNP, number of positive patients (%) 51 (27.1)
- Anti-Sm, number of positive patients (%) 38 (20.2)
one flare in the 12 and 24 months before and after belimumab
- Anti-SSB, number of positive patients (%) 30 (15.9) initiation. We observed at least one flare in 85/111 (76.6%) patients
- Anti-p-ribosomal, number of positive patients (%) 9 (4.8) in the 12 months before vs 38/111 (34.2%) patients in the 12 months
- Antiphospholipid, number of positive patients (%) 62 (32.9) after belimumab initiation (p < 0.001) and 44/54 (81.5%) patients in
Concomitant treatment
the 24 months before vs 20/54 (37.2%) patients in the 24 months
- Oral corticosteroid, number of patients (%) 188 (100)
- Antimalarials, number of patients (%) 125 (66.5) after belimumab initiation (p < 0.001).
- Immunosuppressants, number of patients (%) 124 (65.9)
BMycophenolate mofetil, number of patients (%) 47 (25.0)
3.7. Damage accrual
BMethotrexate, number of patients (%) 34 (18.1)
BAzathioprine, number of patients (%) 28 (14.9)
BCyclosporine A, number of patients (%) 17 (9.0) Data on damage accrual were available in 155 patients. Only 4
BTacrolimus, number of patients (%) 2 (1.1) patients (2.1%) accrued damage after belimumab initiation. Mean
BLeflunomide, number of patients (%) 1 (0.5) SLICC-DI was 0.59 ± 0.91 five years before belimumab initiation,
SLE: systemic lupus erythematosus; ANA: anti-nuclear antibody; dsDNA: double 0.85 ± 1.11 at baseline and 0.86 ± 1.27 at the last visit available
stranded DNA; PDN: prednisone equivalent; SD: standard deviation; SLEDAI-2K: (Fig. 1). We observed a significant increase in mean SLICC-DI be-
SLE Disease Activity Index-2000, CLASI: Cutaneous Lupus Erythematosus Disease
tween the evaluation performed 5 years before belimumab initia-
Area and Severity Index; ELISA: Enzyme-Linked ImmunoSorbent Assay.
a
CLASI activity score is reported as median (range) due to non parametric dis- tion and baseline (p < 0.001) but not between baseline and the end
tribution of data. of follow-up (p ¼ 0.083).

3.5. Multivariate analysis 3.8. Drug discontinuation and survival

By multivariate logistic regression analysis, baseline Drug discontinuation was observed in 58 patients (30.8%) after a

Table 2
Clinical and serologic disease activity variables in 188 patients with active SLE treated with belimumab. Data are expressed as mean ± SD; CLASI score is expressed as median
(25 e75 ) due to non parametric distribution of data.

N ptsa Baseline 6 months 12 months 18 months 24 months Pb

SLEDAI-2K 188 8.3 ± 3.3 5.3 ± 3.0 4.2 ± 2.7 4.4 ± 3.8 4.0 ± 2.8 <0.001
Prednisone daily dose (mg/day) 188 11.1 ± 7.6 7.2 ± 4.5 4.9 ± 2.9 5.21 ± 6.35 4.2 ± 3.8 <0.001
DAS-28 score 108 4.2 ± 1.1 2.9 ± 1.3 2.2 ± 1.0 2.0 ± 1.0 1.8 ± 1.0 <0.001
CLASI activity score 62 4 (2e8) 1.5 (0e4) 0 (0e1.5) 0 (0e3) 0 (0e4) <0.001
24-h proteinuria (g/die) 39 1.13 ± 0.73 0.70 ± 0.72 0.63 ± 0.54 0.60 ± 0.68 0.54 ± 0.60 0.002
C3 (g/l) 188 0.71 ± 0,21 0.76 ± 0.19 0.70 ± 0.19 0.80 ± 0.19 0.83 ± 0.2 <0.001
C4 (g/l) 188 0.11 ± 0.06 0.14 ± 0.14 0.15 ± 0.07 0.16 ± 0.09 0.16 ± 0.07 0.002
Anti-dsDNA (ELISA, KIU/L) 97 376.1 ± 768.2 185.9 ± 241.4 153.2 ± 210.3 132.5 ± 188.0 124.8 ± 135.7 0.076
Anti-dsDNA (Farr, UI/mL) 29 97.1 ± 194.4 42.6 ± 50.4 41.7 ± 71.0 38.5 ± 54.3 21.1 ± 23.4 ns

SLE: systemic lupus erythematosus; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index-2000; anti-dsDNA: anti-double stranded DNA; CLASI: Cutaneous Lupus
erythematosus Area and Severity Index; DAS-28: disease activity score-28 joints; ELISA: Enzyme-Linked ImmunoSorbent Assay.
a
At baseline.
b
Univariate repeated measures ANOVA was used to test the effect of time (i.e., treatment) on SLEDAI-2K, prednisone daily dosage, DAS28, 24 h-proteinuria, C3, C4, and anti-
dsDNA. Variations in the CLASI score were analyzed using ANOVA for ranks (Friedman's test).

Please cite this article in press as: L. Iaccarino, et al., Clinical predictors of response and discontinuation of belimumab in patients with systemic
lupus erythematosus in real life setting. Results of a large, multicentric, nationwide study, Journal of Autoimmunity (2017), http://dx.doi.org/
10.1016/j.jaut.2017.09.004
 L. Iaccarino et al. / Journal of Autoimmunity xxx (2017) 1e8 5

mean follow-up of 10.4 ± 7.5 months. Reasons for discontinuation Table 3

were AEs in 23 patients (39.6%), inadequate response in 22 (37.9%), Reasons of belimumab discontinuation in 58 patients with SLE.

pregnancy or remission in 10 (17.2%), lost to follow-up in 3 (5.2%). Reason of discontinuation Number of patients (%)
Detailed reasons for discontinuation are reported in Table 3. Drug Adverse Events 23 (39.6)
survival was 86.9% at 6 months, 76.9% at 12 months, 69.4% at 18 - Infusion reactions 4 (6.9)
months, 67.1% at 24 months and 61.9% at 30 months (Fig. 2). No - Depression 3 (5.2)
association was found between baseline variables and drug - Lymphopenia 2 (3.4)
- Bradycardia/chest pain 2 (3.4)
discontinuation by univariate analysis even when patients who
- Recurrent infections 2 (3.4)
discontinued belimumab due to AEs or inadequate response were - Neutropenia 1 (1.7)
separately considered. - Visual loss 1 (1.7)
- Hypersensitivity reactions 1 (1.7)
- Seizures 1 (1.7)
3.9. Safety - Pneumonitis 1 (1.7)
- Thyroid cancer 1 (1.7)
A total of 3689 infusions were analyzed. We observed 453 AEs in - Cerebral venous thrombosis 1 (1.7)
132 patients (70.2%). Infections, non-infectious AEs, hypersensi- - Fatigue 1 (1.7)
- Worsening of pre-existing myositis 1 (1.7)
tivity and infusion reactions were 60.5%, 20.5%, 17.9% and 1.1% of
- Traumatic coma 1 (1.7)
AEs, respectively. One patient had a mild flu-like syndrome 24 h Inadequate response 22 (37.9)
after each infusion of belimumab, which required paracetamol - Renal 9 (15.5)
administration and always recovered within 48 h. We observed one - Musculoskeletal 8 (13.8)
infectious SAE (0.2% of all AEs and 0.7% of infections) and nine non- - Skin 4 (6.9)
- Hematological 1 (1.7)
infectious SAEs (2% of all AEs and 9.6% of non-infectious AEs). No Pregnancy 8 (13.8)
deaths, severe infusions or hypersensitivity reactions were noted. Lost to follow-up 3 (5.2)
Detailed data on safety are summarized in Table 4. No differences Disease remission 2 (3.4)
were found in the frequency of AEs, including infections, between Total 58 (100)
patients concomitantly treated or not with immunosuppressant. Bold and italics represent the sum of the events.
We found the following incidence of AEs per patient/year at 6
months, 1 year and 2 year of follow-up, respectively: infective AEs
0.95, 0.83 and 0.84; non-infective AEs 0.48, 0.44 and 0.40; infusion/
hypersensitivity reaction 0.61, 0.47 and 0.41.

4. Discussion

Our study evaluated effectiveness and safety of belimumab in a

large, nationwide, cohort of SLE patients prospectively followed in
real life setting. Notably, in Italy belimumab is cheaper than in other
Countries (approximately 6500 V/year) and is fully reimbursed by
the Public Health System in patients with active disease despite
standard therapy, positive anti-dsDNA and low C3 and/or C4. Thus,
in our real life cohort belimumab has been used according to the
physician indication without any influence from socio-economic
factors or patient's Medical Insurance. On the other hand, our re-
sults confirm in the real life setting the efficacy and excellent safety

Fig. 2. Kaplan-Meier curve for time to belimumab discontinuation.

of belimumab in this subgroup of patients, already identified as the

Fig. 1. Damage progression before and after belimumab initiation. Damage score
progressively increased over the 5 years before belimumab initiation, but it increased
significantly slower in the two years after belimumab initiation. SDI: SLICC-Damage
Index.
best responders in RCTs [20]. In our cohort belimumab was effective
in patients with a mild-moderate disease (i.e. polyarthritis and skin
rash) as well as in patients with lupus nephritis, in keeping with the
observations on 234 patients with lupus nephritis treated with
belimumab, summarized in a recent systematic review [41].
In our study we also aimed at finding out predictors of response
in order to identify the profile of the patient “best responder” to
belimumab [42,43]. We found a SRI-4 response rate at 12 and 24
months higher than that reported in BLISS52 and BLISS76 studies
[18,19], and we also found that the response was maintained over
time, in keeping with the results of the long term follow-up studies
of patients who completed the RCTs [44].
High disease activity (SLEDAI-2K
10) and higher corticosteroid
dosage (
7.5 mg/day) were predictors of SRI-4 response in our
study, in line with a post-hoc analysis carried out in patients
enrolled in the two phase III RCTs [20]. It has to be mentioned that

Please cite this article in press as: L. Iaccarino, et al., Clinical predictors of response and discontinuation of belimumab in patients with systemic
lupus erythematosus in real life setting. Results of a large, multicentric, nationwide study, Journal of Autoimmunity (2017), http://dx.doi.org/
10.1016/j.jaut.2017.09.004
6 L. Iaccarino et al. / Journal of Autoimmunity xxx (2017) 1e8

Table 4 there are some small differences between SELENA-SLEDAI used in

Adverse events observed in 188 patients with refractory SLE treated with the RCTs and SLEDAI-2K used in our study as the former does not
belimumab.
score persistent disease activity, e.g. persistent proteinuria, while
N. (%) of AEs N. (%) of pts with AE the latter does.
Non severe AEs 443 (97.8) 129 (68.6) We also evaluated clinical manifestations of SLE as potential
Infectious AEs 273 (60.3) 101 (53.7) predictors of response. Polyarthritis but not skin manifestations
Upper respiratory tract 89 (19.6) 51 (27.1) was predictive of response to belimumab, although both DAS28 and
Urinary tract 53 (11.7) 36 (19.1)
CLASI significantly decreased during the follow-up. This figure
Gastroenteric tract 38 (8.4) 28 (14.9)
Flu 19 (4.2) 17 (9.0) could be explained by the structure of SELENA-SLEDAI score.
Vaginal candidiasis 14 (3.1) 9 (4.8) Indeed, it is easier to obtain a decrease by  4 points in patients
Low respiratory tract 11 (2.4) 9 (4.8) with polyarthritis than in those with mucocutaneous manifesta-
Labial HSV 10 (2.2) 8 (4.3)
tions, since polyarthritis per se counts 4-points, while inflammatory
Skin 11 (2.4) 9 (4.9)
Cutaneous Herpes Zoster/HSV 10 (2.2) 7 (3.7)
rash and mucosal ulcers score 2 points each. In addition, relief of
Conjunctivitis 9 (2.0) 8 (4.3) joint symptoms quickly drops the score by 4, even in case minimal
Relapse of vaginal Herpes Zoster/HSV 4 (0.9) 1 (0.5) signs of inflammation persist e.g. morning stiffness or one joint
Teeth 4 (0.9) 4 (2.1) inflammation. Conversely, complete resolution of inflammatory
Orchiepididymitis 1 (0.2) 1 (0.5)
rash or mucosal ulcers is required for a score decrease in muco-
Non infectious AEs 84 (18.5) 57 (30.3)
Chest pain 9 (2.0) 8 (4.3) cutaneous domain.
Headache 9 (2.0) 7 (3.7) Anti-dsDNA negativization and C3 and/or C4 normalization at 6
Neutropenia/leuko-lymphopenia 7 (1.5) 7 (3.7) and 12 months were not associated with SRI-4 response in our
Folliculitis/rash 6 (1.3) 5 (2.7) cohort. This result could be explained by the low number of pa-
Abdominal pain/diarrhea 5 (1.1) 4 (2.2)
Temporary blurred vision 5 (1.1) 5 (2.7)
tients who achieved a complete and durable anti-dsDNA negativ-
Epigastralgias 5 (1.1) 4 (2.2) ization and/or C3 and/or C4 normalization and the high percentage
Temporary mild hair loss 4 (0.9) 4 (2.2) of patient who achieved the SRI-4 at 12 and 24 months.
Dyspnea 3 (0.7) 3 (1.6) Interestingly, concomitant immunosuppressant use at 24
Non-specific chronic ileocolitis 3 (0.7) 3 (1.6)
months was predictive of lack of response probably due to a more
Fracture 3 (0.7) 3 (1.6)
Dizziness 3 (0.7) 3 (1.6) severe, long-standing disease in patients requiring immunosup-
Depression 2 (0.4) 2 (1.1) pressants for disease control.
Nausea 2 (0.4) 2 (1.1) Taken together these results seem to suggest that among pa-
Seizures 2 (0.4) 2 (1.1) tients with positive anti-dsDNA and low complement those with
Lombosciatalgia 2 (0.4) 2 (1.1)
Paresthesia 2 (0.4) 2 (1.1)
polyarthritis and/or skin rashes are the best candidates to beli-
Othersa 12 (2.6) 12 (6.4) mumab treatment. It has to be noted that no major items easily
Hypersensitivity reactions 81 (17.9) 26 (13.8) enhancing the SLEDAI-2K score, e.g. neuropsychiatric SLE, are
Flu-like syndrome 31 (6.8) 2 (1.1) suitable in defining belimumab best candidate in our as well as in
Dizziness 14 (3.1) 1 (0.5)
previous studies.
Fatigue 11 (2.4) 8 (4.3)
Fever (>37.5  C) 7 (1.5) 5 (2.7) We found a significant decrease in flare rate and in the number
Headache 6 (1.3) 4 (2.2) of patients having a flare after belimumab initiation compared with
Skin rash 3 (0.7) 3 (1.6) the corresponding period before, which suggests a real benefit also
Arthralgias 2 (0.4) 2 (1.1) in patients with a relapsing-remitting disease. Notably, the number
Itch 2 (0.4) 1 (0.5)
Diarrhea 2 (0.4) 2 (1.1)
of flares has emerged as one of the major predictors of damage
Arterial hypertension 1 (0.2) 1 (0.5) accrual [45] and as the most significant independent predictor of
Chest pain 1 (0.2) 1 (0.5) SLE direct medical costs in Europe [46]; thus, decreasing flare
Glottis edema 1 (0.2) 1 (0.5) number and rate may improve long term outcome.
Infusion reactions 5 (1.1) 4 (2.1)
In keeping with the study by Bruce et al. [47] carried out in 998
Flushing 2 (0.4) 1 (0.5)
Perioral paresthesias 1 (0.2) 1 (0.5) SLE patients who completed BLISS-52 and BLISS-76 RCTs and
Abdominal pain/diarrhea 1 (0.2) 1 (0.5) entered in the long term extension study, we observed a negligible
Nausea 1 (0.2) 1 (0.5) organ damage accrual during follow-up (Fig. 1). This result means
Severe AEs 10 (2.2) 9 (4.8) the achievement of an important unmet need in SLE with a po-
Infectious severe AEs 1 (0.2) 1 (0.5)
Pneumonitis 1 (0.2) 1 (0.5)
tential favorable impact on patients' survival and quality of life.
Non infectious severe AEs 9 (2.0) 8 (4.3) We also observed a good safety profile of belimumab with a very
Deep vein thrombosis 2 (0.4) 2 (1.1) low frequency of infusion reactions and SAEs in our study (Table 4).
Thyroid cancer 2 (0.4) 2 (1.1) The excellent tolerability in clinical practice confirms the results of
Calcaneal fracture 1 (0.2) 1 (0.5)
belimumab phase II and III RCTs and post-hoc analysis [20,48,49]
Pulmonary embolism 1 (0.2) 1 (0.5)
Worsening of pre-existing myositis 1 (0.2) 1 (0.5) where cases with comorbidities were excluded.
Severe leukopenia 1 (0.2) 1 (0.5) Belimumab is the only biologic drug approved for SLE and, thus,
Severe depression 1 (0.2) 1 (0.5) we cannot compare its survival with that of other biologics in SLE.
Infusion/hypersensitivity reactions 0 (0) 0 (0) However, belimumab survival found in our study is similar to what
Death 0 (0) 0 (0)
Total 453 (100) 132 (70.2)
is reported in patients with inflammatory arthritides treated with
TNF (tumor necrosis factor) inhibitors (TNFi) in clinical practice
N.: number, Pts: patients, AEs: adverse events.
[50]. Notably, TNFi in inflammatory arthritides are usually consid-
Bold and italics represent the sum of the events.
a
A single case of deep vein thrombosis, xerostomia, bradycardia, worsening of ered after the failure of standard therapy, as with belimumab in SLE
pre-existing hypertension, lipothymia, odynophagia, arthralgias, irregular menses, patients.
subcutaneous calcifications, non infectious-keratitis, weight gain, pituitary Our study has several strengths and some limitations. The main
adenoma. strengths are the large sample size and the long follow-up; in
addition, our study is a retrospective analysis of prospectively

Please cite this article in press as: L. Iaccarino, et al., Clinical predictors of response and discontinuation of belimumab in patients with systemic
lupus erythematosus in real life setting. Results of a large, multicentric, nationwide study, Journal of Autoimmunity (2017), http://dx.doi.org/
10.1016/j.jaut.2017.09.004
 L. Iaccarino et al. / Journal of Autoimmunity xxx (2017) 1e8
collected data and, thus, we could use validated clinimetric and
response measures and carefully evaluate the drug safety. On the
other hand, limitations include the lack of a control population and
the potential heterogeneity in background treatment due to the
multicentre design of the study; however, all clinicians who
enrolled patients in this cohort declared to adhere to the EULAR
recommendations for SLE management [37,38].
5. Conclusions
In conclusion, our prospective study confirms the effectiveness
and safety of belimumab in patients with active and refractory SLE
especially in those with musculoskeletal manifestations. Belimu-
mab decreases disease activity, flare rate as well as corticosteroid
daily dosage, which are important targets in SLE treatment, thereby
leading to a minimization of organ damage accrual.
Conflict of interest and funding support statement
Andrea Doria, Angela Tincani: GSK consultant fee less than
$10,000.
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
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Please cite this article in press as: L. Iaccarino, et al., Clinical predictors of response and discontinuation of belimumab in patients with systemic
lupus erythematosus in real life setting. Results of a large, multicentric, nationwide study, Journal of Autoimmunity (2017), http://dx.doi.org/
10.1016/j.jaut.2017.09.004