Effectiveness and safety of abatacept for

the treatment of patients with primary

Sjögren’s syndrome

Adriana Cristiane Machado, Laura

Caldas dos Santos, Tania Fidelix, Ilda
Lekwitch, Simone Barbosa Soares, André
Felipe Gasparini, et al.
Clinical Rheumatology
Journal of the International League of
Associations for Rheumatology

ISSN 0770-3198

Clin Rheumatol
DOI 10.1007/s10067-019-04724-w

1 23
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 Author's personal copy
Clinical Rheumatology
https://doi.org/10.1007/s10067-019-04724-w

BRIEF REPORT

Effectiveness and safety of abatacept for the treatment of patients

with primary Sjögren’s syndrome
Adriana Cristiane Machado 1 & Laura Caldas dos Santos 2 & Tania Fidelix 3,4 & Ilda Lekwitch 4 & Simone Barbosa Soares 5 &
André Felipe Gasparini 5 & Juliana Venturini Augusto 5 & Nelson Carvas Junior 6 & Virginia Fernandes Moça Trevisani 7,8

Received: 9 May 2019 / Revised: 5 July 2019 / Accepted: 30 July 2019

# International League of Associations for Rheumatology (ILAR) 2019

Abstract
Sjögren’s syndrome is an autoimmune disease characterized by inflammation of the exocrine glands. The disease can be primary
or secondary (if it is associated with another autoimmune disease). In Barring symptom management, there is no established
treatment. To evaluate the effectiveness and safety of abatacept as a treatment of primary Sjögren’s syndrome over the course of
24 months. Eleven patients with primary Sjögren’s syndrome from the Rheumatology Department of Universidade Santo Amaro,
Sao Paulo, Brazil were enrolled for a prospective observational study. Eligible participants were diagnosed according to the 2002
American-European consensus criteria and had a score greater than 3 on the EULAR Sjögren’s Syndrome Disease Activity Index
(ESSDAI). Participants received intravenous abatacept for 24 months at a weight-adjusted dose of 500 mg for patients weighing
< 60 kg and 750 mg for those weighing > 60 kg. The outcomes were ESSDAI activity index, non-stimulated salivary flow rate,
ocular dryness (Schirmer test, tear film break-up time, and ocular staining score), SF-36 questionnaire, and Fatigue domain of the
FACIT (Functional Assessment of Chronic Illness Therapy) index. There was a statistically significant reduction in ESSDAI
index and improvement of salivary flow. One subscale of the SF-36 index—emotional role functioning—showed improvement.
There was no change in ocular parameters or in the FACIT index. In this sample of 11 patients with primary Sjögren’s syndrome,
abatacept therapy improved xerostomia and systemic disease activity.

Key Points
• Abatacept is safe and effective for the treatment of primary Sjögren’s syndrome.
• Abatacept can improve salivary flow and ESSDAI index in this patient population.

Keywords Abatacept . Autoimmune diseases . Sicca syndrome . Sjögren’s syndrome . Xerostomia

Introduction diseases, such as rheumatoid arthritis, scleroderma, and sys-

Sjögren’s syndrome (SS) is an autoimmune disease character-
ized by inflammation of the exocrine glands, mainly the lac-
rimal and salivary glands. It may occur either independently
(primary SS or pSS) or in association with other autoimmune
temic lupus erythematosus (secondary SS or sSS) [1]. Up to
25% of patients with pSS have mild to severe extraglandular
involvement [2]. The cornerstones of pSS treatment are symp-
tomatic management of sicca manifestations and immunosup-
pressive agents for systemic disease [3]. Systemic

* Tania Fidelix 4
fidelixtania@gmail.com
5
1 6
Rheumatology Department, Universidade Santo Amaro (UNISA),
Rua Isabel Schmidt, 349, São Paulo, SP 04743-030, Brazil
2 7
Universidade Federal de São Paulo (UNIFESP), Rua Sena Madureira,
1500, São Paulo, SP 04021-001, Brazil
3 8
Department of Evidence-Based Health, UNIFESP, Rua Sena
Madureira, 1500, São Paulo, SP 04021-001, Brazil
RN, UNISA, Rua Isabel Schmidt, 349, São Paulo, SP 04743-030,
Brazil
UNISA, Rua Isabel Schmidt, 349, São Paulo, SP 04743-030, Brazil
Universidade Paulista (UNIP), Av Paulista, 900, São
Paulo, SP 01310100, Brazil
Department of Evidence-Based Health, UNIFESP, Rua Isabel
Schmidt, 349, São Paulo, SP 04743-030, Brazil
Rheumatology Department, UNISA, Rua Isabel Schmidt, 349, São
Paulo, SP 04743-030, Brazil
 Author's personal copy
involvement is closely related to disease prognosis, suggesting
the need for closer follow-up and more robust therapeutic
management [4].
The scientific evidence on the balance between efficacy
and side effects associated with immunosuppressive agents
is still limited [3]. Commonly used immunomodulatory
agents, including hydroxychloroquine (with anti-interferon
activity), prednisone, methotrexate, mycophenolate sodium,
and azathioprine, failed to improve functional parameters of
salivary and lacrimal glands in clinical trials of SS [5–8].
The emergence of biological therapies has expanded the
therapeutic armamentarium available to treat pSS.
Biologics currently used in pSS patients are used off-
label and are overwhelmingly agents targeting B cells.
More recent studies are moving toward investigating how
to target specific cytokines involved in SS pathogenesis.
The most recent etiopathogenic advances in SS are provid-
ing more insight in the search for new highly selective
biological therapies without the adverse effects of the stan-
dard drugs currently used (corticosteroids and immunosup-
pressive drugs) [4].
Abatacept is a fully human soluble co-stimulation modula-
tor that selectively targets the CD80/CD86: CD28 co-
stimulatory signal required for full T cell activation and T
cell-dependent activation of B cells [9]. Given the mechanism
of action of abatacept and the recognized role that T cells and
B cells play in pSS, selective modulation of co-stimulation
could be a rational therapeutic option.
A phase II open-label study in 2014 by Meiners et al. [10]
showed that abatacept could be a promising pSS treatment;
the study authors found a significant decrease in disease ac-
tivity indices such as the EULAR Sjögrens Syndrome Disease
Activity Index (ESSDAI) [11] and the EULAR Sjögren’s
Syndrome Patient Reported Index (ESSPRI). Importantly,
the authors showed that abatacept was safe and that side ef-
fects were limited in pSS patients.
This current open-label study was designed to evaluate the
effectiveness and safety of endovenous abatacept over the
course of 24 months in a cohort of 11 patients with pSS.
Materials and methods
Forty-one patients with a diagnosis of Sjögren’s syndrome
were recruited from the Rheumatology Department of
Universidade Santo Amaro, Sao Paulo, Brazil to take part in
this study. These patients formed a single-center cohort and
were recruited over a period of 12 months (from January 2017
to December 2017). The exclusion criteria were: use of any
other immunobiologic therapy, presence of other connective
tissue disease, presence of any malignant disease, any immu-
nosuppression that might predispose to infections, chronic
obstructive pulmonary disease, or a tuberculin test reaction
Clin Rheumatol
≥ 5 mm. All patients had a diagnosis of pSS assigned using
the 2002 EULAR-ACR criteria [12].
Of the 41 patients invited, 30 were excluded; 10 had an
ESSDAI index < 3, 5 were on rituximab, 5 had comorbidities
with high risk of infection or cancer in the preceding 5 years, 3
had a tuberculin test reaction ≥ 5 mm, and 7 refused participa-
tion (Fig. 1).
Potential volunteers were invited to participate in the study,
and only those who provided written informed consent were
included. The local medical ethics committee approved the
study. A general examination was performed in addition to a
standardized clinical evaluation that obtained and recorded
data on: demographics, symptom duration, medication use,
bilateral Schirmer’s test result (abnormal if ≤ 5 mm/5 min on
one or both sides), unstimulated whole salivary flow rate (ab-
normal if < 0.1 ml/min), and clinical evaluation in order to
establish grades for the ESSDAI domains. Routine laboratory
tests included blood cell counts, serum protein electrophore-
sis, C3 and C4 complement levels, and cryoglobulinemia.
Antinuclear antibodies were assessed on HEp-2 cells, and
anti-SSA/anti-SSB antibodies were determined using com-
mercial enzyme-linked immunosorbent assays. Latex aggluti-
nation was used to measure the rheumatoid factor. All partic-
ipants were evaluated by the same three professionals (a rheu-
matologist, a nurse, and an ophthalmologist) at baseline and at
24-month follow-up.
The dose of the abatacept infusion was set at 500 mg intra-
venously per month if a patient weighed ≤ 60 kg or at 750 mg
intravenously per month if their weight was > 60 kg. The dose
was injected with an infusion pump in a designated infusion
center with medical and nursing support. Each infusion lasted
30 min, and infusions were carried out once a month for
24 months. At baseline and after 24 months, the patients re-
ceived the same tests and were administered two question-
naires, one on quality of life (FS-36) [13] and one on fatigue
(FACIT Fatigue) [14]. Tests included a clinical evaluation
(ESSDAI index), salivary flow measurement in ml/min, and
an ophthalmologic examination performed by an unblinded
cornea specialist that performed both baseline and final exam-
inations in all patients. The ophthalmologic evaluation includ-
ed the Schirmer test without anesthesia, an ocular surface
evaluation using specific dyes for the cornea and conjunctiva
(Ocular Staining Score), and the tear film break-up time test
for both eyes.
Data were expressed as descriptive statistics (mean ±
standard deviation and median [range], as necessary),
and tested for normality of distribution. The effect of
abatacept on ESSDAI score, Schirmer test, tear film
break-up time, and OSS was assessed by the Wilcoxon
signed-rank test, while the effect on quality of life
(measured by the SF-36 and FACIT-Fatigue scales)
was assessed by Student’s t test for paired samples or
the Wilcoxon test as appropriate.
 Author's personal copy
Clin Rheumatol
Fig. 1 Patient selection flowchart
A significance level of 5% was adopted. All analyses were
carried out in R version 3.5.1.
Results
The study sample was made up of 11 women with ages rang-
ing from 25 to 81 years (mean 53.73 ± 15.07 years). The ma-
jority self-described their race as mulatto or brown (pardo)
(54.5%). Of the total, 90.9% had a positive anti-nuclear factor,
81.8% were anti/SSA positive, and 90.9% had a positive rheu-
matoid factor. Overall, 81.8% of the participants had ESSDAI
scores above 5. At baseline, the mean (SD) duration of symp-
toms was 7.45 ± 4.45) years (Table 1).
Abatacept therapy was associated with a statistically sig-
nificant reduction in ESSDAI score (median difference, 2.99;
95% CI − 0.49 to 7.99; P = 0.013). The articular and glandular
ESSDAI subgroups showed the most significant change.
 Author's personal copy
Clin Rheumatol

Table 1 Demographic
characteristics at baseline Patient Age Ethnicity Gender Disease ANA SSA SSB RF Focus scores
(years) duration
(years)

1 59 W F 9 + + – + Not performed
2 51 W F 13 + – – + 3
3 81 B F 11 + + – + Not performed
4 50 W F 5 + + + + Not performed
5 57 B F 4 + + + + Not performed
6 40 B F 3 + + + + Not performed
7 73 B F 6 – + – – Not performed
8 45 W F 3 + + + + Not performed
9 54 B F 12 + + + + 4
10 25 B F 2 + + + + Not performed
11 56 B F 14 + – – + 1

W white, B brown, F female, ANA antinuclear antibody, RF rheumatoid factor

There was also a significant increase in salivary flow (median
difference, − 0.90; 95% CI − 1.50 to − 0.50) after 24 months
of treatment (Table 2).
There was no statistical difference between baseline and
the 24-month time point in the different ophthalmologic eval-
uations. Schirmer test (right eye), break-up time (right eye),
and OSS (right eye) showed no significant changes (Table 2).
In terms of the questionnaires, improvement was obtained
only in the role emotional subscale of the SF-36 (mean differ-
ence 36.4; 95% CI − 67.1 to − 5.57) (Table 3). The FACIT-
Fatigue index showed no evidence of changes in the pre- and
post-treatment means (pre 33.18 ± 10.63 versus post 35.82 ±
11.04; t (10) = − 0.967; P = 0.356).
Discussion
Our study is in line with previous research that has shown that
abatacept can help patients with pSS, especially those with any
grade of systemic involvement. All previous studies have found
acceptable efficacy and a low incidence of adverse effects.
The first published study, by Adler et al. in 2013 [15], was a
pilot study of 11 patients who received abatacept for 24 weeks.
This study evaluated clinical, laboratory, and histopathological
aspects before and after treatment, using biopsies of minor sal-
ivary glands and subpopulations of B and T lymphocytes. The
numbers of lymphocytic foci decreased significantly. Adjusted
for disease duration, saliva production increased significantly.
In our study, we noticed that, even with a disease duration of
more than 5 years, there was an increase in salivary production.
Following this study, in 2014, Meiners et al. [10] followed
15 patients for 48 weeks. Patients were treated with eight
intravenous abatacept infusions. Improvement in clinical
(ESSDAI and ESSPRI) and laboratory (IgG, rheumatoid fac-
tor) parameters was observed, but no increase in salivary flow.
Our study had a duration of 2 years and, thus, we had a longer
period of observation to detect improvement in clinical man-
ifestations and salivary flow.

Table 2 Effect of 24-month

treatment with abatacept on Variable (sample size) Baseline 24 months Median difference [95% CI] P
ESSDAI and ocular parameters
ESSDAI (n = 11) 7.0 (0–30) 2.0 (0–27) 2.99 [−0.49; 7.99] 0.013
Schirmer OD (n = 11) 5.0 (0–35) 3.0 (0–35) 2.26 [−3.50; 12.5] 0.423
Schirmer OS (n = 11) 16.5 (0–35) 3.5 (0–35) 8.11 [−2.49; 23.9] 0.183
Break up time OD (n = 11) 4.0 (2–11) 3.0 (1–10) 0.50 [−1.00; 2.49] 0.307
Break up time OS (n = 11) 3.5 (2–11) 3.0 (1–8) 1.99 [−0.49; 3.50] 0.078
OSS OD (n = 11) 8.0 (2–12) 6.0 (0–12) 0.50 [−2.50; 5.50] 0.721
OSS OS (n = 10) 7.0 (1–12) 7.0 (0–12) 0.43 [−4.49; 4.99] 0.932
Salivary flow (n = 11) 0.0 (0.0) 0.1 (0.0–1,5) −0.90 [−1,50;-0.50] 0.013

ESSDAI European Sjögren’s Syndrome Disease Activity Index, OD right eye, OS left eye, OSS Ocular Staining
Score
All values expressed as median (range) unless stated otherwise. All P values from Wilcoxon’s test. Bold type
denotes statistical significance
 Author's personal copy
Clin Rheumatol

Table 3 SF-36 questionnaire

scores at baseline and endpoint SF-36 categories Baseline Post-treatment Mean difference
Mean (SD) Mean (SD) 95% CI P

Physical role functioning 38.18 (19.66) 49.09 (27.73) −10.9 [−35.4; 13.5] 0.275a
Physical functioning 27.27 (28.40) 40.91 (40.73) −13.6 [−43.1; 15.8] 0.495
Bodily pain 34.82 (27.81) 51.36 (31.83) −16.5 [−45.1; 12.0] 0.226
General health perceptions 56.18 (18.88) 56.27 (20.49) −0.09 [−14.3; 14.1] 0.817a
Vitality 46.36 (14.85) 50.00 (26.65) −3.64 [−22.4; 15.1] 0.675
Social role functioning 67.05 (28.65) 65.91 (30.15) 1.14 [−20.9; 23.2] 0.911
Emotional role functioning 21.21 (40.20) 57.57 (49.65) −36.4 [−67.1; −5.57] 0.025
Mental health 52.36 (20.20) 58.91 (28.23) −6.54 [−22.8; 9.77] 0.392

All P values from Wilcoxon’s test unless stated otherwise. Bold type denotes statistical significance
a
Student’s t test

The ROSE study [16] was an open-labeled, prospective,
observational multicenter study of sSS in 36 patients with rheu-
matoid arthritis. Of these, 33% achieved remission of rheuma-
toid arthritis at 52 weeks. Salivary volume increased signifi-
cantly in 11 patients with a focus score of 1 or 2 on labial
salivary gland biopsy, but no change was noted in 18 patients
with a focus score of 3 or 4. Tear volume by Schirmer’s test
increased significantly in 30 patients. The main value of the
ROSE study was the correlation of salivary flow improvement
with minor salivary gland biopsy findings. This is a weakness
of our study, because we could not assess the presence of glan-
dular reserve before the start of abatacept therapy.
In 2017, Verstappen et al. investigated the influence of
abatacept on the homeostasis of CD4+ T cells and T cell-
dependent B cell hyperactivity in 15 patients with pSS for
24 weeks. The authors found that a particular reduction in fol-
licular T cells was related to the reduction of B cell hyperactiv-
ity, and this coincided with the reduction of ESSDAI scores
[17]. However, these were small, open-label, uncontrolled stud-
ies, thus susceptible to flaws and biases, which calls for urgent
further investigation through better-designed studies.
The first randomized, double blind, placebo-controlled,
phase-III trial was conducted from 2016 to 2018
(ClinicalTrials.gov identification number NCT02915159).
This study investigated the efficacy and safety of
subcutaneous abatacept in 253 adults with active pSS [18]
for 1 year. The primary outcome was ESSDAI score, and the
secondary outcomes were ESSPRI, salivary flow
measurement, anti-abatacept antibody testing, and adverse
events. While the active data collection phase of the study
has been completed, results are not yet available.
This was the first study to report benefits in terms of sali-
vary flow and clinical improvement in patients with pSS. To
confirm salivary gland reserve, it would be interesting to per-
form salivary gland biopsies or even ultrasonography before
and after treatment.
There are still few trials for pSS treatments compared with
RA or SLE. These findings are still preliminary, but demon-
strate that abatacept can be used in selected cases. The clinical
and immunological heterogeneity associated with pSS may be
one of the main explanations for the negative results often
obtained in the small randomized controlled trials often con-
ducted in pSS patients.
Disease-modifying treatments for pSS are still an unmet
clinical need. Continued research is needed to design more
effective and safe therapies for this disease.
Data availability The datasets generated during and/or analyzed during
the current study are available from the corresponding author on reason-
able request.
Compliance with ethical standards
Disclosures None
Ethical approval The study was approved by the local Ethics
Committee. All procedures were in accordance with the ethical standards
of the 1964 Helsinki declaration and its later amendments or comparable
ethical standards.
Informed consent All patients provided written informed consent for
participation before undergoing any procedures.
Financial disclosure The authors have no financial relationships rele-
vant to this article to disclose.

Conclusion

Despite the small sample of 11 patients, our results in terms of

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