Abatacept treatment in patients with primary Sjögren*s syndrome: an open label study

Sjögren*s syndrome (SS) is a chronic inflammatory and lymphoproliferative
disease with autoimmune features. SS is characterised by a progressive
lymphocytic infiltration of the exocrine glands, notably the lacrimal and
salivary glands [1]. The main clinical features are a progressive dryness of
the eyes (keratoconjunctivitis sicca) and dryness of the mouth (xerostomia).
Furthermore, various extraglandular manifestations may develop of which
restricting fatigue is the most common. The fast majority of SS patients (85%)
suffers from fatigue [2]. Other extraglandular manifestations that may occur
are neuropathy, arthritis, vasculitis, and renal or lung involvement. SS can be
primary (pSS) or secondary (sSS), the latter being associated with other
autoimmune diseases such as rheumatoid arthritis (RA) or systemic lupus
erythematosus (SLE). The estimated prevalence of SS in the general population
is between 0.5-2%, which makes SS, after RA, the most common systemic
autoimmune disease [3;4]. Moreover, SS is a disabling disease, particularly in
relatively young patients, of working age. Apart from the symptoms mentioned
above, patients may be restricted in their activities and in their
participation in society, resulting in a reduced health-related quality of life
and an impaired socioeconomic status. The latter results in lower employment
rates and higher disability rates compared to the general population [2].
Histopathological findings in SS-patients include focal lymphocytic
infiltrates, located mainly around the glandular ducts of the salivary and
lacrimal glands and extend to occupy the acinar epithelium, leading to
glandular dysfunction [5;6]. The lymphocytic infiltrates mainly consist of
activated T-cells, B-cells, and plasma cells. Despite extensive studies, the
etiopathogenic factors that lead to the massive infiltration of the exocrine
glands in SS are unknown. It is thought that activated (autoreactive) T cells
play an integral part in the immunopathology and disease development of pSS,
mediating B-cell activation, macrophage activation and cytokine production
that, ultimately, lead to glandular inflammation and destruction.
Most of the traditional anti-rheumatic drugs used in RA and SLE, such as
corticosteroids, methotrexate (MTX), azathioprine, sulphalazine and
leflunomide, have been tried in pSS with unsatisfactory or limited results
[7-11]. Currently, biological agents have been introduced in various systemic
autoimmune diseases, as rheumatoid arthritis and SLE. Biological agents most
frequently applied in autoimmune diseases are monoclonal antibodies (e.g.,
anti-CD20 (rituximab), anti-CD22 (epratuzumab), anti-BAFF (belimumab),
anti-TNF-α (infliximab)) and soluble receptors (e.g., anti-TNF-α (etanercept)).
The biological agents enhance or replace conventional immunosuppressive
therapy. However, in contrast to rheumatoid arthritis and SLE, no biological
agent has yet been approved for the treatment of SS [12]. Moreover, currently
no effective systemic treatment modalities are available for SS, although
recently, in two randomized placebo controlled phase II studies B-cell
depletion with rituximab has shown promising results as improved salivary
secretion, reduction of fatigue and extraglandular manifestations, and
reduction of subjective symptoms as xerostomia and ocular dryness [13;14].
Abatacept, a biological agent not yet tested in SS, is a fully human soluble
co-stimulation modulator that selectively targets the CD80/CD86:CD28
co-stimulatory signal required for full T-cell activation and the T cell
dependent activation of B cells. Abatacept is currently used for the treatment
of rheumatoid arthritis and it appears to be safe and effective [15]. Abatacept
might also be a promising treatment for various other autoimmune diseases.
Given the novel mechanism of action of abatacept and the recognized role of
activated T-cells in the immunopathology of pSS, selective modulation of
costimulation represents a rational therapeutic approach in pSS patients.
Abatacept could be a good alternative for B-cell depletion therapy, possibly
also in patients in whom B-cell depletion is not well tolerated or ineffective.
Furthermore, abatacept is a fusion protein, and may therefore have a more
favourable side effect profile than rituximab, which is a chimeric monoclonal
antibody.
Therefore, the aim of the proposed open label phase II study is to assess
whether abatacept therapy will reduce the objective signs and subjective
complains in pSS patients (see below for the primary and secondary objectives
and endpoints to be studied).

Evaluation of efficacy (as assessed by the stimulated whole saliva flow rate at
24 weeks) and safety of abatacept treatment in 15 patients with pSS.

fase 2 study, open label

Abatacept will be given at week 0, 2, 4 and every 4 weeks there after by
infusion (in total 8 infusions).

The total duration of this study is 48 weeks. Abatacept is administrated in a
30-minute intravenous infusion on day 1, 15, and 29 and every 28 days
thereafter for 5 months. At these visits, blood is drawn from the infuse (43
ml) and therefore venapunction is not necessary. Patients will be seen by their
own physicians: their rheumatologist, their ophthalmologist, and their oral and
maxillofacial surgeon prior to the study (regular visit), and after 4, 12, 24
and 36 weeks.
A parotid gland biopsy will be performed prior to the study and within 2 weeks
after the 24 weeks visit. This biopsy is taken in a 15 minutes during
procedure, under local anaesthesia through a minor incision around the earlobe.
The donor site heals generally without any complications [5].
The visits to the rheumatologist, the ophthalmologist and the maxillofacial
surgeon are all scheduled on the same day. Each specialist visit takes about
20-30 minutes. At the rheumatology department physical examination is
performed. When no infusion is scheduled on the day of the visits, blood is
drawn (43ml) for analysis. At the oral and maxillofacial department salivary
gland function is evaluated by painless collection of saliva, which takes 15
minutes. The ophthalmologist performs the Schirmer test, the Lissamin green
test and the tearfilm break-up time test to evaluate ocular dryness. Patients
will receive a questionnaire, concerning sicca features, fatigue and
health-related quality of life.
Visits to the above mentioned specialists and the performed tests (phycial
examination, venapunction on visit days that no infusions are scheduled,
salivary gland function evaluation, Schirmer test, Lissamin green test,
tearfilm break-up time test) are in the regular follow up protocol as well. In
the regular follow up protocol patients visit their specialists once or twice a
year. Patients that participate in this trial will therefore bring 4 extra
visits to our hospital, besides the visits for the infusions.
Sibilia and Westhovens [16] performed an integrated safety analysis of five
randomized, placebo controlled double-blind abatacept clinical trials in RA
patients that encompassed a total of 1687 patient-years of abatacept exposure.
This analysis suggested that abatacept has acceptable safety and tolerability
in patients with RA.
Overall frequencies of adverse events (AEs; 88.8% vs. 85.1%), serious AEs
(SAEs; 14.0% vs. 12.5%) and malignancies (1.4% vs.1.1%) were similar in
abatacept- versus placebo-treated patients, respectively (regardless of the
potential relationship to the study therapy). The AEs were considered to be at
least possibly related to the study therapy in 52.2% and 46.1% of abatacept-
and placebo reated patients, respectively, leading to discontinuation in 3.4%
and 2.2% of patients (14). The most frequently reported AEs in the abatacept
and placebo groups, regardless of their potential relationship to the study
therapy, were: headache (18.3% vs. 12.7%, respectively), upper respiratory
tract infection
(12.7% vs. 12.1%), nausea (11.6% vs. 10.6%), nasopharyngitis (11.6% vs.9.1%),
diarrhea (9.9% vs. 10.0%) and dizziness (9.5% vs. 7.0%).
Discontinuations due to SAEs were 2.8% in the abatacept group vs. 1.6% in the
placebo group. The frequency of serious infections was low overall (3.0% vs.
1.9% in abatacept- versus placebo-treated patients, respectively). Acute
infusional AEs (9.8% vs. 6.7% in the abatacept versus placebo groups,
respectively) were mostly mild-to-moderate in intensity. Safety data through
cumulative exposure were consistent with those from the double-blind periods;
there was no evidence of an increase in the incidence of serious infections or
malignancies with increasing exposure to abatacept. Abatacept was associated
with low levels of immunogenicity, with no detectable association between
immunogenicity and safely or efficacy. Abatacept treatment did not result in a
higher rate of seroconversion for anti-nuclear or anti-dsDNA antibodies versus
placebo, and was associated with a similar frequency of autoimmune events
versus placebo (1.4% vs. 1.8*, respectively). Moreover, treatment with
abatacept may not markedly impair the response to vaccination in healthy
volunteers or RA patients.