Anti-CD20 for the retreatment of primary Sjögren*s syndrome in patients who were included in the placebo-controlled double blinded rituximab study

SS is a chronic inflammatory and lymphoproliferative disease with autoimmune
features, characterised by a progressive lymphocytic infiltration of the
exocrine glands, notably the lacrimal and salivary glands. The main clinical
features are a progressive dryness of the eyes (keratoconjuctivitis sicca) and
dryness of the mouth (xerostomia). Furthermore, various extraglandular
manifestations may develop, such as neuropathy, arthritis, fatigue, vasculitis,
and renal or lung involvement. B-cell activation is a key feature of SS,
leading to the production of autoantibodies and hypergammaglobulinemia.
Furthermore, SS is also associated with an increased risk of B-cell lymphoma
development.
Rituximab, a chimeric humanised monoclonal antibody which binds to the B cell
surface antigen CD20, leads to a rapid B cell depletion and may lead to a
decrease of SS disease activity. In 2005 a phase II study by our group showed
that rituximab was effective in the treatment of primary SS (1). Currently, a
double blinded randomized placebo-controlled trial with rituximab is being
performed at our departments. In this trial 20 patients are treated with
rituximab, whereas 10 patients received placebo. One patient developed mild
serum sickness, which responded well to corticosteroids. Interim statistical
analysis after 24 weeks follow-up showed improvement on both objective and
subjective variables in the rituximab group compared to the placebo group.
However, 48 weeks follow-up data are not available yet.
In RA and SLE repeated courses of rituximab have resulted in good clinical
responses (2-4). Since the effect of repeated courses of rituximab in primary
SS is not well known, a phase II study will be performed in which patients who
have been treated with rituximab before, receive a second course of rituximab
treatment. Furthermore, patients who received placebo in the above mentioned
trial will also be treated with rituximab, to evaluate the intra-individual
effect of rituximab compared to placebo.

Evaluation of the effect of retreatment with rituximab in 20 patients with
primary Sjögren syndrome, and evaluation of the intra-individual effect of
rituximab compared to placebo, in 10 patients who received placebo in the
double blind randomized placebo-controlled rituximab trial.

Phase II trial

Rituximab infusions (1000 mg), intravenous infusion of 100 mg of
methylprednisolone before infusion of rituximab, together with 60 mg per day of
oral prednisone on days 2, 3, 16 and 17, 30 mg per day on days 4, 5, 18 and 19
and 15 mg per day on days 6 and 20.

The total duration of this study is 68 weeks. Patients will be seen by their
own physicians: their rheumatologist, their eye specialist, and their oral and
maxillofacial surgeon prior to the study (regular visit), and after 16, 24, 36,
48 and 68 weeks. Rituximab is given by infusion on day 1 and 15. At these two
visits, blood is drawn from the infuse (43 ml) and therefore venapunction is
not necessary.
A parotid gland biopsy will be performed prior to the study in patients who
received rituximab before, and at 16 weeks in patients who received placebo in
the double blind randomized placebo-controlled rituximab trial. 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. This approach makes that all patients have been subjected to in
total three parotid biopsies, viz. the former rituximab patients before the
firs t and second trial and at week 12 of the first trial, and former placebo
patients before and at week 12 of the first trial, and at week 12 of the second
trial.
The visit to the rheumatologist, the eye specialist and the maxillofacial
surgeon are all scheduled on the same day. Each specialist visit takes about
20 minutes. At the rheumatology department physical examination is performed
and 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 eye specialist performs the Schirmer test
and the lisamine green 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, salivary gland function evaluation, schirmer test,
lisamine green test, tear break up time) 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.

Experience in oncology showed that rituximab is well tolerated in a variety of
settings, with mild-to-moderate infusion related reactions following the first
infusion being the most common adverse event (5). Also in RA the most
frequently reported adverse events in rituximab treatment were
infusion-related, in particular at the first infusion. However, they responded
well on intravenous infusion of steroids (6;7). Examples of infusion related
event that have been reported in rituximab treatment include pruritus, fever,
urticaria/rash, chills, pyrexia, rigors, sneezing, angioneurotic edema, throat
irritation, cough, bronchospasm, hypotension and hypertension (2).
Keystone et al (2) performed an open-label extension analysis in patients with
active RA. A total of 1039 patients with active RA were treated with repeated
courses of rituximab. The most common adverse events, which were
mild-to-moderate acute infusion related events, decreased with each course. The
serious infection rate after course 1 (5.1 per 100 patient-years) remained
stable through additional courses. It was concluded that RA patients treated
with repeated courses of rituximab have sustained clinical responses with no
new adverse events.