The BRIDGE-PMR study: B-cell depletion with Rituximab for Dose reduction of Glucocorticoids: Efficacy in PolyMyalgia Rheumatica

Polymyalgia rheumatica (PMR) is a debilitating inflammatory rheumatic disorder
which typically occurs in patients older than 50 years and is characterized by
pain and stiffness of the neck, bilateral shoulder, hip girdle and often
elevated inflammatory parameters. PMR is closely related to giant cell
arteritis (GCA) -a form of large vessel vasculitis (LVV)- as 16% to 21% of PMR
patients have concomitant GCA, and 40% to 60% of patients diagnosed with GCA
have concomitant PMR.
Glucocorticoids (GC) are the cornerstone of PMR treatment, however, 29-45% of
PMR patients do not sufficiently respond to GC treatment after 3-4 weeks and
only 33-50% of PMR patients treated in secondary clinics achieve sustained
GC-free remission after 2 years.GC related side effects occur in about 50% of
PMR patients and add significant burden for patients. This emphasizes the need
for treatment alternatives such as conventional synthetic and biologic disease
modifying antirheumatic drugs (csDMARDs and bDMARDs).

The exact value of several csDMARDs in PMR remains unclear. So far most
evidence exists for methotrexate (MTX).The most recent guidelines on management
of PMR recommend rheumatologists to consider early start of MTX in patients
with risk factors for relapses/prolonged GC therapy. It is also recommended to
prescribe MTX in patients who relapse under GC therapy and/or who develop
GC-related adverse events or have comorbidities that worsen due to GC. The data
on the use of concomitant MTX to date is of medium quality and the MTX dosages
are low (7.5-10 mg weekly) compared to the dosages in other rheumatic diseases.
One randomized controlled trial (RCT) with concomitant MTX 7.5 mg showed no
additional GC sparing effect, although there was a high drop-out rate of 48%.
Another RCT found that 10 mg MTX weekly was associated with shorter GC
treatment and fewer flares. Outcomes from this study at 76 weeks showed that 28
of 32 patients in the methotrexate group and 16 of 30 patients in the placebo
group were no longer taking prednisone. (P*= 0.003). Furthermore, patients
receiving concomitant MTX received a median cumulative lower GC dose of 0.9
milligram compared to placebo. However, this finding was not significant.
Furthermore, no difference in incidence of GC-related side effects was seen. An
open randomized trial of 24 non blinded patients found a significant GC-sparing
effect of MTX and notably, significantly better bone mineral density when using
concomitant MTX. Leflunomide (LEF) is another csDMARD that showed promise of
efficacy in two case series with PMR patients and recently a research group in
Groningen initiated a double blinded RCT to examine the relapse sparing effect
of concomitant LEF with GC as opposed to placebo with GC.
The efficacy of several bDMARDs has been examined in PMR. So far no effect of
TNF-alpha blockers infliximab and etanercept has been shown in PMR patients.
There is evidence that anti- IL-6 treatment (tocilizumab) is effective in GCA
and also in PMR itself, showing a higher chance of remission and faster
tapering of GC. Abatacept has also been shown to be effective in patients with
GCA. Currently, tocilizumab, sirukumab, infliximab, etanercept are being
investigated in RCTs. These efforts reflect the research agenda of the
EULAR/ACR on the management of PMR, expressing the need for more studies on the
efficacy and safety of bDMARDs in PMR, as none of the studied bDMARDs have been
established as alternative to GC in the treatment of PMR due to limited effect,
and limited data on safety and costs.

One interesting mode of action that has not yet been studied is the efficacy of
B-cell depletion in PMR. Rituximab (RTX), a chimeric mAb against CD20 which
causes B-cell depletion, has proven to be an effective treatment in rheumatoid
arthritis (RA). One study has shown that a disturbed B-cell homeostasis is
present in newly diagnosed untreated PMR and GCA patients. In a case report one
patient with refractory GCA came in remission after 1000 mg RTX. Additionally,
a patient with refractory Takayasu was treated with RTX and showed remarkable
clinical and laboratory improvement after 500 and 1000 mg RTX.
So far no additional case reports or a proof of principle study on RTX in PMR
patients has been described. As the need for more treatment alternatives in PMR
is clear and in line with the EULAR/ACR research agenda for PMR, it is
important to evaluate whether a bDMARDs such as RTX is an effective alternative
for GC in PMR patients.

The proportion of patients in GC-free remission after 20 weeks.

Our work plan is to conduct a 20 week long uncontrolled open label proof of
concept serendipity study with a total of 40 newly diagnosed patients
fulfilling the EULAR/ACR criteria for PMR. All patients will receive RTX 1*
1000 mg * including standard premedication * according to local protocol. A
systematic review and meta-analysis of RTX-regimens in RA patients showed that
the efficacy of RTX 1* 1000 mg did not differ from 2* 500mg or 2* 1000 mg. We
therefore chose 1* 1000mg as the study dose. Additionally, all patients will
receive prednisone 15 mg during four weeks. Afterwards prednisone will be
tapered to 0 mg by following a rapid tapering schedule up to and including week
16. Patients will be followed for a total of 20 weeks. Outcomes of this
explorative study after 20 weeks are the number of patients in GC-free
remission, cumulative GC dose, estimates of changes in acute phase reactants,
PMR-activity score (AS), inner domain of the OMERACT outcome measures for PMR,
biomarkers (B-cells, T-cells, IL-6, anti-ferritin antibodies) RTX- and
GC-related adverse events, level of serum anti-RTX anti-bodies and function
with the HRQoL (health related quality of life) and HAQ (Health Assessment
Questionnaire) surveys. Assessments will take place at baseline, 2, 6, 10, 16
and 20 weeks. Additional assessments will be made if patients experience a
relapse of symptoms.

All patients will receive 1 * 1000 mg rituximab in combination with an
accelerated tapering scheme of prednisone.

In daily practice, rheumatologists monitor their patients on an ongoing basis
once every two, three or six months. During these regular visits, disease
activity is measured and blood samples are collected. In this study patients
will be scheduled to a visit at week 2, 6, 10, 16 and 20. At baseline,
demographics and disease and treatment related variables will be assessed.
Chest X-ray will be taken once, at baseline and ultrasonography of shoulders
and hips will be performed at baseline and after 20 weeks. Several blood
samples will be collected at all visits. Several short questionnaires will be
completed (HAQ-DI, SF-36, EQ5D-5L, transition question, PASS question) and
patients will be asked for other medication use and the occurrence of GC- and
RTX-related adverse events, during all visits. The extra time required for this
study is estimated to be approximately 1 hour for the baseline visit and 15
minutes for the follow-up visits. This results in a total of 2:15 hours of
extra time required for a patient to take part in the study (excluding travel
time).
Risks of participation in this study include the chance of a temporary increase
in disease activity in the patients exposed to a accelerated tapering scheme of
GC. However, if this happens, the increase in disease activity will probably be
short-lived as the rheumatologist will immediately act upon it by increasing GC
dose. On the other hand, possible benefits include a reduced chance of GC-
related side effects and shorter treatment duration for all patients RTX. This
research will be conducted according to the principles of the Declaration of
Helsinki and all relevant Dutch legislation. METC approval will be requested
and the trial will be submitted to the Dutch Trial Registry.