REDUCE PMR: Rituximab Effect on Decreasing glUcoCorticoid Exposition in newly diagnosed PolyMyalgia Rheumatica

Polymyalgia rheumatica (PMR) is one of the most prevalent inflammatory
rheumatic diseases among people older than 50 years. It is characterized by
pain and stiffness of the neck, bilateral shoulder and hip girdle and is often
associated with elevated inflammatory parameters. Untreated, it leads to a
significant and long-term reduction in quality of life. Glucocorticoids (GC)
are the cornerstone of treatment, but have several drawbacks. First, only a
minority of patients achieves GC-free remission after one or two years. Second,
GC-related adverse events (AE) occur in a large portion of patients, up to 65%
depending on the GC dosage. When a patient experiences a relapse,
intensification and longer duration of GC treatment is needed. This results in
more GC related AE, and therefore, the search for GC-sparing agents is high on
the research agenda. Although the exact pathogenesis of PMR is not known, there
are several indications that B-cells have a role in PMR. This make Rituximab
(RTX), a chimeric monoclonal antibody targeting B-cells via CD-20, a possible
candidate for treatment of PMR. An exploratory proof of concept RCT
demonstrated that a significantly higher proportion of PMR patients treated
with RTX achieved GC-free remission at 21 and 52 weeks compared to placebo. The
efficacy of RTX in patients with newly diagnosed PMR needs confirmation and
should therefore be further investigated in a larger study with longer follow
up.

This study has been transitioned to CTIS with ID 2024-513544-28-00 check the CTIS register for the current data.

The main objective is to study the efficacy of treatment with RTX in patients
with newly diagnosed PMR compared to placebo.

A total of 114 patients wil participate in this study. Patients will be
randomized 1:1 to either RTX of placebo. At baseline treatment consists of
1000mg iv RTX with usual premedication, placebo group will receive 0mg iv RTX
with similar oral pre-medication as the intervention group. Additionally at
baseline all patients receive prednisolone 15mg/day in a 17-week accelerated
tapering protocol with the possibility of increasing GC dose in case of non
response or relapse.
Patients with a need for treatment intensification (based on relapse or
increase of GC dose) will receive an extra dosage of 500mg iv RTX (or 0mg iv
RTX in placebo group) after 24 weeks, unless adverse events occurred at
infusion hampering the possibility of retreatment.

Study visits take place at 4, 12, 21, 32 and 52 weeks. Visits at week 4, 12 and
32 can be performed digitally or by telephone if preferred by patients and
treating phycisian. Disease activity will be measured at every visit using
PMR-AS. PMR-AS is defined by CRP, duration of morning stiffness (minutes),
elevation upper limb score (EUL) and the physicians and patients visual
analogue scale (VAS). Remission is defined as PMR-AS < 10. At every study visit
patients will be asked to fill in a few questionnaires regarding daily
activities and quality of life.

Patients will be randomized 1:1 to either RTX of placebo. At baseline treatment
consists of 1000mg iv RTX with usual premedication, placebo group will receive
0mg iv RTX with similar oral pre-medication as the intervention group.
Additionally at baseline all patients receive prednisolone 15mg/day in a
17-week accelerated tapering protocol with the possibility of increasing GC
dose in case of non response or relapse.

In current practice, patients with PMR visit the outpatient clinic every two,
three or six months, including measurement of disease activity and collecting
blood samples. For this study patients will visit the clinic at baseline, 21
and 52 weeks. Other visits can be performed digitally of by phone if preferred
by patients and treating physician. Blood sampling is done in accordance to
regular practice. Questionnaires entailing a range of domains take a maximum of
30 minutes at every visit.
Possible risks when participating in this study include a chance of temporary
increase of disease activity because of the accelerated GC tapering schema,
especially in the placebo group. However, patients will be instructed to
contact the research physician when this happens and they can immediately act
upon this by increasing the GC dose if deemed necessary. Other possible adverse
effects can be related to RTX treatment, including dose-dependent risk of
infection (e.g. COVID-19) or infusion related side effects.
Based on our previous experience with RTX we expect a minimal risk for patients
treated with RTX. We expect the risk for a severe COVID-19 infection (e.g.
hospital admission required or lethal infection) to be minimal and the risk for
mild COVID-19 comparable to the general population, because most patients will
be vaccinated, RTX treatment initially consist of a one-time dosage and if
retreatment is needed a lower dosage is given. Also patients can benefit from
the reduced dose of GC and a lower chance of GC-related side effects, among
which COVID-19 infections which are more prevalent at higher GC dose.