The efficacy of Methotrexate for glucocorticoid dose reduction in recently diagnosed polymyalgia rheumatica patients: a double-blind randomized placebo controlled multicenter clinical trial.

Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease affecting
mostly people older than 50 years (1). The reported prevalence ranges from
0.85% to 1.53% depending on classification criteria and demographic features
(2,3). Patients generally suffer from acute onset pain and/or morning stiffness
of the neck, bilateral shoulder girdle, and (with less specificity) pelvic
girdle. Morning stiffness usually lasts for more than 45-60 minutes (1,4,5).
Additionally 40-50% of patients may report constitutional symptoms like
low-grade fever, fatigue, asthenia, and weight loss. The duration of the
disease can be up to 2-3 years, and during the first year the chance of relapse
can range up to 20-55% (1,6). During physical examination, PMR may manifest as
a reduction in active motion, but near to normal passive motion of the
shoulders, neck, and hip. Furthermore, muscle weakness is not common despite
diffuse (muscle) pain (1). Untreated PMR leads to a significant reduction in
quality of life (QOL) (7).
In laboratory tests, PMR typically shows a rise in acute phase reactants (5).
PMR is closely related to giant cell arteritis (GCA), a large blood vessel
vasculitis (LVV) occurring in elderly people, as 16-21% of PMR patients have
GCA. Furthermore 40 to 50% of patients diagnosed with GCA have concomitant PMR
(1). The cause of PMR remains unknown and there is no golden standard for the
diagnosis of PMR (1,8).
Glucocorticoids (GC) remain the cornerstone of treatment of PMR (9). The most
recent guidelines recommend a GC initial dosage between 12.5 and 25 mg,
depending on patient characteristics and risk factors. Furthermore, different
tapering regimens, which have not been adequately investigated, have been
suggested (9). However, there are several drawbacks to treatment with GC for
PMR, like treatment duration, lack of efficacy, and GC-related side effects.
Firstly, GC free remission was achieved in only 27% in a PMR primary care
cohort within the first year of treatment (3), and in only 33-50% of a hospital
care cohort of PMR patients after two years of treatment (7,10). Secondly,
GC-related adverse events (AE) have been reported in a large portion of
patients, ranging upwards of 65% dependant on GC dosage (7,11-13). These side
effects can be severe, especially when GCs are used for a long period of time.
Patients using GCs for longer than 2 years for example are more likely to
develop weight gain, osteoporosis, fractures, metabolic and cardiovascular side
effects as well as infections (7,11,13-15). Therefore, GC sparing agents are
warranted to reduce treatment duration, enhance treatment efficacy, and reduce
GC-related side effects.
The exact value of several conventional synthetic disease-modifying
antirheumatic drugs (DMARD) in PMR remains unclear. To date there is no proven
efficacy or data is insufficient on azathioprine, cyclophosphamide, cyclosporin
and dapsone (16). For leflunomide there are two case series that showed some
promise of efficacy in PMR patients (17,18). The evidence regarding biological
DMARD treatment is even scarcer. An open label trial with tocilizumab showed
some promise, although study size was very small and treatment is associated
with high costs (19,20).
The most evidence - three small RCTs - for a GC-sparing treatment exists for
Methotrexate (MTX) (9,16). One RCT with concomitant MTX 7.5 mg showed no
GC-sparing effect, although the high drop-out rate of 48% might be a factor in
this negative finding (21). A RCT with 10 mg concomitant MTX showed fewer
relapses, but no significant difference in GC related AE (22). Long term
outcomes of this trial showed that patients receiving concomitant MTX received
a lower cumulative GC dose compared to placebo, but this finding did not reach
statistical significance (23). Furthermore, no difference in long term
GC-related AE was found, although authors confirm data obtained retrospectively
from elderly patients can be questioned (23). Finally, a small open RCT found
that 24 patients treated with 10mg of concomitant MTX showed a significant
reduction in GC cumulative dose, fewer relapses and earlier discontinuation of
GC (24). No studies using higher dosages of MTX comparable to those used in RA
(up to 25-30 mg per week) have been performed (25,26).
Based on this limited data, the current EULAR/ACR recommendations for the
management of PMR advise an early introduction of MTX 7.5 - 10 mg weekly in
patients prone to relapse or prolonged GC-therapy, as well as in patients where
GC-related AE are more likely to occur, e.g. females, a high initial ESR/CRP,
hypertension, diabetes, cardiovascular disease, and osteoporosis (6,9,27). In
clinical practice, however , MTX is scarcely used, presumably in part because
of the limited evidence. A national database study of German rheumatology
clinics reported that only 19% of patients with PMR received concomitant MTX
(13). In addition, the EULAR/ACR recommendations for the management of PMR also
advise further research regarding MTX (9).
In conclusion, evidence on GC-sparing treatments for PMR patients remains
scarce and MTX seems to be the most promising and best examined treatment.
However, well-designed blinded studies using higher dosages of MTX are lacking.
We therefore set out to study if optimally dosed weekly MTX is indeed
effective in achieving GC-free remission and reducing cumulative GC dose in
PMR.

Primary Objective: To determine whether in recently diagnosed PMR patients
concomitant treatment to glucocorticoids with MTX 25 mg/week compared to a
placebo will lead to a higher proportion of GC-free remission at 52 weeks.

Secondary Objectives: To assess in, and compare between, both groups (MTX
versus placebo):
1. The proportion of GC-free remission at week 32;
2. The time to GC-free remission and first relapse;
3. The proportion of low-dose GC (<= 5mg daily) remission at week 32 and 52;
4. The GC cumulative dose at week 32 and 52;
5. The number of relapses or recurrences during follow up at week 32 and 52;
6. The proportion of patients that relapsed or had a recurrence during follow
up at week 32 and 52;
7. The change in PMR-AS;
8. The change with the core domain sets for outcome measures of PMR as proposed
by the OMERACT, including:
a. Systemic inflammation;
b. Physical Function;
c. Pain;
d. Stiffness;
9. The change in Patient Reported Outcomes (PROs): transition and Patient
Acceptable Symptom states (PASS) questions, Visual Analog Scales (VAS), the
health related quality of life (EQ-5D-5L), Health Assessment Questionnaire
(HAQ), and Patient Reported Outcome Measures Information System
Physical-Function (PROMIS-PF);
10. The frequency and types of GC- and MTX-related adverse events;
11. The proportion of patients that require MTX/placebo (dose) adjustment.
12. Direct healthcare costs at week 52

This study is a double blind, randomized placebo-controlled superiority trial
of recently diagnosed PMR patients fulfilling the 2012 EULAR/ACR classification
criteria. Patients will mainly be recruited from the Sint Maartenskliniek
(patients recruited at locations Nijmegen, Woerden, Boxmeer, CWZ, Geldrop) and
Gelre Ziekenhuizen over the course of 18 months.
After inclusion patients will randomly be allocated into one of two arms with a
1:1 ratio. Patients allocated to the treatment arm will receive oral MTX and
patients assigned to the other arm will receive placebo. All patients will
receive prednisolone using an accelerated tapering protocol (see *Treatment of
subjects* for more details).
The pre-recruitment phase of the study is scheduled to take 6 months . The
recruitment and inclusion phase is expected to take 18 months. Follow-up will
take 12 months for each recruited patient. Data analysis, reporting, and
submitting the written article of the study is scheduled to take 6 months.
Total study time is approximately 42 months (Figure 1).

5.1 Investigational product/treatment
Patients will randomly be allocated into two arms with a 1:1 ratio. Patients
allocated to the treatment arm will receive oral Methotrexate 15 mg per week
for the first 4 weeks, followed by 25 mg per week for the following 48 weeks if
they did not develop significant MTX-related side effects (Table 2). The
placebo arm will receive a placebo of MTX 0mg per week. MTX will be dosed in
capsules of 5mg, allowing both splitting of doses over the course of the day
(to improve bioavailability) and easier dose adjustment without un-blinding
with regards to treatment arm.
5.2 Use of co-intervention (if applicable)
All patients will receive treatment with regular prednisone once per day
starting at 15mg and tapering through an accelerated protocol over the course
of 24 weeks: every 4 weeks a reduction of 2.5mg per day. Tapering will only
occur after an adequate initial response and subsequently if the disease is in
remission at visits (Table 2 and Figure 2). In case of primary non-response
during the first 4 weeks (as defined later) the prednisone dose will be
increased, to 25mg/day, for 2 weeks. After response to this dose, prednisone
will be dosed at 20mg/day for 2 weeks, followed by 15mg/day and the accelerated
tapering protocol as stated above.
When no primary response is obtained during treatment with 25 mg/day,
alternative diagnoses such as giant cell arteritis (GCA) will be ruled out; if
a patient does not respond after 4 weeks, prednisone can be raised further and
the patient will be excluded from the study.
If a patient flares for the first time, prednisone will be increased to the
pre-flare dose for 4 weeks. If response follows prednisone will then again be
tapered through the accelerated tapering protocol (Figure 3). If a patient
flares for the second time, prednisone will be increase to the pre-flare dose
for 7 weeks. If response follows prednisone will then be tapered through a
local hospital usual care tapering protocol. If response does not follow after
raising of prednisone to the pre-flare dose, prednisone dose can then be
increased with increments of 5-10 mg for 4 weeks until there is either response
or prednisone is at 25mg/d. If no response is obtained during treatment with
25mg/day, alternative diagnoses will again be ruled out and if the patient does
not respond after 4 weeks the patient will be excluded from the study.

During this study, patients will be assessed at 6 visits, after the baseline
assessment, over the course of 52 weeks. At baseline, demographics and patient
and disease characteristics are assessed. Additionally, imaging and a several
laboratory tests will be run. At follow-up, blood samples will be collected to
assess acute phase reactants and possible adverse events, patients will
complete questionnaires, and rheumatologists will assess disease activity and
potential adverse events. Compared to usual care, consisting of a visit ranging
from once a month early on to once per 2, 3, or 4 months later on, this means
approximately 2 extra visits for the purpose of this study. The study
questionnaires and measurements will take on average an additional 20 minutes
per visit.
Potential risk associated with participation includes an increase in disease
activity due to the accelerated GC tapering protocol, especially in the placebo
group. In case this happens, patients are instructed to contact their treating
rheumatologist, who will increase GC dose accordingly. Potential side-effects
of MTX are mainly gastro-intestinal of nature, including nausea, abdominal
pain, diarrhea, hematological or liver enzyme abnormalities, and non-basal-cell
skin cancer. However, there is sufficient evidence that indicates that MTX has
a relatively safe treatment profile, and it is registered for a number of
indications. Therefore we expect a minimal risk for patients treated with MTX.
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 and EuropeanTrial Registry.