PolyMyalgia Rheumatica treatment with Methotrexate in Optimal Dose in an Early disease phase

Rationale: Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease affecting about 1% of people older than 50, resulting in pain and stiffness of the neck, shoulder girdle, and pelvic girdle. Untreated, PMR can lead to a significant reduction in quality of life. The mainstay for treating PMR is glucocorticoids (GC). However, a large proportion of patients do not achieve GC-free remission within either the first (more than 70%) or second year of treatment (more than 50%). Furthermore, GC-related adverse events (AE) can be severe and occur in a large proportion of patients, ranging upwards of 65%. Some disease modifying antirheumatic drugs (DMARD) have been studied as possible GC-sparing treatments. Most evidence, although limited, for a GC-sparing treatment exists for methotrexate (MTX) and the current EULAR/ACR guidelines for PMR recommend early introduction of MTX in patient groups at risk for prolonged therapy, relapse, or GC-related AE. However, the previously studied MTX dose was 7.5 – 10 mg, far below the 15 – 25 mg dose at which MTX is used as a DMARD for rheumatoid arthritis (RA), and no studies have been conducted investigating these higher dosages. Objective: The primary objective is to study the efficacy of treatment with optimally dosed MTX compared to placebo in patients recently diagnosed with PMR fulfilling the 2012 EULAR/ACR criteria. Study design: double blind, randomized, placebo-controlled superiority trial. Study population: 100 patients with recently diagnosed PMR according to the 2012 EULAR/ACR classification criteria will be recruited from the Sint Maartenskliniek. Exclusion criteria are not being able to speak, read or write Dutch, extensive previous GC exposure, exposure to other immunosuppressant drugs 3 months prior, other active inflammatory rheumatic diseases, conditions that might interfere with pain or movement evaluation, contra-indications for MTX, or a considerable risk of non-compliance. Intervention: Patients included will be randomly allocated in a 1:1 ratio to receive either MTX 25mg/week or placebo for a total of 52 weeks. All patients will receive folic acid 10mg/week, and prednisolone at an initial dose of 15mg/day, tapered through an accelerated protocol over the course of 24 weeks. In case of primary non-response or relapse, the prednisolone dose can be increased to up to 25mg/day. Patients will be assessed at baseline, 4, 12, 24, 32, and 52 weeks, with additional visits if necessary. Main study parameters/endpoints: The primary study outcome is the difference in proportion of PMR patients in GC-free remission at week 52. Secondary study parameters include proportion GC-free remission at week 32, The proportion of low-dose GC (≤ 5mg daily) remission at week 32 and 52, GC-cumulative dose at week 32 and 52, the time to first relapse and GC-free remission, the number and proportion of patients that had a relapse at week 32 and 52, the proportion of patients that get MTX/placebo dose adjustment, change in PMR-activity score (PMR-AS), change in Patient Reported Outcome Measures (PROMs), and the incidence density and types of AE, and cost-utility (based on EQ-5D and direct healthcare costs). Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients will be assessed at 6 visits 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 performed. At follow-up, data collection will take place to monitor disease activity and adverse events, consisting of blood samples, PROMs, and disease activity and adverse events assessment. Compared to routine care this means approximately 1 or 2 extra visits for the purpose of this study. The study questionnaires and measurements will take about an additional 15 minutes per visit. A potential risk associated with participation includes an increase in disease activity due to the accelerated GC tapering protocol. 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, diarrhoea, liver enzyme abnormalities, as well as haematological 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 Registries.

In patients with recently diagnosed PMR, MTX 25mg/week compared to placebo will lead to a higher proportion of patients in glucocorticoid free remission

Assessments will be at week 0 (baseline), 4 weeks (v1), 12 weeks (v2), 24 weeks (v3), 32 weeks (v4), and 52 weeks (v5). Furthermore lab assessments for MTX related AE (without compulsory visit) is at week 8, week 16, and week 42. Total study duration per patient is 52 weeks.

Methotrexate 25 mg/week