1-year results of treatment with rituximab in polymyalgia rheumatica: an extension study of a randomised double-blind placebo-controlled trial.

BACKGROUND: Rituximab was effective for patients with polymyalgia rheumatica in the 21-week BRIDGE-PMR randomised controlled trial. Here, we aimed to assess rates of glucocorticoid-free remission up to 1 year after infusion in an extension of this trial. METHODS: BRIDGE-PMR was a randomised controlled proof-of-concept trial that enrolled participants with polymyalgia rheumatica according to 2012 European League Against Rheumatism-American College of Rheumatology classification criteria at the Sint Maartenskliniek, Nijmegen, Netherlands. Patients were randomly allocated in a 1:1 ratio to receive one intravenous dose of 1000 mg rituximab or placebo, with identical pre-medication and accelerated glucocorticoid tapering over 17 weeks. After the 21-week study, patients were followed in a double-blind extension until 1 year after infusion during which standard-of-care treatment was provided. The primary outcome after 52 weeks was between-group difference in glucocorticoid-free remission (ie, polymyalgia rheumatica activity score [PMR-AS] <10), assessed in all randomly allocated participants, with data imputed using a predictive mean matching model (provided data were missing at random). A sensitivity analysis restricted to patients with complete data (complete case analysis) was also done. This trial is registered with EudraCT (2018-002641-11) and the Dutch trial database (NL7414). FINDINGS: Between Dec 18, 2019 and June 8, 2021, 47 patients enrolled in the BRIDGE-PMR were followed up in this extension study (23 [11 women and 12 men] allocated rituximab and 24 [13 women and 11 men] allocated placebo), of who 38 had recently diagnosed polymyalgia rheumatica and nine had relapsing polymyalgia rheumatica. Mean (SD) age was 64 (10) years in the rituximab group and 66 (9) years in the placebo group. All participants were White. Missing data were imputed for six participants (four rituximab, two placebo); because the data were probably missing at random, a complete case analysis was added as sensitivity analyses. In the imputed analysis, the between-group absolute difference reached statistical significance (12 [52%] of 23 in the rituximab group in glucocorticoid-free remission vs five [21%] of 24 participants in the placebo group; absolute difference 31% [95% CI 5 to 57], RR 2·5 [1·0 to 6·0]; p=0·04). In the complete case analysis, nine (47%) of 19 patients in the rituximab group were in glucocorticoid-free remission 1 year after infusion compared with five (23%) of 22 in the placebo group (absolute difference 25% [95% CI -4 to 53], relative risk (RR) 2·1 [95% CI 0·8 to 5·2]; p=0·12). Eight (33%) patients in the placebo group and six (26%) in the rituximab group had adverse events. INTERPRETATION: After a single dose of rituximab (1000 mg), the proportion of patients with polymyalgia rheumatica in glucocorticoid-free remission remained stable at 1 year after infusion, and a glucocorticoid sparing effect was evident. A larger trial including possibility for retreatment is warranted to confirm these results. FUNDING: Sint Maartenskliniek.

PolyMyalgia Rheumatica treatment with Methotrexate in Optimal Dose in an Early disease phase (PMR MODE): study protocol for a multicenter double-blind placebo controlled trial.

BACKGROUND: Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease affecting people older than 50, resulting in pain and stiffness of the neck, shoulder, and pelvic girdle. To date, glucocorticoids (GC) remain the cornerstone of treatment, but these have several drawbacks. Firstly, a large proportion of patients do not achieve GC-free remission within either the first (over 70%) or second year of treatment (over 50%). Secondly, GC-related adverse events (AE) occur in up to 65% of patients and can be severe. The current EULAR/ACR guidelines for PMR recommend early introduction of methotrexate (MTX) as a GC sparing agent in patients at risk for worse prognosis. However, earlier trials of low to medium quality only studied MTX dosages of 7.5-10 mg/week with no to modest effect. These doses may be suboptimal as MTX is recommended in higher doses (25 mg/week) for other inflammatory rheumatic diseases. The exact role, timing, and dose of MTX in PMR remain unclear, and therefore, our objective is to study the efficacy of MTX 25 mg/week in recently diagnosed PMR patients. METHODS: We set up a double-blind, randomized, placebo-controlled superiority trial (PMR MODE) to assess the efficacy of MTX 25 mg/week versus placebo in a 1:1 ratio in 100 recently diagnosed PMR patients according to the 2012 EULAR/ACR criteria. All patients will receive prednisolone 15 mg/day, tapered to 0 mg over the course of 24 weeks. In case of primary non-response or disease relapse, prednisolone dose will be temporarily increased. Assessments will take place at baseline, 4, 12, 24, 32, and 52 weeks. The primary outcome is the difference in proportion of patients in GC-free remission at week 52. DISCUSSION: No relapsing PMR patients were chosen, since the possible benefits of MTX may not outweigh the risks at low doses and effect modification may occur. Accelerated tapering was chosen in order to more easily identify a GC-sparing effect if one exists. A composite endpoint of GC-free remission was chosen as a clinically relevant endpoint for both patients and rheumatologist and may reduce second order (treatment) effects. TRIAL REGISTRATION: Dutch Trial Registration, NL8366 . Registered on 10 February 2020.

Polymyalgia rheumatica patients with and without elevated baseline acute phase reactants: distinct subgroups of polymyalgia rheumatica?

OBJECTIVES: Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease characterised by pain and stiffness of neck, shoulder- and hipgirdle, typically with elevated acute phase reactants (APR). However, patients may present with normal APR. Our aim was to explore whether normal APR were due to 1) 'caught early in the disease', 2) misdiagnosis, or 3) a distinct subset of PMR with different clinical presentation and prognosis. METHODS: This was a retrospective cohort study on patients with clinical PMR diagnosis visiting the rheumatologists of the Sint Maartenskliniek from April 2008 to September 2017. RESULTS: Of 454 patients, 62 patients had normal, and 392 elevated APR. Normal APR patients had longer symptom duration before diagnosis (13 vs. 10 weeks; p=0.02), however, during follow-up 31% developed elevated APR. In elevated APR patients with previous APR data available while already symptomatic, 58% had earlier normal APR. Fewer normal APR patients had peripheral arthritis (2% vs. 9%;p=0.04), and anaemia (17% vs. 43%; p=0.001). More often they had a previous PMR diagnosis (16% vs. 8%; p=0.057) and a shorter median time to glucocorticoid-free remission (552 vs. 693 days; n=36 vs. 160; p=0.02). Route of GC administration differed between groups (p=0.026). Fewer patients received methotrexate; 3 vs. 12%; p=0.046). No difference in alternative diagnosis was observed. CONCLUSIONS: PMR patients with long-term normal APR seem to be a milder subset of PMR in clinical presentation and prognosis. Additionally, our data also suggest there is a subgroup with normal APR who are caught early in the disease. Misdiagnosis does not appear to play a role.

Low-flow mediated constriction is endothelium-dependent: effects of exercise training after radial artery catheterization.

BACKGROUND: Radial artery catheterization is associated with endothelial denudation and impaired vasodilator function, while postcatheterization exercise training may enhance artery function. The impact of catheterization and subsequent exercise training on low-flow mediated vasoconstriction (L-FMC) has not previously been studied. The aim of this study was to examine whether radial artery L-FMC is impaired by catheterization and consequent endothelial denudation. A further aim was to examine the effect of local handgrip exercise training on radial artery L-FMC and flow-mediated dilation (FMD) after transradial catheterization. METHODS AND RESULTS: Thirty-two subjects undergoing transradial catheterization underwent assessment of L-FMC and FMD in the catheterized and contralateral radial artery before, and the day after, catheterization. A further 18 patients were recruited and randomly assigned to either a 6-week handgrip exercise training program (N=9) or a nonexercise control period (N=9). L-FMC was attenuated 1 day postcatheterization in the catheterized arm (-2.07±0.84 to 0.35±0.83), but unchanged in the noncatheterized arm (-0.93±0.86 to -0.90±0.92; P<0.05). In the training study, both FMD and L-FMC of the catheterized arm were preserved in the exercise group 7 weeks after catheterization (FMD-pre, 6.84±0.79; FMD-post, 6.85±1.16; L-FMC-pre, -2.14±1.42; L-FMC-post, -3.58±1.04%), but reduced in the control group (FMD-pre, 8.27±1.52; FMD-post, 4.66±0.70; P=0.06; L-FMC-pre, -3.26±1.19; L-FMC-post, -1.34±1.27%; P<0.05). CONCLUSIONS: Catheterization, and associated endothelial denudation, decreases L-FMC in the radial artery, suggesting that it is endothelium-dependent. Moreover, we demonstrate for the first time that exercise training has beneficial impacts on radial artery vasodilator and constrictor function.