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.

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.

Abstract Background To develop and assess a prediction model for polymyalgia rheumatica (PMR) relapse within the first year of glucocorticoid (GC) treatment. Methods A retrospective PMR cohort (clinical diagnosis) from a rheumatology department was used. All visits > 30 days after starting GC treatment and with > 2.5 mg/day oral prednisolone were used as potential relapse visits. Often used relapse criteria (1) rheumatologist judgement, (2) treatment intensification-based relapse) were assessed for agreement in this cohort. The proportion of patients with treatment-based relapse within 1 and 2 years of treatment and the relapse incidence rate were used to assess unadjusted associations with candidate predictors using logistic and Poisson regression respectively. After using a multiple imputation method, a multivariable model was developed and assessed to predict the occurrence (yes/no) of relapse within the first year of treatment. Results Data from 417 patients was used. Relapse occurred at 399 and 321 (of 2422) visits based on the rheumatologist judgement- and treatment-based criteria respectively, with low to moderate agreement between the two (87% (95% CI 0.86–0.88), with κ = 0.49 (95% CI 0.44–0.54)). Treatment-based relapse within the first two years was significantly associated with CRP, ESR, and pre-treatment symptom duration, and incidence rate with only CRP and ESR. A model to predict treatment intensification within the first year of treatment was developed using sex, medical history of cardiovascular disease and malignancies, pre-treatment symptom duration, ESR, and Hb, with an AUC of 0.60–0.65. Conclusion PMR relapse occurs frequently, although commonly used criteria only show moderate agreement, underlining the importance of a uniform definition and criteria of a PMR specific relapse. A model to predict treatment intensification was developed using practical predictors, although its performance was modest.

Objective 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 rheuntatologists 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. Conclusion 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.

Objectives Persons at high risk of rheumatoid arthritis (RA) might benefit from a low-risk pharmacological intervention aimed at primary prevention. Previous studies demonstrated disease-modifying effects of statins in patients with RA as well as an association between statin use and a decreased risk of RA development. A randomised, double-blind, placebo-controlled trial investigated whether atorvastatin could prevent arthritis development in high-risk individuals.Methods Arthralgia patients with anticitrullinated protein antibody (ACPA) >3 xULN or ACPA and rheumatoid factor, without (a history of) arthritis, were randomised to receive atorvastatin 40 mg daily or placebo for 3 years. The calculated sample size was 220 participants. The primary endpoint was clinical arthritis. Cox regression analysis was used to determine the effect of atorvastatin on arthritis development.Results Due to a low inclusion rate, mainly because of an unwillingness to participate, the trial was prematurely stopped. Data of the 62 randomised individuals were analysed. Median follow-up was 14 (inner quartiles 6–35) months. Fifteen individuals (24%) developed arthritis: 9/31 (29%) in the atorvastatin group; 6/31 (19%) in the placebo group: HR 1.40, 95% CI 0.50 to 3.95.Conclusions In this small set of randomised high-risk individuals, we did not demonstrate a protective effect of atorvastatin on arthritis development. The main reason for the low inclusion was unwillingness to participate; this may also impede other RA prevention trials. Further research to investigate and solve barriers for prevention trial participation is needed.

Guidelines on management of polymyalgia rheumatica (PMR) recommend early introduction of methotrexate (MTX), especially in patients with worse prognosis, although evidence on clinical efficacy of MTX in PMR is limited. Our objective was to assess MTX efficacy in real-world PMR care. Retrospective data of newly diagnosed PMR patients who started MTX were compared to control patients in whom MTX was not started at the first flare. Main outcomes were number of flares per year (Poisson regression) and weighted daily glucocorticoid (GC)-dose (linear regression), and flare incidence rate ratio in the MTX group only. 240 patients were selected; 39 patients in the MTX group and 201 in the control group. The yearly incidence rate ratio of flares in the MTX versus control group was 0.80 (95% CI 0.45–1.42). The yearly flare rate was 1.22 before and 0.43 after MTX initiation, resulting in an incidence ratio of 0.35 (95% CI 0.23–0.52). Adjusted time weighted daily GC dose was higher in the MTX versus control group (ratio 1.37, 95% CI 1.04–1.80). No clear effect of MTX on flares was found and time weighted daily GC dose was higher, possibly due to residual confounding by indication. However, the clearly reduced flare rate after MTX start might be suggestive for a beneficial effect of MTX.

Background Glucocorticoids remain the cornerstone of polymyalgia rheumatica treatment, but their use has several drawbacks, such as long treatment duration and glucocorticoid-related adverse events. Effective glucocorticoidsparing agents with a strong evidence base in polymyalgia rheumatica are absent. As B cells have been implicated in the pathogenesis of polymyalgia rheumatica, we aimed to evaluate the efficacy of rituximab for the treatment of polymyalgia rheumatica. Methods We did a double-blind, randomised, placebo-controlled, proof-of-concept trial at Sint Maartenskliniek, Nijmegen, Netherlands. We enrolled patients with polymyalgia rheumatica according to the 2012 European League Against Rheumatism and American College of Rheumatology criteria, who were recently diagnosed or who had relapsed on prednisolone and were unable to taper their dose to less than 7 center dot 5 mg per day. Participants were randomly assigned (1:1) to a single intravenous infusion of rituximab 1000 mg or placebo, with a 17-week glucocorticoid tapering scheme. Participants and care and research personnel were masked to treatment assignment and randomisation sequence. The primary outcome was glucocorticoid-free remission at 21 weeks after infusion in patients who completed the study. This trial is registered with EudraCT (2018-002641-11) and the Dutch trial database (NL7414). Findings Between Jan 14, 2019, and March 10, 2020, 116 patients were screened and 49 (42%) were enrolled. 47 patients (38 who were recently diagnosed, nine who had relapsed on prednisolone) completed the study: 23 (49%) in the rituximab group and 24 (51%) in the placebo group. Mean age (SD) in years was 64 (8) in the rituximab group and 66 (10) in the placebo group, the proportion of women was 11 (48%) of 23 versus 13 (54%) of 24, and all participants were White. 11 (48%) of 23 patients in the rituximab group and five (21%) of 24 in the placebo group achieved glucocorticoid-free remission at 21 weeks (difference 27% [one-sided 95% CI 4]; relative risk 2 center dot 3 [1 center dot 1]; p=0 center dot 049). Ten infusion-related complaints occurred in the rituximab group versus three in the placebo group (relative rate 3 center dot 5 [one-sided 95% CI 1 center dot 3]). One serious adverse event occurred (pulmonary embolism; in the rituximab group), and there were no deaths. Interpretation Rituximab was shown to be efficacious in combination with 17-week glucocorticoid treatment compared with glucocorticoid treatment alone in terms of glucocorticoid-free remission in patients with polymyalgia rheumatica. If these findings are confirmed by larger trials, rituximab could be a valuable glucocorticoid-sparing treatment for patients with polymyalgia rheumatica. Funding Sint Maartenskliniek. Copyright (c) 2021 Elsevier Ltd. All rights reserved.

Sirs, Polymyalgia rheumatica (PMR) is a common inflammatory rheumatic disease of elderly patients. Symptoms typically consist of pain and stiffness affecting the neck, shoulderand hip girdles, and elevated acute phase reactants (1). To date, the exact aetiology of PMR is thought to be multifactorial, with genetic background, immune senescence and environmental factors, such as infections, among the most important contributors to disease onset (1). Interestingly, a seasonal pattern of disease onset has been previously indicated in giant cell arteritis (GCA), a condition often associated with PMR (1). Given the close relation between these two conditions, 40–60% of GCA patients also have PMR at the time GCA is diagnosed and 16-21% of PMR patients have or will develop GCA, one may hypothesise that a similar seasonal pattern could also occur in PMR (1). Various infectious diseases are thought to contribute to the seasonal pattern described in GCA, including Mycoplasma pneumoniae, Chlamydophila pneumoniae, Parvovirus B19 and parainfluenza virus type 1 (2-4). These micro-organisms also have been hypothesised to trigger PMR, as simultaneous peaks between the onset of PMR and epidemics of these infectious agents were described (2). Consistent with the seasonal pattern hypothesis, 16% of PMR patients reported a respiratory tract infection or seasonal influenza before the onset of symptoms (5). In contrast, others reported no associations with presence of parvovirus B19, C. pneumoniae, respiratory syncytial virus, measles virus, herpesviruses type 1 and 2, Epstein-Barr virus or human herpesvirus (2, 4-6). A cyclic pattern of disease onset following seasonal distribution may support the theory of infectious agents as disease trigger in PMR (2, 7-10). We therefore aimed to investigate the occurrence of a seasonal effect in incidence of onset of PMR. We examined data from 454 newly diagnosed PMR patients (clinical diagnosis) who visited our outpatient clinic between April 2008 and September 2017. Patients with other active concomitant inflammatory rheumatic disease at baseline were excluded. Six patients were not included because the date of PMR symptom onset was missing, and therefore a total of 448 patients were finally analysed. Of these patients, 247 (55%) were women and mean age was 66 ± SD 9 years. Patients symptoms started 10 weeks (interquartile range (IQR) 6 to 16 weeks) prior to PMR diagnosis. Patients were further grouped based on the month their symptoms debuted, not on the moment of diagnosis. The chi-square goodness of fit test to determine whether PMR onset was distributed equally throughout the year did not reach statistical significance: p=0.06. Additionally, we obtained data on incidence of the infectious agents from the Dutch National institute for Public health and Environment (RIVM), in which an association was previously described with GCA/PMR. From this data, the index digits was calculated where 100 marks the weighted average of infections at that time point for the years 2007 to 2017. As shown in figure 1, the incidence of PMR symptoms onset is higher in NovemberJanuary and April through June, with a peak in August. However, these peaks are not compatible with peaks of the proposed infectious agents. In addition, no coincidence of peaks between onset of PMR symptoms and the proposed agents were seen when we analysed each year separately (data not shown). We conclude that this bimodal seasonal pattern of PMR onset is insufficiently suggestive for an infectious trigger as cause of PMR. Limitations of this study are the retrospective character resulting in absence of blood samples to test whether patients had experienced a recent infection of the proposed infectious agents.

Background Systemic signs of inflammation such as raised CRP or ESR are a classical feature of PMR, but some patients present with normal acute phase reactants (APR).1,2 It is not known whether these patients represent milder forms of PMR, whether their disease is not yet fully expressed, or whether they represent another pathophysiological subset of PMR or another disease. Data on demographic and clinical differences between PMR patients with normal versus elevated APR might provide some answers. Objectives To explore baseline differences in demographics and clinical characteristics in PMR patients with and without elevated APR. Methods We conducted a retrospective cohort study of clinical characteristics of newly diagnosed PMR patients (clinical diagnosis) who visited our outpatient clinic between April 2012 and September 2017. Patient with concomitant inflammatory rheumatic disease were excluded. Data on patient-, disease,- and treatment characteristics were extracted from the electronic health record. Descriptive statistics were used [using mean (SD), median (p25-p75) or n (%) as appropriate], and differences between patients with high APR(CRP>10 mg/L and/or ESR >30mm/hour) were tested using Fischer’s exact test for categorical data, t-test for normally and Wilcoxon test for non-normally distributed data. Results 454 patients were included (table 1). Sixty-two patients had normal, and 392 had elevated APR. In the group with normal APR, fewer patients had peripheral arthritis (2 versus 9%; p=0.044) and fewer had anemia at diagnosis (17 versus 43%; p= 0.001). Furthermore, patients had a longer median duration of symptoms before diagnosis (13 versus 10 weeks; p= 0.0196) and were more likely to have a history of PMR (16 versus 8%; p= 0.057). No significant differences were found in other clinical characteristics. Conclusion The results of this cohort indeed suggest that patients with normal APR are a different subset of PMR patients. Fewer cases have peripheral arthritis and anemia at diagnosis, suggesting a milder form of PMR. Secondly, our results do not support the hypothesis that PMR of those with normal APR is not yet fully expressed, as they have a longer symptom duration prior to diagnosis. References [1] Buttgereit F, Dejaco C, Matteson EL, Dasgupta B. Polymyalgia Rheumatica and Giant Cell Arteritis: A Systematic Review. JAMA. 2016 Jun;315:2442-58. [2] González-Gay MA1, Matteson EL2 Castaneda S3. Polymyalgia rheumatica. Lancet. 2017 Oct Oct 7;390(10103):1700-1712 Disclosure of Interests None declared

Aims: To examine in adults with type 1 diabetes (a) the effect of initiation of real-time continuous glucose monitoring (RT-CGM) on glycaemic and patient-reported outcomes (PROs), and (b) factors related to clinically relevant improvements and sustained device use. Methods: 60 persons initiating RT-CGM completed questionnaires at device start and six months later. Demographics and clinical characteristics including (dis)continuation up until July 31st 2018 were obtained from medical records. Results: After six months, 54 adults were still using RT-CGM. Short-term discontinuation (10%) was mainly related to end of pregnancy (wish). Longer-term discontinuation in those with an initial non-pregnancy indication was related to changes in the medical condition and behavioural/psychological reasons. After six months, HbA(1c), diabetes-specific worries and self-efficacy improved (range d = vertical bar 0.4 vertical bar-vertical bar 0.8 vertical bar), while hypoglycaemia rate or awareness and more general distress did not change. More suboptimal scores at baseline were related to meaningful improvements in HbA(1c) (>= 10 mmol/mol; 0.9%) and PROs (>= 0.5 SD). Changes in glycaemic variables and PROs were not related. Conclusions: People with more suboptimal HbA(1c) and PRO values appear to benefit most from RT-CGM. Given the lack of association between improvements in medical outcomes and PROs, both should be included in evaluations of RT-CGM therapy on an individual level. (C) 2019 Elsevier B.V. All rights reserved.

- Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disorder in which inflammation markers, both erythrocyte sedimentation rate (ESR) and CRP values, are often elevated. However, a non-abnormal ESR or CRP value does not preclude the diagnosis.- PMR is an arbitrary diagnosis and presents both diagnostic and therapeutic challenges.- Imaging diagnostics, such as echography, MRI or FDG-PET/CT, may potentially be applied more frequently as a second-line investigation when there is doubt concerning the diagnosis. Currently these additional imaging techniques are not applied in first line diagnostics.- Glucocorticoids remain the cornerstone treatment for polymyalgia rheumatica. Often patients react swiftly to this, but in 29-45% of cases an effect is only observed 3-4 weeks later. The treatment course typically lasts 1-3 years.- More research has been conducted into potential glucocorticoid-sparing treatments. Most of the scientific evidence concerns the effectiveness of methotrexate; there is some evidence regarding the effectiveness of azathioprine and leflunomide. Tocilizumab, an IL-6 receptor inhibitor, has shown promise as a treatment, but further evidence is required.