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.

Effect of add-on methotrexate in polymyalgia rheumatica patients flaring on glucocorticoids tapering: a retrospective study.

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.

Use of Mycophenolate Mofetil in Patients with Severe Localized Scleroderma Resistant or Intolerant to Methotrexate.

To assess the efficacy and safety of mycophenolate mofetil (MMF) in patients with localized scleroderma (LoS) resistant or intolerant to previous treatment with methotrexate (MTX). A case series of patients with LoS treated with MMF. Outcome was assessed through clinical examination. Adverse events were documented. Seven patients with LoS were treated with MMF. Median age at MMF initiation was 15 years (range 7-74 years). Three patients received MMF due to MTX ineffectiveness and 4 due to MTX intolerance. Disease remission was achieved in 4 patients and maintained in one patient. One patient showed a favourable response, but had to discontinue treatment due to elevated liver enzymes. The remaining patient experienced disease progression. MMF was shown to improve the clinical condition of patients with refractory LoS and may be a relatively safe alternative in patients who are intolerant to MTX.

A missed diagnosis of acromegaly during a female-to-male gender transition.

We present a case of a 46-year-old transgender male who, during his female-to-male transition, presented with a pituitary apoplexy at the emergency department of a general hospital in the Netherlands. During admission, it turned out that he also suffered from acromegaly due to a growth hormone secreting pituitary adenoma for which he was successfully treated at our university hospital. Previously, his complaints typical of acromegaly were dismissed as attributable to the gender transition. Without the apoplexy, the disease probably would have remained masked by the history of transgenderism for a much longer period of time. It is, therefore, essential to keep looking for additional explanations for new pathology and complaints that cannot typically be attributed to the gender transition in these patients.

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.

(Dis)agreement of polymyalgia rheumatica relapse criteria, and prediction of relapse in a retrospective cohort.

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.

Atorvastatin is unlikely to prevent rheumatoid arthritis in high risk individuals: results from the prematurely stopped STAtins to Prevent Rheumatoid Arthritis (STAPRA) trial.

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.

RT-CGM in adults with type 1 diabetes improves both glycaemic and patient-reported outcomes, but independent of each other.

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, HbA1c, diabetes-specific worries and self-efficacy improved (range d = |0.4|-|0.8|), while hypoglycaemia rate or awareness and more general distress did not change. More suboptimal scores at baseline were related to meaningful improvements in HbA1c (≥10 mmol/mol; 0.9%) and PROs (≥0.5 SD). Changes in glycaemic variables and PROs were not related. CONCLUSIONS: People with more suboptimal HbA1c 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.

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.