Senescent cells in giant cell arteritis display an inflammatory phenotype participating in tissue injury via IL-6-dependent pathways.

OBJECTIVES: Age is the strongest risk factor of giant cell arteritis (GCA), implying a possible pathogenetic role of cellular senescence. To address this question, we applied an established senescence specific multimarker algorithm in temporal artery biopsies (TABs) of GCA patients. METHODS: 75(+) TABs from GCA patients, 22(-) TABs from polymyalgia rheumatica (PMR) patients and 10(-) TABs from non-GCA/non-PMR patients were retrospectively retrieved and analysed. Synovial tissue specimens from patients with inflammatory arthritis and aorta tissue were used as disease control samples. Senescent cells and their histological origin were identified with specific cellular markers; IL-6 and MMP-9 were investigated as components of the senescent associated secretory phenotype by triple costaining. GCA or PMR artery culture supernatants were applied to fibroblasts, HUVECs and monocytes with or without IL-6R blocking agent to explore the induction of IL-6-associated cellular senescence. RESULTS: Senescent cells were present in GCA arteries at higher proportion compared with PMR (9.50% vs 2.66%, respectively, p<0.0001) and were mainly originated from fibroblasts, macrophages and endothelial cells. IL-6 was expressed by senescent fibroblasts, and macrophages while MMP-9 by senescent fibroblasts only. IL-6(+) senescent cells were associated with the extension of vascular inflammation (transmural inflammation vs adventitia limited disease: 10.02% vs 4.37%, respectively, p<0.0001). GCA but not PMR artery culture supernatant could induce IL-6-associated senescence that was partially inhibited by IL-6R blockade. CONCLUSIONS: Senescent cells with inflammatory phenotype are present in GCA arteries and are associated with the tissue inflammatory bulk, suggesting a potential implication in disease pathogenesis.

Subclinical giant cell arteritis increases the risk of relapse in polymyalgia rheumatica.

OBJECTIVE: The aim of the present study was to determine the clinical significance of subclinical giant cell arteritis (GCA) in polymyalgia rheumatica (PMR) and ascertain its optimal treatment approach. METHODS: Patients with PMR who fulfilled the 2012 European Alliance of Associations for Rheumatology/American College of Rheumatology Provisional Classification Criteria for PMR, did not have GCA symptoms and were routinely followed up for 2 years and were stratified into two groups, according to their ultrasound results: isolated PMR and PMR with subclinical GCA. The outcomes (relapses, glucocorticoid use and disease-modifying antirheumatic drug treatments) between groups were compared. RESULTS: We included 150 patients with PMR (50 with subclinical GCA) with a median (IQR) follow-up of 22 (20-24) months. Overall, 47 patients (31.3 %) had a relapse, 31 (62%) in the subclinical GCA group and 16 (16%) in the isolated PMR group (p<0.001). Among patients with subclinical GCA, no differences were found in the mean (SD) prednisone starting dosage between relapsed and non-relapsed patients (32.4±15.6 vs 35.5±12.1 mg, respectively, p=0.722). Patients with subclinical GCA who relapsed had a faster prednisone dose tapering in the first 3 months compared with the non-relapsed patients, with a mean dose at the third month of 10.0±5.2 versus 15.2±7.9 mg daily (p<0.001). No differences were found between relapsing and non-relapsed patients with subclinical GCA regarding age, sex, C reactive protein and erythrocyte sedimentation rate. CONCLUSIONS: Patients with PMR and subclinical GCA had a significantly higher number of relapses during a 2-year follow-up than patients with isolated PMR. Lower starting doses and rapid glucocorticoid tapering in the first 3 months emerged as risk factors for relapse.

Review of phase 2/3 trials in polymyalgia rheumatica and giant cell arteritis.

INTRODUCTION: GCA (giant cell arteritis) and PMR (polymyalgia rheumatica) are two overlapping inflammatory rheumatic conditions that are seen exclusively in older adults, sharing some common features. GCA is a clinical syndrome characterized by inflammation of the medium and large arteries, with both cranial and extracranial symptoms. PMR is a clinical syndrome characterized by stiffness in the neck, shoulder, and pelvic girdle muscles. Both are associated with constitutional symptoms. AREAS COVERED: In this review, we assess the established and upcoming treatments for GCA and PMR. We review the current treatment landscape, completed trials, and upcoming trials in these conditions, to identify new and promising therapies. EXPERT OPINION: Early use of glucocorticoids (GC) remains integral to the immediate management of PMR and GCA but being aware of patient co-morbidities that may influence treatment toxicity is paramount. As such GC sparing agents are required in the treatment of PMR. Currently there are limited treatment options available for PMR and GCA, and significant unmet needs remain. Newer mechanisms of action, and hence therapeutic options being studied include CD4 T cell co-stimulation blockade, IL-17 inhibition, IL-12/23 inhibition, GM-CSF inhibition, IL-1ß inhibition, TNF-α antagonist and Jak inhibition, among others, which will be discussed in this review.

Did the first description of patients with polymyalgia rheumatica take place in Scotland or in Denmark?

The first description of polymyalgia rheumatica (PMR) is generally attributed to Dr. Bruce. In an 1888 article entitled Senile rheumatic gout, he described five male patients aged from 60 to 74 years whom he had visited at the Strathpeffer spa in Scotland. In 1945, Dr. Holst and Dr. Johansen reported on five female patients examined over several months at the Medical Department of Roskilde County Hospital in Denmark. These patients suffered from hip, upper arms, and neck pain associated with elevated ESR and constitutional manifestations such as low-grade fever or loss of weight. In the same year, Meulengracht, another Danish physician, reported on two patients with shoulder pain and stiffness associated with fever, weight loss, and an increased erythrocyte sedimentation rate. As in the five patients reported by Dr. Holst and Dr. Johansen, a prolonged recovery time was recorded. On reading and comparing these three accounts, we question whether it is correct to attribute the first description of PMR to Dr. Bruce and put forward shifting this accolade to the three Danish physicians.

Immune complex-mediated neutrophil activation in patients with polymyalgia rheumatica.

OBJECTIVE: Neutrophils are important in host defence. However, neutrophils are also linked to inflammation and organ damage. The purpose of this study was to assess whether markers of neutrophil activation are increased in PMR. METHODS: Levels of immune complexes (IC), calprotectin and neutrophil extracellular traps (NETs) were measured in plasma of healthy individuals (n = 30) and patients with PMR (n = 60), at flare and upon treatment with glucocorticoids using ELISA. Plasma-mediated neutrophil activation was assessed in presence of an FcγRIIA inhibitory antibody (IV.3). RESULTS: Plasma levels of calprotectin and NETs were elevated in PMR (P < 0.001). Mechanistically, neutrophil activation was driven by ICs, present in plasma, able to up-regulate neutrophil activation markers CD66b and CD11b (P < 0.0001) in an FcγRIIA-dependent manner (P < 0.01). Of note, circulating levels of IC correlated with plasma induced CD66b and CD11b (r = 0.51, P = 0.004, and r = 0.46, P = 0.01, respectively) and decreased after glucocorticoid therapy. In contrast to NETs, calprotectin significantly decreased after glucocorticoid therapy (P < 0.001) and was higher in PMR without overlapping GCA compared with patients with overlapping disease (P = 0.014). Interestingly, musculoskeletal involvement was associated with elevated levels of calprotectin before initiation of glucocorticoid therapy (P = 0.036). CONCLUSIONS: Neutrophil activation, including NET formation, is increased in PMR, through IC-mediated engagement of FcγRIIA. Clinically, neutrophil activation is associated with musculoskeletal involvement, with calprotectin, but not NETs, being a biomarker of treatment response in PMR patients. In all, IC-mediated neutrophil activation is a central process in PMR pathogenesis identifying potential novel therapeutic targets (FcγRIIA), as well as soluble markers for disease monitoring (calprotectin).

[Recommendations of diagnosis and treatment of giant cell arteritis and polymyalgia rheumatic in China].

Polymyalgia rheumatica (PMR) is a syndrome characterized by pain and morning stiffness in the neck and shoulder and pelvic girdles, as well as raised acute-phase reactants, with or without systemic symptoms, such as fever. Giant cell arteritis (GCA) is a systemic vasculitis of unclear etiology that involves systemic arteries, principally affecting medium- and large-sized arteries with skipped, segmental alterations and granulomatous vasculitis seen on histopathology. In China, epidemiological data describing GCA are still limited; thus, the prevalence might be underestimated. The involvement of vessels in GCA can cause irreversible visual impairment or loss and stroke, which are serious complications. PMR is three times more prevalent than GCA, and other specific diseases should be excluded before the diagnosis is established. PMR symptoms can be present in 40%-60% of patients with GCA. Conversely, GCA can develop in 15% of patients with PMR. Chinese Rheumatology Association, based on the clinical diagnosis and treatment guidelines in 2005, utilizing the experience and guidelines of diagnosis and treatment at home and abroad, formulated this specification to standardize the diagnosis and treatment of GCA and PMR and improve the patient's prognosis.

Clinical analysis of gender and pre-existing diabetes mellitus in patients with polymyalgia rheumatica: A retrospective study in a Japanese population.

OBJECTIVE: This study clarifies the involvement of gender and pre-existing diabetes mellitus (DM) in the clinical characteristics of polymyalgia rheumatica (PMR). METHODS: The clinical records of patients diagnosed with PMR in our department between January 2011 and June 2021, especially in terms of gender and DM were retrospectively analysed. RESULTS: We identified 89 patients with the median age of 75.37 cases were men and 52 cases were women. Pre-existing DM was found in 21 patients (23.6%). Male PMR patients exhibited a higher complication rate of pre-existing DM and C-reactive protein (CRP) levels at diagnosis (p = .04 and p < .01, respectively) than female patients, and men were more common in the patient group with pre-existing DM (p = .04). The CRP levels of male PMR patients without pre-existing DM were higher than female PMR patients without pre-existing DM. CONCLUSION: Male PMR patients might have a varying pathophysiology from female patients in terms of high inflammation levels accompanied by a high prevalence rate of pre-existing DM and need a gender-specific approach.

[A case of giant cell arteritis after prednisolone dose reduction during treatment of polymyalgia rheumatica].

Giant cell arteritis (GCA) is closely associated with polymyalgia rheumatica (PMR). We herein report an 82-year-old woman who developed GCA during PMR treatment. She initially presented with shoulder pain and was diagnosed with PMR based on elevated serum C-reactive protein (CRP) levels and bursitis detected in both shoulders on ultrasonography (US). Treatment was initiated with a daily dose of 15 mg prednisolone (PSL), which led to rapid symptom alleviation, and the dosage was tapered to 1 mg/day. One month later, she developed myalgia extending from the lumbar region to the thigh and tenderness in the left temporal region. However, no abnormalities in the temporal artery were observed on US. Although the PSL dose was increased to 2 mg for relapse of PMR, the symptoms did not improve. One week later, she developed occipital pain with an increased CRP level of 9 mg/dL. She was diagnosed with GCA based on the 1990 ACR Classification Criteria. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) detected anomalous accumulations in the bilateral superficial temporal and vertebral arteries, but not in the larger vessels. We therefore diagnosed her with cranial-type GCA. At this time point, we repeated US and found a halo sign in the temporal artery. Although epithelioid and giant cells were not observed in the temporal artery biopsy, vascular inflammatory findings such as disruption of the internal elastic lamina and chronic inflammatory cell infiltration were noted. Symptoms improved immediately and CRP levels decreased after the PSL dose was increased to 30 mg daily. To mitigate the risk of steroid-induced diabetes, tocilizumab was introduced, and gradual tapering of PSL was implemented. In conclusion, we encountered a case of GCA that developed after PSL reduction during the course of PMR. PET/CT confirmed intracranial artery inflammation and facilitated a definitive diagnosis. Although PET/CT cannot be routinely performed for diagnose in Japan, we consider it useful as an adjunctive diagnostic tool.

Risk of venous and arterial thromboembolism in patients with giant cell arteritis and/or polymyalgia rheumatica: A Veterans Health Administration population-based study in the United States.

BACKGROUND: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are systemic inflammatory diseases that primarily affect elderly women. OBJECTIVES: To compare the risk of thromboembolic events and retinal vascular occlusions in GCA and/or PMR with that in osteoarthritis (OA), evaluating a veteran-based population. METHODS: A total of 1535 patients with GCA, 10,265 with PMR, and 1203 with overlapping disease, as well as 39,009 age- and sex-matched patients with OA were identified in this retrospective study. The incidence rate ratios (IRRs) of pulmonary embolism (PE), deep venous thrombosis (DVT), arterial thromboembolism, central retinal artery occlusion, and central retinal vein occlusion were calculated and examined over time. The cumulative incidence was plotted and hazard ratios (HRs) of thromboembolic events were calculated, adjusting for independent risk factors of thromboembolism. RESULTS: Patients with GCA and overlapping disease exhibited higher IRRs for all thromboembolic events compared to patients with OA. Patients with GCA had a higher risk of developing DVT and retinal vascular occlusions than those with overlapping disease (HR: 2.01, 95% confidence interval [CI]: 1.35-2.99, p < 0.001; HR: 2.37, 95% CI: 1.23-4.53, p = 0.009, respectively) or PMR alone (HR: 1.89, 95% CI: 1.50-2.41, p < 0.001; HR: 4.68, 95% CI: 3.10-7.07, p < 0.001, respectively). Patients with GCA had a higher risk of developing PE than those with PMR (HR: 1.55, 95% CI: 1.1-2.18, p = 0.01). CONCLUSION: The risk of thromboembolic events differs between GCA, PMR, and overlapping diseases. Our findings may help predict the risk of thromboembolic events based on disease phenotype.

An update on polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease affecting people older than 50 years and is 2-3 times more common in women. The most common symptoms are pain and morning stiffness in the shoulder and pelvic girdle and the onset may be acute or develop over a few days to weeks. General symptoms such as fatigue, fever and weight loss may occur, likely driven by systemic IL-6 signalling. The pathology includes synovial and periarticular inflammation and muscular vasculopathy. A new observation is that PMR may appear as a side effect of cancer treatment with checkpoint inhibitors. The diagnosis of PMR relies mainly on symptoms and signs combined with laboratory markers of inflammation. Imaging modalities including ultrasound, magnetic resonance imaging and positron emission tomography with computed tomography are promising new tools in the investigation of suspected PMR. However, they are still limited by availability, high cost and unclear performance in the diagnostic workup. Glucocorticoid (GC) therapy is effective in PMR, with most patients responding promptly to 15-25 mg prednisolone per day. There are challenges in the management of patients with PMR as relapses do occur and patients with PMR may need to stay on GC for extended periods. This is associated with high rates of GC-related comorbidities, such as diabetes and osteoporosis, and there are limited data on the use of disease-modifying antirheumatic drugs and biologics as GC sparing agents. Finally, PMR is associated with giant cell arteritis that may complicate the disease course and require more intense and prolonged treatment.

Risk of adrenal insufficiency in patients with polymyalgia rheumatica versus patients with rheumatoid arthritis: A cross-sectional study.

OBJECTIVE: To determine whether patients with polymyalgia rheumatica (PMR) are more susceptible to glucocorticoid-induced adrenal insufficiency, one of the barriers to glucocorticoid tapering strategies, compared to patients with rheumatoid arthritis (RA). METHODS: This cross-sectional study included PMR and RA patients who underwent adrenocorticotropic hormone (ACTH) tests to assess adrenal function. The eligibility criteria were as follows: previous use of prednisolone (PSL) ≥ 5 mg/day, use of PSL for six consecutive months before ACTH test, and current use of PSL at 5 mg/day or less. The association between disease type (PMR vs. RA) and insufficient adrenal response was assessed using logistic regression models. RESULTS: Twenty-six of 34 (76.5%) patients with PMR and 13 of 37 (35.1%) patients with RA had insufficient adrenal response. Compared to patients with RA, patients with PMR were more likely to have insufficient adrenal response, even after adjusting for age, sex, and PSL dose (adjusted odds ratio, 6.75; 95% confidence interval, 1.78-25.60). CONCLUSION: Patients with PMR have a higher risk of glucocorticoid-induced adrenal insufficiency than patients with RA. Assessing the adrenal function in patients with PMR will contribute to establishing a more appropriate glucocorticoid reduction strategy.

Low dose IL-2 in patients with steroid-dependent dysimmune manifestations associated with myelodysplastic syndromes: a three-case report.

OBJECTIVES: Systemic inflammatory and autoimmune diseases can be associated with myelodysplastic syndromes. Current treatments (steroids, immunosuppressive agents, biologics) are unsatisfactory because of their low response rate, dependence or adverse events. We aimed at evaluating the effects of low doses of IL-2 (ld-IL2) as a regulatory T-cell inducer in this context. METHODS: We treated three patients with ld-IL2 with myelodysplastic syndromes and an associated dysimmune disorder (polymyalgia rheumatic, relapsing polychondritis associated with Sweet's syndrome and vasculitis with cutaneous and joint involvement, respectively). All three patients were dependent on steroids and refractory to biologics or azacitidine. They received doses of 1-1.5 million units of proleukin/day during 5 days and then every fortnight. RESULTS: The treatment led to a clinical improvement and steroid sparing in 2/3 patients with no serious adverse events, and no progression of the disease. CONCLUSION: Our results support the investigation of ld-IL2 in MDS associated with immune disorders in controlled clinical studies.

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.

Fracture Risk and Its Prevention Patterns in Korean Patients with Polymyalgia Rheumatica: a Retrospective Cohort Study.

BACKGROUND: To evaluate the incidence of fractures and fracture risk factors in Korean patients with polymyalgia rheumatica (PMR). METHODS: All PMR patients who visited a rheumatology clinic at a tertiary referral hospital between March 2005 and March 2018 were retrospectively assessed. We estimated bone mineral density (BMD) screening rate within 6 months of the first visit and classified the patients according to the performance and results of BMD screening. Incidence rates (IRs) of fractures were calculated in each group and risk factors for fractures were identified using Poisson regression analysis. RESULTS: A total of 95 PMR patients with median (interquartile range) age of 64.0 (56.0-72.0) years were included. Baseline BMD was assessed in only 55.8% of these patients (n = 53); 24 patients with osteoporosis, 20 with osteopenia, and 9 with normal BMD. During 433.1 person-years (PYs) of observation, 17 fractures occurred in 12 patients (IR, 3.93 [95% confidence interval (CI), 2.46-6.26]/100 PYs); 8.32 (95% CI, 4.09-16.90)/100 PYs in the osteopenia group, 3.40 (95% CI, 1.30-8.90)/100 PYs in the osteoporosis group, and 3.37 (95% CI, 1.53-7.39)/100 PYs in the no BMD test group. Risk factors for fractures were female sex, advanced age (≥ 65 years), longer follow-up duration, initial glucocorticoid dose ≥ 10 mg/day, and higher cumulative glucocorticoid dose over the first 6 months. CONCLUSION: The incidence rate of fractures in Korean patients with PMR was 3.93/100 PYs. Female sex, advanced age, longer follow-up duration, and increased glucocorticoid dose are risk factors for osteoporotic fracture.

The Spectrum of Pericardial Involvement in Giant Cell Arteritis and Polymyalgia Rheumatica: A Systematic Review of Literature.

BACKGROUND: Giant cell arteritis (GCA) is a systemic vasculitis that commonly co-occurs with polymyalgia rheumatica (PMR) in elderly patients. Pericardial disease is an unusual manifestation of these inflammatory conditions, which has been reported only in case reports and small observational studies. However, no extensive research has been performed to study the demographics and clinical history of GCA or PMR patients with concomitant pericardial features. As a result, the medical evidence to help guide the physicians when evaluating such individuals is limited. OBJECTIVE: To perform a systematic review of the medical literature in order to summarize the epidemiological and clinicopathological aspects of this unique association. METHODS: We conducted an extensive search of PubMed, Cochrane Library, Ovid, Google Scholar, and gray literature to identify all the cases of GCA and PMR with pericardial involvement. The demographics, clinical features, and outcomes of the final cohort were reviewed and analyzed. RESULTS: The analysis comprised 52 clinical cases (51 identified from 46 articles and 1 from the residents' clinic). These included 44 patients with GCA and 8 with PMR. The mean age at presentation was 69.5 years, with only 46% of patients older than 70 years. The most common abnormality was pericardial effusion (85%), and in 37%, the pericardial event was the initial disease manifestation. Although a significant proportion of the patients were symptomatic (69%), the classic cranial symptoms were present in only 40%. Overall, the outcome was good even in the presence of large-vessel disease, which is usually a poor prognostic factor in classic GCA. On group analysis, patients with PMR were more likely to develop cardiac tamponade (37.5%; odds ratio, 25.8; confidence interval, 2.2-297.5; p = 0.01), whereas those with GCA were more likely to have large-vessel vasculitis (43%; odds ratio, 5.18; confidence interval, 0.58-252.1; p = 0.04). CONCLUSIONS: This study illustrates that patients with pericardial involvement represent a clinical phenotype of GCA (and possibly PMR), which is quite different from the cranial or large-vessel forms. These patients have a better prognosis likely due to younger age and presence of more overt symptoms resulting in early diagnosis.

Antimitochondrial Antibodies and Primary Biliary Cholangitis in Patients with Polymyalgia Rheumatica/Giant Cell Arteritis.

Background and Objectives: Laboratory liver abnormalities can be observed in patients affected with polymyalgia rheumatica (PMR) and/or giant cell arteritis (GCA), especially with a cholestatic pattern. The first objective of our review article is to discuss the potential link between antimitochondrial antibodies (AMA) and/or primary biliary cholangitis (PBC) and PMR/GCA, according to the evidences of literature. The second objective is to discuss the association of PMR/GCA with the other rheumatic diseases having PBC as a common manifestation. Materials and Methods: A literature search was performed on PubMed and Medline (OVID interface) using these terms: polymyalgia rheumatica, giant cell arteritis, antimitochondrial antibodies, primary biliary cholangitis, primary Sjogren's syndrome, systemic sclerosis, and systemic lupus erythematosus. The search was restricted to all studies and case reports published in any language. Reviews, conference abstracts, comments, and non-original articles were excluded; however, each review's reference list was scanned for additional publications meeting this study's aim. When papers reported data partially presented in previous articles, we referred to the most recent published data. Results and Conclusions: Our literature search highlighted that cases reporting an association between AMA, PBC and PMR/GCA were very uncommon; AMA antigenic specificity had never been detected and biopsy-proven PBC was reported only in one patient with PMR/GCA. Finally, the association of PMR/GCA with autoimmune rheumatic diseases in which PBC is relatively common was anecdotal.

Clinical outcomes of hospitalised patients with COVID-19 and chronic inflammatory and autoimmune rheumatic diseases: a multicentric matched cohort study.

OBJECTIVES: The impact of inflammatory rheumatic diseases on COVID-19 severity is poorly known. Here, we compare the outcomes of a cohort of patients with rheumatic diseases with a matched control cohort to identify potential risk factors for severe illness. METHODS: In this comparative cohort study, we identified hospital PCR+COVID-19 rheumatic patients with chronic inflammatory arthritis (IA) or connective tissue diseases (CTDs). Non-rheumatic controls were randomly sampled 1:1 and matched by age, sex and PCR date. The main outcome was severe COVID-19, defined as death, invasive ventilation, intensive care unit admission or serious complications. We assessed the association between the outcome and the potential prognostic variables, adjusted by COVID-19 treatment, using logistic regression. RESULTS: The cohorts were composed of 456 rheumatic and non-rheumatic patients, in equal numbers. Mean age was 63 (IQR 53-78) years and male sex 41% in both cohorts. Rheumatic diseases were IA (60%) and CTD (40%). Most patients (74%) had been hospitalised, and the risk of severe COVID-19 was 31.6% in the rheumatic and 28.1% in the non-rheumatic cohort. Ageing, male sex and previous comorbidity (obesity, diabetes, hypertension, cardiovascular or lung disease) increased the risk in the rheumatic cohort by bivariate analysis. In logistic regression analysis, independent factors associated with severe COVID-19 were increased age (OR 4.83; 95% CI 2.78 to 8.36), male sex (1.93; CI 1.21 to 3.07) and having a CTD (OR 1.82; CI 1.00 to 3.30). CONCLUSION: In hospitalised patients with chronic inflammatory rheumatic diseases, having a CTD but not IA nor previous immunosuppressive therapies was associated with severe COVID-19.

Longitudinal clusters of pain and stiffness in polymyalgia rheumatica: 2-year results from the PMR Cohort Study.

OBJECTIVES: To investigate potential subgroups of primary care-diagnosed patients with PMR based on self-reported pain and stiffness severity over time. METHODS: A total of 652 people with an incident PMR diagnosis were recruited from English general practices and completed a baseline postal questionnaire. They were followed up with a further six questionnaires over a 2 year period. A total of 446 people completed the 2 year follow-up. Pain and stiffness were reported on a 0-10 numerical rating scale. Latent class growth analysis was used to estimate the joint trajectories of pain and stiffness over time. A combination of statistical and clinical considerations was used to choose the number of clusters. Characteristics of the classes were described. RESULTS: Five clusters were identified. One cluster represented the profile of 'classical' PMR symptoms and one represented sustained symptoms that may not be PMR. The other three clusters displayed a partial recovery, a recovery followed by worsening and a slow, but sustained recovery. Those displaying classical PMR symptoms were in better overall health at diagnosis than the other groups. CONCLUSION: PMR is a heterogeneous condition, with a number of phenotypes. The spectrum of presentation, as well as varying responses to treatment, may be related to underlying health status at diagnosis. Future research should seek to stratify patients at diagnosis to identify those likely to have a poor recovery and in need of an alternative treatment pathway. Clinicians should be aware of the different experiences of patients and monitor symptoms closely, even where there is initial improvement.

High angiopoietin-2 levels associate with arterial inflammation and long-term glucocorticoid requirement in polymyalgia rheumatica.

OBJECTIVES: PMR frequently co-occurs with GCA. So far, a simple biomarker for detecting concomitant arterial inflammation in PMR patients is lacking. Furthermore, biomarkers predicting disease course in PMR are awaited. We here investigated the diagnostic and prognostic value of acute-phase markers (ESR, CRP, IL-6, serum amyloid A) and angiogenesis markers (VEGF, soluble Tie2, angiopoietin-1, angiopoietin-2) in isolated PMR and PMR/GCA overlap patients. METHODS: We prospectively included 39 treatment-naïve PMR patients, of whom 10 patients also showed evidence of large vessel GCA by PET-CT. Age-matched healthy controls (n = 32) and infection controls (n = 13) were included for comparison. Serum marker levels were measured by an ELISA or Luminex assay. Receiver operating characteristic and Kaplan-Meier analyses were used to asses diagnostic and prognostic accuracy, respectively. RESULTS: All acute-phase and angiogenesis markers, except angiopoietin-1, were higher in isolated PMR patients than in healthy controls. Angiopoietin-2, ESR and soluble Tie-2 were significantly higher in patients with PMR/GCA overlap than in isolated PMR patients. Angiopoeietin-2, but not soluble Tie2, outperformed ESR and CRP in discriminating patients with and without overlapping GCA (area under the curve: 0.90; sensitivity: 100%; specificity: 76%). Moreover, high angiopoietin-2 levels were associated with long-term glucocorticoid requirement. CONCLUSION: Assessment of angiopoietin-2 at baseline may assist diagnosis of concomitant vasculitis in PMR. Moreover, high levels of angiopoietin-2 were associated with an unfavourable disease course in isolated PMR patients. These findings imply that angiopoietin-2 is an interesting diagnostic and prognostic biomarker in PMR.

Subclinical atherosclerosis and endothelial dysfunction in patients with polymyalgia rheumatica: a pilot study.

Objective: The aim of the study was to investigate endothelial function in treatment-naïve polymyalgia rheumatica (PMR) patients and its modification during steroid therapy, in relation to changes in clinical and laboratory parameters.Method: This prospective observational study involved patients with a new diagnosis of PMR according to provisional American College of Rheumatology/European League Against Rheumatism 2012 criteria, who were naïve to steroid therapy, and control subjects matched for age, gender, and comorbidities. All participants underwent clinical and vascular ultrasound evaluations at baseline and after 1, 3, 6, and 12 months of steroid therapy. For the study of endothelial function, we evaluated the brachial artery reactivity, which has emerged as the most well-established technique used in adults, by assessing flow-mediated dilatation (FMD), which measures the endothelium-dependent vasodilatation.Results: Sixteen newly diagnosed PMR patients were compared with a population of 16 matched controls. FMD values in all subjects showed an inverse correlation with the values of erythrocyte sedimentation rate and C-reactive protein. At baseline, the FMD of PMR patients was significantly lower than controls and remained significantly lower with respect to controls until the sixth month of therapy, despite a clinical improvement already being evident after 1 month of therapy.Conclusions: PMR is characterized by an important chronic subclinical inflammatory component. This pilot study demonstrates that affected patients show endothelial dysfunction that slowly responds to steroid therapy. Further studies are needed to investigate the clinical relevance of these observations and, in particular, to monitor the cardiovascular risk profile of PMR patients.