EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors.

BACKGROUND: Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management. METHODS: First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed. RESULTS: The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies. CONCLUSION: These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.

Association of the CXCL9-CXCR3 and CXCL13-CXCR5 axes with B-cell trafficking in giant cell arteritis and polymyalgia rheumatica.

OBJECTIVE: B-cells are present in the inflamed arteries of giant cell arteritis (GCA) patients and a disturbed B-cell homeostasis is reported in peripheral blood of both GCA and the overlapping disease polymyalgia rheumatica (PMR). In this study, we aimed to investigate chemokine-chemokine receptor axes governing the migration of B-cells in GCA and PMR. METHODS: We performed Luminex screening assay for serum levels of B-cell related chemokines in treatment-naïve GCA (n = 41), PMR (n = 31) and age- and sex matched healthy controls (HC, n = 34). Expression of chemokine receptors on circulating B-cell subsets were investigated by flow cytometry. Immunohistochemistry was performed on GCA temporal artery (n = 14) and aorta (n = 10) and on atherosclerosis aorta (n = 10) tissue. RESULTS: The chemokines CXCL9 and CXCL13 were significantly increased in the circulation of treatment-naïve GCA and PMR patients. CXCL13 increased even further after three months of glucocorticoid treatment. At baseline CXCL13 correlated with disease activity markers. Peripheral CXCR3+ and CXCR5+ switched memory B-cells were significantly reduced in both patient groups and correlated inversely with their complementary chemokines CXCL9 and CXCL13. At the arterial lesions in GCA, CXCR3+ and CXCR5+ B-cells were observed in areas with high CXCL9 and CXCL13 expression. CONCLUSION: Changes in systemic and local chemokine and chemokine receptor pathways related to B-cell migration were observed in GCA and PMR mainly in the CXCL9-CXCR3 and CXCL13-CXCR5 axes. These changes can contribute to homing and organization of B-cells in the vessel wall and provide further evidence for an active involvement of B-cells in GCA and PMR.

Association of mucosal-associated invariant T cells with different disease phases of polymyalgia rheumatica.

OBJECTIVES: Although T cells are thought to be involved in the pathogenesis of PMR, whether innate-like T cells are involved in the process remains unknown. METHODS: The serum levels of 27 cytokines/chemokines in patients with PMR were measured by a multiplex immunoassay (Bio-Plex Assay). The cytokine-producing capacity of T and innate-like T cells was assessed by intracellular cytokine staining and flow cytometry. The frequency and activated status of T and innate-like T cells were investigated by flow cytometry and their associations with clinical parameters were assessed. RESULTS: The levels of inflammatory cytokines were associated with disease activity in PMR. The cytokine-producing capacity by CD8+ T and innate-like T cells was associated with disease activity. The frequency of HLA-DR+ CD38+ cells among CD8+ T cells was increased in patients with active disease. The frequencies of HLA-DR+ CD38+ cells among CD4+ T, mucosal-associated invariant T (MAIT) and γδ T cells were higher in patients with inactive disease. The frequency of HLA-DR+ CD38+ MAIT cells was associated with the PMR activity score and CRP levels in patients in remission. CONCLUSION: The inflammatory cytokine-producing capacity and expression of activation markers of CD8+ T and innate-like T cells were associated with the disease activity of PMR. MAIT cell activation in patients in remission may contribute to the subclinical activity of the disease.

Rheumatic Manifestations in Patients Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system, aiming at enhancing antitumor immunity. Their clinical efficacy is well-documented, but the side effects associated with their use are still under investigation. These drugs cause several immune-related adverse events (ir-AEs), some of which stand within the field of rheumatology. Herein, we present a literature review performed in an effort to evaluate all publicly available clinical data regarding rheumatic manifestations associated with ICIs. The most common musculoskeletal ir-AEs are inflammatory arthritis, polymyalgia rheumatica and myositis. Non-musculoskeletal rheumatic manifestations are less frequent, with the most prominent being sicca, vasculitides and sarcoidosis. Cases of systemic lupus erythematosus or scleroderma are extremely rare. The majority of musculoskeletal ir-AEs are of mild/moderate severity and can be managed with steroids with no need for ICI discontinuation. In severe cases, more intense immunosuppressive therapy and permanent ICI discontinuation may be employed. Oncologists should periodically screen patients receiving ICIs for new-onset inflammatory musculoskeletal complaints and seek a rheumatology consultation in cases of persisting symptoms.

Identification of an activated neutrophil phenotype in polymyalgia rheumatica during steroid treatment: a potential involvement of immune cell cross-talk.

We have reported the existence of a distinct neutrophil phenotype in giant cell arteritis (GCA) patients arising at week 24 of steroid treatment. In the present study, we investigated whether longitudinal analysis of neutrophil phenotype in patients with polymyalgia rheumatica (PMR) could reveal a novel association with disease status and immune cell cross-talk. Thus, we monitored PMR patient neutrophil phenotype and plasma microvesicle (MV) profiles in blood aliquots collected pre-steroid, and then at weeks 1, 4, 12 and 24 post-steroid treatment.Using flow cytometric and flow chamber analyses, we identified 12-week post-steroid as a pivotal time-point for a marked degree of neutrophil activation, correlating with disease activity. Analyses of plasma MVs indicated elevated AnxA1+ neutrophil-derived vesicles which, in vitro, modulated T-cell reactivity, suggesting distinct neutrophil phenotypic and cross-talk changes at 24 weeks, but not at 12-week post-steroid.Together, these data indicate a clear distinction from GCA patient neutrophil and MV signatures, and provide an opportunity for further investigations on how to 'stratify' PMR patients and monitor their clinical responses through novel use of blood biomarkers.

Dissecting the inflammatory response in polymyalgia rheumatica: the relative role of IL-6 and its inhibition.

The efficacy of tocilizumab (TCZ), a monoclonal antibody to the interleukin (IL)-6 receptor, in suppressing disease activity in glucocorticoid-naïve patients with new-onset polymyalgia rheumatica (PMR) was studied. Its effect on a panel of cytokines and growth factors was evaluated. Three patients, fulfilling the PMR ACR/EULAR criteria, received TCZ at the dosage of 8 mg/kg every 4 weeks for three times followed by prednisone 0.2 mg/kg in case of inefficacy. Concentrations of IL-10, IL-6, tumour necrosis factor (TNF)-α, IL-1ß, IL-10, IL-17, interferon (IFN)-γ, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and leukaemia inhibitory factor (LIF) were measured at baseline, after 72 h of the first TCZ infusion and then at weeks 1, 4, 5, 8, 9, 12, 13, 14, 16, and 22. A slight clinical improvement was seen only after the first TCZ infusion, but was largely inferior to that of conventional doses of GC administered subsequently. An ischaemic visual accident suggestive of GCA occurred in one patient during TCZ treatment. IL-6 was increased at baseline compared to controls, further increased after the first TCZ infusion, and was suppressed by GC. IL-17 production decreased during TCZ treatment and reverted to pre-treatment levels after GC. VEGF e PDGF showed a less constant pattern, but an increase of VEGF concentration antedated visual symptoms. The other cytokines were not detectable in patients and controls. In our small sample, TCZ was not able to suppress inflammation at the same degree as GC. As a result, monotherapy with TCZ in PMR cannot be recommended, although its efficacy as adjunctive treatment in GC-resistant patients should be further evaluated.

Pathogenesis of polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is a chronic, inflammatory disorder of unknown cause, almost exclusively occurring in people aged over 50 and often associated with giant cell arteritis. The evidence that PMR occurs almost exclusively in individuals aged over 50 may indicate that age-related immune alterations in genetically predisposed subjects contribute to development of the disease. Several infectious agents have been investigated as possible triggers of PMR even though the results are inconclusive. Activation of the innate and adaptive immune systems has been proved in PMR patients as demonstrated by the activation of dendritic cells and monocytes/macrophages and the altered balance between Th17 and Treg cells. Disturbed B cell distribution and function have been also demonstrated in PMR patients suggesting a pathogenesis more complex than previously imagined. In this review we will discuss the recent findings regarding the pathogenesis of PMR.

Serum immunoglobulin G4 in giant cell arteritis and polymyalgia rheumatica.

OBJECTIVES: To date, no specific serum marker for giant cell arteritis and polymyalgia rheumatica has been established in routine practice. Therefore, the aim of this study was to examine whether immunoglobulin G4 serum concentrations could be a potential biomarker for the differentiation of both diseases. METHODS: Serum immunoglobulin G4 (IgG4) concentrations were measured in patients with giant cell arteritis (n=41) and polymyalgia rheumatica (n=27) by an in-house enzyme-linked immunosorbent assay. In the subgroup of untreated patients with disease activity (polymyalgia rheumatica n=27, giant cell arteritis n=19) additional parameters of T-helper 2 cell inflammatory responses were analysed. RESULTS: IgG4-values above the prior determined cut-off value of 1400 µg/ml in giant cell arteritis were rare and also significantly less frequent in giant cell arteritis than in polymyalgia rheumatica patients (7.3% vs. 44.4%; p<0.001). The relative risk that patients with clinical features of PMR, presenting without elevated IgG4 levels, have simultaneously GCA was 5.8 compared to those patients with elevated IgG4 levels. In untreated patients absolute counts of eosinophilic leukocytes were lower in giant cell arteritis than in polymyalgia rheumatica (p=0.002) and the cytokines interleukin-4 (p=0.013) and interleukin-10 (p=0.033) were less frequently detectable in giant cell arteritis than in polymyalgia rheumatica. CONCLUSIONS: In giant cell arteritis serum levels of IgG4 usually are within the normal range. In polymyalgia rheumatica however, increased IgG4 serum levels are frequently found. Normal IgG4 serum levels in polymyalgia rheumatica may have predictive value in identifying patients with additional, clinically non-apparent giant cell arteritis.

Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) case presentation and comparison with other polyarthritides affecting older people.

Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome mainly affects elderly men and responds well to steroids. Since this syndrome can resemble other diseases, its diagnosis is a significant challenge. Through the following paper, we hope to improve the diagnosis of RS3PE by presenting a table comparing RS3PE to two other common polyarthritic conditions affecting the elderly.

[Large vessel vasculitis : Giant cell arteritis and Takayasu arteritis]. / Großgefäßvaskulitiden : Riesenzellarteriitis und Takayasu-Arteriitis.

According to the Chapel Hill Classification, large vessel vasculitides encompass giant cell arteritis (GCA) and the histologically related Takakaysu arteritis (TAK). The two diseases lack autoantibodies and present with a systemic inflammatory response. GCA typically shows a sudden onset with profound sickness, loss of appetite and of body weight, and temporal headache. Due to the substantial risk of sudden blindness, diagnostic work-up has to be performed immediately and treatment started without delay. A close association between polymyalgia rheumatica (PMR) and GCA is well established. Takayasu arteritis very often begins in adolescence. In contrast to GCA, the general symptoms are much less pronounced and aside from occasional carotidodynia there is a lack of diagnostic symptoms. TAK is often diagnosed in late stages due to exercise-induced claudication.

Secondary Antibody Deficiency in Glucocorticoid Therapy Clearly Differs from Primary Antibody Deficiency.

PURPOSE: The aim of this study was to identify characteristics of hypogammaglobulinemia secondary to glucocorticoid therapy and their value in the differential diagnosis to primary forms of antibody deficiency. METHODS: We investigated prevalence and character of hypogammaglobulinemia in a cohort of 36 patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) on glucocorticoid therapy in comparison to a gender- and age-matched cohort of hospital controls. We therefore determined serum immunoglobulin levels as well as B- and T cell-subsets in the peripheral blood of all participants. In addition, prior serum immunoglobulin levels and clinical data of the GCA and PMR patients were extracted from the electronic patient data-base. RESULTS: 21/36 GCA/PMR patients on glucocorticoid treatment developed antibody deficiency. In 19 patients this included IgG and in 13 patients IgG was the only affected isotype. The reduction of IgG was persistent in nearly 50 % of these patients during the observed period. GCA/PMR patients had reduced circulating naive and transitional B cells (p = 0.0043 and p = 0.0002 respectively) while IgM, IgG and IgA memory B cells were preserved. Amongst T-cell subsets, we found a reduction of CD4 memory T cells (p < 0.0001), CD4 regulatory T cells (p = 0.0002) and few CD8 memory T-cell subtypes. CONCLUSION: Persistent humoral immunodeficiency occurs in about a quarter of GCA/PMR patients under glucocorticoid therapy. Because most patients have isolated IgG deficiency, preserved IgA production and class-switched memory B cells, by these markers this form of secondary hypogammaglobulinemia can be clearly distinguished from common variable immunodeficiency (CVID).

Performance of the new 2012 EULAR/ACR classification criteria for polymyalgia rheumatica: comparison with the previous criteria in a single-centre study.

OBJECTIVE: To compare the performance of published classification/diagnostic criteria for polymyalgia rheumatica (PMR), including the new 2012 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria, in a single-centre study. METHODS: We studied all consecutive patients with new-onset PMR seen in our centre over 6 years, whose diagnosis was confirmed during a prospective 12-month follow-up period. Subjects were classified by each of the seven different criteria. Sensitivity and specificity were compared. Control population consisted of all consecutive patients aged ≥50 years seen in a 4-year period in our early arthritis clinic who had a 12-month confirmation of a diagnosis of rheumatoid arthritis (RA) or other inflammatory articular diseases. RESULTS: Data were collected from 136 cases and 149 controls, including 94 patients with RA. The most sensitive criteria were the new 2012 EULAR/ACR classification criteria (92.6%). Adding ultrasound (US) specificity increased from 81.5% to 91.3% in total cases and from 79.7% to 89.9% in RA. Bird criteria had a sensitivity of 89.2% but the lowest specificity (40.2% in total cases and 72.5% in RA). Jones and Nobunaga criteria were the most specific criteria (96.7% and 97.8% in total cases and 98.6% and 99.5% in RA) but the less sensitive (63.1% and 58.2%) ones. Overall, discriminatory ability, as reflected by the area under the receiver operating characteristic curve, was better for the 2012 US EULAR/ACR criteria (0.920 in total cases and 0.910 in RA). CONCLUSIONS: The new EULAR/ACR criteria in new-onset PMR patients perform best in discriminating PMR from RA and other inflammatory articular diseases. Ultrasound further increases the specificity of the criteria.

Influence of interleukin 10 promoter polymorphisms in polymyalgia rheumatica: disease susceptibility and functional consequences.

OBJECTIVES: To investigate the functional consequences of IL10 (-592C/A and -1082A/G) gene polymorphisms and their association with susceptibility to, and disease phenotype, in patients with polymyalgia rheumatica (PMR). METHODS: A total number of 168 with PMR and 124 age-matched controls were genotyped using allele-specific primers and restriction fragment length polymorphism analysis. The levels of circulating IL10 and the production of IL10 by PBMCs after in vitro stimulation were studied by Cytometric Bead Array. RESULTS: No significant differences were observed in genotype or allele frequency distribution between patients and controls. The clinical characteristics and prognosis of these patients were also unrelated to the presence of these polymorphisms. No significant differences between PMR patients with low ESR (<40 mm/hr) and classic PMR (>40 mm/hr) were found. Furthermore, we did not observe any influence of circulating IL10 with the intensity of the acute phase response. In both, PMR patients and age-matched controls, no differences in circulating IL10 levels or IL10 production were observed depending on the genotypes of the IL10 gene. CONCLUSIONS: These results do not support the impact of IL10 variants in susceptibility or clinical phenotype of PMR patients. In this aged population no functional association was found between IL10 gene variants and IL10 production.

Polymyalgia rheumatica and giant cell arteritis induced by immune checkpoint inhibitors: A systematic literature review highlighting differences from the idiopathic forms.

INTRODUCTION: An altered immune tolerance disturbed by immune checkpoint inhibitors (ICIs) may contribute to new-onset polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). This systematic literature review (SLR) examines the characteristics of PMR and GCA-like syndromes following anticancer treatment with ICIs, summarizing their demographic, clinical and treatment-related features to provide insights whether they differ from the idiopathic forms. METHODS: The SLR was conducted in Medline and EMBASE databases from inception to July 2024, and in the EULAR/ACR abstract database (2021-2023). ICI-induced PMR and GCA syndromes were compared to the primary forms of the diseases using data from studies that included both groups as comparators. For manuscripts lacking direct comparisons, we summarized the main findings and discussed the differences using systematic reviews or large observational studies on the primary forms. RESULTS: From 1237 screened abstracts, 46 met the inclusion criteria, involving 358 patients (314 with ICI-PMR and 44 with ICI-GCA). ICI-PMR had an estimated pooled prevalence of 0.1% [95% CI: 0.07%, 0.14%] among ICI recipients and 15.9% [95% CI: 12.6%, 19.9%] among patients experiencing rheumatic immune-related adverse events. Patients with ICI-PMR had a male-to-female ratio of 1.7:1 and a mean age of 71 ± 4 years. Most cases were associated with PD1/PDL1 blockers (87%). Clinical features included inflammatory pain in the girdles (100%), though pelvic girdle involvement was under-reported in some cases (3/28 studies). Peripheral arthritis was present in 35% of patients. Laboratory tests showed normal or slightly elevated inflammatory markers in 26% of cases. Glucocorticoids (GCs) led to symptom improvement in 84% of cases although 20% required immunosuppressive treatment and 14% experienced relapses. ICI-GCA had a prevalence of 0.06% among ICI recipients, with equal gender distribution and a mean age of 71 ± 5 years. Most patients received anti-PD1/PDL1 blockers (57%). Clinical manifestations included cephalic symptoms (75%), permanent visual loss (23%) and symptoms related to large-vessel involvement (54%). High-dose GCs were effective, with 96% achieving remission, though 17% experienced relapses. CONCLUSIONS: ICI-induced PMR and GCA may have distinct clinical profiles compared to idiopathic forms, with potentially milder symptoms and better treatment responses. Further studies are needed to confirm these findings and better understand the long-term outcomes and pathophysiology of these conditions.

Epitope mapping of antibodies against ferritin heavy chain in giant cell arteritis and polymyalgia rheumatica.

OBJECTIVES: In a previous study we found an association between antibodies against the human ferritin heavy chain (HFC) protein and giant cell arteritis (GCA) and/or polymyalgia rheumatica (PMR), especially in GCA/PMR patients prior to glucocorticoid treatment. Antibodies against the N-terminal part of ferritin were present in 92% of untreated patients, 69% of patients with disease flare, and 13% of patients in remission. These antibodies appeared to be markers for the early detection of a disease complex usually diagnosed with considerable delay. Our aim in this study was to optimize the diagnostic test by epitope mapping of antibodies against HFC using peptide antigens in enzyme-linked immunosorbent assays (ELISAs). METHOD: We evaluated serum samples from a selected group of GCA/PMR patients in whom the sensitivity of antibodies against the N-terminal ferritin peptide was only 35%. Patients with late-onset rheumatoid arthritis (LORA), patients with fever, patients with granulomatosis with polyangiitis (GPA), patients without any autoimmune disease at age > 65 years, and blood donors served as controls. RESULTS: By combining different ELISAs we were able to increase the frequency of human ferritin peptide antibodies in GCA/PMR (p < 0.0001) without significantly altering the false-positive rate (FPR) of the diagnostic test. The frequency of antibodies against human ferritin peptide increased from 53% to 74% in GCA/PMR patients with disease flare, from 29% to 40% in GCA/PMR patients in partial remission, and from 8% to 45% in GCA/PMR patients in complete remission. CONCLUSIONS: The potential diagnostic test for GCA/PMR can be improved by combining three human ferritin peptide antibodies.

Discontinuation of therapies in polymyalgia rheumatica and giant cell arteritis.

Glucocorticoids are highly effective in treating polymyalgia rheumatica and giant cell arteritis, but their use is associated with numerous adverse events. Therefore, it is important to use them for the shortest period of time possible. The published evidence suggests that discontinuation of GC is feasible in a substantial number of patients with polymyalgia rheumatica and giant cell arteritis after an adequate period of treatment, provided that glucocorticoids are tapered gradually. Recurrences are relatively infrequent in polymyalgia rheumatica and somewhat more common in giant cell arteritis. Immunosuppressive agents may be used in patients with frequently relapsing or recurring disease to decrease exposure to glucocorticoids.

Th1 and Th17 lymphocytes expressing CD161 are implicated in giant cell arteritis and polymyalgia rheumatica pathogenesis.

OBJECTIVE: Giant cell arteritis (GCA) is the most frequently occurring vasculitis in elderly individuals, and its pathogenesis is not fully understood. The objective of this study was to decipher the role of the major CD4+ T cell subsets in GCA and its rheumatologic form, polymyalgia rheumatica (PMR). METHODS: A prospective study of the phenotype and the function of major CD4+ T cell subsets (Th1, Th17, and Treg cells) was performed in 34 untreated patients with GCA or PMR, in comparison with 31 healthy control subjects and with the 27 treated patients who remained after the 7 others withdrew. RESULTS: Compared with control subjects, patients with GCA and patients with PMR had a decreased frequency of Treg cells and Th1 cells, whereas the percentage of Th17 cells was significantly increased. Furthermore, an analysis of temporal artery biopsy specimens obtained from patients affected by GCA for whom biopsy results were positive demonstrated massive infiltration by Th17 and Th1 lymphocytes without any Treg cells. After glucocorticoid treatment, the percentages of circulating Th1 and Th17 cells decreased, whereas no change in the Treg cell frequency was observed. The frequency of CD161+CD4+ T cells, which are considered to be Th17 cell precursors, was similar in patients and control subjects. However, these cells highly infiltrated GCA temporal artery biopsy specimens, and their ability to produce interleukin-17 in vitro was significantly enhanced in patients with GCA and patients with PMR and was correlated with a decrease in the phosphorylated form of STAT-1. CONCLUSION: This study is the first to demonstrate that the frequency of Treg cells is decreased in patients with GCA and patients with PMR, and that CD161+CD4+ T lymphocytes, differentiated into Th1 cells and Th17 cells, are involved in the pathogenesis of GCA and PMR.

Imbalance between endothelial injury and repair in patients with polymyalgia rheumatica: improvement with corticosteroid treatment.

OBJECTIVES: Polymyalgia rheumatica (PMR) is a rheumatic disease that is characterized by intense activation of systemic inflammation. Systemic inflammation has been associated with an imbalance between endothelial injury and repair, defined by an increased number of circulating endothelial microparticles (EMPs) and a reduced number of endothelial progenitor cells (EPCs). We investigated the association between inflammation and endothelial injury and repair in patients with PMR and evaluated the effects of corticosteroid therapy on EMP and EPC levels. DESIGN, SETTING AND SUBJECTS: We conducted a case-control study in 34 patients with never-treated active PMR and 34 healthy age- and sex-matched controls. Patients with PMR participated in a 1-month intervention open-label study with corticosteroid therapy. Circulating EMPs (CD31+/CD42-) and EPCs (CD34+/KDR+) were quantified by fluorescence-activated cell sorting analysis. RESULTS: Patients with PMR had an increased EMP/EPC ratio compared with controls [median (IQR): 6.5 (3.0-11.5) vs. 1.1 (0.7-1.5), P < 0.001], because of both increased EMP and reduced EPC levels. Levels of C-reactive protein (CRP) were associated with an increased EMP/EPC ratio (ß = 0.48, P = 0.001), irrespective of traditional cardiovascular risk factors. Corticosteroid therapy led to a significant CRP reduction [from 3.9 (1.5-6.7) to 0.6 (0.2-1.2) mg dL(-1) , P < 0.05], paralleled by a consistent 81% decline in the EMP/EPC ratio. CRP and EMP/EPC ratio reductions were significantly correlated (rho = 0.37, P = 0.04). CONCLUSIONS: Polymyalgia rheumatica is associated with a significant imbalance between endothelial injury and repair, which is dependent on the degree of systemic inflammation. Attenuation of inflammation by short-term corticosteroid therapy might have a role in limiting endothelial fragmentation and promote endothelial repair.