Immune checkpoint inhibitor-mediated polymyalgia rheumatica versus primary polymyalgia rheumatica: comparison of disease characteristics and treatment requirement.

OBJECTIVES: To compare clinical characteristics, imaging findings and treatment requirements of patients with immune checkpoint inhibitor-mediated polymyalgia rheumatica (ICI-PMR) and primary PMR. METHODS: This single centre, retrospective cohort study compared ICI-PMR in patients with cancer (n = 15) to patients with primary PMR (n = 37). A comparison was made between clinical symptoms, laboratory markers, ultrasonography,18F-FDG-PET/CT findings and treatment requirements related to PMR. RESULTS: Patients with ICI-PMR less frequently fulfilled the EULAR/ACR classification criteria for PMR (66.7%) than patients with primary PMR (97.3%). Morning stiffness, weight loss and elevation of the ESR were less frequently seen in patients with ICI-PMR. No differences were observed regarding the presence of inflammatory lesions on ultrasound of the shoulders and hips between the two groups. The Leuven and the Leuven/Groningen 18F-FDG-PET/CT scores were significantly lower in the ICI-PMR group. Finally, the ICI-PMR group could be managed with less glucocorticoids than the primary PMR group. CONCLUSION: Our findings indicate that ICI-PMR may have a milder course with less inflammation than primary PMR on 18F-FDG-PET/CT. ICI-mediated PMR patients can be managed with a relatively low glucocorticoid dose. Our study underscores that ICI-PMR should be regarded as PMR-like syndrome.

A direct comparison in diagnostic performance of CDUS, FDG-PET/CT and MRI in patients suspected of giant cell arteritis.

OBJECTIVES: This study directly compares diagnostic performance of Colour Duplex Ultrasound (CDUS), Fluor-18-deoxyglucose Positron Emission Tomography Computed Tomography (FDG-PET/CT) and Magnetic Resonance Imaging (MRI) in patients suspected of giant cell arteritis (GCA). METHODS: Patients with suspected GCA were included in a nested-case control pilot study. CDUS, whole body FDG-PET/CT and cranial MRI were performed within 5 working days after initial clinical evaluation. Clinical diagnosis after six months follow-up by experienced rheumatologists in the field of GCA, blinded for imaging, was used as reference standard. Diagnostic performance of the imaging modalities was determined. Stratification for GCA subtype was performed and imaging results were evaluated in different risk stratification groups. RESULTS: In total, 23 patients with GCA and 19 patients suspected of but not diagnosed with GCA were included. Sensitivity was 69.6% (95%CI 50.4%-88.8%) for CDUS, 52.2% (95%CI 31.4%-73.0%) for FDG-PET/CT and 56.5% (95%CI 35.8%-77.2%) for MRI. Specificity was 100% for CDUS, FDG-PET/CT and MRI. FDG-PET/CT was negative for GCA in all isolated cranial GCA patients (n = 8), while MRI was negative in all isolated extracranial GCA patients (n = 4). In 4 GCA patients with false-negative (n = 2; intermediate and high risk) or inconclusive (n = 2; low and intermediate risk) CDUS results, further imaging confirmed diagnosis. CONCLUSIONS: Sensitivity of CDUS was highest, while specificity was excellent in all imaging modalities. Nevertheless, confidence intervals of all imaging modalities were overlapping. Following EULAR recommendations, CDUS can be used as a first test to diagnose GCA. With insufficient evidence for GCA, further testing considering GCA subtype is warranted.

Multimodality imaging to assess diagnosis and evaluate complications of large vesselarteritis.

Different types of vasculitis can be distinguished according to the blood vessel's size that is preferentially affected: large-vessel, medium-vessel, and small-vessel vasculitides. Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are the main forms of large-vessel vasculitis, and may lead to lumen narrowing. Clinical manifestations of arterial narrowing on the short- and long term include vision loss, stroke, limb ischemia, and heart failure. Imaging tools are well established diagnostic tests for large-vessel vasculitis and may aid therapy monitoring in selected cases while providing important information regarding the occurrence of vascular damage, tissue and organ complications. This review aims to provide the current status of multimodality imaging for the diagnosis and identification of vascular complications in the field of large vessel vasculitis.

Cytokine producing B-cells and their capability to polarize macrophages in giant cell arteritis.

OBJECTIVE: The lack of disease-specific autoantibodies in giant cell arteritis (GCA) suggests an alternative role for B-cells readily detected in the inflamed arteries. Here we study the cytokine profile of tissue infiltrated and peripheral blood B-cells of patients with GCA. Moreover, we investigate the macrophage skewing capability of B-cell-derived cytokines. METHODS: The presence of various cytokines in B-cell areas in temporal artery (n = 11) and aorta (n = 10) was identified by immunohistochemistry. PBMCs of patients with GCA (n = 11) and polymyalgia rheumatica (n = 10), and 14 age- and sex-matched healthy controls (HC) were stimulated, followed by flow cytometry for cytokine expression in B-cells. The skewing potential of B-cell-derived cytokines (n = 6 for GCA and HC) on macrophages was studied in vitro. RESULTS: The presence of IL-6, GM-CSF, TNFα, IFNγ, LTß and IL-10 was documented in B-cells and B-cell rich areas of GCA arteries. In vitro, B-cell-derived cytokines (from both GCA and HC) skewed macrophages towards a pro-inflammatory phenotype with enhanced expression of IL-6, IL-1ß, TNFα, IL-23, YKL-40 and MMP-9. In vitro stimulated peripheral blood B-cells from treatment-naïve GCA patients showed an enhanced frequency of IL-6+ and TNFα+IL-6+ B-cells compared to HCs. This difference was no longer detected in treatment-induced remission. Erythrocyte sedimentation rate positively correlated with IL-6+TNFα+ B-cells. CONCLUSION: B-cells are capable of producing cytokines and steering macrophages towards a pro-inflammatory phenotype. Although the capacity of B-cells in skewing macrophages is not GCA specific, these data support a cytokine-mediated role for B-cells in GCA and provide grounds for B-cell targeted therapy in GCA.

An international survey of current management practices for polymyalgia rheumatica by general practitioners and rheumatologists.

OBJECTIVES: To explore current management practices for PMR by general practitioners (GPs) and rheumatologists including implications for clinical trial recruitment. METHODS: An English language questionnaire was constructed by a working group of rheumatologists and GPs from six countries. The questionnaire focused on: 1: Respondent characteristics; 2: Referral practices; 3: Treatment with glucocorticoids; 4: Diagnostics; 5: Comorbidities; and 6: Barriers to research. The questionnaire was distributed to rheumatologists and GPs worldwide via members of the International PMR/Giant Cell Arteritis Study Group. RESULTS: In total, 394 GPs and 937 rheumatologists responded to the survey. GPs referred a median of 25% of their suspected PMR patients for diagnosis and 50% of these were returned to their GP for management. In general, 39% of rheumatologists evaluated patients with suspected PMR >2 weeks after referral, and a median of 50% of patients had started prednisolone before rheumatologist evaluation. Direct comparison of initial treatment showed that the percentage prescribing >25 mg prednisolone daily for patients was 30% for GPs and 12% for rheumatologists. Diagnostic imaging was rarely used. More than half (56%) of rheumatologists experienced difficulties recruiting people with PMR to clinical trials. CONCLUSION: This large international survey indicates that a large proportion of people with PMR are not referred for diagnosis, and that the proportion of treatment-naive patients declined with increasing time from referral to assessment. Strategies are needed to change referral and management of people with PMR, to improve clinical practice and facilitate recruitment to clinical trials.

Phenotypic, transcriptomic and functional profiling reveal reduced activation thresholds of CD8+ T cells in giant cell arteritis.

OBJECTIVES: Evidence from temporal artery tissue and blood suggests involvement of CD8+ T cells in the pathogenesis of GCA, but their exact role is poorly understood. Therefore, we performed a comprehensive analysis of circulating and lesional CD8+ T cells in GCA patients. METHODS: Circulating CD8+ T cells were analysed for differentiation status (CD45RO, CCR7), markers of activation (CD69 and CD25) and proliferation (Ki-67) in 14 newly diagnosed GCA patients and 18 healthy controls by flow cytometry. Proliferative capacity of CD8+ T cells upon anti-CD3 and anti-CD3/28 in vitro stimulation was assessed. Single-cell RNA sequencing of peripheral blood mononuclear cells of patients and controls (n = 3 each) was performed for mechanistic insight. Immunohistochemistry was used to detect CD3, CD8, Ki-67, TNF-α and IFN-γ in GCA-affected tissues. RESULTS: GCA patients had decreased numbers of circulating effector memory CD8+ T cells but the percentage of Ki-67-expressing effector memory CD8+ T cells was increased. Circulating CD8+ T cells from GCA patients demonstrated reduced T cell receptor activation thresholds and displayed a gene expression profile that is concurrent with increased proliferation. CD8+ T cells were detected in GCA temporal arteries and aorta. These vascular CD8+ T cells expressed IFN-γ but not Ki-67. CONCLUSION: In GCA, circulating effector memory CD8+ T cells demonstrate a proliferation-prone phenotype. The presence of CD8+ T cells in inflamed arteries seems to reflect recruitment of circulating cells rather than local expansion. CD8+ T cells in inflamed tissues produce IFN-γ, which is an important mediator of local inflammatory responses in GCA.

Comparison and validation of FDG-PET/CT scores for polymyalgia rheumatica.

OBJECTIVES: To compare and validate the diagnostic accuracy of fluorodeoxyglucose (FDG)-PET/CT scores for PMR; and to explore their association with clinical factors. METHODS: This retrospective study included 39 consecutive patients diagnosed with PMR and 19 PMR comparators. The final clinical diagnosis was established after 6 months follow-up. Patients underwent FDG-PET/CT prior to glucocorticoid treatment. Visual grading of FDG uptake was performed at 30 anatomic sites. Three FDG-PET/CT scores (the Leuven Score, two Besançon Scores) and two algorithms (the Saint-Etienne and Heidelberg Algorithms) were investigated. Receiver operating characteristic (ROC) analysis with area under the curve (AUC) was performed. Diagnostic accuracy was assessed at predefined cut-off points. RESULTS: All three FDG-PET/CT scores showed high diagnostic accuracy for a clinical diagnosis of PMR in the ROC analysis (AUC 0.889-0.914). The Leuven Score provided a sensitivity of 89.7% and specificity of 84.2% at its predefined cut-off point. A simplified Leuven Score showed similar diagnostic accuracy to that of the original score. The Besançon Scores showed limited specificity at their predefined cut-off points (i.e. 47.4% and 63.2%), while ROC analysis suggested that substantially higher cut-off points are needed for these scores. The Heidelberg and Saint-Etienne Algorithms demonstrated high sensitivity, but lower specificity (i.e. 78.9% and 42.1%, respectively) for PMR. Female sex and presence of large-vessel vasculitis were associated with lower FDG-PET/CT scores in patients with PMR. CONCLUSION: The Leuven Score showed the highest diagnostic utility for PMR. A modified, concise version of the Leuven Score provided similar diagnostic accuracy to that of the original score.

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.

Ultrasonographic Halo Score in giant cell arteritis: association with intimal hyperplasia and ischaemic sight loss.

OBJECTIVES: We investigated the relationship between the ultrasonographic Halo Score and temporal artery biopsy (TAB) findings in GCA. METHODS: This is a prospective study including 90 patients suspected of having GCA. Ultrasonography of temporal/axillary arteries and a TAB were obtained in all patients at baseline. An experienced pathologist evaluated whether TAB findings were consistent with GCA, and whether transmural inflammation, giant cells and intimal hyperplasia were present. Ultrasonographic Halo Scores were determined. Receiver operating characteristic analysis was performed. RESULTS: Twenty-seven patients had a positive TAB, while 32 patients with a negative TAB received a clinical diagnosis of GCA after 6 months of follow-up. Patients with a positive TAB showed higher Halo Scores than patients with a negative TAB. The presence of intimal hyperplasia in the biopsy, rather than the presence of transmural inflammation or giant cells, was associated with elevated Halo Scores in patients with GCA. The Halo Score discriminated well between TAB-positive patients with and without intimal hyperplasia, as indicated by an area under the curve of 0.82 in the receiver operating characteristic analysis. Patients with a positive TAB and intimal hyperplasia more frequently presented with ocular ischaemia (40%) than the other patients with GCA (13-14%). CONCLUSION: The ultrasonographic Halo Score may help to identify a subset of GCA patients with intimal hyperplasia, a TAB feature associated with ischaemic sight loss.

Novel ultrasonographic Halo Score for giant cell arteritis: assessment of diagnostic accuracy and association with ocular ischaemia.

OBJECTIVES: Ultrasound of temporal and axillary arteries may reveal vessel wall inflammation in patients with giant cell arteritis (GCA). We developed a ultrasound scoring system to quantify the extent of vascular inflammation and investigated its diagnostic accuracy and association with clinical factors in GCA. METHODS: This is a prospective study including 89 patients suspected of having GCA, of whom 58 had a confirmed clinical diagnosis of GCA after 6 months follow-up. All patients underwent bilateral ultrasound examination of the three temporal artery (TA) segments and axillary arteries, prior to TA biopsy. The extent of vascular inflammation was quantified by (1) counting the number of TA segments and axillary arteries with a halo and (2) calculating a composite Halo Score that also incorporated the thickness of each halo. RESULTS: Halo counts and Halo Scores showed moderate diagnostic accuracy for a clinical diagnosis of GCA. They correlated positively with systemic inflammation. When compared with the halo count, the Halo Score correlated better with C-reactive protein (CRP) levels and allowed to firmly establish the diagnosis of GCA in more patients. Higher halo counts and Halo Scores were associated with a higher risk of ocular ischaemia. They allowed to identify subgroups of patients with low risk (≤5%) and high risk of ocular ischaemia (>30%). CONCLUSIONS: Ultrasound halo scoring allows to quantify the extent of vascular inflammation in GCA. Extensive vascular inflammation on ultrasound may provide strong diagnostic confirmation and associates with ocular ischaemia in GCA.

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.

Markers of angiogenesis and macrophage products for predicting disease course and monitoring vascular inflammation in giant cell arteritis.

OBJECTIVE: GCA, a systemic vasculitis, is characterized by an IL-6-dependent acute-phase response. This response is typically suppressed by treatment rendering CRP/ESR unreliable for monitoring vascular inflammation. Also, there are no accurate biomarkers predicting a non-favourable disease course. Here we investigated macrophage products and markers of angiogenesis as biomarkers for prognosis and monitoring of vascular inflammation. METHODS: Forty-one newly diagnosed, glucocorticoid-naive GCA patients were prospectively followed for relapses and glucocorticoid requirement for a median of 30 months (range 0-71). Serum markers at baseline and during follow-up were compared with 33 age-matched healthy controls and 13 infection controls. Concentrations of IL-6, serum amyloid A, soluble CD163, calprotectin, YKL-40, VEGF, angiopoietin-1 and -2 and sTie2 were determined by ELISA/Luminex assay. RESULTS: Serum concentrations of all markers, but not angiopoietin-1, were elevated in GCA patients at baseline when compared with healthy controls. High VEGF (P = 0.0025) and angiopoietin-1 (P = 0.0174) and low YKL-40 (P = 0.0369) levels at baseline were predictive of a short time to glucocorticoid-free remission. Elevated angiopoietin-2 levels were associated with an imminent relapse during treatment (P < 0.05). IL-6 correlated strongly with acute-phase markers and soluble CD163 but not with markers of angiogenesis, YKL-40 or calprotectin. Glucocorticoid treatment down-modulated all markers except for calprotectin and YKL-40. Tissue expression of markers in temporal arteries was confirmed. CONCLUSION: Markers of angiogenesis at baseline and during treatment predict GCA disease course, suggesting utility in patient stratification for glucocorticoid-sparing therapy. Calprotectin and YKL-40 are candidate markers for monitoring vessel wall inflammation.

Enhanced expression of PD-1 and other activation markers by CD4+ T cells of young but not old patients with metastatic melanoma.

The biological behavior of melanoma is unfavorable in the elderly when compared to young subjects. We hypothesized that differences in T-cell responses might underlie the distinct behavior of melanoma in young and old melanoma patients. Therefore, we investigated the circulating T-cell compartment of 34 patients with metastatic melanoma and 42 controls, which were classified as either young or old. Absolute numbers of CD4+ T cells were decreased in young and old melanoma patients when compared to the age-matched control groups. Percentages of naive and memory CD4+ T cells were not different when comparing old melanoma patients to age-matched controls. Percentages of memory CD4+ T cells tended to be increased in young melanoma patients compared to young controls. Proportions of naive CD4+ T cells were lower in young patients than in age-matched controls, and actually comparable to those in old patients and controls. This was accompanied with increased percentages of memory CD4+ T cells expressing HLA-DR, Ki-67, and PD-1 in young melanoma patients in comparison to the age-matched controls, but not in old patients. Proportions of CD45RA-FOXP3high memory regulatory T cells were increased in young and old melanoma patients when compared to their age-matched controls, whereas those of CD45RA+FOXP3low naive regulatory T cells were similar. We observed no clear modulation of the circulating CD8+ T-cell repertoire in melanoma patients. In conclusion, we show that CD4+ T cells of young melanoma patients show signs of activation, whereas these signs are less clear in CD4+ T cells of old patients.

Towards precision medicine in ANCA-associated vasculitis.

ANCA-associated vasculitis (AAV) is characterized by inflammation and destruction of small and medium-sized vessels. Current management strategies for AAV have been validated in large groups of patients. However, recent insights indicate that distinct patient subsets may actually exist within AAV, thereby justifying the development of more personalized treatment strategies. In this review, we discuss current evidence for a better classification of AAV based on ANCA type. We describe how thus defined categories of AAV patients may differ in genetic background, clinical presentation, immune pathology, response to treatment and disease outcome. We also explore how these insights may provide a rationale for targeted treatments in different categories of AAV patients. Finally, we provide recommendations on how to further establish precision medicine in AAV.

Changes in peripheral immune cell numbers and functions in octogenarian walkers - an acute exercise study.

BACKGROUND: Age-related changes of the immune system, termed immunosenescence, may underlie the increased risk of infections and morbidity in the elderly. Little is known about the effects of acute exercise on peripheral immune parameters in octogenarians. Therefore, we investigated acute exercise-induced changes in phenotype and function of the immune system in octogenarians participating in the 2013 edition of the Nijmegen Four Days Marches. Blood sampling was performed at baseline and immediately after 4 days of the walking exercise (30 km/day). A comprehensive set of adaptive and innate immune traits were enumerated and analyzed by flow-cytometry. Peripheral blood mononuclear cells, isolated before and after walking were stimulated with LPS and supernatants were analysed for IL-1ß, IL-6, IL-8 and TNF-α concentrations by ELISA. CMV serostatus was determined by ELISA. RESULTS: The walking exercise induced a clear leucocytosis with numerical increases of granulocytes, monocytes and lymphocytes. These exercise-induced changes were most profound in CMV seropositive subjects. Within lymphocytes, numerical increases of particularly CD4+ T cells were noted. Further T cell differentiation analysis revealed profound increases of naïve CD4+ T cells, including naïve Treg. Significant increases were also noted for CD4+ memory T cell subsets. In contrast, only slight increases in naïve and memory CD8+ T cell subsets were detected. Exercise did not affect markers of immune exhaustion in memory T cell subsets. NK cells demonstrated a numerical decline and a change in cellular composition with a selective decrease of the mature CD56dim NK cells. The latter was seen in CMV seronegative subjects only. Also, a higher IL-6 and IL-8 production capacity of LPS-stimulated PBMC was seen after walking. CONCLUSION: In this exceptional cohort of octogenarian walkers, acute exercise induced changes in immune cell numbers and functions. A clear response of CD4+ T cells, rather than CD8+ T cells or NK cells was noted. Remarkably, the response to exercise within the CD4+ T cell compartment was dominated by naïve CD4+ subsets.