Publications by authors named "Kornelis S M van der Geest"

47 Publications

Dr. Conway et al reply.

J Rheumatol 2022 Jan;49(1):120-121

Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

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http://dx.doi.org/10.3899/jrheum.2100913DOI Listing
January 2022

Semi-Quantitative and Quantitative [F]FDG-PET/CT Indices for Diagnosing Large Vessel Vasculitis: A Critical Review.

Diagnostics (Basel) 2021 Dec 14;11(12). Epub 2021 Dec 14.

Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.

To confirm the diagnosis of large vessel vasculitis (LVV) with high accuracy, one of the recommended imaging techniques is [F]Fluoro-2-deoxy-d-glucose positron emission tomography with computed tomography ([F]FDG-PET/CT). Visual assessment of [F]FDG uptake in the arterial wall compared to liver uptake is the mainstay for diagnosing LVV in routine clinical practice. To date, there is no consensus on the preferred semi-quantitative or quantitative parameter for diagnosing LVV. The aim of this review is to critically update the knowledge on the available evidence of semi-quantitative and quantitative [F]FDG uptake parameters for diagnosing LVV and to provide future directions for methodological standardization and research.
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http://dx.doi.org/10.3390/diagnostics11122355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700698PMC
December 2021

Toward Reliable Uptake Metrics in Large Vessel Vasculitis Studies.

Diagnostics (Basel) 2021 Oct 26;11(11). Epub 2021 Oct 26.

Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

The aim of this study is to investigate the influence of sex, age, fat mass, fasting blood glucose level (FBGL), and estimated glomerular filtration rate (eGFR) on blood pool activity in patients with large vessel vasculitis (LVV). Blood pool activity was measured in the superior caval vein using mean, maximum, and peak standardized uptake values corrected for body weight (SUVs) and lean body mass (SULs) in 41 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scans of LVV patients. Sex influence on the blood pool activity was assessed with t-tests, while linear correlation analyses were used for age, fat mass, FBGL, and eGFR. Significantly higher SUVs were found in women compared with men, whereas SULs were similar between sexes. In addition, higher fat mass was associated with increased SUVs (r = 0.56 to 0.65; all < 0.001) in the blood pool, but no correlations were found between SULs and fat mass (r = -0.25 to -0.15; all > 0.05). Lower eGFR was associated with a higher FDG blood pool activity for all uptake values. In FDG-PET/CT studies with LVV patients, we recommend using SUL over SUV, while caution is advised in interpreting SUV and SUL measures when patients have impaired kidney function.
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http://dx.doi.org/10.3390/diagnostics11111986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617769PMC
October 2021

Functionally Heterogenous Macrophage Subsets in the Pathogenesis of Giant Cell Arteritis: Novel Targets for Disease Monitoring and Treatment.

J Clin Med 2021 Oct 26;10(21). Epub 2021 Oct 26.

Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

Giant cell arteritis (GCA) is a granulomatous large-vessel vasculitis that affects adults above 50 years of age. In GCA, circulating monocytes are recruited to the inflamed arteries. With cues from the vascular microenvironment, they differentiate into macrophages and play important roles in the pathogenesis of GCA via pro-inflammatory cytokine production and vascular remodeling. However, a deeper understanding of macrophage heterogeneity in GCA pathogenesis is needed to assist the development of novel diagnostic tools and targeted therapies. Here, we review the current knowledge on macrophage heterogeneity and diverse functions of macrophage subsets in the pathogenesis of GCA. We next discuss the possibility to exploit their heterogeneity as a source of novel biomarkers and as targets for nuclear imaging. Finally, we discuss novel macrophage-targeted therapies and future directions for targeting these cells in GCA.
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http://dx.doi.org/10.3390/jcm10214958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585092PMC
October 2021

Dr. Conway et al reply.

J Rheumatol 2021 Oct 1. Epub 2021 Oct 1.

Department of Rheumatology, St James's Hospital, Dublin, Ireland; Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, UK; Centre for Inflammation and Tissue Repair, UCL Respiratory, Division of Medicine, University College London, and Department of Rheumatology, University College London Hospital (UCLH) NHS Trust, London, UK; Medical College of Wisconsin, Milwaukee, Wisconsin, USA; University of Queensland Faculty of Medicine, Brisbane, Australia; Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. The authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. S.L. Mackie, Leeds Institute of Rheumatic and Musculoskeletal Medicine, Chapel Allerton Hospital, Leeds LS7 4SA, UK. Email:

We thank Sauret et al for their interest in our systematic literature review that explored potential diagnostic confusion between giant cell arteritis (GCA) and the coronavirus disease 2019 (COVID-19). This was a particularly important consideration during the early months of the COVID-19 pandemic, when community testing for SARS-CoV-2 was limited and diagnostic tests for GCA were restricted or unavailable due to redeployment of staff..
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http://dx.doi.org/10.3899/jrheum.210913DOI Listing
October 2021

Role of the halo sign in the assessment of giant cell arteritis: a systematic review and meta-analysis.

Rheumatol Adv Pract 2021 19;5(3):rkab059. Epub 2021 Aug 19.

Department of Rheumatology, Southend University Hospital, Mid and South Essex University Hospital Groups, Westcliff-On-Sea.

Objectives: This systematic review and meta-analysis aimed to evaluate the diagnostic value of the halo sign in the assessment of GCA.

Methods: A systematic literature review was performed using MEDLINE, EMBASE and Cochrane central register databases up to August 2020. Studies informing on the sensitivity and specificity of the US halo sign for GCA (index test) were selected. Studies with a minimum of five participants were included. Study articles using clinical criteria, imaging such as PET-CT and/or temporal artery biopsy (TAB) as the reference standards were selected. Meta-analysis was conducted with a bivariate model.

Results: The initial search yielded 4023 studies. Twenty-three studies (patients  = 2711) met the inclusion criteria. Prospective (11 studies) and retrospective (12 studies) studies in academic and non-academic centres were included. Using clinical diagnosis as the standard (18 studies) yielded a pooled sensitivity of 67% (95% CI: 51, 80) and a specificity of 95% (95% CI: 89, 98%). This gave a positive and negative likelihood ratio for the diagnosis of GCA of 14.2 (95% CI: 5.7, 35.5) and 0.375 (95% CI: 0.22, 0.54), respectively. Using TAB as the standard (15 studies) yielded a pooled sensitivity of 63% (95% CI: 50, 75) and a specificity of 90% (95% CI: 81, 95).

Conclusion: The US halo sign is a sensitive and specific approach for GCA assessment and plays a pivotal role in diagnosis of GCA in routine clinical practice.

Registration: PROSPERO 2020 CRD42020202179.
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http://dx.doi.org/10.1093/rap/rkab059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421813PMC
August 2021

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

J Autoimmun 2021 09 6;123:102684. Epub 2021 Jul 6.

Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, the Netherlands. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jaut.2021.102684DOI Listing
September 2021

CD27CD38CD21 B-Cells Are Increased in Axial Spondyloarthritis.

Front Immunol 2021 8;12:686273. Epub 2021 Jun 8.

Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

B-cells have received little attention in axial spondyloarthritis (axSpA) and for this reason their role in pathogenesis remains unclear. However, there are indications that B-cells may be involved in the disease process. Our objective was to obtain insights into the composition of the peripheral B-cell compartment of axSpA patients compared to healthy donors (HD) and patients with primary Sjögren's syndrome (pSS), a typical B-cell-associated autoimmune disease. Special emphasis was given to CD27-negative B-cells expressing low levels of CD21 (CD21 B-cells), since this subset is implicated in autoimmune diseases with strong involvement of B-cells. Transitional B-cells (CD38) were excluded from the analysis of the CD27CD21 B-cell compartment. This study included 45 axSpA patients, 20 pSS patients and 30 HDs. Intriguingly, compared to HDs the frequency of CD27CD38CD21 B-cells was significantly elevated in both axSpA and pSS patients (P<0.0001 for both comparisons). The frequency of CD27CD38CD21 B-cells expressing the activation-induced immune markers T-bet and CD11c was decreased in axSpA patients compared to HDs. A higher proportion of CD27CD38CD21 B-cells expressed the chemokine receptor CXCR3 in axSpA compared to HDs, suggestive for active involvement of these cells in an inflammatory process. The frequency of CD27CD38CD21 B-cells in axSpA patients correlated positively with age and erythrocyte sedimentation rate. Furthermore, axSpA patients with extra-skeletal manifestations (ESM) showed increased frequencies of CD27CD38CD21 B-cells compared to patients without ESM. In conclusion, our findings are suggestive of active B-cell involvement in the pathogenesis of axSpA, against prevailing dogma.
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http://dx.doi.org/10.3389/fimmu.2021.686273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217653PMC
October 2021

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

Rheumatology (Oxford) 2021 Jun 12. Epub 2021 Jun 12.

Medical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Objectives: To compare and validate the diagnostic accuracy of FDG-PET/CT scores for polymyalgia rheumatica (PMR); and to explore their relationship 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 (one by Henckaerts, two by Sondag) and two algorithms (by Flaus and Owen) 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 to 0.914). The Henckaerts Score provided a sensitivity of 89.7% and specificity of 84.2% at its predefined cut-off point. A simplified Henckaerts Score showed similar diagnostic accuracy as the original score. The Sondag 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 Owen and Flaus 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 Henckaerts Score showed the highest diagnostic utility for PMR. A modified, concise version of the Henckaerts Score provided similar diagnostic accuracy as the original score.
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http://dx.doi.org/10.1093/rheumatology/keab483DOI Listing
June 2021

A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis: Implication of the YKL-40/Interleukin-13 Receptor α2 Axis.

Arthritis Rheumatol 2021 12 1;73(12):2327-2337. Epub 2021 Nov 1.

University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

Objective: Macrophages mediate inflammation, angiogenesis, and tissue destruction in giant cell arteritis (GCA). Serum levels of the macrophage-associated protein YKL-40 (chitinase 3-like protein 1), previously linked to angiogenesis and tissue remodeling, remain elevated in GCA despite glucocorticoid treatment. This study was undertaken to investigate the contribution of YKL-40 to vasculopathy in GCA.

Methods: Immunohistochemistry was performed on GCA temporal artery biopsy specimens (n = 12) and aortas (n = 10) for detection of YKL-40, its receptor interleukin-13 receptor α2 (IL-13Rα2), macrophage markers PU.1 and CD206, and the tissue-destructive protein matrix metalloproteinase 9 (MMP-9). Ten noninflamed temporal artery biopsy specimens served as controls. In vitro experiments with granulocyte-macrophage colony-stimulating factor (GM-CSF)- or macrophage colony-stimulating factor (M-CSF)-skewed monocyte-derived macrophages were conducted to study the dynamics of YKL-40 production. Next, small interfering RNA-mediated knockdown of YKL-40 in GM-CSF-skewed macrophages was performed to study its effect on MMP-9 production. Finally, the angiogenic potential of YKL-40 was investigated by tube formation experiments using human microvascular endothelial cells (HMVECs).

Results: YKL-40 was abundantly expressed by a CD206+MMP-9+ macrophage subset in inflamed temporal arteries and aortas. GM-CSF-skewed macrophages from GCA patients, but not healthy controls, released significantly higher levels of YKL-40 compared to M-CSF-skewed macrophages (P = 0.039). In inflamed temporal arteries, IL-13Rα2 was expressed by macrophages and endothelial cells. Functionally, knockdown of YKL-40 led to a 10-50% reduction in MMP-9 production by macrophages, whereas exposure of HMVECS to YKL-40 led to significantly increased tube formation.

Conclusion: In GCA, a GM-CSF-skewed, CD206+MMP-9+ macrophage subset expresses high levels of YKL-40 which may stimulate tissue destruction and angiogenesis through IL-13Rα2 signaling. Targeting YKL-40 or GM-CSF may inhibit macrophages that are currently insufficiently suppressed by glucocorticoids.
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http://dx.doi.org/10.1002/art.41887DOI Listing
December 2021

Therapy response evaluation in large-vessel vasculitis: a new role for [18F]FDG-PET/CT?

Rheumatology (Oxford) 2021 08;60(8):3494-3495

Vasculitis Expertise Centre Groningen, University of Groningen, Groningen, the Netherlands.

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http://dx.doi.org/10.1093/rheumatology/keab375DOI Listing
August 2021

CD8+ T Cells in GCA and GPA: Bystanders or Active Contributors?

Front Immunol 2021 18;12:654109. Epub 2021 Mar 18.

Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Vasculitis refers to inflammation of blood vessels and can cause a variety of serious complications depending on which vessels are affected. Two different forms of vasculitis are Giant Cell Arteritis (GCA) and Granulomatosis with Polyangiitis (GPA). GCA is the most common form of vasculitis in adults affecting the large arteries and can lead to visual impairment and development of aneurysms. GPA affects small- and medium-sized blood vessels predominantly in the lungs and kidneys resulting in organ failure. Both diseases can potentially be fatal. Although the pathogenesis of GCA and GPA are incompletely understood, a prominent role for CD4+ T cells has been implicated in both diseases. More recently, the role of CD8+ T cells has gained renewed interest. CD8+ T cells are important players in the adaptive immune response against intracellular microorganisms. After a general introduction on the different forms of vasculitis and their association with infections and CD8+ T cells, we review the current knowledge on CD8+ T-cell involvement in the immunopathogenesis of GCA and GPA focusing on phenotypic and functional features of circulating and lesional CD8+ T cells. Furthermore, we discuss to which extent aging is associated with CD8+ T-cell phenotype and function in GCA and GPA.
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http://dx.doi.org/10.3389/fimmu.2021.654109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015776PMC
September 2021

Clinical pathways for patients with giant cell arteritis during the COVID-19 pandemic: an international perspective.

Lancet Rheumatol 2021 Jan 8;3(1):e71-e82. Epub 2020 Dec 8.

Division of Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, NY, USA.

Giant cell arteritis, a common primary systemic vasculitis affecting older people, presents acutely as a medical emergency and requires rapid specialist assessment and treatment to prevent irreversible vision loss. Disruption of the health-care system caused by the COVID-19 pandemic exposed weak points in clinical pathways for diagnosis and treatment of giant cell arteritis, but has also permitted innovative solutions. The essential roles played by all professionals, including general practitioners and surgeons, in treating these patients have become evident. Patients must also be involved in the reshaping of clinical services. As an international group of authors involved in the care of patients with giant cell arteritis, we reflect in this Viewpoint on rapid service adaptations during the first peak of COVID-19, evaluate challenges, and consider implications for the future.
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http://dx.doi.org/10.1016/S2665-9913(20)30386-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834492PMC
January 2021

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

Rheumatology (Oxford) 2021 09;60(9):4361-4366

Department of Rheumatology.

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.
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http://dx.doi.org/10.1093/rheumatology/keaa806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410002PMC
September 2021

Giant Cell Arteritis and COVID-19: Similarities and Discriminators. A Systematic Literature Review.

J Rheumatol 2021 07 15;48(7):1053-1059. Epub 2020 Oct 15.

S.L. Mackie, Associate Clinical Professor and Honorary Consultant Rheumatologist, PhD, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Objective: To identify shared and distinct features of giant cell arteritis (GCA) and coronavirus disease 2019(COVID-19) to reduce diagnostic errors that could cause delays in correct treatment.

Methods: Two systematic literature reviews determined the frequency of clinical features of GCA and COVID-19 in published reports. Frequencies in each disease were summarized using medians and ranges.

Results: Headache was common in GCA but was also observed in COVID-19 (GCA 66%, COVID-19 10%). Jaw claudication or visual loss (43% and 26% in GCA, respectively) generally were not reported in COVID-19. Both diseases featured fatigue (GCA 38%, COVID-19 43%) and elevated inflammatory markers (C-reactive protein [CRP] elevated in 100% of GCA, 66% of COVID-19), but platelet count was elevated in 47% of GCA but only 4% of COVID-19 cases. Cough and fever were commonly reported in COVID-19 and less frequently in GCA (cough, 63% for COVID-19 vs 12% for GCA; fever, 83% for COVID-19 vs 27% for GCA). Gastrointestinal upset was occasionally reported in COVID-19 (8%), rarely in GCA (4%). Lymphopenia was more common in COVID-19 than GCA (53% in COVID-19, 2% in GCA). Alteration of smell and taste have been described in GCA but their frequency is unclear.

Conclusion: Overlapping features of GCA and COVID-19 include headache, fever, elevated CRP and cough. Jaw claudication, visual loss, platelet count and lymphocyte count may be more discriminatory. Physicians should be aware of the possibility of diagnostic confusion. We have designed a simple checklist to aid evidence-based evaluation of patients with suspected GCA.
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http://dx.doi.org/10.3899/jrheum.200766DOI Listing
July 2021

Management of immune checkpoint inhibitor-induced polymyalgia rheumatica.

Ann Rheum Dis 2020 Sep 4. Epub 2020 Sep 4.

Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1136/annrheumdis-2020-218276DOI Listing
September 2020

Halo score (temporal artery, its branches and axillary artery) as a diagnostic, prognostic and disease monitoring tool for Giant Cell Arteritis (GCA).

BMC Rheumatol 2020 18;4:35. Epub 2020 Aug 18.

Rheumatology, Mid and South Essex University Hospital Groups, Southend University Hospital, Westcliff-On-Sea, Essex, UK.

Background: Giant cell arteritis (GCA) is a common large vessel vasculitis of the elderly, often associated with sight loss. Glucocorticoids (GC remain the mainstay of treatment, although biologic treatments have been approved. Biomarkers predicting disease severity, relapse rates and damage are lacking in GCA.EULAR recommends ultrasound (US) as the first investigation for suspected GCA. The cardinal US finding, a non-compressible halo, is currently categorised as either negative or positive. However, the extent and severity of this finding may vary.In this study, we hypothesise whether the extent and severity of the halo sign [calculated as a single composite Halo score (HS)] of temporal and axillary arteries may be of diagnostic, prognostic and monitoring importance; whether baseline HS is linked to disease outcomes, relapses and damage; whether HS can stratify GCA patients for individual treatment needs; whether HS can function as an objective monitoring tool during follow up.

Methods: This is a prospective, observational study. Suspected GCA Participants will be selected from the GCA FTC at the participating centres in the UK. Informed consent will be obtained, and patients managed as part of standard care. Patients with GCA will have HS (temporal and axillary arteries) measured at baseline and months 1,3,6 and 12 long with routine clinical assessments, blood sampling and patient-reported outcomes (EQ5D). Non-GCA patients will be discharged back to the referral team and will have a telephone interview in 6 months.We aim to recruit 272 suspected GCA referrals which should yield 68 patients (25% of referrals) with confirmed GCA. The recruitment will be completed in 1 year with an estimated total study period of 24 months.

Discussion: The identification of prognostic factors in GCA is both timely and needed. A prognostic marker, such as the HS, could help to stratify GCA patients for an appropriate treatment regimen. Tocilizumab, an IL-6R blocking agent, switches off the acute phase response (C-Reactive Protein), making it difficult to measure the disease activity. Therefore, an independent HS, and changes in that score during treatment and follow-up, maybe a more objective measure of response compare to patient-reported symptoms and clinical assessment alone.
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http://dx.doi.org/10.1186/s41927-020-00136-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433165PMC
August 2020

Diagnostic Accuracy of Symptoms, Physical Signs, and Laboratory Tests for Giant Cell Arteritis: A Systematic Review and Meta-analysis.

JAMA Intern Med 2020 10;180(10):1295-1304

Leeds Institute of Rheumatic and Musculoskeletal Medicine, NIHR (National Institute for Health Research) Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS (National Health Service) Trust, University of Leeds, Leeds, United Kingdom.

Importance: Current clinical guidelines recommend selecting diagnostic tests for giant cell arteritis (GCA) based on pretest probability that the disease is present, but how pretest probability should be estimated remains unclear.

Objective: To evaluate the diagnostic accuracy of symptoms, physical signs, and laboratory tests for suspected GCA.

Data Sources: PubMed, EMBASE, and the Cochrane Database of Systematic Reviews were searched from November 1940 through April 5, 2020.

Study Selection: Trials and observational studies describing patients with suspected GCA, using an appropriate reference standard for GCA (temporal artery biopsy, imaging test, or clinical diagnosis), and with available data for at least 1 symptom, physical sign, or laboratory test.

Data Extraction And Synthesis: Screening, full text review, quality assessment, and data extraction by 2 investigators. Diagnostic test meta-analysis used a bivariate model.

Main Outcome(s) And Measures: Diagnostic accuracy parameters, including positive and negative likelihood ratios (LRs).

Results: In 68 unique studies (14 037 unique patients with suspected GCA; of 7798 patients with sex reported, 5193 were women [66.6%]), findings associated with a diagnosis of GCA included limb claudication (positive LR, 6.01; 95% CI, 1.38-26.16), jaw claudication (positive LR, 4.90; 95% CI, 3.74-6.41), temporal artery thickening (positive LR, 4.70; 95% CI, 2.65-8.33), temporal artery loss of pulse (positive LR, 3.25; 95% CI, 2.49-4.23), platelet count of greater than 400 × 103/μL (positive LR, 3.75; 95% CI, 2.12-6.64), temporal tenderness (positive LR, 3.14; 95% CI, 1.14-8.65), and erythrocyte sedimentation rate greater than 100 mm/h (positive LR, 3.11; 95% CI, 1.43-6.78). Findings that were associated with absence of GCA included the absence of erythrocyte sedimentation rate of greater than 40 mm/h (negative LR, 0.18; 95% CI, 0.08-0.44), absence of C-reactive protein level of 2.5 mg/dL or more (negative LR, 0.38; 95% CI, 0.25-0.59), and absence of age over 70 years (negative LR, 0.48; 95% CI, 0.27-0.86).

Conclusions And Relevance: This study identifies the clinical and laboratory features that are most informative for a diagnosis of GCA, although no single feature was strong enough to confirm or refute the diagnosis if taken alone. Combinations of these symptoms might help direct further investigation, such as vascular imaging, temporal artery biopsy, or seeking evaluation for alternative diagnoses.
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http://dx.doi.org/10.1001/jamainternmed.2020.3050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432275PMC
October 2020

Response to: ''Halo Score': missing large vessel giant cell arteritis- do we need a modified 'Halo Score?'' by Chattopadhyay and Ghosh.

Ann Rheum Dis 2020 Jul 10. Epub 2020 Jul 10.

Rheumatology, Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea, UK.

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http://dx.doi.org/10.1136/annrheumdis-2020-218262DOI Listing
July 2020

Imaging in immune checkpoint inhibitor-induced polymyalgia rheumatica.

Ann Rheum Dis 2020 Apr 2. Epub 2020 Apr 2.

Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

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http://dx.doi.org/10.1136/annrheumdis-2020-217381DOI Listing
April 2020

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

Ann Rheum Dis 2020 03 3;79(3):393-399. Epub 2020 Jan 3.

Rheumatology, Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea, Essex, UK

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.
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http://dx.doi.org/10.1136/annrheumdis-2019-216343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034352PMC
March 2020

Leukocyte Dynamics Reveal a Persistent Myeloid Dominance in Giant Cell Arteritis and Polymyalgia Rheumatica.

Front Immunol 2019 22;10:1981. Epub 2019 Aug 22.

Vasculitis Expertise Centre Groningen, Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory diseases requiring long-term glucocorticoid treatment. Limited data on dynamics in leukocyte counts before, during and after treatment are available. Leukocyte counts were measured, as cellular markers of inflammation, at fixed time points in our prospectively studied cohort of pre-treatment glucocorticoid-naive GCA ( = 42) and PMR ( = 31) patients. Values were compared with age-matched healthy controls (HCs; = 51) and infection controls ( = 16). We report that before start of treatment monocyte and neutrophil counts were higher in GCA and PMR patients than in HCs, while NK- and B-cell counts were lower. C-reactive protein (CRP) levels correlated positively with monocyte counts in GCA, and negatively with B-cell and NK-cell counts in PMR. During glucocorticoid treatment, myeloid subsets remained elevated whereas lymphoid subsets tended to fluctuate. Interestingly, erythrocyte sedimentation rate (ESR) outperformed CRP as marker for relapses in GCA. We defined stable treatment-free remission groups in both GCA and PMR. GCA patients in treatment-free remission still demonstrated elevated monocytes, neutrophils, ESR, and platelets. PMR patients in treatment-free remission had normalized levels of inflammation markers, but did have elevated monocytes, lowered CD8+ T-cell counts and lowered NK-cell counts. Finally, we showed that low hemoglobin level was predictive for long-term GC treatment in PMR. Overall, leukocyte composition shifts toward the myeloid lineage in GCA and PMR. This myeloid profile, likely induced by effects of inflammation on hematopoietic stem cell differentiation, persisted during glucocorticoid treatment. Surprisingly, the myeloid profile was retained in treatment-free remission, which may reflect ongoing subclinical inflammation.
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http://dx.doi.org/10.3389/fimmu.2019.01981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714037PMC
September 2020

Decreased Expression of Negative Immune Checkpoint VISTA by CD4+ T Cells Facilitates T Helper 1, T Helper 17, and T Follicular Helper Lineage Differentiation in GCA.

Front Immunol 2019 16;10:1638. Epub 2019 Jul 16.

Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Loss of immune checkpoint (IC) Programmed Death-1 (PD-1) and PD-Ligand1 (PD-L1) expression has been implicated in the immunopathology of Giant Cell Arteritis (GCA). The contribution of the negative immune checkpoint V-domain Immunoglobulin-containing suppressor of T cell activation (VISTA) to GCA pathology has not yet been studied. The aim of our study was to investigate if expression of VISTA and other IC molecules by peripheral blood (PB) immune cells is modulated in GCA and at the site of vascular inflammation. In addition, we assessed the effect of VISTA-Ig engagement on CD4+ T helper (Th) lineage differentiation. To this end, frequencies of monocytes expressing CD80/86, PD-L1, PD-L2, and VISTA were determined in blood samples from 30 GCA patients and 18 matched healthy controls by flow cytometry. In parallel, frequencies of CD4+ cells expressing CD28, Cytotoxic T-Lymphocyte-associated antigen-4 (CTLA-4), PD-1, and VISTA were determined. Immunohistochemistry was employed to detect VISTA, PD-1, and PD-L1-expressing cells in temporal artery biopsies (TABs) diagnostic of GCA. Furthermore, the effect of VISTA-Ig on CD4+ Th lineage differentiation in patients and controls was determined. Our study shows that frequencies of CD80/CD86+ and VISTA+ monocytes were decreased in treated GCA patients only. Moreover, proportions of PD-1+ and VISTA+ Th cells were significantly decreased in GCA patients. Clear infiltration of VISTA+, PD1+, and PD-L1+ cells was seen in GCA TABs. Finally, VISTA-Ig engagement failed to suppress Th1, Th17, and Tfh lineage development in GCA. Our results indicate that decreased expression of VISTA may facilitate development of pathogenic Th1 and Th17 cells in GCA.
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http://dx.doi.org/10.3389/fimmu.2019.01638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646729PMC
October 2020

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

Rheumatology (Oxford) 2020 01;59(1):176-184

Vasculitis Expertise Center Groningen, Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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.
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http://dx.doi.org/10.1093/rheumatology/kez261DOI Listing
January 2020

Methotrexate in Giant Cell Arteritis Deserves a Second Chance - A High-dose Methotrexate Trial Is Needed.

J Rheumatol 2019 05;46(5):453-454

Department of Rheumatology and Clinical Immunology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, the Netherlands.

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http://dx.doi.org/10.3899/jrheum.181306DOI Listing
May 2019

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

Rheumatology (Oxford) 2019 Feb 25. Epub 2019 Feb 25.

Vasculitis Expertise Center Groningen, Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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.
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http://dx.doi.org/10.1093/rheumatology/kez034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649803PMC
February 2019

Impact of Aging on the Frequency, Phenotype, and Function of CD161-Expressing T Cells.

Front Immunol 2018 19;9:752. Epub 2018 Apr 19.

Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Immune-aging is associated with perturbed immune responses in the elderly. CD161-expressing T cells, i.e., the previously described subsets of CD161 CD4 T cells, CD161 CD8 T cells, and CD161 CD8 T cells, are highly functional, pro-inflammatory T cells. These CD161-expressing T cells are critical in immunity against microbes, while possibly contributing to autoimmune diseases. So far, little is known about the impact of aging on the frequency, phenotype, and function of these CD161-expressing T cells. In the current study, we investigated the impact of aging on CD161 CD4 T cells, CD161 CD8 T cells, and CD161 CD8 T cells in peripheral blood samples of 96 healthy subjects (age 20-84). Frequencies of CD161 CD4 T cells and CD161 CD8 T cells were stable with aging, whereas frequencies of CD161 CD8 T cells declined. Although CD161 CD8 T cells were mostly T cell receptor-Vα7.2 mucosal-associated invariant T cells, CD161 expressing CD4 and CD8 T cells showed a limited expression of markers for gamma-delta T cells or invariant natural killer (NK) T cells, in both young and old subjects. In essence, CD161-expressing T cells showed a similar memory phenotype in young and old subjects. The expression of the inhibitory NK receptor KLRG1 was decreased on CD161 CD4 T cells of old subjects, whereas the expression of other NK receptors by CD161-expressing T cells was unaltered with age. The expression of cytotoxic effector molecules was similar in CD161 and CD161 CD8 T cells of young and old subjects. The ability to produce pro-inflammatory cytokines was preserved in CD161 and CD161 CD8 T cells of old subjects. However, the percentages of IFN-γ and interleukin-17 cells were significantly lower in CD161 CD4 T cells of old individuals than those of young individuals. In addition, aging was associated with a decrease of nonclassic T helper 1 cells, as indicated by decreased percentages of CD161-expressing cells within the IFN-γ CD4 T cell compartment of old subjects. Taken together, aging is associated with a numerical decline of circulating CD161 CD8 T cells, as well as a decreased production of pro-inflammatory cytokines by CD161 CD4 T cells. These aging-associated changes could contribute to perturbed immunity in the elderly.
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http://dx.doi.org/10.3389/fimmu.2018.00752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917671PMC
June 2019

Review: What Is the Current Evidence for Disease Subsets in Giant Cell Arteritis?

Arthritis Rheumatol 2018 09 30;70(9):1366-1376. Epub 2018 Jul 30.

University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

Giant cell arteritis (GCA) is an autoimmune vasculitis affecting large and medium-sized arteries. Ample evidence indicates that GCA is a heterogeneous disease in terms of symptoms, immune pathology, and response to treatment. In the current review, we discuss the evidence for disease subsets in GCA. We describe clinical and immunologic characteristics that may impact the risk of cranial ischemic symptoms, relapse rates, and long-term glucocorticoid requirements in patients with GCA. In addition, we discuss both proven and putative immunologic targets for therapy in patients with GCA who have an unfavorable prognosis. Finally, we provide recommendations for further research on disease subsets in GCA.
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http://dx.doi.org/10.1002/art.40520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175064PMC
September 2018

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

Cancer Immunol Immunother 2018 06 15;67(6):925-933. Epub 2018 Mar 15.

Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.

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-FOXP3 memory regulatory T cells were increased in young and old melanoma patients when compared to their age-matched controls, whereas those of CD45RA+FOXP3 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.
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http://dx.doi.org/10.1007/s00262-018-2148-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951899PMC
June 2018

Decreased Immunity to Varicella Zoster Virus in Giant Cell Arteritis.

Front Immunol 2017 24;8:1377. Epub 2017 Oct 24.

Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands.

Introduction: Herpes zoster, which can have a major impact on quality of life, results from reactivation of a latent varicella zoster virus (VZV) infection. We hypothesized that giant cell arteritis (GCA) patients are at increased risk of herpes zoster because of treatment with high-dose glucocorticoids and advanced age. Aim of the study, therefore, was to determine cell-mediated and humoral immunity to VZV in patients with GCA, patients with closely related disease polymyalgia rheumatica (PMR; treated with lower doses of glucocorticoids) and healthy controls (HCs).

Methods: Cell-mediated immunity to VZV was determined by performing interferon-γ (IFNγ) enzyme-linked immunospot and intracellular cytokine flow cytometry measurements in 11 GCA and 15 PMR patients and in 26 age/sex-matched HCs. Immunoglobulin G antibodies to VZV glycoprotein (VZV-IgG) were measured in serum samples of 35 GCA and 26 PMR patients at different times of follow-up and in 58 age and sex-matched HCs by an enzyme-linked immunosorbent assay.

Results: The number of VZV-specific IFNγ spot-forming cells was significantly lower in GCA patients on treatment, than in age-matched HCs ( = 0.029), but was not different in PMR patients on treatment. Similar levels of VZV-IgG were found in GCA and PMR patients at baseline, compared to HCs.

Conclusion: The finding of a decreased cell-mediated immunity to VZV, known to be of great importance in defense to the virus, indicates an increased herpes zoster risk in GCA patients compared to an already at-risk elderly population. Herpes zoster vaccination is, therefore, of special importance in GCA patients, and would ideally be administered at time of diagnosis. Interestingly, as VZV was suggested to be the trigger in GCA pathogenesis, similar levels of VZV-IgG were found in GCA patients at time of diagnosis and age-matched HCs, indicating that GCA patients did not experience herpes zoster substantially more often in the months preceding diagnosis than controls.
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http://dx.doi.org/10.3389/fimmu.2017.01377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661055PMC
October 2017
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