Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

Impaired IL-6-induced JAK-STAT signaling in CD4+ T cells associates with longer treatment duration in giant cell arteritis.

INTRODUCTION: The IL-12-IFNγ-Th1 and the IL-6-IL-23-Th17 axes are considered the dominant pathogenic pathways in Giant Cell Arteritis (GCA). Both pathways signal via activation of the downstream JAK/STAT proteins. We hypothesized that phosphorylated STAT (pSTAT) signatures in circulating immune cells may aid to stratify GCA-patients for personalized treatment. METHODS: To investigate pSTAT expression, PBMCs from treatment-naive GCA-patients (n = 18), infection controls (INF, n = 11) and age-matched healthy controls (HC, n = 15) were stimulated in vitro with IL-6, IL-2, IL-10, IFN-γ, M-CSF or GM-CSF, and stained with CD3, CD4, CD19, CD45RO, pSTAT1, pSTAT3, pSTAT5 antibodies, and analyzed by flow cytometry. Serum IL-6, sIL-6-receptor and gp130 were measured by Luminex. The change in percentages of pSTAT3+CD4+T-cells was evaluated at diagnosis and at 3 months and 1-year of follow-up. Kaplan-Meier analyses was used to asses prognostic accuracy. RESULTS: Analysis of IL-6 stimulated immune cell subsets revealed a significant decrease in percentages of pSTAT3+CD4+T-cells of GCA-patients and INF-controls compared to HCs. Following patient stratification according to high (median>1.5 pg/mL) and low (median<1.5 pg/mL) IL-6 levels, we observed a reduction in the pSTAT3 response in GCA-patients with high serum IL-6. Percentages of pSTAT3+CD4+T-cells in patients with high serum IL-6 levels at diagnosis normalized after glucocorticoid (GC) treatment. Importantly, we found that patients with low percentages of pSTAT3+CD4+T-cells at baseline require longer GC-treatment. CONCLUSION: Overall, in GCA, the percentages of in vitro IL-6-induced pSTAT3+CD4+T-cells likely reflect prior in vivo exposure to high IL-6 and may serve as a prognostic marker for GC-treatment duration and may assist improving personalized treatment options in the future.

Altered Plasma Levels and Tissue Expression of Fibroblast Activation Protein Alpha in Giant Cell Arteritis.

OBJECTIVE: Giant cell arteritis (GCA) is characterized by granulomatous inflammation of the medium- and large-sized arteries accompanied by remodeling of the vessel wall. Fibroblast activation protein alpha (FAP) is a serine protease that promotes both inflammation and fibrosis. Here, we investigated the plasma levels and vascular expression of FAP in GCA. METHODS: Plasma FAP levels were measured with enzyme-linked immunosorbent assay in treatment-naive patients with GCA (n = 60) and polymyalgia rheumatica (PMR) (n = 63) compared with age- and sex-matched healthy controls (HCs) (n = 42) and during follow-up, including treatment-free remission (TFR). Inflamed temporal artery biopsies (TABs) of patients with GCA (n = 9), noninflamed TABs (n = 14), and aorta samples from GCA-related (n = 9) and atherosclerosis-related aneurysm (n = 11) were stained for FAP using immunohistochemistry. Immunofluorescence staining was performed for fibroblasts (CD90), macrophages (CD68/CD206/folate receptor beta), vascular smooth muscle cells (desmin), myofibroblasts (α-smooth muscle actin), interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9). RESULTS: Baseline plasma FAP levels were significantly lower in patients with GCA compared with patients with PMR and HCs and inversely correlated with systemic markers of inflammation and angiogenesis. FAP levels decreased even further at 3 months on remission in patients with GCA and gradually increased to the level of HCs in TFR. FAP expression was increased in inflamed TABs and aorta of patients with GCA compared with control tissues. FAP was abundantly expressed in fibroblasts and macrophages. Some of the FAP+ fibroblasts expressed IL-6 and MMP-9. CONCLUSION: FAP expression in GCA is clearly modulated both in plasma and in vessels. FAP may be involved in the inflammatory and remodeling processes in GCA and have utility as a target for imaging and therapeutic intervention.

Effects of ageing and frailty on circulating monocyte and dendritic cell subsets.

Ageing is associated with dysregulated immune responses, resulting in impaired resilience against infections and low-grade inflammation known as inflammageing. Frailty is a measurable condition in older adults characterized by decreased health and physical impairment. Dendritic cells (DCs) and monocytes play a crucial role in initiating and steering immune responses. To assess whether their frequencies and phenotypes in the blood are affected by ageing or frailty, we performed a flow cytometry study on monocyte and DC subsets in an immune ageing cohort. We included (n = 15 in each group) healthy young controls (HYC, median age 29 years), healthy older controls (HOC, 73 years) and Frail older controls (76 years). Monocyte subsets (classical, intermediate, non-classical) were identified by CD14 and CD16 expression, and DC subsets (conventional (c)DC1, cDC2, plasmacytoid (p)DC) by CD11c, CD1c, CD141 and CD303 expression. All subsets were checked for TLR2, TLR4, HLA-DR, CD86, PDL1, CCR7 and CD40 expression. We observed a lower proportion of pDCs in HOC compared to HYC. Additionally, we found higher expression of activation markers on classical and intermediate monocytes and on cDC2 in HOC compared to HYC. Frail participants had a higher expression of CD40 on classical and non-classical monocytes compared to the HOC group. We document a substantial effect of ageing on monocytes and DCs. Reduced pDCs in older people may underlie their impaired ability to counter viral infections, whereas enhanced expression of activation markers could indicate a state of inflammageing. Future studies could elucidate the functional consequences of CD40 upregulation with frailty.

Humoral SARS-CoV-2 Vaccine Responses in Patients With Giant Cell Arteritis and Polymyalgia Rheumatica: Decay After Primary Vaccination and Effects of the Booster.

OBJECTIVE: Vaccination remains essential in preventing morbidity of SARS-CoV-2 infections. We previously showed that >10 mg/day of prednisolone and methotrexate was associated with reduced antibody concentrations after primary vaccination in patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). This follow-up study was undertaken to measure the decay of antibody concentrations and the immunogenicity of SARS-CoV-2 booster vaccination. METHODS: Patients with GCA/PMR included in the primary vaccination (BNT162b2 [Pfizer-BioNTech] or ChAdOx1 [Oxford/AstraZeneca]) study were asked again to donate blood samples 6 months after primary vaccination (n = 24) and 1 month after booster vaccination (n = 46, BNT162b2 or mRNA1273). Data were compared to those of age-, sex-, and vaccine-matched controls (n = 58 and n = 42, respectively). Multiple linear regression was performed with post-booster antibody concentrations as dependent variable and post-primary vaccination antibodies, prednisolone >10mg/day, and methotrexate use as predicting variables. RESULTS: Antibody concentrations decreased faster over time in GCA/PMR patients than in controls, which was associated with prednisolone treatment during primary vaccination. Post-booster antibody concentrations were comparable between patients and controls. Antibody concentrations post primary vaccination, but not treatment during booster vaccination, were predictive for antibody concentrations post booster vaccination. CONCLUSION: These results indicate that the decay of humoral immunity after primary vaccination is associated with prednisolone treatment, whereas the subsequent increase after booster vaccination, was not. Patients with low antibody concentrations following primary vaccination remained at an immunogenic disadvantage after a single booster vaccination. This longitudinal study in GCA/PMR patients stresses the importance of repeated booster vaccination for patients with poor responses to primary vaccination.

Frailty is related to serum inflammageing markers: results from the VITAL study.

Frailty describes an age-associated state in individuals with an increased vulnerability and less resilience against adverse outcomes. To score frailty, studies have employed the questionnaires, such as the SF-36 and EQ-5D-3L, or the Frailty Index, a composite score based on deficit accumulation. Furthermore, ageing of the immune system is often accompanied by a state of low-grade inflammation (inflammageing). Here, we aimed to associate 29 circulating markers of inflammageing with frailty measures in a prospective cohort study to understand the mechanisms underlying ageing.Frailty measures and inflammageing markers were assessed in 317 participants aged 25-90. We determined four different measures of frailty: the Frailty Index based on 31 deficits, the EQ-5D-3L and two physical domains of the SF-36. Serum/plasma levels of inflammageing markers and CMV/EBV seropositivity were measured using different techniques: Quanterix, Luminex or ELISA.All four measures of frailty strongly correlated with age and BMI. Nineteen biomarkers correlated with age, some in a linear fashion (IL-6, YKL-40), some only in the oldest age brackets (CRP), and some increased at younger ages and then plateaued (CCL2, sIL-6R). After correcting for age, biomarkers, such as IL-6, CRP, IL-1RA, YKL-40 and elastase, were associated with frailty. When corrected for BMI, the number of associations reduced further.In conclusion, inflammageing markers, particularly markers reflecting innate immune activation, are related to frailty. These findings indicate that health decline and the accumulation of deficits with age is accompanied with a low-grade inflammation which can be detected by specific inflammatory markers.

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.

Aberrant phenotype of circulating antigen presenting cells in giant cell arteritis and polymyalgia rheumatica.

Background: Giant Cell Arteritis (GCA) and Polymyalgia Rheumatica (PMR) are overlapping inflammatory diseases. Antigen-presenting cells (APCs), including monocytes and dendritic cells (DCs), are main contributors to the immunopathology of GCA and PMR. However, little is known about APC phenotypes in the peripheral blood at the time of GCA/PMR diagnosis. Methods: APCs among peripheral blood mononuclear cells (PBMCs) of treatment-naive GCA and PMR patients were compared to those in age- and sex-matched healthy controls (HCs) using flow cytometry (n=15 in each group). We identified three monocyte subsets, and three DC subsets: plasmacytoid DCs (pDCs), CD141+ conventional DCs (cDC1) and CD1c+ conventional DCs (cDC2). Each of these subsets was analyzed for expression of pattern recognition receptors (TLR2, TLR4), immune checkpoints (CD86, PDL1, CD40) and activation markers (HLA-DR, CD11c). Results: t-SNE plots revealed a differential clustering of APCs between GCA/PMR and HCs. Further analyses showed shifts in monocyte subsets and a lower proportion of the small population of cDC1 cells in GCA/PMR, whereas cDC2 proportions correlated negatively with CRP (r=-0.52). Classical monocytes of GCA/PMR patients show reduced expression of TLR2, HLA-DR, CD11c, which was in contrast to non-classical monocytes that showed higher marker expression. Additionally, single cell RNA sequencing in GCA patients identified a number of differentially expressed genes related to inflammation and metabolism in APCs. Conclusion: Circulating non-classical monocytes display an activated phenotype in GCA/PMR patients at diagnosis, whereas classical monocytes show reduced expression of activation markers. Whether these findings reflect APC migration patterns or the effects of long-term inflammation remains to be investigated.

Evidence for increased interferon type I activity in CD8+ T cells in giant cell arteritis patients.

Introduction: Giant cell arteritis (GCA) is a vasculitis of the medium- and large-sized arteries. Interferon type I (IFN-I) is increasingly recognized as a key player in autoimmune diseases and might be involved in GCA pathogenesis, however evidence is limited. IFN-I activates Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways, leading to increased expression of interferon stimulated genes. In this study, IFN-I activity in GCA is explored, focusing on CD8+ T cells. Methods: Expression of phospho-STAT (pSTAT) 1, 3 and 5 was investigated in IFN-α-stimulated peripheral mononuclear cells (PBMCs) gated separately for CD8+ T cells of patients with GCA (n=18), healthy controls (HC, n=15) and infection controls (n=11) by Phosphoflow method combined with fluorescent cell barcoding technique. Furthermore, IFN-I induced myxovirus-resistance protein A (MxA) and CD8+ T cell expression was investigated by immunohistochemistry in temporal artery biopsies (TAB) of GCA patients (n=20) and mimics (n=20), and in aorta tissue of GCA (n=8) and atherosclerosis patients (n=14). Results: pSTAT1 expression was increased in IFN-α stimulated CD8+ T cells from GCA patients, whereas no difference was observed in pSTAT3 and pSTAT5 expression. MxA was present in TABs of 13/20 GCA patients compared to 2/20 mimics and in 8/8 GCA+ compared to 13/14 GCA- aorta tissues. MxA location partially co-localized with CD8+T cells. Conclusions: Our results provide evidence for increased IFN-I activity in CD8+ T cells of GCA patients, both systemically and locally. These findings warrant further investigation regarding IFN-I induced biomarkers and IFN-I related novel therapeutic options in GCA.

Biomarkers in the era of targeted therapy in giant cell arteritis and polymyalgia rheumatica: is it possible to replace acute-phase reactants?

Research into giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) has become more important in the last few decades. Physicians are facing several challenges in managing the diagnosis, treatment, and relapses of GCA and PMR patients. The search for biomarkers could provide elements to guide a physician's decision. In this review, we aim to summarize the scientific publications about biomarkers in GCA and PMR in the past decade. The first point raised by this review is the number of clinical situations in which biomarkers could be useful: differential diagnosis of either GCA or PMR, diagnosis of underlying vasculitis in PMR, prediction of relapse or complications, disease activity monitoring, choice, and modification of treatments. The second point raised by this review is the large number of biomarkers studied, from common markers like C-reactive protein, erythrocyte sedimentation rate, or elements of blood count to inflammatory cytokines, growth factors, or immune cell subpopulations. Finally, this review underlines the heterogeneity between the studies and proposes points to consider in studies evaluating biomarkers in general and particularly in the case of GCA and PMR.

Effect of DMARDs on the immunogenicity of vaccines.

Vaccines are important for protecting individuals at increased risk of severe infections, including patients undergoing DMARD therapy. However, DMARD therapy can also compromise the immune system, leading to impaired responses to vaccination. This Review focuses on the impact of DMARDs on influenza and SARS-CoV-2 vaccinations, as such vaccines have been investigated most thoroughly. Various data suggest that B cell depletion therapy, mycophenolate mofetil, cyclophosphamide, azathioprine and abatacept substantially reduce the immunogenicity of these vaccines. However, the effects of glucocorticoids, methotrexate, TNF inhibitors and JAK inhibitors on vaccine responses remain unclear and could depend on the dosage and type of vaccination. Vaccination is aimed at initiating robust humoral and cellular vaccine responses, which requires efficient interactions between antigen-presenting cells, T cells and B cells. DMARDs impair these cells in different ways and to different degrees, such as the prevention of antigen-presenting cell maturation, alteration of T cell differentiation and selective inhibition of B cell subsets, thus inhibiting processes that are necessary for an effective vaccine response. Innovative modified vaccination strategies are needed to improve vaccination responses in patients undergoing DMARD therapy and to protect these patients from the severe outcomes of infectious diseases.

Disease stratification in GCA and PMR: state of the art and future perspectives.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are closely related conditions characterized by systemic inflammation, a predominant IL-6 signature, an excellent response to glucocorticoids, a tendency to a chronic and relapsing course, and older age of the affected population. This Review highlights the emerging view that these diseases should be approached as linked conditions, unified under the term GCA-PMR spectrum disease (GPSD). In addition, GCA and PMR should be seen as non-monolithic conditions, with different risks of developing acute ischaemic complications and chronic vascular and tissue damage, different responses to available therapies and disparate relapse rates. A comprehensive stratification strategy for GPSD, guided by clinical findings, imaging and laboratory data, facilitates appropriate therapy and cost-effective use of health-economic resources. Patients presenting with predominant cranial symptoms and vascular involvement, who usually have a borderline elevation of inflammatory markers, are at an increased risk of sight loss in early disease but have fewer relapses in the long term, whereas the opposite is observed in patients with predominant large-vessel vasculitis. How the involvement of peripheral joint structures affects disease outcomes remains uncertain and understudied. In the future, all cases of new-onset GPSD should undergo early disease stratification, with their management adapted accordingly.

Indication of Activated Senescence Pathways in the Temporal Arteries of Patients With Giant Cell Arteritis.

OBJECTIVE: Giant cell arteritis (GCA) affects almost exclusively individuals above 50 years old, suggesting a role of aging-related changes such as cellular senescence in its pathobiology. The kinases p21(WAF1/CIP1) and p16/INK4A play key roles in 2 distinct pathways leading to senescence. The proinflammatory molecules interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are key components of the senescence-associated secretory phenotype (SASP), are effective targets of treatment in GCA. Here, we aimed to investigate the presence of p21+ and p16+ cells producing these SASP cytokines in temporal artery biopsies (TABs) of patients with GCA. METHODS: Eight patients with GCA and 14 age-matched, non-GCA individuals who underwent a TAB were included. Immunohistochemical staining of p21, p16, IL-6, and GM-CSF was performed. Multiplex immunofluorescent staining was performed to investigate the colocalization of p21 and p16 with IL-6, GM-CSF, and immune cell markers (CD68, CD3, CD20). RESULTS: We found that expression levels of p16, p21, IL-6, and GM-CSF were elevated in the TABs of patients with GCA. Both p16- and p21-expressing cells were mainly found near the internal lamina elastica, especially among giant cells and macrophages, although p21 and p16 expression could be found in all 3 layers of the vessels. Expression of p16 and p21 was occasionally found in T cells but not B cells. The p16+ and p21+ cells expressing GM-CSF/IL-6 were detected throughout the TABs. CONCLUSION: Our data suggest the presence of activated senescence pathways at the site of vascular inflammation in GCA and support further research into the role of senescence in the pathophysiology of GCA.

A randomized phase I/II safety and immunogenicity study of the Montanide-adjuvanted SARS-CoV-2 spike protein-RBD-Fc vaccine, AKS-452.

BACKGROUND: Previous interim data from a phase I study of AKS-452, a subunit vaccine comprising an Fc fusion of the respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor binding domain (SP/RBD) emulsified in the water-in-oil adjuvant, Montanide™ ISA 720, suggested a good safety and immunogenicity profile in healthy adults. This phase I study was completed and two dosing regimens were further evaluated in this phase II study. METHODS: This phase II randomized, open-labelled, parallel group study was conducted at a single site in The Netherlands with 52 healthy adults (18 - 72 years) receiving AKS-452 subcutaneously at one 90 µg dose (cohort 1, 26 subjects) or two 45 µg doses 28 days apart (cohort 2, 26 subjects). Serum samples were collected at the first dose (day 0) and at days 28, 56, 90, and 180. Safety and immunogenicity endpoints were assessed, along with induction of IgG isotypes, cross-reactive immunity against viral variants, and IFN-γ T cell responses. RESULTS: All AEs were mild/moderate (grades 1 or 2), and no SAEs were attributable to AKS-452. Seroconversion rates reached 100% in both cohorts, although cohort 2 showed greater geometric mean IgG titers that were stable through day 180 and associated with enhanced potencies of SP/RBD-ACE2 binding inhibition and live virus neutralization. AKS-452-induced IgG titers strongly bound mutant SP/RBD from several SARS-CoV-2 variants (including Omicrons) that were predominantly of the favorable IgG1/3 isotype and IFN-γ-producing T cell phenotype. CONCLUSION: These favorable safety and immunogenicity profiles of the candidate vaccine as demonstrated in this phase II study are consistent with those of the phase I study (ClinicalTrials.gov: NCT04681092) and suggest that a total of 90 µg received in 2 doses may offer a greater duration of cross-reactive neutralizing titers than when given in a single dose.

Metabolic features and glucocorticoid-induced comorbidities in patients with giant cell arteritis and polymyalgia rheumatica in a Dutch and Danish cohort.

OBJECTIVES: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are age-associated inflammatory diseases that frequently overlap. Both diseases require long-term treatment with glucocorticoids (GCs), often associated with comorbidities. Previous population-based cohort studies reported that an unhealthier metabolic profile might prevent the development of GCA. Here, we report metabolic features before start of treatment and during treatment in patients with GCA and PMR. METHODS: In the Dutch GCA/PMR/SENEX (GPS) cohort, we analysed metabolic features and prevalence of comorbidities (type 2 diabetes, hypercholesterolaemia, hypertension, obesity and cataract) in treatment-naïve patients with GCA (n=50) and PMR (n=42), and compared those with the population-based Lifelines cohort (n=91). To compare our findings in the GPS cohort, we included data from patients with GCA (n=52) and PMR (n=25) from the Aarhus cohort. Laboratory measurements, comorbidities and GC use were recorded for up to 5 years in the GPS cohort. RESULTS: Glycated haemoglobin levels tended to be higher in treatment-naïve patients with GCA, whereas high-density lipoprotein, low-density lipoprotein and cholesterol levels were lower compared with the Lifelines population. Data from the Aarhus cohort were aligned with the findings obtained in the GPS cohort. Presence of comorbidities at baseline did not predict long-term GC requirement. The incidence of diabetes, obesity and cataract among patients with GCA increased upon initiation of GC treatment. CONCLUSION: Data from the GCA and PMR cohorts imply a metabolic dysregulation in treatment-naïve patients with GCA, but not in patients with PMR. Treatment with GCs led to the rise of comorbidities and an unhealthier metabolic profile, stressing the need for prednisone-sparing targeted treatment in these vulnerable patients.

Contribution of pathogenic T helper 1 and 17 cells to bursitis and tenosynovitis in polymyalgia rheumatica.

Background: Although polymyalgia rheumatica (PMR) is a very common rheumatic inflammatory disease, current insight into the pathobiology of PMR is limited and largely based on studies in blood. We investigated T helper 1 (TH1) and T helper 17 (TH17) cell responses in blood, synovial fluid and bursa tissue of patients with PMR. Materials and methods: Blood samples were collected from 18 patients with new-onset PMR and 32 healthy controls. Synovial fluid was aspirated from the inflamed shoulder bursae or biceps tendon sheath of 13 patients. Ultrasound-guided biopsies of the subacromial-subdeltoid (SASD) bursa were obtained from 11 patients. T cells were examined by flow cytometry, immunohistochemistry and immunofluorescence staining. Results: Besides an increase of TH17 (CD4+IL-17+IFN-γ-) cells and T cytotoxic 17 (TC17; CD8+IL-17+IFN-γ-) cells, no other major changes were noted in the circulating T cell compartment of patients with PMR. Absolute numbers of CD4+ and CD8+ T cells were similar in blood and synovial fluid of patients with PMR. Synovial fluid T cells showed an effector-memory (CD45RO+CCR7-) phenotype. Percentages of TH1 (CD4+IFN-γ+IL-17-) cells and TH1/TH17 (CD4+IFN-γ+IL-17+) cells, but not TH17 or TC17 cells, were increased in the synovial fluid. Bursa tissue biopsies contained a small number of T cells, which were mostly CD8 negative. The majority of bursa tissue T cells produced IFN-γ but not IL-17. For comparison, B cells were scarcely detected in the bursa tissue. Conclusion: Although the circulating TH17 cell pool is expanded in patients with PMR, our findings indicate that TH1 cells are involved in the inflammation of bursae and tendon sheaths in this condition. Our study points towards the TH1 cell pathway as a potential target for therapy in PMR.

Subclinical giant cell arteritis in new onset polymyalgia rheumatica A systematic review and meta-analysis of individual patient data.

OBJECTIVES: To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). METHODS: PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). RESULTS: We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). CONCLUSION: More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed.

Immunogenicity and safety of COVID-19 vaccination in patients with primary Sjögren's syndrome.

OBJECTIVES: To evaluate humoral and cellular immune responses and adverse events (AEs) after COVID-19 vaccination in patients with primary Sjögren's syndrome (pSS) compared to healthy controls (HC), and disease activity following vaccination in patients with pSS. METHODS: 67 patients with pSS and 33 HC (ratio 2:1) received COVID-19 vaccinations following the Dutch vaccination programme. Patients with pSS did not use immunomodulatory drugs, except hydroxychloroquine. Anti-spike 1 receptor binding domain IgG serum antibody levels were measured 28 days after complete vaccination. AEs were collected 7 days after vaccination. In a subgroup, salivary anti-SARS-CoV-2 antibodies and T-cell response by interferon-γ enzyme-linked immune absorbent spot was measured. RESULTS: 47 patients with pSS (70%) and 14 HC (42%) received BNT162b2 (Pfizer-BioNtech), 13 (19%) and 5 (15%) received ChAdOx1 nCoV-19 (AstraZeneca), 6 (9%) and 8 (24%) received mRNA-1273 (Moderna), and 1 (1%) and 6 (18%) received Ad.26.COV2.S (Janssen). All participants had positive anti-SARS-CoV-2 antibody levels (>2500 AU/mL) postvaccination. No differences in anti-SARS-CoV-2 antibody levels were observed between patients with pSS and HC, for each vaccine type. Salivary anti-SARS-CoV-2 IgG antibodies also increased, and a T-cell response was observed in patients with pSS and HC. Frequencies of systemic AEs were comparable between patients with pSS and HC (first vaccination: 34/67 (51%) vs 16/33 (48%), p=0.83; second: 41/66 (62%) vs 14/25 (56%), p=0.59). No significant worsening was observed in patient-reported and systemic disease activity, including auto-antibodies. CONCLUSIONS: Patients with pSS had similar humoral and cellular immune responses as HC, suggesting COVID-19 vaccination is effective in patients with pSS. AEs were also comparable, and no increase in disease activity was seen in patients with pSS.

Angiopoietin-2/-1 ratios and MMP-3 levels as an early warning sign for the presence of giant cell arteritis in patients with polymyalgia rheumatica.

BACKGROUND: Diagnosing patients with giant cell arteritis (GCA) remains difficult. Due to its non-specific symptoms, it is challenging to identify GCA in patients presenting with symptoms of polymyalgia rheumatica (PMR), which is a more common disease. Also, commonly used acute-phase markers CRP and ESR fail to discriminate GCA patients from PMR and (infectious) mimicry patients. Therefore, we investigated biomarkers reflecting vessel wall inflammation for their utility in the accurate diagnosis of GCA in two international cohorts. METHODS: Treatment-naïve GCA patients participated in the Aarhus AGP cohort (N = 52) and the Groningen GPS cohort (N = 48). The AGP and GPS biomarker levels and symptoms were compared to patients presenting phenotypically as isolated PMR, infectious mimicry controls and healthy controls (HCs). Serum/plasma levels of 12 biomarkers were measured by ELISA or Luminex. RESULTS: In both the AGP and the GPS cohort, we found that weight loss, elevated erythrocyte sedimentation rate (ESR) and higher angiopoietin-2/-1 ratios but lower matrix metalloproteinase (MMP)-3 levels identify concomitant GCA in PMR patients. In addition, we confirmed that elevated platelet counts are characteristic of GCA but not of GCA mimicry controls and that low MMP-3 and proteinase 3 (PR3) levels may help to discriminate GCA from infections. CONCLUSION: This study, performed in two independent international cohorts, consistently shows the potential of angiopoietin-2/-1 ratios and MMP-3 levels to identify GCA in patients presenting with PMR. These biomarkers may be used to select which PMR patients require further diagnostic workup. Platelet counts may be used to discriminate GCA from GCA look-alike patients.