Biopsy-positive Giant Cell Arteritis Research Articles

Can a Giant Cell Arteritis (GCA) Risk Stratification Score Be Helpful in Clinical Practice?

Giant cell arteritis (GCA) is the most common type of large vessel vasculitis.The diagnosis of GCA is often challenging and there is a difficult balance of over- and underinvestigation. There have been several proposed scoring systems to help clinicians risk stratify patients who may present with suspected GCA. A retrospective cohort study was performed using electronic medical records of patients referred for a temporal artery biopsy (TAB) and temporal artery ultrasound scan (USS) for suspected GCA. All TABs performed at the Royal Wolverhampton NHS Trust between June 2014 and June 2018 and all USS procedures performed between January 2015 and January 2019 were analysed. Patients who undergo a USS for suspected GCA at our centre routinely have scanned bilateral temporal and axillary arteries. Patients were excluded if they already had a previous diagnosis of GCA (and the clinical question was suspected flare), or if there was insufficient information available. The total number of patients who underwent a confirmatory diagnostic test (either TAB or USS) for suspected GCA was 187. Thirteen of these patients met the exclusion criteria, the remaining 174 patients were included for analysis. A total of 126 of 174 patients underwent a TAB and 63 of 174 had aUSS performed; 15 of 174 who had both these were included in the USS cohort because for all these patients, the ultrasound was the first diagnostic test performed. Our results appear to closely mirror the original multi-centre results with regardto the prediction of biopsy-positive GCA, with the centiles closely following those in the inception cohort. Also, 0% of the 'low' risk probability biopsy cohort were misclassified; none had a positive biopsy. However, 8% of the low-risk-probability ultrasound cohort were misclassified, as two had a positive ultrasound. Our studyhighlights that a probability score for GCA derived from a large multi-centre cohort of patients who were biopsy positivepredicts ultrasound positivity with similar accuracy. Our work reveals that scoring systems are not infallible but can be helpful in guiding clinical decision making.

Targeted RNA Sequencing of Formalin-Fixed, Paraffin-Embedded Temporal Arteries From Giant Cell Arteritis Cases Reveals Viral Signatures.

Background and ObjectivesVaricella zoster virus (VZV) antigen has been detected in temporal arteries (TAs) of individuals with giant cell arteritis (GCA), the most common systemic vasculitis in older adults. Thus, we explored the contribution of VZV to GCA pathogenesis.MethodsFormalin-fixed, paraffin-embedded TA sections from biopsy-positive GCA participants with VZV antigen (GCA/VZV-positive; n = 20) and without (GCA/VZV-negative, n = 20) and from normal participants with VZV antigen (control/VZV-positive, n = 11) and without (control/VZV-negative, n = 20) were analyzed by targeted RNA sequencing of the whole human transcriptome (BioSpyder TempO-Seq). Ingenuity pathway analysis and R-computational program were used to identify differentially expressed genes and pathways between groups.ResultsCompared with control/VZV-negative TAs, GCA/VZV-negative and GCA/VZV-positive TAs were significantly enriched for human transcripts specific for pathways involved in viral infections, including viral entry, nuclear factor kappa B activation by viruses, and other pathogen-related immune activation pathways. Similarly, human gene sets supporting viral infection were found in control/VZV-positive TAs that showed no morphological signs of inflammation, suggesting that the enriched pathways were not nonspecific signatures of infiltrating immune cells. All GCA TAs and control/VZV-positive TAs showed enrichment of transcripts involved in vascular remodeling, including smooth muscle cell migration.DiscussionThe detection of viral and immune activation pathways in GCA TAs supports a role for virus infection in GCA pathogenesis. In addition, the detection of viral pathways in control/VZV-positive TAs, along with vascular remodeling pathways, suggests that these samples may represent early infection with progression to clinical disease, depending on host and other environmental factors.

Limited utility of novel serological biomarkers in patients newly suspected of having giant cell arteritis.

Diagnosing and monitoring vascular activity in giant cell arteritis (GCA) is difficult due to the paucity of specific serological biomarkers. We assessed the utility of 8 novel biomarkers in an inception cohort of newly suspected GCA patients. Consecutive patients were enrolled between May 2016 and December 2017. Serum was collected within 72hours of commencing corticosteroids and at 6months. It was analyzed for levels of intra-cellular adhesion molecule 1, vascular endothelial growth factor (VEGF), pentraxin 3, von Willebrand factor and procalcitonin (5-plex R&D Systems multiplex assay) and interleukin (IL)6, IL12 and interferon-γ (high-sensitivity 3-plex ProcartaPlex multiplex assay). A GCA specific positron emission tomography / computed tomography (PET/CT) scan was performed at enrolment with uptake in each vascular territory graded and summed to derive a total vascular score (TVS). For the 63 patients enrolled, 12 (19%) had a final diagnosis of biopsy-positive GCA and a further 9 had a clinical diagnosis of biopsy-negative GCA. None of the 8 biomarkers was significantly higher in GCA patients compared with those with alternative diagnoses, or demonstrated a positive correlation with the PET/CT TVS. This was in contrast to the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) which were higher in the biopsy-positive GCA cohort (P<.04) and showed weak positive correlations with the TVS (correlation coefficient 0.34, P<.01). Procalcitonin did not distinguish between GCA and infection. Concentrations of CRP, ESR, VEGF and pentraxin 3 decreased between diagnosis and 6months in GCA patients. This study did not identify new serological biomarkers to assist in diagnosing or assessing the vasculitis burden in GCA.

AB0488 CAN A GCA RISK STRATIFICATION SCORE BE HELPFUL IN CLINICAL PRACTICE?

Background:Giant cell arteritis (GCA) is the most common type of large vessel vasculitis. Typically it presents in patients over the age of 50 with a combination of temporal headaches, scalp tenderness, jaw claudication, raised inflammatory markers and visual disturbance. The diagnosis of GCA is often challenging and there is a difficult balance of over and under investigation. There have been several proposed scoring systems to help clinicians risk stratify patients who may present with suspected GCA. One such scoring system, published in 2017, showed clinical utility in a large international multi-centre study. Following analysis by logistic regression on data from 530 biopsies, Ing et al. developed a parsimonious prediction model comprising 5 candidate criteria: age, jaw claudication, ischemia-related loss of visual acuity, platelet count and logCRP (Figure 1).[1]Objectives:Increasingly, ultrasound doppler imaging is recognised and accepted as satisfactory means of confirming the diagnosis of GCA, with the presence of the halo sign characteristic for GCA. The aim of our study was to determine whether this GCA prediction model accurately predicts positive temporal artery biopsies in a large, real world UK cohort. In addition, we assessed whether this model accurately predicts positive temporal artery ultrasounds.Methods:A retrospective cohort study was performed using electronic medical records of patients referred for temporal artery biopsy (TAB) and temporal artery ultrasound (USTA) for suspected GCA. All TAB performed at the Royal Wolverhampton NHS Trust between June 2014 - June 2018 and all USTA performed between January 2015 - January 2019 were analysed. Patients who undergo USTA for suspected GCA at our centre routinely have bilateral temporal and axillary arteries scanned. Patients were excluded if they already had a previous diagnosis of GCA (and the clinical question was suspected flare), or if there was insufficient information available.Results:The total number of patients who underwent a confirmatory diagnostic test (either TAB or USTA) for suspected GCA was 187. Thirteen of these patients met the exclusion criteria, the remaining 174 patients were included for analysis. 126/174 patients underwent a TAB, 63/174 had an USTA. 15/174 had both these were included in the USS cohort because for all these patients the ultrasound was the first diagnostic test performed (Table 1). Our results appear to closely mirror the original multi-centre results with regards to prediction of biopsy positive GCA, with the centiles closely following those in the inception cohort. 0% of the ‘low’ risk probability biopsy cohort were misclassified - none had a positive biopsy. However, 8% of the ‘low’ risk probability ultrasound cohort were misclassified - 2 had a positive ultrasound.Table 1.Investigation outcome summaryTotal number of patients who underwent TAB +/or USS TA for?GCA187 - 13 patients rejectedN = 174TAB = 111USS = 63Of these 15 patients hadbothUSS &amp; TABPositive TAB =31 (28%)Negative TAB =80 (72%)Positive USS =24 (38%)Negative USS =39 (62%)Conclusion:Our study, highlights that a probability score for GCA derived from a large multi-centre cohort of patients who were biopsy positive, predicts ultrasound positivity with similar accuracy. Our work reveals that scoring systems are not infallible but can be helpful in guiding clinical decision making

The Microbiome of Temporal Arteries.

Objective:A role for microorganisms in giant cell arteritis (GCA) has long been suspected. We describe the microbiomes of temporal arteries from patients with GCA and controls.Methods:Temporal artery biopsies from patients suspected to have GCA were collected under aseptic conditions and snap-frozen. Fluorescence in situ hybridization (FISH) and long-read 16S rRNA-gene sequencing was used to examine microbiomes of temporal arteries. Taxonomic classification of bacterial sequences was performed to the genus level and relative abundances were calculated. Microbiome differential abundances were analyzed by principal coordinate analysis (PCoA) with comparative Unifrac distances and predicted functional profiling using PICRUSt.Results:Forty-seven patients, including 9 with biopsy-positive GCA, 15 with biopsy-negative GCA and 23 controls without GCA, were enrolled. FISH for bacterial DNA revealed signal in the arterial media. Beta, but not alpha, diversity differed between GCA and control temporal arteries (P = 0.042). Importantly, there were no significant differences between biopsy-positive and biopsy-negative GCA (P > 0.99). The largest differential abundances seen between GCA and non-GCA temporal arteries included Proteobacteria (P), Bifidobacterium (g), Parasutterella (g), and Granulicatella (g) [Log 2-fold change ≥ 4].Conclusion:Temporal arteries are not sterile, but rather are inhabited by a community of bacteria. We have demonstrated that there are microbiomic differences between GCA and non-GCA temporal arteries, but not between biopsy-positive and biopsy-negative GCA.

Is vascular endothelial growth factor a useful biomarker in giant cell arteritis?

ObjectivesTo assess the performance of circulating vascular endothelial growth factor (VEGF) levels as a tool for diagnosing giant cell arteritis (GCA) in a cohort of patients referred for assessment of...

Incidence, Prevalence, and Survival of Biopsy-Proven Giant Cell Arteritis in Northern Italy During a 26-Year Period.

To investigate the epidemiology and mortality in patients with biopsy-proven giant cell arteritis (GCA) in northern Italy. All patients with incident temporal-artery biopsy-positive GCA, diagnosed between 1986 and 2012 and living in the Reggio Emilia area, were identified by using a pathology register and by reviewing all histopathologic specimens. For each patient, we identified 1 comparison subject from the same geographic area, matched for age and sex. Mortality rates and specific causes of death were reported. There were 285 incident cases of biopsy-proven GCA (210 women) during the 26-year study period. The overall age- and sex-adjusted incidence per 100,000 persons ages ≥50 years was 5.8 (95% confidence interval [95% CI] 5.1, 6.5). Incidence was significantly higher in women (7.8 [95% CI 6.7, 8.9]) than in men (3.3 [95% CI 2.6, 4.1]) (P < 0.0001). Annual age- and sex-adjusted incidence rates significantly increased by 15.9% per 3 years from 1986 to 2000, then significantly fell by -4.8% per 3 years from 2001-2012. The prevalence of GCA on December 31, 2012 was 87.9 (95% CI 75.8, 101.4). No significant differences in the mortality rates were observed between GCA patients (4.9 per 100 person-years [95% CI 4.1, 5.8]) and non-GCA subjects (5.6 [95% CI 4.7, 6.6]). No significant differences in causes of death were observed comparing GCA patients to non-GCA subjects. This large population-based study of biopsy-proven GCA confirmed the lower incidence of GCA in Mediterranean countries and did not observe any increased mortality risk.

Analysis of Varicella-Zoster Virus in Temporal Arteries Biopsy Positive and Negative for Giant Cell Arteritis.

Giant cell arteritis (GCA) is the most common systemic vasculitis in elderly individuals. Diagnosis is confirmed by temporal artery (TA) biopsy, although biopsy results are often negative. Despite the use of corticosteroids, disease may progress. Identification of causal agents will improve outcomes. Biopsy-positive GCA is associated with TA infection by varicella-zoster virus (VZV). To analyze VZV infection in TAs of patients with clinically suspected GCA whose TAs were histopathologically negative and in normal TAs removed post mortem from age-matched individuals. A cross-sectional study for VZV antigen was performed from January 2013 to March 2015 using archived, deidentified, formalin-fixed, paraffin-embedded GCA-negative, GCA-positive, and normal TAs (50 sections/TA) collected during the past 30 years. Regions adjacent to those containing VZV were examined by hematoxylin-eosin staining. Immunohistochemistry identified inflammatory cells and cell types around nerve bundles containing VZV. A combination of 17 tertiary referral centers and private practices worldwide contributed archived TAs from individuals older than 50 years. Presence and distribution of VZV antigen in TAs and histopathological changes in sections adjacent to those containing VZV were confirmed by 2 independent readers. Varicella-zoster virus antigen was found in 45 of 70 GCA-negative TAs (64%), compared with 11 of 49 normal TAs (22%) (relative risk [RR] = 2.86; 95% CI, 1.75-5.31; P < .001). Extension of our earlier study revealed VZV antigen in 68 of 93 GCA-positive TAs (73%), compared with 11 of 49 normal TAs (22%) (RR = 3.26; 95% CI, 2.03-5.98; P < .001). Compared with normal TAs, VZV antigen was more likely to be present in the adventitia of both GCA-negative TAs (RR = 2.43; 95% CI, 1.82-3.41; P < .001) and GCA-positive TAs (RR = 2.03; 95% CI, 1.52-2.86; P < .001). Varicella-zoster virus antigen was frequently found in perineurial cells expressing claudin-1 around nerve bundles. Of 45 GCA-negative participants whose TAs contained VZV antigen, 1 had histopathological features characteristic of GCA, and 16 (36%) showed adventitial inflammation adjacent to viral antigen; no inflammation was seen in normal TAs. In patients with clinically suspected GCA, prevalence of VZV in their TAs is similar independent of whether biopsy results are negative or positive pathologically. Antiviral treatment may confer additional benefit to patients with biopsy-negative GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined.

FRI0472 Correlations between Different Histological Subsets of GIANT Cell Arteritis and Clinical Manifestations in A Large Monocentric Cohort of Biopsy Positive GCA Patients

BackgroundTemporal artery biopsy (TAB) showing transmural inflammation is considered the gold standard for the diagnosis of giant cell arteritis (GCA). In some cases of GCA, inflammation is confined to the...

Statin Use in Giant Cell Arteritis: A Retrospective Study

(1) To examine the association between statin use and giant cell arteritis (GCA); (2) to compare the clinical features and disease course of GCA among statin users and nonusers. For this retrospective study, we reviewed the medical records of all patients with biopsy-positive GCA diagnosed between 1998 and 2008. Using a case-control design, we compared the frequency of statin use in GCA patients to non-GCA population-based subjects who were randomly selected and individually matched by sex, age, and calendar year to the GCA cases. Statin use at diagnosis or index date and during followup was abstracted. In subjects with GCA, clinical information at diagnosis and followup was collected. We included 594 patients, 297 with GCA (73% female), mean age at diagnosis 75 years. The rate of statin exposure at index date was 18.1% for GCA patients versus 33.3% for controls (p < 0.001). Patients using statins were less likely to develop GCA compared with patients not using statins (OR 0.31, 95% CI 0.15-0.6, p < 0.001), even after adjustment for cardiovascular risk factors. Among patients with GCA, the presenting clinical features and acute-phase reactants were similar in patients receiving statins compared to those not on statin therapy. These 2 groups were also similar with regard to relapse rate, prednisone tapering, and overall survival. Patients using statins may be less likely to develop GCA compared to patients who are not using statins. Statin use does not appear to modify the clinical presentation or the course of the disease.

Prevalence of Diabetes Mellitus in Biopsy-Positive Giant Cell Arteritis

We tested the hypothesis that patients with diabetes mellitus (DM) develop biopsy-positive giant cell arteritis (GCA) significantly less frequently than nondiabetic patients. We compared the prevalence of DM in patients with positive temporal artery biopsy (TAB) with that in patients with negative TAB via a retrospective study of 215 patients who underwent TAB. Patients were classified as having biopsy-positive GCA if microscopic examination disclosed active or healed arteritis. Patients were classified as having DM if they had a diagnosis of diabetes in their medical history or were taking oral hypoglycemic medications and/or insulin at or before the time of biopsy. In addition, we performed a meta-analysis of 8 previously published articles with a total of 1,401 additional biopsy-proven cases of GCA in patients whose status was recorded as diabetic or nondiabetic. Of 44 cases with biopsy-positive GCA in our patient cohort, only 4 (9.1%) were diabetic at or before the time of biopsy. Of 171 patients with negative TAB, 61 (35.7%) had DM (P = 0.0006). The prevalence of DM among recorded cases of biopsy-positive GCA ranged from 0% to 13.8% in the 8 studies included in our meta-analysis, with a combined frequency of 89 diabetic patients in a total of 1,401 cases (6.35%). The low frequency of a positive TAB in diabetic GCA suspects should be considered when formulating an index of suspicion in the evaluation of patients with possible GCA. More research is needed to delineate the nature of the interaction between DM and GCA.

Statin or Nonsteroidal Anti-Inflammatory Drug Use Is Associated With Lower Erythrocyte Sedimentation Rate in Patients With Giant Cell Arteritis

Previous studies have found that nonsteroidal anti-inflammatory drugs (NSAIDs) and statins may impact erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) levels in patients. The current study was performed to determine if NSAID or statin use is associated with lower ESR and CRP in patients with biopsy-proven giant cell arteritis (GCA). A retrospective cross-sectional study was conducted that included 161 patients via chart review. Charts of patients with GCA seen at the University of Iowa Hospitals and Clinics from 1960 to 2008 were reviewed. Inclusion criteria were adequate medication records, serum ESR and/or CRP on record, no prior corticosteroid use, and biopsy-positive GCA. Exclusion criteria were the presence of diseases known to elevate ESR or CRP. Main outcome measures included ESR and CRP values measured while evaluating patients for GCA but prior to receiving treatment. Statin nonusers had an ESR of 85.0 mm per hour (interquartile range [IQR] = 60-110 mm per hour) and a CRP of 8.7 mg/dL (IQR = 2.7-16.2 mg/dL). Statin users had an ESR of 57.5 mm per hour (IQR = 35-85) and a CRP of 2.4 mg/dL (IQR = 0.8-15.9 mg/dL). Statin use was associated with a lower ESR (P = 0.005), while there was no significant association with a lower CRP (P = 0.127). NSAID nonusers had an ESR of 98.0 mm per hour (IQR = 64-116) and a CRP of 8.7 mg/dL (IQR = 2.1-16.2 mg/dL). NSAID users had an ESR of 75.0 mm per hour (IQR = 46-98.5 mm per hour) and CRP of 8.0 mg/dL (IQR. = 1.5-16.2 mg/dL). NSAID use was associated with a lower ESR (P = 0.004), but there was no significant association with a lower CRP (P = 0.522). Statin use and NSAID use were associated with a lower ESR; however, they were not associated with lower CRP values. Clinicians should be aware that statin or NSAID use is associated with lower ESR in patients with GCA, and this test may therefore have lower sensitivity and specificity for recognizing patients with GCA, and CRP may be a superior test to evaluate patients for GCA.

IFN-γ and IL-17: the two faces of T-cell pathology in giant cell arteritis

Granuloma formation in giant cell arteritis (GCA) emphasizes the role of adaptive immunity and highlights the role of antigen-specific T cells. Recent data demonstrate that at least two separate lineages of CD4 T cells participate in vascular inflammation, providing an important clue that multiple disease instigators may initiate pathogenic immunity. IFN-γ-producing Th1 cells and IL-17-producing Th17 cells have been implicated in GCA. Patients with biopsy-positive GCA underwent two consecutive temporal artery biopsies, one prior to therapy and one while on corticosteroids. In untreated patients, Th1 and Th17 cells co-existed in the vascular lesions. Following therapy, Th17 cells were essentially lost, whereas Th1 cells persisted almost unaffected. In the peripheral blood of untreated patients Th17 frequencies were increased eight-fold, but normalized with therapy. Blood Th1 cells were doubled in frequency, independent of therapy. Corticosteroids functioned by selectively suppressing IL-1β, IL-6 and IL-23-releasing antigen-presenting cells (APCs), disrupting induction of Th17 cells. At least two distinct CD4 T-cell subsets promote vascular inflammation in GCA. In early disease, APCs promote differentiation of Th17 as well as Th1 cells. Chronic disease is characterized by persistent Th1-inducing signals, independent of IL-17-mediated inflammation. More than one disease instigator may trigger APCs to induce multiple T-cell lineages. Cocktails of therapies will be needed for appropriate disease control.

The epidemiology of biopsy-positive giant cell arteritis: special reference to cyclic fluctuations.

The aim of this work was to study changes in the incidence of biopsy-proven giant cell arteritis (GCA) over a period of 20 yr in Göteborg, Sweden. All cases of biopsy-verified GCA between 1976 and 1995 were included in the study. The annual incidence was calculated for the whole material, for women and men separately, and its fluctuations were tested statistically. In addition, the monthly variation during the last 9 yr could be statistically analysed for the whole material. In total, 665 patients were diagnosed with biopsy-verified GCA during the 20 yr period. The average annual incidence was 22.2/100000 inhabitants over 50 yr of age (women 29.8, men 12.5). The annual incidence increased significantly with time (P<0.001) for both men and women. Statistical analysis did not reveal any cyclic fluctuation in the annual incidence (P=0.26), while the monthly number of positive biopsies showed significant fluctuation with peaks in late winter and autumn (P=0.041). The annual incidence of biopsy-positive GCA increased during the years 1976 through 1995. The significant seasonal variation, as well as considerable variation in annual incidence, might be due to the influence of exogenous triggering factors, such as infections. Further support for an exogenous aetiology, in terms of a statistically significant cyclic fluctuation of the annual incidence, was not found, however.