Transorbital ultrasound in the diagnosis of giant cell arteritis.

OBJECTIVES: The objective of this study was to prospectively evaluate the diagnostic efficacy of transorbital ultrasound (TOS) in patients newly diagnosed with giant cell arteritis (GCA), presenting with visual symptoms. METHODS: Patients with newly diagnosed, untreated GCA were examined using TOS, assessing central retinal artery flow velocity [peak systolic velocity (PSV), end-diastolic velocity (EDV), resistance index (RI)], and optic nerve diameter (OND). Vascular ultrasound was conducted to evaluate the superficial temporal arteries, their branches, facial, axillary, carotid, and vertebral arteries. RESULTS: We enrolled 54 GCA patients, 27 with visual symptoms, and 27 healthy controls. Eyes of GCA patients with visual symptoms demonstrated significantly lower PSV and EDV (PSV: ß = -1.91; P = 0.029; EDV: ß = -0.57; P = 0.032) and significantly elevated OND (ß = 0.79; P = 0.003) compared with controls. RI did not significantly differ from controls (ß = -0.06, P = 0.129). Vascular ultrasound identified an average of 8.7 (SD ± 2.8) pathological vessels per GCA patient. A significant negative association was observed between the number of affected vessels and both PSV (P = 0.048) and EDV (P = 0.040). No association was found with RI (P = 0.249), while a positive significant association was noted with OND (P < 0.001). CONCLUSIONS: This study pioneers the application of TOS to assess structural eye changes in newly diagnosed, untreated GCA patients with visual symptoms. Our findings suggest reduced central retinal artery flow and increased optic nerve diameter as potential biomarkers for serious ocular involvement in GCA. The detected association between internal and external carotid artery involvement indicates a common pathophysiological mechanism underlying systemic and ocular manifestations of GCA.

Long-term follow-up of 89 patients with giant cell arteritis: a retrospective observational study on disease characteristics, flares and organ damage.

The objective of the study is to investigate the clinical characteristics and long-term prognosis including flares and organ damage in patients with giant cell arteritis (GCA) from a tertiary referral centre and compare these features in different subgroups. In this retrospective observational study, patients with GCA who were followed up in our vasculitis clinic between 1998 and 2018 were evaluated by a predefined protocol. Patients with and without cranial symptoms were compared for clinical and laboratory features, flares and permanent damage findings. Vasculitis Damage Index and Large Vessel Vasculitis Index of Damage were used for damage assessment. Records of 89 patients (median follow-up time 46 months) were analysed; mean time to diagnosis after initial symptom was longer in patients with acute vision loss (11 ± 4 vs. 4.8 ± 1.1 months p = 0.002). EGG (n = 19) was younger (63 ± 2 vs. 69 ± 1 years old p = 0.01); had higher mean CRP (141.8 ± 107.3 vs. 76.6 ± 67.9 mg/dL p = 0.023) and ESR (120.8 ± 25.1 vs. 99.3 ± 24.3 mm/h p = 0.004) at diagnosis. PET-CT detected large vessel vasculitis in 42/48 (87.5%) cases of the entire cohort. Thirty-one patients had flares and proportion of flared patients was significantly higher in patients with cranial symptoms. At least one damage item (DI) was present in 54 (60.7%) patients. The development of damage was found to be associated with flares. Evaluation of our cohort revealed the importance of early diagnosis for prevention of vision loss in GCA. Patients without cranial symptoms were younger, present with higher inflammatory response and for these, PET-CT was the main diagnostic tool. Relapse rate was higher in patients with cranial symptoms. Flares and accompanying corticosteroid treatment may contribute to organ damage in GCA.

An immunohistochemical analysis of fibroblasts in giant cell arteritis.

BACKGROUND: Giant cell arteritis (GCA) is a systemic vasculitis of large and medium vessels characterized by an inflammatory arterial infiltrate. GCA begins in the adventitia and leads to vascular remodeling by promoting proliferation of myofibroblasts in the intima. The morphology of the fibroblasts in the adventitia in GCA is unclear. Access to temporal artery biopsies allows morphological studies and evaluation of the microenvironment of the arterial wall. We evaluated the distribution of vascular fibroblasts and of markers of their activation in GCA. METHODS: Formalin-fixed paraffin-embedded tissue sections from 29 patients with GCA and 36 controls were examined. Immunohistochemistry was performed for CD90, vimentin, desmin, alpha-smooth muscle actin (ASMA), prolyl-4-hydroxylase (P4H), and myosin to evaluate the distribution of fibroblasts within the intima, media, and adventitia. RESULTS: Temporal arteries from patients with GCA showed increased levels of CD90, vimentin, and ASMA in the adventitia and intima compared to the controls. Desmin was expressed only in the media in both groups. P4H was expressed similarly in the adventitia and intima in the two groups. Adventitial and intimal CD90+ cells co-expressed P4H, ASMA, and myosin at a high level in GCA. CONCLUSION: The results suggest a role for adventitial fibroblasts in GCA. Inhibiting the differentiation of adventitial fibroblasts to myofibroblasts has therapeutic potential for GCA.

Cardiovascular risk factors associated with polymyalgia rheumatica and giant cell arteritis in a prospective cohort: EPIC-Norfolk Study.

OBJECTIVES: PMR and GCA are associated with increased risk of vascular disease. However, it remains unclear whether this relationship is causal or reflects a common underlying propensity. The aim of this study was to identify whether known cardiovascular risk factors increase the risk of PMR and GCA. METHODS: Clinical records were examined using key word searches to identify cases of PMR and GCA, applying current classification criteria in a population-based cohort. Associations between cardiovascular risk factors and incident PMR and GCA were analysed using Cox proportional hazards. RESULTS: In 315 022 person years of follow-up, there were 395 incident diagnoses of PMR and 118 incident diagnoses of GCA that met the clinical definition. Raised diastolic blood pressure (>90 mmHg) at baseline/recruitment was associated with subsequent incident PMR [hazard ratio=1.35 (95% CI 1.01, 1.80) P=0.045], and ever-smoking was associated with incident GCA [hazard ratio=2.01 (95% CI 1.26, 3.20) P=0.003]. Estimates were similar when the analysis was restricted to individuals whose diagnoses satisfied the current classification criteria sets. CONCLUSION: PMR and GCA shares common risk factors with vascular disease onset, suggesting a common underlying propensity. This may indicate a potential for disease prevention strategies through modifying cardiovascular risk.

[18F]FDG positron emission tomography and ultrasound in the diagnosis of giant cell arteritis: congruent or complementary imaging methods?

OBJECTIVES: [18F]Fluorodeoxyglucose (FDG)-PET/CT and US are both well established for diagnosing GCA. The present study investigates their accuracy and whether they provide overlapping or complementary information in a cohort of patients presenting with suspicion of GCA. METHODS: We selected consecutive patients from our cohort of suspected GCA cases that underwent both extended vascular US and PET/CT for diagnostic work-up between December 2006 and August 2012. RESULTS: A total of 102 patients were included. Diagnosis of GCA was confirmed in 68 patients and excluded in 34 patients (controls). Vasculitic changes in US were most often found in the temporal artery with 32 positive findings on each side, followed by the popliteal artery (10 right, 9 left) and the subclavian/axillary artery (7 right, 8 left). By contrast, PET/CT showed vasculitis most frequently in the vertebral (23 right, 33 left) and common carotid arteries (32 right, 24 left), followed by the subclavian arteries (16 right, 18 left), and the thoracic (17) and abdominal aorta (23). In 37/68 GCA patients PET/CT and US both revealed vasculitic findings, 11/68 had positive findings in US only and 14/68 in PET/CT only. Specificity of US was higher (one false-positive vs five false-positive in PET/CT). On a single segment level, only 20 of 136 positive segments were positive in both imaging modalities. CONCLUSION: PET/CT measuring vessel wall metabolism and US vessel wall morphology showed a comparable diagnostic accuracy for GCA. However PET/CT and US were often discrepant within single vascular regions. Thus PET/CT and US should be considered as complementary methods, with a second imaging modality increasing the diagnostic yield by 16-20%.

Comparison of biopsy-proven giant cell arteritis in North America and Southern Europe: a population-based study.

OBJECTIVES: To compare clinical characteristics, treatment and prognosis of two population-based cohorts of patients with biopsy-proven giant cell arteritis (GCA) from Olmsted County, Minnesota, USA (Olmsted cohort) and the Reggio Emilia area, Northern Italy (Reggio cohort). METHODS: All patients residing in Olmsted County and the Reggio Emilia area with a new diagnosis of biopsy-proven GCA in 1986-2007 were retrospectively identified. Patients were followed from GCA diagnosis to death, migration or September 2011. RESULTS: The study included 110 patients in the Olmsted and 144 in the Reggio cohort. Compared with the Olmsted cohort, patients from the Reggio cohort had longer duration of symptoms prior to diagnosis (median 1.4 months vs. 0.7, p<0.001) and were younger (mean 74.6 years vs. 77.8, p=0.002), more likely to have cranial symptoms (93% vs. 86%, p=0.048), permanent vision loss (21% vs. 6%, p=0.001) and systemic symptoms (67% vs. 46%, p=0.001). ESR and CRP were higher (mean 88 mm/h vs. 73, and 89.0 mg/L vs. 35.2, both p<0.001) in the Reggio cohort. Patients from the Olmsted cohort received a higher initial prednisone dose (mean 53.6 mg/day vs. 49.5, p=0.001). There were no differences in relapse rates, cumulative glucocorticoid (GC) dosages at 1, 2 and 5 years, and time to first GC discontinuation. CONCLUSIONS: Geographical, genetic and/or environmental factors may contribute to the different clinical features at onset of GCA observed in this study.

Updates in the Diagnosis and Management of Giant Cell Arteritis.

PURPOSE OF REVIEW: Giant cell arteritis is a systemic large vessel vasculitis that affects the older population and can cause progressive and at times, devastating complications including vision loss. While this has been commonly diagnosed and treated among vasculitides, the treatment options are limited and can have long-term adverse effects. The purpose of our review on GCA is to identify and discuss the pathophysiology and clinical aspects of GCA as they relate to the most recent data. The review will describe any new data on the diagnosis and treatment of this systemic large vessel vasculitis. RECENT FINDINGS: The latest data suggests that the mainstay of treatment of GCA remains glucocorticoids but alternate agents are being identified and used in an attempt to reduce the cumulative exposure to glucocorticoids and reduce treatment-related adverse effects while managing and maintaining remission of this systemic disease. There is much more information to collect in terms of identification and standardization of the optimal length of time to treat with glucocorticoids as well as regarding the long-term efficacy of alternate treatments. In addition, investigation continues to identify measureable risk factors to predict outcomes of individual patients with this diagnosis.

Accelerated atheromatosis and arteriosclerosis in primary systemic vasculitides: current evidence and future perspectives.

PURPOSE OF REVIEW: Primary systemic vasculitides (PSV) encompass a subset of autoimmune diseases, characterized by inflammation of blood vessels. Atheromatosis and arteriosclerosis may be accelerated in several PSV and account for the increased rate of cardiovascular morbidity that some exhibit. We aimed to summarize recent studies reporting on the acceleration of atheromatosis and/or arteriosclerosis in each type of PSV, using state-of-the-art noninvasive vascular biomarkers with clinical value as end points. RECENT FINDINGS: Limited number of PSV patients and methodology limitations reduce the value of many published studies. Accelerated atheromatosis, as measured by the use of carotid ultrasonagraphy (plaques and intimal-medial thickening) and increased arterial stiffening, as measured by the use of applanation tonometry (carotid to femoral pulse wave velocity), are currenly well established in Takayasu arteritis, Kawasaki disease and Behcet's disease. The association of atheromatosis and arteriosclerosis with polyarteritis nodosa and small vessel vasculitides remains less established and studied, so far. SUMMARY: Accelerated atheromatosis and arteriosclerosis or arteriosclerosis are established in some PSV. The potential clinical value of easy-to-measure and clinically useful noninvasive vascular biomarkes prompts the need for large prospective cohorts in order to provide useful future guidance regarding the prognosis and treatment of PSV patients.

Physiological effects of modulating the interleukin-6 axis.

IL-6 is a pleiotropic cytokine involved in many biological functions that affect tissues beyond the immune system and the vasculature. This multifunctional cytokine exerts its actions via the classic signalling pathway when it binds to the transmembrane IL-6 receptor (IL-6R) or via the trans-signalling pathway upon binding to the soluble form of IL-6R (sIL-6R). In general, classic IL-6 signalling is responsible for the anti-inflammatory properties of IL-6, whereas trans-signalling is responsible for the pro-inflammatory actions of IL-6. As a result, dysregulation of the IL-6 axis can lead to the onset or development of several disease states, particularly autoimmune and inflammatory disorders, including RA and GCA. This pathological role of IL-6 means that pharmacologic modulation of the IL-6 axis is a rational therapeutic approach; however, multiple predictable, but often underappreciated, effects on tissues and organs beyond the blood vessels may also occur.

Giant Cell Arteritis: Practical Pearls and Updates.

PURPOSE OF REVIEW: The purpose of this review is to summarize recent updates and distill practical points from the literature which can be applied to the care of patients with suspected and confirmed giant cell arteritis (GCA). RECENT FINDINGS: Contemporary thinking implicates a fundamental failure of T regulatory cell function in GCA pathophysiology, representing opportunity for novel therapeutic avenues. Tocilizumab has become the first Food and Drug Administration-approved treatment for GCA following demonstration of efficacy and safety in a phase 3 clinical trial. There have been significant parallel advances in both our understanding of GCA pathophysiology and treatment. Tocilizumab, and other agents currently under investigation in phase 2 and 3 clinical trials, presents a new horizon of hope for both disease remission and avoidance of glucocorticoid-related complications.

Treatment of giant-cell arteritis, a literature review.

Giant-cell arteritis (GCA) is the most common vasculitis in people aged more than 50 years. Despite the frequency of this disease, there is currently no international consensus on its therapeutic modalities. The aim of this study was to conduct a review on an international literature about the treatment of GCA, whatever the clinical pattern might be. Oral corticosteroids remain the cornerstone treatment, possibly preceded by intravenous bolus in complicated forms. In cases of glucocorticoid (GC) dependence or GC-related side effects, a GC-sparing agent may be necessary. Methotrexate is one of the most used treatments despite its low level of evidence and mild efficacy. Cyclophosphamide and tocilizumab look promising but require validation in further studies. The results for TNF-α blockers and azathioprine are disappointing. Preventing complications of prolonged corticosteroid therapy is a world challenge and the management of GC-induced osteoporosis is not the same from one country to another. There is a significant risk of arterial thrombosis, mainly at treatment onset, which may encourage to associate an antiplatelet therapy, especially in patients with other cardiovascular risk factors. Place of statins in the treatment of the disease is uncertain.

[A rare concurrence of polymyalgia rheumatica and AA-amyloidosis]. / Redkoe sochetanie revmaticheskoi polimialgii s AA-amiloidozom.

Polymyalgia rheumatica (PMR) is a rare chronic inflammatory disease. It predominantly affects the elderly. The disease has a slow onset, pain and stiffness in the muscles of the shoulder and pelvic girdle, fever, weight loss, and a high acute-phase inflammatory response. The disease is concurrent with giant cell arteritis in a quarter of cases, which allows some authors to consider them as two different manifestations of the same pathological process. The kidneys are rarely involved. This disease is rarely complicated by AA amyloidosis. The authors describe a case of RPM in a patient who has developed secondary AA amyloidosis.

[Giant cell arteritis: Genetic and epigenetic aspects]. / Gigantokletochnyi arteriit: geneticheskie i épigeneticheskie aspekty.

The paper describes clinical cases in 2 patients (brothers) with giant cell arteritis. It analyzes the genetic and epigenetic aspects of the disease. The data available in the Russian and foreign literature are given.

[Large vessel vasculitis : pathogenesis, diagnostic and medical management]. / Artérites des grands vaisseaux : pathogenèse, diagnostic et prise en charge.

Large vessels vasculitis includes two diseases : 1) giant cell arteritis, formerly known as Horton's arteritis and 2) Takayasu arteritis. In this article, we will describe and compare the epidemiology, pathogenesis, diagnostic criteria and medical management of both vasculitis. T helper (Th) 1 and Th17 responses, genetic links and the role of viral (varicella zoster) and bacterial infection (Mycoplasma pneumoniae or Chlamydia pneumoniae) will be discussed. Classification criteria, inflammation biomarkers and progress in imaging tools will also be described. Finally, we will review the medical management including corticosteroids, aspirin and biologicals.

Les artérites ou vasculites des grands vaisseaux regroupent deux maladies : 1) l'artérite à cellules géantes ou gigantocellulaire (GCA), anciennement dénommée maladie de Horton et 2) l'artérite de Takayasu (TA). Le but de cet article est de détailler et comparer l'épidémiologie, la pathogenèse, les critères diagnostiques ainsi que la prise en charge de ces deux vasculites. Nous discuterons en particulier du rôle de la signature immune T helper (Th) 1 versus Th17, l'influence de la génétique et aussi le lien avec des infections virale (varicelle zoster) ou bactérienne (Mycoplasma pneumoniae/Chlamydia pneumoniae). Les critères de classification, les biomarqueurs de l'inflammation ainsi que le rôle de l'imagerie seront aussi discutés. Finalement, nous ferons la revue des corticostéroïdes, de l'aspirine et des biologiques dans la prise en charge de ces patients.

GIANT CELL AORTITIS DIAGNOSED WITH PET/CT - PARANEOPLASTIC SYNDROME?

Vasculitides are heterogenic group of autoimmune connective tissue diseases which often present difficulties in early diagnosing. Giant cell arteritis is vasculitis of large and medium arteries. It predominantly presents with symptoms of affection of the external carotid artery branches. Furthermore, the only symptoms can be constitutional. In clinical practice, vasculitides are sometimes considered as paraneoplastic, but no definite association with malignancies has been established and the mechanisms are still debated. The gold standard for diagnosing giant cell arteritis is a positive temporal artery biopsy, but the results can often be false negative. Additionally, more than half of the patients have aorta and its main branches affected. Considering aforementioned, imaging studies are essential in confirming large-vessel vasculitis, amongst which is highly sensitive PET/CT. We present the case of a 70-year-old female patient with constitutional symptoms and elevated sedimentation rate. After extensive diagnostic tests, she was admitted to our Rheumatology unit. Aortitis of the abdominal aorta has been confirmed by PET/CT and after the introduction of glucocorticoids the disease soon went into clinical and laboratory remission. Shortly after aortitis has been diagnosed, lung carcinoma was revealed of which the patient died. At the time of the comprehensive diagnostics, there was no reasonable doubt for underlying malignoma. To the best of our knowledge, there are no recent publications concerning giant cell arteritis and neoplastic processes in the context of up-to-date non-invasive diagnostic methods (i.e. PET/CT). In the light of previous research results, we underline that the sensitivity of PET/CT is not satisfactory when estimating cancer dissemination in non-enlarged lymph nodes and that its value can at times be overestimated.

Giant Cell Arteritis Presenting as Unilateral Anterior Ischemic Optic Neuropathy Associated With Bilateral Optic Nerve Sheath Enhancement on Magnetic Resonance Imaging.

A 67-year-old man developed jaw claudication followed by loss of vision in the left eye caused by anterior ischemic optic neuropathy (AION). An erythrocyte sedimentation rate was normal, but C-reactive protein was slightly elevated. Although the patient had no evidence of a right optic neuropathy, magnetic resonance imaging (MRI) revealed bilateral optic nerve sheath enhancement. A temporal artery biopsy was consistent with active giant cell arteritis (GCA). Our case demonstrates that bilateral optic nerve sheath enhancement on MRI can be seen in the setting of unilateral AION. This unique combination of clinical and imaging findings has not been reported previously and extends the clinical spectrum of presentation of GCA.

Isolated aortitis versus giant cell arteritis: are they really two sides of the same coin?

OBJECTIVES: The aim of the study was to compare epidemiological data, clinical findings and results of investigations in patients with isolated aortitis and those with giant cell arteritis (GCA) to establish whether patients with isolated aortitis differ from those with GCA. METHODS: We reviewed the medical notes of all patients consecutively seen in two Rheumatology centres in the last two decades with a suspicion of GCA, searching for cases characterised by abnormal [18F] fluorodeoxyglucose (FDG) PET uptake of the aorta. 'Isolated aortitis' was defined as increased FDG uptake in the aorta not explained by atherosclerosis in the absence of FDG uptake in other large vessels. RESULTS: Comparing the epidemiological and clinical data of patients with isolated arteritis with those with GCA, we observed many statistical significant differences. First of all, the male/female ratio was reversed, with a predominant male involvement in isolated arteritis. Moreover, the mean age of patients with isolated arteritis was significantly lower than that of GCA patients (62 vs. 78.4 yrs; p<0.0001). None of the patients with isolated aortitis presented at any time of the disease course the typical symptoms of GCA, while in a low percentage of cases constitutional symptoms represented the only clinical features. Beside the aortic arch, the sites more frequent involved were the thoracic and abdominal tracts, in all cases without an uptake of the aortic branches. CONCLUSIONS: It is not known whether our patients with isolated aortitis represent variants of GCA or TA, nor is it known how they will evolve, but we can certainly conclude that these patients have a different epidemiologic and clinical profile, and do not necessarily represent two sides of the same coin.

Temporal arteritis in a young patient.

Temporal arteritis in the young is clinically and histologically different from classic giant cell arteritis of the elderly population. A male patient, aged 36 years, presented with headache and a nodule in his left temporal region. Histological examination of the nodule showed that the left temporal artery was encircled by a lymphoid tissue with prominent germinal centres. The arterial wall was infiltrated with mixed inflammatory cells, the internal elastic lamina was disrupted, and there was marked intimal hyperplasia. The patient was diagnosed with juvenile temporal arteritis. Because of persistent headache after surgical excision of the lesion, the patient was treated with prednisolone. Systemic vasculitides, classic giant cell arteritis, Kimura's disease, and angiolymphoid hyperplasia with eosinophilia should be considered in the differential diagnosis of the disease.