Giant cell arteritis: a review of classification, pathophysiology, geoepidemiology and treatment

Giant cell arteritis is a chronic vasculitis affecting large and medium-sized arteries, most commonly the temporal and other cranial arteries. Temporal artery biopsy has long been the gold standard for establishing the diagnosis of giant cell arteritis. There is growing evidence that simultaneous color Doppler and duplex ultrasonography of temporal arteries of GCA patients represents a valid alternative for this somewhat invasive procedure. Ultrasonography and other imaging modalities such as magnetic resonance imaging and positron emission tomography have also provided evidence that involvement of the aorta and its proximal branches is much more common in giant cell arteritis than previously appreciated; it will be important to clarify whether these patients need to be treated more aggressively. It has long been known that patients with giant cell arteritis face a markedly increased risk of developing aortic aneurysms and of dying from aortic dissection. This raises important questions as to whether patients should be screened regularly for extra-cranial large-vessel involvement and whether and how treatment of patients with positive screening results should be adjusted. In this review we discuss the pathophysiology of this disease and also the issues of epidemiology and sex differences.     

Case of microscopic polyangiitis and giant cell arteritis after influenza vaccination

We report a case of microscopic polyangiitis (mPA) and giant cell arteritis (GCA) (polyangiitis overlap syndrome) after influenza vaccination. A 67-year-old female with chronic kidney disease, who had been observed by a physician, presented fever and headache after immunization of influenza vaccine. She was diagnosed as having with mPA and GCA based on symptoms, worsening of renal function, biopsy of temporal artery (giant cell arteritis) and skin (microscopic polyangiitis), pulmonary involvement and the presence of myeloperoxidase-specific anti-neutrophil cytoplasmic antibodies (MPO-ANCA). She was treated with prednisolone (PSL) and the symptoms were improved. However, two months later she was presented with general physical weariness. She was diagnosed as having with pneumocystis pneumonia, cytomegalovirus infection and cryptococcosis. Despite intensive treatment, she was died and autopsy was performed. The present case suggests that the influenza vaccination may cause different types of vasculitis, mPA and GCA, through the common mechanism in pathophysiology. This patient is also the first case of mPA and GCA proven by histological examination.     

Cranial giant cell arteritis mimickers: A masquerade to unveil

Giant cell arteritis (GCA) is a large-vessel vasculitis that affects cranial and extra-cranial arteries. Extra-cranial GCA presents mainly with non-specific symptoms and the differential diagnosis is very broad, while the cranial form has more typical clinical picture and physicians have a lower threshold for diagnosis and treatment. Although temporal artery biopsy (TAB) has an established role, ultrasound (US) is being increasingly used as the first-line imaging modality in suspected GCA. Vasculitides (especially ANCA-associated), hematological disorders (mainly amyloidosis), neoplasms, infections, atherosclerosis and local disorders can affect the temporal arteries or might mimic the symptoms of cranial GCA and produce US and TAB findings that resemble those of temporal vasculitis. Given that prompt diagnosis is essential and proper treatment varies significantly among these diseases, in this review we aimed to collectively present disorders that can masquerade cranial GCA.     

Headache due to temporal arteritis

Pain associated with geant cell arteritis (GCA) is typically continuous, with exacerbations that often occur at night. Contact is painful and can precipitate an exacerbation of pain lasting several hours. The superficial temporal artery is the most common target of GCA but symptoms vary according to the predominant site of arterial inflammation. As a result, GCA can present in different ways with headaches being mild or absent in some patients. In nearly 40% of patients with biopsy-documented GCA, palpation of the branches of the external carotid artery fails to demonstrate any abnormalities. This arteritis affects the aortic arch and all its branches giving rise to a broad range of neurologic symptoms, for example, ocular disease, ischemic stroke, aortic dissection, etc. About 30% of patients also have symptoms of polymyalgia rheumatica. Demonstration of an inflammatory syndrome is important and temporal artery biopsy is the last element of the diagnostic. In some locations of the GCA angiography is useful. Treatment, commonly including corticosteroids, should be initiated as early as possible. Prevention of osteoporosis should be initiated especially in elderly subjects. In some cases other treatments are useful anticoagulants, immunosuppressive therapies, dapsone.     

Evaluation of deeper levels in initially negative temporal artery biopsies and likelihood of a positive result

Giant cell arteritis is a vasculitis that affects large- and medium-sized vessels in patients over the age of 50 years. The demonstration of granulomatous arteritis is the criterion standard to establish a definitive diagnosis. However, temporal arteritis is known to discontinuously involve the artery, and there is no standardization of the number of sections which should be examined in a length of sampled artery. The goal of the study is to determine, if by examining additional sections from temporal artery (TA) biopsy cases initially interpreted as negative, do we uncover cases of vasculitis. We conducted a retrospective review of the clinical and histologic features of 75 consecutive temporal artery biopsy cases. Our findings showed that the vast majority (94%) of cases that were biopsy “proven” to be negative for temporal arteritis on initial examination remained negative after examination of all subsequent deeper levels (median of 337 total levels examined). These cases were less likely to show classical GCA signs and symptoms and typically presented at a younger age than the biopsy-positive cases. However, 4 (6%) of the initially “biopsy-negative” cases did turn out to be positive on deeper levels, with 56, 109, 346, and 590 total levels examined, respectively. At least 2 of these 4 patients did not receive prednisone or were weaned off prednisone treatment and experienced persistent/recurrent GCA symptoms. We conclude that routine sampling may miss the diagnosis in a subset of cases and in some cases, sectioning deeper into the paraffin block may be warranted.     

Fatal vertebral giant cell arteritis.

Death due to giant cell arteritis (GCA) is rare, and is usually caused by coronary or vertebral arteritis in the acute phase of the disease. A case of fatal GCA is reported in a woman with a normal erythrocyte sedimentation rate, who had been treated for temporal arteritis for eight months. Post mortem examination showed a dissection and thrombosis of the intracranial portion of the left vertebral artery caused by giant cell arteritis. Focal coronary artery GCA was also found. As far as is known, this is the only case in which dissection of the vertebral artery attributable to GCA has been reported.     

Diagnosis and Management of Polymyalgia Rheumatica/Giant Cell Arteritis

There are no standardised diagnostic criteria for polymyalgia rheumatica. The combination of persistent pain (at least 1 month) with marked morning stiffness in at least 2 of the neck, shoulder or pelvic girdle is characteristic of polymyalgia rheumatica. The other criteria are age >50 years, erythrocyte sedimentation rate (ESR) >40 mm/hour, rapid response to corticosteroids and an absence of other diseases capable of causing the musculoskeletal symptoms. A normal ESR does not exclude a diagnosis of polymyalgia rheumatica. Diagnostic temporal artery biopsy is recommended in all patients suspected of having giant cell arteritis. The segment of temporal artery with abnormality on physical examination should be biopsied. The drugs of choice in the treatment of polymyalgia rheumatica/giant cell arteritis are corticosteroids. An initial prednisone dosage of 40 to 60 mg/day is adequate in almost all cases of giant cell arteritis. Higher dosages and/or intravenous pulse methylprednisolone can be tried on patients with partial response or with recent visual loss. Polymyalgia rheumatica in the absence of giant cell arteritis requires an initial dose of prednisone 10 to 20 mg/day. In some cases of mild polymyalgia rheumatica, a short course of nonsteroidal anti-inflammatory drugs may be tried. Long term corticosteroid therapy in polymyalgia rheumatica and giant cell arteritis is complicated by serious adverse effects in between 48 and 65% of patients. Vertebral fractures and infections are among the most dangerous and frequent complications. Although there are limited data on the use of cytotoxic or immunosuppressive drugs, such as methotrexate, azathioprine and cyclosporin, in these indications, they might be effective either in sparing corticosteroids or in treating patients who do not respond to treatment with corticosteroids.     

No detection of parvovirus B19 or herpesvirus DNA in giant cell arteritis.

BACKGROUND: Compelling arguments exist for a role of infectious agent in giant cell arteritis (GCA). Parvovirus B19 and several herpesviruses have focussed the attention in recent years, but the few studies to date have yielded inconsistent results. OBJECTIVES: To study the relationship between the presence of parvovirus B19 DNA or major known herpesviruses and the histopathological features of GCA. STUDY DESIGN: Between January 1997 and March 2002, 147 consecutive temporal artery biopsies were performed in our center because of a clinical suspicion of GCA. Using polymerase chain reaction (PCR) procedures validated by the World Health Organization and employed routinely by our laboratory, we examined the paraffin-embedded specimens for DNA from parvovirus B19, herpes simplex viruses (HSV) 1 and 2, Epstein-Barr virus (EBV), varicella-zoster virus (VZV), human cytomegalovirus (HCMV), and human herpesvirus 6 (HHV-6). We investigated positive results further with immunohistochemistry studies. RESULTS: Fifty of the 147 temporal artery biopsies (34%) showed histological features of GCA. Three biopsies (2.5%) were initially PCR positive for parvovirus B19. None of the herpesvirus PCR assays were positive. Upon repeat testing by both PCR and immunohistochemistry, none of the three initially positive parvovirus B19 assays were confirmed. The results of both positive and negative control assays in these studies validated these findings. We confirmed the presence of amplifiable DNA in the temporal artery biopsy specimens using PCR primers for beta-globin and indoleamine 2,3-dioxygenase (IDO). CONCLUSIONS: The results of our study do not support a role in the etiopathogenesis of GCA for either parvovirus B19 or any of these six herpesviruses.     

Epithelioid hemangioma of the temporal artery clinically mimicking temporal arteritis

A rare case of epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) arising in the right temporal artery of a 68-year-old Japanese woman was investigated. The patient had been treated with corticosteroids (Predonine 5 mg/day p.o.) for 4 years for idiopathic thrombocytopenic purpura. Headaches in the right temporal region with repeated high fevers first appeared 1 year prior to the biopsy of a nodule at the artery. The clinical diagnosis was temporal arteritis (giant cell arteritis). The specimen consisted of a short segment of the superior arterial branch having a sheet-like proliferation of the epithelioid endothelial cells in the lumen, which was almost occluded, focal rupture of the media, and marked proliferation of the capillaries (neovascularization) radiating out from the media to the adventitia. There were scattered foci of inflammatory cell infiltration composed mainly of small lymphocytes in the adventitia, but there were no histological changes suggestive of giant cell arteritis. The lesion was thus characterized by the proliferation of epithelioid endothelial cells in the lumen of the artery, and neovascularization between the media and adventitia. The histological features were very close to epithelioid hemangioma except for the absence of an eosinophilic reaction. The long-term administration of corticosteroids may have suppressed it. The authors believe this is the first case of epithelioid hemangioma arising from the temporal artery without a history of trauma. It showed some unique features both clinically and histopathologically, which contributed to the study of the yet not clearly classified vascular proliferative lesion, epithelioid hemangioma.     

Diagnostic performance of temporal artery ultrasound for the diagnosis of giant cell arteritis: a systematic review and meta-analysis of the literature

Despite major recent advances in the therapeutic management of Giant cell arteritis (GCA), the diagnosis accuracy of temporal artery ultrasound remains controversial in this disease. We performed a systematic review to determine the sensitivity, specificity, and summary positive (LR+) and negative (LR-) likelihood ratios of temporal artery ultrasound for the diagnosis of GCA. For this, we searched EMBASE, MEDLINE and the Cochrane Database of Systematic Reviews without language restriction. Original articles reporting on diagnostic accuracy of temporal artery ultrasound compared to temporal artery biopsy, for the diagnosis of GCA, were selected. Sensitivity and specificity from each study were used to fit a bivariate diagnosis accuracy model. Of 1280 articles identified, 48 underwent full-text review, and 25 were included. Based on a total of 20 studies, the sensitivity and specificity of hypoechoic halo compared to positive temporal artery biopsy were respectively of 68% (95% CI: 57–78) and 81% (95%CI: 75–86). The summary mean positive and negative likelihood ratios were respectively of 3.64 (95%CI: 2.76–4.73) and 0.40 (0.28–0.52). Taking into account 11 studies reporting on the presence of any abnormal sign on temporal artery ultrasound yielded similar results with largely overlapping 95% confidence interval regions. This study provides the summary estimates of the diagnostic properties of temporal artery ultrasound compared to temporal artery biopsy, for the diagnosis of GCA. Those parameters allow the calculation of the post-test probability of GCA in a given patient, based on the results of temporal artery ultrasound and will help improving the diagnosis strategy for this common disease.     

Failure to detect human herpes simplex virus, cytomegalovirus, and Epstein-Barr virus viral genomes in giant cell arteritis biopsy specimens by real-time quantitative polymerase chain reaction.

A study provided evidence of human herpes simplex virus (HSV) DNA in giant cell arteritis (GCA) biopsy specimens. This prompted us to study our own GCA biopsy specimens using real-time quantitative polymerase chain reaction for the detection of HSV1, cytomegalovirus, and Epstein-Barr virus DNAs. Our study failed to confirm an association between HSV1 and GCA, revealing no viral genome in 35 biopsy specimens of histologically positive temporal arteries.     

Juvenile temporal arteritis associated with Kimura's disease

A case of juvenile temporal arteritis, which is a rare vascular lesion in children and young adults, associated with Kimura's disease in a healthy 23-year-old asymptomatic man is described. The patient presented with a painless 2.5 cm nodule with eosinophilia and normal erythrocyte sedimentation rate. Histologically, the left superficial artery showed marked intimal thickening with moderate eosinophilic infiltrates, constriction of the vascular lumen, focal disruptions of the internal elastic lamina and media, moderate eosinophilic infiltrates in the adventia, and absence of giant cells. The subcutaneous tissue surrounding the artery was characterized by lymphofollicular hyperplasia, marked eosinophilic infiltrates in the intra- and extra-follicles with abscess, capillary proliferations, lymphocytic, plasma cell and mast cell infiltrates, and fibrosis in the interfollicular region. Immunohistochemically, reticular, positive IgE staining was observed in the germinal centers. Clinically and histologically, the lesion was consistent with juvenile temporal arteritis associated with Kimura's disease. The findings indicate that both entities are closely related and juvenile temporal arteritis may be secondary to Kimura's disease.     

An Uneven Expression of T Cell Receptor V Genes in the Arterial Wall and Peripheral Blood in Giant Cell Arteritis

The aim of the study was to investigate T cell receptor (TCR) usage at the time of diagnosis of giant cell arteritis (GCA) and to estimate the degree of clonality of T-cells infiltrating the lesion. Seven patients with biopsy-proven giant cell arteritis were included in the study. Immunocytochemistry in biopsies from the temporal arteries and flow cytometric analysis of peripheral blood lymphocytes (PBL) was performed using monoclonal antibodies specific for CD3, CD4 and CD8 and 13 TCR Vα and Vβ gene segment products. The CDR3 fragment length polymorphism was assessed by gel electrophoresis of PCR-amplified TCR segments. The T lymphocytes were found to be concentrated to the adventitia rather than the media or intima. Six of the seven patients with GCA had expansions of T lymphocytes, expressing selected TCR V genes in the arterial wall. None of these expansions was found in PBL. The infiltrating T-cells were poly- or oligoclonal. In conclusion, the dominating part of the inflammatory infiltrate in GCA emanates from the adventitial microvessels. There is an uneven expression of TCR V genes by T lymphocytes in the inflammatory infiltrates as compared to peripheral blood T lymphocytes at the time of diagnosis, consistent with an antigen-driven immunological reaction in the arterial wall.     

An overview of the perspectives on experimental models and new therapeutic targets in giant cell arteritis

Giant cell arteritis (GCA) is the most frequent systemic vasculitis occurring in adults older than 50 years, and aortitis is described in 40% to 80% of patients. The treatment relies on corticosteroids, but it is complicated by high rates of relapses and adverse effects and may be unable to completely inhibit aortic inflammation. Moreover, most of the current data regarding the pathophysiology of GCA have been obtained from bioassays using blood and temporal arteries, as well as histological analyses of temporal arteries and very few aortic aneurysms from patients with GCA. The limitations of these analyses prevent researchers from determining the implications of specific targets and studying the effects of targeted treatments. Several experimental models have been developed, but to date, a perfect model is not available for GCA, particularly for studies of large-vessel vasculitis. The review focuses on the perspectives on experimental models and new therapeutic targets in giant cell arteritis.     

Giant cell arteritis: a multicenter observational study in Brazil

OBJECTIVE:

To describe demographic features, disease manifestations and therapy in patients with giant cell arteritis from referral centers in Brazil.

METHODS:

A retrospective cohort study was performed on 45 giant cell arteritis patients from three university hospitals in Brazil. Diagnoses were based on the American College of Rheumatology classification criteria for giant cell arteritis or temporal artery biopsy findings.

RESULTS:

Most patients were Caucasian, and females were slightly more predominant. The frequencies of disease manifestations were as follows: temporal headache in 82.2%, neuro-ophthalmologic manifestations in 68.9%, jaw claudication in 48.9%, systemic symptoms in 44.4%, polymyalgia rheumatica in 35.6% and extra-cranial vessel involvement in 17.8% of cases. Aortic aneurysms were observed in 6.6% of patients. A comparison between patients with biopsy-proven giant cell arteritis and those without temporal artery biopsies did not yield significant differences in disease manifestations. All patients were treated with oral prednisone, and intravenous methylprednisolone was administered to nearly half of the patients. Methotrexate was the most commonly used immunosuppressive agent, and low-dose aspirin was prescribed to the majority of patients. Relapses occurred in 28.9% of patients, and aspirin had a protective effect against relapses. Females had higher prevalences of polymyalgia rheumatica, systemic manifestations and jaw claudication, while permanent visual loss was more prevalent in men.

CONCLUSIONS:

Most of the clinical features of Brazilian giant cell arteritis patients were similar to those found in other studies, except for the high prevalence of neuro-ophthalmic manifestations and permanent blindness in the Brazilian patients. Aspirin had a protective effect on relapses.     

Disseminated visceral giant cell arteritis: histopathologic description and differentiation from other granulomatous vasculitides

Disseminated visceral giant cell arteristic, a previously unknown entity, was observed in four autopsied patients, all men, aged 33, 67, 59 and 45 years. None of the patients had temporal arteritis, collagen disease, sarcoidosis, hepatitis or other infections, and vasculitis was diagnosed only after death. All had giant cell arteritis of extracranial arteries and arterioles in at least three of the following organs: the heart, lungs, kidneys, liver, pancreas, and stomach in various combinations. Despite some histopathologic similarities, disseminated visceral giant cell arteritis can be distinguished from other necrotizing and granulomatous vasculitides by the type of vessels principally affected and the presence or absence of giant cells, vascular fibrinoid necrosis and eosinophilic infiltrates. The observations suggest that it is a distinctive type of systemic vasculitis.     

Histological interpretation of temporal artery biopsies

Temporal artery biopsy is recommended for diagnosis of suspected giant cell arteritis, a systemic vasculitis of older adults. There is currently no formal consensus for histological interpretation of the biopsies. Typical histological findings include a transmural lymphocytic infiltrate with a population of macrophages resulting in destruction of the internal elastic lamina. However, it is a patchy process and multiple tissue levels must be examined. It is important to be aware of various subtle features that may lead to a diagnosis of arteritis, and immunohistochemistry can be helpful in some cases. Some biopsies show unusual features that could raise a differential diagnosis of alternative vasculitides. When there is no evidence of arteritis in a specimen, there are often non-specific features seen in the context of age-related changes. All of these histological patterns require close clinicopathological correlation to ensure correct interpretation.     

Pericardial effusion and aortitis: unusual main manifestations of giant cell arteritis

Giant cell arteritis is a systemic vasculitis with segmentary vascular localisation, usually manifesting as temporal arteritis (Horton's disease). The predominant localisation in different vascular districts leads to clinical heterogeneity and poses a considerable diagnostic challenge. We describe a 77-year old woman with atypical presentation of giant cell arteritis, suffering from fever, weight loss and fatigue, but without classical symptoms such as polymyalgias, arthralgias and headache. The findings of pericardial effusion and thickening of aortic wall in chest-CT suggested the diagnosis of giant cell arteritis, fully confirmed by the following biopsy and histologic examination of a macroscopically and palpatory normal arteria temporalis. Undergoing an appropriate corticosteroid-medication the patient has been free of symptoms since 8 months.     

Lingual infarction and sudden blindness due to giant cell arteritis

A 72-year-old woman suffered from giant cell arteritis (GCA) which developed into lingual infarction and monocular blindness. Temporary obscuration of vision and lingual symptoms such as increasing malaise, pain and intermittent claudication may precede the catastrophic results of arteritis. Emphasis is laid on early recognition and treatment of GCA.     

Temporal artery biopsy: is there any value in examining biopsies at multiple levels?

AIMS: To analyse the cost-effectiveness of three strategies for examining temporal artery biopsies based on data from cases examined over the past 10 years. METHODS: Of a total of 172 temporal artery biopsies, five were unsuitable for further analysis, 47 had already had levels cut, and 120 had levels cut as part of the study. All the biopsies were examined blind before and after levels. A tree with eventual diagnostic outcomes for different strategies was constructed and economic and sensitivity analyses performed. Welcan units were used to assess technical workload. RESULTS: Only one of the 132 initially normal cases and two of 14 diagnosed with periarterial lymphocytic infiltration (PALI) revealed giant cell arteritis after examining the tissue at multiple levels. Fifteen cases (8.9%) showed PALI not previously observed. The marginal cost for each extra case of giant cell arteritis detected was 83.5 Welcan units for a strategy of routine levels on all sections, and 21 Welcan units for a strategy of only cutting levels if PALI was present on the initial section. These costs were sensitive to the frequency of giant cell arteritis in cases with PALI and to the relative extra cost of moving from cutting single section to routine levels. CONCLUSIONS: Routinely examining a temporal artery biopsy at multiple levels does not increase the diagnostic yield of the test, although selective further examination may be indicated in some cases. The significance of PALI is uncertain. The cost-benefit of the different strategies in terms of clinical decision making revolve around the perceived risk inherent in not making a diagnosis of giant cell arteritis.