Pathogenesis of giant cell arteritis.
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Giant Cell Arteritis↗
Biomedical subjects
G G Hunder
Publications and source records attributed to G G Hunder.
Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis.
OBJECTIVE: To explore the role of proinflammatory cytokines in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR), two clinically related syndromes characterized by an intense acute-phase reaction. In particular, to determine plasma concentrations of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) and to correlate changes in plasma IL-6 levels with clinical symptoms during corticosteroid therapy. METHODS: IL-6 and TNF alpha concentrations were determined in plasma samples from patients with untreated PMR or GCA, and plasma IL-6 levels were monitored in patients receiving long-term therapy (14 months) with corticosteroids. To identify IL-6-producing cells, the polymerase chain reaction was used to detect IL-6 messenger RNA. In vitro production of IL-6 and IL-2 by peripheral blood mononuclear cells (PBMC) from treated and untreated patients was quantified using IL-6- and IL-2-specific bioassay systems. RESULTS: IL-6 concentrations were increased in PMR and GCA patients, whereas TNF alpha concentrations were similar to those in normal donors. Administration of corticosteroids rapidly reduced the levels of circulating IL-6 but did not correct the underlying mechanism inducing the increased IL-6 production. In individual patients, changes in plasma IL-6 levels and clinical manifestations during prolonged therapy were closely correlated. Short-term withdrawal of corticosteroids, even after several months of treatment, was followed by an immediate increase in plasma IL-6 concentrations. To identify the cellular source of plasma IL-6, PBMC from treated and untreated patients with PMR or GCA were analyzed for their ability to secrete IL-6 and the T cell-specific cytokine IL-2. Polyclonal T cell stimulation caused a rapid release of IL-6, which was shown to be derived exclusively from CD14+ cells. CONCLUSION: Increased production of IL-6, but not TNF alpha, is a characteristic finding in patients with PMR or GCA. Corticosteroids rapidly suppress IL-6 production but do not correct the underlying mechanism inducing the increased IL-6 production. The close correlation of plasma IL-6 concentrations with clinical symptoms suggests a direct contribution of this cytokine to the disease manifestations and presents the possibility that monitoring IL-6 levels would be useful in making decisions on adjustment of corticosteroid dosage in individual patients.
Aged↗
Classification of vasculitis.
The sensitivities and specificities of the classification rules of the seven major forms of vasculitis studied varied considerably from 70% to over 99% (Table 2.) High values as found for giant cell (temporal) arteritis, Takayasu arteritis, and Churg-Strauss syndrome, indicate clinically well defined conditions. In contrast, the lowest sensitivity and specificity resulted for the classification of hypersensitivity vasculitis, in which definitions and manifestations are subject to great variation. In a number of instances collection of important clinical data was incomplete. This may have had the effect of reducing sensitivities and specificities to some extent. Because all the cases studied had vasculitis, these criteria are not appropriate to use for diagnosis of individual patients. Development of diagnostic criteria also requires comparison of patients who do not have vasculitis. Development of criteria by two different methods provides some flexibility. Both formats should prove easy to use. Although biopsy is not needed in all patients for classification purposes, histology should be performed as frequently as possible to document the vasculitic nature of the disorder. These criteria sets should be used in the description of patients with vasculitis to enhance uniformity of reporting. As other characteristics of these disorders are identified, more accurate classification rules may be revised.
Granulomatosis with Polyangiitis↗
Visual prognosis in giant cell arteritis.
PURPOSE: The visual prognosis in giant cell arteritis (GCA) was evaluated over a 5-year period. METHODS: The authors reviewed the records of all patients with a diagnosis of GCA established at the Mayo Clinic over a 5-year period regarding visual status. Follow-up data for these patients were obtained 5 years later. RESULTS: Of the 245 patients studied, 34 (14%) permanently lost vision because of GCA. In 32 of these patients, the visual deficit developed before glucocorticoid therapy for GCA was begun; in the 2 other patients, the visual loss occurred after the diagnosis was made and therapy was started. Visual loss progressed in three patients after initiation of oral glucocorticoids, and in five other patients vision improved. After 5 years, the probability of loss of vision developing after initiating oral glucocorticoid treatment was determined to be 1% (Kaplan-Meier technique), and the probability of additional loss was 13% in patients with GCA who had a visual deficit at the time therapy was begun. CONCLUSION: The development or progression of visual loss was rare after the initiation of glucocorticoid therapy.
Aged↗
Polymyalgia rheumatica and giant cell arteritis in emergency department patients.
Elderly patients with undiagnosed polymyalgia rheumatica and giant cell arteritis are not uncommon, and they may present to the emergency department with nonspecific physical complaints. We describe the cases of two patients who had the "typical" constellation of symptoms. It is important that emergency physicians consider the diagnosis and provide appropriate testing, therapy, and follow-up.
Aged↗
Serum ELAM-1 is increased in vasculitis, scleroderma, and systemic lupus erythematosus.
OBJECTIVE: To investigate the state of endothelial cell activation in vasculitis, scleroderma, and systemic lupus erythematosus (SLE). METHODS: We used a sandwich ELISA to quantitate a soluble form of endothelial leukocyte adhesion molecule-1 (sELAM) in serum. RESULTS: sELAM was detected in serum from healthy individuals (mean 0.92 ng/ml). Levels were significantly higher in patients with giant cell arteritis (mean 2.04 ng/ml), polyarteritis nodosa (mean 2.08 ng/ml), scleroderma (mean 2.27 ng/ml), and SLE (mean 3.93 ng/ml). Elevated values were present in patients with both active and inactive disease. sELAM levels of > 3 ng/ml identified most patients with recent onset or active disease. CONCLUSION: Our findings may reflect a low degree of endothelial cell activation in healthy persons that is increased in inflammatory diseases involving blood vessels. Elevated serum sELAM levels may reflect ongoing inflammatory processes in these diseases.
Adolescent↗
Neurologic aspects of giant cell (temporal) arteritis.
Headache is the most frequent symptom for which a patient with giant cell arteritis (GCA) presents to a neurologist. Amaurosis fugax and ischemic optic neuropathy are well-recognized complications. Less commonly recognized neurologic complications include transient ischemic attacks, cerebral infarctions, acute confusional states (due to multi-infarct dementia), ischemic cervical myelopathy, and ischemic mononeuropathies. Because patients with GCA generally respond well to corticosteroid therapy, prompt diagnosis can minimize neurologic damage.
Cerebrovascular Disorders↗
Overtraining in neural networks that interpret clinical data.
Backpropagation neural networks are a computer-based pattern-recognition method that has been applied to the interpretation of clinical data. Unlike rule-based pattern recognition, backpropagation networks learn by being repetitively trained with examples of the patterns to be differentiated. We describe and analyze the phenomenon of overtraining in backpropagation networks. Overtraining refers to the reduction in generalization ability that can occur as networks are trained. The clinical application we used was the differentiation of giant cell arteritis (GCA) from other forms of vasculitis (OTH) based on results for 807 patients (593 OTH, 214 GCA) and eight clinical predictor variables. The 807 cases were randomly assigned to either a training set with 404 cases or to a cross-validation set with the remaining 403 cases. The cross-validation set was used to monitor generalization during training. Results were obtained for eight networks, each derived from a different random assignment of the 807 cases. Training error monotonically decreased during training. In contrast, the cross-validation error usually reached a minimum early in training while the training error was still decreasing. Training beyond the minimum cross-validation error was associated with an increased cross-validation error. The shape of the cross-validation error curve and the point during training corresponding to the minimum cross-validation error varied with the composition of the data sets and the training conditions. The study indicates that training error is not a reliable indicator of a network's ability to generalize. To find the point during training when a network generalizes best, one must monitor cross-validation error separately.
Bias↗
Giant cell arteritis and polymyalgia rheumatica.
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Aged↗
The HLA-DRB1 locus as a genetic component in giant cell arteritis. Mapping of a disease-linked sequence motif to the antigen binding site of the HLA-DR molecule.
Giant cell arteritis (GCA) is a granulomatous vasculitis affecting persons over 50 years of age. The inflammatory infiltrate, which is targeted at the aorta and its proximal branches, includes activated CD4+ helper T cells, histiocytes, and giant cells. To investigate whether the genetic polymorphism of the HLA-DRB1 genes contributes to the local accumulation of activated T cells, we have analyzed both HLA-DRB1 alleles in a cohort of 42 patients with biopsy-proven GCA. The majority of patients (60%) expressed the B1*0401 or B1*0404/8 variant of the HLA-DR4 haplotype, both of which also represent the major genetic factors underlying the disease association in RA. GCA patients negative for the disease-linked HLA-DR4 alleles were characterized by a nonrandom distribution of HLA-DRB1 alleles. Sequence comparison among the allelic products identified in the GCA cohort demonstrated heterogeneity for the sequence polymorphism of the third hypervariable region (HVR), but homology for the polymorphic residues within the HVR2 of the HLA-DRB1 gene. The GCA patients shared a sequence motif spanning amino acid positions 28-31 of the HLA-DR beta 1 chain. In the structural model for HLA-DR molecules, this sequence motif can be mapped to the antigen-binding site of the HLA complex, suggesting a crucial role of antigen selection and presentation in GCA. In contrast, the sequence polymorphism linked to RA has been mapped to the HVR3 of the HLA-DRB1 gene and translates into a distinct domain of the HLA-DR molecule, the alpha-helical loop surrounding the antigen-binding groove. A consecutive case series study demonstrated that GCA and RA rarely co-occurred, supporting the interpretation that distinct functional domains of the HLA-DR molecule are implicated in the pathomechanisms of these two autoimmune diseases.
Age Factors↗
Hypersensitivity vasculitis and Henoch-Schönlein purpura: a comparison between the 2 disorders.
Leukocytoclastic vasculitis of small vessels and predominant involvement of the skin are common features of both hypersensitivity vasculitis (HV) and Henoch-Schönlein purpura. In a study comparing 93 patients with HV and 85 patients with Henoch-Schönlein purpura we found major differences with respect to frequencies and type of organ involvement (gastrointestinal tract, kidneys, skin and joints) which were present in both younger and older patients when analyzed separately. To investigate which clinical criteria best differentiate between these 2 vasculitides, 2 methodologies were employed. A rule requiring 3 or more criteria to be present from a list of 6 yielded 87.1% of correctly classified Henoch-Schönlein purpura cases; and 2 or fewer criteria from the same list of 6 correctly classified 74.2% of HV cases. A classification tree was associated with respective values of 83.5 and 84.9%. The results indicate that HV and Henoch-Schönlein purpura are similar but separable clinical syndromes.
Adolescent↗
Inducible release of an endothelial cell-specific protein.
The authors investigated the release of an endothelial cell-specific protein (E92) by cultured porcine aortic endothelial cell cultures. Under normal culture conditions, endothelial cells released little or no E92 into the culture supernatant. Treatment with thrombin (0.01 to 10 units/ml), endotoxin (0.01 to 10 micrograms/ml), or interleukin-1 (0.01 to 3.0 units/ml), however, caused significant, dose-dependent increases in E92 detectable in the culture supernatants. Time-course experiments showed that maximum release of E92 into cellular supernatants occurred 24 hours after stimulation with all mediators. Parallel experiments used 51Cr-loaded endothelial cells as a measure of lethal cellular injury. None of the mediators caused significant injury at the doses observed to induce release of E92. These results suggest that the release of E92 into the supernatants of cultured endothelial cells is an inducible event. The data also support the hypothesis that detection of E92 antigen in sera from patients with rheumatic disease represents a marker of in vivo vascular endothelial cell activity.
Animals↗
Detection of circulating endothelial antigen.
In order to determine whether endothelial cell antigens are detectable in serum from patients with rheumatic disease characterized by vascular involvement, we developed an ELISA using a monoclonal antibody directed against a 92,000 molecular weight endothelial cell specific antigen designated E92. Sera were assayed from 191 patients and 34 healthy controls. E92 was undetectable or present in very low concentrations in healthy controls and was elevated in most patients with an active rheumatic disease. Our results indicate that circulating endothelial antigens are present in rheumatic vascular syndromes and may provide a measure of endothelial cell function.
Adolescent↗
The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction.
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Humans↗
The American College of Rheumatology 1990 criteria for the classification of vasculitis. Patients and methods.
The American College of Rheumatology Subcommittee on Classification of Vasculitis of the Diagnostic and Therapeutic Criteria Committee developed classification criteria for 7 forms of vasculitis: polyarteritis nodosa, Churg-Strauss syndrome, Wegener's granulomatosis, hypersensitivity vasculitis, Henoch-Schönlein purpura, giant cell (temporal) arteritis, and Takayasu arteritis. The data collection methods, quality control, and analytic procedures used to derive the classification rules are discussed herein.
Data Collection↗
The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa.
Criteria for the classification of polyarteritis nodosa were developed by comparing 118 patients who had this disease with 689 control patients who had other forms of vasculitis. For the traditional format classification, 10 criteria were selected: weight loss greater than or equal to 4 kg, livedo reticularis, testicular pain or tenderness, myalgias, mononeuropathy or polyneuropathy, diastolic blood pressure greater than 90 mm Hg, elevated blood urea nitrogen or serum creatinine levels, presence of hepatitis B reactants in serum, arteriographic abnormality, and presence of granulocyte or mixed leukocyte infiltrate in an arterial wall on biopsy. The presence of 3 or more of these 10 criteria was associated with a sensitivity of 82.2% and specificity of 86.6%. A classification tree was also constructed, with 6 criteria being selected. Three of these, angiographic abnormality, biopsy-proven granulocyte or mixed leukocyte infiltrate in arterial wall, and neuropathy, were criteria used in the traditional format. The other 3 criteria used in the tree format included the patient's sex, weight loss greater than 6.5 kg, and elevated serum aspartate aminotransferase or alanine aminotransferase levels above the range of normal. The classification tree yielded a sensitivity of 87.3% and a specificity of 89.3%.
Diagnosis, Differential↗
The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis).
Criteria for the classification of Churg-Strauss syndrome (CSS) were developed by comparing 20 patients who had this diagnosis with 787 control patients with other forms of vasculitis. For the traditional format classification, 6 criteria were selected: asthma, eosinophilia greater than 10% on differential white blood cell count, mononeuropathy (including multiplex) or polyneuropathy, non-fixed pulmonary infiltrates on roentgenography, paranasal sinus abnormality, and biopsy containing a blood vessel with extravascular eosinophils. The presence of 4 or more of these 6 criteria yielded a sensitivity of 85% and a specificity of 99.7%. A classification tree was also constructed with 3 selected criteria: asthma, eosinophilia greater than 10% on differential white blood cell count, and history of documented allergy other than asthma or drug sensitivity. If a subject has eosinophilia and a documented history of either asthma or allergy, then that subject is classified as having CSS. For the tree classification, the sensitivity was 95% and the specificity was 99.2%. Advantages of the traditional format compared with the classification tree format, when applied to patients with systemic vasculitis, and their comparison with earlier work on CSS are discussed.
Adolescent↗
The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis.
Criteria for the classification of Wegener's granulomatosis (WG) were developed by comparing 85 patients who had this disease with 722 control patients with other forms of vasculitis. For the traditional format classification, 4 criteria were selected: abnormal urinary sediment (red cell casts or greater than 5 red blood cells per high power field), abnormal findings on chest radiograph (nodules, cavities, or fixed infiltrates), oral ulcers or nasal discharge, and granulomatous inflammation on biopsy. The presence of 2 or more of these 4 criteria was associated with a sensitivity of 88.2% and a specificity of 92.0%. A classification tree was also constructed with 5 criteria being selected. These criteria were the same as for the traditional format, but included hemoptysis. The classification tree was associated with a sensitivity of 87.1% and a specificity of 93.6%. We describe criteria which distinguish patients with WG from patients with other forms of vasculitis with a high level of sensitivity and specificity. This distinction is important because WG requires cyclophosphamide therapy, whereas many other forms of vasculitis can be treated with corticosteroids alone.
Biopsy↗