Giant Cell Arteritis: Disease Patterns of Clinical Presentation in a Series of 240 Patients : Medicine

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Giant Cell Arteritis

Disease Patterns of Clinical Presentation in a Series of 240 Patients

Gonzalez-Gay, Miguel A. MD, PhD; Barros, Sonia MD; Lopez-Diaz, Maria J. MD; Garcia-Porrua, Carlos MD, PhD; Sanchez-Andrade, Amalia MD; Llorca, Javier MD, PhD

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Medicine 84(5):p 269-276, September 2005. | DOI: 10.1097/01.md.0000180042.42156.d1
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Abstract

INTRODUCTION

Giant cell arteritis (GCA) is the most common type of systemic vasculitis in North America and Europe in patients over the age of 50 years15. It is characterized by the granulomatous involvement of large and medium-sized blood vessels of the aorta with predilection for the extracranial branches of the carotid artery35,41.

Classically, GCA patients present with cranial ischemic manifestations that are directly related to vascular involvement35,41. Headache is the main symptom in more than two-thirds of patients30, and is also the most frequent initial complaint32. This classical manifestation of GCA is characteristically of sudden onset, severe, and predominantly temporal. However, headaches in patients with GCA may also occur in the occipital, frontal, and parietal regions. The new onset of headache in a patient more than 50 years of age should alert the clinician to the possibility of GCA.

GCA patients often present clinical manifestations of polymyalgia rheumatica (PMR)9,41,42, characterized by sudden or gradual onset of morning stiffness, pain in the neck, shoulders, or hips, and pain during the night. In biopsy-proven GCA, PMR manifestations are observed in 40%-60% of cases13,28,30,41. PMR may also be the presenting feature in patients who later develop typical cranial ischemic manifestations of GCA38,40.

The outcome of a patient with GCA is related to the development of severe ischemic manifestations26. Among them, jaw claudication, intermittent claudication of the muscles of mastication, may be a presenting symptom of this vasculitis. This severe ischemic manifestation is observed in about 50% of patients30,32. Visual manifestations constitute the most feared aspects of GCA1. They occur in about 30% of patients, with loss of vision in 15%1,19. Visual symptoms are usually secondary to ischemia of the optic nerve due to arteritis of branches of the ciliary or ophthalmic arteries. Although visual manifestations may be intermittent initially, visual deficit is usually irreversible once established12. Less commonly, other severe ischemic complications such as large-artery involvement manifested by claudication of the extremities26 and stroke, in particular in the vertebrobasilar territory, may be observed at the time of diagnosis of GCA or within the first month after the onset of steroid therapy12,39.

However, a variable proportion of GCA patients may present without obvious vascular manifestations2,8,29. In these patients with subclinical ("silent") GCA, isolated PMR or fever of unknown origin may be the clue to suspect GCA17.

The incidence of GCA increases with patients' age and peaks in those groups of patients older than 70 years21,34. As pointed out by Hellmann30, the mean age of onset is about 72 years, and the disease rarely occurs in persons younger than 50 years.

Since a high index of suspicion of this condition in individuals over the age of 50 years is needed to prevent the development of severe complications, mainly permanent vision loss, we studied the different patterns of disease presentation in a large series of biopsy-proven patients diagnosed at the single hospital for the well-defined population from the Lugo region in northwestern Spain. Moreover, we examined the potential influence of age at the time of disease diagnosis in the clinical spectrum of this vasculitis.

PATIENTS AND METHODS

We retrospectively reviewed the medical records of all patients diagnosed with biopsy-proven GCA at the Department of Medicine, Hospital Xeral-Calde (Lugo, Spain) between January 1, 1981, and June 15, 2004. This hospital is the reference center for a mixed rural and urban population of almost a quarter of a million people. Information about the characteristics of this white population has been previously described14,20. The current study and the companion study25a reported in this issue are an extension of the population study20,26 published in Medicine in 2004.

The temporal artery biopsy (TAB) procedure in Lugo patients has been reported elsewhere19,24. As previously reported, TAB was routinely performed in all patients with clinical manifestations of GCA10,23. The side with predominant local temporal, neck, or shoulder symptoms and signs was selected for biopsy. Segments longer than 2.5 cm were generally obtained. In those patients with clinically isolated PMR, without any vascular manifestation of GCA, biopsies were also considered if they had constitutional syndrome (asthenia, anorexia, and weight loss of at least 4 kg) and/or the erythrocyte sedimentation rate (ESR; by Westergren method) was greater than 80 mm/h23,24. Patients included in this study were diagnosed as having biopsy-proven GCA when the TAB resulted in a compatible pathology report, describing the characteristic mononuclear cell infiltration of the arterial wall, with or without the presence of granulomas and/or multinucleated giant cells36.

Clinical Definitions

Clinical definitions of GCA manifestations and treatment in the Lugo population have been reported elsewhere14,19,24. As previously described, patients were considered to have severe ischemic manifestations if they suffered visual manifestations (transient visual loss including amaurosis fugax, permanent visual loss, or diplopia), cerebrovascular accidents (stroke and/or transient ischemic attacks), jaw claudication, or large-artery stenosis of the extremities that caused signs of occlusive manifestations (limb claudication) of recent onset18,26. Biopsy-proven GCA patients were considered as having no clinically evident vascular involvement related to GCA if at the time of diagnosis or during follow-up they did not exhibit cranial or any other vascular manifestations that might be attributed to this vasculitis17. Thus, patients with PMR without any ischemic manifestation of GCA who had a positive TAB for GCA were included in this category.

The purpose of the current study was to assess the clinical spectrum of presenting manifestations of GCA. Clinical manifestations were considered to be presenting features of the disease if they occurred between the onset of GCA symptoms and 4 weeks after the start of corticosteroid therapy (initial dose 40-60 mg prednisone/day for 3-4 weeks or intravenous methylprednisolone pulse therapy [1 g daily for 3 days] followed by 60 mg prednisone/day for 3-4 weeks in most patients who had visual manifestations)18.

Data Collection

We analyzed demographic and clinical data from the time of diagnosis or within the 4 weeks after the onset of treatment for all patients with biopsy-proven GCA. We also assessed ESR, hemoglobin value, platelet count, and alkaline phosphatase (ALP) data on admission for all patients.

Statistical Analysis

We described continuous data as mean and standard deviation (mean ± SD), and categorical variables as percentage. We performed the chi-square test to analyze categorical data. When the minimum expected value was less than 5, the Fisher exact test was used. A chi-square-based p value for trend was obtained for age-group distributions. For continuous variables, equality of means was tested with the Student t test.

We recently reported26 that the presence of atherosclerosis risk factors at the time of diagnosis of GCA, in particular the presence of hypertension, may influence the development of severe ischemic manifestations of the disease. Because of that, to obtain a predictive model for severe ischemic manifestations of GCA, we performed a forward stepwise logistic regression with an entry p value of 0.20, but results, shown as odds ratios (OR) and 95% confidence intervals (CI), were adjusted by the presence of classic (traditional) atherosclerosis risk factors at the time of disease diagnosis (hypertension, diabetes, dyslipidemia, and smoking).

Statistical significance was defined as p ≤ 0.05. Calculations were performed with the statistical package Stata 8/SE (Stata Corporation, College Station, TX).

RESULTS

Between January 1, 1981, and June 15, 2004, 240 consecutive patients were diagnosed with biopsy-proven GCA in Lugo. All patients met the 1990 American College of Rheumatology criteria for the classification of GCA33.

Headache

During the study period, 203 (86.4%) patients with biopsy-proven GCA presented with the classical pattern of headache at the time of disease diagnosis. Differences between patients who presented with headache and those who did not are shown in Table 1. As expected, patients presenting with this typical feature of GCA had a statistically significant shorter delay to diagnosis (9.2 ± 9.9 versus 16.6 ± 15.0 wk; p < 0.001). Likewise, those with headache described more commonly the presence of scalp tenderness than the remaining GCA patients (38.9% versus 5.4%; p < 0.001). Not surprisingly, since headache is the best example of cranial involvement of GCA, patients with headache were also found to have an abnormal temporal artery on physical examination more commonly than other GCA patients (79.8% versus 35.1%; p < 0.001). The frequency of cerebrovascular accidents in the time between the onset of GCA symptoms until 1 month after the onset of steroid therapy was marginally reduced in patients who presented with headache (see Table 1). Of note, the frequency of PMR was significantly reduced in patients who presented with this classical feature of GCA compared with those who did not (36.5% versus 59.5%; p = 0.009).

T1-2
TABLE 1:
Characteristics of Patients With Biopsy-Proven GCA Who Presented With the Classical Pattern of Headache at Time of Disease Diagnosis and Those Who Did Not

Polymyalgia Rheumatica

Patients who presented with PMR manifestations at the time of diagnosis (n = 96; 40%) were younger (73.4 ± 6.3 versus 75.6 ± 6.9 yr; p = 0.013) and had a longer delay to diagnosis than the remaining GCA patients (13.4 ± 12.2 versus 8.3 ± 10.0 wk). Those with PMR exhibited a significantly reduced frequency of headache and visual ischemic manifestations (Table 2). However, no differences in the incidence of irreversible visual loss were found between those patients who presented with PMR and those who did not (see Table 2).

T2-2
TABLE 2:
Characteristics of Patients With PMR at Time of Disease Diagnosis and Those Without

Severe Ischemic Manifestations

One hundred thirty-one (54.6%) patients presented with severe ischemic manifestations in the time between the onset of the disease and 1 month after the start of steroid therapy. Detailed information about the main ischemic complications observed in 210 of the 240 patients has been recently described26.

Differences according to the presence of severe ischemic manifestations of the vasculitis or not at the time of disease diagnosis are shown in Table 3. When a diagnosis of GCA was made, patients who developed severe disease were found to have abnormal temporal arteries on physical examination more frequently (80.2% versus 64.2%; p = 0.006) and anemia less frequently (hemoglobin 12.0 ± 1.5 versus 11.5 ± 1.7 g/dL; p = 0.015) than the remaining patients with biopsy-proven GCA. No other differences between patients with or without severe ischemic disease were found (see Table 3).

T3-2
TABLE 3:
Characteristics of Patients With Severe Ischemic Manifestations of the Vasculitis at Time of Disease Diagnosis and Those Without

Predictors of Severe Ischemic Disease

Abnormal temporal artery on physical examination (OR, 2.25) was the best positive predictor of severe ischemic manifestations. In contrast, the presence of anemia at the time of disease diagnosis was found to have a protective role (OR, 0.53), since the 95% CI was lower than 1.0 (Table 4).

T4-2
TABLE 4:
Predictors of Severe Ischemic Manifestations in 240 Patients With Biopsy-Proven GCA Obtained Using Stepwise Logistic Regression

Subclinical Biopsy-Proven GCA (Silent GCA)

Eighteen (7.5%) patients with biopsy-proven GCA fulfilled definitions for the subclinical pattern of disease presentation, since no overt ischemic manifestations of GCA were observed in the time between the onset of symptoms and 1 month after the start of steroid therapy. Eleven of them presented with PMR. Two patients who fulfilled criteria for fever of unknown origin7 experienced a rapid clinical improvement once prednisone therapy was initiated17. The remaining 5 patients presented at the hospital because of asthenia, anorexia, weight loss, and/or anemia. As expected, patients who at disease diagnosis did not exhibit cranial or other ischemic manifestations related to the vasculitis had a statistically significant longer delay to diagnosis than the remaining biopsy-proven GCA patients (16.3 ± 15.0 versus 9.9 ± 10.7 wk; p = 0.018). Comparison of clinical and laboratory features between these 2 groups of patients disclosed that patients with silent GCA had lower hemoglobin values (11.0 ± 1.5 versus 11.8 ± 1.6 g/dL; p = 0.030) and a marginally increased frequency of PMR, which was not statistically significant probably due to the low number of biopsy-proven GCA patients who presented with subclinical GCA (Table 5).

T5-2
TABLE 5:
Clinical and Laboratory Features in Patients With Subclinical GCA* ("Silent GCA") and the Remaining Patients With Biopsy-Proven GCA

Influence of Age at Disease Onset in the Clinical Spectrum of GCA

Patients younger than 70 years of age at the time of diagnosis had a significantly longer delay to diagnosis (Table 6). Also, those with the youngest age exhibited more commonly PMR and elevated ALP than patients older than 70 years of age. A statistically significant negative trend to exhibit PMR manifestations and increased ALP was found in the older age-groups (see Table 6).

T6-2
TABLE 6:
Clinical and Laboratory Features in 240 Patients According to Age at Disease Onset

To further investigate the influence of the age in the spectrum of clinical features of the disease, we stratified our patients according the different patterns of clinical presentation (Table 7). However, the only positive finding was that the clinical pattern of PMR suffered a progressive inversion with the age.

T7-2
TABLE 7:
Relationship Between Age at Disease Onset and Clinical Pattern of Disease Presentation in 240 Patients

DISCUSSION

To our knowledge, the present report is the first population-based study to specifically assess the different patterns of clinical presentation of GCA in a large series of southern European patients diagnosed by a positive TAB.

Headache is the best symptomatic expression of the vasculitic process involving cranial arteries. The frequency of this feature in the current unselected series was almost similar to that of 90% reported by Huston et al34 in patients from Olmsted County, Minnesota. As expected, patients from northwestern Spain presenting with headache more commonly had other cranial features of GCA such as scalp tenderness and abnormal temporal arteries on physical examination.

GCA and PMR are common and often concurrent diseases in the elderly41. Although in some cases PMR manifestations may be observed in patients with biopsy-proven GCA, PMR by itself may be the only clinical feature or the phenotypic expression of a great variety of conditions9.

Some differences between isolated PMR and PMR associated with GCA seem to exist. In this regard, in examining the current series of PMR and GCA patients, we observed that patients with isolated PMR were significantly younger than those with PMR associated with biopsy-proven GCA. Isolated PMR patients had a lower frequency of asthenia, anorexia, and weight loss, and seemed to have a milder inflammatory disease as shown by significantly less abnormality in the majority of laboratory parameters of inflammation23. Northwestern Spanish patients with PMR associated with biopsy-proven GCA exhibited higher elevation of ESR and platelet counts, and lower values of hemoglobin than those with isolated PMR23. Studies in different populations have also suggested immunogenetic differences between GCA and isolated PMR9,11.

Former reports4,27 pointed out that in a variable proportion of cases, generally 15%-20%, TAB taken from patients with isolated PMR, without any cranial manifestation related to vascular involvement in the setting of GCA, yielded inflammatory changes of GCA. However, this frequency seems to be lower in unselected patients. With respect to this, in a 2004 review, Cantini et al3 reported that during the period 1996-2000 12 of 76 (16%) PMR patients from Prato, Italy, had histologic evidence of GCA. It is noteworthy that only 1 (1.3%) of these 76 PMR patients was found to have a positive TAB without any clinical feature of GCA. In the remaining 11 PMR patients, cranial manifestations of GCA were present at the time of the TAB3. Based on the criteria described in the Methods section to perform a TAB in our population23,24, only 9% of the patients with isolated PMR were found to have positive biopsy results for GCA21. Also, in our experience, the potential development of cranial manifestations of GCA in those patients initially diagnosed as having isolated PMR generally occurs within the first 2 years after the onset of PMR symptoms. In series from northwestern Spain, only 2% of patients diagnosed as having isolated PMR, who did not exhibit symptoms of GCA within the first 2 years after the diagnosis of PMR, developed features of GCA later during their extended follow-up9. Thus, our observations are in agreement with those reported by Cantini et al and support differences between isolated PMR and GCA.

PMR has been reported in 34%-60% of patients with GCA37,41. The frequency of 40% observed in the current series is in keeping with those data. In our series, biopsy-proven GCA patients who presented with PMR had a significantly reduced frequency of headache. This may be explained by the inclusion within this subset of some patients with subclinical GCA, without overt vascular manifestations of GCA, on whom a TAB yielded positive results for GCA.

The prognosis of GCA is closely related to the development of ischemic complications. Among these severe ischemic complications, jaw claudication was the most common presenting symptom in our patients with GCA. The frequency of this complication in the current study of 40.8%, which was associated in 1 patient with tongue necrosis, was slightly lower than that of about 50% described in previous studies of this condition30,32. As recently described26, other severe ischemic complications were less commonly observed at the time of disease diagnosis.

An important step in the understanding of GCA and its complications may be to assess the best predictors of severe ischemic complications. Since in a 2004 study26 we described that the presence of traditional risk factors of atherosclerosis at the time of diagnosis of this vasculitis increased significantly the risk of developing severe ischemic complications of GCA, to determine the best predictors of severe ischemic manifestations all the results were adjusted by the presence of classic atherosclerosis risk factors. Following this procedure, in our series, GCA patients presenting severe ischemic complications more commonly had abnormal temporal artery on physical examination and also significantly reduced levels of hemoglobin compared with the rest of GCA patients. With respect to this, the risk of presenting severe ischemic complications was found to be more than double in patients with abnormality of temporal arteries on physical examination.

In contrast, anemia was found to be protective against the development of these ominous complications. The reasons for this effect of anemia, as the result of a chronic inflammatory response, are unknown. A negative association between a strong inflammatory response and the risk of developing cranial ischemic complications was also reported by Cid et al5. Previous studies19,22 on our population supported that observation. Anemia was found to be a negative predictive factor for the development of ischemic visual manifestations in GCA patients from northwestern Spain19.

Cid et al6 have provided an attractive clinical explanation for that paradox of reduced risk of severe ischemic complications in patients with high inflammatory response. These authors examined the clinical relevance of neovascularization in 31 patients with GCA. Patients without ischemic complications had significantly higher tissue angiogenesis scores than the patients with ischemic events. Angiogenesis was also significantly more severe in those with a strong acute phase response compared with those with a weak systemic inflammatory response6. Based on these results, an inflammation-induced angiogenic activity may play a compensatory role for ischemia in GCA patients6.

GCA patients with a strong systemic inflammatory response have elevated tissue expression of proinflammatory cytokines interleukin (IL)-1β, tumor necrosis factor-α, and IL-631. Weyand et al44 found that TAB specimens from GCA patients with ocular ischemia expressed high amounts of interferon (IFN)-γ mRNA, whereas those from GCA patients with fever had less IFN-γ mRNA. Thus, clinical correlates suggest a role of IFN-γ in the process of luminal obstruction and in the long run in the development of ischemic manifestations. By regulating giant cell formation, IFN-γ could indirectly control intimal hyperplasia43. According to these authors, IFN-γ may dictate the functional properties of other cell populations in the vascular infiltrates and, by means of this mechanism, guide the response-to-injury reaction of the artery43. In keeping with this observation, we have found that a microsatellite dinucleotide (CA) repeat polymorphism in the first intron of the IFN-γ gene may be associated with some differences between biopsy-proven GCA and isolated PMR25. It was especially true for specific clinical manifestations of GCA such as visual ischemic complications. We observed an association between the 126 base pairs allele-allele 3 (high IFN-γ producer) with GCA patients with visual ischemic manifestations, and an inverse correlation with the 128 base pairs allele-allele 4 (low IFN-γ producer)25. The polymorphism in the IFN-γ gene may be implicated in GCA by directly affecting IFN-γ production. Alternatively, it is possible that these alleles may be in linkage disequilibrium with alleles at other loci directly implicated in the regulation of IFN-γ production.

In the current series, 7.5% of patients with biopsy-proven GCA presented without overt vascular manifestations of this vasculitis. A follow-up of at least 6 months was performed in all the cases, and most of them have been followed for more than 2 years without the development of any ischemic complications. Due to this, it is possible that these patients may constitute a subgroup of GCA with a good outcome. Of note, anemia, a feature that was found to be protective against the development of severe ischemic complications, was present in most of the patients included in this category.

In a former study16, we assessed the influence of gender, site of residence, and age in 210 patients from Lugo. In that study we stratified patients into 2 age-groups, <70 years and ≥70 years16. The higher number of patients assessed in the present study and the stratification in 3 different age-groups, <70 years, 70-79 years, and ≥80 years, allowed us to confirm that GCA was diagnosed later in the youngest age-group. This longer delay to diagnosis might be due to a lower physician awareness of this condition among individuals younger than 70 years in our area. The group of patients aged <70 years presented more commonly with PMR and exhibited a greater inflammatory response, manifested by lower hemoglobin values and higher levels of ALP. A negative trend to develop PMR and elevation of ALP with aging was also observed.

In the present reappraisal of the influence of age at the time of disease diagnosis in the clinical spectrum of GCA, we have also observed that the age only influences the disease pattern of PMR.

Although limitations related to the retrospective nature of the current study may exist, the large series of uniformly diagnosed and treated patients supports the evidence of different clinical patterns of disease presentation in GCA. Our results reinforce the importance of the presence of abnormal temporal artery on physical examination and anemia at the time of disease diagnosis as factors that may predict in a positive or negative way the risk of severe ischemic complications related to GCA.

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This article has been cited 7 time(s).

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Giant Cell Arteritis in Northwestern Spain: A 25-Year Epidemiologic Study
Llorca, J; Gonzalez-Gay, MA; Miranda-Filloy, JA; Lopez-Diaz, MJ; Perez-Alvarez, R; Gonzalez-Juanatey, C; Sanchez-Andrade, A; Martin, J
Medicine, 86(2): 61-68.
10.1097/md.0b013e31803d1764
PDF (129) | CrossRef
Medicine
Gynecologic Vasculitis: An Analysis of 163 Patients
Hernández-Rodríguez, J; Tan, CD; Rodríguez, E; Hoffman, GS
Medicine, 88(3): 169-181.
10.1097/MD.0b013e3181a577f3
PDF (612) | CrossRef
Medicine
The High Prevalence of Subclinical Atherosclerosis in Patients With Ankylosing Spondylitis Without Clinically Evident Cardiovascular Disease
Gonzalez-Juanatey, C; Vazquez-Rodriguez, TR; Miranda-Filloy, JA; Dierssen, T; Vaqueiro, I; Blanco, R; Martin, J; Llorca, J; Gonzalez-Gay, MA
Medicine, 88(6): 358-365.
10.1097/MD.0b013e3181c10773
PDF (158) | CrossRef
Medicine
Strokes at Time of Disease Diagnosis in a Series of 287 Patients With Biopsy-Proven Giant Cell Arteritis
Gonzalez-Gay, MA; Vazquez-Rodriguez, TR; Gomez-Acebo, I; Pego-Reigosa, R; Lopez-Diaz, MJ; Vazquez-Triñanes, MC; Miranda-Filloy, JA; Blanco, R; Dierssen, T; Gonzalez-Juanatey, C; Llorca, J
Medicine, 88(4): 227-235.
10.1097/MD.0b013e3181af4518
PDF (235) | CrossRef
Medicine
Giant Cell Arteritis: Laboratory Tests at the Time of Diagnosis in a Series of 240 Patients
Gonzalez-Gay, MA; Lopez-Diaz, MJ; Barros, S; Garcia-Porrua, C; Sanchez-Andrade, A; Paz-Carreira, J; Martin, J; Llorca, J
Medicine, 84(5): 277-290.
10.1097/01.md.0000180043.19285.54
PDF (144) | CrossRef
Medicine
Long-Term Follow-Up of Aortic Involvement in Giant Cell Arteritis: A Series of 48 Patients
Marie, I; Proux, A; Duhaut, P; Primard, E; Lahaxe, L; Girszyn, N; Louvel, J; Levesque, H
Medicine, 88(3): 182-192.
10.1097/MD.0b013e3181a68ae2
PDF (807) | CrossRef
Medicine
Development of Ischemic Complications in Patients With Giant Cell Arteritis Presenting With Apparently Isolated Polymyalgia Rheumatica: Study of a Series of 100 Patients
Hernández-Rodríguez, J; Font, C; García-Martínez, A; Espígol-Frigolé, G; Sanmartí, R; Cañete, JD; Grau, JM; Cid, MC
Medicine, 86(4): 233-241.
10.1097/MD.0b013e318145275c
PDF (91) | CrossRef
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