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Giant Cell Arteritis

Laboratory Tests at the Time of Diagnosis in a Series of 240 Patients

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

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doi: 10.1097/01.md.0000180043.19285.54
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Abstract

INTRODUCTION

Giant cell arteritis (GCA) or temporal arteritis is the most common type of systemic vasculitis affecting white individuals over 50 years11,33. 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 artery33,43.

The temporal artery biopsy remains the gold standard diagnostic modality for GCA34. Blood tests are of value in supporting the clinical diagnosis, but sometimes they are nonspecific. A raised erythrocyte sedimentation rate (ESR) has been found to be among the most valuable data for GCA: an ESR greater than 50 mm/h is 1 of the 1990 American College of Rheumatology criteria for the classification of GCA29. However, although classic reports describe a raised ESR in 95%-100% of cases5,30, as observed in patients with isolated polymyalgia rheumatica (PMR)22, a low or normal ESR in active GCA may occur37,40. In 2001 Salvarani and Hunder45 emphasized this point, reporting 9 patients with ESR less than 40 mm/h (Westergren method) at diagnosis.

Acute phase proteins, particularly C-reactive protein (CRP), are also elevated in GCA patients. CRP may be a more sensitive indicator of disease activity than ESR in patients with GCA. However, it is unclear whether its use in clinical practice for diagnosing GCA has some apparent advantage over ESR44.

Other laboratory tests have been found abnormal in patients with GCA. Normochromic-normocytic anemia is common and may be the presenting manifestation of GCA25. High platelet counts have also been widely described, but their frequency varies among series23,38. Immunoglobulin levels may be increased in GCA patients39. Abnormal liver function tests, in particular elevated alkaline phosphatase (ALP) of liver origin, have also been described in these patients31,39.

The outcome of a patient with GCA is related to the development of severe ischemic manifestations9,21, which may be observed in about 50% of the cases26,28. Among them, visual manifestations constitute the most feared aspect of this vasculitis1. They may be observed in about 30% of patients, with permanent loss of vision in 12%-15%1,14. 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 established9. It has been postulated that the presence of a strong acute-phase response at diagnosis was associated with a very low risk of developing visual loss3. However, in a 2004 study by Nesher et al41, laboratory parameters of inflammation did not differ between patients with or without cranial ischemic complications.

Due to the special characteristics of Hospital Xeral-Calde, which is the single reference center for a defined population of northwestern Spain, we have studied the implications of routine laboratory tests obtained at the time of admission in the clinical spectrum of a large series of consecutive patients diagnosed with biopsy-proven GCA. Moreover, we have examined whether the laboratory markers of inflammation may be predictors of severe ischemic manifestations and the potential correlation of these laboratory markers of inflammation at the time of diagnosis 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. Patients were sent to the hospital by general practitioners or they self-referred to the emergency unit. 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 described6,10,15,16. The current study and the companion study8a reported in this issue are an extension of the population study15,21 published in Medicine in 2004.

The temporal artery biopsy (TAB) procedure in Lugo patients has been reported elsewhere14,16,19. As previously reported, TAB was routinely performed in all patients with clinical manifestations of GCA7,18. 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 ESR (by Westergren method) was greater than 80 mm/h18,19. Patients included in this study were diagnosed as having biopsy-proven GCA when the TAB showed 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 cells35.

Data Collection

We analyzed demographic and clinical data at the time of diagnosis or within the 4 weeks after the onset of treatment of all patients with biopsy-proven GCA. Due to the special characteristics of our center, the vast majority of patients included in this and in previous studies on this condition was admitted to hospital for diagnosis21. Full blood cell count and ESR were determined when the patient presented at the hospital. Other biochemistry parameters assessed in the current study were analyzed if they were determined before the onset of steroid therapy or within the first 24 hours after the initiation of this treatment. However, for the purpose of this study and to minimize the effect of treatment, when available, CRP levels were analyzed only if they were determined before steroid therapy or within the first 12 hours after the onset of this medication.

In the current study we assessed the following laboratory parameters: white blood cell count (WBC), platelet count, hemoglobin, ESR, CRP, ALP, and serum albumin, alpha-2 globulin, and gamma globulin.

Clinical Definitions

Clinical definitions of GCA manifestations and treatment in the Lugo population have been reported elsewhere10,14,19. As previously described, biopsy-proven GCA 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 onset13,21.

Because the purpose of this study was to determine the potential implications of laboratory markers of inflammation in the clinical spectrum of presenting manifestations of GCA, in particular in the development of severe ischemic manifestations, 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)13.

Laboratory Definitions

ESR was considered elevated if it was greater than 20 mm/h. Leukocytosis was if WBC was greater than 11,000/mm3. Thrombocytosis, if platelet count was greater than 400,000/mm3. Anemia, if hemoglobin value was less than 12 g/dL. Since the normal cutoff limit of ALP changed over the 24-year study period according to the different methods used at Hospital Xeral-Calde to determine this parameter, as previously reported12,13 and for the purpose of this analysis, ALP was considered abnormal if values at diagnosis were more than 2 times above the upper normal range. Hypoalbuminemia was if serum albumin level fell below 3.0 g/dL. High serum alpha-2 and gamma globulins, if values were greater than 0.8 and 1.6 g/dL, respectively. CRP levels (measured until 2002 by nephelometry and since then by a latex immunoturbidity method) were considered abnormal if CRP values were greater than 5 mg/L.

Statistical Analysis

Continuous data were described as mean and standard deviation (mean ± SD), and categorical variables as percentage. To analyze categorical data we performed the chi-square test. When the minimum expected value was less than 5, the Fisher exact test was used. Equality of means was tested with the Student t test (2 means) or analysis of variance (ANOVA) (for 3 means). The correlation between continuous variables was assessed using Pearson linear correlation coefficients.

We have recently reported 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 disease21. Because of that, to obtain a predictive model of laboratory tests 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 heavy 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 the Lugo region. All of them met the 1990 American College of Rheumatology criteria for the classification of GCA29.

Laboratory Parameters at the Time of Diagnosis

Tables 1 and 2 show the main abnormalities observed in the laboratory parameters analyzed in the current study. The mean value of hemoglobin was 11.8 ± 1.6 g/dL. Anemia was observed in 131 (54.6%) of 240 patients. One hundred seventeen patients (48.8%) exhibited platelet counts greater than 400,000/mm3. WBCs greater than 11,000/mm3 were observed in 68 (28.3%) patients. However, only 11 (16.2%) of the 68 patients with leukocytosis had already received a dose of steroids when the elevated white blood count was recorded. The percentage of patients showing a significant increase of ALP and hypoalbuminemia was similar (25% and 27.8%, respectively). Although a significant increase of alpha-2 globulin was observed in most cases, hypergammaglobulinemia was observed in only 43.1% of the patients in whom this parameter was determined (see Table 2). The mean value of ESR was 93 ± 23 mm/h. Most patients had ESR levels greater than 70 mm/h, and 41.8% had ESR levels greater than 100 mm/h. Of note, only 1 patient had an ESR level less than 40 mm/h (see Table 2). In keeping with ESR levels, CRP levels were greater than 5 mg/L in all 97 patients in whom this parameter was analyzed. The mean CRP was around 100 mg/L (see Table 1), and this parameter was greater than 100 mg/L in 40.2% of the cases (see Table 2).

TABLE 1
TABLE 1:
Laboratory Parameters at Time of Disease Diagnosis in 240 Patients With Biopsy-Proven Giant Cell Arteritis
TABLE 2
TABLE 2:
Main Abnormalities of Laboratory Parameters at Time of Disease Diagnosis in 240 Patients

Differences Between Patients According to the Presence of Leukocytosis at Time of Diagnosis

Patients with WBCs greater than 11,000/mm3 had a shorter delay to diagnosis from the onset of GCA manifestations (Table 3). They also had significantly higher platelet counts and lower serum albumin values. However, no statistically significant differences between patients with or without leukocytosis with respect to ESR and CRP values were found.

TABLE 3
TABLE 3:
Characteristics of Patients With Leukocytosis (WBC >11,000/mm3) at Time of Disease Diagnosis and Those Without

Differences Between Patients According to the Presence of Thrombocytosis at Time of Diagnosis

Patients with platelet counts greater than 400,000/mm3 more commonly had constitutional syndrome. In contrast, these patients showed a reduced frequency of scalp tenderness and dysphagia (Table 4). The presence of thrombocytosis was associated with leukocytosis; greater values of ESR, CRP, and ALP; and lower values of hemoglobin and serum albumin (in all cases p < 0.05).

TABLE 4
TABLE 4:
Characteristics of Patients With Thrombocytosis (Platelet Count >400,000/mm3) at Time of Disease Diagnosis and Those Without

Influence of Anemia in the Clinical Spectrum of GCA

When patients were stratified by the presence of anemia, interesting observations were observed (Table 5). Besides a significantly increased frequency of hemoglobin values less than 12 g/dL in women, anemia was more commonly observed in patients without severe ischemic manifestations (61.5% versus 48.9% in those with severe ischemic manifestation; p = 0.05). In contrast, the presence of anemia was more commonly observed in patients with constitutional syndrome or fever (p < 0.001). Patients with anemia showed statistically higher values of ESR, CRP, and platelet counts. Also, the presence of anemia was associated with lower serum albumin and raised ALP levels (p ≤ 0.001).

TABLE 5
TABLE 5:
Characteristics of Patients With Anemia (Hemoglobin <12 g/dL) at Time of Disease Diagnosis and Those Without

Influence of ESR in the Clinical Spectrum of GCA

The stratification of patients according to ESR also yielded interesting results. Patients with ESR greater than 100 mm/h more commonly exhibited constitutional syndrome (p < 0.001). In addition, the group of patients with the higher ESR values had a statistically significant reduction in the incidence of visual ischemic complications (p < 0.025) (Table 6). This was especially true in patients with permanent visual loss, since only 7 (22.6%) of those 31 patients had an ESR at the time of disease diagnosis greater than 100 mm/h. However, no differences were observed when the spectrum of severe ischemic manifestations was considered as a whole and analyzed according to ESR values. As expected, patients with ESR greater than 100 mm/h also showed significantly higher platelet counts and CRP levels, as well as raised values of ALP and alpha-2 globulin and decreased values of serum albumin (p < 0.001).

TABLE 6
TABLE 6:
Characteristics of Patients With High ESR (>100 mm/h) at Time of Disease Diagnosis and Those Without

In an attempt to define the range of ESR values associated with the highest frequency of permanent visual loss, we further stratified those patients with ESR less than or equal to 100 mm/h into 2 more subgroups (Table 7). By this stratification we found that the highest incidence of permanent visual loss was in patients presenting at the time of disease diagnosis with ESR values between 70 mm/h and 100 mm/h (p = 0.006): 22 (71%) of the 31 patients with permanent blindness had ESR values within this range (see Table 7).

TABLE 7
TABLE 7:
Characteristics of Patients According to ESR Values at Time of Disease Diagnosis

Influence of CRP in the Clinical Spectrum of GCA

Although CRP levels greater than 100 mg/L were more commonly observed in women and in patients with fever (p ≤ 0.04), they were not useful in discriminating patients with severe ischemic manifestations or, specifically, with or without permanent visual loss (Table 8). Biopsy-proven GCA patients with CRP greater than 100 mg/L also had higher ESR and platelet counts and lower hemoglobin levels than those with CRP levels less than or equal to 100 mg/L (p ≤ 0.01) (see Table 8). The further stratification of patients with CRP levels less than or equal to 100 mg/dL showed that those with CRP values less than 50 mg/L more commonly had visual ischemic manifestations (Table 9). However, no differences in terms of permanent visual loss were achieved, probably due to the small number of patients with permanent visual loss in whom CRP was tested. Also, there was a positive correlation between the CRP levels and the platelet counts and ESR values (p ≤ 0.007) (see Table 9).

TABLE 8
TABLE 8:
Characteristics of Patients With High CRP (>100 mg/L) at Time of Disease Diagnosis and Those Without
TABLE 9
TABLE 9:
Characteristics of Patients According to CRP Values at Time of Disease Diagnosis

Hypoalbuminemia at the Time of Diagnosis

As observed in patients with anemia, those who had serum albumin values less than 3 g/dL more commonly had constitutional syndrome or fever (p ≤ 0.05) (Table 10). Moreover, hypoalbuminemia was less commonly observed in patients with abnormal temporal arteries on physical examination (p = 0.023). There was also a significantly inverse association between hypoalbuminemia and raised ALP values (p = 0.001). In addition, this group of patients with low serum albumin levels had significantly increased levels of ESR and platelet counts and lower hemoglobin values than the remaining GCA patients (p ≤ 0.004) (see Table 10).

TABLE 10
TABLE 10:
Characteristics of Patients With Hypoalbuminemia (Serum Albumin <3 g/dL) at Time of Disease Diagnosis and Those Without

Alkaline Phosphatase at the Time of Diagnosis

Patients with raised ALP were younger and had fever more commonly than the rest of the patients in the current study without this abnormality (p < 0.01) (Table 11). Also, these patients exhibited higher ESR levels and platelet counts and lower hemoglobin and albumin values (p < 0.001). However, as observed for hypoalbuminemia, no association between elevation of ALP and ischemic manifestations was found.

TABLE 11
TABLE 11:
Characteristics of Patients With Raised ALP (>2 Times Above the Upper Normal Range) at Time of Disease Diagnosis and Those Without

Influence of High Alpha-2 Globulin and Hypergammaglobulinemia in the Clinical Spectrum of GCA

Information about high alpha-2 globulin and high gamma globulin is shown in Tables 12 and 13. Apart from a significant association between high values of alpha-2 globulin and CRP levels (p < 0.001) and an unexpected higher mean value of hemoglobin in the group of patients with increased alpha-2 globulins, which may be due to the small number (n = 8) of patients with alpha-2 globulin levels ≤0.8 g/dL, no other significant associations were observed.

TABLE 12
TABLE 12:
Characteristics of Patients With High Alpha-2 Globulin (>0.8 g/dL) at Time of Disease Diagnosis and Those Without
TABLE 13
TABLE 13:
Characteristics of Patients With High Gamma Globulin (>1.6 g/dL) at Time of Disease Diagnosis and Those Without

Correlation Between the Different Laboratory Parameters at the Time of Diagnosis

Table 14 describes the correlation among the different laboratory parameters analyzed in the current study. Correlation with ALP was not assessed since, due to methodologic limitations discussed before, this parameter had to be analyzed as a dichotomous variable instead of a continuous variable. High correlations among ESR, CRP, hemoglobin, and platelet count were found. Albumin level correlated with ESR, hemoglobin value, and platelet count. However, WBC exhibited correlation only with ESR and platelet counts. Both alpha-2 and gamma globulin serum levels had poor correlation with most laboratory parameters (see Table 14).

TABLE 14
TABLE 14:
Correlation Between the Different Laboratory Parameters at Time of Diagnosis in 240 Patients*

Laboratory Predictors of Severe Ischemic Disease in Patients With Biopsy-Proven GCA

When laboratory parameters were assessed to determine the best predictors of severe ischemic manifestations, only anemia yielded positive results. The presence of hemoglobin values less than 12 g/dL at the time of disease diagnosis was found to have a protective role (OR, 0.53) since the 95% CI (0.30-0.94) was lower than 1.0 (p = 0.03).

DISCUSSION

To our knowledge, the current report is the first population-based study to analyze specifically the implications of routine laboratory parameters found at the time of diagnosis in a large series of consecutive southern European patients diagnosed with GCA by a positive TAB. Our results confirm a strong correlation among most laboratory markers of inflammation at the time of disease diagnosis. They also highlight the negative association between some laboratory parameters of inflammation, in particular the presence of anemia, and the development of severe ischemic complications.

For years, a high ESR has been considered a hallmark for the diagnosis of GCA. Although several reports have described cases of GCA with low ESR levels at the time of disease diagnosis30,40,44,45,49, as Smetana and Shmerling46 pointed out in a review of 21 studies, a normal ESR makes a diagnosis of GCA very unlikely. In the current series only 1 (0.4%) of the 240 patients had an ESR lower than 40 mm/h, and the median ESR value was 93 mm/h.

Due to the small number of studies and the differences in how results have been reported, it is difficult to establish a role for CRP in the diagnosis of GCA. In 2004, Younge et al50 conducted a study of 1113 patients with suspected GCA and positive results for GCA in 33.5% of them, designed to identify clinical findings that may help clinicians decide when to initiate glucocorticoid therapy. They specifically excluded CRP, claiming that too few CRP tests were performed in their patients to provide meaningful results. However, we feel that the number of patients in whom CRP was determined in our series (n = 97) may be enough to yield information about the relevance of this inflammatory marker at the time of diagnosis of GCA. This observation might be quite novel, since most previous studies have reported relationship to levels of ESR only. However, although a strong correlation between CRP and ESR was observed in our series, the stratification of GCA patients according to CRP values did not yield information useful to predict the risk of severe ischemic complications.

Hamilton et al23 reported thrombocytosis in only 4% of their patients. In a series of 68 patients with GCA, 42 of them histologically confirmed by a positive TAB, Malmvall and Bengtsson38 observed that while high ESR was seen in all cases, an elevated platelet count was found in only 24 (35%) patients. However, platelet counts generally tend to be increased in GCA patients, probably because they behave as acute-phase reactants in an inflammatory response. In our series, thrombocytosis was observed in 117 (48.8%) of the 240 patients with biopsy-proven GCA.

Kyle et al31 assessed liver involvement before treatment in 74 patients with PMR/GCA. Twenty-seven (36%) of them had elevated ALP levels. In the current series, ALP was increased in 25% of patients. Likewise, hypoalbuminemia was found in 27.8% of Lugo patients in whom it was determined. We observed a strong correlation between raised ALP levels and hypoalbuminemia.

Moderate anemia has frequently been found at the time of diagnosis in patients with GCA25. The hypoproliferative character of this anemia is similar to that reported in other conditions, such as chronic infectious diseases and rheumatoid arthritis2. In our series the median hemoglobin value was 11.7 g/dL, and 131 (54.6%) of 240 patients had hemoglobin levels less than 12 g/dL. Of main importance, patients with anemia had a reduced incidence of severe ischemic complications. This result is in concordance with previous studies on 161 patients with biopsy-proven GCA from Lugo that emphasized the role of anemia as a negative predictive factor for the development of visual ischemic manifestations of this vasculitis14,17. This lower hemoglobin value in GCA patients without visual ischemic events or specifically without severe ischemic complications was also reported by Cid et al3 in their series of 200 patients from 3 different hospitals of northeastern Spain. High immunoglobulin serum levels have also been observed in GCA patients39. In the current series, we observed increased values of alpha-2 globulins in more than 90% and hypergammaglobulinemia in almost 50% of the patients. However, these serum globulins correlated poorly with the other routine laboratory markers we assessed.

In assessing patients with GCA, an issue of major importance is the potential value of laboratory markers to predict the risk of severe ischemic complications14,42. In a 1998 collaborative study9 performed with 2 other centers from northern Spain, which comprised 239 GCA patients, 114 of them with biopsy-proven GCA from the Lugo region diagnosed between June 1981 and June 1996, we found that the absence of constitutional symptoms was associated with an increased risk of permanent visual loss. In that study no association between laboratory parameters of inflammation and the risk of irreversible visual loss was confirmed9. However, in the same year, in the retrospective study of 200 consecutive patients diagnosed by a positive TAB in 3 different centers from northeastern Spain, Cid et al3 found that besides a significantly reduced incidence of fever and weight loss in their patients with irreversible cranial ischemic complications, the mean ESR was significantly reduced in these patients compared with the rest of the patients with biopsy-proven GCA. Moreover, the mean serum albumin and hemoglobin values were significantly increased in their patients with irreversible cranial ischemic events3.

Also in 1998, Hayreh et al24 reported the presence of fever as a clinical feature associated with a lower incidence of visual manifestations in GCA patients. However, although the patients with visual ischemic manifestations had lower ESR values, no differences in CRP levels or in the prevalence of anemia were observed between patients with or without ocular manifestations in that series24. In 2001, Liozon et al36 reported visual loss in 23 (13%) of 174 GCA patients, 147 of them confirmed by a positive TAB, which was also associated with constitutional symptoms and lower CRP levels. However, in that study ESR and hemoglobin values were not different between the group of patients with or without visual loss36. They also described that 32 (37%) of 87 patients who had platelet counts greater than 400,000/mm3 at disease diagnosis developed ischemic visual symptoms, compared with 16 (18%) of those without thrombocytosis36. In another recent report Nesher et al41 assessed risk factors for cranial ischemic complications in 175 patients with GCA, 166 of them confirmed by a positive TAB. These authors confirmed that in Jewish individuals with GCA the presence of systemic symptoms was associated with a protective effect against the development of cranial ischemic complications of GCA41. However, Nesher and colleagues did not find an association between cranial ischemic complications and laboratory parameters of inflammation41.

The current report is among the largest studies specifically assessing routine laboratory markers of inflammation at disease diagnosis in a single and well-defined homogeneous population. The higher number of patients in the current study may explain the differences observed in terms of the relationship between laboratory markers of inflammation and the risk of severe ischemic complications with respect to the former multicenter study9 that included partial information about the series of patients assessed in the present report. Interestingly, similarities between the current data and those by Cid et al3 seem to exist. As discussed before, in their multicenter study from northeastern Spain3, the mean hemoglobin value was higher in the group of patients with irreversible cranial ischemic complications. In the current study, a multivariate logistic regression analysis disclosed that a hemoglobin value less than 12 g/dL was the only routine laboratory marker associated with a negative predictive value for developing severe ischemic complications. However, Cid et al3 did not undertake a multivariate analysis to determine the relationship between the different clinical and laboratory variables and the risk of severe ischemic manifestations of GCA.

The reasons for this potential protective effect of anemia, as the result of a chronic inflammatory response, against the development of ominous complications of GCA are unknown. Cid et al4 provided data supporting the idea that inflammation-induced angiogenic activity could counteract the risk of ischemic complications in patients with GCA. These authors studied the clinical relevance of neovascularization in a series of 31 GCA patients and found that those without ischemic complications had significantly higher tissue angiogenesis scores than those with ischemic events. Angiogenesis was also more severe in GCA patients with a strong acute phase response compared with those with a weak systemic inflammatory response4. Based on these results, it is likely that an inflammation-induced angiogenic activity plays a compensatory role for ischemia in GCA patients4.

GCA patients with a strong systemic inflammatory response have elevated tissue expression of proinflammatory cytokines interleukin (IL)-1β, tumor necrosis factor-α, and IL-627. Weyand et al48 described 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 emphasize a potential role of IFN-γ in the process of luminal obstruction and in the development of ischemic manifestations. By regulating giant cell formation, IFN-γ could indirectly control intimal hyperplasia47. According to these authors, IFN-γ may dictate the functional properties of other cell populations in the vascular infiltrates and guide the response-to-injury reaction of the artery47. In agreement 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 with and without visual ischemic manifestations. We found an association between the 126 base pair allele-allele 3 (high IFN-γ producer) with GCA patients who suffered visual ischemic events, and an inverse correlation with the 128 base pair allele-allele 4 (low IFN-γ producer)20. The polymorphism in the IFN-γ gene may be implicated in GCA by directly affecting IFN-γ production. It is possible, however, that these alleles may be in linkage disequilibrium with alleles at other loci directly implicated in the regulation of IFN-γ production. Since GCA is a polygenic disease8, additional evidence suggests that different gene expression may modulate the clinical spectrum and the development of severe ischemic manifestations in patients with GCA. With respect to this, we have found that a functional variant of vascular endothelial growth factor (VEGF) gene is associated with severe ischemic complications in patients with biopsy-proven GCA42a. A biallelic VEGF -634 G→C polymorphism assessed in 103 biopsy-proven GCA patients from Lugo disclosed that the VEGF-634 G allele of this genetic polymorphism was significantly overrepresented in GCA patients with ischemic complications, and, additionally, a higher risk of developing severe ischemic complications was observed for VEGF -634 GG homozygous individuals. Functional studies have demonstrated that the VEGF -634 G allele is associated with lower circulating VEGF levels in vivo, reduced VEGF transcription, and less VEGF expression32. According to our data, GCA patients carrying the VEGF -634 G allele might suffer an inhibition of angiogenesis, and therefore they might be more susceptible to developing severe ischemic complications.

In conclusion, although limitations due to the retrospective nature of this study may exist, the results from the routine laboratory parameters assessed at the time of diagnosis in this large series of uniformly diagnosed and treated patients suggest that some laboratory markers of inflammation, in particular the presence of anemia, may negatively predict the risk of severe ischemic complications in GCA patients.

ACKNOWLEDGMENTS

The authors thank Drs. Teresa Armada and Jaime Capellá, from the Medical Record Department of the Hospital Xeral-Calde, for the great collaboration given to perform this study.

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