Temporal 67gallium uptake is increased in temporal arteritis

T. Généreau 1,2, O. Lortholary 1, L. Guillevin 1, P. Cacoub 3, N. Galezowski 4, P. Chérin 2, P. Babinet 5, G. Herreman 4, B. Wechsler 3, P. Cohen 1, S. Herson2 and N. Caillat-Vigneron6

1 Departments of Internal Medicine of Hôpital Avicenne, Université Paris-Nord, 125, route de Stalingrad, 93009 Bobigny,
2 La Salpêtrière and
3 La Pitié, 47–83, bd de l'Hôpital, 75651 Paris Cedex 13,
4 Hôpital Saint-Joseph, 7, rue Pierre-Larrousse, 75674 Paris Cedex 14,
5 Hôpital Delafontaine, 93205 Saint-Denis Cedex 1 and
6 Service de Médecine Nucléaire, Hôpital Avicenne, Université Paris-Nord, 125, route de Stalingrad, 93009 Bobigny, France

Correspondence to: T. Généreau, Médecine Interne, La Salpêtrière, 47–83, bd de l'Hôpital, 75651 Paris Cedex 13, France.


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. We evaluated temporal 67gallium (Ga) uptake in temporal arteritis (TA) and the contribution of Ga scans to the diagnosis of TA.

Methods. Ga scans were performed prospectively in 19 patients with biopsy-proven TA and five TA patients with negative temporal artery biopsy. Controls were 18 elderly patients undergoing Ga scans for various inflammatory diseases. The temporal region of interest on head profiles was defined for comparison of uptake with a control parietal region of the same area. The Ga uptake ratio (GaUR) [(temporal region-parietal region)/parietal region] was evaluated for each temple by a computer and intra- and intergroup comparisons were made.

Results. GaUR was significantly higher in biopsy-proven TA patients (0.35±0.19) and biopsy-negative TA patients (0.31±0.03) than in controls (0.18±0.12) (P<0.001), independently of recent temporal artery biopsy or short-duration steroid therapy. High GaUR (>0.4) had a 94% specificity and a 90% positive predictive value for TA diagnosis. After 6 months of steroid therapy, when patients were in remission, GaUR returned to baseline.

Conclusion. Ga is specifically incorporated into the temporal area in TA patients which may be due to the granulomatous vasculitic process. Ga uptake ceases during remission. A high GaUR may contribute to TA diagnosis in temporal artery biopsy-negative patients and its role in the diagnosis of other localizations of the disease requires further evaluation.

KEY WORDS: Temporal arteritis, Vasculitis, 67Gallium radionuclide imaging, Scintigraphy.


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Temporal (giant cell) arteritis (TA) is a systemic vasculitis occurring most frequently in individuals older than 50 yr [1]. Its diagnosis is suggested by non-specific manifestations such as persistent unexplained headaches, fever or elevated erythrocyte sedimentation rate (ESR), and more typical ones such as jaw claudication and an abnormal temporal artery. No biological test illustrates the diagnosis of TA better than the demonstration of a marked inflammatory syndrome. When suspected, the diagnosis of TA can only be definitively confirmed by histological examination of a temporal artery biopsy (TAB), which exhibits typical changes in 60–97% of cases [2]. However, TAB can be negative owing to the segmentary topography of the vasculitic process within the temporal artery wall [3].

Very few indirect diagnostic procedures, such as imaging techniques, have proven to be useful for the diagnosis of TA. Invasive procedures, like temporal or superficial carotid arteriography [4, 5], have low sensitivity for identifying arterial lesions and also frequently give false-positive results [6]. Doppler sonography may be useful for experienced operators [7, 8], but can be normal in biopsy-proven TA [9]; colour Doppler sonography was recently described as useful in the diagnosis of TA when a periarterial hypoechogenic halo is seen [10], but these observations have not yet been confirmed [11]. Finally, these procedures do not discriminate between inflammatory and the various non-inflammatory temporal artery diseases that have been described [12].

67Gallium citrate (Ga) binds to the transferrin receptor expressed on the surface of activated macrophages [13]. Ga scintigraphy is widely used in the diagnosis and follow-up of infections, lymphomas and granulomatous diseases, such as sarcoidosis [1416]. As granuloma with activated macrophages [17] is a prominent histological feature of TA, we prospectively evaluated the Ga temporal uptake in 42 elderly patients with inflammatory syndrome. The diagnostic contribution of Ga scans in this population was also evaluated.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study population
The study was conducted from August 1993 to December 1995 in five internal medicine departments from university and non-teaching hospitals. Ga scintigraphy was performed prospectively in 19 consecutive patients with biopsy-proven TA (18 new-onset TA and one TA relapse). This diagnosis was based on clinical grounds (Table 1Go) and confirmed by TAB, which showed typical histological findings with mononuclear infiltrate (19/19), disruption of the internal elastic lamina (19/19) and multinucleated giant cells (16/19). All patients fulfilled the American College of Rheumatology criteria for the classification of TA [18].


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TABLE 1.  The main characteristics of temporal arteritis patients upon diagnosis
 
TAB had been performed 4–38 days before Ga scintigraphy in nine TA patients. For 16 TA patients, a unilateral TAB was performed because temporal symptoms were absent contralaterally, whereas for the three other patients, bilateral TAB were taken because of bilateral symptoms. At the time of Ga scintigraphy, none of the patients had any other known or clinically evident cutaneous, bone or cerebral inflammatory, or granulomatous disease which could enhance Ga binding on the temporal area.

At the time of Ga scintigraphy, 11 patients who had been diagnosed as having TA were taking corticosteroids: 0.7–1 mg/kg/day for 10 days (range 2–38 days) and 0.15 mg/kg/day for a patient known to have TA for 2 yr and for whom TA relapse was ultimately diagnosed.

Eight biopsy-proven TA patients had a second Ga scintigraphy 6 months later while in clinical (disappearance of clinical symptoms attributed to TA) and biological (ESR normalization) remission under low-dose steroid therapy.

During the same period, Ga scans were performed in five consecutive patients for whom the diagnosis of TA was made, according to ACR criteria [18], but without arteritis on the TAB (Table 1Go). At the time of Ga scintigraphy, none of these five patients had had TAB or were taking corticosteroids.

Control group
During the same period, 18 consecutive patients older than 50 yr underwent Ga scintigraphy for an inflammatory disease and comprised the control group (13 females/5 males; mean age 69±10 yr, range 51–87 yr). The final diagnoses were isolated polymyalgia rheumatica without vasculitis on TAB (n=5), bacterial infection (n=4, prostatitis, pneumonia, pyelonephritis, apical dental granuloma), digestive or thoracic neoplasm (n=3), pulmonary sarcoidosis (n=3), osteoarthritis (n=2), late-onset rheumatoid arthritis (n=1) and unexplained spontaneously resolving inflammatory syndrome (n=1). The mean ESR in these patients was 69±11 mm/1st h (range 44–100). The patients with polymyalgia rheumatica were included in the control group because they had negative TAB and no symptoms suggesting co-existing TA [19].

67Gallium scan
All scintigraphies were performed in the Nuclear Medicine Unit of Avicenne Hospital, Bobigny, France. Ga scan was performed with a conventional Anger gamma-camera (General Electric, Waukesha, WI, USA) fitted with a medium energy collimator. The patients received Ga (1.8 MBq/kg body weight) i.v. Bilateral profiles were acquired for the three main photopeaks of Ga 48 h later. Ga uptake was analysed on a dedicated Sun Sparc station (Bartec, Manchester, UK). Two of us, who were blind to the diagnosis and the clinical and biological data, defined two regions of interest (ROI): the temporal region (just above the orbitomeatal line and behind the lachrymal gland uptake) and a control zone of the same area in the parietal region (Fig. 1Go). For these ROI, Ga uptake was quantitatively assessed by the computer and the Ga uptake ratio (GaUR) [(temporal ROI - parietal ROI)/parietal ROI] was calculated. The GaUR was considered separately for each temple in the expression of the results.



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FIG. 1.  Definition of temporal (grey square) and control (white square) areas on head profile scans.

 
We evaluated recently biopsied temples (TAB taken <30 days before Ga scintigraphy) separately because we considered that Ga uptake might have been artificially increased in the TAB scar tissue.

Statistical analysis
Results are presented as means±S.D. The mean quantitative values for the groups were compared using the two-tailed Student's t-test. A P value of <0.05 was considered statistically significant.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The mean GaUR was significantly higher for the TA group than for controls [0.35±0.19 (range 0.07–1.07) vs 0.18±0.12 (range 0–0.47), P <0.001]. The mean GaUR for the eight recently biopsied temples was 0.37±0.12 and not statistically different from the mean GaUR of TA temples not recently biopsied (0.35±0.21). The mean GaUR for not recently biopsied temples was significantly higher (P<0.001) than the mean GaUR for the control group. GaUR were also significantly higher in the five TA patients with negative TAB (0.31±0.03, range 0.14–0.45) compared with the control group (P<0.001). Mean GaUR with 95% confidence intervals for TA patients and controls are presented in Fig. 2Go.



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FIG. 2.  Mean and 95% confidence interval of the temporal Ga uptake ratio in patients with positive TAB TA patients (n=19), negative TAB TA patients (n=5) and controls (n=18).

 
A GaUR above 0.55 was only observed for five TA patients and a GaUR above 0.4 was observed in only one control patient with osteoarthritis and nine TA patients (seven with positive TAB and two with negative TAB). The specificity of a GaUR >0.4 was 94% and its predictive positive value was 90%, while its sensitivity was 38%. However, TA patient and control GaUR values overlapped extensively: GaUR of <0.4 were observed in 32 patients.

Temporal GaUR were comparable for the 16 temples that were clinically considered inflammatory and from which unilateral TAB had been taken (0.37±0.17), and the contralateral temple (0.28±0.11, P=0.083). Mean Ga uptake in the latter was significantly higher than that of controls (P<0.004).

The evolution under corticosteroids of GaUR for the eight patients in clinical and biological remission is shown in Fig. 3Go. Six months after diagnosis, the mean temporal GaUR was significantly lower than that recorded at the time of diagnosis in these patients (0.11±0.07 vs 0.36±0.10, P<0.001). It should be noted that short-duration steroid treatment (<38 days) did not affect the GaUR (0.38±0.25 vs 0.33±0.10).



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FIG. 3.  Evolution of the Ga uptake ratio in eight TA patients upon diagnosis and after 6 months of steroid therapy.

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Our study demonstrated significantly increased Ga binding in the temporal areas of patients with TA compared to elderly control patients presenting with various inflammatory diseases. This enhanced uptake was independent of the time of TAB and can be ascribed to active granuloma [17], a major pathological finding in TA. The uptake on one profile could not be relative to shining from the other side through the skull as Ga energy is strongly attenuated by soft tissues and bones. Ga scintigraphy is a non-invasive procedure that may assess the inflammatory process at work in the temporal artery, unlike arteriography, Doppler and sonography. However, the cost and 48 h lag time for the realization of Ga scans may make its routine use for TA diagnosis difficult. It should be noted that when TA is strongly suspected on clinical grounds, treatment should be initiated immediately, as it does not interfere with the interpretation of TAB.

Scintigraphies are non-invasive diagnostic procedures that could help the clinician to localize the vasculitic process precisely, assess the extent of non-symptomatic localizations and then orientate biopsies [20]. Some experiences of scintigraphic imaging of the vasculitic process have been reported (Table 2Go) [2034]. Interestingly, Ga scintigraphy has been used in the assessment of some patients with Takayasu's disease [3234], which, like TA, is a granulomatous vasculitis involving large- and medium-sized arteries. In these studies [3234], Ga uptake was correlated with the localizations of the disease, proved by other imaging procedures (angiography, gadolinium-enhanced magnetic resonance imaging, enhanced computed tomography scan).


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TABLE 2.  Experience of scintigraphic imaging in systemic vasculitides
 
Our results showed that Ga binding was bilateral in TA and not only localized to the temple that seemed to be clinically inflamed. These data confirm that the temporal vasculitis in TA is indeed bilateral [9]. Ga binding was also enhanced in five TA patients with no arteritis seen on the TAB. TAB may be negative owing to the segmentary topography of the vasculitis [3], particularly when the biopsy specimen is too short. We did not evaluate the contribution of Ga scans to help clinicians choose the site to be biopsied in order to enhance the chances of obtaining positive tissue as their resolution is not sufficient to localize an affected segment of the temporal artery precisely. Clinical symptoms and arterial Doppler [9] are better able to select a biopsy site.

Despite a large overlap among GaUR for TA and non-TA patients, a GaUR>0.4 has a 94% specificity and a 90% positive predictive value. These high uptake ratios could be useful in ascertaining the diagnosis of TA when TAB cannot be performed or is falsely negative owing to the segmentary nature of the vasculitis [3] and in helping the clinician to begin steroid therapy without a pathological demonstration of the vasculitis.

In the eight patients retested after 6 months of steroid therapy, Ga uptake returned to control values when they were in clinical and biological remission, a finding that could be very useful in the management of patients under treatment to identify subsequent inflammatory events, such as TA relapses or infectious complications that may share similar clinical and biological features [35].

Because TA is not localized exclusively to the superficial temporal artery and may involve all cephalic [36] and extracranial arteries [37], we are evaluating Ga uptake in whole-body scans of TA patients.

In conclusion, we have demonstrated increased temporal Ga uptake in TA. In the case of a high GaUR (>0.4), Ga scintigraphy appears to be a useful diagnostic tool for TA, but does not replace TAB. Low GaUR (<0.4) are observed in both TA and control patients. Ga scans may also be used in the follow-up of TA patients under treatment. Because of the potentially severe consequences of not treating TA rapidly with steroids, no time should be lost in initiating treatment when TA is clinically suspected. Importantly, our findings also showed that 1 month of such therapy did not hamper the contribution of Ga scans to the diagnosis of TA.


    Acknowledgments
 
We thank Mrs Janet Jacobson for her help in editing the English used in the manuscript. This work was presented in part at the 59th National Meeting, American College of Rheumatology, San Francisco, October 1995.


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 18 August 1998; revised version accepted 5 March 1999.