Giant cell arteritis without clinically evident vascular involvement in a defined population
To examine the frequency and clinical presentation of biopsy-proven giant cell arteritis (GCA) patients who do not exhibit overt clinical vascular manifestations. To assess whether differences exist between this group of patients and the rest of biopsy-proven GCA patients.
Retrospective study of biopsy-proven GCA patients diagnosed from 1981 through 2001 at the single hospital for a well-defined population of almost 250,000 people. Patients were considered as having no evident vascular involvement if cranial ischemic manifestations or other vascular complications of GCA were not present at the time of diagnosis or during at least 12 months' followup.
Between 1981 and 2001, 210 patients from the Lugo region of northwest Spain were diagnosed with biopsy-proven GCA. Eleven patients did not show overt vascular manifestations of GCA. Nine of them presented with polymyalgia rheumatica (PMR) and another 2 fulfilled criteria for fever of unknown origin. Patients without clinically evident vascular involvement had a significantly longer delay to diagnosis than those with vascular manifestations. Also, PMR manifestations were more frequently observed in this group of patients.
Biopsy-proven GCA without clinically evident vascular involvement is not exceptional. Despite having a longer delay to diagnosis, these patients constitute a more benign subgroup of GCA.
Giant cell arteritis (GCA) is the most common vasculitis in Western countries (1). It usually involves large and medium-sized blood vessels with a predisposition to the cranial arteries in the elderly (1). Classically, GCA patients present with clinical manifestations that are the result of vascular involvement. Due to this, diagnosis in these patients is relatively straightforward. However, a variable proportion of patients may present without obvious vascular manifestations (2–4). In this study, we have assessed in a defined population the frequency and clinical presentations of GCA patients without clinically evident cranial manifestations or any other ischemic complications related to this vasculitis. Also, an analysis was performed of differences between these patients and the rest of biopsy-proven GCA patients who presented clinical features of vascular involvement.
PATIENTS AND METHODS
A retrospective review was conducted of the case records of all patients diagnosed with GCA at the Department of Medicine of the Hospital Xeral-Calde (Lugo, Spain) between January 1981 and December 2001. Information about the characteristics of this white population of almost 250,000 people has been described extensively (5).
For the purpose of this study, only patients with biopsy-proven GCA were included in this analysis. Biopsy-proven GCA patients were considered as having no clinically evident vascular involvement related to GCA if at the time of diagnosis or during their followup (at least 1 year) they did not exhibit cranial or any other vascular manifestations that might be attributed to this vasculitis. Thus, patients with polymyalgia rheumatica (PMR) without any ischemic manifestation of GCA who had a positive temporal artery biopsy for GCA were included in this category.
Temporal artery biopsy procedure
As previously described, temporal artery biopsy was routinely performed on all patients with clinical manifestations of GCA (6). In those patients with clinically isolated PMR, without any vascular manifestation of GCA, biopsies were also considered if they had constitutional syndrome or their erythrocyte sedimentation rate (ESR; by Westergren method) was >80 mm/hour (7).
Clinical definitions related to vascular involvement in the setting of GCA have been previously described (6). PMR was diagnosed if the patient had marked aching and stiffness bilaterally without other apparent cause in at least 2 of 3 regions, namely the neck, shoulder girdle, or hip girdle (7, 8). Fever was present if the axillary temperature at the time of admission or while the patient was followed before the onset of therapy was ≥38°C. Constitutional syndrome was defined as asthenia, anorexia, and weight loss of at least 4 kg. Increased alkaline phosphatase was defined as a value at diagnosis >2 times above the upper normal range.
Demographic and clinical data at the time of diagnosis of all the patients with biopsy-proven GCA were analyzed. Also, ESR, hemoglobin, platelet count, and alkaline phosphatase data on admission (always prior to the onset of steroid therapy) were assessed. Information about followup in the group of GCA patients without obvious vascular involvement was also examined.
Comparisons between 2 categories were made using Student's t-test (2 tailed) for continuous variables. To analyze categorical data, a chi-square test or Fisher's exact test was performed. Statistical significance was defined as P < 0.05.
Between January 1981 and December 2001, 210 consecutive patients were diagnosed with biopsy-proven GCA.
Clinical features of patients without obvious vascular involvement
Eleven patients with biopsy-proven GCA (8 women and 3 men; 5.2%) did not exhibit clinical features of vascular involvement. Nine of them presented with PMR and another 2 fulfilled criteria for fever of unknown origin (9). The main epidemiologic, clinical, and laboratory features of these patients are summarized in Table 1. None of these patients developed overt vascular involvement related to GCA during followup (minimum 21 months; median 4.5 years).
Table 1. Comparison of clinical and laboratory features between patients without clinically evident vascular involvement and the rest of biopsy-proven GCA patients*
|Age at diagnosis, years, mean ± SD||73.8 ± 5.3||74.6 ± 7.0||0.70|
|Women||8 (72.7)||105 (52.8)||0.23|
|Delay to diagnosis, weeks, mean ± SD†||20.2 ± 17.6||9.8 ± 10.8||0.003|
|Headache||0 (0.0)||183 (92.0)||<0.001|
|Scalp tenderness||0 (0.0)||72 (36.2)||0.017|
|Constitutional syndrome‡||8 (72.7)||127 (63.8)||0.75|
|Abnormal temporal arteries§||0 (0.0)||159 (79.9)||<0.001|
|Jaw claudication||0 (0.0)||86 (43.2)||0.003|
|Dysphagia||0 (0.0)||11 (5.5)||1.00|
|Polymyalgia rheumatica||9 (81.8)||78 (39.2)||0.009|
|Fever, temperature ≥38°C||2 (18.2)||19 (9.6)||0.30|
|Visual manifestations||0 (0.0)||49 (24.6)||0.07|
|Permanent visual loss||0 (0.0)||27 (13.6)||0.37|
|Cerebrovascular accidents||0 (0.0)||4 (2.0)||1.00|
|Limb claudication of recent onset||0 (0.0)||6 (3.0)||1.00|
|ESR, mm/first hour, mean ± SD||90.4 ± 14.9||93.1 ± 22.8||0.69|
|Hemoglobin, g/dl, mean ± SD||11.1 ± 1.7||11.8 ± 1.6||0.18|
|Platelet count, mm3, mean ± SD||377,182 ± 117,356||411,141 ± 136,400||0.42|
|Raised ALP¶||2 (18.2)||54 (27.3)||0.73|
Differences between biopsy-proven GCA groups
As expected, GCA patients without overt vascular manifestations had a significantly longer delay to diagnosis compared with the rest of GCA patients (Table 1). Age at the time of diagnosis was similar in both groups. PMR manifestations were more common in patients without overt vascular features. These patients also had lower values of hemoglobin than the rest of GCA patients, but the difference was not statistically significant. Other clinical and laboratory differences between both groups are summarized in Table 1.
All GCA patients with cranial ischemic or other vascular manifestations were initially treated with prednisone at 40–60 mg/day. Some patients with visual ischemic manifestations were also treated with intravenous pulses of methylprednisolone (1 gm daily for 3 consecutive days). Patients without evident vascular involvement who presented with PMR manifestations received an initial dose of prednisone of 10–20 mg/day. However, prednisone dosage in these patients was increased to 40 mg/day as soon as information about a positive temporal artery biopsy sample was available.
The present study confirms that biopsy-proven GCA without clinically evident vascular involvement is not exceptional. In our series, these patients presented with isolated PMR or fever of unknown origin.
Former reports pointed out that in a variable proportion of cases, generally 15–20%, temporal artery biopsy samples taken from patients with isolated PMR, without any cranial manifestation related to vascular involvement in the setting of GCA, yielded inflammatory changes of GCA (8). Also in some studies, GCA and PMR exhibited similar HLA–DRB1 genotype associations (10). These observations have supported the concept, maintained by many authorities, that both conditions are the same disease.
More recent studies in different countries, however, have underlined some immunogenetic differences between GCA and PMR, particularly in terms of HLA–DRB1 genotype associations (11), and subtle clinical differences between isolated PMR and PMR associated with biopsy-proven GCA (12). In a previous study (following the same procedure described in the Patients and Methods section here), we reported that the frequency of positive temporal artery biopsy samples in a series of Lugo patients with clinically isolated PMR was 9% (13). Based on the followup of patients with isolated PMR, we have observed that in northwest Spain 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 onset of PMR symptoms. In Lugo, 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 followup (14). Due to this, we do not consider isolated PMR as a clinical feature of vascular involvement in the setting of GCA.
Fever of unknown origin has been reported as a presenting manifestation of silent GCA (3). As with our 2 cases, severe visual complications have been reported to be exceptional in these patients (3, 15). Thus, the presence of this clinical marker of inflammatory response may be considered a protective factor against severe ischemic events in these patients. The very low proportion of fever of unknown origin in our series of biopsy-proven GCA may have 2 possible explanations. We may have opted not to perform temporal artery biopsy in some elderly patients with fever. However, this seems unlikely in our area because, due to our interest in this type of vasculitis, internal medicine staff members from our hospital are aware of this type of vasculitis and temporal artery biopsy is routinely considered in patients with fever of unknown origin. In addition, since the rheumatology division was established in 1987, meticulous history taking and physical examination for GCA is routinely performed in all patients presenting with fever.
In 1980, Strachan et al stated that the delay to reach a diagnosis of GCA was the main factor implicated in the development of serious sequelae in patients with silent GCA (16). In contrast, a longer delay to diagnosis in our unselected patients without overt clinical manifestations of vasculitis was not associated with an increased risk of severe vascular complications.
A few years ago, the group led by Cid reported a negative association between a strong inflammatory response and the risk of developing cranial ischemic complications (17). Further analyses in our population supported that observation (6, 18). In patients from northwest Spain, anemia was a negative predictive factor for the development of ischemic visual manifestations in the setting of GCA (6). However, the reason for a lower risk of severe visual manifestations in GCA patients with protracted inflammatory response remains to be elucidated. It is possible that this subgroup of patients with more protracted disease may have a different cytokine profile (19) and, due to this, a lower risk of ischemic complications. Recently, Cid et al (20) have described an attractive explanation that may shed light to this paradox. These authors examined the clinical relevance of neovascularization in GCA. In their series of 31 GCA patients, those without ischemic complications had significantly higher tissue angiogenesis scores than the patients with ischemic events. Of note, angiogenesis was also significantly more prominent in patients with a strong acute phase response compared with those with a weak systemic inflammatory response (20). According to their results, inflammation-induced angiogenic activity may play a compensatory role for ischemia in GCA patients (20).
In conclusion, isolated PMR and fever of unknown origin are the presenting manifestations of Lugo biopsy-proven GCA patients without clinically evident vascular manifestations. Despite having a longer delay to diagnosis, these patients do not exhibit ischemic complications during their followup. Therefore, they constitute a subgroup of GCA with a good outcome.