In the present study, 19% of patients with biopsy-proven GCA had diagnosed LVI during the follow-up, corresponding to an incidence of 2.4/100 person–years of follow-up. We confirmed a negative association between the presence of giant cells in the TAB and subsequent development of LVI in patients with GCA. We also observed a trend toward reduced risk of LVI with increasing age at GCA-onset, in keeping with previous studies [5, 11, 16, 17, 26]. The shift towards onset of GCA below age 70 in the subgroup with LVI, with a corresponding reduction in the number of patients aged > 80 years at diagnosis, is compatible with previous findings in a study that compared the same age categories [16]. The lower risk in elderly patients in the present study could be due to less extensive investigations with increasing age. On the other hand, in the other study with similar observations, all patients were scanned for LVI [16].
We did not observe an increased risk with elevated laboratory inflammatory markers.
Previously, a higher ESR was negatively associated with LVI in some studies [5, 18, 23] but not in others [7, 10, 11, 13, 19, 22, 24, 25].
In accordance with some [10, 11], but in contrast to other studies [5, 16, 17, 26], there was no major difference between females and males in the occurrence of LVI in this study.
Previous studies indicate that cranial symptoms at the time of GCA diagnosis are negatively associated with LVI [5, 7, 11, 16–20]. In the present study, severe ocular involvement tended to be less frequent among those with LVI. Other types of cranial symptoms were not evaluated.
In contrast to our previous study of a smaller sample [22], we did not find any association between PMR symptoms at GCA diagnosis and subsequent LVI. Other previous studies of PMR as a risk factor have yielded divergent results: one reported a negative association with LVI [16], others showed no difference between the two groups [5, 10, 13, 18, 19, 21], one other study showed a higher proportion with PMR at GCA diagnosis in the LVI group [17] and one study found more patients with PMR prior to GCA diagnosis in the LVI group [11]. Differences in case selection, and in the ascertainment and management of PMR, may explain these discrepancies.
Histopathological features or patterns have been the subject of several studies of possible associations with specific clinical features or clinical course. Previous studies on clinical correlations with giant cells are summarized in Supplementary Table 2. The focus of these studies has been on cranial ischemic symptoms and signs, usually presence of headache/ocular and jaw manifestations, systemic manifestations and laboratory analysis in varying degrees. The number and type of histopathological features investigated also varied. Two studies found significant associations between the occurrence of giant cells and cranial ischemic complications [32, 36]. Two other studies found a trend towards a higher occurrence of cranial ischemic complications in the group with giant cells compared to those without [37, 38].
Giant cells are fused macrophages, formed through interferon-γ (IFN-γ) stimulation [45]. These macrophages produce among others: reactive oxygen species, matrix metalloproteinases, platelet-derived growth factor and vascular endothelial growth factor [46]. IFN-γ is produced by differentiated Th1 cells [46]. The differentiation is driven by interleukin 12 (IL-12) [46]. High levels of IL-12 [47] and IFN-γ [48] are associated with more ischemic complications. It is possible that the LVI phenotype of GCA is less dominated by Th1 mechanisms considering less frequent presence of giant cells in the TAB, fewer cranial ischemic manifestations and the massive presence of artery tertiary lymphoid organs that lack macrophages [49].
Limitations of this study are related to the retrospective design. Data collection was limited to the recorded information in patient charts, and no standardized physical evaluation was performed. In contrast with other studies [16], we did not limit our analysis to patients that had been investigated with ≥ 1 large vessel imaging scan. Imaging modalities during study period were heterogeneous, non-structured and often performed due to other indications than suspected vasculitis. Therefore, the incidence of LVI and its extent is likely underestimated due to lack of systematic imaging studies. LVI detected in this study reflect the clinical practice of the time period. Based on the study design, we cannot rule out that some of the changes may be of atherosclerotic origin.
Strengths of this study include the population-based study design, the relatively large patient cohort with a long follow-up period, and the systematic review of pathology reports. Furthermore, we focused on objectively verified (biopsy-proven) GCA, which had an incidence in our population that was similar to other studies of Scandinavian populations [2, 50].
This study suggests that diverse disease mechanisms may be involved in GCA with different clinical presentation and disease progression. This could affect treatment response and raises the question of whether or not GCA should be treated differently based on phenotype and understanding of the underlying pathophysiology.
Future research should include prospective studies with structured imaging evaluations and standardized quantification of the giant cells and other histopathologic features in TABs.
In conclusion, in this study of patients with biopsy-positive GCA, LVI was detected in 1 in 5 patients during follow-up. There was a significantly lower risk of LVI in patients with giant cells in the biopsy. This may suggest particular disease mechanisms in LVI of GCA.