Giant cell arteritis (GCA) is the most common form of vasculitis in the Western world (1). GCA is a disease of older adults—it is exceedingly rare in persons younger than 50 years, and the greatest risk of developing the disease is seen among those aged 75–85 years (2). The pathologic signature of GCA is granulomatous inflammation of medium and large vessels. In the involved vasculature, intimal hyperplasia and luminal obstruction may lead to ischemic manifestations, including headache, jaw claudication, scalp tenderness, and temporal artery involvement (3). Permanent visual loss occurs in 10%–20% of patients (4–7). A majority of patients with GCA also present with a syndrome of systemic inflammation, which may variably include fever, fatigue, weight loss, anorexia, night sweats, depression, elevations in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, and thrombocytosis (8–11).
These clinical signs can be particularly difficult to assess in the diabetic patient, since ESR and CRP levels in diabetic patients can be altered for reasons other than GCA (12,13). Additionally, focal temporal or facial pain can be a presentation of trigeminal nerve irritation or ischemia in diabetic patients, unrelated to GCA (14,15). Finally, a falsely high index of suspicion for GCA in diabetic patients may lead to the use of high-dose steroids until temporal artery biopsy (TAB) can be performed, complicating blood glucose control.
The clinical impression among many physicians is that diabetic patients presenting with symptoms suspicious for GCA are rarely found to have positive TABs. This has support in the medical literature. In a study assessing the influence of traditional risk factors for atherosclerosis on the development of ischemic complications in GCA, Gonzalez-Gay et al (16) noted a low prevalence of diabetes mellitus (DM) in their series of GCA patients [17 (8.1%) of 210 patients with biopsy-positive GCA]. A study by Duhaut et al (17) found that the prevalence of DM in women with GCA was approximately half that of sex- and age-matched controls (6.43% and 11.83%, respectively, P = 0.042).
While a multitude of studies have sought to identify predictive factors for positive TAB in patients with suspected GCA (18–24), to our knowledge, no studies have sought to determine, as a primary objective, the prevalence of DM among patients with biopsy-positive GCA compared with a control group of patients with negative TAB.
Subjects undergoing TAB were identified by searching the medical records database of Dean A. McGee Eye Institute for all patients who had received a billing code for the procedure from November 1, 1992, to February. 1, 2011. A total of 215 patients who had cumulatively undergone 226 biopsies were selected for inclusion. In each case, TAB was performed because GCA was suspected after a careful consideration of each patient's history, symptoms, signs, and the results of ancillary tests, including laboratory values. Two patients were excluded—a 55-year-old man due to incomplete medical records and a 17-year-old woman who received a TAB during a workup that eventually resulted in the diagnosis of angioedema.
Data were analyzed as a case–control study. Cases were defined as patients whose TABs were read as having either active or healed arteritis. Controls were defined as patients with TAB negative for active or healed arteritis. In the 11 patients who underwent bilateral biopsy, only the second biopsy was included. The individual medical records were consulted to determine each patient's status as diabetic or nondiabetic. Diabetic patients were defined as all patients with a diagnosis of DM in their medical history and/or all patients taking oral hypoglycemic medications and/or insulin at or before the time of biopsy. The prevalence of DM was determined for both cases and controls and compared via χ2 test for statistical significance.
For each group of patients, the mean age and gender were calculated and included for comparison, as well as ESR and CRP levels (when available), and the number of patients within each group with decreased visual acuity at presentation.
A search of the medical literature was conducted via PubMed using the search terms biopsy positive giant cell arteritis, biopsy positive temporal arteritis, temporal artery biopsy, giant cell arteritis and diabetes, temporal arteritis and diabetes, and diabetes mellitus and temporal artery biopsy. Secondary searches of the bibliographies of all relevant articles were conducted to achieve greater inclusiveness. Articles were selected for inclusion in the meta-analysis if they contained both cases of biopsy-positive GCA and sufficient information to determine the percentage of diabetic patients among the biopsy-proven cases.
Of 215 patients who underwent TAB at our institution, 44 (20.5%) were found to have biopsy-positive GCA. Among these positive cases, 4 patients (9.1%) were diabetic at or before the time of biopsy. In the control group of 171 patients with negative TAB (79.5% of the total cohort), 61 (35.7%) were found to be diabetic [odds ratio (OR) = 0.18, P = 0.0006]. These results are depicted in Table 1.
Patients ranged in age from 46 to 91 years, with one patient younger than 50 years. Comparison of gender, age, ESR and CRP levels (at the time of initial presentation, when available), and number of patients presenting with decreased visual acuity is presented in Table 2. In the total cohort of 215 patients, ESR and CRP values were available for 189 and 140 patients, respectively.
Our meta-analysis included a total of 8 studies that reported both cases of biopsy-positive GCA and sufficient information to determine the frequency of DM among the positive cases (16–18,25–29). Taken together, these studies included a total of 1,401 cases of biopsy-positive GCA. Only 89 patients (6.35%) had a concurrent diagnosis of DM as it was variably defined within each study. The frequency of DM among biopsy-positive cases ranged from 0% to 13.8%. The statistics of each study are summarized in Table 3.
Our finding of a low prevalence of DM among patients with biopsy-positive GCA raises an important question: does this result reflect a true decrease in the likelihood of developing GCA or instead a greater tendency of diabetic patients to develop the biopsy-negative form of the disease? This question could be answered by comparing the prevalence of biopsy-negative GCA among diabetic patients with negative TAB with that of nondiabetic patients with negative TAB.
The frequency of DM in our control group (35.7%) was high when compared with the estimate of 24.1% of the general population of Oklahoma residents aged 60 years or older (30). The high prevalence in our controls is not surprising. Many underwent TAB in the course of a workup ultimately resulting in a diagnosis of non-arteritic anterior ischemic optic neuropathy (NAAION), and diabetes is a well-known risk factor for NAAION (31,32). Additionally, because ESR and CRP can be elevated in diabetic patients for reasons other than GCA (12,13), such elevations may lead to a greater likelihood of TAB being performed when diabetic patients present with symptoms suggestive of GCA compared to nondiabetic patients. It should be cautioned that our study population differs in many ways from the general population. Our subjects were overwhelmingly female and typically older than 70 years, and our study included data from as far back as 1992, while the data cited on the prevalence of DM in the general population of Oklahoma contains a more uniform gender distribution and greater ethnic diversity. The data for the general population also is more recent (2003–2007), which is problematic due to the fact that the prevalence of DM is increasing over time (33). Nevertheless, our findings have clinical relevance: they assist in formulating an index of suspicion in potential GCA patients and raise caution assessing diabetic patients with elevated ESR and CRP and those with facial/scalp pain.
The exact nature of the interplay between GCA and DM appears to be complex. In our literature review, we found only one report comparing the rate of DM in positive TAB cases with a control group of negative biopsies (25). The difference in frequency of DM between cases and controls in that study (10.7% and 19.1%, respectively) was not statistically significant. In assessing the role of cardiovascular risk factors in the pathogenesis of GCA, Duhaut et al (17) found a similar proportion of cases and controls with DM among men. This probably was due to the inclusion of both biopsy-negative GCA patients and polymyalgia rheumatica patients, as well as controls being population based, sex and age matched, not those with negative biopsies. Despite this, a history of DM was associated with a 50% reduction in the odds of developing GCA in women (OR = 0.51, P = 0.042). In another study, these investigators found that during the course of a 3-year follow-up (mean = 23 months), patients with biopsy-negative GCA were more likely to develop new-onset DM than patients with biopsy-positive GCA (incidence density, 17.66 cases/year/100 patients vs 8.00 cases/year/100 patients, respectively, P = 0.0005) (18). Similarly, in a study reviewing the final diagnoses rendered in a group of biopsy-negative patients, Roth et al (34) found a high prevalence of DM (5 of 33, 15%).
The pathogenesis of GCA as an antigen-driven inflammatory process has been well described, although the inciting antigen has yet to be elucidated (35). Recent advances in our understanding of the pathogenesis of DM have also characterized the disease within the paradigm of an inflammatory disorder (36). There are several opportunities for the two disorders to potentially overlap, and we offer three testable hypotheses to explain the low frequency of biopsy-positive patients among diabetic patients.
First, multiple studies have demonstrated that cytokine profiles are a major determinant of GCA clinical phenotype and disease severity (4,37–39). Cytokine profiles can also influence TAB results. For example, a subgroup of GCA patients with large artery involvement defined by subclavian and axillary disease demonstrates a distinct cytokine pattern marked by high levels of interleukin-2 gene transcripts in arterial samples. These patients also demonstrate a low rate of positive TAB of only 33% (39). Furthermore, alterations in cytokine levels have also been observed in patients with type 2 DM, with elevated levels of interleukin-1β, interleukin-6, and CRP being predictive of the development of DM (12,40). The commonality of derangements in inflammatory cytokines in both diseases raises an intriguing possibility, and we therefore hypothesize that in individuals with DM, the cytokine profile may be altered in such a way as to preclude the development of GCA or, alternatively, shifted toward a cytokine pattern more likely to result in biopsy-negative disease.
Second, the T cells of diabetic patients may be less responsive to the inciting antigens being presented by the dendritic cells (DCs) of the arterial adventitia, a process that is understood to be crucial in the development of GCA (35,40). Studies have demonstrated a decreased responsiveness to various antigens in the T cells of diabetic patients (41).
Third is the possibility that there is decreased activation of DCs in patients with DM (42). The process of nonenzymatic glycosylation in hyperglycemic states has been well described, and it is possible that diabetic patients may alter the inciting antigen(s)of GCA, rendering them unable to activate vascular DCs. It is also possible that multiple mechanisms are involved. The potential interaction of GCA and DM clearly is a subject that merits further study.
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