Our detailed and comprehensive database of an inception cohort of patients with GCA and PMR followed in a rheumatology clinic for a median period of 6.46 years was used to compare the rate and risk of comorbidity and mortality of patients with GCA and PMR, as well as analyze disease outcome with respect to GC therapy. Our data suggest that accrual of comorbidities, defined as ∆CCI or ∆RDCI ≥ 1, as well as the mortality rate did not differ despite the significantly higher initial and cumulative dose of prednisone in the GCA group compared to the PMR group.
Nevertheless, accrual of comorbidities during the study period defined as ∆CCI ≥ 1 was significantly associated with atherosclerosis CAD and DM, as well as higher number of disease relapses (Table 7). Of note, neither aspirin nor statin use had a protective effect with respect to accrual of comorbidities in our cohort of patients with GCA and PMR.
Although the rate of mortality was not significantly different in the GCA and PMR groups, Cox regression analysis showed that older age, CAD, stroke, CHF, and aortic dilatation/aneurysm were significantly associated with an increased risk of mortality; in addition to HTN, DM, dyslipidemia and tobacco smoking that are all known to be associated with atherosclerotic CVD. Adrenal hypofunction diagnosed during the follow up period, which probably is a result of long-term GC treatment, was significantly associated with higher risk of death.
GC is the cornerstone treatment for both GCA and PMR with median treatment duration of 2–3 years [1–10]. GC-related adverse effects are common and have not changed since GC was first used for managing GCA/PMR [5, 6, 8]. A population-based study of incident GCA cases derived from the Rochester Epidemiology Project between 1950 and 2009 has shown that GC adverse effects (excluding HTN, dyslipidemia and cataract), were recorded in 95 percent of patients with no difference in the risk of developing adverse effects for patients diagnosed in later years (1980–2009) compared to earlier years of GC therapy (1950–1979) . A nested case-control analysis of serious GC-related adverse effects found that a trend of increasing risk of DM and osteoporosis was associated with increasing cumulative prednisolone dose; higher average daily dose (30 mg/d) was associated with an increased risk of DM, osteoporosis, fractures, glaucoma, serious infection, and death compared with lower dose (5 mg/d) . A prospective study of patients with GCA and PMR using the National Database of the German Collaborative Arthritis Centers has shown that of the examined comorbidities, only osteoporosis was observed at increased rate within 3 years and that persistent disease activity within the first year was a good predictor of long-term GC therapy . Moreover, previous studies including five randomized controlled trials [13–15], failed to demonstrate a significant association between GC dose and the development of adverse effects. Our results are in accordance with studies showing no correlation between either initial daily GC dose or cumulative GC dose with risk of developing GC-related adverse effects or comorbidities. However, other studies have shown association of adverse effects with a higher GC cumulative dose . A recent retrospective study showed that each 1000 mg increase GC cumulative dose exposure was associated with an increase of HR for GC-related adverse effects by three percent . Moreover, our data suggest that despite a significant difference in the initial and cumulative GC dose in patients with GCA compared to PMR, the risk of developing adverse effects are similar in GCA and PMR.
Petri et al.  have also performed a retrospective analysis of GCA patients, and described comorbidities associated with GCA, including several related to GC use. Their data was based on the UK clinical practice research datalink, a database that reflects primary care. In contrast, our study only included patients diagnosed by a rheumatologist and followed up for at least one year at our rheumatology clinic.
To assess comorbidity accrual in GCA and PMR during the disease course, we've scored the comorbidities at the time of diagnosis and at end of the follow-up period using the age-adjusted CCI  and RDCI , and calculated the ∆CCI and ∆RDCI as comorbidity accrual scores (Table 5). Neither diagnosis of GCA or PMR and patient's age, nor GC cumulative dose or GC treatment duration, were associated with increase of comorbidity scores during the study follow-up period, but disease flare as well as DM and CAD were significantly associated with a greater CCI at the end of this period.
Our results of similar comorbidity and mortality rate in GCA and PMR patients despite the significant higher prednisone initial, as well as significantly higher cumulative dose in the treatment of GCA compared to PMR, raised concerns about the outcome and GC-related adverse effects in patients with PMR. PMR is the most prevalent chronic inflammatory disease of the elderly [1, 14, 15, and 32]. To date, GC remains the main therapy for PMR [19, 33] and other conventional treatments such as methotrexate have not shown significant benefits in ameliorating disease symptoms and reducing GC-related adverse effects [34, 35].
Survival rate in our cohort was similar for patients with GCA and PMR. Mortality was positively correlated with atherosclerotic CVD, such as CAD, stroke, and aortic dilatation/aneurysm, as well as the presence of known risk factors for atherosclerosis such as HTN, DM, dyslipidemia and smoking. Moreover, higher CCI and RDCI at diagnosis and higher CCI at the last study encounter were associated with increased risk of mortality. GC cumulative dose was not associated with higher risk of death in our cohort (Table 8). Recent studies seeking associations between GCA, PMR and CVD , including a meta-analysis , did not find evidence of increased risk of CAD in patients with GCA compared to the non-GCA population. A population-based longitudinal study comparing 12 CVDs in patients with and without GCA and/or PMR did not find an increased risk of CVD . Previous studies have shown that the mortality rate of patients with GCA [41–43] and PMR  is similar to the age-matched general population. Nevertheless, our findings showing an increased risk of death in patients who had evidence of CAD, stroke, DM, and HTN at the time of diagnosis of GCA or PMR emphasize the importance of controlling CVD in this patient population. Indeed, our results are in line with recent population-based studies that suggest increased prevalence of CVD as a leading cause of death in GCA and/or PMR [41–45]. Moreover, this is the first study to demonstrate increased risk of death in patients with PMR as well as GCA with higher comorbidity (CCI and RDCI) score.
Recently, Tocilizumab was approved for the treatment of GCA following the GiACTA study that showed superiority of tocilizumab combined with prednisone compared to prednisone alone in achieving sustained remission at one year . Several studies have shown that either tocilizumab monotherapy , or in combination with prednisone , are effective in controlling PMR symptoms. Our data suggest that disease relapse was significantly associated with comorbidity accrual during the disease course as well as increased risk of death of patients with PMR or GCA, and thus warrant randomized controlled trials in the effort to find biologic therapies to improve disease outcome and ameliorate GC-related adverse effects as well as atherosclerotic vascular comorbidity in patients with PMR similar to GCA.
Our study has some limitations inherent with its retrospective design and relatively small cohort. On the other hand, this study has certain strengths. First, we analyzed a population that has been diagnosed and followed continuously by rheumatologists in a single center for a median duration of 14.5 years. Second, the CHS database as well as the electronic charts establish a continuous comprehensive documentation of long-term real-life data made by all the physicians involved in medical care of the patients through the entire life span, thus allowing us to derive reliable data on disease course and outcome, GC therapy dose and duration, that allow us to compare end points between the GCA and PMR groups.