Health Science Center, San Antonio, Texas), W. Michael. O'Fallon, PhD, Gene G. ... emergency room (including out-call medical visits) were reviewed. Patients ...
Arthritis & Rheumatism (Arthritis Care & Research) Vol. 49, No. 5, October 15, 2003, pp 703–708 DOI 10.1002/art.11388 © 2003, American College of Rheumatology
ORIGINAL ARTICLE
Glucocorticoid Therapy in Giant Cell Arteritis: Duration and Adverse Outcomes ANNE PROVEN, SHERINE E. GABRIEL, CARLOS ORCES, W. MICHAEL O’FALLON, AND GENE G. HUNDER
Objective. To evaluate the course of glucocorticoid (GC) therapy and associated adverse events in a population-based cohort of patients with giant cell arteritis (GCA). Methods. We identified 125 Olmsted County residents with GCA diagnosed between 1950 and 1991 and obtained followup information on the 120 patients who were diagnosed antemortem and agreed to participate in this study. Clinical variables, GC doses, and GC adverse events on each patient were recorded. The relationship between GC therapy and the development of adverse events was studied by the Cox and Anderson-Gill proportional hazards models. Results. All patients were treated with GCs and responded rapidly (median initial dosage 60 mg prednisone/day). The dosage was later reduced according to the treating physicians’ judgment. The median duration required to reach 7.5 mg/day was 6.5 months and the median duration required to reach 5 mg/day was 7.5 months. Relapses or recurrences occurred in 57 patients. For the 87 patients followed to discontinuation of GC therapy and permanent remission of GCA (median of 22 months), the total median dose of prednisone was 6.47 gm. Adverse events associated with GCs were recorded in 103 (86%) patients and 2 or more events occurred in 70 patients (58%). Age and higher cumulative dose of GCs were associated with the development of adverse GC side effects. Conclusion. GCs are therapeutically effective in GCA and the prednisone dosage was reduced to physiologic levels in three-fourths of the patients within 1 year. However, most patients developed serious adverse side effects related to GCs, indicating that less toxic therapeutic measures are needed. KEY WORDS. Steroids; Adverse events; Giant cell arteritis; Treatment.
INTRODUCTION In many populations, giant cell arteritis (GCA) is the most common form of vasculitis, especially in those over the age of 50 years (1–3). Although inflammatory vascular lesions may be found in many arteries, vessels originating from the arch of the aorta are generally affected to the greatest degree (4,5). The mean age at onset is approximately 70 years. The presenting symptoms vary widely but most patients have findings related to the arteries at some time during the course of the illness. Common early manifestations include constitutional symptoms, headache, visual
Anne Proven, MD (current address: Martina Hansens Hospital, Baerum Postterminal, Norway), Sherine E. Gabriel, MD, Carlos Orces, MD (current address: University of Texas Health Science Center, San Antonio, Texas), W. Michael O’Fallon, PhD, Gene G. Hunder, MD: Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Address correspondence to Gene G. Hunder, MD, Mayo Clinic and Mayo Foundation, 200 First Street, SW, Rochester, MN 55905. Submitted for publication May 13, 2002; accepted in revised form August 28, 2002.
loss, polymyalgia rheumatica (PMR), and jaw claudication (6,7). The diagnosis is generally made by temporal artery biopsy. Glucocorticoids (GCs) are the drugs of choice in treatment and patients often note an improvement in symptoms within hours of the first dose. Although GCs have been used for many years for GCA, there is no universal agreement regarding the initial dosage and length of treatment needed (8 –12). The duration of GC therapy in individual patients with GCA has been difficult to predict from presenting manifestations (6). In some series, the mean duration has been 5– 6 years (13–14). Studies of long-term treatment with GC of patients have shown adverse events to be substantial (15,16). The objective of this study was to assess GC therapy in patients diagnosed with GCA between 1950 and 1991 in the population of Olmsted County, Minnesota (2) to determine the duration of treatment and the frequency and type of adverse GC events.
METHODS The population of Olmsted County, Minnesota is well suited for the investigation of the epidemiology of GCA 703
704 because of the availability of comprehensive unit medical records for all residents seeking medical care and the unique population-based data resources of the Rochester Epidemiology Project (REP), as described before (2,15,17). We identified an incidence cohort of all Olmsted County residents first diagnosed with GCA between 1950 and 1991. All patients with GCA fit the American College of Rheumatology criteria (18). The diagnosis of PMR was as described before (19). The medical records of each patient were reviewed especially with regard to starting dosage of GC and course of GC therapy, the use of steroid-sparing drugs, response to therapy, and the frequency and type of adverse events. Records of all outpatient, inpatient, and emergency room (including out-call medical visits) were reviewed. Patients were seen by various Mayo Clinic physicians and a small number of community physicians over the years and were not treated according to a specific protocol. The initial GC dosage, as well as lower subsequent dosages, were determined by the treating physician according to his/her judgement of the activity of the disease based on laboratory tests and the presence or absence of symptoms considered related to GCA. We recorded the age at diagnosis, the date of initiation of GC therapy, and the occurrence(s) of adverse events. We also recorded the initial GC dosage and changes in dosage throughout the course of treatment, the duration of GC therapy, and duration of followup. Followup for all patients continued until death, migration from Olmsted County, or to the most recent visit. No patient in this study had been treated with GCs for more than 1 week prior to the diagnosis of GCA. Relapses and recurrences (20) and the times they occurred during the course of therapy were recorded. Data regarding antiosteoporosis therapy were not uniformly recorded in the records and are not included in the results. The adverse events selected for the study were the most commonly reported complications of GC therapy (15). These included diabetes mellitus (2 readings of fasting plasma glucose ⬎140 mg/dl or glucose tolerance test levels ⬎200 mg/dl, excluding readings obtained during emergency room or inpatient care); symptomatic vertebral fractures; Colles’ fracture of the wrists; hip fracture; femoral neck fracture; avascular necrosis (the latter 5 clinical findings confirmed by radiography); cataracts (diagnosed or confirmed by an ophthalmologist); bacteremia or sepsis (confirmed by blood culture); pneumonitis (confirmed by radiography); other infections (diagnosed by a physician and/or confirmed by culture), excluding urinary tract infections and viral upper respiratory infections; upper gastrointestinal bleeding (endoscopic or clinical diagnosis supported by a drop in hemoglobin concentration of ⬎1 gm); hypertension (2 consecutive blood pressure readings of at least 140/90 mm Hg, excluding readings obtained during emergency room or inpatient care); and myopathy (physician’s diagnosis supported by documented proximal muscle weakness on physical examination). A new or incident diagnosis of any of the above conditions occurring after the diagnosis of GCA was defined as an adverse event. The relationship between the occurrence of the first adverse event and the therapy-related variables (including
Proven et al type of drug, duration of therapy, initial dose, and cumulative dose), age, sex, and diagnosis of GCA were studied by Cox proportional hazards model similar to an earlier study (15), and by the Anderson-Gill proportional hazards model (21). The latter model allowed us to examine all adverse events occurring in each patient. Cumulative doses of GC were examined as time-dependent covariates in these models. To test whether GCA patients receiving either GC therapy or nonsteroidal antiinflammatory drug (NSAID) therapy in combination with GC therapy had an excess risk of experiencing these events relative to the general population, we compared the incidence of adverse events following the diagnosis of GCA in this cohort with the expected incidence rates of the same events in the same underlying population (i.e., Olmsted County residents of similar age and sex), using available data from certain other published REP reports (22–24).
RESULTS Demographics. During the period 1950 through the end of 1991, 125 Olmsted County residents were diagnosed with GCA. Five of these were excluded, 3 because we were unable to secure their authorization to participate in research, 1 who was diagnosed at autopsy, and 1 whose diagnosis was uncertain at onset of therapy. Thus, the final study population was 120 patients. Of these, 100 (83%) were women and 20 (17%) were men. The mean age at diagnosis was 75 years (range 56 –92 years). The median duration of followup was 10 years (range 0.1–34 years). Twenty-three patients (19%) died during the follow-up period before GC treatment was discontinued. Three of these deaths were related to GCA. The remaining 97 patients were followed to the end of treatment or the study period. Response and course of GC treatment. GC therapy was started at the time of diagnosis. The median initial GC dosage was 60 mg/day of prednisone (mean dosage 54 mg/day) or equivalent of another GC (Table 1). The range of the initial dosages was 10 –100 mg/day. All patients had a favorable response to GC treatment with resolution of reversible symptoms and return of inflammatory markers to normal. The median time to initial response recorded in the patients’ charts was 8 days with a range of ⬍1– 44 days. However, among patients whose records contained information regarding the response over the first week of therapy, it was noted that improvement usually began within hours or days after starting GC. The symptoms that reversed earliest included fever, malaise, headache, and PMR. Pain due to vascular insufficiency, such as jaw claudication, improved over days or weeks, and arm claudication improved over months or longer. Fixed visual deficits tended to improve little if any. In some records, symptoms were described as having resolved but the exact day was not included. As a result, a more detailed analysis of the sequential response to therapy was not possible. Patients with PMR were not treated differently than those without these symptoms. The median time from onset of therapy to reach 7.5
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Table 1. Duration of glucocorticoid (GC) treatment in 120 patients with giant cell arteritis
Category Initial dose of GC, mg/day Time to reduce to 7.5 mg/day, months Time to reduce to 5.0 mg/day, months Time to permanent remission and discontinuation of GC, months Taking GC at last followup, years
Number of patients in category
Duration of time to event median (range)
120 112 109 87
60 (10–100) 6.5 (0.03–24) 7.5 (0.2–62) 21.6 (2.3–122)
7
10 (0.1–34)*
* Length of followup for entire group.
mg/day in the 112 patients followed to that level was 6.5 months (mean 7.7 months) with a range of 0.03–24 months (Table 1, Figure 1). Seventy-five percent of the patients had reached this dosage by 11 months. Seven patients had died before reaching 7.5 mg/day and another stopped prednisone abruptly above this level because of an adverse side effect. The median time to reach 5 mg/day in the 109 patients followed to that level was 7.5 months (mean 9.4 months) with a range of 0.2– 62 months (Table 1). By 13 months, 75% of the patients had reached this level. Ten patients had died before reaching this dosage, and, as noted above, 1 had discontinued prednisone at a higher level because of side effects. In 87 patients, GCs were discontinued and permanent remission achieved. The median time for this to occur was 21.6 months (mean 26.2 months) with a range of 2.3–122 months (Table 1). Therapy had been discontinued in 75% of the patients by 37 months. Three other patients stopped GCs at low doses before remission occurred. Seven others were still on GCs at the last visit. Total median GC dose taken by the patients to reach 7.5 mg/day was 3.78 gm, to reach 5.0 mg/day was 4.26 gm, and to discontinue prednisone with remission was 6.47 gm (Table 2). The median cumulative GC dose of the 90, including 3 not achieving remission when GCs were stopped, was 5.79 gm, and the median dose for the entire
group of patients during the entire follow-up period, including those who hadn’t discontinued GC therapy at last visit, was 7.35 gm (mean 9.68 gm). The median daily dose of prednisone during the entire course of therapy was 11.5 mg/day (mean 13.6 mg/day). We found no correlation between the initial GC dose nor the length of GC treatment and the presence of permanent visual loss, jaw claudication, or initial erythrocyte sedimentation rate. Relapses or recurrences were recorded in 57 (48%) of the patients and occurred throughout most of the course of therapy. Nineteen (16%) patients had 2 or more relapses. The greatest number of relapses in any patient was 7. Median time from onset of GC treatment to first relapse was 7 months, with a range of 1–97 months. The median prednisone dosage (or equivalent) at the first relapse was 5 mg/day (mean 7.6 mg/day) with a range of 0 –33 mg/day. Of the 87 who went into permanent remission and discontinued GC, 39 had 1 or more relapses (13 had 2 or more relapses) prior to permanent remission. Of the 33 who did not achieve permanent remission and discontinue prednisone prior to death or last followup, 18 had 1 or more relapses (6 had 2 or more relapses). Thus, the proportion of those with relapses was not different in the 2 groups. Glucocorticoid-sparing therapy. NSAIDs were given to 25 (21%) patients in various doses and durations, and disease-modifying drugs were used in 2 (2%). One patient Table 2. Total glucocorticoid doses in 120 patients with giant cell arteritis
Treatment category
Figure 1. Glucocorticoid (GC) treatment in 120 patients with giant cell arteritis. Fifty percent of patients had the initial high dosages of prednisone lowered to 7.5 mg/day by 6.5 months and 75% of patients reached 7.5 mg/day by 11 months.
Total dose to reach 7.5 mg/day, grams Total dose to reach 5.0 mg/day, grams Total dose to permanent remission and discontinuation of GC therapy, grams Median daily prednisone dose over period of therapy, mg/day
Doses of prednisone or equivalent median dose (range) 3.78 (0.02–14.5) 4.26 (0.04–20.9) 6.47 (0.2–33.4)
11.5 (1.4–50.1)
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Table 3. Major adverse events that occurred in 103 of 120 patients with giant cell arteritis
Type of adverse event Diabetes mellitus Total fractures Hip fracture Vertebral fracture Colles’ fracture Other fractures Gastrointestinal bleeding Hypertension Infection Posterior subcapsular cataract
Patients with the event, number (%) 11 (9) 46 (38) 19 (16) 27 (23) 3 (2.5) 11 (9) 5 (4) 26 (22) 37 (31) 49 (41)
was treated with methotrexate and 1 with azathioprine. Neither type of drug was significantly related to a shorter course of GC treatment (data not shown). Adverse events. Most patients were observed to have some degree of hypercortisolism, such as puffy cheeks, easy bruising, and muscle weakness. However, the detailed data about these events were not recorded uniformly and neither the exact numbers of patients affected nor the degree of severity could be accurately determined in the group. Other specific adverse events related to GC that occurred after the diagnosis of GCA were recorded in 103 (86%) patients. These included bone fractures in 46 patients (vertebral fracture in 27, hip/femoral neck fracture in 19, Colles’ fracture of the wrist in 3, other fractures in 11), avascular necrosis of the hip in 3, diabetes mellitus in 11, infections in 37 (bacteremia/sepsis in 2, pneumonitis in 18, and other infections in 25), gastrointestinal bleeding in 5, posterior subcapsular cataract in 49, and hypertension in 26 (Table 3). Two or more adverse events occurred in 70 (58%) patients, and as many as 7 events developed in 1 patient (Table 4). These adverse events often caused severe symptoms and at times required hospitalization. Among those experiencing an adverse event, the median time from initiation of therapy to the first adverse event was 1.1 years (mean 2.7 years). Univariate results from the proportional hazards model failed to indicate age, sex, higher initial GC dose, or higher cumulative dose as significant risk factors for the development of any specific Table 4. Number of adverse glucocorticoid events per patient that occurred in the cohort Number of adverse events
Number of patients having events
0 1 2 3 4 5 6 7
17 41 30 16 10 2 3 1
type of first adverse event (e.g., hip fracture). However, age (P ⫽ 0.003) was a significant risk factor for the development of any adverse event, whereas sex and higher initial GC dose were still not significantly related. Anderson-Gill modeling indicated that, adjusting for age and sex, higher cumulative GC dose, but not higher initial GC dose, was significantly associated with the development of any adverse event. No significant interactions between various risk factors for adverse events were identified (plots not shown). Person-year analysis revealed that the risks of diabetes mellitus, vertebral fractures, femoral neck fractures, and hip fractures were 1.3–3.3 times greater in the GCA cohort when compared with age- and sex-matched individuals from the same population (22–24).
DISCUSSION We used the detailed information available from the medical records of our population-based cohort of patients with GCA to analyze GC therapy and adverse events that developed over a median follow-up period of 10 years. All patients experienced an early response to these drugs with resolution of reversible manifestations, as noted in many previous studies (7,12,25). In the first years of the study period, shortly after the advent of GC use in GCA, cortisone acetate was given to patients in relatively smaller amounts for short periods of time (25). However, the most common starting dosage over the study period was 60 mg of prednisone per day (Table 1). Higher initial dosages were given to some patients, especially those in whom a vascular complication, such as blindness, had occurred or appeared imminent at diagnosis. The initial dosages of GCs were reduced relatively rapidly to reach a physiologic or near physiologic dose (7.5 mg/day) in half the patients by approximately 6 months and three-quarters of the patients within 1 year (Figure 1). The median time to reach 5.0 mg/day was longer at 7.5 months (Table 1). Reducing GCs in the lower ranges was slower than at higher dosages. The median time to permanently discontinue GC in the 87 patients followed over the entire course of GC therapy was 21.6 months (Table 1). Thus, although the vast majority of patients were able to discontinue GCs, it took more than twice as long to reduce the median GC dosage from 7.5 mg/day to 0 mg/day (15.1 months) than from the initial 60 mg/day to 7.5 mg/day (6.5 months). There are several possible reasons for the slower reduction at lower levels. First, the disease may persist longer at a lower intensity requiring the small GC doses. Alternatively, symptoms of hypoadrenalism at low GC dosages may have been difficult to distinguish from mild active disease, which may have caused some physicians to continue small dosages for longer times. Relapses were frequent, and developed in nearly half of the patients. These tended to appear at reduced GC doses and prolonged the treatment period at low dosages in many patients. It is likely that all of these factors and possibly others were operative in some patients. It should be noted that there was great individual variation in the time to reach these lower dosages and discontinue GCs, suggesting
Glucocorticoid Therapy in Giant Cell Arteritis a diversity of the duration and severity of GCA in different patients. However, we found no relationship between the length of therapy and severity of disease as measured by the presence of visual loss, jaw claudication, or initial erythrocyte sedimentation rate. Even though GCs have been the therapy of choice for GCA for many years, long-term followup information about the duration of their use and associated adverse effects occurring in populations of patients is not extensive. Andersson and coworkers (13) followed 90 patients with GCA diagnosed in a medical department in Goteborg, Sweden for a median of 11.3 years. The mean duration of GC therapy was 5.8 years. Five years after the diagnosis, 43% of patients remained on GC therapy. After 9 years, 15 of the 60 surviving patients were still on treatment. Delecoeuillerie and colleagues (9) followed 78 patients with GCA diagnosed in a rheumatology department in France. The mean duration of treatment was 30.9 months. In contrast to our findings, patients started on higher dosages had more GC side effects. Hachulla et al (26) assessed outcome in 133 patients with GCA treated in a department of internal medicine in France. The mean duration of GC therapy was 40 months in 56 patients followed until the drugs were discontinued. Lundberg and Hedfors (11) found that the average period of GC therapy in 51 patients with GCA diagnosed in a department of rheumatology in Sweden was 21 months. The duration of GC therapy in the first 3 studies above (9,13,26) was longer than ours and the last similar. The reasons for the differences in length of therapy are not clear. Patients in the previous studies were derived from medical or rheumatology departments selected from an unknown total population of patients. Patients with a more severe form of an illness are often sent to referral centers and may be given more therapy than a mild case not referred. None of the above reported investigations, nor ours, included prospectively studied cases with uniform treatment protocols. Because the duration of active GCA is not accurately known and the detection of mild persistent disease is not precisely clinically determinable by current tests, concepts of what constitutes adequate therapy of GCA by individual physicians may have influenced decisions regarding GC administration. GC adverse events were frequent and diverse. They occurred in 105 of 120 patients (86%) and were multiple in 70 (58%). They caused serious morbidity and added health care expense. Although the study period extended back before current measures were available to reduce steroid-induced osteoporosis, it is likely that bone fractures, as well as other events, will continue to occur at least to some extent whenever large doses of GCs are given for extended lengths of time. Increasing age and larger cumulative dose increased the risk for adverse effects. The lack of association between initial high GC dosage and subsequent adverse events is likely due to rapid lowering of the daily GC amounts in many patients who started at high levels. Patient population size may also have influenced the results. In patients who had no permanent vascular complications but did have extensive adverse GC events, the morbidity and costs associated with their treatment were major factors in the overall illness. Steroid-
707 sparing agents were used in too few patients in our population to evaluate any potential effect they may have. In an earlier study, Nesher and colleagues (27) analyzed steroid-related complications in 43 patients with GCA diagnosed in 1 center over a 15-year period. Twenty-five (58%) developed major steriod-related adverse events in the mean 3-year period of followup. Most common were bone fractures and infections. Steroid-related complications were related to the dosage and occurred more commonly in older patients. Seven of 19 deaths that occurred during followup were considered to be related to steroid treatment. The authors concluded that GC treatment caused major morbidity and possible mortality in GCA. Previously we analyzed adverse outcomes of antiinflammatory therapy in patients with PMR, a syndrome related to GCA (15). That study included 232 residents of Rochester, MN with PMR diagnosed between 1970 and 1991. The median duration of therapy in the 175 patients treated with GCs was 22 months, almost identical to the 21.6 months duration found in the current study. However, as might be expected, the median total cumulative GC dose of 5.4 gm given in the PMR population was lower than the 7.35 gm given in the current patients with GCA, because lower GC dosages are generally given in PMR. Nevertheless, 1 or more adverse GC-related side effects occurred in 122 of the 175 patients with PMR given GC. Bone fractures and infections were the most common severe side effects. Adverse events in the PMR study were related to increasing age at diagnosis, female sex, and a cumulative dose of prednisone of ⱖ1,800 mg. Although the type of steroidrelated complications in the previous study on PMR and in the current investigation were similar, they were more frequent in the current series (85% versus 70%) and occurred earlier in the course of treatment (median time after initiation of GC treatment in GCA of 1.1 year versus 1.6 year in PMR) (15), most likely because larger dosages of GCs are used in GCA. In the earlier study, the frequency of adverse events increased after a cumulative prednisone dose of about 1.8 gm. In the current study, GC side effects occurred more continuously over a broader dose range. In conclusion, although GCs were reduced to physiologic levels at a median of 6.5 months and discontinued completely at a median of less than 2 years, the frequency of adverse side effects was high. These complications of GC therapy caused important morbidity and increased health care costs. Because adverse events were related to increased total GC dose, efforts should be made to use the lowest doses of GCs for the shortest time possible when treating patients GCA. This is especially true in older patients because increasing age was also related to increased side effects. Measures to prevent GC-induced osteoporosis should be considered in all patients (28). However, because of the high frequency of GC side effects observed in patients with PMR who were given lower dosages (15), it seems unlikely that simply reducing the amount of GC alone will be a satisfactory answer to the adverse GC events in GCA therapy. The development of equally effective but less toxic therapy for GCA should be a high priority for researchers in this disease.
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