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ARTHRITIS & RHEUMATISMVol. 46, No. 5, May 2002, pp 1309–1318DOI 10.1002/art.10262 2002, American College of Rheumatology A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Adjuvant Methotrexate Treatment for Gary S. Hoffman,1 Maria C. Cid,2 David B. Hellmann,3 Loic Guillevin,4 John H. Stone,3 John Schousboe,5 Pascal Cohen,4 Leonard H. Calabrese,1 Howard Dickler,6 Peter A. Merkel,7 Paul Fortin,8 John A. Flynn,3 Geri A. Locker,1 Kirk A. Easley,1 Eric Schned,5 Gene G. Hunder,9 Michael C. Sneller,6 Carol Tuggle,1 Howard Swanson,10 J. Herna´ndez-Rodrı´guez,2 Alfons Lopez-Soto,2 Debora Bork,1 Diane B. Hoffman,1 Kenneth Kalunian,11 David Klashman,11 William S. Wilke,1 Raymond J. Scheetz,1 Brian F. Mandell,1 Barri J. Fessler,1 Gregory Kosmorsky,1 Richard Prayson,1 Raashid A. Luqmani,12 George Nuki,12 Euan McRorie,12 Yvonne Sherrer,13 Shawn Baca,14 Bridgit Walsh,15 Diane Ferland,7 Martin Soubrier,4 Hyon K. Choi,7 Wolfgang Gross,16 Allen M. Segal,1 Charles Ludivico,17 and Xavier Puechal,4 for the International Network for the Study of Systemic Vasculitides (INSSYS) Objective. To evaluate treatment with methotrex-
arteritis (GCA) to determine if MTX reduces GCA
ate (MTX) in patients with newly diagnosed giant cell
relapses and cumulative corticosteroid (CS) require-
ments and diminishes disease- and treatment-related
morbidity.
Supported in part by grants from the Food and Drug Admin- Methods. This was a multicenter, randomized,
istration and the Office of Orphan Products Development (FD-R 001040). Dr. Hoffman’s work was supported by the George B. Storer double-blind study. Over 4 years, 16 centers from the
Foundation and the Ayhan Sahenk Foundation. Dr. Cid’s work was International Network for the Study of Systemic Vascu-
supported by a grant (FIS 98/0443) from Fondo de Investigacio´n litides enrolled patients with unequivocal GCA. The
Sanitaria.1Gary S. Hoffman, MD, Leonard H. Calabrese, DO, Geri A.
initial treatment was 1 mg/kg/day (<60 mg every day)
Locker, BS, Kirk A. Easley, MS, Carol Tuggle, RN, Debora Bork, MA, prednisone, plus either 0.15 mg/kg/week MTX (in-
Diane B. Hoffman, MSN, William S. Wilke, MD, Raymond J. Scheetz, creased to 0.25 mg/kg/week, for a maximum weekly
MD, Brian F. Mandell, MD, PhD, Barri J. Fessler, MD, Gregory Kosmorsky, DO, Richard Prayson, MD, Allen M. Segal, DO: Cleve- dosage of 15 mg) or placebo. Two physicians, both
land Clinic Foundation, Cleveland, Ohio; 2Maria C. Cid, MD, J. Her- blinded to treatment allocation, evaluated each patient
na´ndez-Rodrı´guez, MD, Alfons Lopez-Soto, MD: Hospital Clinic ı´ at every trial visit. One physician was responsible for
Provincial, Barcelona, Spain; 3David B. Hellmann, MD, John H.
Stone, MD, MPH, John A. Flynn, MD: Johns Hopkins University providing global medical care. The other assessed GCA
School of Medicine, Baltimore, Maryland; 4Loic Guillevin, MD, Pascal status according to a standard protocol. Treatment
Cohen, MD, Martin Soubrier, MD, Xavier Puechal, MD: Universite Paris XIII, Paris, France; 5John Schousboe, MD, Eric Schned, MD: Park Nicollet Medical Foundation, St. Louis Park, Minnesota; Florida, and Rheumatology Association of South Florida, Delray 6Howard Dickler, MD, Michael C. Sneller, MD: NIH, Bethesda, Beach; 14Shawn Baca, MD: Center for Rheumatology, Immunology & Maryland; 7Peter A. Merkel, MD, MPH, Diane Ferland, RN, Hyon K.
Arthritis, Fort Lauderdale, Florida; 15Bridgit Walsh, DO: University of Choi, MD, MPH: Massachusetts General Hospital, Boston; 8Paul Arizona, Tucson; 16Wolfgang Gross, MD, PhD: Medizinische Univer- Fortin, MD, MPH: Montreal General Hospital/McGill University, sitat zu Lubeck, Lubeck, Germany; 17Charles Ludivico, MD, Bethle- Montreal, Quebec, Canada; 9Gene G. Hunder, MD: Mayo Clinic, Rochester, Minnesota; 10Howard Swanson, MD: Marshfield Clinic, Address correspondence and reprint requests to Gary S.
Marshfield, Wisconsin; 11Kenneth Kalunian, MD, David Klashman, Hoffman, MD, Harold C. Schott Chair of Rheumatic and Immuno- MD: University of California, Los Angeles; 12Raashid A. Luqmani, logic Diseases, Cleveland Clinic Foundation A50, 9500 Euclid Avenue, DM, FRCP, George Nuki, MB, FRCP, Euan McRorie, MD: Western Cleveland, OH 44915. E-mail: hoffmag@ccf.org.
General Hospital, Edinburgh, Scotland; 13Yvonne Sherrer, MD: Cen- Submitted for publication September 25, 2001; accepted in ter for Rheumatology, Immunology & Arthritis, Fort Lauderdale, failure was defined as 2 distinct relapses or persistence
population-based study, 17% of GCA patients devel- of disease activity after the first relapse, in spite of
oped aortic aneurysms that were sometimes associated increased CS therapy.
with dissection or vessel rupture (18). Aortic branch Results. Ninety-eight patients were enrolled. No
vessel stenoses may cause extremity (upper more fre- significant differences between treatment groups were
quently than lower) claudication (15%). Patients may noted with regard to age, frequency of positive findings
also experience polymyalgia rheumatica (PMR) on temporal artery biopsy (placebo 87%, MTX 79%), or
(ϳ50%), constitutional symptoms (ϳ50%), and stroke comorbidities at the time of enrollment. The median
dosage of MTX was 15 mg/week. The incidence of
Studies of other vasculitides, including Wegener’s treatment failure was comparable between groups after
granulomatosis (21–24) and Takayasu arteritis (25), 12 months: 57.5% in the MTX group failed treatment
have demonstrated that methotrexate (MTX) is an (95% confidence interval [95% CI] 41.6–73.4%) com-
effective treatment and may reduce CS requirements.
pared with 77.3% in the placebo group (95% CI 61.9–
The treatment combination of MTX and CS for GCA 92.8%) (P ؍ 0.26). In a Cox regression analysis, MTX
has never been evaluated in a multicenter, randomized, was not associated with a reduced risk of treatment
failure (relative risk 0.72; 95% CI 0.41–1.28). There were
double-blind, placebo-controlled trial.
no significant differences between groups with regard to
This trial was conducted to determine if treat- abnormal elevations of the erythrocyte sedimentation
ment with MTX 1) reduces the risk of treatment failure rate following initial remissions, serious morbidity due
after induction of remission with CS; 2) diminishes to GCA, cumulative CS dose, or treatment toxicity. In
GCA-related morbidity; and 3) decreases treatment- the MTX group, there were fewer cases of GCA relapse
induced toxicity in patients with newly diagnosed GCA.
heralded by symptoms of isolated polymyalgia rheu-
matica (1 case versus 5 in the placebo group; P ؍ 0.05).
PATIENTS AND METHODS
Conclusion. The results of this randomized, mul-
ticenter trial do not support the adjunctive use of MTX
Members of the International Network for the Study of Systemic Vasculitides (INSSYS) designed a randomized, to control disease activity or to decrease the cumulative
double-blind, placebo-controlled trial to evaluate the benefits dose and toxicity of CS in patients with GCA.
of adjunctive use of MTX in newly diagnosed GCA. Between 1994 and 1998, patients were enrolled at 16 INSSYS centers. In Giant cell (temporal) arteritis (GCA) is a disease the absence of early withdrawal, treatment failure, or loss to of unknown cause that affects large- and medium-sized followup, every patient was followed up for a minimum of 1 arteries. GCA generally occurs in individuals Ͼ50 years Eligibility criteria. All patients were required to be
of age. Women are affected at least twice as often as Ͼ50 years old and to have a Westergren erythrocyte sedimen- men (1,2). In the US, the annual incidence is ϳ2.5/ tation rate (ESR) of Ն40 mm/hour. In addition, patients had to 100,000 population, and 18/100,000 among persons Ͼ50 have at least 1 of the following: 1) a temporal artery biopsy years old. The disease prevalence in this age group in the revealing features of GCA; 2) unequivocal symptoms of GCA US has been estimated to be 223/100,000 population (1).
(e.g., new-onset atypical headaches, scalp or temporal artery Treatment of GCA consists of corticosteroids tenderness, ischemia-related vision loss, or otherwise unex- plained mouth or jaw pain); 3) circumstantial proof of large- (CS), which may be required for 1–5 years and often vessel vasculitis (angiographic abnormalities); and 4) symp- results in substantial toxicity. Essentially all patients toms of PMR plus ischemia-related vision loss, newly develop Cushing’s syndrome. In addition, 20–50% of identified tenderness over a temporal artery, or new onset of individuals develop other CS-related toxicity, including jaw or mouth pain. All patients had to have had onset of GCA fractures, cataracts, peripheral edema, myopathy, infec- tions, and diabetes (3–5). Following initial improvement Exclusion criteria. Patients were excluded from the
study for any of the following criteria: prednisone therapy and CS dose reduction, 1 or more relapses of GCA occur initiated Ͼ21 days prior to study entry, renal impairment in 27–62% of patients (6–10). Relapses require reintro- (serum creatinine Ն2.0 mg/dl), white blood cell count Ͻ4,000/ duction or dose escalation of CS, which often results in mm3, platelet count Ͻ120,000/mm3, inability to comply with the protocol, history of medical noncompliance, liver disease, Morbidity from GCA itself is substantial. In the ingestion of Ͼ2 ounces of 100-proof liquor or Ͼ1 beer per week, insulin-dependent diabetes plus morbid obesity (Ͼ33% era preceding the availability of CS, 30–60% of patients ideal body weight), prior diagnosis of GCA or PMR that had experienced vision loss, compared with 5–20% of CS- been previously treated with CS and had relapsed, peptic ulcer treated patients in more recent series (11–17). In 1 disease within the prior 3 months, serologic proof of infection METHOTREXATE TREATMENT FOR GIANT CELL ARTERITIS with human immunodeficiency virus, or malignancy within 6 experimental medication, after resolution of toxicity, the med- ication could be restarted at a dosage of 2 tablets/week less Because it is characteristic for GCA to markedly than the dosage at which the side effect occurred.
improve following Յ72 hours of CS therapy, the absence of Indications for permanent removal from the trial in- such a response within 5 days constituted a dubious diagnosis cluded 1) drug-induced pneumonitis; 2) severe dermatitis and the patient was deemed ineligible for the study. This clause (Ͼ10% total surface area); 3) severe oral ulcerations (no was included because other forms of vasculitis, less responsive improvement after 2 weeks of experimental therapy discontin- to CS, may affect temporal arteries (26–31).
uation); 4) hepatic transaminase values Ն3 times the upper Frequency of visits. Patients were evaluated 2 weeks
limits of normal, that did not diminish to Ͻ11⁄2 times the upper after the baseline visit and then every month. Additional visits limits of normal within 1 month after drug withdrawal; 5) severe hemocytopenia; 6) elevations of the serum creatinine to Treatment. Therapy was initiated with 1 mg/kg/day of
Ͼ2.0 mg/dl; 7) alcohol abuse; 8) newly discovered malignancy; prednisone, not to exceed 60 mg. Each patient either received 9) life-threatening infections; or 10) patient’s decision to leave oral MTX at a dosage of 0.15 mg/kg/week (rounded to the nearest 2.5-mg tablet increment) or identical placebo tablets.
Outcome measures. Outcome measures included the
Twenty-four hours after taking the experimental therapy, all number of disease relapses and treatment failures in the 2 patients also received folinic acid (5 mg/week). In the absence groups (see definitions below), the clinical features associated of adverse effects, the MTX/placebo was increased within 2 with relapse, disease-related morbidity, the total dose and weeks to a maximum of 0.25 mg/kg or 15 mg/week MTX (or duration of CS treatment, treatment-associated toxicities, and matching placebo). The protocol called for continuation of death. Because of the inherent difficulties in interpreting the experimental therapy for 12 months after the achievement of clinical significance of some symptoms and signs of disease remission. At that juncture, experimental therapy was to be relapses (e.g., an isolated headache, the occurrence of PMR tapered by 1 tablet/month until discontinuation.
symptoms alone, and ESR elevation in the absence of symp- CS tapering. Four weeks after trial entry, prednisone
was reduced by 5 mg every 4 days according to an alternate-day toms), we required that 2 features meet the protocol definition schedule. Dosage reduction calendars were provided to pa- tients. In the absence of relapse, this dosage reduction sched- Definition of relapse. GCA relapse was defined as a
ule led to a dosage of 60 mg every other day after 3 months. If change in ESR from normal to Ն40 mm/hour, plus at least 1 remission continued, the alternate-day prednisone dosage was other feature of GCA not attributable to other conditions.
reduced by 5 mg/week until discontinuation (total duration of These additional features could include 1) fever (Ն38°C for at prednisone use ϭ 6 months). If a relapse occurred, the patient least 7 days); 2) PMR; 3) headache, scalp pain, or tenderness; resumed taking the last dosage of prednisone that effectively 4) vision loss; 5) jaw or mouth pain; 6) extremity claudication; controlled the disease, plus an additional 10 mg. After main- 7) angiographic abnormalities compatible with vasculitis; 8) tenance of the higher dosage for 1 month, another slow cerebral ischemia/infarction; or 9) other features judged by the prednisone taper was attempted, using the same schedule 2 evaluating physicians and confirmed by the MAC after review to be consistent with a relapse.
Bone-conserving therapy. All patients received 1,000
Definition of treatment failure. Treatment failure was
mg of elemental calcium/day and 0.5 ␮g of 1,25 vitamin D defined as the occurrence of 2 distinct disease relapses, or a twice a week (32). Other therapy for osteoporosis was left to relapse treated with prednisone (10 mg greater than the previously effective dosage) that did not lead to improvement.
Monitoring disease status and therapy. Two investiga-
Following the occurrence of treatment failure, patients discon- tors, both blinded to treatment allocation, evaluated each tinued the experimental treatment and were treated according patient at every visit. One physician was responsible for providing complete medical care and the other for assessing Patient randomization. All 16 centers enrolled pa-
GCA activity with a formal score, using a standardized form.
tients. The randomization process was administered centrally Laboratory studies were performed at least once a month.
at the coordinating center (the Cleveland Clinic Foundation).
Complete blood counts, serum creatinine, albumin, hepatic Random permuted blocks (size 2 or 4) were designed to ensure transaminase levels, and an ESR were obtained at least once a Statistical analysis. All analyses were performed on an
Monitoring advisory committee (MAC). The MAC
intent-to-treat basis. The primary end points for this trial were reviewed adverse events and the progress of the trial at least first disease relapse and treatment failure. Clinical character- every month. The MAC possessed the treatment code. Un- istics were compared between groups, with Wilcoxon’s rank equivocal differences between treatment groups in toxicity or sum test for continuous variables and with a chi-square test or efficacy (intent-to-treat analyses) were grounds for the MAC Fisher’s exact test for proportions. The cumulative incidence of relapse, and the occurrence of elevated ESR, headache, vision Adjustment of medications in the setting of toxicity. A
loss, PMR, and treatment failures were estimated with the standardized protocol for reduction or discontinuation of the Kaplan-Meier method. Relapse rates and morbidity between experimental medication was followed in the event of throm- groups were compared using log-rank tests. Total prednisone bocytopenia, leukopenia, elevations in hepatic transaminase dose and time on therapy were compared with Wilcoxon’s rank values, or dermatologic or mucosal abnormalities. When ad- sum test. Using a Cox proportional hazards model, relative verse events necessitated the temporary discontinuation of the risks were calculated to quantify the relationships between Table 1. Baseline characteristics*
* Except for age, values are the number (%). CS ϭ corticosteroids; MTX ϭ methotrexate.
treatment, relapse, and treatment failure. All statistical tests placebo group and 24.4% of patients in the MTX group had failed therapy. At 12 months, 77.3% in the placebo Sample size calculations. The trial was originally de-
signed to enroll 300 patients. Assuming a 30% relapse rate group and 57.5% in the MTX group had failed therapy during the first year of followup, the study would have had 80% (Table 2). These differences were not statistically signif- power to detect a 50% reduction in GCA relapses (␣ ϭ 0.05).
icant (P ϭ 0.26). When all relapses and treatment However, a later review of the cumulative data by the MAC failures were considered for each month through the revealed an observed relapse rate in the placebo group that first 12 months following trial entry, there were no was much higher, 60%. This resulted in the trial having 80% power to detect a 50% reduction in relapses with 98 patients differences between groups (Figure 1). The risk of treatment failure was not significantly reduced for the MTX group (relative risk 0.72, 95% confidence interval [95% CI] 0.41–1.28). A separate analysis of only the first observed relapse (as opposed to treatment failure as Among the 98 patients enrolled, 47 were random- defined) in each group also failed to reveal significant ized to receive CS ϩ placebo and 51 to receive CS ϩ differences (Figure 2). Significant differences in relapse MTX. Apart from an overrepresentation of women in rates and treatment failures between men and women the MTX group, there were no significant differences in were not apparent (P ϭ 0.90).
baseline characteristics (Table 1). The median age was Timing and clinical features of relapse. The
74 years (range 55–89). Eighty percent of patients had number of relapses increased as CS therapy was re- been treated with CS (median 11 days) prior to enroll- duced: 15% occurred during daily therapy (first 3 ment. There was no difference between groups in the months of the trial), 51% occurred during the period of number of patients treated with CS before entry (P ϭ every-other-day therapy, and 34% occurred after CS discontinuation. Table 3 outlines the 1-year cumulative Treatment failures and disease relapses. Six
incidences of clinical manifestations of GCA at the time months following trial entry, 35.4% of the patients in the of a relapse in both treatment groups. The most com- Table 2. Cumulative incidence of first relapses and treatment failures (Kaplan-Meier analyses)*
* CS ϭ corticosteroids; MTX ϭ methotrexate; NR ϭ number of patients at risk who have not had a relapse at 6 months and 12 months followup; NE ϭ number of patients who experienced a relapse at 6 months and 12 months followup; % ϭ percent of patients who have had the outcome on or before 6 months or 12 months; 95% CI ϭ 95% confidence interval for the estimated percentage.
† One patient in the placebo group and 1 in the MTX group relapsed after 1 year.
‡ Outcome of a second relapse or treatment failure. One patient in the MTX group had a second relapse after 1 year.
METHOTREXATE TREATMENT FOR GIANT CELL ARTERITIS Figure 1. Cumulative incidence of treatment failure by treatment group. The rates of treatment
failure over time were not statistically different between the 2 treatment groups. (Treatment
failure is defined as 2 distinct relapses or failure to improve following an increase in therapy after
1 relapse.)
mon features of relapse in both groups were an increase cebo group had either PMR or fever at the time of in ESR plus recurrent headache or scalp pain and/or relapse than patients in the CS ϩ MTX group.
PMR. At the time of relapses, no differences were seen The cumulative incidences of isolated occurrence between groups in rates of new increases in ESR, of headache or scalp pain (P ϭ 0.50), tongue, jaw, or headache, jaw, tongue, or mouth pain, or vision loss.
other oral pain (P ϭ 0.14), or vision loss (P ϭ 0.29) did However, significantly more patients in the CS ϩ pla- not differ significantly between groups. Isolated occur- Figure 2. Cumulative incidence of first relapse by treatment group. The rates of first relapse
over time were not statistically different between the 2 treatment groups.
Table 3. One-year cumulative incidence of clinical characteristics
(Figure 3). Among 20 patients with isolated increases in ESR, subsequent relapses were noted in 16 cases (pos- itive predictive value of ESR elevation for relapse ϭ 80%). The 16 relapses occurred at a median of 7 weeks (range 2–21 weeks, interquartile range [IQR] 8 weeks) after the detection of an isolated increase in ESR. In 4 cases, a significant rise in ESR occurred in the absence of a subsequent relapse (false-positive results). Eight patients had relapses, as judged by both the evaluating physicians and the MAC, without concomitant eleva- * Relapse defined as a rise in erythrocyte sedimentation rate (ESR) tions of ESR (false-negative results). In 18 patients, the (from normal to Ն40 mm/hour, not attributable to a comorbid event), ESR remained normal throughout the period of obser- and at least 1 other feature of giant cell arteritis. Exceptions could be considered by the monitoring advisory committee (see Patients and vation, and relapses did not occur (true-negative re- Methods). Values are the mean Ϯ SEM cumulative rate. CS ϭ sults). An isolated increase in ESR had a relative risk for corticosteroids; MTX ϭ methotrexate.
relapse of 4.32 (95% CI 1.87–10.01) compared with patients whose ESRs did not increase (P Ͻ 0.001).
rence of PMR in the absence of any other feature GCA-associated morbidity. Serious disease-
defining relapse occurred in only 6 patients, 5 in the associated morbidity included subclavian artery stenosis placebo group and 1 in the MTX group (P ϭ 0.05).
(2%) and vision loss. The prevalence of vision loss at Following the development of isolated PMR, protocol- study entry was 18%. New vision loss at 1 year was defined relapses eventually occurred in all 6 patients, 13.8% (4 patients in each group). Three patients who over intervals that ranged from 4 weeks to 13 weeks.
had already had 1 episode of vision loss at study entry ESR as a predictor of disease relapse. The num-
experienced additional vision loss during the first year bers of patients with ESR elevations (Ն40 mm/hour) after enrollment. Stroke did not occur in any patient.
following achievement of normal values were the same Treatment. The median dosage of MTX was 15
between groups, regardless of relapse status (P ϭ 0.49) mg/week (range 5–15; 13 patients received 5–12.5 mg/ Figure 3. Number of patients with erythrocyte sedimentation rate (ESR) elevations. Following
remission, significant differences were not observed between the incidence of increases in ESR
from normal to Ն40 mm/hour in the prednisone group and in the prednisone ϩ methotrexate
METHOTREXATE TREATMENT FOR GIANT CELL ARTERITIS week). The mean and median cumulative doses of CS whose clinical characteristics at presentation were simi- were comparable in both groups. The median total dose lar to those of patients in previously reported studies of prednisone in the placebo group was 5,275 mg (range (3,11,33–38). Thus, our results are broadly applicable to 1,020–8,605 mg, IQR 1,695 mg), versus 5,375 mg in the the population of GCA patients at large.
MTX group (range 1,980–8,270 mg, IQR 1,560 mg) The incidence of GCA relapse that we observed (P ϭ 0.5). The median duration of CS treatment was 5.6 in the course of CS reduction (58% and 77% in the months in the placebo group (range 0.6–20.4 months, MTX and placebo groups, respectively) is similar to IQR 2.4 months) and 5.4 months in the MTX group rates previously reported by others. In recent years, the (range 1–10 months, IQR 2.1 months) (P ϭ 0.5).
relapsing nature of GCA and its long-term associated Treatment-related morbidity. Treatment-related
morbidity have become more apparent. Reports from toxicity was infrequent apart from universal, but tran- the 1980s described the frequency of relapse to be in the sient, cushingoid features. Only 3 patients experienced range of ϳ30% (6,7,9). In contrast, more recent reports fractures. One patient in the placebo group had a pelvic have described relapse frequencies of 60–84% among fracture and 2 in the MTX group had vertebral com- patients followed up for periods of 12–52 months pression fractures. Three patients with serious infections (8,39,40). A population-based analysis of 125 GCA required hospitalization and were withdrawn from the patients revealed that only about half were able to trial (2 placebo, 1 MTX). Four patients required MTX discontinue CS therapy within 2 years (41).
reductions, of whom 3 were withdrawn from the trial The effectiveness of conventional long-term because of persistent elevation in hepatic transaminase treatment with CS in GCA has also recently been values, MTX-related fever, and persistent thrombocyto- questioned by Weyand and colleagues (40), who found penia, respectively. There were no withdrawals because that soluble interleukin-6 (IL-6) concentrations corre- of drug-induced pneumonitis, oral ulcers, dermatitis, lated better with GCA activity than either the ESR or C-reactive protein level. In two-thirds of their patients, Deaths. Three deaths occurred, 2 in the MTX
IL-6 levels did not normalize after treatment, even in the group (1 related to congestive heart failure, the other setting of apparent clinical remission. The notion that cause unknown) and 1 in the placebo group (pneumo- some patients with GCA, who appear to be clinically nia). No deaths were attributed to GCA.
well, may continue to have active disease is further supported by findings of active GCA in aortic bypass specimens or postmortem examinations in patients DISCUSSION
whose disease was thought to be in remission (18,42).
This is the first large multicenter, randomized, While findings of recent studies have succeeded double-blinded, placebo-controlled trial of any form of in changing concepts about the long-term effectiveness adjunctive therapy for new-onset GCA. The results of CS therapy in GCA, differing opinions persist about suggest that MTX does not have a substantial effect on preferred CS dosage and treatment regimens for GCA.
the course of GCA, the incidence of strictly defined During the planning of this trial, investigators achieved relapse, cumulative CS dose, or treatment-related mor- consensus on a standardized plan for CS therapy. The bidity. In a secondary analysis of isolated disease fea- process of consensus revealed a broad range of clinical tures, the only discernible benefit of MTX treatment was practices, even among individuals regarded as experts.
a significant reduction in the emergence of isolated There was unanimity among investigators that severe PMR (5 cases in the placebo group versus 1 case in the systemic vasculitis, including GCA, requires high daily MTX group). In all 6 cases, isolated PMR heralded dosages of CS at the start of treatment (34). The eventual GCA relapses within 4–13 weeks.
investigators also acknowledged the importance of Our trial has a number of important strengths.
avoiding long-term daily CS exposure. The conversion of This trial 1) is the first multicenter comparison of CS ϩ CS dosage from daily to an alternate-day regimen has MTX versus CS alone; 2) included a relatively large been the basis of numerous National Institutes of sample size from an international group of academic Health–based protocols for several types of vasculitis medical centers; 3) involved a rigorous protocol for and has been tested in GCA (43–46). Agreement was patient evaluation, in which all patients were monitored reached on a strategy of 1 month of daily prednisone (1 by 2 physicians, both blinded to treatment assignment; 4) mg/kg), followed by gradual tapering, to eventually used a standardized regimen for medication dosage achieve a 60-mg dosage on alternate days after 3 months.
reduction during remission; and 5) included patients In reaching this consensus, the investigators recognized that the optimal schedule of CS therapy in GCA re- treatment group experienced new-onset vision loss. In our trial, protocol-defined relapses were characterized The rationale for choosing MTX as adjunctive by an increase in ESR plus either PMR and/or cranial therapy for GCA was based on its success in other symptoms. In the course of relapse, 13.8% of our vasculitides (21–25). Some of these studies used a similar CS tapering protocol (21–23,25). Previous studies have Several factors may have contributed to the dif- attempted to assess MTX or other agents in GCA. The ferences in outcomes reported between our study and interpretations of these studies have been confounded that of Jover et al. Most important, it is likely that by several factors, including both the enrollment of differences in guidelines for defining relapses partly patients with GCA and patients with isolated PMR explain the disparate results. For example, although the (47,48), lack of controls (49), the use of low dosages of study by Jover et al obtained ESR values on all patients, MTX (e.g., 7.5 mg/week) (47), and the inclusion of it is not clear how those data were applied to the patients with longstanding, relapsing disease (48). One assessment of disease activity. It is also not clear whether randomized, double-blind, placebo-controlled trial of 21 isolated PMR symptoms or headaches, in the absence of patients failed to demonstrate significant differences other findings (e.g., ESR elevation), were sufficient to between CS treatment and CS ϩ MTX. The authors’ constitute relapses. In our study, isolated increases in conclusions were cautiously interpreted because of the ESR were not considered to represent relapses. Eighty limited numbers of patients enrolled (50).
percent of our patients who had an isolated increase in In a recently published article, Jover and col- ESR eventually experienced a relapse during the ensu- leagues from Madrid (39) reported that adjunctive ther- ing 2–21 weeks (median 7 weeks). In our trial, the apy with MTX had beneficial effects in GCA, in regard relative risk of relapse following an isolated rise in ESR to both maintenance of remission and decreasing the was 4.32, compared with patients in whom ESR values cumulative requirement for CS. The results of that remained normal. Even in retrospect, we believe the single-center trial, which enrolled 42 patients and used a decision not to use an isolated elevation in ESR as a less intensive regimen of MTX and CS than ours, are measure of relapse was clinically correct. Whereas an difficult to reconcile with our own. The clinical and ESR elevation has a high positive predictive value for demographic features of the patient populations in both relapse, that event may not occur for months in some studies, apart from geographic residence, appear to be patients. Intensifying treatment in response to only a comparable. In the Madrid trial, CS tapering was actu- change in ESR may lead to additional and unnecessary ally more rapid than in our trial. Although Jover et al did CS-induced morbidity. However, a rise in ESR should not convert prednisone dosing to every other day after 3 indicate a need for more vigilant clinical surveillance.
months, their patients, barring relapse, achieved pred- In our trial, all 6 patients with isolated PMR (not nisone dosages of 40 mg daily at the end of 1 month and judged to be a relapse) eventually satisfied relapse a dosage of 20 mg daily at the end of 2 months. In the criteria. Patients in our MTX group had a significant absence of relapse, complete CS withdrawal was accom- reduction in isolated PMR (at 12 months followup, plished in 4 months in the Madrid trial.
MTX group 2.6% versus placebo group 25.8%; P ϭ In contrast, our protocol called for the treatment 0.05). One could argue that our protocol may have been of patients with 60 mg of prednisone daily for 4 weeks too restrictive in identifying relapses that would other- and then tapering according to an alternate-day sched- wise have led to providing earlier increases in CS ule, such that by the end of 2 months patients were still therapy. More liberal criteria would have led to earlier receiving 60 mg on 1 day and 20 mg the next. In the treatment in the 6 patients who had isolated PMR, and absence of relapse, total CS withdrawal was accom- subsequently relapsed, and in earlier increased treat- plished by 6 months. The median dosage of MTX in our ment of the 20 patients who had isolated increases in trial was 15 mg/week, whereas Jover et al (39) used 10 mg/week (mean/median values were not provided). Both Our aggressive CS tapering schedule may have trials included folic or CS folinic acid supplementation led to a high rate of relapse. However, when one to diminish or prevent MTX toxicity. In both trials, compares the relapse rates in our trial with those of relapses occurred in the majority of patients, most often other recent prospective studies (6–9,39,40), including when CS dosages were very low or CS had been discon- that from Madrid, the outcomes for CS therapy alone tinued. Most of the relapses in the Madrid study (39) are not dissimilar. More important, if MTX contributed were in the form of PMR, and no patient in either substantially to the maintenance of remission in GCA, it METHOTREXATE TREATMENT FOR GIANT CELL ARTERITIS should have allowed for aggressive CS reduction without evolution in a cohort of 133 patients with giant cell arteritis. Clin the high incidence of relapse observed. It is also possible 9. Kyle V, Hazleman BL. Treatment of polymyalgia rheumatica and that higher doses of MTX may have achieved greater giant cell arteritis. I. Steroid regimens in the first two months. Ann efficacy. However, previous publications and investiga- tors’ experience with MTX in the elderly cautioned 10. Kyle V, Hazleman BL. Treatment of polymyalgia rheumatica and giant cell arteritis. II. Relation between steroid dose and steroid against the use of higher doses. Age-related reductions associated side effects. Ann Rheum Dis 1989;48:662–6.
in renal clearance and serum albumin may lead to 11. Myklebust G, Gran JT. A prospective study of 287 patients with greater numbers of MTX-associated complications (51– polymyalgia rheumatica and temporal arteritis: clinical and labo- ratory manifestations at onset of disease and at the time of 53). Even so, the finding that only 8% of our MTX- diagnosis. Br J Rheumatol 1996;35:1161–8.
treated patients had side effects of that drug that 12. Bengtsson BA, Malmvall BE. The epidemiology of giant cell required dosage reductions indicates that higher doses arteritis including temporal arteritis and polymyalgia rheumatica: incidences of different clinical presentations and eye complica- may be safe in a subset of carefully selected elderly tions. Arthritis Rheum 1981;24:899–904.
13. Gonzalez-Gay MA, Blanco R, Rodriguez-Valverde V, Martinez- In conclusion, this large, randomized, double- Taboada VM, Delgado-Rodriguez M, Figueroa M, et al. Perma- nent visual loss and cerebrovascular accidents in giant cell arteritis: blinded, placebo-controlled trial did not demonstrate predictors and response to treatment. Arthritis Rheum 1998;41: statistically significant effects of MTX in reducing either the relapse rate of strictly defined GCA remissions, 14. Gordon LK, Levin LA. Visual loss in giant cell arteritis. JAMA cumulative doses of CS, or serious CS- and disease- 15. Font C, Cid MC, Coll-Vincent B, Lopez-Soto A, Grau JM. Clinical related morbidity. However, adjunctive treatment with features in patients with permanent visual loss due to biopsy- MTX did appear to diminish recurrences of isolated proven giant cell arteritis. Br J Rheumatol 1997;36:251–4.
16. Cid MC, Font C, Oristrell J, de la Sierra A, Coll-Vincent B, Lopez-Soto A, et al. Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis. Arthritis ACKNOWLEDGMENT
17. Hunder GG. Giant cell (temporal) arteritis. Rheum Dis Clin The authors thank Lederle Pharmaceuticals/Wyeth- Ayerst for providing the methotrexate, placebo, and folinic 18. Evans JM, O’Fallon WM, Hunder GG. Increased incidence of aortic aneurysm and dissection in giant cell (temporal) arteritis: a population-based study. Ann Intern Med 1995;122:502–7.
19. Greene GM, Lain D, Sherwin RM, Wilson JE, McManus BM.
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