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
Giant Cell Arteritis
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
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: [email protected]
General Hospital, Edinburgh, Scotland; 13Yvonne Sherrer, MD: Cen-
Submitted for publication September 25, 2001; accepted in
ter for Rheumatology, Immunology & Arthritis, Fort Lauderdale,
revised form January 11, 2002.
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
(⬃50%), constitutional symptoms (⬃50%), 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
ⴝ 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
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 ⬎50 years
All patients were required to be
of age. Women are affected at least twice as often as
⬎50 years old and to have a Westergren erythrocyte sedimen-
men (1,2). In the US, the annual incidence is ⬃2.5/
tation rate (ESR) of ⱖ40 mm/hour. In addition, patients had to
100,000 population, and 18/100,000 among persons ⬎50
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-
symptoms within 6 months of entry.
tions, and diabetes (3–5). Following initial improvement
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 ⬎21 days prior to study entry, renal impairment
in 27–62% of patients (6–10). Relapses require reintro-
(serum creatinine ⱖ2.0 mg/dl), white blood cell count ⬍4,000/
duction or dose escalation of CS, which often results in
mm3, platelet count ⬍120,000/mm3, inability to comply with
the protocol, history of medical noncompliance, liver disease,
Morbidity from GCA itself is substantial. In the
ingestion of ⬎2 ounces of 100-proof liquor or ⬎1 beer per
week, insulin-dependent diabetes plus morbid obesity (⬎33%
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-
months of enrollment.
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 ⱕ72 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
(⬎10% 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 ⱖ3 times the upper
Frequency of visits.
Patients were evaluated 2 weeks
limits of normal, that did not diminish to ⬍11⁄2 times the upper
after the baseline visit and then every month. Additional visits
limits of normal within 1 month after drug withdrawal; 5)
were arranged as needed.
severe hemocytopenia; 6) elevations of the serum creatinine to
Therapy was initiated with 1 mg/kg/day of
⬎2.0 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 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-
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-
of disease relapse.
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 ⱖ40 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 (ⱖ38°C for at
prednisone use ⫽ 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.
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
the discretion of the physician.
previously effective dosage) that did not lead to improvement.
Monitoring disease status and therapy.
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
to usual medical care.
providing complete medical care and the other for assessing
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
balance between the groups.
All analyses were performed on an
Monitoring advisory committee (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
to terminate the trial.
relapse, and the occurrence of elevated ESR, headache, vision
Adjustment of medications in the setting of toxicity.
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
Headache or scalp pain
Unexplained tongue or jaw pain
Temporal artery biopsy positive
Age, median (range)
* Except for age, values are the number (%). CS ⫽ corticosteroids; MTX ⫽ 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 (␣ ⫽ 0.05).
⫽ 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 ⫹ placebo and 51 to receive CS ⫹
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
baseline characteristics (Table 1). The median age was
Timing and clinical features of relapse.
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
every-other-day therapy, and 34% occurred after CS
discontinuation. Table 3 outlines the 1-year cumulative
Treatment failures and disease relapses.
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-
Cumulative incidence of first relapses and treatment failures (Kaplan-Meier analyses)*
CS ⫹ placebo (n ⫽ 47)
CS ⫹ MTX (n ⫽ 51)
* CS ⫽ corticosteroids; MTX ⫽ methotrexate; NR ⫽ number of patients at risk who have not had a relapse at 6 months and 12 months followup;
NE ⫽ number of patients who experienced a relapse at 6 months and 12 months followup; % ⫽ percent of patients who have had the outcome on
or before 6 months or 12 months; 95% CI ⫽ 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
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
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 ⫹ 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
⫽ 0.50), tongue, jaw, or
headache, jaw, tongue, or mouth pain, or vision loss.
other oral pain (P
⫽ 0.14), or vision loss (P
⫽ 0.29) did
However, significantly more patients in the CS ⫹ pla-
not differ significantly between groups. Isolated occur-
Cumulative incidence of first relapse by treatment group. The rates of first relapse
over time were not statistically different between the 2 treatment groups.
One-year cumulative incidence of clinical characteristics
(Figure 3). Among 20 patients with isolated increases in
identified at the time of a relapse*
ESR, subsequent relapses were noted in 16 cases (pos-
itive predictive value of ESR elevation for relapse ⫽
80%). The 16 relapses occurred at a median of 7 weeks
(range 2–21 weeks, interquartile range [IQR] 8 weeks)
Headache or scalp pain
after the detection of an isolated increase in ESR. In 4
Tongue or jaw pain
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 ⱖ40 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 ⫾ SEM cumulative rate. CS ⫽
sults). An isolated increase in ESR had a relative risk for
corticosteroids; MTX ⫽ methotrexate.
relapse of 4.32 (95% CI 1.87–10.01) compared with
patients whose ESRs did not increase (P
rence of PMR in the absence of any other feature
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
(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.
experienced additional vision loss during the first year
bers of patients with ESR elevations (ⱖ40 mm/hour)
after enrollment. Stroke did not occur in any patient.
following achievement of normal values were the same
The median dosage of MTX was 15
between groups, regardless of relapse status (P
mg/week (range 5–15; 13 patients received 5–12.5 mg/
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 ⱖ40 mm/hour in the prednisone group and in the prednisone ⫹ 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
⫽ 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
relapsing nature of GCA and its long-term associated
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 ⬃30% (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
enteric symptoms, or leukopenia.
C-reactive protein level. In two-thirds of their patients,
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
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 ⫹
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
patients had new-onset vision loss.
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 ⫹ 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
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
ESR, of whom 16 later relapsed.
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
Exp Rheumatol 2001;19:171–6.
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THE HAMILTON SPECTATOR FRIDAY, OCTOBER 27, 2006 LOCALBusiness owner defends himself in contempt case ing an earlier court decision from 2003 The Eyelogic machine was invented by "I have the utmost respect for the porations that are also named in the that ordered the chain to comply with Alberta ophthalmologist Dr. Alan Dyer. court," Bergez said. "I don't have contempt case. But Justice Crane
Jacob B. Minah and Florence M. MargaiThe use of malaria nosodes to reduce malaria prevalence in vulnerable communities* This pilot study was designed to assess the effectiveness of malaria nosodes as a homeopathic prophylaxis. The primary goal was to reduce malaria parasitic density among residents in a low-income community in Freetown, Sierra Leone. In 2006, 731 participants were recruited and tested for malaria and after receipt of their test results, healthy subjects were enrolled in a double-blind, randomized study. The implementation of the clinical study was then carried out in four phases. About half of the subjects (54%) were assigned to a homeopathic group and during the beginning of each phase (every 4 months), they were administered 5 granules of malaria nosode D200. The remaining 45% of the participants were in the control group and they received 5 placebo granules per phase. Within a year, the malaria parasitic load decreased significantly among all residents. However, the overall efficacy of the homeopathic therapy could not be confirmed after the second phase of the study. Despite this setback, the results of this study generated information regarding the malaria-risk profiles and treatment seeking behaviors of residents in the community. The results also provided valuable insights and meaningful strategies for developing full scale intervention programs in vulnerable communities.