Home
Current Issue
Archives
Guidelines for Authors
Classified Ads
Links
Subscriptions
Subscriber Registration
Guidelines for Website Users
JRheum Update Service
Contact Info |
 |
Giant Cell Arteritis — The Methotrexate Debate Revisited
To the Editor:
Giant cell arteritis (GCA) is a common vasculitis that may result in significant
morbidity including blindness if left untreated1. Corticosteroids, the mainstay
therapy of GCA, are administered for prolonged periods, with substantial associated
toxicity2. Numerous efforts have been made to minimize corticosteroid side-effects
by utilizing steroid-sparing regimens. Methotrexate (MTX) was found to have
such a sparing effect in one randomized controlled trial (RCT)3, but that observation
was not confirmed in other studies2,4.
We describe 2 cases of GCA that initially developed in patients under treatment
with MTX which was adequate to control their underlying rheumatoid arthritis
(RA).
Case 1. An 80-year-old man with seropositive erosive RA had been followed in
our rheumatology clinic for 5 years, with complete remission taking MTX 10 mg/week
for the previous 2 years. One month prior to admission, he experienced occipital
headaches, jaw claudication, malaise, and low grade fever (38°C). On admission,
his temperature was 37.7°C. No active synovitis was detected. Nontender
normally pulsating temporal arteries were evident. Laboratory tests revealed
hemoglobin 11.6 g/dl; elevated C-reactive protein, 51 mg/l (normal 0–6
mg/l); and erythrocyte sedimentation rate (ESR) 80 mm/h. Funduscopic examination
was normal. Temporal artery biopsy (TAB) was characteristic for GCA. Treatment
with prednisone 60 mg/day resulted in prompt alleviation of symptoms and normalization
of blood tests.
Case 2. A 73-year-old woman with seropositive RA had been followed in our clinic
for 7 years, with complete remission taking MTX 10 mg weekly for the previous
3 years. Two weeks before admission to an internal medicine department in another
hospital she began to suffer headaches and pain in both shoulders, accompanied
by fever of 38.8°C. On admission, neither peripheral synovitis nor abnormal
temporal arteries were noted. Laboratory tests showed ESR 96 mm/h; blood cultures
were sterile; whole-body computerized tomography and gallium scans were unrevealing.
Right TAB was normal. She was discharged with no specific diagnosis for the
headaches. Two weeks later she developed sudden left-eye blindness. Left TAB
was diagnostic of GCA. Treatment with 60 mg prednisone resulted in rapid alleviation
of fever, other systemic symptoms, and myalgias, but the blindness was irreversible.
Both patients continued MTX 7.5 mg/week and prednisone was reduced to 10 mg/day
by 6 months, and they continued this regimen for one year after onset of GCA.
In 2001, Jover, et al raised renewed interest in the therapeutic role of MTX
in GCA3. They found that 10 mg MTX weekly (or 15 mg weekly after a flare) decreased
the cumulative prednisone dose needed to treat GCA and reduced the occurrence
of relapses. However, 2 more recent trials arrived at a different conclusion2,4.
Hoffman, et al evaluated 98 patients with GCA in a multicenter RCT: a regimen
of 0.15–0.25 mg/kg MTX was not found to be corticosteroid-sparing. Potential
weaknesses of that study included the use of alternate-day steroids after 4
weeks and the relatively early analysis of results2. The second RCT trial, by
Spiera, et al, also showed no benefit for the adjunct use of MTX. That study
has been criticized, however, for being underpowered (21 patients) and for the
use of a low dose of MTX (7.5 mg weekly)4.
Despite limited evidence, clinicians continue to use MTX as adjuvant therapy
to corticosteroids in patients with relapsing or resistant GCA, extrapolating
from the data presented above, as no other options, aside from anti-tumor necrosis
factor (TNF) therapy, are at hand yet.
The cases we have described do not support the corticosteroid-sparing effect
of MTX in GCA, and several issues remain to be considered. First, MTX is not
intended as single therapy for GCA, and our patients were not treated with prednisone
at the onset of GCA. Second, the controlled inflammation of RA is not an equivalent
to the more substantial inflammatory burden of GCA. Third, in Jover’s
trial almost none of the patients whose MTX regimen was increased to 12.5 mg
weekly relapsed again, while our patients received only 10 mg weekly. RA and
GCA are both T helper-1-mediated diseases. Yet while interferon-g (IFN-γ) and
interleukin 12 (cytokines that activate macrophages) are elevated in both diseases5,6,
TNF-α, a product of activated macrophages, is elevated only in RA5,7,8. MTX
reduces TNF-α production by macrophages and T cells, having only a marginal
effect on IFN-γ9,10. This may account for the lack of effect of MTX in GCA.
Our cases illustrate 2 points: first, care should attend evaluation of systemic
inflammation in patients with RA when there is no apparent synovitis, the differential
diagnosis of which should include GCA. Second, in our patients, clinical onset
of GCA occurred during treatment with MTX, findings that are in agreement with
those of Hoffman and Spiera.
DORON RIMAR, MD, Department of Internal Medicine A, Carmel Medical Center; MICHAEL
ROZENBAUM, MD, Department of Rheumatology, Bnai Zion Medical Center; DEVY ZISMAN,
MD, Head, Rheumatology Service, Department of Internal Medicine A, Carmel Medical
Center; NINA BOULMAN, MD; GLEB SLOBODIN, MD, Department of Rheumatology, Bnai
Zion Medical Center; LIHI EDER, MD; JOY FELD, MD, Department of Internal Medicine
A, Carmel Medical Center; ITZHAK ROSNER, MD, Head, Department of Rheumatology,
Bnai Zion Medical Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Address reprint requests to Dr. R. Doron, Department of Internal Medicine A,
Carmel Medical Center, Haifa 34362, Israel.
E-mail: doronrimar@gmail.com
REFERENCES
1. Nuenninghoff DM, Matteson EL. The role of disease-modifying antirheumatic
drugs in the treatment of giant cell arteritis. Clin Exp Rheumatol 2003;21 Suppl
32:S29-34.
2. Hoffman GS, Cid MC, Hellman DB, et al. A multicenter, randomized, double-blind,
placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis.
Arthritis Rheum 2002;46:1309-18.
3. Jover J, Hernandez-Garcia C, Morado I, Vargas E, Banares A, Fernandez-Gutierrez
B. Combined treatment of giant cell arteritis with methotrexate and prednisone.
A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;134:106-14.
4. Spiera RF, Mitnick HJ, Kupersmith M, et al. A prospective, double-blind,
randomized, placebo controlled trial of methotrexate in the treatment of giant
cell arteritis. Clin Exp Rheumatol 2001; 19:495-501.
5. Gerli R, Lunardi C, Pitzalis C. Unmasking the anti-inflammatory cytokine
response in rheumatoid synovitis. Rheumatology Oxford 2002;41:1341-5.
6. Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis.
N Engl J Med 2003;349:160-9.
7. Roche NE, Fulbright JW, Wagner AD, Hunder GG, Goronzy JJ, Weyand CM. Correlation
of interleukin-6 production and disease activity in polymyalgia rheumatica and
giant cell arteritis. Arthritis Rheum 1993;36:1286-94.
8. Roblot P, Morel F, Lelievre E, Gascan H, Wijdenes J, Lecron JC. Serum cytokine
and cytokine receptor levels in patients with giant cell arteritis during corticotherapy.
J Rheumatol 1996;23:408-10.
9. Neurath MF, Hildner K, Becker C, et al. Methotrexate specifically modulates
cytokine production by T cells and macrophages in murine collagen-induced arthritis:
a mechanism for methotrexate-mediated immunosuppression. Clin Exp Immunol 1999;115:42-55.
10. Rudwaleit M, Yin Z, Siegert S, et al. Response to methotrexate in early
rheumatoid arthritis is associated with a decrease of T cell derived tumour
necrosis factor alpha, increase of interleukin 10, and predicted by the initial
concentration of interleukin 4. Ann Rheum Dis 2000;59:311-4.
|
