Giant cell arteritis (GCA), also named temporal arteritis, is a systemic vasculitis involving large- and medium-size vessels, particularly the extracranial branches of the carotid arteries (1, 2). This disorder almost exclusively affects individuals older than age 50 years and is characterized by a combination of constitutional symptoms and cranial manifestations, such as headache, jaw claudication, scalp tenderness, visual loss, and, in ∼50% of patients, polymyalgia rheumatica. GCA is considered a medical emergency because of the potential for severe general and ophthalmic complications, with blindness being the most feared consequence (1, 2).
For patients with GCA, the treatment of choice consists of systemic corticosteroids, and guidelines usually recommend administration of prednisone or its equivalent for 1–2 years at an initial dosage of 40–60 mg/day (1, 2). This corticosteroid regimen almost always controls the disease and prevents progressive blindness but is associated with substantial toxicity. Approximately 50% of patients with GCA experience at least 1 severe disease flare that requires prolonged corticosteroid therapy (3, 4). Moreover, 53–86% of patients develop major side effects related to corticosteroid treatment, including fractures, diabetes, infections, cataracts, and other problems (4–6).
The high rate of relapse and potential toxicity of corticosteroids have prompted investigations of alternative therapies for GCA. Notably, several randomized, double-blind, placebo-controlled trials have studied the effect of combining low-dose methotrexate (MTX) with corticosteroids for treatment of patients with GCA (7–9) or for a mixed population of patients with GCA and isolated polymyalgia rheumatica (10). These trials have yielded inconsistent conclusions, in that the findings have suggested that MTX provides either a clear advantage (8) or no benefit (9, 10) in terms of a lowered risk of relapse or reduced exposure to corticosteroids, or that MTX has only a preventive effect on relapses of GCA presenting as isolated polymyalgia rheumatica (7).
Thus, the utility of adjunctive treatment with MTX in the management of GCA remains highly controversial. Accurate appraisal of this matter is hampered by the possibility that the discrepancies among trials reflect differing trial designs or inadequate sample sizes (11) or by the lack of uniformity in the choice of outcome measures. We therefore performed a meta-analysis of individual patient data from 3 randomized placebo-controlled trials to reevaluate the effects of MTX and its potential toxicity in patients with GCA.
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- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
This individual patient data meta-analysis of 3 randomized placebo-controlled trials in patients with newly diagnosed GCA demonstrates that adjunctive MTX administered in dosages of 7.5–15 mg/week reduces the risk of first relapse by 35% and the risk of second relapse by 51%. In addition, this regimen reduces the cumulative exposure to corticosteroids and increases the probability of achieving a sustained discontinuation of corticosteroid treatment. Sensitivity and subgroup analyses consistently favored adjunctive MTX, notably in showing comparable effect sizes among patients with biopsy-proven GCA and for relapses of cranial signs and symptoms, and suggest that the pooled estimates are both robust and applicable to various clinical situations. Furthermore, at the prescribed dosages, MTX appeared to be well tolerated in patients with GCA.
By pooling the data from the 3 principal trials addressing this question, we aimed to obtain a more reliable estimate of the treatment effect of adjunctive low-dose MTX in GCA. In contrast to the use of summary statistics (as has been done in the majority of published meta-analyses ), analysis of the data at an individual patient level enabled us to homogenize the outcome measures and to evaluate time-to-event outcomes in order to maximally exploit the information available. An additional advantage of conducting meta-analyses of individual patient data is that it allows a more powerful exploration of potential sources of between-trial inconsistencies (14, 15). With respect to the possible shortcoming that the data pooling was inappropriate because of dissimilarities between studies, we did not identify statistical heterogeneity in the primary outcomes across trials, and comparison of the respective study samples did not demonstrate any major clinical heterogeneity that would have suggested that the trials had enrolled dissimilar populations.
The findings of our meta-analysis support the possibility that the differences in length of followup might have contributed to the disparate results of the individual trials (11). The appearance of the relapse curves, and our sensitivity analyses that censored the duration of followup at different time points, indeed suggest that the superiority of the treatment effect of MTX over placebo fully appears only after 24–36 weeks. This observation is consistent with that from a placebo-controlled trial of MTX in patients with isolated polymyalgia rheumatica (16), in whom a beneficial effect on relapse risk became apparent only after 24 weeks of treatment. The most likely explanation for these findings may be that there is a latency period before MTX exerts its pharmacologic action in patients with GCA and in those with isolated polymyalgia rheumatica.
The benefit conferred by MTX demonstrated in our study has to be balanced against several realizations. The absolute reduction in relapse risk by MTX remains moderate, as exemplified by the fact that 4, 5, or 11 individuals would have to be treated to prevent one first relapse, one second relapse, or one first relapse of cranial symptoms up to 48 weeks. Although a main goal of prescribing MTX is to reduce the occurrence of corticosteroid-related adverse events, our findings did not demonstrate a significant difference in therapy-related side effects, presumably because none of the trials included in this meta-analysis had been specifically designed to study this issue. The followup periods in the original studies were likely too short to demonstrate such a difference in effect, given that the mean interval up to the occurrence of the first corticosteroid-related adverse events after initiation of therapy for GCA has been shown to be 2.7 years (4). Nonetheless, there is evidence that the occurrence of corticosteroid-associated morbidity in GCA is directly related to the cumulative dose of corticosteroids (4).
Therefore, the question arises whether an 800-mg decrease in the cumulative dose of prednisone by week 48 is a clinical outcome sufficiently meaningful to justify the additional risk of MTX-induced side effects. Indeed, whereas low-dose MTX has been proven to have a favorable toxicity profile even in populations of elderly patients (17, 18), other observations indicate that increasing age is a risk factor for severe side effects, including myelosuppression (19–21) and liver disease (22). On the other hand, the true corticosteroid-sparing effect of MTX was perhaps underestimated in our study, because one of the original trials did not extend the followup of participants beyond the occurrence of a first or second relapse (7), thereby overlooking the period in which the greatest corticosteroid-sparing potential of MTX could be observed.
The present study has some limitations. Although this is the largest effort made to address this topic thus far, the number of individuals included in the meta-analysis was relatively small and the mean observation time did not exceed 55 weeks. Therefore, our study might have lacked statistical power to adequately assess the benefit of MTX in specific subgroups. Similarly, the small number of studies assembled in this meta-analysis prevented us from more in-depth investigation of further sources of heterogeneity, such as the potential effects of the differing corticosteroid-tapering schemes as well as the influence of corticosteroid treatment prior to initiation of MTX. Because the MTX regimen used in the trials fell within a small dose range, we could not evaluate a potential dose-response effect, and it remains unknown whether increased MTX dosages, such as 20–25 mg/week, as has been routinely used in treatment of other vasculitides (23–25), might be both more efficacious and acceptably safe in this elderly population.
Our study results lead to questions of how MTX should be incorporated in the therapeutic armamentarium for GCA. MTX had a favorable impact on almost all of the investigated outcomes. Whereas our findings may not provide sufficient evidence to establish MTX plus prednisone as the current standard of care for patients with GCA, this treatment could be considered as an option at the time of diagnosis. MTX might be particularly useful in treating individuals at highest risk of experiencing corticosteroid-related side effects because of comorbid conditions such as diabetes mellitus, severe hypertension, and severe osteoporosis or because of older age (4, 6). The results of our study also imply, but do not directly demonstrate, that MTX may be a reasonable choice for treatment of the subset of individuals who have a prolonged GCA course.
To summarize, this individual patient data meta-analysis supports low-dose MTX as an effective corticosteroid-sparing agent, which should be considered as a therapeutic option for patients with GCA. Further studies are warranted to clarify the benefits conferred by MTX in terms of reductions in side effects, and to assess the efficacy and safety of higher doses of MTX for GCA.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Dr. Merkel had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Mahr, Jover, Hernández-García, Fernández-Gutiérrez, Merkel.
Acquisition of data. Mahr, Jover, Spiera, Hernández-García, Fernández-Gutiérrez, Merkel.
Analysis and interpretation of data. Mahr, Jover, Spiera, Hernández-García, Fernández-Gutiérrez, LaValley, Merkel.
Manuscript preparation. Mahr, Jover, Fernández-Gutiérrez, LaValley, Merkel.
Statistical analysis. Mahr, LaValley, Merkel.