Giant cell (temporal) arteritis (GCA) is a systemic vasculitis primarily targeting large and medium-sized arteries in people over the age of 50 years. It is characterized by transmural inflammation of the arteries that induces luminal occlusion through intimal hyperplasia. Clinical symptoms are developed by end-organ ischemia and, in almost all patients with GCA, a syndrome of systemic inflammation. GCA is characterized by a vigorous acute-phase response that includes increased levels of C-reactive protein (PCR) and, particularly, a very high erythrocyte sedimentation rate (ESR).

Morbidity from GCA itself is substantial including vision loss, aortic aneurysms, aortic branch vessel stenoses, polymyalgia rheumatica (PMR), constitutional symptoms and stroke. Treatment with corticosteroids (CS) is mandatory,1 initial dosage must be high (40–60mg/d) with subsequent tapering to a lower maintenance dose that is given for an average of two years. Following initial improvement, up to 60% of patients experience disease relapse during CS tapering requiring reintroduction or dose escalation of CS.2,3 This long-term CS therapy leads to CS-related adverse events in up 80% of patients being a major problem in the management of GCA in already frail patients.4

Current data reflect that standard CS regimens only partially suppress vascular inflammation and that ongoing subclinical disease activity may expose GCA patients to the risk of progressive vascular disease and chronic systemic complications.5 Indeed, it has not been demonstrated that corticosteroid treatment induces changes in the course of the disease. This hypothesis is supported by the absence of revascularization of affected vessels, a higher incidence of aneurysms in previously GCA patients, the findings of positive artery biopsies after a successful course of treatment, and the fact that percentage of asymptomatic GCA patients present sustained ESR or CRP elevations after treatment.

In a previous study we have shown that methotrexate plus CS is a safe alternative to CS therapy alone in patients with GCA and is more effective in controlling disease than standard CS therapy.6 Methotrexate plus CS was also more efficient than CS alone in maintaining disease remission supporting the notion that methotrexate may exert not only a role as steroid-sparing agent but also a role as disease-modifying agent in GCA.

In this work, we study the effect of combined treatment with prednisone and MTX versus prednisone alone over laboratory parameters, particularly ESR as a marker of inflammation, in GCA.

There were no significant differences among groups in terms of baseline characteristics (Table 1). All patients had an elevated ESR at baseline that normalized shortly after initiation of treatment.

Time-course analysis of ESR values demonstrated that mean values of ESR were higher in those patients treated with placebo than in patients treated with methotrexate and this difference was evident after the fifth week of treatment (Fig. 1). The mean ESR value followed a parallel course in both groups, but was lower in the group with MTX than in the group with placebo in 18 of 20 time points of follow-up. Median value of ESR was 33 [18–56] in patients with placebo and 26 [15–44] in patients with MTX (P=0.0002). The area under the curve was significantly lower in patients treated with MTX than in patients treated with placebo (19,598.4±8,117 vs. 28,461.7±12,326, respectively; mean difference 8,863, 95% CI 1.542–16.184; P<0.01). This result was independent of prednisone dose, relapse status, age and sex.

Fig. 1.

Time course of ESR in each group. The gray line indicates the mean ESR in every time point for the patients treated with methotrexate and prednisone and the black line the same value for patients treated with prednisone alone. Differences are apparent after the first month of treatment, and from then on, the mean ESR value was higher in the group treated with prednisone alone.

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Time course of relapses along the study period and prednisone use in both groups of treatment is shown in Fig. 2. ESR was elevated in 90% of relapses, median value 59mm/h, range 22–127 and no differences were observed in both groups. There was a peak of ESR between the third and fourth month that coincided with most relapses in both groups and with prednisone dose below 20mg/day. Differences in ESR appeared few weeks after treatment initiation and were maintained all along the treatment course even after one year of therapy when the median dose of prednisone was below 10mg in all patients.

Fig. 2.

Relationship between ESR and prednisone dose in each group. The gray line and gray rhombs indicate the mean ESR and median prednisone dose respectively in every time point for the patients treated with methotrexate and prednisone. The black line and black rectangles indicate the mean ESR and median prednisone dose in every time point for patients treated with prednisone alone. Arrows indicate the time at which relapses occurred in both groups. As you can see, relapses were more frequent in the first year of treatment in both groups and were accompanied by a significant rise in the mean ESR value.

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The course of other laboratory parameters paralleled those observed for ESR but without statistical significance, with a trend to more normal parameters in patients treated with MTX, i.e., lower incidence of anemia, leucocytosis and thrombocytosis.

We presented the analysis of the laboratory parameters in a group of patients with GCA treated with an identical schedule of prednisone plus methotrexate or placebo along a two-year study period. These patients were participants in a randomized, double-blind, placebo-controlled study that showed that combined treatment with prednisone and methotrexate reduced the proportions of patients suffering relapses and the mean cumulative dose of prednisone suggesting that methotrexate in association with CS are more effective in disease control than standard CS therapy. In this report, we go further suggesting that methotrexate may act as an anti-inflammatory modulator, and probably a disease-modifying factor, for GCA due to the observed decrease in acute-phase reactants.

The differences appeared few weeks after treatment initiation and were maintained all along the treatment course even after one year of therapy when the mean dose of prednisone was below 10mg in all patients. Although not statistically significant, the course of other laboratory parameters paralleled those of ESR, with a better trend in patients treated with MTX. Due to the year of the original protocol design, 1992, neither CRP nor IL-6 or other pro-inflammatory cytokine levels were routinely considered, what would have been useful at the light of these results. However, differences observed point toward MTX not merely as a steroid-sparing agent but an anti-inflammatory modulator, and probably a disease-modifying factor, for GCA.

The anti-inflammatory modulator concept is not new for rheumatologists but is a challenging new hypothesis for GCA.7 None will now discuss that CS alone is not a proper treatment for chronic inflammatory diseases such as rheumatoid arthritis (RA). In fact, the concept of modification of inflammation versus symptoms modification has extended from RA to other several rheumatic and non-rheumatic diseases. Trials with MTX in GCA and polymyalgia rheumatica have been more that anecdotical in the literature.8–13

Although clinical results of other studies with MTX have been conflicting with ours and difficult to interpret,14–19,1 ESR showed also a trend favoring MTX in previous studies.20,21 Anti-TNF-α have also been studied and used in patients with GCA22–24 and failed to show efficacy in GCA, thus, anti-TNF therapies have not shown benefit in GCA.

Other DMDs have been studied such as azathioprine25 and leflunomide.26,27

Activated T cells have also been implicated in the pathogenesis of GCA, hence, abatacept (ABA) has been studied in a multicentre, randomized study28 with promising results.

IL-12 and IL-23 in the Th1 and Th17 responses are also recognized actors in the pathogenesis of GCA, therefore, ustekinumab, was studied in an open-label study of 14 patients with CGA.29

The new prospects for GCA as well as polymyalgia rheumatica (PMR) include fairly evidence for a role of IL-6 in both GCA and PMR. Interleukin-6 includes acute-phase response and has a central role in the pathogenesis of GCA.30–32 The tocilizumab has been reported to be effective in several published randomized clinical trials.33,34

Although there is evidence in favor of treatment with other immunosuppressive drugs, in this article, we want to point out/emphasize the role of methotrexate as an anti-inflammatory modulator just decreasing VSG. Probably MTX could also act as a disease-modifying drug on its own taking into account the widespread evidence supporting/showing that MTX is safe and effective in the treatment of GCA and, in the background, it decreases acute-phase reactants.

The authors declare that they have no conflict of interest.