Glucocorticoids

 

 

 

Although never formally tested in randomized controlled trials (RCTs), glucocorticoids are considered the drug of choice to treat GCA. Recent empirical observations compared with data from historical case series suggest that glucocorticoids are highly effective in treating the clinical manifestations of GCA and in preventing its ischemic complications, while they do not seem to be able to shorten the disease duration nor to reverse visual loss.^[3-7] Glucocorticoids act quickly, which is of paramount importance since GCA-related ischemic complications including visual loss occur early on in the disease course. Therefore, therapy should be commenced as soon as the diagnosis of GCA is established. An initial dose of 40-60 mg daily of prednisone(equivalent) is considered adequate in the vast majority of cases.^[2,8] Patients at high risk of developing ischemic complications, however, require initial dosages of around 1 mg/kg/day.^[2,8] Higher-dose pulse glucocorticoid therapy has been advocated for patients with visual disturbances,^[9,10] but an observational study and a RCT failed to demonstrate superiority of pulse over oral glucocorticoid therapy in preventing ischemic complications.^[11,12] A small RCT,^[13*] however, showed that pulse methylprednisolone (15 mg/kg/day for 3 days) given at disease onset allowed more rapid tapering of glucocorticoid dose and resulted in a higher frequency of remission after discontinuation of oral glucocorticoid therapy.

Initial treatment with low-dose (10-40 mg/day) prednisone^[14,15] and alternate-day glucocorticoid administration have also been proposed, at least in part, to reduce the risk of glucocorticoid-related adverse reactions. Initial treatment with low-dose glucocorticoids, however, has been tried in too few patients to allow confident conclusions to be reached, while alternate-day administration has been shown in a RCT^[16] to be associated with a much higher rate of treatment failure (70% versus 20%), and is thus not recommended.

There are no definite rules to establish treatment duration. Most patients need treatment for 1-2 years, but some patients with a chronic-relapsing course may require (usually low-dose) glucocorticoids for several years. There is some evidence that patients with coexisting GCA and polymyalgia rheumatica (PMR) may demand longer treatment compared with those with GCA or PMR alone.^[17,18]

After response to initial therapy, glucocorticoid doses are titrated to lower levels against a combination of clinical symptoms and inflammatory markers. In GCA patients with predominant or exclusive ocular involvement, however, glucocorticoid tapering can be primarily guided by the levels of erythrocyte sedimentation rate (ESR) or of C-reactive protein.^[12] Conversely, in the subset of GCA patients with normal inflammatory indices, tapering of glucocorticoid dosage should be based on the clinical course.^[2,19,20]

The benefit conferred by glucocorticoids has to be balanced against the well known complications related to long-term glucocorticoid use, which are largely dose related. In a population-based study of 120 patients with GCA, 86% of patients suffered glucocorticoid-related complications, including bone fractures, avascular necrosis of the hip, diabetes mellitus, infections, gastrointestinal hemorrhage, posterior subcapsular cataract, and hypertension.^[21] Therefore, tapering of glucocorticoid dose should be implemented as quickly as possible. A common schedule to gradually reduce prednisone dose is e.g. by 5 mg decrements every 1-2 weeks until the dose is 10 mg daily, and subsequently by 1 mg every 2-6 weeks under close monitoring of clinical and laboratory parameters.^[2,9,22] Tapering should be adapted to the requirements of each specific patient, since individual variations can be quite large.^[9] Encouragingly, judicious tapering of glucocorticoid dose has been shown to decrease glucocorticoid-related toxicity from 50% to under 20%.^[23] Osteoporosis prophylaxis should be implemented in all patients.^[24]

In patients with longstanding, glucocorticoid-resistant disease and in those at risk for glucocorticoid-related adverse events, the use of a glucocorticoid-sparing agent should be considered. Two agents have been tested for efficacy for use in GCA in proper RCTs: methotrexate and azathioprine.

Methotrexate

Three recent RCTs have assessed the efficacy of methotrexate in recent-onset GCA; however, these studies have arrived at different conclusions.

One small study performed in 21 patients with newly diagnosed GCA compared methotrexate (n = 12) with placebo (n = 9) in addition to glucocorticoid therapy.^[23] All patients were treated with high-dose glucocorticoid therapy and methotrexate starting at 7.5 mg/week or placebo. Glucocorticoids were tapered according to the clinical response, while the dose of methotrexate or placebo was increased by 2.5 mg/week for disease flare up to 20 mg/week. After a clinically defined remission and discontinuation of glucocorticoid therapy, methotrexate or placebo was tapered off by 2.5 mg/week.

At study end, no significant difference was found between methotrexate and placebo-treated patients with regard to the cumulative glucocorticoid dose and the number of weeks to taper off glucocorticoids. Side effects did not significantly differ between groups. The authors thus concluded^[23] that the combination of methotrexate and glucocorticoid had no glucocorticoid-sparing effect in patients with GCA.^[23] The main limitations of this trial were an insufficient statistical power, the lack of a standardized protocol of glucocorticoid administration and the relatively low initial dosage of methotrexate.

In another, larger controlled trial, 42 patients with new-onset, biopsy-proven GCA treated with high initial doses of glucocorticoid were randomized to receive methotrexate or placebo.^[25] The dose of glucocorticoid was tapered off quickly. Methotrexate or placebo was given weekly from the start of glucocorticoid therapy for 24 months. Outcome measures were the number of relapses and the cumulative dose of glucocorticoid. Combined treatment with prednisone and methotrexate significantly reduced the proportion of patients who experienced at least one relapse (45% in the prednisone-methotrexate group versus 84.2% in the prednisone-placebo group) as well as the proportion of patients who experienced multiple relapses. The mean cumulative dose of prednisone was 4187 ± 1529 mg in the methotrexate group and 5489.5 ± 1396 mg in the placebo group. The rate and severity of adverse events were similar between groups. In sensitivity analysis that included patients lost to follow up, differences between groups in number of relapses and cumulative dose of prednisone were significant. The authors thus concluded^[25] that combination therapy with glucocorticoid and methotrexate is more effective in controlling GCA activity compared with glucocorticoid therapy alone.^[25]

The largest RCT assessing the role of methotrexate in GCA enrolled 98 patients with newly diagnosed GCA.^[26] Outcome measures were similar to those used in the study quoted above,^[25] including number of relapses and cumulative glucocorticoid dose. The initial treatment was 1 mg/kg/day (≤60 mg/day) prednisone, plus 0.15 mg/kg/week methotrexate (increased to 0.25 mg/kg/week, for a maximum of 15 mg/week) or placebo. Treatment failure was defined as two relapses or persistence of disease activity after the first relapse despite increased glucocorticoid therapy. The median dosage of methotrexate was 15 mg/weekly. The incidence of treatment failure was comparable between groups after 12 months: 57.5% in the methotrexate group and 77.3% in the placebo group. In a Cox-regression analysis, methotrexate was not associated with a reduced risk of treatment failure. There were no significant differences between groups with regard to serious morbidity due to GCA, cumulative glucocorticoid dose, or treatment toxicity. Therefore, the authors concluded that the adjunctive use of methotrexate is not useful to control disease activity or to decrease the cumulative dose and toxicity of glucocorticoid in GCA.^[26]

The data from the above trials have recently been the subject of a formal meta-analysis.^[27**] According to this analysis, adjunctive methotrexate treatment for GCA reduced the risk of both a first and a second relapse (hazard ratios 0.65 and 0.49, respectively). Despite a significant between-group difference in the cumulative glucocorticoid dose by 842 mg within 48 weeks, however, the incidence of glucocorticoid-related side effects was similar in both groups. On the basis of these data, methotrexate appears to be clinically beneficial in GCA patients, although quite worryingly methotrexate use did not result in a decreased incidence of glucocorticoid-related complications. In addition, methotrexate would not appear to act quickly, and cannot thus be recommended as a replacement for glucocorticoids at disease onset.

Azathioprine

Azathioprine (150 mg/day) has been tested in a 52-week, double-blind, placebo-controlled study in 31 patients with PMR, GCA, or both.^[28] All patients had been receiving prednisolone at a stable dose for at least 3 months prior to study entry. Nine patients in the azathioprine group and 11 patients in the placebo group completed the study. A significant difference in mean prednisolone dose (1.9 ± 0.84 mg in the azathioprine group versus 4.2 ± 0.58 mg in the placebo group) was noted between the two groups only at week 52.^[28] This study thus demonstrated the efficacy of azathioprine in the treatment of GCA, but the benefit appeared to be unimpressive and of late onset. In addition, since the patient population included both PMR and GCA patients, it is difficult to extrapolate the study's results to patients with isolated GCA. Despite these limitations, we feel that azathioprine may be given a try in GCA if a glucocorticoid-sparing agent is needed but methotrexate is contraindicated or not tolerated.