Page 350 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

324 Vanessa Quick and John Kirwan

24 to 191 weeks, with an equivalent cumulative dose of prednisone that ranged from 5,275
mg to 9,194 mg. Such broad differences in the duration and dosage of administered
glucocorticoids would be expected to translate into a spectrum of relapse rates so noted in
27% to 84.2% of patients, with increased rates among those receiving the highest initial
glucocorticoid doses with more rapid tapering.

A meta-analysis of the use of adjuvant treatment with methotrexate [152] calculated the
time-to-event outcomes in three randomized, placebo-controlled trials of patients with newly
diagnosed GCA treated with initial high-dose glucocorticoids and randomly assigned to 7.5
mg to 15 mg per week of oral methotrexate therapy or placebo [122, 123, 153]. There was a
reduction in the cumulative equivalent dose of prednisone by 842 mg in 48 weeks (P< 0.001),
but prednisone only treatment was reduced rapidly, and the rate of relapse in this group was
80% and it did not reflect current treatment practice. Current guidelines [12] of a
recommended glucocorticoid tapering regimen (Table 2) were loosely based on clinical
experience at the Mayo Clinic [142] with the consensus of a group of international clinicians.
Some clinicians prefer slower dose reduction regimens with a lower anticipated rate of
relapse [13] (Table 2), while others [126, 128, 154] favor individualized dose reduction
schedules based on regular clinical review The main drive to keep the glucocorticoid dose to
a minimum is the fear of adverse glucocorticoid effects, particularly cardiovascular and bone
fractures. Several cohort studies [90, 142, 146, 155, 156] suggested the clear association
between the cumulative dose of steroids and the rate of glucocorticoid complications
other than cardiovascular and bone fracture, whereas others [67, 68, 71] were variably
confounded by patients with differing severe disease requiring more aggressive treatment.
The meta-analysis by Mahr and colleagues [152] noted adverse events in two-thirds of
patients treated with glucocorticoids alone, with methotrexate or placebo that included
infection, abnormal liver function tests, fractures, diabetes, malignancy, thrombocytopenia,
and leukopenia in descending order of frequency.

There is evidence from single case reports and small patient series of a clinical benefit in
GCA employing the pyrimidine inhibitor leflunomide [157], and the immunosuppressants
mycophenolate mofetil [158] and cyclophosphamide [159], however their efficacy has not yet
been confirmed in RCT. Cyclosporin showed no additional glucocorticoid-sparing effect in
GCA [160].

Therapy with the anti-tumor necrosis factors (TNF) infliximab and etanercept [161-163]
was of no benefit and potentially harmful in newly diagnosed GCA. Tocilizumab, an
IL-6 receptor antagonist, induced remission and reduce glucocorticoid requirements in
patients with refractory GCA [44, 164-167]. A multicenter RCT testing the ability of
tocilizumab to maintain disease remission in patients with GCA is currently underway with
approximately 100 participating centers intending to enroll 250 patients with active disease
into a 52-week blinded treatment phase followed by 104 weeks of open-label extension [168].
The impact of aspirin use on ischemic cranial complications was demonstrated in GCA as a
basis for management of GCA [169, 170] however an impact was not shown in retrospective
cohorts [171-173].

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