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in whom it is particularly important to limit the corticosteroid dose? And what are its adverse effects?

infections); hypersensitivity reactions, including anaphylaxis; neutropenia and thrombocyto- penia; gastrointestinal bleeding and perforation; transaminase elevation; hypercholesterolaemia; cancers; and demyelinating disorders. Subcutane- ous injection of tocilizumab can provoke injection site reactions. As tocilizumab is an immunosup- pressant, concomitant use with a corticosteroid increases the risk of immunosuppression and infections (7,8,10,11). The data from the double-blind trial in patients with giant cell arteritis provided no new information about the adverse effect profile of tocilizumab . The most frequent adverse events were infections: 200 per 100 person-years in the tocilizumab group, ver- sus 156 per 100 person-years in the “placebo group with 26-week taper”, versus 210 per 100 person-years in the “placebo group with 52-week taper” (5,9). In patients with giant cell arteritis, the value of adding tocilizumab to prolonged corticosteroid therapy tapered gradually over a period of 18 months to 2 years (in accordance with French guidelines) has not been evaluated. Corticosteroid therapy alone, with gradual dose reduction, remains the standard treatment. For the rare patients who cannot tolerate cortico- steroids, tocilizumab has not been compared with methotrexate . But in one trial, adding tocilizumab to corticosteroid therapy reduced the cumulative corticosteroid dose. The adverse effect profile of tocilizumab differs from that of methotrexate , making it a useful option for some patients. ©Prescrire ▶▶ Excerpted from Rev Prescrire March 2019 Volume 39 N° 425 • Pages 177-179 Literature search up to 8 January 2019 In response to our request for information, Roche provided us with published articles and packaging items. 1- Prescrire Rédaction “Artérite à cellules géantes” Premiers Choix Prescrire, updated December 2017: 4 pages. 2- HAS - Commission de la Transparence “Avis-RoActemra” 19 Sep- tember 2018: 26 pages. 3- Mahr A et al. “Protocole national de diagnostic et de soins PNDS. Artérite à cellules géantes (Horton)” 2017: 35 pages. 4- DockenWP et al.“Treatment of giant cell arteritis”UpToDate. www. uptodate.com accessed 28 November 2018: 19 pages. 5- EMA - CHMP “Public assessment report for RoActemra. EMEA/ H/C/000955/II/0066” 20 July 2017: 117 pages. 6- Mahr AD et al. “Adjunctive methotrexate for treatment of giant cell arteritis” Arthritis Rheum 2007; 56 (8): 2789-2797. 7- Prescrire Rédaction “méthotrexate” + “tocilizumab” Interactions Médicamenteuses Prescrire 2019. 8- European Commission “SPC-RoActemra” 18 September 2017: 64 pages. 9- Stone JH et al. “Trial of tocilizumab in giant-cell arteritis” N Engl J Med 2017; 377 (4): 317-328 + appendices: 13 pages. 10- Prescrire Rédaction “Tocilizumab SC et polyarthrite rhumatoïde: pas de comparaison directe au rituximab” Rev Prescrire 2015; 35 (383): 660. 11- Prescrire Editorial Staff “Tocilizumab. Rheumatoid arthritis: another“mab”, no therapeutic advantage” Prescrire Int 2009; 18 (103): 198-201. In practice

Placebo-controlled trial: corticosteroid tapered too rapidly? Clinical evaluation of tocilizumab in this situation is mainly based on a double-blind ran- domised placebo-controlled trial in 251 adults (three-quarters of whomwere women) aged 50 years or older (median age 70 years) with giant cell arter- itis, either newly diagnosed (about half of cases) or relapsed despite corticosteroid treatment (2,5,9). The patients all received the corticosteroid pred­ nisone .The dose was tapered to zero over 26 weeks or 52 weeks, in accordance with a strict schedule as determined by the protocol. Patients were ran- domised to one of the four following groups: tocili­ zumab 162 mg weekly for 52 weeks, plus cortico- steroid therapy tapered over 26 weeks ( tocilizumab group); placebo with the same corticosteroid taper (“placebo group with 26-week taper”); placebo plus corticosteroid tapered over 52 weeks (“placebo group with 52-week taper”); or tocilizumab 162 mg every other week, a group not addressed in this article. A short course of corticosteroid therapy was permitted in patients whose disease worsened (2,5). After 52 weeks of treatment, the proportion of patients in sustained remission (mainly defined by the absence of symptoms and normalisation of CRP levels for 10 months, from week 12 to week 52) was 56% in the tocilizumab group, versus 14% in the “placebo group with 26-week taper”, versus 18% in the “placebo group with 52-week taper” (statistical- ly significant differences between the tocilizumab group versus both placebo groups) (5,9). The me- dian cumulative dose of prednisone was 1862 mg in the tocilizumab group, versus 3296 mg in the “pla- cebo group with 26-week taper” and 3818 mg in the “placebo group with 52-week taper” (p<0.0001) (5). Only a small proportion of patients in the placebo groups entered remission in this trial.This result may be related to the fact that prednisone was tapered and withdrawn over a shorter period of time than the 18 to 24 months generally recommended in France (1-3). After the initial analysis, 45 patients in sustained remission were followed for an additional two years after cessation of tocilizumab or placebo. At the start of this period, three patients were still on cor- ticosteroid therapy, one patient was receiving a corticosteroid plus methotrexate , and two patients were taking methotrexate . According to a preliminary analysis, relapses appeared more frequent in pa- tients who had received tocilizumab than in those who had received placebo (33% versus 20%) (no statistical analysis performed) (5). It is not possible to reach conclusions as to whether the risk of relapse is increased after tocilizumab cessation, due to the small number of patients included in this follow-up and its limited duration.

Mainly infections. The adverse effect profile of tocilizumab mainly comprises: sometimes serious and occasionally fatal infections (including lung and skin

Prescrire Int • June 2019

P rescrire I nternational S pecial E dition 2019 • P age 7