Randomized Trial of Tocilizumab in the Treatment of Refractory Adult Polymyositis and Dermatomyositis

Abstract

Objective To assess the efficacy and tolerability of tocilizumab in a multicenter, randomized, double‐blind, placebo‐controlled trial in refractory adult patients with dermatomyositis (DM) and polymyositis (PM). Methods Thirty‐six subjects with probable or definite DM/PM were enrolled in a 6‐month phase 2B clinical trial and randomized 1:1 to receive tocilizumab (8 mg/kg intravenously) or placebo every 4 weeks for 24 weeks. Eligible subjects had either a DM rash, a myositis‐associated autoantibody or an adjudicated PM diagnosis. Active disease was defined by at least three of six abnormal core set measures (CSMs), including a manual muscle testing (MMT)‐8 score of less than 136/150. If the MMT‐8 score was greater than 136, then a cutaneous score of 3 or more (10 cm visual analogue scale) was required along with three additional abnormal CSMs indicating disease activity. The primary endpoint compared the Total Improvement Score (TIS) between both arms from week 4 to 24. Secondary outcomes included time to meeting minimal TIS improvement, changes in CSMs, time to worsening, steroid‐sparing effect, proportion of subjects meeting more stringent improvement criteria, and safety outcomes. Results There was no significant difference (P = 0.86) in the TIS over 24 weeks between tocilizumab and placebo arms. The secondary endpoints of time to improvement (minimal, moderate, or major), time to worsening, CSM changes, safety outcomes, and steroid‐sparing effect were also not significantly different between arms. Conclusion Tocilizumab was safe and well tolerated but did not meet the primary or secondary efficacy outcomes in refractory DM and PM in this 24‐week phase 2B study.

A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases

“…Inhibiting IL-6R with vobarilizumab (ALX-0061) did not meet the primary endpoint of dose response in patients with active SLE 72. Likewise, TCZ failed to show clinical improvement in patients with refractory adult polymyositis and dermatomyositis73 as well as in patients with pSS with moderate or high systemic disease activity 11…”

Biological Therapies in Inflammatory Myopathies

“…Tocilizumab was well tolerated but not more effective than the placebo. 43 Conversely, in a case-control study with 11 patients with refractory immune-mediated necrotizing myopathy, including 3 with anti-3-hydroxy-3-methyl glutaryl-CoA reductase and positive anti-signal recognition particles, 63% achieved clinically significant responses. 44 Responders had higher baseline serum IL-6 and muscle IL-6 mRNA levels and higher percentages of CD56-positive muscle fibers than did non-responders.…”

Immune checkpoint inhibitor-related myositis: from pathophysiology to treatment

“…Nonsteroidal immunosuppressive agents such as rituximab, and possibly TNF-alpha inhibitors, and IL-6 antagonists can be attempted if there is still no improvement after steroids and IVIG or PLEX, but data are often anecdotal and mostly from case reports and series (50,56). Caution with use of TNF-alpha blockers is recommended as they can trigger myositis whereas the randomized controlled trial of tocilizumab in the treatment of refractory adult myositis was negative (57,58). Azathioprine, mycophenolate, and methotrexate can also be employed, as in IIMs, but can take months to have a therapeutic effect (12,59,60).…”