REVIEW - Tocilizumab: a review of its use in the managment of RA

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Drugs. 2009;69(5):609-32. doi: 10.2165/00003495-200969050-00007.

Tocilizumab: a review of its use in the management of rheumatoid arthritis.

Oldfield V, Dhillon S, Plosker GL.

Wolters Kluwer Health mid R: Adis, Auckland, New Zealand, an editorial

office of Wolters Kluwer Health, Philadelphia, Pennsylvania, USA.

Tocilizumab (RoActemra® or Actemra®) is a recombinant humanized

monoclonal antibody that acts as an interleukin (IL)-6 receptor

antagonist. Intravenous tocilizumab 8 mg/kg (and no less than 4.8 mg),

in combination with methotrexate, is approved in the EU for the

treatment of moderate to severe active rheumatoid arthritis in adult

patients with inadequate response to, or who are intolerant of, prior

disease-modifying anti-rheumatic drug (DMARD) or tumour necrosis

factor (TNF) antagonist therapy. It may also be administered as

monotherapy in patients intolerant of methotrexate or in whom

methotrexate therapy is inappropriate.

Tocilizumab is also approved in Japan for the treatment of

polyarticular-course juvenile idiopathic arthritis, systemic-onset

juvenile idiopathic arthritis and Castleman's disease. Intravenous

tocilizumab was effective and generally well tolerated when

administered either as monotherapy or in combination with conventional

DMARDs in several well designed clinical studies in adult patients

with moderate to severe rheumatoid arthritis. Tocilizumab-based

therapy was consistently more effective than placebo, methotrexate or

other DMARDs in reducing disease activity, and some trials also showed

significant benefits with tocilizumab in terms of reducing structural

joint damage and improving health-related quality of life (HR-QOL).

Notably, tocilizumab-based therapy was effective in patients with

long-standing disease in whom anti-TNF therapy had previously failed.

More data are required to determine the comparative efficacy and

safety of tocilizumab versus other biological agents and to establish

their relative cost effectiveness. However, the present data suggest

that tocilizumab is an important emerging treatment option in adult

patients with moderate to severe rheumatoid arthritis.

Elevated levels of IL-6 in the serum and synovial fluid of rheumatoid

arthritis patients contribute to the chronic inflammatory process

characterizing this disease and correlate positively with disease

activity. Tocilizumab binds selectively and competitively to soluble

and membrane-expressed IL-6 receptors, blocking IL-6 signal

transduction. In vivo, maximum (>90%) IL-6 receptor saturation was

achieved when serum tocilizumab concentrations were >1 mug/mL. In

dose-ranging studies, serum levels of inflammatory markers were

normalized in rheumatoid arthritis patients who had detectable levels

of tocilizumab in the serum. Tocilizumab displays dose-dependent,

non-linear pharmacokinetics and has a long elimination half-life,

allowing administration every 4 weeks. Several well designed studies

in patients with early or long-standing rheumatoid arthritis,

including those with treatment-refractory disease, demonstrated the

efficacy of intravenous tocilizumab 8 mg/kg every 4 weeks in improving

disease activity, structural joint damage and/or HR-QOL.

Monotherapy with tocilizumab 8 mg/kg was noninferior to methotrexate

for achievement of a clinical response in patients who had not

experienced any prior treatment failures in the AMBITION study;

subsequent superiority analyses in the intent-to-treat population

demonstrated that significantly more tocilizumab than methotrexate

recipients achieved American College of Rheumatology (ACR) clinical

responses at week 24. Tocilizumab recipients also demonstrated

significant improvements at week 24 in HR-QOL measures. Among patients

with early (mean disease duration <3 years) rheumatoid arthritis whose

previous treatment with methotrexate or other conventional DMARDs had

failed, monotherapy with tocilizumab 8 mg/kg for up to 1 year was

significantly more effective than methotrexate or other DMARDs for

achieving an ACR20 response, preventing radiographic disease

progression and/or improving HR-QOL.

Tocilizumab 8 mg/kg in combination with methotrexate was also more

effective than methotrexate alone in this patient population. Patients

with long-standing treatment-refractory disease achieved significantly

better clinical responses with tocilizumab 8 mg/kg monotherapy than

with placebo or methotrexate. These beneficial effects were maintained

for up to 5 years with tocilizumab in a noncomparative extension of a

placebo-controlled trial. Four studies of tocilizumab-based

combination therapy for up to 52 weeks in patients with long-standing,

treatment-refractory disease demonstrated better clinical responses

with tocilizumab 8 mg/kg plus methotrexate or other DMARDs than with

methotrexate or other DMARDs alone. Improvements in the levels of

inflammatory markers were also observed, including serum C-reactive

protein levels, which reduced as early as week 2. The mean changes

from baseline in HR-QOL outcomes also favoured patients receiving

tocilizumab-based combination therapy. The RADIATE trial found that

generally better clinical responses were achieved with tocilizumab 8

mg/kg plus methotrexate than methotrexate alone in patients whose

therapy with at least one anti-TNF agent had failed. In LITHE,

significantly less radiographic disease progression was seen with

tocilizumab plus methotrexate than with methotrexate alone.

Intravenous tocilizumab was generally well tolerated in adult patients

with early or long-standing rheumatoid arthritis.

The rates of withdrawal because of treatment-emergent adverse events

among patients receiving tocilizumab 8 mg/kg monotherapy or in

combination with DMARDs were generally low (</=12% of patients) and

similar to those observed in active comparator groups. Most

treatment-emergent adverse events were mild to moderate in intensity;

upper respiratory tract infections, nasopharyngitis, headache,

hypertension and ALT elevations were the most frequently reported

adverse events in patients receiving tocilizumab monotherapy or

combination therapy for up to 52 weeks. Mild infusion reactions were

also common, but were generally transient.

Serious adverse events generally occurred with similar incidence among

patients receiving tocilizumab, alone or in combination (with

methotrexate or other DMARDs), and patients receiving methotrexate or

other DMARDs alone. The incidence of serious treatment-emergent

infections was generally low with tocilizumab (1-8% of patients) and

similar to the incidence observed with methotrexate or other DMARDs.

Moderate, reversible increases in mean serum levels of total

cholesterol, low- and high-density lipoprotein cholesterol and

triglycerides occurred in tocilizumab recipients. No corresponding

increases in vascular adverse events were observed with tocilizumab

plus methotrexate versus methotrexate alone during 24 weeks of therapy

and few changes were observed in the atherogenic index in patients

receiving tocilizumab for up to 1 year. Dose-dependent increases in

serum ALT and AST levels were also frequently observed in patients

receiving tocilizumab, with elevations in ALT and AST generally

occurring more frequently with tocilizumab monotherapy than

combination therapy (with methotrexate or other DMARDs).

Hypersensitivity reactions and the development of antibodies are

uncommon with tocilizumab.

PMID: 19368420

http://www.ncbi.nlm.nih.gov/pubmed/19368420

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