Tocilizumab Effectively Treats Rheumatoid Arthritis and Juvenile Idiopathic Arthritis

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Tocilizumab Effectively Treats Rheumatoid Arthritis and Juvenile Idiopathic

Arthritis CME

http://www.medscape.com/viewarticle/572397

News Author: Laurie Barclay, MD

CME Author: Penny Murata, MD

Release Date: April 2, 2008

Learning Objectives

Upon completion of this activity, participants will be able to:

Describe the efficacy and safety of tocilizumab treatment in patients with

incomplete response to methotrexate treatment of rheumatoid arthritis.

Describe the efficacy and safety of tocilizumab treatment in patients with

incomplete response to conventional treatment of systemic juvenile

idiopathic arthritis.

April 2, 2008 - Tocilizumab may be effective in treating rheumatoid

arthritis (RA) and juvenile idiopathic arthritis (JIA), according to

findings from 2 double-blind, randomized trials reported in the March 22

issue of The Lancet.

" Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via

its broad effects on immune and inflammatory responses, " write f S.

Smolen, MD, from the Medical University of Vienna in Vienna, Austria, and

colleagues from the tOcilizumab Pivotal Trial in methotrexate Inadequate

responders investigators. " Our aim was to assess the therapeutic effects of

blocking interleukin 6 by inhibition of the interleukin-6 receptor with

tocilizumab in patients with rheumatoid arthritis. "

In this double-blind, parallel-group, phase 3 study, a total of 623 patients

with moderate to severe active RA were randomized to receive tocilizumab 8

mg/kg (n = 205), tocilizumab 4 mg/kg (n = 214), or placebo (n= 204)

intravenously every 4 weeks. Randomization was accomplished with an

interactive voice-response system, stratified by site with a randomization

list provided by the study sponsor. Patients were permitted to continue

methotrexate at stable prestudy doses (10 - 25 mg/week).

At week 16, patients with less than 20% improvement in both swollen and

tender joint counts were offered rescue therapy with tocilizumab 8 mg/kg.

The main outcome was the proportion of patients with 20% improvement in

signs and symptoms of RA based on American College of Rheumatology criteria

(ACR20 response) at week 24.

There were 622 patients in the intent-to-treat analysis population; 1

patient in the 4-mg/kg group was excluded for not receiving study treatment.

ACR20 responses at 24 weeks were more common in patients receiving

tocilizumab vs those receiving placebo (120 [59%] patients in the 8-mg/kg

group, 102 [48%] in the 4-mg/kg group, 54 [26%] in the placebo group.

Compared with participants in the placebo group, more participants in the

tocilizumab group had at least 1 adverse event (143 [69%] in the 8-mg/kg

group, 151 [71%] in the 4-mg/kg group, and 129 [63%] in the placebo group).

Serious infections or infestations were the most common serious adverse

events reported by 6 patients in the 8-mg/kg group, 3 in the 4-mg/kg group,

and 2 in the placebo group.

" These data provide evidence that inhibition of interleukin-6-mediated

proinflammatory effects significantly and rapidly improves the signs and

symptoms of rheumatoid arthritis, " the study authors write. " Tocilizumab

could be an effective therapeutic approach in patients with moderate to

severe active rheumatoid arthritis. "

Limitations of the study include lack of long-term follow-up, failure to

assess inhibition of structural damage, lack of long-term safety data, and

actual number of patients enrolled slightly less than planned.

F. Hoffmann-La Roche, which developed tocilizumab in collaboration with the

sponsor, and Chugai Pharmaceutical, which supplied the study medication,

funded this study by Smolen and colleagues. Roche employs 2 of the study

authors. Five of the study authors have disclosed various financial

relationships with Roche, Centocor/Schering-Plough, Amgen, Wyeth,

sanofi-aventis, Abbott, Bristol-Myers Squibb, UCB, AstraZeneca, Novartis,

Essex, Merck Sharp & Dohme, Merck, and Merck Pharma GmbH.

The second study regarding tocilizumab described the efficacy and safety in

patients with systemic-onset JIA.

" Systemic-onset juvenile idiopathic arthritis does not always respond to

available treatments, including antitumour necrosis factor agents, " write

Shumpei Yokota, MD, from Yokohama City University School of Medicine in

Yokohama, Japan, and colleagues. " We investigated the efficacy and safety of

tocilizumab, an anti-interleukin-6-receptor monoclonal antibody, in children

with this disorder. "

In this double-blind, withdrawal phase 3 trial, a total of 56 children with

disease refractory to conventional treatment received 3 doses of tocilizumab

8 mg/kg every 2 weeks during a 6-week, open-label, lead-in phase. Age range

was 2 to 19 years. In the double-blind phase, patients who achieved an ACR

Pediatric (ACR Pedi) 30 response and a C-reactive protein (CRP)

concentration of less than 5 mg/L were then randomized to receive placebo or

to continue tocilizumab treatment for 12 weeks or until withdrawal for

rescue medication.

The main outcome for the double-blind phase was an ACR Pedi 30 response and

CRP concentration of less than 15 mg/L. Those patients who responded to

tocilizumab and who needed additional treatment were enrolled in an

open-label extension phase for at least 48 weeks. Analysis was by

intent-to-treat.

ACR Pedi 30, 50, and 70 responses were achieved by 51 (91%), 48 (86%), and

38 (68%) patients, respectively, at the end of the open-label, lead-in

phase. Of 43 patients who continued to the double-blind phase and were

included in the efficacy analysis, 4 (17%) of 23 patients in the placebo

group maintained an ACR Pedi 30 response and a CRP concentration of less

than 15 mg/L vs 16 (80%) of 20 in the tocilizumab group (P < .0001).

ACR Pedi 30, 50, and 70 responses were achieved by 47 (98%), 45 (94%), and

43 (90%) of 48 patients, respectively, by week 48 of the open-label

extension phase.

" Serious adverse events were anaphylactoid reaction, gastrointestinal

haemorrhage, bronchitis, and gastroenteritis, " the study authors write.

" Tocilizumab is effective in children with systemic-onset juvenile

idiopathic arthritis. It might therefore be a suitable treatment in the

control of this disorder, which has so far been difficult to manage. "

Because of the small sample size and short duration of follow-up, malignant

diseases and autoimmunity were not clearly evaluated.

Chugai Pharmaceuticals funded this study by Yokota and colleagues. One of

the study authors has received a consulting fee from the sponsor and works

as a scientific advisory board member of Hoffman-La Roche, which developed

tocilizumab in collaboration with the sponsor. Another study author holds a

patent for tocilizumab for the treatment of inflammatory disorders,

including RA and Castleman's disease. The other study authors have disclosed

no relevant financial relationships.

In an accompanying comment, Tim Bongartz, MD, from the Mayo Clinic College

of Medicine in Rochester, Minnesota, states he is " excited about the ongoing

expansion of therapeutic options for rheumatoid arthritis and, especially,

systemic JIA. "

" At the same time, the evidence on tocilizumab therapy for these disorders

does not allow me to make a comprehensive treatment decision on the basis of

comparative effectiveness and safety, " Dr. Bongartz writes.

" Interleukin-6-receptor targeting might be a promising key to effective

treatment in a certain subset of patients with inflammatory arthritis, but

future research will have to show us which lock it will be most useful for. "

Dr. Bongartz has disclosed various financial relationships with Abbott,

Amgen, and Wyeth.

Lancet. 2008;371:961-963, 987-997, 998-1006.

Clinical Context

The pathogenesis of RA involves the overexpression of interleukin 6, a

cytokine with increased levels in serum and synovial fluid. The

interleukin-6 receptor is expressed on the cell surface and in a circulating

form.

Tocilizumab, a monoclonal antibody, blocks interleukin 6 by binding to the

interleukin-6 receptor.

Phase 2 studies by Nishimoto and colleagues in the June 2004 issue of

Arthritis and Rheumatism and Maini and colleagues in the September 2006

issue of Arthritis and Rheumatism found that tocilizumab use was clinically

effective in treating RA.

The double-blind, randomized, placebo-controlled phase 3 study by Smolen and

colleagues evaluates the effectiveness and adverse events of tocilizumab

treatment of adults with RA who had incomplete response to methotrexate. The

open-label lead-in, double-blind phase, open-label extension-phase study by

Yokota and colleagues evaluates the effectiveness and adverse events of

tocilizumab treatment for children with systemic-onset JIA.

Study Highlights

Smolen and colleagues

623 adults with moderate to severe active RA for at least 6 months and

methotrexate use for at least 12 weeks were randomized to 1 of 3 groups for

24 weeks.

214 patients received tocilizumab 4 mg/kg intravenously every 4 weeks.

205 patients received tocilizumab 8 mg/kg intravenously every 4 weeks.

204 patients received placebo.

Active RA was defined by at least 6 swollen joints plus at least 8 tender

joints and CRP level more than 10 mg/L or erythrocyte sedimentation rate

(ESR) at least 28 mm/hour.

Exclusion criteria were other autoimmune diseases, RA-related systemic

conditions, class IV RA, non-RA inflammatory joint disease, recurrent

infections, chest radiograph abnormalities, liver disease, and unsuccessful

antitumor necrosis factor treatment.

All other disease-modifying antirheumatic drugs were discontinued.

All patients received weekly methotrexate 10 to 25 mg plus folic acid 5 mg.

The groups had similar baseline characteristics.

At week 16, patients with less than 20% improvement in RA signs and symptoms

per ACR20 response could receive rescue therapy with tocilizumab 8 mg/kg.

By week 24, ACR20 response occurred in more patients receiving tocilizumab 8

mg/kg (59%; OR, 4.0; P < .0001) and 4 mg/kg (48%; OR, 2.6; P <.0001) vs

placebo group (26%).

Both tocilizumab groups showed improvement vs placebo in patient pain,

clinician assessment, CRP levels, ESR, hemoglobin, rheumatoid factor,

disease activity score using 28 joints, European League Against RA response,

Health Assessment Questionnaire-Disability Index, Medical Outcomes Study

36-Item Short-Form General Health Survey, and Functional Assessment of

Chronic Illness Therapy-Fatigue assessment.

More patients in the tocilizumab vs placebo group reported at least 1

adverse event, cutaneous events, or abnormal laboratory results.

Incidence of serious adverse events was similar in all groups.

Yokota and colleagues

56 children aged 2 to 19 years with systemic-onset JIA and inadequate

response to corticosteroids were hospitalized 2 weeks before study until end

of double-blind phase.

Exclusion criteria were significant medical or surgical conditions, white

blood count less than 3.5 x 109/L or platelet count less than 100 x 109/L,

cardiac disease, or macrophage-activation syndrome.

Disease-modifying antirheumatic drugs were not permitted during study.

Treatment and placebo groups had similar baseline characteristics.

During 6-week, open-label, lead-in phase, all children received tocilizumab

8 mg/kg intravenously every 2 weeks.

51 (91%) had ACR Pedi 30 response (? 3 of 6 variables improved by 30% with

no variable worsened by > 30%).

48 (86%) had improved CRP levels to less than 5 mg/L.

44 (79%) had both ACR Pedi 30 response and CRP levels of less than 5 mg/L.

Patients with both ACR Pedi 30 and CRP levels less than 5 mg/L were

randomized to receive either tocilizumab 8 mg/kg or placebo every 2 weeks

for the 12-week double-blind phase.

More patients in tocilizumab vs placebo group had ACR Pedi 30 response and

CRP levels less than 15 mg/L.

Patients randomized from double-blind phase and those who had reduced CRP

levels after open-label lead-in phase entered the 48-week open-label

extension phase.

47 (98%) of 50 patients had ACR Pedi 30 response.

Hemoglobin and platelet levels improved.

Serious adverse events reported during all study phases included

anaphylactoid reaction, gastrointestinal tract hemorrhage, bronchitis, and

gastroenteritis.

Pearls for Practice

In adults with incomplete response to methotrexate treatment of RA, ACR20

response at 24 weeks is more common after use of tocilizumab 8 mg/kg and 4

mg/kg vs us of placebo.

In children with incomplete response to conventional treatment of

systemic-onset JIA, ACR Pedi 30 response and improvement in CRP levels

persist more commonly with tocilizumab 8 mg/kg vs placebo use.

Serious adverse events include anaphylactoid reaction, gastrointestinal

tract hemorrhage, bronchitis, and gastroenteritis.