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1.  Performance of the new 2011 ACR/EULAR remission criteria with tocilizumab using the phase IIIb study TAMARA as an example and their comparison with traditional remission criteria 
Annals of the Rheumatic Diseases  2011;70(11):1986-1990.
Remission is the established goal in rheumatoid arthritis (RA) treatment. Although originally defined by a disease activity score in 28 joints (DAS28) <2.6, more stringent criteria may imply the absence of disease activity. The 2011 ACR/EULAR remission criteria provide the newest and most stringent definition of remission.
To evaluate post hoc the remission by ACR/EULAR criteria and compare the criteria with the conventional DAS28 in TAMARA, an open-label phase IIIb tocilizumab (TCZ) trial including patients with active RA receiving inadequate disease-modifying antirheumatic drugs (DMARDs) or tumour necrosis factor α (TNFα) inhibitor treatment.
286 patients were enrolled, 99.7% of patients were receiving a conventional DMARD and 41.6% had TNFα inhibitor pretreatment. Baseline mean DAS28 of 6.0 ± 1.0 fell to 2.6 ± 1.5 at week 24. DAS28 <2.6 was achieved by 47.6% at week 24. Remission rates with the new ACR/EULAR Boolean-based criteria for clinical studies were 15.0% after 12 weeks and 20.3% after 24 weeks. Of note, 13.5% of patients with previous TNFα blocker inadequate response still achieved remission according to the new ACR/EULAR criteria after 24 weeks. Clinical Disease Activity Index and Simplified Disease Activity Index remission rates were 24.1% and 25.2%, respectively.
Under the definition of the new stringent 2011 ACR/EULAR remission criteria, patients with active RA despite DMARD treatment and even after inadequate response to TNFα inhibitors, receiving TCZ showed significant rates of remission. Similar remission rates were achieved, when clinical practice criteria, not inclusive of acute phase reactants, were used.
PMCID: PMC3184242  PMID: 21875873
2.  A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study) 
This study compared the efficacy and safety of subcutaneous (SC) versus intravenous (IV) formulations of tocilizumab in patients with rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs (DMARD).
Patients (n=1262) were randomly assigned to receive tocilizumab-SC 162 mg weekly+placebo-IV every 4 weeks or tocilizumab-IV 8 mg/kg every 4 weeks+placebo-SC weekly in combination with traditional DMARD. The primary outcome was to demonstrate the non-inferiority of tocilizumab-SC to tocilizumab-IV with regard to the proportion of patients in each group achieving an American College of Rheumatology (ACR) 20 response at week 24 using a 12% non-inferiority margin (NIM). Secondary outcomes were disease activity score using 28 joints (DAS28), ACR responses, health assessment questionnaire scores and safety assessments.
At week 24, 69.4% (95% CI 65.5 to 73.2) of tocilizumab-SC-treated patients versus 73.4% (95% CI 69.6 to 77.1) of tocilizumab-IV-treated patients achieved an ACR20 response (weighted difference between groups −4.0%, 95% CI −9.2 to 1.2); the 12% NIM was met. ACR50/70 responses, DAS28 and physical function improvements were comparable between the tocilizumab-SC and tocilizumab-IV groups. The safety profiles of tocilizumab-SC and tocilizumab-IV were similar, and the most common adverse event was infection. Injection-site reactions (ISR) occurred more frequently in the tocilizumab-SC group than in the tocilizumab-IV (placebo-SC) group. No anaphylaxis was reported over the 24 weeks.
Tocilizumab-SC 162 mg weekly demonstrated comparable efficacy to tocilizumab-IV 8 mg/kg. The safety profile of tocilizumab-SC is consistent with the known and well-established safety profile of tocilizumab-IV, with the exception of a higher incidence of ISR, which were more common with tocilizumab-SC administration.
PMCID: PMC3888614  PMID: 23904473
Rheumatoid Arthritis; DMARDs (biologic); Disease Activity
3.  Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice 
Annals of the Rheumatic Diseases  2012;71(12):1950-1954.
To evaluate the safety and efficacy of tocilizumab in clinical practice in patients with rheumatoid arthritis (RA) with inadequate responses (IR) to disease-modifying antirheumatic drugs (DMARDs) or both DMARDs and tumour necrosis factor α inhibitors (TNFis).
Patients—categorised as TNFi-naive, TNFi-previous (washout) or TNFi-recent (no washout) —received open-label tocilizumab (8 mg/kg) every 4 weeks ± DMARDs for 24 weeks. Adverse events (AEs) and treatment discontinuations were monitored. Efficacy end points included American College of Rheumatology (ACR) responses, 28-joint disease activity score (DAS28) and European League Against Rheumatism responses.
Overall, 1681 (976 TNF-naive, 298 TNFi-previous and 407 TNFi-recent) patients were treated; 5.1% discontinued treatment because of AEs. The AE rate was numerically higher in TNFi-recent (652.6/100 patient-years (PY)) and TNFi-previous (653.6/100PY) than in TNFi-naive (551.1/100PY) patients. Serious AE rates were 18.0/100PY, 28.0/100PY and 18.6/100PY; serious infection rates were 6.0/100PY, 6.8/100PY and 4.2/100PY, respectively. At week 4, 36.5% of patients achieved ACR20 response and 14.9% DAS28 remission (<2.6); at week 24, 66.9%, 46.6%, 26.4% and 56.8% achieved ACR20/ACR50/ACR70 responses and DAS28 remission, respectively. Overall, 61.6% (TNFi-naive), 48.5% (TNFi-previous) and 50.4% (TNFi-recent) patients achieved DAS28 remission.
In patients with RA who were DMARD-IR/TNFi-IR, tocilizumab ± DMARDs provided rapid and sustained efficacy without unexpected safety concerns.
PMCID: PMC3595980  PMID: 22615456
4.  Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study 
The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis.
To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed.
This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24.
The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p<0.001), and 28-joint Disease Activity Score (DAS28) <2.6 rate (33.6 vs 12.1%) at week 24. Mean high-sensitivity C-reactive protein was within the normal range from week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events with tocilizumab was 3.8% versus 2.8% with methotrexate (p = 0.50), and of serious infections, 1.4% versus 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs 0.4%) and increased total cholesterol ⩾240 mg/dl (13.2% vs 0.4%), and a lower incidence of alanine aminotransferase elevations >3×–<5× upper limit of normal (1.0% vs 2.5%), respectively.
Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit–risk, in patients for whom treatment with methotrexate or biological agents has not previously failed.
Trial registration number:
PMCID: PMC3747519  PMID: 19297346
5.  Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy 
Modern Rheumatology  2008;19(1):12-19.
We investigated the clinical efficacy and safety of tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (tocilizumab group) or tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the tocilizumab group achieved ACR20 response. The tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.
PMCID: PMC2638601  PMID: 18979150
Clinical trial; Interleukin-6; Rheumatoid arthritis; Tocilizumab; Vascular endothelial growth factor
6.  Laboratory and febrile features after joint surgery in patients with rheumatoid arthritis treated with tocilizumab 
Annals of the Rheumatic Diseases  2008;68(5):654-657.
To understand the acute phase responses to surgical intervention in patients with rheumatoid arthritis (RA) treated with the anti-interleukin (IL)6 receptor antibody, tocilizumab.
In a retrospective 1:1 pair-matched case-control study, 22 tocilizumab-treated RA cases and 22 cases treated with conventional disease-modifying antirheumatic drugs (DMARDs) and matched for type of surgery, age and sex were evaluated for body temperature every day, and blood C-reactive protein (CRP) levels and white blood cell (WBC), neutrophil and lymphocyte counts on days −1, 1, 3 and weeks 1 and 2 after joint surgery. Safety issues were also monitored.
No complications of infection or delay of wound healing occurred in either patient group. Tocilizumab partially, but significantly, suppressed the increase in body temperature on postoperative days 1 and 2, compared with DMARDs (average (SD) maximum increase in temperature was 0.45 (0.1)°C in the tocilizumab group and 0.78 (0.1)°C in the DMARD group; p<0.01). Tocilizumab completely suppressed the increase in CRP after surgery, whereas all cases treated with DMARDs showed a significant increase of CRP at postoperative day 1 (5.5 (0.6) mg/dl; p<0.001). WBC, neutrophil and lymphocyte counts showed no remarkable change after surgery, and there was no significant difference in any cell counts between the patient groups.
Within this small number of cases, safe operations on patients were performed during tocilizumab treatment. Tocilizumab suppressed fever and increase of CRP after surgery, whereas there was no influence on the transition in number of leukocytes. This characteristic postoperative response should be considered during tocilizumab treatment.
PMCID: PMC2663710  PMID: 18519424
7.  Review of tocilizumab in the treatment of rheumatoid arthritis 
Biologics : Targets & Therapy  2008;2(1):75-82.
Constitutively overproduced in proliferating synovial tissues, interleukin-6 (IL-6) is deeply involved in the pathology of rheumatoid arthritis (RA). Tocilizumab is a humanized anti-human IL-6 receptor antibody that binds to soluble and membrane-bound IL-6 receptor, and at detectable levels in blood, tocilizumab is capable of almost completely blocking the transmembrane signaling of IL-6. In clinical trials for patients with RA in Japan, tocilizumab monotherapy has shown clinical efficacy equaling that of tumor necrosis factor (TNF) inhibitor in combination with methotrexate, and in an extension study in patients who responded to tocilizumab, almost no patients showed a decrease in the efficacy of tocilizumab. Evidence obtained in a phase III study in Japan demonstrated that tocilizumab monotherapy had a sig-nificant inhibitory effect on the progression of structural joint damage compared with that of conventional disease modifying antirheumatic drugs (DMARDs). Furthermore it has been shown that tocilizumab has an excellent ability to suppress serum amyloid A levels and could therefore be an important therapeutic strategy in amyloid A amyloidosis secondary to rheumatic diseases. The safety profile of tocilizumab appears to be satisfactory. However, several serious infections were also reported, and careful monitoring is therefore important during use.
PMCID: PMC2727785  PMID: 19707430
tocilizumab; rheumatoid arthritis; interleukin-6; treatment; amyloidosis; biologics
8.  Adalimumab alone and in combination with disease‐modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial 
Annals of the Rheumatic Diseases  2007;66(6):732-739.
To evaluate the safety and effectiveness of adalimumab alone or in combination with standard disease‐modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA).
Patients with active RA despite treatment with DMARDs or prior treatment with a tumour necrosis factor antagonist participated in a multicentre, open‐label clinical study of adalimumab 40 mg every other week for 12 weeks with an optional extension phase. Patients were allowed to continue with pre‐existing traditional DMARDs. Long‐term safety results are reported for all patients (4210 patient‐years (PYs) of adalimumab exposure). The observed effectiveness results at week 12 are reported using American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria.
Among the 6610 treated patients, adalimumab was generally well tolerated. Serious infections occurred in 3.1% of patients (5.5/100 PYs, including active tuberculosis, 0.5/100 PYs). Demyelinating disease (0.06%) and systemic lupus erythematosus (0.03%) were rare serious adverse events. The standardised incidence ratio of malignancy was 0.71 (95% CI 0.49 to 1.01). The standardised mortality ratio was 1.07 (95% CI 0.75 to 1.49). At week 12, 69% of patients achieved an ACR20 response, 83% a moderate, and 33% a good EULAR response. Adalimumab was effective in combination with a variety of DMARDs. The addition of adalimumab to antimalarials was comparably effective to the combination of adalimumab and methotrexate.
Considering the limitations of an open‐label study, adalimumab alone or in combination with standard DMARDs appeared to be well tolerated and effective in 6610 difficult‐to‐treat patients with active RA treated in clinical practice.
PMCID: PMC1954645  PMID: 17329305
adalimumab; rheumatoid arthritis; tumour necrosis factor; monoclonal antibody; antirheumatic agents
9.  Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study 
Annals of the Rheumatic Diseases  2008;68(10):1580-1584.
To evaluate the safety and efficacy of 5-year, long-term tocilizumab monotherapy for patients with rheumatoid arthritis.
In an open-label, long-term extension trial following an initial 3-month randomised phase II trial, 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy (8 mg/kg) every 4 weeks. Concomitant therapy with non-steroidal anti-inflammatory drugs and/or oral prednisolone (10 mg daily maximum) was permitted. All patients were evaluated with American College of Rheumatology (ACR) improvement criteria, disease activity score (DAS) in 28 joints, and the European League Against Rheumatism response, as well as for safety issues.
143 patients were enrolled in the open-label, long-term extension trial and 94 (66%) patients had completed 5 years as of March 2007. 32 patients (22%) withdrew from the study due to adverse events and one patient (0.7%) due to unsatisfactory response. 14 patients withdrew because of the patient’s request or other reasons. The serious adverse event rate was 27.5 events per 100 patient-years, with 5.7 serious infections per 100 patient-years, based on a total tocilizumab exposure of 612 patient-years. Of the 88 patients receiving corticosteroids at baseline, 78 (88.6%) were able to decrease their corticosteroid dose and 28 (31.8%) discontinued corticosteroids. At 5 years, 79/94 (84.0%), 65/94 (69.1%) and 41/94 (43.6%) of the patients achieved ACR20, ACR50, and ACR70 improvement criteria, respectively. Remission defined as DAS28 less than 2.6 was achieved in 52/94 (55.3%) of the patients.
In this 5-year extension study, tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile.
PMCID: PMC2732899  PMID: 19019888
10.  Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement 
Annals of the Rheumatic Diseases  2012;72(4):583-589.
Suppression of the immunoinflammatory cascade by targeting interleukin 6 (IL-6) mediated effects constitutes a therapeutic option for chronic inflammatory diseases. Tocilizumab is the only IL-6 inhibitor (IL-6i) licensed for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), but also other agents targeting either IL-6 or its receptor are investigated in various indications.
To review published evidence on safety and efficacy of IL-6i in inflammatory diseases.
We performed systematic literature searches in Medline and Cochrane, screened EULAR and American College of Rheumatology meeting-abstracts, and accessed
Comprehensive evidence supports the efficacy of tocilizumab in RA in DMARD-naïve patients, and after DMARD- and TNFi-failure. Randomised comparisons demonstrate superiority of tocilizumab in JIA, but not ankylosing spondylitis (AS). Other indications are currently investigated. Additional IL-6i show similar efficacy; safety generally appears acceptable.
IL-6i is effective and safe in RA and JIA, but not in AS. Preliminary results in other indications need substantiation.
PMCID: PMC3595140  PMID: 23144446
Rheumatoid Arthritis; Juvenile Idiopathic Arthritis; Treatment; DMARDs (biologic)
11.  Mechanism-based approach using a biomarker response to evaluate tocilizumab subcutaneous injection in patients with rheumatoid arthritis with an inadequate response to synthetic DMARDs (MATSURI study) 
Journal of Clinical Pharmacology  2013;54(1):109-119.
A multicenter, open-label, dose-escalation phase 1/2 study was undertaken to evaluate the optimal subcutaneous tocilizumab dose that would result in exposure comparable to the intravenous tocilizumab 8-mg/kg approved dose in patients with rheumatoid arthritis. A pharmacokinetic and biomarker approach was used to estimate the clinical optimal dose regimen of subcutaneous tocilizumab. Safety and efficacy of subcutaneous tocilizumab were assessed as secondary end points. Patients received subcutaneous tocilizumab at 81 mg every 2 weeks (q2w) (n = 8), 162 mg q2w (n = 12), or 162 mg weekly (qw) (n = 12) for 24 weeks. 88% of 162-mg q2w patients and 100% of 162-mg qw patients maintained mean serum trough tocilizumab concentrations of ≥1 µg/mL, and had exposure comparable with the approved intravenous tocilizumab dose of 8 mg/kg; this resulted in normalized C-reactive protein levels and improvement in ACR20/50/70 responses. The most common adverse events were abnormal laboratory results, which were mild in severity. Anti-tocilizumab antibodies were detected in a few patients in the 81-mg q2w and 162-mg qw groups. In conclusion, coupled with efficacy and tolerability results, the appropriate dose of subcutaneous tocilizumab was determined to be 162 mg q2w for Japanese patients.
PMCID: PMC3908364  PMID: 24115082
tocilizumab; subcutaneous injection; pharmacokinetics; CRP; biomarker
12.  Efficacy and tolerability of tocilizumab in rheumatoid arthritis patients seen in daily clinical practice in Japan: results from a retrospective study (REACTION study) 
Modern Rheumatology  2010;21(2):122-133.
Tocilizumab, a humanized monoclonal antibody to the interleukin 6 (IL-6) receptor, was approved for use as rheumatoid arthritis (RA) therapy in Japan in 2008, but its efficacy and tolerability in daily practice has not yet been reported. We report the results of a multicenter retrospective study on the efficacy and safety of tocilizumab involving all patients (n = 229) who were started on tocilizumab therapy at three rheumatology institutes in Japan from April 2008 through to March 2009. Tocilizumab was infused every 4 weeks at a dose of 8 mg/kg according to the drug labeling. Among the 229 patients, 55% concomitantly received methotrexate (MTX) and 63% had previously received anti-tumor necrosis factor (TNF) therapy. Average disease activity score (DAS) 28 of all 229 patients significantly decreased from 5.70 to 3.25 after 24 weeks of therapy. A European League Against Rheumatism (EULAR) good response and DAS28 remission was achieved in 57.4 and 40.7% of the patients, respectively, at 24 weeks. White blood cell counts significantly decreased and liver enzymes and total cholesterol slightly but significantly increased; however, liver enzyme levels did not increase in patients without MTX. Tocilizumab was discontinued in 47 cases (20.5%) due to lack of efficacy (5.2%), adverse events (11.4%), and other reasons (3.9%). The overall retention rate at 24 weeks was 79.5%. Based on these results, we conclude that tocilizumab therapy in daily rheumatology practice appears to be highly efficacious and well tolerated among active RA patients, including the anti-TNF therapy-refractory population. Tocilizumab infusion is therefore applicable not only as an alternative approach for anti-TNF therapy-resistant patients, but also as primary biologic therapy for active RA patients.
PMCID: PMC3071926  PMID: 20953815
Rheumatoid arthritis; Tocilizumab; IL-6; Remission; Retrospective study
13.  IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial 
Annals of the Rheumatic Diseases  2008;67(11):1516-1523.
The phase III RADIATE study examined the efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis (RA) refractory to tumour necrosis factor (TNF) antagonist therapy.
499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. ACR20 responses, secondary efficacy and safety endpoints were assessed.
ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p<0.001 both tocilizumab groups versus control). At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 <2.6) rates at week 24 were clearly dose related, being achieved by 30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Most adverse events were mild or moderate with overall incidences of 84.0%, 87.1% and 80.6%, respectively. The most common adverse events with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache. The incidence of serious adverse events was higher in controls (11.3%) than in the 8 mg/kg (6.3%) and 4 mg/kg (7.4%) groups.
Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile.
Trial registration number:
PMCID: PMC3811149  PMID: 18625622
14.  Tocilizumab: A Novel Humanized Anti-Interleukin 6 Receptor Antibody for the Treatment of Patients with Rheumatoid Arthritis 
Tocilizumab (TCZ; RoActemra® or Actemra®) is a recombinant humanized monoclonal antibody that acts as an interleukin 6 (IL-6) receptor antagonist. For rheumatoid arthritis (RA), intravenous (IV) TCZ 8 mg/kg every 4 weeks has been approved since 2008 in Japan (where it is also approved for polyarticular juvenile idiopathic arthritis, systemic-onset juvenile idiopathic arthritis and Castleman's disease), and since 2009 in Europe in combination with methotrexate (MTX) for the treatment of moderate to severe active RA in adult patients with inadequate response to, or intolerance of, disease-modifying antirheumatic drug (DMARD) or tumor necrosis factor (TNF) antagonist therapy. It may also be administered as monotherapy in the same dose regimen in patients with methotrexate intolerance or with inadequate response to MTX. Since January 2011 in the United States, the indication for treatment with TCZ for RA patients with an inadequate response to one or more TNF antagonists was extended to patients with moderately to severely active RA, and the recommended starting dose is 4 mg/kg every 4 weeks, with an increase to 8 mg/kg based on clinical response. All of these approvals are based on the effectiveness and safety of the 8 mg/kg dose regimen when administered either as monotherapy or in combination with conventional DMARDs in well-designed clinical studies in adult patients with moderate to severe RA. TCZ at this dose is more effective than placebo, MTX or other DMARDs in reducing disease activity and improving health-related quality of life (HR-QoL). Although there were fewer responses with the 4 mg/kg dose, this dose every 4 weeks was not statistically different to 8 mg/kg when administered in combination with MTX, and this dose is the recommended starting dose in the US. Both doses have also been shown to inhibit structural joint damage in patients with an inadequate response to MTX. Thus, TCZ is an important new treatment option in patients with moderate to severe RA.
PMCID: PMC3389389  PMID: 22870473
interleukin 6; monoclonal antibody; rheumatoid arthritis; tocilizumab
15.  Early intervention in the treatment of rheumatoid arthritis: focus on tocilizumab 
Tocilizumab is a fully humanized monoclonal antibody against interleukin-6 receptors that was approved for the treatment of patients with rheumatoid arthritis (RA). Several lines of evidence, obtained both from conventional disease-modifying anti-rheumatic drugs (DMARDs) and tumor necrosis factor (TNF) inhibitors, have supported the concept of “window of opportunity” as showing that these therapies consistently work better in early disease as compared to established RA. This review addresses the question of whether a window of opportunity gained with conventional DMARDs and TNF inhibitors can also be achieved with tocilizumab. To this end, data regarding the use of tocilizumab in early RA patients are summarized. Currently available data suggest that the earlier the treatment with tocilizumab, the better the clinical outcome can be, which may have implications for various aspects of RA treatment strategies.
PMCID: PMC3810895  PMID: 24179334
rheumatoid arthritis; tocilizumab; early intervention
16.  Evaluation of composite measures of treatment response without acute-phase reactants in patients with rheumatoid arthritis 
Rheumatology (Oxford, England)  2009;48(6):686-690.
Objectives. To evaluate composite measures of response without acute-phase reactants in RA patients. Specifically, Clinical Disease Activity Index (CDAI)-derived response criteria were compared with the European League Against Rheumatism (EULAR) response criteria, and the modified ACR (mACR) response criteria were compared to the ACR response criteria.
Methods. Data from 10 108 RA patients enrolled in the Consortium of Rheumatology Researchers of North America registry were examined, including 649 patients initiating DMARD therapy. CDAI cut-off points for disease activity levels and responses were derived using receiver operating characteristic curves with the DAS28 and EULAR response criteria as gold standards. The κ-statistics were applied to assess agreement between CDAI-derived and EULAR-defined responses, as well as ACR20 and ACR50 with mACR20- and mACR50-defined responses, respectively.
Results. For the components of the EULAR response, the derived CDAI cut-off points for DAS28 levels of 3.2 and 5.1 were 7.6 and 19.6, respectively. The derived CDAI cut-off points were 4.3 and 10.0 for DAS28 changes of 0.6 and 1.2, respectively. There were moderate to substantial agreements between CDAI-derived and EULAR responses (κ = 0.57–0.71). Agreement of ACR20 and ACR50 with mACR20 and mACR50 responses, respectively, was excellent (κ = 0.88–0.95).
Conclusions. Agreement between composite measures of response without acute-phase reactants and standard measures ranged from moderate to excellent. The mACR20 and mACR50 criteria as well as CDAI-derived response criteria, can serve as composite measures of response in clinical practice and research settings without access to acute-phase reactants.
PMCID: PMC2722796  PMID: 19395544
Rheumatoid arthritis; Acute-phase reactants; Response criteria
17.  Targeting Interleukin-6: All the Way to Treat Autoimmune and Inflammatory Diseases 
Interleukin (IL)-6, a cytokine featuring redundancy and pleiotropic activity, contributes to host defense against acute environmental stress, while dysregulated persistent IL-6 production has been demonstrated to play a pathological role in various autoimmune and chronic inflammatory diseases. Targeting IL-6 is thus a rational approach to the treatment of these diseases. Indeed, clinical trials of tocilizumab, a humanized anti-IL-6 receptor antibody have verified its efficacy and tolerable safety for patients with rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis, resulting in approval of this innovative biologic for treatment of these diseases. Moreover, a considerable number of case reports and pilot studies of off-label use of tocilizumab point to the beneficial effects of tocilizumab for a variety of other phenotypically different autoimmune and chronic inflammatory diseases. Elucidation of the source of IL-6 and of mechanisms through which IL-6 production is dysregulated can thus be expected to lead to clarification of the pathogenesis of various diseases.
PMCID: PMC3491446  PMID: 23136551
interleukin-6; a humanized anti-interleukin-6 receptor antibody; tocilizumab; autoimmune; inflammation.
18.  Critical appraisal of tocilizumab in the treatment of moderate to severe rheumatoid arthritis 
Recent advances in our understanding of the role of interleukin (IL)-6 in autoimmunity and in particular rheumatoid arthritis (RA) have brought about important changes in the way we think about autoimmune diseases. Encouraging data from several phase III clinical trials of tocilizumab, a humanized monoclonal antibody against IL-6R, have led to its approval in Europe for the treatment of moderate to severe RA. Data on clinical efficacy, patient-reported outcomes, safety, and cost-effectiveness with the use of tocilizumab in patients with RA will be summarized in this review, with particular emphasis on phase III clinical trials. Furthermore, adverse events associated with the use of tocilizumab will be reviewed. Future clinical trials will evaluate the role of tocilizumab in other autoimmune diseases. The goal of this review is to describe the current understanding of the role of IL-6 in mediating the inflammatory response in RA, as well as the role of tocilizumab in the treatment of RA and the evolving role of this agent in other autoimmune diseases.
PMCID: PMC2857613  PMID: 20421913
tocilizumab; rheumatoid arthritis; IL-6; methotrexate
19.  Tocilizumab in rheumatoid arthritis: efficacy, safety and its place in therapy 
Tocilizumab is a humanized antihuman interleukin-6 (IL-6) receptor monoclonal antibody. It was developed in Japan as the first biological disease-modifying antirheumatic drug targeting IL-6 receptors. Many large-scale global studies have demonstrated its efficacy and safety, and in April 2008 it was approved in Japan for use in the treatment of rheumatoid arthritis, sooner than in other countries. In this paper, I review the efficacy and safety of tocilizumab in the light of front-line clinical data and data from large-scale studies, and I consider the place of tocilizumab treatment in real clinical practice.
PMCID: PMC3539265  PMID: 23342244
biological disease-modifying antirheumatic drug; interleukin-6; rheumatoid arthritis; tocilizumab
20.  Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2) 
Annals of the Rheumatic Diseases  2012;72(2):204-210.
To assess the efficacy and safety of low-dose prednisone chronotherapy using a new modified-release (MR) formulation for the treatment of rheumatoid arthritis (RA).
In this 12-week, double-blind, placebo-controlled study, patients with active RA (n=350) were randomised 2:1 to receive MR prednisone 5 mg or placebo once daily in the evening in addition to their existing RA disease-modifying antirheumatic drug (DMARD) treatment. The primary end point was the percentage of patients achieving a 20% improvement in RA signs and symptoms according to American College of Rheumatology criteria (ie, an ACR20 response) at week 12. Changes in morning pain, duration of morning stiffness, 28-joint Disease Activity Score and health-related quality of life were also assessed.
MR prednisone plus DMARD treatment produced higher response rates for ACR20 (48% vs 29%, p<0.001) and ACR50 (22% vs 10%, p<0.006) and a greater median relative reduction from baseline in morning stiffness (55% vs 35%, p<0.002) at week 12 than placebo plus DMARD treatment. Significantly greater reductions in severity of RA (Disease Activity Score 28) (p<0.001) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue score) (p=0.003) as well as a greater improvement in physical function (36-item Short-Form Health Survey score) (p<0.001) were seen at week 12 for MR prednisone versus placebo. The incidence of adverse events was similar for MR prednisone (43%) and placebo (49%).
Low-dose MR prednisone added to existing DMARD treatment produced rapid and relevant improvements in RA signs and symptoms., number
PMCID: PMC3553491  PMID: 22562974
21.  Interleukin-6 Receptor Blockade Selectively Reduces IL-21 Production by CD4 T Cells and IgG4 Autoantibodies in Rheumatoid Arthritis 
Interleukin-6 (IL-6) levels are known to be increased in patients with rheumatoid arthritis (RA). Tocilizumab, a monoclonal antibody to the IL-6 receptor (IL-6R), reduces disease activity in RA, although its mechanisms of action remain unclear. Since IL-6 regulates cytokine production by CD4 T cells during activation, we investigated whether treatment with tocilizumab altered the phenotype and cytokine production by CD4 T cells in patients with rheumatoid arthritis. We show here that tocilizumab treatment does not change the production of cytokines by naïve CD4 T cells. However, tocilizumab treatment causes a selective decrease of IL-21 production by memory/activated CD4 T cells. Since IL-21 is known to promote plasma cell differentiation, we examined the effect of tocilizumab on the production of autoantibodies. We show that there is a decrease in the levels of IgG4 anti-CCP antibodies, but there is no effect on IgG1 anti-CCP antibodies. In addition, we show that IL-21 is a powerful inducer of IgG4 production by B cells. Thus, IL-6 contributes to the presence of IgG4-specific anti-CCP autoantibodies in RA patients, likely through its effect on IL-21 production by CD4 T cells, and IL-6R blockade down-regulates this pathway.
PMCID: PMC3596713  PMID: 23493630
Interleukin-6; IL-6; IL-21; CD4 T; rheumatoid arthritis; IgG4; auti-CCP; tocilizumab
22.  Clinical efficacy of abatacept compared to adalimumab and tocilizumab in rheumatoid arthritis patients with high disease activity 
Clinical Rheumatology  2013;33:39-47.
Favourable clinical results in rheumatoid arthritis (RA) patients with high disease activity (HDA) are difficult to achieve. This study evaluated the clinical efficacy of abatacept according to baseline disease activity compared to adalimumab and tocilizumab. This study included all patients registered in a Japanese multicenter registry treated with abatacept (n = 214), adalimumab (n = 175), or tocilizumab (n = 143) for 24 weeks. Clinical efficacy of abatacept in patients with HDA (DAS28-CRP > 4.1) and low and moderate disease activity was compared. Clinical efficacy of abatacept, adalimumab, and tocilizumab was compared in patients with HDA at baseline. In patients treated with abatacept, multivariate logistic regression identified HDA at baseline as an independent predictor for achieving low disease activity (LDA; DAS28-CRP < 2.7) [OR 0.26, 95 % CI 0.14–0.50] or remission (DAS28-CRP < 2.3) [OR 0.26, 95 % CI 0.12–0.56] at 24 weeks. In patients with HDA at baseline, logistic regression did not identify treatment with adalimumab or tocilizumab as independent predictors of LDA or remission compared to abatacept. Retention rates based on insufficient efficacy were significantly higher in patients treated with abatacept compared to adalimumab and lower than tocilizumab. Retention rates based on adverse events in patients treated with abatacept were significantly lower compared to tocilizumab. Clinical efficacy of abatacept was affected by baseline disease activity. There were no significant differences between the three different classes of biologics regarding clinical efficacy for treating RA patients with HDA, although definitive conclusions regarding long-term efficacy will require further research.
PMCID: PMC3890049  PMID: 24057092
Abatacept; Adalimumab; High disease activity; Japanese multicenter registry system; Rheumatoid arthritis; Tocilizumab
23.  Assessment of the validity of the 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) as a disease activity index of rheumatoid arthritis in the efficacy evaluation of 24-week treatment with tocilizumab: subanalysis of the SATORI study 
Modern Rheumatology  2010;20(6):539-547.
As tocilizumab (TCZ) greatly inhibits inflammatory markers, methods of evaluating rheumatoid arthritis (RA) disease activity that include inflammatory markers may overestimate the effect of TCZ treatment. We have evaluated the impact of inflammatory markers on the efficacy of TCZ by comparing the efficacy indicated by the 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) with that indicated by the clinical and simplified disease activity indexes (CDAI and SDAI, respectively) and the American College of Rheumatology (ACR) core set criteria in a double-blind study of TCZ—the SATORI study. The Spearman correlation coefficient between DAS28-ESR and CDAI was comparable between that at week 24 and that at baseline [correlation coefficient at baseline and week 24 was 0.823 (p < 0.0001) and 0.818 (p < 0.0001), respectively]. A large difference between the DAS28 remission rate and CDAI remission rate was observed at week 24. However, these results are comparable to those of a previous study conducted with non-TCZ-treated patients. Moreover, the same results were obtained in the comparison between the DAS28-ESR and SDAI, even though the SDAI includes an inflammatory parameter as a component. These results confirm that the DAS28-ESR has a validity comparable to that of other methods in terms of evaluating the RA treatment efficacy of TCZ, despite its strong inflammatory marker-inhibiting effects.
PMCID: PMC2999727  PMID: 20617358
Interleukin 6; Clinical disease activity index; Simplified disease activity index; Acute phase protein; Inflammatory markers
24.  Case Report: Safety and Efficacy of Tocilizumab in a Patient with Rheumatoid Arthritis and Chronic Hepatitis C 
Case Reports in Medicine  2012;2012:212381.
Tocilizumab is a monoclonal humanized anti-IL-6-receptor antibody used for the treatment of rheumatoid arthritis. The safety of tocilizumab in HCV patients is an open question. We report on safety and efficacy of tocilizumab in a 71-year-old female with rheumatoid arthritis and chronic hepatitis C. Monotherapy with tocilizumab (8 mg/kg every 4 weeks, i.v.) was prescribed after the discontinuation, determined by clinical inefficacy, of anti-TNF-alfa agents (adalimumab and, subsequently, etanercept). We have registered an optimal and rapid clinical response to tocilizumab with early remission (SDAI <3.3 since 4 weeks). The safety was good with no adverse events and maintenance, during a six-month followup, of normal liver enzymes. These data suggest a good safety profile of tocilizumab in patients with rheumatoid arthritis and chronic hepatitis C virus pathology.
PMCID: PMC3295620  PMID: 22431927
25.  Selective involvement of ERK and JNK mitogen-activated protein kinases in early rheumatoid arthritis (1987 ACR criteria compared to 2010 ACR/EULAR criteria): a prospective study aimed at identification of diagnostic and prognostic biomarkers as well as therapeutic targets 
Annals of the Rheumatic Diseases  2011;71(3):415-423.
To investigate the expression and activation of mitogen-activated protein kinases in patients with early arthritis who are disease-modifying antirheumatic drug (DMARD) naïve.
A total of 50 patients with early arthritis who were DMARD naïve (disease duration <1 year) were prospectively followed and diagnosed at baseline and after 2 years for undifferentiated arthritis (UA), rheumatoid arthritis (RA) (1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria), or spondyloarthritis (SpA). Synovial biopsies obtained at baseline were examined for expression and phosphorylation of p38, extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) by immunohistochemistry and digital analysis. Synovial tissue mRNA expression was measured by quantitative PCR (qPCR).
ERK and JNK activation was enhanced at inclusion in patients meeting RA criteria compared to other diagnoses. JNK activation was enhanced in patients diagnosed as having UA at baseline who eventually fulfilled 1987 ACR RA criteria compared to those who remained UA, and in patients with RA fulfilling 2010 ACR/EULAR criteria at baseline. ERK and JNK activation was enhanced in patients with RA developing progressive joint destruction. JNK activation in UA predicted 1987 ACR RA classification criteria fulfilment (R2=0.59, p=0.02) after follow-up, and disease progression in early arthritis (R2=0.16, p<0.05). Enhanced JNK activation in patients with persistent disease was associated with altered synovial expression of extracellular matrix components and CD44.
JNK activation is elevated in RA before 1987 ACR RA classification criteria are met and predicts development of erosive disease in early arthritis, suggesting JNK may represent an attractive target in treating RA early in the disease process.
PMCID: PMC3277721  PMID: 21953337

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