Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement

Background 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. Objective To review published evidence on safety and efficacy of IL-6i in inflammatory diseases. Methods We performed systematic literature searches in Medline and Cochrane, screened EULAR and American College of Rheumatology meeting-abstracts, and accessed http://www.clinicaltrials.gov. Results 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. Conclusions IL-6i is effective and safe in RA and JIA, but not in AS. Preliminary results in other indications need substantiation.

[1]  Y. Saeki,et al.  Retreatment efficacy and safety of tocilizumab in patients with rheumatoid arthritis in recurrence (RESTORE) study , 2013, Modern rheumatology.

[2]  M. Aringer,et al.  AB0520 Tocilizumab in rheumatoid arthritis – one year interim analysis of the non-interventional ichiban study , 2013 .

[3]  M. Weinblatt,et al.  THU0100 Results from a 2-part, proof-of-concept, dose-ranging, randomized, double-blind, placebo-controlled, phase 2 study of sirukumab, a human anti-IL-6 monoclonal antibody, in patients with active rheumatoid arthritis despite methotrexate therapy , 2013 .

[4]  J. Kremer,et al.  SAT0103 Lithe: Tocilizumab (TCZ) Inhibits Radiographic Progression and Improves Physical Function in Patients (PTS) With Rheumatoid Arthritis (RA) at 5 Years With Maintenance of Clinical Efficacy Over Time , 2013 .

[5]  R. Burgos-Vargas,et al.  OP0049 The lenght of remission and rate of relapse after tocilizumab withdrawal in rheumatoid arthritis patients , 2013 .

[6]  V. Bykerk,et al.  FRI0179 Comparison of tocilizumab as monotherapy or in combination with non-biological disease-modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) and an inadequate response to anti-TNF agents , 2013 .

[7]  P. Emery,et al.  THU0089 Response to abatacept and tocilizumab in patients who had failed rituximab– initial single centre experience , 2013 .

[8]  G. Filippou,et al.  AB0535 Effects of tocilizumab on bone density and metabolism in patients with active rheumatoid arthritis , 2013 .

[9]  A. Ogata.  FRI0180 The musashi study: Comparison of subcutaneous tocilizumab monotherapy versus intravenous tocilizumab monotherapy: Results from a double-blind, parallel-group, comparative phase III non-inferiority study in japanese patients with rheumatoid arthritis , 2013 .

[10]  T. Takeuchi,et al.  AB0544 Efficacy and safety of tocilizumab in patients with rheumatoid arthritis in the presence or absence of previous treatment with biologics and concomitant treatment with methotrexate , 2013 .

[11]  A. Sudo,et al.  AB0533 Tocilizumab improves treatment outcomes in patients with rheumatoid arthritis for whom anti-TNF agents has failed , 2013 .

[12]  C. Wouters,et al.  FRI0328 Efficacy and safety of tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (SJIA): 2-year data from tender, a phase 3 clinical trial , 2013 .

[13]  H. Yamanaka,et al.  THU0092 The advantage of early intervention by tocilizumab for rheumatoid arthritis - full analysis of all-case postmarketing surveillance in 7,901 patients in japan , 2013 .

[14]  S. Shim,et al.  AB0562 A double-blind, placebo-controlled, multicenter trial of tocilizumab in moderate to severe active RA patients with inadequate response to methotrexate in korean population , 2013 .

[15]  M. Genovese,et al.  OP0023 Sarilumab for the treatment of moderate-to-severe rheumatoid arthritis: Results of a phase 2, randomized, double-blind, placebo-controlled, international study , 2013 .

[16]  M. Dougados,et al.  Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY) , 2012, Annals of the rheumatic diseases.

[17]  S. Unizony,et al.  Tocilizumab for the treatment of large‐vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica , 2012, Arthritis care & research.

[18]  A. Ogata,et al.  Psoriatic arthritis in two patients with an inadequate response to treatment with tocilizumab. , 2012, Joint, bone, spine : revue du rhumatisme.

[19]  P. Emery,et al.  LB0003 Tocilizumab (TCZ) monotherapy is superior to adalimumab (ADA) monotherapy in reducing disease activity in patients with rheumatoid arthritis (RA): 24-week data from the phase 4 adacta trial , 2012 .

[20]  J. Zwerina,et al.  Risk of infections in rheumatoid arthritis patients treated with tocilizumab. , 2012, Rheumatology.

[21]  V. Kraus,et al.  Biologics in relapsing polychondritis: a literature review. , 2012, Seminars in arthritis and rheumatism.

[22]  J. Singh,et al.  Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor. , 2012, Clinical therapeutics.

[23]  V. Strand,et al.  A phase II, double-blind, randomised, placebo-controlled study of BMS945429 (ALD518) in patients with rheumatoid arthritis with an inadequate response to methotrexate , 2012, Annals of the rheumatic diseases.

[24]  T. Kishimoto,et al.  Safety and efficacy of tocilizumab, an anti-IL-6-receptor monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis , 2012, Modern rheumatology.

[25]  H. Yamanaka,et al.  Incidence of serious respiratory infections in patients with rheumatoid arthritis treated with tocilizumab , 2012, Modern rheumatology.

[26]  J. Wong,et al.  Comparative effectiveness and safety of biological treatment options after tumour necrosis factor α inhibitor failure in rheumatoid arthritis: systematic review and indirect pairwise meta-analysis , 2012, Annals of the rheumatic diseases.

[27]  R. Geenen,et al.  Physical activity and physical activity cognitions are potential factors maintaining fatigue in patients with primary Sjögren's syndrome , 2011, Annals of the rheumatic diseases.

[28]  P. Fenaux,et al.  Efficacy of tocilizumab in rituximab-refractory cryoglobulinemia vasculitis , 2011, Annals of the rheumatic diseases.

[29]  J. Smolen,et al.  Tocilizumab inhibits progression of joint damage in rheumatoid arthritis irrespective of its anti-inflammatory effects: disassociation of the link between inflammation and destruction , 2011, Annals of the rheumatic diseases.

[30]  A. Kavanaugh,et al.  Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study , 2011, Annals of the rheumatic diseases.

[31]  R. Schneider,et al.  Efficacy and safety of tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (SJIA): tender 52-week data , 2011, Pediatric Rheumatology.

[32]  G. Deshpande,et al.  An observational study of tocilizumab and TNF-α inhibitor use in a Japanese community hospital: different remission rates, similar drug survival and safety , 2011, Rheumatology.

[33]  J. Kremer,et al.  Integrated safety in tocilizumab clinical trials , 2011, Arthritis research & therapy.

[34]  H. Yamanaka,et al.  Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients , 2011, Annals of the rheumatic diseases.

[35]  H. Yamanaka,et al.  Clinical, radiographic and functional effectiveness of tocilizumab for rheumatoid arthritis patients—REACTION 52-week study , 2011, Rheumatology.

[36]  T. Amezyane,et al.  Les antagonistes de l’interleukine-6 (tocilizumab) dans la maladie de still réfractaire de l’adulte , 2011 .

[37]  C. Jorgensen,et al.  Ankylosing Spondylitis Refractory to Tumor Necrosis Factor Blockade Responds to Tocilizumab , 2011, The Journal of Rheumatology.

[38]  H. Leffers,et al.  Efficacy of abatacept and tocilizumab in patients with rheumatoid arthritis treated in clinical practice: results from the nationwide Danish DANBIO registry , 2011, Annals of the rheumatic diseases.

[39]  R. Schneider,et al.  TOCILIZUMAB IN PATIENTS WITH SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS: EFFICACY DATA FROM THE PLACEBO-CONTROLLED 12-WEEK PART OF THE PHASE III TENDER TRIAL , 2011 .

[40]  A. Yamada,et al.  Successful tocilizumab treatment in a patient with adult-onset Still’s disease complicated by chronic active hepatitis B and amyloid A amyloidosis , 2011, Modern rheumatology.

[41]  Tomoyuki Saito,et al.  Radiographic improvement of damaged large joints in children with systemic juvenile idiopathic arthritis following tocilizumab treatment , 2011, Annals of the rheumatic diseases.

[42]  A. Sudo,et al.  Do biologics-naïve patients with rheumatoid arthritis respond better to tocilizumab than patients for whom anti-TNF agents have failed? A retrospective study. , 2011, Clinical and experimental rheumatology.

[43]  Ricardo Blanco,et al.  Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. , 2011, Arthritis and rheumatism.

[44]  A. Sagawa.  The efficacy and safety of reinstitution of tocilizumab in patients with relapsed active rheumatoid arthritis after long-term withdrawal of tocilizumab , 2011, Modern rheumatology.

[45]  G. Guyatt,et al.  Adverse effects of biologics: a network meta-analysis and Cochrane overview. , 2011, The Cochrane database of systematic reviews.

[46]  Y. Shima,et al.  Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorated clinical symptoms and MRI findings of a patient with ankylosing spondylitis , 2011, Modern rheumatology.

[47]  Y. Gokhale,et al.  Tocilizumab in refractory adult-onset Still's disease with aseptic meningitis--efficacy of interleukin-6 blockade and review of the literature. , 2011, Seminars in arthritis and rheumatism.

[48]  A. Mimori,et al.  Benefit and a possible risk of tocilizumab therapy for adult-onset Still’s disease accompanied by macrophage-activation syndrome , 2011, Modern rheumatology.

[49]  S. Reichenbach,et al.  Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. , 2011, Swiss medical weekly.

[50]  J. Sibilia,et al.  Tocilizumab in refractory adult Still's disease , 2011, Arthritis care & research.

[51]  G. Burmester,et al.  Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA) , 2010, Annals of the rheumatic diseases.

[52]  H. Yamanaka,et al.  Efficacy and tolerability of tocilizumab in rheumatoid arthritis patients seen in daily clinical practice in Japan: results from a retrospective study (REACTION study) , 2010, Modern rheumatology.

[53]  G. Schett,et al.  Successful treatment of adult-onset Still's disease refractory to TNF and IL-1 blockade by IL-6 receptor blockade , 2010, Annals of the rheumatic diseases.

[54]  K. Yokota,et al.  Tocilizumab improved both clinical and laboratory manifestations except for interleukin-18 in a case of multiple drug-resistant adult-onset Still's disease. , 2011, Internal medicine.

[55]  C. Gabay,et al.  Tocilizumab in a patient with ankylosing spondylitis and Crohn's disease refractory to TNF antagonists. , 2010, Joint, bone, spine : revue du rhumatisme.

[56]  M. Kawai,et al.  The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab , 2010, Rheumatology.

[57]  M. Tomšič,et al.  A case of refractory adult-onset Still’s disease successfully controlled with tocilizumab and a review of the literature , 2010, Clinical Rheumatology.

[58]  S. Lonial,et al.  Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease. , 2010, Journal of Clinical Oncology.

[59]  M. Hochberg,et al.  Indirect comparison of tocilizumab and other biologic agents in patients with rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs. , 2010, Seminars in arthritis and rheumatism.

[60]  Y. Iwamoto,et al.  Clinical evaluation of tocilizumab for patients with active rheumatoid arthritis refractory to anti-TNF biologics: tocilizumab in combination with methotrexate , 2010, Modern rheumatology.

[61]  K. Hagihara,et al.  Tocilizumab Ameliorates Clinical Symptoms in Polymyalgia Rheumatica , 2010, The Journal of Rheumatology.

[62]  K. Hagihara,et al.  Treatment of a patient with remitting seronegative, symmetrical synovitis with pitting oedema with a humanized anti-interleukin-6 receptor antibody, tocilizumab. , 2010, Rheumatology.

[63]  S. Puttonen,et al.  Is shift work a risk factor for rheumatoid arthritis? The Finnish Public Sector study , 2010, Annals of the rheumatic diseases.

[64]  Y. Ubara,et al.  Etanercept-refractory adult-onset Still’s disease with thrombotic thrombocytopenic purpura successfully treated with tocilizumab , 2010, Clinical Rheumatology.

[65]  N. Nishimoto,et al.  Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions , 2010, Modern rheumatology.

[66]  P. Lipsky,et al.  Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. , 2010, Arthritis and rheumatism.

[67]  A. Filer,et al.  Anti-modified citrullinated vimentin (MCV) antibodies in patients with very early synovitis , 2009, Annals of the rheumatic diseases.

[68]  S. Bierma-Zeinstra,et al.  Familial influence on tibiofemoral alignment , 2009, Annals of the rheumatic diseases.

[69]  M. Genovese,et al.  Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study , 2009, Annals of the rheumatic diseases.

[70]  K. Migita,et al.  Successful treatment with tocilizumab in a patient with refractory adult-onset Still's disease (AOSD). , 2010, Clinical and experimental rheumatology.

[71]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. , 2010, International journal of surgery.

[72]  Amy Ka Man Yung,et al.  ▼Tocilizumab for rheumatoid arthritis , 2009, Drug and Therapeutics Bulletin.

[73]  M. Kawai,et al.  Successful treatment of reactive arthritis with a humanized anti-interleukin-6 receptor antibody, tocilizumab. , 2009, Arthritis and rheumatism.

[74]  Byron C. Wallace,et al.  Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data , 2009, BMC medical research methodology.

[75]  N. Miyasaka,et al.  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 , 2008, Annals of the rheumatic diseases.

[76]  Kazuhiko Yamamoto,et al.  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 , 2008, Modern rheumatology.

[77]  M. Kawai,et al.  Sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in two patients with refractory relapsing polychondritis. , 2008, Rheumatology.

[78]  B. Saint-Marcoux,et al.  Tocilizumab for multirefractory adult-onset Still’s disease , 2008, Annals of the rheumatic diseases.

[79]  Y. Miki,et al.  Leukoencephalopathy with cognitive impairment following tocilizumab for the treatment of rheumatoid arthritis (RA). , 2009, Internal medicine.

[80]  M. Genovese,et al.  Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. , 2008, Arthritis and rheumatism.

[81]  J. Kremer,et al.  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 , 2008, Annals of the rheumatic diseases.

[82]  N. Nishimoto,et al.  Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor antibody. , 2008, Arthritis and rheumatism.

[83]  T. Kishimoto,et al.  Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial , 2008, The Lancet.

[84]  J. Smolen,et al.  Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial , 2008, The Lancet.

[85]  D. M. van der Heijde,et al.  Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab , 2007, Annals of the rheumatic diseases.

[86]  B. Cronstein.  Interleukin-6--a key mediator of systemic and local symptoms in rheumatoid arthritis. , 2007, Bulletin of the NYU hospital for joint diseases.

[87]  P. Emery,et al.  Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. , 2006, Arthritis and rheumatism.

[88]  Takeo Tanaka,et al.  A severe case of chronic infantile neurologic, cutaneous, articular syndrome treated with biologic agents. , 2006, Arthritis and rheumatism.

[89]  F. Breedveld,et al.  The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. , 2006, Arthritis and rheumatism.

[90]  L. Staudt,et al.  Clinical Trials and Observations , 2007 .

[91]  E. Giannini,et al.  Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. , 2004, The Journal of rheumatology.

[92]  N. Miyasaka,et al.  Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. , 2004, Arthritis and rheumatism.

[93]  T. Hibi,et al.  A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. , 2004, Gastroenterology.

[94]  L. Terslev,et al.  [Pregnancy in women with rheumatoid arthritis]. , 2003, Ugeskrift for laeger.

[95]  R. Price,et al.  Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. , 2002, Arthritis and rheumatism.

[96]  Y. Shima,et al.  Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy. , 2000, Blood.

[97]  D. Wendling,et al.  Combination therapy of anti-CD4 and anti-IL6 monoclonal antibodies in a case of severe spondylarthropathy. , 1996, British journal of rheumatology.

[98]  A R Jadad,et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? , 1996, Controlled clinical trials.

[99]  B. Klein,et al.  Brief report: alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody. , 1994, The New England journal of medicine.

[100]  D. Wendling,et al.  Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody. , 1993, The Journal of rheumatology.