Skip to main content
Log in

Efficacy and safety of interleukin-1 antagonists in rheumatoid arthritis: a systematic review and meta-analysis

Rheumatology International Aims and scope Submit manuscript

Abstract

Rheumatoid arthritis patients have a high level of pro-inflammatory interleukin-1. Augmenting the blockade of interleukin-1 receptors by external interleukin-1 receptor antagonist modifies the progression of the disease. Therefore, the aim of this study was to evaluate the clinical efficacy and safety of interleukin-1 receptor antagonist (anakinra) in the treatment of rheumatoid arthritis. Clinical trials and extension studies that compared anakinra with placebo or other medications were included. Electronic bibliographic databases: PubMed, Scopus, and Web of Sciences were searched from inception to November 2017. The American College of Rheumatology 20% (ACR20) improvement was the primary efficacy outcome measure. Total number of adverse drug events, serious adverse drug events, total treatment withdrawals, and treatment-related withdrawals were safety outcome measures. Ten studies were included in this review. One study did not fulfil quantitative criteria and was assessed qualitatively. Six clinical trials and three extension studies were included in meta-analysis. Patients treated with anakinra are 42% more likely to have ACR20 response than patients without IL-1Ra (pooled RR 1.42; 95% CI 1.01, 2.00). Patients on 30–150 mg anakinra have lower Health Assessment Questionnaire (HAQ) score than patients without IL-1Ra (SMD − 0.28; 95% CI − 0.53, − 0.03). The inflammatory marker erythrocyte sedimentation rate (ESR) was significantly lower among patients treated with 30–150 mg anakinra (SMD − 0.44; 95% CI − 0.65, − 0.23). Patients on anakinra have a 34% more risk of treatment-related withdrawal than placebo. The other parameters were not found to be statistically significant. Anakinra has a significant improvement in ACR20, HAQ, and ESR. The ACR20 response is maintained after 48 weeks of treatment. Anakinra shows higher episodes of treatment-related withdrawals than placebo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15

References

  1. Singh JA, Saag KG, Bridges SL et al (2016) 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 68(1):1–26

    Article  Google Scholar 

  2. Smolen JS, Breedveld FC, Burmester GRet al (2016) Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 75(1):3–15

    Article  Google Scholar 

  3. Cross M, Smith E, Hoy D et al (2014) The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 73:1316–1322

    Article  Google Scholar 

  4. Blumenauer B, Cranney A, Clinch J, Tugwell P (2003). Quality of life in patients with rheumatoid arthritis: which drugs might make a difference. Pharmacoeconomics 21(13):927–940

    Article  Google Scholar 

  5. McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365(23):2205–2219

    Article  CAS  Google Scholar 

  6. Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423(6937):356–361

    Article  CAS  Google Scholar 

  7. Smolen JS, Landewe R, Breedveld FC et al (2010) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 69(6):964–975

    Article  CAS  Google Scholar 

  8. Doan T, Massarotti E (2005) Rheumatoid arthritis: an overview of new and emerging therapies. J Clin Pharmacol 45:751–762

    Article  CAS  Google Scholar 

  9. Hashemi-Meshkini A, Nikfar S, Glaser E, Jamshidi A, Hosseini SA (2016) Cost-effectiveness analysis of tocilizumab in comparison with infliximab in iranian rheumatoid arthritis patients with inadequate response to tDMARDs: a multistage Markov model. Value Health Reg Issues 9:42–48

    Article  Google Scholar 

  10. Ahmadiani S, Nikfar S, Karimi S, Jamshidi AR, Akbari-Sari A, Kebriaeezadeh A (2016) Rituximab as first choice for patients with refractory rheumatoid arthritis: cost-effectiveness analysis in Iran based on a systematic review and meta-analysis. Rheumatol Int 36(9):1291–1300

    Article  CAS  Google Scholar 

  11. Firestein GS (2005) Immunologic mechanisms in the pathogenesis of rheumatoid arthritis. J Clin Rheumatol 11(3):S39–S44

    Article  Google Scholar 

  12. Kosek E, Altawil R, Kadetoff D et al (2015) Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain—interleukin-8 in fibromyalgia and interleukin-1 β in rheumatoid arthritis. J Neuroimmunol 280:49–55

    Article  CAS  Google Scholar 

  13. Bao J, Yue T, Liu W et al (2011) Secondary failure to treatment with recombinant human IL-1 receptor antagonist in Chinese patients with rheumatoid arthritis. Clin Rheumatol 30(5):697–701

    Article  Google Scholar 

  14. Cohen SB, Moreland LW, Cush JJ et al (2004) A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. Ann Rheum Dis 63(9):1062–1068

    Article  CAS  Google Scholar 

  15. Genovese MC, Cohen S, Moreland L et al (2004) Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheumatol 50(5):1412–1419

    Article  CAS  Google Scholar 

  16. Lungoci ER, Hacard F, Nicolas JF, Berard F (2015). Anakinra delayed skin allergy expressing as both injection site reactions and generalized exanthema. Eur J Dermatol 5:503–504

    Google Scholar 

  17. Fleischmann RM, Schechtman J, Bennett R et al (2003) Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: a large, international, multicenter, placebo-controlled trial. Arthritis Rheumatol 48(4):927–934

    Article  CAS  Google Scholar 

  18. Clark W, Jobanputra P, Barton P, Burls A (2004) The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis. Health Technol Assess (Winch Engl) 8(18):iii–iv (ix–x, 1–105)

    CAS  Google Scholar 

  19. Gartlehner G, Hansen RA, Jonas BL, Thieda P, Lohr KN (2006) The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol 33(12):2398–2408

    CAS  PubMed  Google Scholar 

  20. Singh JA, Wells GA, Christensen R et al (2011) Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane database of systematic reviews 2:Cd008794

    Google Scholar 

  21. Jansen JP, Buckley F, Dejonckheere F, Ogale S (2014). Comparative efficacy of biologics as monotherapy and in combination with methotrexate on patient reported outcomes (PROs) in rheumatoid arthritis patients with an inadequate response to conventional DMARDs: a systematic review and network meta-analysis. Health Qual Life Outcomes 12:102

    Article  Google Scholar 

  22. Cabral VP, Andrade CA, Passos SR, Martins MF, Hokerberg YH (2016) Severe infection in patients with rheumatoid arthritis taking anakinra, rituximab, or abatacept: a systematic review of observational studies. Rev Bras Reumatol 56(6):543–550

    Article  Google Scholar 

  23. Nixon R, Bansback N, Brennan A (2007) The efficacy of inhibiting tumour necrosis factor α and interleukin 1 in patients with rheumatoid arthritis: a meta-analysis and adjusted indirect comparisons. Rheumatology 46:1140–1147

    Article  CAS  Google Scholar 

  24. Mertens M, Singh JA (2009) Anakinra for rheumatoid arthritis: a systematic review. J Rheumatol 36(6):1118–1125

    Article  CAS  Google Scholar 

  25. Gasparyan AY, Ayvazyan L, Blackmore H et al (2011) Writing a narrative biomedical review: considerations for authors, peer reviewers, and edithors. Rheumatol Int 31:1409–1417

    Article  Google Scholar 

  26. Balshem H, Helfand M, Schünemann HJ et al (2011) GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 64(4):401–406

    Article  Google Scholar 

  27. Nuki G, Bresnihan B, Bear MB, McCabe D (2002) Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol 46(11):2838–2846

    Article  CAS  Google Scholar 

  28. Le Loët X, Nordström D, Rodriguez M et al (2008) Effect of anakinra on functional status in patients with active rheumatoid arthritis receiving concomitant therapy with traditional disease modifying antirheumatic drugs: evidence from the OMEGA trial. J Rheumatol 35(8):1538–1544

    PubMed  Google Scholar 

  29. Bresnihan B, Newmark R, Robbins S, Genant HK (2004) Effects of anakinra monotherapy on joint damage in patients with rheumatoid arthritis. Extension of a 24-week randomized, placebo-controlled trial. J Rheumatol 31(6):1103–1111

    CAS  PubMed  Google Scholar 

  30. Fleischmann RM, Tesser J, Schiff MH et al (2006) Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis 65(8):1006–1012

    Article  CAS  Google Scholar 

  31. Bresnihan B, Alvaro-Gracia JM, Cobby M et al (1998) Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheumatol 41(12):2196–2204

    Article  CAS  Google Scholar 

  32. Cohen S, Hurd E, Cush J et al (2002) Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol 46(3):614–624

    Article  CAS  Google Scholar 

  33. Gaujoux-Viala C, Nam J, Ramiro S et al (2014) Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis 73(3):510–515

    Article  CAS  Google Scholar 

  34. Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordström DC, Blom M (2012) Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS One 7(1):e30275

    Article  CAS  Google Scholar 

  35. Stevenson M, Archer R, Tosh J et al (2016) Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with disease-modifying antirheumatic drugs and after the failure of conventional disease-modifying antirheumatic drugs only: systematic review and economic evaluation. Health Technol Assess 20(35):1–610

    Article  Google Scholar 

  36. Galloway JB, Hyrich KL, Mercer LK et al (2011). The risk of serious infections in patients receiving anakinra for rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology 50(7):1341–1342

    Article  Google Scholar 

  37. Salliot C, Dougados M, Gossec L (2009) Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials. Ann Rheum Dis 68(1):25–32

    Article  CAS  Google Scholar 

  38. Food and Drug Administration (2012) Kineret (anakinra), highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103950s5136lbl. Accessed Dec 2012

  39. Alten R, Gomez-Reino J, Durez P (2011) Efficacy and safety of the human anti-ILbeta monoclonal antibody canakinumab in rheumatoid arthritis: result of 12-week, phase II, dose-finding study. BMC Musculoskelet Disord 12(1):153

    Article  CAS  Google Scholar 

  40. Alten R1, Gomez-Reino J, Durez P et al (2011) Efficacy and safety of the human anti-IL-1β monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, Phase II, dose-finding study. BMC Musculoskelet Disord. https://doi.org/10.1186/1471-2474-12-153

    Article  PubMed  PubMed Central  Google Scholar 

  41. Hoffman MH, Throne LM, Amar JN et al (2012) Long-term efficacy and safety profile of rilonacept in the treatment of cryopryin-associated periodic syndromes: results of a 72-week open-label extention study. Clin Ther 34(10):2091–2103

    Article  CAS  Google Scholar 

  42. Petryana O, Cush JJ, Efthimiou P (2012) IL-1 Trap rilonacept in refractory adult onset Still’s disease. Ann Rheum Dis 71(12):2056–2057

    Article  Google Scholar 

  43. Liberati A, Altman GD, Tetzlaff et al (2009) The PRISMA statement for reporting systematic review and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mohammad Abdollahi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nikfar, S., Saiyarsarai, P., Tigabu, B.M. et al. Efficacy and safety of interleukin-1 antagonists in rheumatoid arthritis: a systematic review and meta-analysis. Rheumatol Int 38, 1363–1383 (2018). https://doi.org/10.1007/s00296-018-4041-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-018-4041-1

Keywords

Navigation