Skip to main content

The lessebo effect in randomized controlled trials of rituximab in patients with rheumatoid arthritis: a meta-analysis

Der Lesseboeffekt in randomisierten kontrollierten Studien mit Rituximab bei Patienten mit rheumatoider Arthritis: eine Metaanalyse



The goal of this study was to assess the impact of negative expectations associated with receiving a placebo (the lessebo effect) on efficacy outcomes in randomized clinical trials (RCTs) of rituximab in patients with rheumatoid arthritis (RA).


We performed a meta-analysis on the American College of Rheumatology 20%, 50%, and 70% (ACR20, 50, 70) response rates in the placebo and active (biosimilar)-controlled groups (reference-pbo and reference-bs) of rituximab showing an insufficient response to methotrexate or tumor necrosis factor. We evaluated the difference in ACR20, 50, 70 response rates between the two groups (reference-bs vs. reference-pbo).


Nine RCTs included a total of 2734 patients with RA. The pooled incidence of ACR20 response rate in the placebo- and active-controlled groups of the rituximab RCTs for RA was 53.1% (95% confidence interval [CI] 49.9–56.3%) and 75.0% (95% CI 71.2–78.4%), respectively. The difference in the ACR20 response rate between the placebo- and active-controlled groups was −20.9% (95% CI −26.9 to 61.9%, p < 0.001). The pooled incidence of ACR50 response rate in the placebo- and active-controlled groups of the rituximab RCTs for RA was 29.0% (95% CI 26.2–32.0%) and 47.4% (95% CI 43.2–51.6%), respectively. The ACR50 response rates were significantly higher in the active-controlled groups than in the placebo-controlled groups (−18.4%; 95% CI −18.4 to −13.4%, p < 0.001). The difference in the ACR70 response rate between the placebo- and active-controlled groups was −14.9% (95% CI −22.2 to −7.6%, p < 0.001). The ACR20, 50, 70 response rates were significantly higher in the active-controlled groups than in the placebo-controlled group.


This study shows that the use of a placebo can be associated with a clinically significant reduction in the magnitude of change of the ACR20, 50, 70 response rates in rituximab RCTs for RA. The lessebo effect has potential implications for the development of new treatments and appraisal of current treatment options for RA.



Ziel dieser Studie war es, den Einfluss negativer Erwartungen, die mit dem Erhalt eines Placebos verbunden sind (Lessebo-Effekt), auf die Ergebnisse von randomisierten klinischen Studien (RCTs) zur Wirksamkeit von Rituximab bei Patienten mit rheumatoider Arthritis (RA) zu untersuchen.


Wir führten eine Metaanalyse der 20-, 50- und 70-prozentigen ACR(American College of Rheumatology)-Ansprechraten (ACR20, 50, 70) in den Placebo- und den aktiven (Biosimilar-)kontrollierten Gruppen (Referenz-pbo und Referenz-bs) von Rituximab durch, die nicht ausreichend auf Methotrexat oder Tumornekrosefaktor ansprachen. Wir bewerteten den Unterschied in den ACR20-, -50- und -70-Ansprechraten zwischen den beiden Gruppen (Referenz-bs vs. Referenz-pbo).


Neun RCTs umfassten insgesamt 2734 RA-Patienten. Die gepoolte Inzidenz der ACR20-Ansprechrate in den placebo- und aktiv kontrollierten Gruppen der Rituximab-RCTs bei RA betrug 53,1% (95 %-Konfidenzintervall [95 %-KI] 49,9-56,3 %%) bzw. 75,0% (95 %-KI 71,2-78,4 %). Der Unterschied in der ACR20-Ansprechrate zwischen der placebo- und der aktiv kontrollierten Gruppe betrug -20,9 % (95 %-KI -26,9 bis 61,9 %, p < 0,001). Die gepoolte Inzidenz der ACR50-Ansprechrate in der Placebo- und der aktiv kontrollierten Gruppe der Rituximab-RCTs zur RA betrug 29,0 % (95 %-KI 26,2-32,0%) bzw. 47,4 % (95 %-KI 43,2–51,6 %). Die ACR50-Ansprechraten waren in den aktiv kontrollierten Gruppen signifikant höher als in den placebokontrollierten Gruppen (‑18,4 %; 95 %-KI -18,4 bis -13,4 %, p < 0,001). Der Unterschied bei der ACR70-Ansprechrate zwischen der Placebo- und der aktiv kontrollierten Gruppe betrug -14,9 % (95 %-KI -22,2 bis -7,6 %, p < 0,001). Die ACR20-, -50- und -70-Ansprechraten waren in den aktiv kontrollierten Gruppen signifikant höher als in der placebokontrollierten Gruppe.


Diese Studie zeigt, dass die Verwendung eines Placebos mit einer klinisch signifikanten Verringerung des Ausmaßes der Veränderung der ACR20-, 50- und 70-Ansprechraten in Rituximab-RCTs bei RA verbunden sein kann. Der Lessebo-Effekt hat potenzielle Implikationen für die Entwicklung neuer Therapien und für die Bewertung aktueller Behandlungsoptionen für RA.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2


  1. 1.

    Aletaha D, Landewe R, Karonitsch T et al (2008) Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations. Arthritis Care Res 59:1371–1377

    CAS  Article  Google Scholar 

  2. 2.

    Burmester G, Drescher E, Hrycaj P et al (2020) Efficacy and safety results from a randomized double-blind study comparing proposed biosimilar ABP 798 with rituximab reference product in subjects with moderate-to-severe rheumatoid arthritis. Clin Rheumatol 39:3341–3352

    Article  Google Scholar 

  3. 3.

    Cohen SB, Emery P, Greenwald MW et al (2006) Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54:2793–2806

    CAS  Article  Google Scholar 

  4. 4.

    Edwards JC, Szczepanski L, Szechinski J et al (2004) Efficacy of B‑cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350:2572–2581

    CAS  Article  Google Scholar 

  5. 5.

    Egger M, Davey Smith G, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    CAS  Article  Google Scholar 

  6. 6.

    Emery P, Deodhar A, Rigby WF et al (2010) Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab’s Efficacy in MTX iNadequate rEsponders (SERENE)). Ann Rheum Dis 69:1629–1635

    CAS  Article  Google Scholar 

  7. 7.

    Emery P, Fleischmann R, Filipowicz-Sosnowska A et al (2006) The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 54:1390–1400

    CAS  Article  Google Scholar 

  8. 8.

    Goetz CG, Janko K, Blasucci L et al (2003) Impact of placebo assignment in clinical trials of Parkinson’s disease. Mov Disord 18:1146–1149

    Article  Google Scholar 

  9. 9.

    Haridas VM, Katta R, Nalawade A et al (2020) Pharmacokinetic similarity and comparative pharmacodynamics, safety, efficacy, and Immunogenicity of DRL_RI versus reference rituximab in biologics-Naïve patients with moderate-to-severe rheumatoid arthritis: a double-blind, randomized, three-arm study. BioDrugs 34:183–196

    CAS  Article  Google Scholar 

  10. 10.

    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    Article  Google Scholar 

  11. 11.

    Hochberg MC, Chang RW, Dwosh I et al (1992) The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum 35:498–502

    CAS  Article  Google Scholar 

  12. 12.

    Jadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12

    CAS  Article  Google Scholar 

  13. 13.

    Kim H, Sung YK (2021) Epidemiology of rheumatoid arthritis in Korea. J Rheum Dis 28:60–67

    Article  Google Scholar 

  14. 14.

    Lee YH (2018) An overview of meta-analysis for clinicians. Korean J Intern Med 33:277–283

    Article  Google Scholar 

  15. 15.

    Lee YH, Bae SC, Song GG (2012) Omega‑3 polyunsaturated fatty acids and the treatment of rheumatoid arthritis: a meta-analysis. Arch Med Res 43:356–362

    CAS  Article  Google Scholar 

  16. 16.

    Lee YH, Song GG (2021) The gut microbiome and osteoarthritis: a two-sample mendelian randomization study. J Rheum Dis 28:94–100

    Article  Google Scholar 

  17. 17.

    Mease PJ, Cohen S, Gaylis NB et al (2010) Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE trial. J Rheumatol 37:917–927

    CAS  Article  Google Scholar 

  18. 18.

    Mestre TA (2020) Nocebo and lessebo effects. Int Rev Neurobiol 153:121–146

    Article  Google Scholar 

  19. 19.

    Mestre TA, Shah P, Marras C et al (2014) Another face of placebo: the lessebo effect in Parkinson disease: meta-analyses. Neurology 82:1402–1409

    Article  Google Scholar 

  20. 20.

    Mitsikostas DD, Chalarakis NG, Mantonakis LI et al (2012) Nocebo in fibromyalgia: meta-analysis of placebo-controlled clinical trials and implications for practice. Eur J Neurol 19:672–680

    CAS  Article  Google Scholar 

  21. 21.

    Mitsikostas DD, Mantonakis L, Chalarakis N (2014) Nocebo in clinical trials for depression: a meta-analysis. Psychiatry Res 215:82–86

    Article  Google Scholar 

  22. 22.

    Moher D, Liberati A, Tetzlaff J et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269

    Article  Google Scholar 

  23. 23.

    Nagai K, Matsubayashi K, Ide K et al (2020) Factors influencing placebo responses in rheumatoid arthritis clinical trials: a meta-analysis of randomized, double-blind, placebo-controlled studies. Clin Drug Investig 40:197–209

    CAS  Article  Google Scholar 

  24. 24.

    Park W, Božić-Majstorović L, Milakovic D et al (2018) Comparison of biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: a randomized controlled Phase 3 trial. mAbs 10:934–943

    CAS  Article  Google Scholar 

  25. 25.

    Reff ME, Carner K, Chambers KS et al (1994) Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435–445

    CAS  Article  Google Scholar 

  26. 26.

    Sinyor M, Levitt AJ, Cheung AH et al (2010) Does inclusion of a placebo arm influence response to active antidepressant treatment in randomized controlled trials? Results from pooled and meta-analyses. J Clin Psychiatry 71:270–279

    CAS  Article  Google Scholar 

  27. 27.

    Smith GD, Egger M (1997) Meta-analyses of randomised controlled trials. Lancet 350:1182

    Article  Google Scholar 

  28. 28.

    Smolen JS, Cohen SB, Tony HP et al (2021) Efficacy and safety of Sandoz biosimilar rituximab for active rheumatoid arthritis: 52-week results from the randomized controlled ASSIST-RA trial. Rheumatology 60:256–262

    CAS  Article  Google Scholar 

Download references


This research was supported by a grant of Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI19C0481, HC19C0052).

Author information



Corresponding author

Correspondence to Young Ho Lee MD PhD.

Ethics declarations

Conflict of interest

Y.-K. Sung and Y.H. Lee declare that they have no competing interests.

For this article no studies with human participants or animals were performed by any of the authors. All studies performed were in accordance with the ethical standards indicated in each case.

Additional information


Scan QR code & read article online


Ulf Müller-Ladner, Bad Nauheim

Uwe Lange, Bad Nauheim

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sung, YK., Lee, Y.H. The lessebo effect in randomized controlled trials of rituximab in patients with rheumatoid arthritis: a meta-analysis. Z Rheumatol (2021).

Download citation


  • Lessebo effect
  • Rituximab
  • Efficacy
  • Rheumatoid arthritis
  • Response rate


  • Lesseboeffekt
  • Rituximab
  • Wirksamkeit
  • Rheumatoide Arthritis
  • Ansprechrate