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Placebo and nocebo responses in randomized controlled trials of non-tumor necrosis factor biologics and Janus kinase inhibitors in patients with active rheumatoid arthritis showing insufficient response to tumor necrosis factor inhibitors: A meta-analysis

Ansprechen auf Placebo und Nocebo in randomisierten kontrollierten Studien zu Non-Tumornekrosefaktor-Biologika und Januskinaseinhibitoren bei Patienten mit aktiver rheumatoider Arthritis und insuffizienter Reaktion auf Tumornekrosefaktorinhibitoren: Eine Metaanalyse

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Abstract

Objective

This study evaluated the frequency and magnitude of placebo and nocebo responses in placebo-controlled RCTs of non-tumor necrosis factor (TNF) biologics and Janus kinase (JAK) inhibitors in rheumatoid arthritis (RA) patients with insufficient response to TNF inhibitors.

Methods

A meta-analysis on rates of placebo response, adverse effects (AEs), severe AEs (SAEs), and withdrawal due to AEs in placebo-controlled RCTs of non-TNF biologics and JAK inhibitors in patients with RA and an insufficient response to TNF inhibitors was conducted.

Results

In 9 RCTs containing 3442 patients the pooled incidence of ACR20 response rate in placebo-treated patients was 22.1 (95% CI 16.4–29.1%) and 27.9% (95% CI 24.5–31.6%) in RCTs of non-TNF and JAK inhibitors, respectively. Strong negative correlation was observed between ACR20 response and AE rates in the placebo arm, indicating that the greater the placebo response, the weaker the nocebo response (r = −0.762, P = 0.017). Strong positive correlation was observed between ACR20 response in the placebo and active comparator arms, indicating that the greater the placebo response, the greater the treatment response (r = 0.737, P = 0.003). The pooled estimate in placebo-treated patients with ≥1 AE was 71.8 (95% CI 57.4–82.7%) and 58.7% (95% CI 52.8–64.3%) in RCTs of non-TNF and JAK inhibitors, respectively. The pooled estimate in placebo-treated patients withdrawing due to an AE was 3.8 (95% CI 2.7–5.3%) and 4.0% (95% CI 2.7–6.0%) in RCTs of non-TNF and JAK inhibitors, respectively. Strong positive correlation was observed between AE rates in the placebo and active arms, indicating that the greater the nocebo response, the stronger the AE rate in the active arm (r = 0.855, P = 0.003).

Conclusion

There were higher placebo and less nocebo effects of JAK vs. non-TNF inhibitors in RA patients with an insufficient response to TNF inhibitors, and the greater the placebo response, the weaker the nocebo response and the greater the efficacy.

Zusammenfassung

Hintergrund

In der vorliegenden Studie wurden die Häufigkeit und die Ausprägung des Ansprechens auf Placebo und Nocebo in placebokontrollierten randomisierten kontrollierten Studien (RCT) zu Non-Tumornekrosefaktor(TNF)-Biologika und Januskinase(JAK)-Inhibitoren bei Patienten mit aktiver rheumatoider Arthritis (RA) und insuffizientem Ansprechen auf TNF-Inhibitoren untersucht.

Methoden

Dazu wurde eine Metaanalyse der Ansprechraten auf Placebo, der Nebenwirkungen (NW), der schweren NW (SNW) und des Studienabbruchs aufgrund von NW in placebokontrollierten RCT zu Non-TNF-Biologika und JAK-Inhibitoren bei Patienten mit RA und insuffizientem Ansprechen auf TNF-Inhibitoren durchgeführt.

Ergebnisse

In 9 RCT mit 3442 Patienten betrug die gepoolte Inzidenz einer ACR20-Ansprechrate (20% Besserung gemäß den Kriterien des American College of Rheumatology) bei placebobehandelten Patienten 22,1 (95%-Konfidenzintervall, 95%-KI: 16,4–29,1%) bzw. 27,9% (95%-KI: 24,5–31,6%) in RCT zu Non-TNF und JAK-Inhibitoren. Eine starke negative Korrelation wurden zwischen der ACR20-Response und den NW-Raten im Placeboarm festgestellt, was zeigt, dass je stärker das Ansprechen auf Placebo war, desto schwächer war das Ansprechen auf Nocebo (r = −0,762; p = 0,017). Dagegen wurde eine starke positive Korrelation zwischen der ACR20-Response im Placeboarm und im Studienarm mit aktivem Vergleichspräparat festgestellt, was zeigt, dass je stärker das Ansprechen auf Placebo war, desto stärker war das Ansprechen auf Therapie (r = 0,737; p = 0,003). Der gepoolte Schätzwert bei placebobehandelten Patienten mit ≥1 NW betrug 71,8 (95%-KI: 57,4–82,7%) bzw. 58,7% (95%-KI: 52,8–64,3%) in RCT zu Non-TNF und JAK-Inhibitoren. Dagegen betrug der gepoolte Schätzwert bei placebobehandelten Patienten mit Studienabbruch aufgrund von NW 3,8 (95%-KI: 2,7–5,3%) bzw. 4,0% (95%-KI: 2,7–6,0%) in RCT zu Non-TNF und JAK-Inhibitoren. Eine starke positive Korrelation wurde zwischen den NW-Raten im Placeboarm und im aktiven Studienarm festgestellt, was zeigt, dass je stärker das Ansprechen auf Nocebo war, desto schwächer war die NW-Rate im aktiven Studienarm (r = 0,855; p = 0,003).

Schlussfolgerung

Es fanden sich höhere Placebo- und geringere Noceboeffekte von JAK vs. Non-TNF-Inhibitoren bei RA-Patienten mit insuffizientem Ansprechen auf TNF-Inhibitoren, und je stärker das Ansprechen auf Placebo war, desto schwächer war das Ansprechen auf Nocebo und desto größer war die Wirksamkeit.

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Acknowledgements

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

Funding

The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author information

Authors and Affiliations

  1. Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea (Republic of)

    Yoon-Kyoung Sung

  2. Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 73, Goryeodae-ro, 02841, Seongbuk-gu, Seoul, Korea (Republic of)

    Young Ho Lee MD PhD

Authors
  1. Yoon-Kyoung Sung
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Contributions

YKS conceived of the study, participated in its design, and critically revised the manuscript. YHL had full access to all the data collection, analysis, interpretation, and drafted the manuscript. YKS and YHL were study investigators and contributed to the process of data collection. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Young Ho Lee MD PhD.

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Conflict of interest

Y.-K. Sung and Y.H. Lee have no financial or non-financial conflict of interest to declare.

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

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U. Lange, Bad Nauheim

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Sung, YK., Lee, Y.H. Placebo and nocebo responses in randomized controlled trials of non-tumor necrosis factor biologics and Janus kinase inhibitors in patients with active rheumatoid arthritis showing insufficient response to tumor necrosis factor inhibitors: A meta-analysis. Z Rheumatol 82 (Suppl 1), 59–67 (2023). https://doi.org/10.1007/s00393-021-01047-7

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