AB0199 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

Background:Placebo and nocebo responses have important consequences for the development of pharmaceutical drugs and the design of randomized controlled trials (RCTs). They can lead to the incorrect measurement of treatment-related efficacy and adverse effects (AEs).Objectives:The goal of this study was to evaluate 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 patients with rheumatoid arthritis (RA) showing an insufficient response to TNF inhibitors.Methods:We performed a meta-analysis on the rates of placebo response, AEs, severe AEs (SAEs), and withdrawal owing to AEs in placebo-controlled randomized clinical trials (RCTs) of non-TNF biologics and JAK inhibitors in patients with RA showing an insufficient response to TNF inhibitors.Results:Nine RCTs contained a total of 3,442 patients (1,840 experimental subjects and 1,602 controls). The pooled incidence of an 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 inhibitors and JAK inhibitors, respectively. A strong negative correlation was observed between drug efficacies (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). A strong positive correlation was observed between drug efficacies (ACR20 response) in the placebo and active comparator, 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 at least one AE was 71.8% (95% CI 57.4–82.7%) and 58.7% (95% CI 52.8–64.3%) in RCTs of non-TNF inhibitors and JAK inhibitors, respectively. The pooled estimate in placebo-treated patients who withdrew from treatment owing 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 inhibitors and JAK inhibitors, respectively. A 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:The frequency of the placebo and nocebo responses was 22.1% vs. 27.9% and 71.8% vs. 58.7% in placebo-controlled RCTs of non-TNF inhibitors and JAK inhibitors for RA, respectively, and the greater the placebo response, the weaker the nocebo response and the greater the efficacy.References:[1]Mitsikostas DD, Chalarakis NG, Mantonakis LI, Delicha EM, Sfikakis PP. Nocebo in fibromyalgia: meta-analysis of placebo-controlled clinical trials and implications for practice. Eur J Neurol 2012;19:672-80.[2]Kravvariti E, Kitas GD, Mitsikostas DD, Sfikakis PP. Nocebos in rheumatology: emerging concepts and their implications for clinical practice. Nat Rev Rheumatol 2018;14:727-40.[3]Colloca L, Barsky AJ. Placebo and Nocebo Effects. N Engl J Med 2020;382:554-61.Disclosure of Interests:None declared

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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

Zeitschrift für Rheumatologie ◽

10.1007/s00393-021-01047-7 ◽

2021 ◽

Author(s):

Yoon-Kyoung Sung ◽

Young Ho Lee

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Active Rheumatoid Arthritis ◽

Kinase Inhibitors ◽

Meta Analysis ◽

Janus Kinase ◽

Janus Kinase Inhibitors ◽

Randomized Controlled ◽

Insufficient Response ◽

Necrosis Factor

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Anti-Ro/SSA Antibodies Are an Independent Factor Associated with an Insufficient Response to Tumor Necrosis Factor Inhibitors in Patients with Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.101295 ◽

2011 ◽

Vol 38 (11) ◽

pp. 2346-2354 ◽

Cited By ~ 12

Author(s):

RAN MATSUDAIRA ◽

NAOTO TAMURA ◽

FUMIO SEKIYA ◽

MICHIHIRO OGASAWARA ◽

KENJIRO YAMANAKA ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Tumor Necrosis Factor ◽

Clinical Response ◽

Tumor Necrosis ◽

Tnf Inhibitors ◽

Multivariable Logistic Regression Analysis ◽

Discontinuation Rate ◽

Eular Response ◽

Insufficient Response ◽

Necrosis Factor

Objective.To study the significance of anti-Ro/SSA antibodies (anti-Ro) in the clinical response to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis (RA).Methods.The clinical responses of a cohort of 190 patients with RA who were treated with infliximab, etanercept, or adalimumab (n = 112, 64, and 14, respectively) as the first biologics were examined using the Disease Activity Score in 28 joints (DAS28) at 24 weeks and the discontinuation rate at 56 weeks. The baseline characteristics of responders and the nonresponders were compared. The clinical response was compared between anti-Ro-negative and -positive patients. The factors associated with the inefficiency of TNF inhibitors were estimated with a multivariable logistic regression analysis.Results.The positive rate of anti-Ro was significantly higher in patients with no European League Against Rheumatism (EULAR) response at 24 weeks (OR 3.64, 95% CI 1.45–9.01, p = 0.003). In anti-Ro-positive patients, a moderate or good EULAR response rate was significantly lower with a sustaining higher median DAS28 (p = 0.006), and this difference was greater among infliximab-treated patients. The discontinuation rate for TNF inhibitors due to inefficacy at 56 weeks was also higher in anti-Ro-positive patients (OR 4.68, 95% CI 1.82–11.99, p = 0.0005), and 75% of these patients received infliximab. The presence of anti-Ro was strongly associated with no EULAR response at 24 weeks and a higher discontinuation rate of TNF inhibitors by 56 weeks (OR 5.22, 95% CI 1.75–15.57, p = 0.003 and OR 10.18, 95% CI 2.18–49.56, p = 0.003).Conclusion.The presence of anti-Ro might be related to the lesser clinical response to infliximab compared to other TNF inhibitors, suggesting that the presence of anti-Ro should be considered when choosing the appropriate biologics for patients with RA.

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Tuberculosis and targeted synthetic or biologic DMARDs, beyond tumor necrosis factor inhibitors

Therapeutic Advances in Musculoskeletal Disease ◽

10.1177/1759720x20930116 ◽

2020 ◽

Vol 12 ◽

pp. 1759720X2093011 ◽

Cited By ~ 2

Author(s):

Gerasimos Evangelatos ◽

Vasiliki Koulouri ◽

Alexios Iliopoulos ◽

George E Fragoulis

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Real Life ◽

Janus Kinase ◽

Current Evidence ◽

Tumor Necrosis Factor Inhibitors ◽

Jak Inhibitors ◽

Latent Tb ◽

Endemic Areas ◽

Necrosis Factor

Patients with autoimmune rheumatic diseases (ARD) have an increased risk for tuberculosis (TB). The use of tumor necrosis factor inhibitors (TNFi) and glucocorticoids in these patients has been associated with an increased prevalence of latent TB reactivation. Over the last few years, several biologic disease-modifying anti-rheumatic drugs (bDMARDs), other than TNFi (e.g. rituximab, abatacept, tocilizumab, secukinumab) and targeted synthetic DMARDs (tsDMARDs) [e.g. apremilast, Janus kinase (JAK) inhibitors] have been used for the treatment of patients with ARD. For many of these drugs, especially the newer ones like JAK inhibitors or antibodies against interleukin (IL)-23, most data stem from randomized clinical trials and few are available from real life clinical experience. We sought to review the current evidence for TB risk in patients with ARD treated with tsDMARDs or bDMARDs, other than TNFi. It seems that some of these drugs are associated with a lower TB risk, indirectly compared with TNFi treatment. In fact, it appears that rituximab, apremilast and inhibitors of IL-17 and IL-23 might be safer, while more data are needed for JAK inhibitors. As seen in TNFi, risk for TB is more pronounced in TB-endemic areas. Screening for latent TB must precede initiation of any tsDMARDs or bDMARDs. The growing use of non-TNFi agents has raised the need for more real-life studies that would compare the risk for TB between TNFi and other treatment modalities for ARD. Knowledge about the TB-safety profile of these drugs could help in the decision of drug choice in patients with confirmed latent TB infection or in TB endemic areas.

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Tumor necrosis factor-α −308G/A and −238G/A polymorphisms are associated with increased risks of sepsis: evidence from an updated meta-analysis

Apmis ◽

10.1111/apm.12661 ◽

2017 ◽

Vol 125 (5) ◽

pp. 459-467 ◽

Cited By ~ 8

Author(s):

Mu Zhang ◽

Yu Zhao ◽

Qiong Liu

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Meta Analysis ◽

Factor Α ◽

Necrosis Factor

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Association of tumor necrosis factor-alpha -308 G/A and -238 G/A polymorphism with diabetic retinopathy: a systematic review and updated meta-analysis.

Ophthalmic Research ◽

10.1159/000513586 ◽

2020 ◽

Author(s):

Wenna Gao ◽

Ruilin Zhu ◽

liu yang

Keyword(s):

Diabetic Retinopathy ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Meta Analysis ◽

Entire Group ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

Background: Mounting evidence has suggested tumor necrosis factor-alpha (TNF-α) can promote the development of diabetic retinopathy (DR), and TNF-α gene variants may influence DR risk. However, the results are quite different. Objectives: To comprehensively address this issue, we performed the meta-analysis to evaluate the association of TNF-α-308 G/A and -238 G/A polymorphism with DR. Method: Data were retrieved in a systematic manner and analyzed using STATA Statistical Software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Allelic and genotypic comparisons between cases and controls were evaluated. Results: For the TNF-α-308 G/A polymorphism, overall analysis suggested a marginal association with DR [the OR(95%CI) of (GA versus GG), (GA + AA) versus GG, and (A versus G) are 1.21(1.04, 1.41), 1.20(1.03, 1.39), and 1.14(1.01, 1.30), respectively]. And the subgroup analysis indicated an enhanced association among the European population. For the TNF-α-238 G/A polymorphism, there was mild correlation in the entire group [the OR(95%CI) of (GA versus GG) is 1.55(1.14,2.11) ], which was strengthened among the Asian population. Conclusion: The meta-analysis suggested that -308 A and -238 A allele in TNF-α gene potentially increased DR risk and showed a discrepancy in different ethnicities.

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